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Child of The New Gastroenterologist
Management of gastroparesis in 2022
Introduction
Patients presenting with the symptoms of gastroparesis (Gp) are commonly seen in gastroenterology practice.
Presentation
Patients with foregut symptoms of Gp have characteristic presentations, with nausea, vomiting/retching, and abdominal pain often associated with bloating and distension, early satiety, anorexia, and heartburn. Mid- and hindgut gastrointestinal and/or urinary symptoms may be seen in patients with Gp as well.
The precise epidemiology of gastroparesis syndromes (GpS) is unknown. Classic gastroparesis, defined as delayed gastric emptying without known mechanical obstruction, has a prevalence of about 10 per 100,000 population in men and 30 per 100,000 in women with women being affected 3 to 4 times more than men.1,2 Some risk factors for GpS, such as diabetes mellitus (DM) in up to 5% of patients with Type 1 DM, are known.3 Caucasians have the highest prevalence of GpS, followed by African Americans.4,5
The classic definition of Gp has blurred with the realization that patients may have symptoms of Gp without delayed solid gastric emptying. Some patients have been described as having chronic unexplained nausea and vomiting or gastroparesis like syndrome.6 More recently the NIH Gastroparesis Consortium has proposed that disorders like functional dyspepsia may be a spectrum of the two disorders and classic Gp.7 Using this broadened definition, the number of patients with Gp symptoms is much greater, found in 10% or more of the U.S. population.8 For this discussion, GpS is used to encompass this spectrum of disorders.
The etiology of GpS is often unknown for a given patient, but clues to etiology exist in what is known about pathophysiology. Types of Gp are described as being idiopathic, diabetic, or postsurgical, each of which may have varying pathophysiology. Many patients with mild-to-moderate GpS symptoms are effectively treated with out-patient therapies; other patients may be refractory to available treatments. Refractory GpS patients have a high burden of illness affecting them, their families, providers, hospitals, and payers.
Pathophysiology
Specific types of gastroparesis syndromes have variable pathophysiology (Figure 1). In some cases, like GpS associated with DM, pathophysiology is partially related to diabetic autonomic dysfunction. GpS are multifactorial, however, and rather than focusing on subtypes, this discussion focuses on shared pathophysiology. Understanding pathophysiology is key to determining treatment options and potential future targets for therapy.
Intragastric mechanical dysfunction, both proximal (fundic relaxation and accommodation and/or lack of fundic contractility) and distal stomach (antral hypomotility) may be involved. Additionally, intragastric electrical disturbances in frequency, amplitude, and propagation of gastric electrical waves can be seen with low/high resolution gastric mapping.
Both gastroesophageal and gastropyloric sphincter dysfunction may be seen. Esophageal dysfunction is frequently seen but is not always categorized in GpS. Pyloric dysfunction is increasingly a focus of both diagnosis and therapy. GI anatomic abnormalities can be identified with gastric biopsies of full thickness muscle and mucosa. CD117/interstitial cells of Cajal, neural fibers, inflammatory and other cells can be evaluated by light microscopy, electron microscopy, and special staining techniques.
Small bowel, mid-, and hindgut dysmotility involvement has often been associated with pathologies of intragastric motility. Not only GI but genitourinary dysfunction may be associated with fore- and mid-gut dysfunction in GpS. Equally well described are abnormalities of the autonomic and sensory nervous system, which have recently been better quantified. Serologic measures, such as channelopathies and other antibody mediated abnormalities, have been recently noted.
Suspected for many years, immune dysregulation has now been documented in patients with GpS. Further investigation, including genetic dysregulation of immune measures, is ongoing. Other mechanisms include systemic and local inflammation, hormonal abnormalities, macro- and micronutrient deficiencies, dysregulation in GI microbiome, and physical frailty. The above factors may play a role in the pathophysiology of GpS, and it is likely that many of these are involved with a given patient presenting for care.9
Diagnosis of GpS
Diagnosis of GpS is often delayed and can be challenging; various tools have been developed, but not all are used. A diagnostic approach for patients with symptoms of Gp is listed below, and Figure 2 details a diagnostic approach and treatment options for symptomatic patients.
Symptom Assessment: Initially Gp symptoms can be assessed using Food and Drug Administration–approved patient-reported outcomes, including frequency and severity of nausea, vomiting, anorexia/early satiety, bloating/distention, and abdominal pain on a 0-4, 0-5 or 0-10 scale. The Gastrointestinal Cardinal Symptom Index or visual analog scales can also be used. It is also important to evaluate midgut and hindgut symptoms.9-11
Mechanical obstruction assessment: Mechanical obstruction can be ruled out using upper endoscopy or barium studies.
Physiologic testing: The most common is radionuclide gastric emptying testing (GET). Compliance with guidelines, standardization, and consistency of GETs is vital to help with an accurate diagnosis. Currently, two consensus recommendations for the standardized performance of GETs exist.12,13 Breath testing is FDA approved in the United States and can be used as an alternative. Wireless motility capsule testing can be complimentary.
Gastric dysrhythmias assessment: Assessment of gastric dysrhythmias can be performed in outpatient settings using cutaneous electrogastrogram, currently available in many referral centers. Most patients with GpS have an underlying gastric electrical abnormality.14,15
Sphincter dysfunction assessment: Both proximal and distal sphincter abnormalities have been described for many years and are of particular interest recently. Use of the functional luminal imaging probe (FLIP) shows patients with GpS may have decreased sphincter distensibility when examining the comparisons of the cross-sectional area relative to pressure Using this information, sphincter therapies can be offered.16-18
Other testing: Neurologic and autonomic testing, along with psychosocial, genetic and frailty assessments, are helpful to explore.19 Nutritional evaluation can be done using standardized scales, such as subjective global assessment and serologic testing for micronutrient deficiency or electrical impedance.20
Treatment of GpS
Therapies for GpS can be viewed as the five D’s: Diet, Drug, Disruption, Devices, and Details.
Diet and nutrition: The mainstay treatment of GpS remains dietary modification. The most common recommendation is to limit meal size, often with increased meal frequency, as well as nutrient composition, in areas that may retard gastric emptying. In addition, some patients with GpS report intolerances of specific foods, such as specific carbohydrates. Nutritional consultation can assist patients with meals tailored for their current nutritional needs. Nutritional supplementation is widely used for patients with GpS.20
Pharmacological treatment: The next tier of treatment for GpS is drugs. Review of a patient’s medications is important to minimize drugs that may retard gastric emptying such as opiates and GLP-1 agonists. A full discussion of medications is beyond the scope of this article, but classes of drugs available include: prokinetics, antiemetics, neuromodulators, and investigational agents.
There is only one approved prokinetic medication for gastroparesis – the dopamine blocker metoclopramide – and most providers are aware of metoclopramide’s limitations in terms of potential side effects, such as the risk of tardive dyskinesia and labeling on duration of therapy, with a maximum of 12 weeks recommended. Alternative prokinetics, such as domperidone, are not easily available in the United States; some mediations approved for other indications, such as the 5-HT drug prucalopride, are sometimes given for GpS off-label. Antiemetics such as promethazine and ondansetron are frequently used for symptomatic control in GpS. Despite lack of positive controlled trials in Gp, neuromodulator drugs, such as tricyclic or tetracyclic antidepressants like amitriptyline or mirtazapine are often used; their efficacy is more proven in the functional dyspepsia area. Other drugs such as the NK-1 drug aprepitant have been studied in Gp and are sometimes used off-label. Drugs such as scopolamine and related compounds can also provide symptomatic relief, as can the tetrahydrocannabinol-containing drug, dronabinol. New pharmacologic agents for GpS include investigational drugs such as ghrelin agonists and several novel compounds, none of which are currently FDA approved.21,22
Fortunately, the majority of patients with GpS respond to conservative therapies, such as dietary changes and/or medications. The last part of the section on treatment of GpS includes patients that are diet and drug refractory. Patients in this group are often referred to gastroenterologists and can be complex, time consuming, and frustrating to provide care for. Many of these patients are eventually seen in referral centers, and some travel great distances and have considerable medical expenses.
Pylorus-directed therapies: The recent renewed interest in pyloric dysfunction in patients with Gp symptoms has led to a great deal of clinical activity. Gastropyloric dysfunction in Gp has been documented for decades, originally in diabetic patients with autonomic and enteric neuropathy. The use of botulinum toxin in upper- and lower-gastric sphincters has led to continuing use of this therapy for patients with GpS. Despite initial negative controlled trials of botulinum toxin in the pyloric sphincter, newer studies indicate that physiologic measures, such as the FLIP, may help with patient selection. Other disruptive pyloric therapies, including pyloromyotomy, per oral pyloromyotomy, and gastric peroral endoscopic myotomy, are supported by open-label use, despite a lack of published positive controlled trials.17
Bioelectric therapy: Another approach for patients with symptomatic drug refractory GpS is bioelectric device therapies, which can be delivered several ways, including directly to the stomach or to the spinal cord or the vagus nerve in the neck or ear, as well as by electro-acupuncture. High-frequency, low-energy gastric electrical stimulation (GES) is the best studied. First done in 1992 as an experimental therapy, GES was investigational from 1995 to 2000, when it became FDA approved as a humanitarian-use device. GES has been used in over 10,000 patients worldwide; only a small number (greater than 700 study patients) have been in controlled trials. Nine controlled trials of GES have been primarily positive, and durability for over 10 years has been shown. Temporary GES can also be performed endoscopically, although that is an off-label procedure. It has been shown to predict long-term therapy outcome.23-26
Nutritional support: Nutritional abnormalities in some cases of GpS lead to consideration of enteral tubes, starting with a trial of feeding with an N-J tube placed endoscopically. An N-J trial is most often performed in patients who have macro-malnutrition and weight loss but can be considered for other highly symptomatic patients. Other endoscopic tubes can be PEG or PEG-J or direct PEJ tubes. Some patients may require surgical placement of enteral tubes, presenting an opportunity for a small bowel or gastric full-thickness biopsy. Enteral tubes are sometimes used for decompression in highly symptomatic patients.27
For patients presenting with neurological symptoms, findings and serologic abnormalities have led to interest in immunotherapies. One is intravenous immunoglobulin, given parenterally. Several open-label studies have been published, the most recent one with 47 patients showing better response if glutamic acid decarboxylase–65 antibodies were present and with longer therapeutic dosing.28 Drawbacks to immunotherapies like intravenous immunoglobulin are cost and requiring parenteral access.
Other evaluation/treatments for drug refractory patients can be detailed as follows: First, an overall quality of life assessment can be helpful, especially one that includes impact of GpS on the patients and family. Nutritional considerations, which may not have been fully assessed, can be examined in more detail. Frailty assessments may show the need for physical therapy. Assessment for home care needs may indicate, in severe patients, needs for IV fluids at home, either enteral or parenteral, if nutrition is not adequate. Psychosocial and/or psychiatric assessments may lead to the need for medications, psychotherapy, and/or support groups. Lastly, an assessment of overall health status may lead to approaches for minimizing visits to emergency rooms and hospitalizations.29,30
Conclusion
Patients with Gp symptoms are becoming increasingly recognized and referred to gastroenterologists. Better understandings of the pathophysiology of the spectrum of gastroparesis syndromes, assisted by innovations in diagnosis, have led to expansion of existing and new therapeutic approaches. Fortunately, most patients can benefit from a standardized diagnostic approach and directed noninvasive therapies. Patients with refractory gastroparesis symptoms, often with complex issues referred to gastroenterologists, remain a challenge, and novel approaches may improve their quality of life.
Dr. Mathur is a GI motility research fellow at the University of Louisville, Ky. He reports no conflicts of interest. Dr. Abell is the Arthur M. Schoen, MD, Chair in Gastroenterology at the University of Louisville. His main funding is NIH GpCRC and NIH Definitive Evaluation of Gastric Dysrhythmia. He is an investigator for Cindome, Vanda, Allergan, and Neurogastrx; a consultant for Censa, Nuvaira, and Takeda; a speaker for Takeda and Medtronic; and a reviewer for UpToDate. He is also the founder of ADEPT-GI, which holds IP related to mucosal stimulation and autonomic and enteric profiling.
References
1. Jung HK et al. Gastroenterology. 2009;136(4):1225-33.
2. Ye Y et al. Gut. 2021;70(4):644-53.
3. Oshima T et al. J Neurogastroenterol Motil. 2021;27(1):46-54.
4. Soykan I et al. Dig Dis Sci. 1998;43(11):2398-404.
5. Syed AR et al. J Clin Gastroenterol. 2020;54(1):50-4.
6.Pasricha PJ et al. Clin Gastroenterol Hepatol. 2011;9(7):567-76.e1-4.
7. Pasricha PJ et al. Gastroenterology. 2021;160(6):2006-17.
8. Almario CV et al. Am J Gastroenterol. 2018;113(11):1701-10.
9. Abell TL et al. Dig Dis Sci. 2021 Apr;66(4):1127-41.
10. Abell TL et al. Neurogastroenterol Motil. 2019;31(3):e13534.
11. Elmasry M et al. Neurogastroenterol Motil. 2021 Oct 26;e14274.
12. Maurer AH et al. J Nucl Med. 2020;61(3):11N-7N.
13. Abell TL et al. J Nucl Med Technol. 2008 Mar;36(1):44-54.
14. Shine A et al. Neuromodulation. 2022 Feb 16;S1094-7159(21)06986-5.
15. O’Grady G et al. Am J Physiol Gastrointest Liver Physiol. 2021;321(5):G527-g42.
16. Saadi M et al. Rev Gastroenterol Mex (Engl Ed). Oct-Dec 2018;83(4):375-84.
17. Kamal F et al. Aliment Pharmacol Ther. 2022;55(2):168-77.
18. Harberson J et al. Dig Dis Sci. 2010;55(2):359-70.
19. Winston J. Gastrointestinal Disorders. 2021;3(2):78-83.
20. Parkman HP et al. Gastroenterology. 2011;141(2):486-98, 98.e1-7.
21. Heckroth M et al. J Clin Gastroenterol. 2021;55(4):279-99.
22. Camilleri M. Clin Gastroenterol Hepatol. 2022;20(1):19-24.
23. Payne SC et al. Nat Rev Gastroenterol Hepatol. 2019;16(2):89-105.
24. Ducrotte P et al. Gastroenterology. 2020;158(3):506-14.e2.
25. Burlen J et al. Gastroenterology Res. 2018;11(5):349-54.
26. Hedjoudje A et al. Neurogastroenterol Motil. 2020;32(11):e13949.
27. Petrov RV et al. Gastroenterol Clin North Am. 2020;49(3):539-56.
28. Gala K et al. J Clin Gastroenterol. 2021 Dec 31. doi: 10.1097/MCG.0000000000001655.
29. Abell TL et al. Neurogastroenterol Motil. 2006;18(4):263-83.
30. Camilleri M et al. Am J Gastroenterol. 2013;108(1):18-37.
Introduction
Patients presenting with the symptoms of gastroparesis (Gp) are commonly seen in gastroenterology practice.
Presentation
Patients with foregut symptoms of Gp have characteristic presentations, with nausea, vomiting/retching, and abdominal pain often associated with bloating and distension, early satiety, anorexia, and heartburn. Mid- and hindgut gastrointestinal and/or urinary symptoms may be seen in patients with Gp as well.
The precise epidemiology of gastroparesis syndromes (GpS) is unknown. Classic gastroparesis, defined as delayed gastric emptying without known mechanical obstruction, has a prevalence of about 10 per 100,000 population in men and 30 per 100,000 in women with women being affected 3 to 4 times more than men.1,2 Some risk factors for GpS, such as diabetes mellitus (DM) in up to 5% of patients with Type 1 DM, are known.3 Caucasians have the highest prevalence of GpS, followed by African Americans.4,5
The classic definition of Gp has blurred with the realization that patients may have symptoms of Gp without delayed solid gastric emptying. Some patients have been described as having chronic unexplained nausea and vomiting or gastroparesis like syndrome.6 More recently the NIH Gastroparesis Consortium has proposed that disorders like functional dyspepsia may be a spectrum of the two disorders and classic Gp.7 Using this broadened definition, the number of patients with Gp symptoms is much greater, found in 10% or more of the U.S. population.8 For this discussion, GpS is used to encompass this spectrum of disorders.
The etiology of GpS is often unknown for a given patient, but clues to etiology exist in what is known about pathophysiology. Types of Gp are described as being idiopathic, diabetic, or postsurgical, each of which may have varying pathophysiology. Many patients with mild-to-moderate GpS symptoms are effectively treated with out-patient therapies; other patients may be refractory to available treatments. Refractory GpS patients have a high burden of illness affecting them, their families, providers, hospitals, and payers.
Pathophysiology
Specific types of gastroparesis syndromes have variable pathophysiology (Figure 1). In some cases, like GpS associated with DM, pathophysiology is partially related to diabetic autonomic dysfunction. GpS are multifactorial, however, and rather than focusing on subtypes, this discussion focuses on shared pathophysiology. Understanding pathophysiology is key to determining treatment options and potential future targets for therapy.
Intragastric mechanical dysfunction, both proximal (fundic relaxation and accommodation and/or lack of fundic contractility) and distal stomach (antral hypomotility) may be involved. Additionally, intragastric electrical disturbances in frequency, amplitude, and propagation of gastric electrical waves can be seen with low/high resolution gastric mapping.
Both gastroesophageal and gastropyloric sphincter dysfunction may be seen. Esophageal dysfunction is frequently seen but is not always categorized in GpS. Pyloric dysfunction is increasingly a focus of both diagnosis and therapy. GI anatomic abnormalities can be identified with gastric biopsies of full thickness muscle and mucosa. CD117/interstitial cells of Cajal, neural fibers, inflammatory and other cells can be evaluated by light microscopy, electron microscopy, and special staining techniques.
Small bowel, mid-, and hindgut dysmotility involvement has often been associated with pathologies of intragastric motility. Not only GI but genitourinary dysfunction may be associated with fore- and mid-gut dysfunction in GpS. Equally well described are abnormalities of the autonomic and sensory nervous system, which have recently been better quantified. Serologic measures, such as channelopathies and other antibody mediated abnormalities, have been recently noted.
Suspected for many years, immune dysregulation has now been documented in patients with GpS. Further investigation, including genetic dysregulation of immune measures, is ongoing. Other mechanisms include systemic and local inflammation, hormonal abnormalities, macro- and micronutrient deficiencies, dysregulation in GI microbiome, and physical frailty. The above factors may play a role in the pathophysiology of GpS, and it is likely that many of these are involved with a given patient presenting for care.9
Diagnosis of GpS
Diagnosis of GpS is often delayed and can be challenging; various tools have been developed, but not all are used. A diagnostic approach for patients with symptoms of Gp is listed below, and Figure 2 details a diagnostic approach and treatment options for symptomatic patients.
Symptom Assessment: Initially Gp symptoms can be assessed using Food and Drug Administration–approved patient-reported outcomes, including frequency and severity of nausea, vomiting, anorexia/early satiety, bloating/distention, and abdominal pain on a 0-4, 0-5 or 0-10 scale. The Gastrointestinal Cardinal Symptom Index or visual analog scales can also be used. It is also important to evaluate midgut and hindgut symptoms.9-11
Mechanical obstruction assessment: Mechanical obstruction can be ruled out using upper endoscopy or barium studies.
Physiologic testing: The most common is radionuclide gastric emptying testing (GET). Compliance with guidelines, standardization, and consistency of GETs is vital to help with an accurate diagnosis. Currently, two consensus recommendations for the standardized performance of GETs exist.12,13 Breath testing is FDA approved in the United States and can be used as an alternative. Wireless motility capsule testing can be complimentary.
Gastric dysrhythmias assessment: Assessment of gastric dysrhythmias can be performed in outpatient settings using cutaneous electrogastrogram, currently available in many referral centers. Most patients with GpS have an underlying gastric electrical abnormality.14,15
Sphincter dysfunction assessment: Both proximal and distal sphincter abnormalities have been described for many years and are of particular interest recently. Use of the functional luminal imaging probe (FLIP) shows patients with GpS may have decreased sphincter distensibility when examining the comparisons of the cross-sectional area relative to pressure Using this information, sphincter therapies can be offered.16-18
Other testing: Neurologic and autonomic testing, along with psychosocial, genetic and frailty assessments, are helpful to explore.19 Nutritional evaluation can be done using standardized scales, such as subjective global assessment and serologic testing for micronutrient deficiency or electrical impedance.20
Treatment of GpS
Therapies for GpS can be viewed as the five D’s: Diet, Drug, Disruption, Devices, and Details.
Diet and nutrition: The mainstay treatment of GpS remains dietary modification. The most common recommendation is to limit meal size, often with increased meal frequency, as well as nutrient composition, in areas that may retard gastric emptying. In addition, some patients with GpS report intolerances of specific foods, such as specific carbohydrates. Nutritional consultation can assist patients with meals tailored for their current nutritional needs. Nutritional supplementation is widely used for patients with GpS.20
Pharmacological treatment: The next tier of treatment for GpS is drugs. Review of a patient’s medications is important to minimize drugs that may retard gastric emptying such as opiates and GLP-1 agonists. A full discussion of medications is beyond the scope of this article, but classes of drugs available include: prokinetics, antiemetics, neuromodulators, and investigational agents.
There is only one approved prokinetic medication for gastroparesis – the dopamine blocker metoclopramide – and most providers are aware of metoclopramide’s limitations in terms of potential side effects, such as the risk of tardive dyskinesia and labeling on duration of therapy, with a maximum of 12 weeks recommended. Alternative prokinetics, such as domperidone, are not easily available in the United States; some mediations approved for other indications, such as the 5-HT drug prucalopride, are sometimes given for GpS off-label. Antiemetics such as promethazine and ondansetron are frequently used for symptomatic control in GpS. Despite lack of positive controlled trials in Gp, neuromodulator drugs, such as tricyclic or tetracyclic antidepressants like amitriptyline or mirtazapine are often used; their efficacy is more proven in the functional dyspepsia area. Other drugs such as the NK-1 drug aprepitant have been studied in Gp and are sometimes used off-label. Drugs such as scopolamine and related compounds can also provide symptomatic relief, as can the tetrahydrocannabinol-containing drug, dronabinol. New pharmacologic agents for GpS include investigational drugs such as ghrelin agonists and several novel compounds, none of which are currently FDA approved.21,22
Fortunately, the majority of patients with GpS respond to conservative therapies, such as dietary changes and/or medications. The last part of the section on treatment of GpS includes patients that are diet and drug refractory. Patients in this group are often referred to gastroenterologists and can be complex, time consuming, and frustrating to provide care for. Many of these patients are eventually seen in referral centers, and some travel great distances and have considerable medical expenses.
Pylorus-directed therapies: The recent renewed interest in pyloric dysfunction in patients with Gp symptoms has led to a great deal of clinical activity. Gastropyloric dysfunction in Gp has been documented for decades, originally in diabetic patients with autonomic and enteric neuropathy. The use of botulinum toxin in upper- and lower-gastric sphincters has led to continuing use of this therapy for patients with GpS. Despite initial negative controlled trials of botulinum toxin in the pyloric sphincter, newer studies indicate that physiologic measures, such as the FLIP, may help with patient selection. Other disruptive pyloric therapies, including pyloromyotomy, per oral pyloromyotomy, and gastric peroral endoscopic myotomy, are supported by open-label use, despite a lack of published positive controlled trials.17
Bioelectric therapy: Another approach for patients with symptomatic drug refractory GpS is bioelectric device therapies, which can be delivered several ways, including directly to the stomach or to the spinal cord or the vagus nerve in the neck or ear, as well as by electro-acupuncture. High-frequency, low-energy gastric electrical stimulation (GES) is the best studied. First done in 1992 as an experimental therapy, GES was investigational from 1995 to 2000, when it became FDA approved as a humanitarian-use device. GES has been used in over 10,000 patients worldwide; only a small number (greater than 700 study patients) have been in controlled trials. Nine controlled trials of GES have been primarily positive, and durability for over 10 years has been shown. Temporary GES can also be performed endoscopically, although that is an off-label procedure. It has been shown to predict long-term therapy outcome.23-26
Nutritional support: Nutritional abnormalities in some cases of GpS lead to consideration of enteral tubes, starting with a trial of feeding with an N-J tube placed endoscopically. An N-J trial is most often performed in patients who have macro-malnutrition and weight loss but can be considered for other highly symptomatic patients. Other endoscopic tubes can be PEG or PEG-J or direct PEJ tubes. Some patients may require surgical placement of enteral tubes, presenting an opportunity for a small bowel or gastric full-thickness biopsy. Enteral tubes are sometimes used for decompression in highly symptomatic patients.27
For patients presenting with neurological symptoms, findings and serologic abnormalities have led to interest in immunotherapies. One is intravenous immunoglobulin, given parenterally. Several open-label studies have been published, the most recent one with 47 patients showing better response if glutamic acid decarboxylase–65 antibodies were present and with longer therapeutic dosing.28 Drawbacks to immunotherapies like intravenous immunoglobulin are cost and requiring parenteral access.
Other evaluation/treatments for drug refractory patients can be detailed as follows: First, an overall quality of life assessment can be helpful, especially one that includes impact of GpS on the patients and family. Nutritional considerations, which may not have been fully assessed, can be examined in more detail. Frailty assessments may show the need for physical therapy. Assessment for home care needs may indicate, in severe patients, needs for IV fluids at home, either enteral or parenteral, if nutrition is not adequate. Psychosocial and/or psychiatric assessments may lead to the need for medications, psychotherapy, and/or support groups. Lastly, an assessment of overall health status may lead to approaches for minimizing visits to emergency rooms and hospitalizations.29,30
Conclusion
Patients with Gp symptoms are becoming increasingly recognized and referred to gastroenterologists. Better understandings of the pathophysiology of the spectrum of gastroparesis syndromes, assisted by innovations in diagnosis, have led to expansion of existing and new therapeutic approaches. Fortunately, most patients can benefit from a standardized diagnostic approach and directed noninvasive therapies. Patients with refractory gastroparesis symptoms, often with complex issues referred to gastroenterologists, remain a challenge, and novel approaches may improve their quality of life.
Dr. Mathur is a GI motility research fellow at the University of Louisville, Ky. He reports no conflicts of interest. Dr. Abell is the Arthur M. Schoen, MD, Chair in Gastroenterology at the University of Louisville. His main funding is NIH GpCRC and NIH Definitive Evaluation of Gastric Dysrhythmia. He is an investigator for Cindome, Vanda, Allergan, and Neurogastrx; a consultant for Censa, Nuvaira, and Takeda; a speaker for Takeda and Medtronic; and a reviewer for UpToDate. He is also the founder of ADEPT-GI, which holds IP related to mucosal stimulation and autonomic and enteric profiling.
References
1. Jung HK et al. Gastroenterology. 2009;136(4):1225-33.
2. Ye Y et al. Gut. 2021;70(4):644-53.
3. Oshima T et al. J Neurogastroenterol Motil. 2021;27(1):46-54.
4. Soykan I et al. Dig Dis Sci. 1998;43(11):2398-404.
5. Syed AR et al. J Clin Gastroenterol. 2020;54(1):50-4.
6.Pasricha PJ et al. Clin Gastroenterol Hepatol. 2011;9(7):567-76.e1-4.
7. Pasricha PJ et al. Gastroenterology. 2021;160(6):2006-17.
8. Almario CV et al. Am J Gastroenterol. 2018;113(11):1701-10.
9. Abell TL et al. Dig Dis Sci. 2021 Apr;66(4):1127-41.
10. Abell TL et al. Neurogastroenterol Motil. 2019;31(3):e13534.
11. Elmasry M et al. Neurogastroenterol Motil. 2021 Oct 26;e14274.
12. Maurer AH et al. J Nucl Med. 2020;61(3):11N-7N.
13. Abell TL et al. J Nucl Med Technol. 2008 Mar;36(1):44-54.
14. Shine A et al. Neuromodulation. 2022 Feb 16;S1094-7159(21)06986-5.
15. O’Grady G et al. Am J Physiol Gastrointest Liver Physiol. 2021;321(5):G527-g42.
16. Saadi M et al. Rev Gastroenterol Mex (Engl Ed). Oct-Dec 2018;83(4):375-84.
17. Kamal F et al. Aliment Pharmacol Ther. 2022;55(2):168-77.
18. Harberson J et al. Dig Dis Sci. 2010;55(2):359-70.
19. Winston J. Gastrointestinal Disorders. 2021;3(2):78-83.
20. Parkman HP et al. Gastroenterology. 2011;141(2):486-98, 98.e1-7.
21. Heckroth M et al. J Clin Gastroenterol. 2021;55(4):279-99.
22. Camilleri M. Clin Gastroenterol Hepatol. 2022;20(1):19-24.
23. Payne SC et al. Nat Rev Gastroenterol Hepatol. 2019;16(2):89-105.
24. Ducrotte P et al. Gastroenterology. 2020;158(3):506-14.e2.
25. Burlen J et al. Gastroenterology Res. 2018;11(5):349-54.
26. Hedjoudje A et al. Neurogastroenterol Motil. 2020;32(11):e13949.
27. Petrov RV et al. Gastroenterol Clin North Am. 2020;49(3):539-56.
28. Gala K et al. J Clin Gastroenterol. 2021 Dec 31. doi: 10.1097/MCG.0000000000001655.
29. Abell TL et al. Neurogastroenterol Motil. 2006;18(4):263-83.
30. Camilleri M et al. Am J Gastroenterol. 2013;108(1):18-37.
Introduction
Patients presenting with the symptoms of gastroparesis (Gp) are commonly seen in gastroenterology practice.
Presentation
Patients with foregut symptoms of Gp have characteristic presentations, with nausea, vomiting/retching, and abdominal pain often associated with bloating and distension, early satiety, anorexia, and heartburn. Mid- and hindgut gastrointestinal and/or urinary symptoms may be seen in patients with Gp as well.
The precise epidemiology of gastroparesis syndromes (GpS) is unknown. Classic gastroparesis, defined as delayed gastric emptying without known mechanical obstruction, has a prevalence of about 10 per 100,000 population in men and 30 per 100,000 in women with women being affected 3 to 4 times more than men.1,2 Some risk factors for GpS, such as diabetes mellitus (DM) in up to 5% of patients with Type 1 DM, are known.3 Caucasians have the highest prevalence of GpS, followed by African Americans.4,5
The classic definition of Gp has blurred with the realization that patients may have symptoms of Gp without delayed solid gastric emptying. Some patients have been described as having chronic unexplained nausea and vomiting or gastroparesis like syndrome.6 More recently the NIH Gastroparesis Consortium has proposed that disorders like functional dyspepsia may be a spectrum of the two disorders and classic Gp.7 Using this broadened definition, the number of patients with Gp symptoms is much greater, found in 10% or more of the U.S. population.8 For this discussion, GpS is used to encompass this spectrum of disorders.
The etiology of GpS is often unknown for a given patient, but clues to etiology exist in what is known about pathophysiology. Types of Gp are described as being idiopathic, diabetic, or postsurgical, each of which may have varying pathophysiology. Many patients with mild-to-moderate GpS symptoms are effectively treated with out-patient therapies; other patients may be refractory to available treatments. Refractory GpS patients have a high burden of illness affecting them, their families, providers, hospitals, and payers.
Pathophysiology
Specific types of gastroparesis syndromes have variable pathophysiology (Figure 1). In some cases, like GpS associated with DM, pathophysiology is partially related to diabetic autonomic dysfunction. GpS are multifactorial, however, and rather than focusing on subtypes, this discussion focuses on shared pathophysiology. Understanding pathophysiology is key to determining treatment options and potential future targets for therapy.
Intragastric mechanical dysfunction, both proximal (fundic relaxation and accommodation and/or lack of fundic contractility) and distal stomach (antral hypomotility) may be involved. Additionally, intragastric electrical disturbances in frequency, amplitude, and propagation of gastric electrical waves can be seen with low/high resolution gastric mapping.
Both gastroesophageal and gastropyloric sphincter dysfunction may be seen. Esophageal dysfunction is frequently seen but is not always categorized in GpS. Pyloric dysfunction is increasingly a focus of both diagnosis and therapy. GI anatomic abnormalities can be identified with gastric biopsies of full thickness muscle and mucosa. CD117/interstitial cells of Cajal, neural fibers, inflammatory and other cells can be evaluated by light microscopy, electron microscopy, and special staining techniques.
Small bowel, mid-, and hindgut dysmotility involvement has often been associated with pathologies of intragastric motility. Not only GI but genitourinary dysfunction may be associated with fore- and mid-gut dysfunction in GpS. Equally well described are abnormalities of the autonomic and sensory nervous system, which have recently been better quantified. Serologic measures, such as channelopathies and other antibody mediated abnormalities, have been recently noted.
Suspected for many years, immune dysregulation has now been documented in patients with GpS. Further investigation, including genetic dysregulation of immune measures, is ongoing. Other mechanisms include systemic and local inflammation, hormonal abnormalities, macro- and micronutrient deficiencies, dysregulation in GI microbiome, and physical frailty. The above factors may play a role in the pathophysiology of GpS, and it is likely that many of these are involved with a given patient presenting for care.9
Diagnosis of GpS
Diagnosis of GpS is often delayed and can be challenging; various tools have been developed, but not all are used. A diagnostic approach for patients with symptoms of Gp is listed below, and Figure 2 details a diagnostic approach and treatment options for symptomatic patients.
Symptom Assessment: Initially Gp symptoms can be assessed using Food and Drug Administration–approved patient-reported outcomes, including frequency and severity of nausea, vomiting, anorexia/early satiety, bloating/distention, and abdominal pain on a 0-4, 0-5 or 0-10 scale. The Gastrointestinal Cardinal Symptom Index or visual analog scales can also be used. It is also important to evaluate midgut and hindgut symptoms.9-11
Mechanical obstruction assessment: Mechanical obstruction can be ruled out using upper endoscopy or barium studies.
Physiologic testing: The most common is radionuclide gastric emptying testing (GET). Compliance with guidelines, standardization, and consistency of GETs is vital to help with an accurate diagnosis. Currently, two consensus recommendations for the standardized performance of GETs exist.12,13 Breath testing is FDA approved in the United States and can be used as an alternative. Wireless motility capsule testing can be complimentary.
Gastric dysrhythmias assessment: Assessment of gastric dysrhythmias can be performed in outpatient settings using cutaneous electrogastrogram, currently available in many referral centers. Most patients with GpS have an underlying gastric electrical abnormality.14,15
Sphincter dysfunction assessment: Both proximal and distal sphincter abnormalities have been described for many years and are of particular interest recently. Use of the functional luminal imaging probe (FLIP) shows patients with GpS may have decreased sphincter distensibility when examining the comparisons of the cross-sectional area relative to pressure Using this information, sphincter therapies can be offered.16-18
Other testing: Neurologic and autonomic testing, along with psychosocial, genetic and frailty assessments, are helpful to explore.19 Nutritional evaluation can be done using standardized scales, such as subjective global assessment and serologic testing for micronutrient deficiency or electrical impedance.20
Treatment of GpS
Therapies for GpS can be viewed as the five D’s: Diet, Drug, Disruption, Devices, and Details.
Diet and nutrition: The mainstay treatment of GpS remains dietary modification. The most common recommendation is to limit meal size, often with increased meal frequency, as well as nutrient composition, in areas that may retard gastric emptying. In addition, some patients with GpS report intolerances of specific foods, such as specific carbohydrates. Nutritional consultation can assist patients with meals tailored for their current nutritional needs. Nutritional supplementation is widely used for patients with GpS.20
Pharmacological treatment: The next tier of treatment for GpS is drugs. Review of a patient’s medications is important to minimize drugs that may retard gastric emptying such as opiates and GLP-1 agonists. A full discussion of medications is beyond the scope of this article, but classes of drugs available include: prokinetics, antiemetics, neuromodulators, and investigational agents.
There is only one approved prokinetic medication for gastroparesis – the dopamine blocker metoclopramide – and most providers are aware of metoclopramide’s limitations in terms of potential side effects, such as the risk of tardive dyskinesia and labeling on duration of therapy, with a maximum of 12 weeks recommended. Alternative prokinetics, such as domperidone, are not easily available in the United States; some mediations approved for other indications, such as the 5-HT drug prucalopride, are sometimes given for GpS off-label. Antiemetics such as promethazine and ondansetron are frequently used for symptomatic control in GpS. Despite lack of positive controlled trials in Gp, neuromodulator drugs, such as tricyclic or tetracyclic antidepressants like amitriptyline or mirtazapine are often used; their efficacy is more proven in the functional dyspepsia area. Other drugs such as the NK-1 drug aprepitant have been studied in Gp and are sometimes used off-label. Drugs such as scopolamine and related compounds can also provide symptomatic relief, as can the tetrahydrocannabinol-containing drug, dronabinol. New pharmacologic agents for GpS include investigational drugs such as ghrelin agonists and several novel compounds, none of which are currently FDA approved.21,22
Fortunately, the majority of patients with GpS respond to conservative therapies, such as dietary changes and/or medications. The last part of the section on treatment of GpS includes patients that are diet and drug refractory. Patients in this group are often referred to gastroenterologists and can be complex, time consuming, and frustrating to provide care for. Many of these patients are eventually seen in referral centers, and some travel great distances and have considerable medical expenses.
Pylorus-directed therapies: The recent renewed interest in pyloric dysfunction in patients with Gp symptoms has led to a great deal of clinical activity. Gastropyloric dysfunction in Gp has been documented for decades, originally in diabetic patients with autonomic and enteric neuropathy. The use of botulinum toxin in upper- and lower-gastric sphincters has led to continuing use of this therapy for patients with GpS. Despite initial negative controlled trials of botulinum toxin in the pyloric sphincter, newer studies indicate that physiologic measures, such as the FLIP, may help with patient selection. Other disruptive pyloric therapies, including pyloromyotomy, per oral pyloromyotomy, and gastric peroral endoscopic myotomy, are supported by open-label use, despite a lack of published positive controlled trials.17
Bioelectric therapy: Another approach for patients with symptomatic drug refractory GpS is bioelectric device therapies, which can be delivered several ways, including directly to the stomach or to the spinal cord or the vagus nerve in the neck or ear, as well as by electro-acupuncture. High-frequency, low-energy gastric electrical stimulation (GES) is the best studied. First done in 1992 as an experimental therapy, GES was investigational from 1995 to 2000, when it became FDA approved as a humanitarian-use device. GES has been used in over 10,000 patients worldwide; only a small number (greater than 700 study patients) have been in controlled trials. Nine controlled trials of GES have been primarily positive, and durability for over 10 years has been shown. Temporary GES can also be performed endoscopically, although that is an off-label procedure. It has been shown to predict long-term therapy outcome.23-26
Nutritional support: Nutritional abnormalities in some cases of GpS lead to consideration of enteral tubes, starting with a trial of feeding with an N-J tube placed endoscopically. An N-J trial is most often performed in patients who have macro-malnutrition and weight loss but can be considered for other highly symptomatic patients. Other endoscopic tubes can be PEG or PEG-J or direct PEJ tubes. Some patients may require surgical placement of enteral tubes, presenting an opportunity for a small bowel or gastric full-thickness biopsy. Enteral tubes are sometimes used for decompression in highly symptomatic patients.27
For patients presenting with neurological symptoms, findings and serologic abnormalities have led to interest in immunotherapies. One is intravenous immunoglobulin, given parenterally. Several open-label studies have been published, the most recent one with 47 patients showing better response if glutamic acid decarboxylase–65 antibodies were present and with longer therapeutic dosing.28 Drawbacks to immunotherapies like intravenous immunoglobulin are cost and requiring parenteral access.
Other evaluation/treatments for drug refractory patients can be detailed as follows: First, an overall quality of life assessment can be helpful, especially one that includes impact of GpS on the patients and family. Nutritional considerations, which may not have been fully assessed, can be examined in more detail. Frailty assessments may show the need for physical therapy. Assessment for home care needs may indicate, in severe patients, needs for IV fluids at home, either enteral or parenteral, if nutrition is not adequate. Psychosocial and/or psychiatric assessments may lead to the need for medications, psychotherapy, and/or support groups. Lastly, an assessment of overall health status may lead to approaches for minimizing visits to emergency rooms and hospitalizations.29,30
Conclusion
Patients with Gp symptoms are becoming increasingly recognized and referred to gastroenterologists. Better understandings of the pathophysiology of the spectrum of gastroparesis syndromes, assisted by innovations in diagnosis, have led to expansion of existing and new therapeutic approaches. Fortunately, most patients can benefit from a standardized diagnostic approach and directed noninvasive therapies. Patients with refractory gastroparesis symptoms, often with complex issues referred to gastroenterologists, remain a challenge, and novel approaches may improve their quality of life.
Dr. Mathur is a GI motility research fellow at the University of Louisville, Ky. He reports no conflicts of interest. Dr. Abell is the Arthur M. Schoen, MD, Chair in Gastroenterology at the University of Louisville. His main funding is NIH GpCRC and NIH Definitive Evaluation of Gastric Dysrhythmia. He is an investigator for Cindome, Vanda, Allergan, and Neurogastrx; a consultant for Censa, Nuvaira, and Takeda; a speaker for Takeda and Medtronic; and a reviewer for UpToDate. He is also the founder of ADEPT-GI, which holds IP related to mucosal stimulation and autonomic and enteric profiling.
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7. Pasricha PJ et al. Gastroenterology. 2021;160(6):2006-17.
8. Almario CV et al. Am J Gastroenterol. 2018;113(11):1701-10.
9. Abell TL et al. Dig Dis Sci. 2021 Apr;66(4):1127-41.
10. Abell TL et al. Neurogastroenterol Motil. 2019;31(3):e13534.
11. Elmasry M et al. Neurogastroenterol Motil. 2021 Oct 26;e14274.
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13. Abell TL et al. J Nucl Med Technol. 2008 Mar;36(1):44-54.
14. Shine A et al. Neuromodulation. 2022 Feb 16;S1094-7159(21)06986-5.
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30. Camilleri M et al. Am J Gastroenterol. 2013;108(1):18-37.
The management of inflammatory bowel disease in pregnancy
Inflammatory bowel disease (IBD) incidence is rising globally.1-3 In the United States, we have seen a 123% increase in prevalence of IBD among adults and a 133% increase among children from 2007 to 2016, with an annual percentage change of 9.9%.1 The rise of IBD in young people, and the overall higher prevalence in women compared with men, make pregnancy and IBD a topic of increasing importance for gastroenterologists.1 Here, we will discuss management and expectations in women with IBD before conception, during pregnancy, and post partum.
Preconception
Disease activity
Achieving both clinical and endoscopic remission of disease prior to conception is the key to ensuring the best maternal and fetal outcomes. Patients with IBD who conceive while in remission remain in remission 80% of the time.4,5 On the other hand, those who conceive while their disease is active may continue to have active or worsening disease in nearly 70% of cases.4 Active disease has been associated with an increased incidence of preterm birth, low birth weight, and small-for-gestational-age birth.6-8 Active disease can also exacerbate malnutrition and result in poor maternal weight gain, which is associated with intrauterine growth restriction.9,7 Pregnancy outcomes in patients with IBD and quiescent disease are similar to those in the general population.10,11
Health care maintenance
Optimizing maternal health prior to conception is critical. Alcohol, tobacco, recreational drugs, and marijuana should all be avoided. Opioids should be tapered off prior to conception, as continued use may result in neonatal opioid withdrawal syndrome and long-term neurodevelopmental consequences.12,13 In addition, aiming for a healthy body mass index between 18 and 25 months prior to conception allows for better overall pregnancy outcomes.13 Appropriate cancer screening includes colon cancer screening in those with more than 8 years of colitis, regular pap smear for cervical cancer, and annual total body skin cancer examinations for patients on thiopurines and biologic therapies.14
Nutrition
Folic acid supplementation with at least 400 micrograms (mcg) daily is necessary for all women planning pregnancy. Patients with small bowel involvement or history of small bowel resection should have a folate intake of a minimum of 2 grams per day. Adequate vitamin D levels (at least 20 ng/mL) are recommended in all women with IBD. Those with malabsorption should be screened for deficiencies in vitamin B12, folate, and iron.13 These nutritional markers should be evaluated prepregnancy, during the first trimester, and thereafter as needed.15-18
Preconception counseling
Steroid-free remission for at least 3 months prior to conception is recommended and is associated with reduced risk of flare during pregnancy.16,19 IBD medications needed to control disease activity are generally safe preconception and during pregnancy, with some exception (Table).
Misconceptions regarding heritability of IBD have sometimes discouraged men and women from having children. While genetics may increase susceptibility, environmental and other factors are involved as well. The concordance rates for monozygotic twins range from 33.3%-58.3% for Crohn’s disease and 13.4%-27.9% for ulcerative colitis (UC).20 The risk of a child developing IBD is higher in those who have multiple relatives with IBD and whose parents had IBD at the time of conception.21 While genetic testing for IBD loci is available, it is not commonly performed at this time as many genes are involved.22
Pregnancy
Coordinated care
A complete team of specialists with coordinated care among all providers is needed for optimal maternal and fetal outcomes.23,24 A gastroenterologist, ideally an IBD specialist, should follow the patient throughout pregnancy, seeing the patient at least once during the first or second trimester and as needed during pregnancy.16 A high-risk obstetrician or maternal-fetal medicine specialist should be involved early in pregnancy, as well. Open communication among all disciplines ensures that a common message is conveyed to the patient.16,24 A nutritionist, mental health provider, and lactation specialist knowledgeable about IBD drugs may be of assistance, as well.16
Disease activity
While women with IBD are at increased risk of spontaneous abortion, preterm birth, and labor complications, this risk is mitigated by controlling disease activity.25 The risk of preterm birth, small-for-gestational-age birth, and delivery via C-section is much higher in women with moderate-to-high disease activity, compared with those with low disease activity.26 The presence of active perianal disease mandates C-section over vaginal delivery. Fourth-degree lacerations following vaginal delivery are most common among those patients with perianal disease.26,27 Stillbirths were shown to be increased only in those with active IBD when compared with non-IBD comparators and inactive IBD.28-31;11
Noninvasive methods for disease monitoring are preferred in pregnancy, but serum markers such as erythrocyte sedimentation rate and C-reactive protein may not be reliable in the pregnant patient (Figure).32 Fecal calprotectin does rise in correlation with disease activity, but exact thresholds have not been validated in pregnancy.33,34
An unsedated, unprepped flexible sigmoidoscopy can be safely performed throughout pregnancy.35 When there is a strong indication, a complete colonoscopy can be performed in the pregnant patient as well.36 Current American Society for Gastrointestinal Endoscopy (ASGE) guidelines suggest placing the patient in the left lateral tilt position to avoid decreased maternal and placental perfusion via compression of the aorta or inferior vena cava and performing endoscopy during the second trimester, although trimester-specific timing is not always feasible by indication.37
Medication use and safety
IBD medications are a priority topic of concern among pregnant patients or those considering conception.38 Comprehensive data from the PIANO (Pregnancy in Inflammatory Bowel Disease and Neonatal Outcomes) registry has shown that most IBD drugs do not result in adverse pregnancy outcomes and should be continued.39 The use of biologics and thiopurines, either in combination or alone, is not related to an increased risk of congenital malformations, spontaneous abortion, preterm birth, low birth weight, or infections during the child’s first year of life.7,39 Developmental milestones also remain unaffected.39 Here, we will discuss safety considerations during pregnancy (see Table).
5-aminosalycylic acid. 5-aminosalicylic acid (5-ASA) agents are generally low risk during pregnancy and should be continued.40-41 Sulfasalazine does interfere with folate metabolism, but by increasing folic acid supplementation to 2 grams per day, sulfasalazine can be continued throughout pregnancy, as well.42
Corticosteroids. Intrapartum corticosteroid use is associated with an increased risk of gestational diabetes and adrenal insufficiency when used long term.43-45 Short-term use may, however, be necessary to control an acute flare. The lowest dose for the shortest duration possible is recommended. Because of its high first-pass metabolism, budesonide is considered low risk in pregnancy.
Methotrexate. Methotrexate needs to be stopped at least 3 months prior to conception and should be avoided throughout pregnancy. Use during pregnancy can result in spontaneous abortions, as well as embryotoxicity.46
Thiopurines (6-mercaptopurine and azathioprine). Patients who are taking thiopurines prior to conception to maintain remission can continue to do so. Data on thiopurines from the PIANO registry has shown no increase in spontaneous abortions, congenital malformations, low birth weight, preterm birth, rates of infection in the child, or developmental delays.47-51
Calcineurin inhibitors (cyclosporine and tacrolimus). Calcineurin inhibitors are reserved for the management of acute severe UC. Safety data on calcineurin inhibitors is conflicting, and there is not enough information at this time to identify risk during pregnancy. Cyclosporine can be used for salvage therapy if absolutely needed, and there are case reports of its successful using during pregnancy.16,52
Biologic therapies. With the exception of certolizumab, all of the currently used biologics are actively transported across the placenta.39,53,54 Intrapartum use of biologic therapies does not worsen pregnancy or neonatal outcomes, including the risk for intensive care unit admission, infections, and developmental milestones.39,47
While drug concentrations may vary slightly during pregnancy, these changes are not substantial enough to warrant more frequent monitoring or dose adjustments, and prepregnancy weight should be used for dosing.55,56
Antitumor necrosis factor agents used in IBD include infliximab, adalimumab, certolizumab, and golimumab.57 All are low risk for pregnant patients and their offspring. Dosage timings can be adjusted, but not stopped, to minimize exposure to the child; however, it cannot be adjusted for certolizumab pegol because of its lack of placental transfer.58-59
Natalizumab and vedolizumab are integrin receptor antagonists and are also low risk in pregnancy.57;60-62;39
Ustekinumab, an interleukin-12/23 antagonist, can be found in infant serum and cord blood, as well. Health outcomes are similar in the exposed mother and child, however, compared with those of the general population.39;63-64
Small molecule drugs. Unlike monoclonal antibodies, which do not cross the placenta in large amounts until early in the second trimester, small molecules can cross in the first trimester during the critical period of organogenesis.
The two small molecule agents currently approved for use in UC are tofacitinib, a janus kinase inhibitor, and ozanimod, a sphingosine-1-phosphate receptor agonist.65-66 Further data are still needed to make recommendations on the use of tofacitinib and ozanimod in pregnancy. At this time, we recommend weighing the risks (unknown risk to human pregnancy) vs. benefits (controlled disease activity with clear risk of harm to mother and baby from flare) in the individual patient before counseling on use in pregnancy.
Delivery
Mode of delivery
The mode of delivery should be determined by the obstetrician. C-section is recommended for patients with active perianal disease or, in some cases, a history of ileal pouch anal anastomosis (IPAA).67-68 Vaginal delivery in the setting of perianal disease has been shown to increase the risk of fourth-degree laceration and anal sphincter dysfunction in the future.26-27 Anorectal motility may be impacted by IPAA construction and vaginal delivery independently of each other. It is therefore suggested that vaginal delivery be avoided in patients with a history of IPAA to avoid compounding the risk. Some studies do not show clear harm from vaginal delivery in the setting of IPAA, however, and informed decision making among all stakeholders should be had.27;69-70
Anticoagulation
The incidence of venous thromboembolism (VTE) is elevated in patients with IBD during pregnancy, and up to 12 weeks postpartum, compared with pregnant patients without IBD.71-72 VTE for prophylaxis is indicated in the pregnant patient while hospitalized and potentially thereafter depending on the patient’s risk factors, which may include obesity, prior personal history of VTE, heart failure, and prolonged immobility. Unfractionated heparin, low molecular weight heparin, and warfarin are safe for breastfeeding women.16,73
Postpartum care of mother
There is a risk of postpartum flare, occurring in about one third of patients in the first 6 months postpartum.74-75 De-escalating therapy during delivery or immediately postpartum is a predictor of a postpartum flare.75 If no infection is present and the timing interval is appropriate, biologic therapies should be continued and can be resumed 24 hours after a vaginal delivery and 48 hours after a C-section.16,76
NSAIDs and opioids can be used for pain relief but should be avoided in the long-term to prevent flares (NSAIDs) and infant sedation (associated with opioids) when used while breastfeeding.77 The LactMed database is an excellent resource for clarification on risk of medication use while breastfeeding.78
In particular, contraception should be addressed postpartum. Exogenous estrogen use increases the risk of VTE, which is already increased in IBD; nonestrogen containing, long-acting reversible contraception is preferred.79-80 Progestin-only implants or intrauterine devices may be used first line. The efficacy of oral contraceptives is theoretically reduced in those with rapid bowel transit, active small bowel inflammation, and prior small bowel resection, so adding another form of contraception is recommended.16,81
Source: American Gastroenterological Association
Postdelivery care of baby
Breastfeeding
Guidelines regarding medication use during breastfeeding are similar to those in pregnancy (see Table). Breastfeeding on biologics and thiopurines can continue without interruption in the child. Thiopurine concentrations in breast milk are low or undetectable.82,78 TNF receptor antagonists, anti-integrin therapies, and ustekinumab are found in low to undetectable levels in breast milk, as well.78
On the other hand, the active metabolite of methotrexate is detectable in breast milk and most sources recommend not breastfeeding on methotrexate. At doses used in IBD (15-25 milligrams per week), some experts have suggested avoiding breastfeeding for 24 hours following a dose.57,78 It is the practice of this author to recommend not breastfeeding at all on methotrexate.
5-ASA therapies are low risk for breastfeeding, but alternatives to sulfasalazine are preferred. The sulfapyridine metabolite transfers to breast milk and may cause hemolysis in infants born with a glucose-6-phosphate dehydrogenase deficiency.78
With regards to calcineurin inhibitors, tacrolimus appears in breast milk in low quantities, while cyclosporine levels are variable. Data from the National Transplantation Pregnancy Registry suggest that these medications can be used at the time of breastfeeding with close monitoring.78
There is not enough data on small molecule therapies at this time to support breastfeeding safety, and it is our practice to not recommend breastfeeding in this scenario.
The transfer of steroids to the child via breast milk does occur but at subtherapeutic levels.16 Budesonide has high first pass metabolism and is low risk during breastfeeding.83-84 As far as is known, IBD maintenance medications do not suppress lactation. The use of intravenous corticosteroids can, however, temporarily decrease milk production.16,85
Vaccines
Vaccination of infants can proceed as indicated by the Center for Disease Control and Prevention guidelines, with one exception. If the child’s mother was exposed to any biologic agents (not including certolizumab) during the third trimester, any live vaccines should be withheld in the first 6 months of life. In the United States, this restriction currently only applies to the rotavirus vaccine, which is administered starting at the age of 2 months.16,86 Notably, inadvertent administration of the rotavirus vaccine in the biologic-exposed child does not appear to result in any adverse effects.87 Immunity is achieved even if the child is exposed to IBD therapies through breast milk.88
Developmental milestones
Infant exposure to biologics and thiopurines has not been shown to result in any developmental delays. The PIANO study measured developmental milestones at 48 months from birth and found no differences when compared with validated population norms.39 A separate study observing childhood development up to 7 years of age in patients born to mothers with IBD found similar cognitive scores and motor development when compared with those born to mothers without IBD.89
Conclusion
Women considering conception should be optimized prior to pregnancy and maintained on appropriate medications throughout pregnancy and lactation to achieve a healthy pregnancy for both mother and baby. To date, biologics and thiopurines are not associated with adverse pregnancy outcomes. More data are needed for small molecules.
Dr. Chugh is an advanced inflammatory bowel disease fellow in the division of gastroenterology at the University of California San Francisco. Dr. Mahadevan is professor of medicine and codirector at the Center for Colitis and Crohn’s Disease in the division of gastroenterology at the University of California San Francisco. Dr. Mahadevan has potential conflicts related to AbbVie, Janssen, BMS, Takeda, Pfizer, Lilly, Gilead, Arena, and Prometheus Biosciences.
References
1. Ye Y et al. Inflamm Bowel Dis. 2020;26:619-25.
2. Sykora J et al. World J Gastroenterol. 2018;24:2741-63.
3. Murakami Y et al. J Gastroenterol 2019;54:1070-7.
4. Hashash JG and Kane S. Gastroenterol Hepatol. (N Y) 2015;11:96-102.
5. Miller JP. J R Soc Med. 1986;79:221-5.
6. Cornish J et al. Gut. 2007;56:830-7.
7. Leung KK et al. Inflamm Bowel Dis. 2021;27:550-62.
8. O’Toole A et al. Dig Dis Sci. 2015;60:2750-61.
9. Nguyen GC et al. Inflamm Bowel Dis. 2008;14:1105-11.
10. Lee HH et al. Aliment Pharmacol Ther. 2020;51:861-9.
11. Kim MA et al. J Crohns Colitis. 2021;15:719-32.
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15. Lee S et al. J Crohns Colitis. 2018;12:702-9.
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35. Ko MS et al. Dig Dis Sci. 2020;65:2979-85.
36. Cappell MS et al. J Reprod Med. 2010;55:115-23.
37. Committee ASoP et al. Gastrointest Endosc. 2012;76:18-24.
38. Aboubakr A et al. Dig Dis Sci. 2021;66:1829-35.
39. Mahadevan U et al. Gastroenterology. 2021;160:1131-9.
40. Diav-Citrin O et al. Gastroenterology. 1998;114:23-8.
41. Rahimi R et al. Reprod Toxicol. 2008;25:271-5.
42. Norgard B et al. Aliment Pharmacol Ther. 2001;15:483-6.
43. Leung YP et al. J Crohns Colitis. 2015;9:223-30.
44. Schulze H et al. Aliment Pharmacol Ther. 2014;40:991-1008.
45. Szymanska E et al. J Gynecol Obstet Hum Reprod. 2021;50:101777.
46. Weber-Schoendorfer C et al. Arthritis Rheumatol. 2014;66:1101-10.
47. Nielsen OH et al. Clin Gastroenterol Hepatol. 2022 Jan;20(1):74-87.e3.
48. Coelho J et al. Gut. 2011;60:198-203.
49. Sheikh M et al. J Crohns Colitis. 2015;9:680-4.
50. Kanis SL et al. Clin Gastroenterol Hepatol. 2017;15:1232-41 e1.
51. Mahadevan U et al. Inflamm Bowel Dis. 2018;24:2494-500.
52. Rosen MH et al. Inflamm Bowel Dis. 2020;26:971-3.
53. Porter C et al. J Reprod Immunol. 2016;116:7-12.
54. Mahadevan U et al. Clin Gastroenterol Hepatol. 2013;11:286-92; quiz e24.
55. Picardo S and Seow CH. Best Pract Res Clin Gastroenterol. 2020;44-5:101670.
56. Flanagan E et al. Aliment Pharmacol Ther. 2020;52:1551-62.
57. Singh S et al. Gastroenterology. 2021;160:2512-56 e9.
58. de Lima A et al. Gut. 2016;65:1261-8.
59. Julsgaard M et al. Inflamm Bowel Dis. 2020;26:93-102.
60. Wils P et al. Aliment Pharmacol Ther. 2021;53:460-70.
61. Mahadevan U et al. Aliment Pharmacol Ther. 2017;45:941-50.
62. Bar-Gil Shitrit A et al. Am J Gastroenterol. 2019;114:1172-5.
63. Klenske E et al. J Crohns Colitis. 2019;13:267-9.
64. Matro R et al. Gastroenterology. 2018;155:696-704.
65. Feuerstein JD et al. Gastroenterology. 2020;158:1450-61.
66. Sandborn WJ et al. J Crohns Colitis. 2021 Jul 5;15(7):1120-1129.
67. Lamb CA et al. Gut. 2019;68:s1-s106.
68. Nguyen GC et al. Gastroenterology. 2016;150:734-57 e1.
69. Ravid A et al. Dis Colon Rectum. 2002;45:1283-8.
70. Seligman NS et al. J Matern Fetal Neonatal Med. 2011;24:525-30.
71. Kim YH et al. Medicine (Baltimore). 2019;98:e17309.
72. Hansen AT et al. J Thromb Haemost. 2017;15:702-8.
73. Bates SM et al. J Thromb Thrombolysis. 2016;41:92-128.
74. Bennett A et al. Inflamm Bowel Dis. 2021 May 17;izab104.
75. Yu A et al. Inflamm Bowel Dis. 2020;26:1926-32.
76. Mahadevan U et al. Gastroenterology. 2017;152:451-62 e2.
77. Long MD et al. J Clin Gastroenterol. 2016;50:152-6.
78. Drugs and Lactation Database (LactMed). 2006 ed. Bethesda, MD: National Library of Medicine (US), 2006-2021.
79. Khalili H et al. Gut. 2013;62:1153-9.
80. Long MD and Hutfless S. Gastroenterology. 2016;150:1518-20.
81. Centers for Disease Control and Prevention. U S. Medical Eligibility Criteria for Contraceptive Use, 2010. MMWR Recomm Rep. 2010;59:1-86.
82. Angelberger S et al. J Crohns Colitis. 2011;5:95-100.
83. Vestergaard T et al. Scand J Gastroenterol. 2018;53:1459-62.
84. Beaulieu DB et al. Inflamm Bowel Dis. 2009;15:25-8.
85. Anderson PO. Breastfeed Med. 2017;12:199-201.
86. Wodi AP et al. MMWR Morb Mortal Wkly Rep. 2021;70:189-92.
87. Chiarella-Redfern H et al. Inflamm Bowel Dis. 2022 Jan 5;28(1):79-86.
88. Beaulieu DB et al. Clin Gastroenterol Hepatol. 2018;16:99-105.
89. Friedman S et al. J Crohns Colitis. 2020 Dec 2;14(12):1709-1716.
Inflammatory bowel disease (IBD) incidence is rising globally.1-3 In the United States, we have seen a 123% increase in prevalence of IBD among adults and a 133% increase among children from 2007 to 2016, with an annual percentage change of 9.9%.1 The rise of IBD in young people, and the overall higher prevalence in women compared with men, make pregnancy and IBD a topic of increasing importance for gastroenterologists.1 Here, we will discuss management and expectations in women with IBD before conception, during pregnancy, and post partum.
Preconception
Disease activity
Achieving both clinical and endoscopic remission of disease prior to conception is the key to ensuring the best maternal and fetal outcomes. Patients with IBD who conceive while in remission remain in remission 80% of the time.4,5 On the other hand, those who conceive while their disease is active may continue to have active or worsening disease in nearly 70% of cases.4 Active disease has been associated with an increased incidence of preterm birth, low birth weight, and small-for-gestational-age birth.6-8 Active disease can also exacerbate malnutrition and result in poor maternal weight gain, which is associated with intrauterine growth restriction.9,7 Pregnancy outcomes in patients with IBD and quiescent disease are similar to those in the general population.10,11
Health care maintenance
Optimizing maternal health prior to conception is critical. Alcohol, tobacco, recreational drugs, and marijuana should all be avoided. Opioids should be tapered off prior to conception, as continued use may result in neonatal opioid withdrawal syndrome and long-term neurodevelopmental consequences.12,13 In addition, aiming for a healthy body mass index between 18 and 25 months prior to conception allows for better overall pregnancy outcomes.13 Appropriate cancer screening includes colon cancer screening in those with more than 8 years of colitis, regular pap smear for cervical cancer, and annual total body skin cancer examinations for patients on thiopurines and biologic therapies.14
Nutrition
Folic acid supplementation with at least 400 micrograms (mcg) daily is necessary for all women planning pregnancy. Patients with small bowel involvement or history of small bowel resection should have a folate intake of a minimum of 2 grams per day. Adequate vitamin D levels (at least 20 ng/mL) are recommended in all women with IBD. Those with malabsorption should be screened for deficiencies in vitamin B12, folate, and iron.13 These nutritional markers should be evaluated prepregnancy, during the first trimester, and thereafter as needed.15-18
Preconception counseling
Steroid-free remission for at least 3 months prior to conception is recommended and is associated with reduced risk of flare during pregnancy.16,19 IBD medications needed to control disease activity are generally safe preconception and during pregnancy, with some exception (Table).
Misconceptions regarding heritability of IBD have sometimes discouraged men and women from having children. While genetics may increase susceptibility, environmental and other factors are involved as well. The concordance rates for monozygotic twins range from 33.3%-58.3% for Crohn’s disease and 13.4%-27.9% for ulcerative colitis (UC).20 The risk of a child developing IBD is higher in those who have multiple relatives with IBD and whose parents had IBD at the time of conception.21 While genetic testing for IBD loci is available, it is not commonly performed at this time as many genes are involved.22
Pregnancy
Coordinated care
A complete team of specialists with coordinated care among all providers is needed for optimal maternal and fetal outcomes.23,24 A gastroenterologist, ideally an IBD specialist, should follow the patient throughout pregnancy, seeing the patient at least once during the first or second trimester and as needed during pregnancy.16 A high-risk obstetrician or maternal-fetal medicine specialist should be involved early in pregnancy, as well. Open communication among all disciplines ensures that a common message is conveyed to the patient.16,24 A nutritionist, mental health provider, and lactation specialist knowledgeable about IBD drugs may be of assistance, as well.16
Disease activity
While women with IBD are at increased risk of spontaneous abortion, preterm birth, and labor complications, this risk is mitigated by controlling disease activity.25 The risk of preterm birth, small-for-gestational-age birth, and delivery via C-section is much higher in women with moderate-to-high disease activity, compared with those with low disease activity.26 The presence of active perianal disease mandates C-section over vaginal delivery. Fourth-degree lacerations following vaginal delivery are most common among those patients with perianal disease.26,27 Stillbirths were shown to be increased only in those with active IBD when compared with non-IBD comparators and inactive IBD.28-31;11
Noninvasive methods for disease monitoring are preferred in pregnancy, but serum markers such as erythrocyte sedimentation rate and C-reactive protein may not be reliable in the pregnant patient (Figure).32 Fecal calprotectin does rise in correlation with disease activity, but exact thresholds have not been validated in pregnancy.33,34
An unsedated, unprepped flexible sigmoidoscopy can be safely performed throughout pregnancy.35 When there is a strong indication, a complete colonoscopy can be performed in the pregnant patient as well.36 Current American Society for Gastrointestinal Endoscopy (ASGE) guidelines suggest placing the patient in the left lateral tilt position to avoid decreased maternal and placental perfusion via compression of the aorta or inferior vena cava and performing endoscopy during the second trimester, although trimester-specific timing is not always feasible by indication.37
Medication use and safety
IBD medications are a priority topic of concern among pregnant patients or those considering conception.38 Comprehensive data from the PIANO (Pregnancy in Inflammatory Bowel Disease and Neonatal Outcomes) registry has shown that most IBD drugs do not result in adverse pregnancy outcomes and should be continued.39 The use of biologics and thiopurines, either in combination or alone, is not related to an increased risk of congenital malformations, spontaneous abortion, preterm birth, low birth weight, or infections during the child’s first year of life.7,39 Developmental milestones also remain unaffected.39 Here, we will discuss safety considerations during pregnancy (see Table).
5-aminosalycylic acid. 5-aminosalicylic acid (5-ASA) agents are generally low risk during pregnancy and should be continued.40-41 Sulfasalazine does interfere with folate metabolism, but by increasing folic acid supplementation to 2 grams per day, sulfasalazine can be continued throughout pregnancy, as well.42
Corticosteroids. Intrapartum corticosteroid use is associated with an increased risk of gestational diabetes and adrenal insufficiency when used long term.43-45 Short-term use may, however, be necessary to control an acute flare. The lowest dose for the shortest duration possible is recommended. Because of its high first-pass metabolism, budesonide is considered low risk in pregnancy.
Methotrexate. Methotrexate needs to be stopped at least 3 months prior to conception and should be avoided throughout pregnancy. Use during pregnancy can result in spontaneous abortions, as well as embryotoxicity.46
Thiopurines (6-mercaptopurine and azathioprine). Patients who are taking thiopurines prior to conception to maintain remission can continue to do so. Data on thiopurines from the PIANO registry has shown no increase in spontaneous abortions, congenital malformations, low birth weight, preterm birth, rates of infection in the child, or developmental delays.47-51
Calcineurin inhibitors (cyclosporine and tacrolimus). Calcineurin inhibitors are reserved for the management of acute severe UC. Safety data on calcineurin inhibitors is conflicting, and there is not enough information at this time to identify risk during pregnancy. Cyclosporine can be used for salvage therapy if absolutely needed, and there are case reports of its successful using during pregnancy.16,52
Biologic therapies. With the exception of certolizumab, all of the currently used biologics are actively transported across the placenta.39,53,54 Intrapartum use of biologic therapies does not worsen pregnancy or neonatal outcomes, including the risk for intensive care unit admission, infections, and developmental milestones.39,47
While drug concentrations may vary slightly during pregnancy, these changes are not substantial enough to warrant more frequent monitoring or dose adjustments, and prepregnancy weight should be used for dosing.55,56
Antitumor necrosis factor agents used in IBD include infliximab, adalimumab, certolizumab, and golimumab.57 All are low risk for pregnant patients and their offspring. Dosage timings can be adjusted, but not stopped, to minimize exposure to the child; however, it cannot be adjusted for certolizumab pegol because of its lack of placental transfer.58-59
Natalizumab and vedolizumab are integrin receptor antagonists and are also low risk in pregnancy.57;60-62;39
Ustekinumab, an interleukin-12/23 antagonist, can be found in infant serum and cord blood, as well. Health outcomes are similar in the exposed mother and child, however, compared with those of the general population.39;63-64
Small molecule drugs. Unlike monoclonal antibodies, which do not cross the placenta in large amounts until early in the second trimester, small molecules can cross in the first trimester during the critical period of organogenesis.
The two small molecule agents currently approved for use in UC are tofacitinib, a janus kinase inhibitor, and ozanimod, a sphingosine-1-phosphate receptor agonist.65-66 Further data are still needed to make recommendations on the use of tofacitinib and ozanimod in pregnancy. At this time, we recommend weighing the risks (unknown risk to human pregnancy) vs. benefits (controlled disease activity with clear risk of harm to mother and baby from flare) in the individual patient before counseling on use in pregnancy.
Delivery
Mode of delivery
The mode of delivery should be determined by the obstetrician. C-section is recommended for patients with active perianal disease or, in some cases, a history of ileal pouch anal anastomosis (IPAA).67-68 Vaginal delivery in the setting of perianal disease has been shown to increase the risk of fourth-degree laceration and anal sphincter dysfunction in the future.26-27 Anorectal motility may be impacted by IPAA construction and vaginal delivery independently of each other. It is therefore suggested that vaginal delivery be avoided in patients with a history of IPAA to avoid compounding the risk. Some studies do not show clear harm from vaginal delivery in the setting of IPAA, however, and informed decision making among all stakeholders should be had.27;69-70
Anticoagulation
The incidence of venous thromboembolism (VTE) is elevated in patients with IBD during pregnancy, and up to 12 weeks postpartum, compared with pregnant patients without IBD.71-72 VTE for prophylaxis is indicated in the pregnant patient while hospitalized and potentially thereafter depending on the patient’s risk factors, which may include obesity, prior personal history of VTE, heart failure, and prolonged immobility. Unfractionated heparin, low molecular weight heparin, and warfarin are safe for breastfeeding women.16,73
Postpartum care of mother
There is a risk of postpartum flare, occurring in about one third of patients in the first 6 months postpartum.74-75 De-escalating therapy during delivery or immediately postpartum is a predictor of a postpartum flare.75 If no infection is present and the timing interval is appropriate, biologic therapies should be continued and can be resumed 24 hours after a vaginal delivery and 48 hours after a C-section.16,76
NSAIDs and opioids can be used for pain relief but should be avoided in the long-term to prevent flares (NSAIDs) and infant sedation (associated with opioids) when used while breastfeeding.77 The LactMed database is an excellent resource for clarification on risk of medication use while breastfeeding.78
In particular, contraception should be addressed postpartum. Exogenous estrogen use increases the risk of VTE, which is already increased in IBD; nonestrogen containing, long-acting reversible contraception is preferred.79-80 Progestin-only implants or intrauterine devices may be used first line. The efficacy of oral contraceptives is theoretically reduced in those with rapid bowel transit, active small bowel inflammation, and prior small bowel resection, so adding another form of contraception is recommended.16,81
Source: American Gastroenterological Association
Postdelivery care of baby
Breastfeeding
Guidelines regarding medication use during breastfeeding are similar to those in pregnancy (see Table). Breastfeeding on biologics and thiopurines can continue without interruption in the child. Thiopurine concentrations in breast milk are low or undetectable.82,78 TNF receptor antagonists, anti-integrin therapies, and ustekinumab are found in low to undetectable levels in breast milk, as well.78
On the other hand, the active metabolite of methotrexate is detectable in breast milk and most sources recommend not breastfeeding on methotrexate. At doses used in IBD (15-25 milligrams per week), some experts have suggested avoiding breastfeeding for 24 hours following a dose.57,78 It is the practice of this author to recommend not breastfeeding at all on methotrexate.
5-ASA therapies are low risk for breastfeeding, but alternatives to sulfasalazine are preferred. The sulfapyridine metabolite transfers to breast milk and may cause hemolysis in infants born with a glucose-6-phosphate dehydrogenase deficiency.78
With regards to calcineurin inhibitors, tacrolimus appears in breast milk in low quantities, while cyclosporine levels are variable. Data from the National Transplantation Pregnancy Registry suggest that these medications can be used at the time of breastfeeding with close monitoring.78
There is not enough data on small molecule therapies at this time to support breastfeeding safety, and it is our practice to not recommend breastfeeding in this scenario.
The transfer of steroids to the child via breast milk does occur but at subtherapeutic levels.16 Budesonide has high first pass metabolism and is low risk during breastfeeding.83-84 As far as is known, IBD maintenance medications do not suppress lactation. The use of intravenous corticosteroids can, however, temporarily decrease milk production.16,85
Vaccines
Vaccination of infants can proceed as indicated by the Center for Disease Control and Prevention guidelines, with one exception. If the child’s mother was exposed to any biologic agents (not including certolizumab) during the third trimester, any live vaccines should be withheld in the first 6 months of life. In the United States, this restriction currently only applies to the rotavirus vaccine, which is administered starting at the age of 2 months.16,86 Notably, inadvertent administration of the rotavirus vaccine in the biologic-exposed child does not appear to result in any adverse effects.87 Immunity is achieved even if the child is exposed to IBD therapies through breast milk.88
Developmental milestones
Infant exposure to biologics and thiopurines has not been shown to result in any developmental delays. The PIANO study measured developmental milestones at 48 months from birth and found no differences when compared with validated population norms.39 A separate study observing childhood development up to 7 years of age in patients born to mothers with IBD found similar cognitive scores and motor development when compared with those born to mothers without IBD.89
Conclusion
Women considering conception should be optimized prior to pregnancy and maintained on appropriate medications throughout pregnancy and lactation to achieve a healthy pregnancy for both mother and baby. To date, biologics and thiopurines are not associated with adverse pregnancy outcomes. More data are needed for small molecules.
Dr. Chugh is an advanced inflammatory bowel disease fellow in the division of gastroenterology at the University of California San Francisco. Dr. Mahadevan is professor of medicine and codirector at the Center for Colitis and Crohn’s Disease in the division of gastroenterology at the University of California San Francisco. Dr. Mahadevan has potential conflicts related to AbbVie, Janssen, BMS, Takeda, Pfizer, Lilly, Gilead, Arena, and Prometheus Biosciences.
References
1. Ye Y et al. Inflamm Bowel Dis. 2020;26:619-25.
2. Sykora J et al. World J Gastroenterol. 2018;24:2741-63.
3. Murakami Y et al. J Gastroenterol 2019;54:1070-7.
4. Hashash JG and Kane S. Gastroenterol Hepatol. (N Y) 2015;11:96-102.
5. Miller JP. J R Soc Med. 1986;79:221-5.
6. Cornish J et al. Gut. 2007;56:830-7.
7. Leung KK et al. Inflamm Bowel Dis. 2021;27:550-62.
8. O’Toole A et al. Dig Dis Sci. 2015;60:2750-61.
9. Nguyen GC et al. Inflamm Bowel Dis. 2008;14:1105-11.
10. Lee HH et al. Aliment Pharmacol Ther. 2020;51:861-9.
11. Kim MA et al. J Crohns Colitis. 2021;15:719-32.
12. Conradt E et al. Pediatrics. 2019;144.
13. ACOG Committee Opinion No. 762: Prepregnancy Counseling. Obstet Gynecol. 2019;133:e78-e89.
14. Farraye FA et al. Am J Gastroenterol. 2017;112:241-58.
15. Lee S et al. J Crohns Colitis. 2018;12:702-9.
16. Mahadevan U et al. Inflamm Bowel Dis. 2019;25:627-41.
17. Ward MG et al. Inflamm. Bowel Dis 2015;21:2839-47.
18. Battat R et al. Inflamm Bowel Dis. 2014;20:1120-8.
19. Pedersen N et al. Aliment Pharmacol Ther. 2013;38:501-12.
20. Annese V. Pharmacol Res. 2020;159:104892.
21. Bennett RA et al. Gastroenterology. 1991;100:1638-43.
22. Turpin W et al. Inflamm Bowel Dis. 2018;24:1133-48.
23. de Lima A et al. Clin Gastroenterol Hepatol. 2016;14:1285-92 e1.
24. Selinger C et al. Frontline Gastroenterol. 2021;12:182-7.
25. Mahadevan U et al. Gastroenterology. 2007;133:1106-12.
26. Hatch Q et al. Dis Colon Rectum. 2014;57:174-8.
27. Foulon A et al. Inflamm Bowel Dis. 2017;23:712-20.
28. Norgard B et al. Am J Gastroenterol. 2007;102:1947-54.
29. Broms G et al. Scand J Gastroenterol 2016;51:1462-9.
30. Meyer A et al. Aliment Pharmacol Ther. 2020;52:1480-90.
31. Kammerlander H et al. Inflamm Bowel Dis. 2017;23:1011-8.
32. Tandon P et al. J Clin Gastroenterol. 2019;53:574-81.
33. Kammerlander H et al. Inflamm Bowel Dis. 2018;24:839-48.
34. Julsgaard M et al. Inflamm Bowel Dis. 2017;23:1240-6.
35. Ko MS et al. Dig Dis Sci. 2020;65:2979-85.
36. Cappell MS et al. J Reprod Med. 2010;55:115-23.
37. Committee ASoP et al. Gastrointest Endosc. 2012;76:18-24.
38. Aboubakr A et al. Dig Dis Sci. 2021;66:1829-35.
39. Mahadevan U et al. Gastroenterology. 2021;160:1131-9.
40. Diav-Citrin O et al. Gastroenterology. 1998;114:23-8.
41. Rahimi R et al. Reprod Toxicol. 2008;25:271-5.
42. Norgard B et al. Aliment Pharmacol Ther. 2001;15:483-6.
43. Leung YP et al. J Crohns Colitis. 2015;9:223-30.
44. Schulze H et al. Aliment Pharmacol Ther. 2014;40:991-1008.
45. Szymanska E et al. J Gynecol Obstet Hum Reprod. 2021;50:101777.
46. Weber-Schoendorfer C et al. Arthritis Rheumatol. 2014;66:1101-10.
47. Nielsen OH et al. Clin Gastroenterol Hepatol. 2022 Jan;20(1):74-87.e3.
48. Coelho J et al. Gut. 2011;60:198-203.
49. Sheikh M et al. J Crohns Colitis. 2015;9:680-4.
50. Kanis SL et al. Clin Gastroenterol Hepatol. 2017;15:1232-41 e1.
51. Mahadevan U et al. Inflamm Bowel Dis. 2018;24:2494-500.
52. Rosen MH et al. Inflamm Bowel Dis. 2020;26:971-3.
53. Porter C et al. J Reprod Immunol. 2016;116:7-12.
54. Mahadevan U et al. Clin Gastroenterol Hepatol. 2013;11:286-92; quiz e24.
55. Picardo S and Seow CH. Best Pract Res Clin Gastroenterol. 2020;44-5:101670.
56. Flanagan E et al. Aliment Pharmacol Ther. 2020;52:1551-62.
57. Singh S et al. Gastroenterology. 2021;160:2512-56 e9.
58. de Lima A et al. Gut. 2016;65:1261-8.
59. Julsgaard M et al. Inflamm Bowel Dis. 2020;26:93-102.
60. Wils P et al. Aliment Pharmacol Ther. 2021;53:460-70.
61. Mahadevan U et al. Aliment Pharmacol Ther. 2017;45:941-50.
62. Bar-Gil Shitrit A et al. Am J Gastroenterol. 2019;114:1172-5.
63. Klenske E et al. J Crohns Colitis. 2019;13:267-9.
64. Matro R et al. Gastroenterology. 2018;155:696-704.
65. Feuerstein JD et al. Gastroenterology. 2020;158:1450-61.
66. Sandborn WJ et al. J Crohns Colitis. 2021 Jul 5;15(7):1120-1129.
67. Lamb CA et al. Gut. 2019;68:s1-s106.
68. Nguyen GC et al. Gastroenterology. 2016;150:734-57 e1.
69. Ravid A et al. Dis Colon Rectum. 2002;45:1283-8.
70. Seligman NS et al. J Matern Fetal Neonatal Med. 2011;24:525-30.
71. Kim YH et al. Medicine (Baltimore). 2019;98:e17309.
72. Hansen AT et al. J Thromb Haemost. 2017;15:702-8.
73. Bates SM et al. J Thromb Thrombolysis. 2016;41:92-128.
74. Bennett A et al. Inflamm Bowel Dis. 2021 May 17;izab104.
75. Yu A et al. Inflamm Bowel Dis. 2020;26:1926-32.
76. Mahadevan U et al. Gastroenterology. 2017;152:451-62 e2.
77. Long MD et al. J Clin Gastroenterol. 2016;50:152-6.
78. Drugs and Lactation Database (LactMed). 2006 ed. Bethesda, MD: National Library of Medicine (US), 2006-2021.
79. Khalili H et al. Gut. 2013;62:1153-9.
80. Long MD and Hutfless S. Gastroenterology. 2016;150:1518-20.
81. Centers for Disease Control and Prevention. U S. Medical Eligibility Criteria for Contraceptive Use, 2010. MMWR Recomm Rep. 2010;59:1-86.
82. Angelberger S et al. J Crohns Colitis. 2011;5:95-100.
83. Vestergaard T et al. Scand J Gastroenterol. 2018;53:1459-62.
84. Beaulieu DB et al. Inflamm Bowel Dis. 2009;15:25-8.
85. Anderson PO. Breastfeed Med. 2017;12:199-201.
86. Wodi AP et al. MMWR Morb Mortal Wkly Rep. 2021;70:189-92.
87. Chiarella-Redfern H et al. Inflamm Bowel Dis. 2022 Jan 5;28(1):79-86.
88. Beaulieu DB et al. Clin Gastroenterol Hepatol. 2018;16:99-105.
89. Friedman S et al. J Crohns Colitis. 2020 Dec 2;14(12):1709-1716.
Inflammatory bowel disease (IBD) incidence is rising globally.1-3 In the United States, we have seen a 123% increase in prevalence of IBD among adults and a 133% increase among children from 2007 to 2016, with an annual percentage change of 9.9%.1 The rise of IBD in young people, and the overall higher prevalence in women compared with men, make pregnancy and IBD a topic of increasing importance for gastroenterologists.1 Here, we will discuss management and expectations in women with IBD before conception, during pregnancy, and post partum.
Preconception
Disease activity
Achieving both clinical and endoscopic remission of disease prior to conception is the key to ensuring the best maternal and fetal outcomes. Patients with IBD who conceive while in remission remain in remission 80% of the time.4,5 On the other hand, those who conceive while their disease is active may continue to have active or worsening disease in nearly 70% of cases.4 Active disease has been associated with an increased incidence of preterm birth, low birth weight, and small-for-gestational-age birth.6-8 Active disease can also exacerbate malnutrition and result in poor maternal weight gain, which is associated with intrauterine growth restriction.9,7 Pregnancy outcomes in patients with IBD and quiescent disease are similar to those in the general population.10,11
Health care maintenance
Optimizing maternal health prior to conception is critical. Alcohol, tobacco, recreational drugs, and marijuana should all be avoided. Opioids should be tapered off prior to conception, as continued use may result in neonatal opioid withdrawal syndrome and long-term neurodevelopmental consequences.12,13 In addition, aiming for a healthy body mass index between 18 and 25 months prior to conception allows for better overall pregnancy outcomes.13 Appropriate cancer screening includes colon cancer screening in those with more than 8 years of colitis, regular pap smear for cervical cancer, and annual total body skin cancer examinations for patients on thiopurines and biologic therapies.14
Nutrition
Folic acid supplementation with at least 400 micrograms (mcg) daily is necessary for all women planning pregnancy. Patients with small bowel involvement or history of small bowel resection should have a folate intake of a minimum of 2 grams per day. Adequate vitamin D levels (at least 20 ng/mL) are recommended in all women with IBD. Those with malabsorption should be screened for deficiencies in vitamin B12, folate, and iron.13 These nutritional markers should be evaluated prepregnancy, during the first trimester, and thereafter as needed.15-18
Preconception counseling
Steroid-free remission for at least 3 months prior to conception is recommended and is associated with reduced risk of flare during pregnancy.16,19 IBD medications needed to control disease activity are generally safe preconception and during pregnancy, with some exception (Table).
Misconceptions regarding heritability of IBD have sometimes discouraged men and women from having children. While genetics may increase susceptibility, environmental and other factors are involved as well. The concordance rates for monozygotic twins range from 33.3%-58.3% for Crohn’s disease and 13.4%-27.9% for ulcerative colitis (UC).20 The risk of a child developing IBD is higher in those who have multiple relatives with IBD and whose parents had IBD at the time of conception.21 While genetic testing for IBD loci is available, it is not commonly performed at this time as many genes are involved.22
Pregnancy
Coordinated care
A complete team of specialists with coordinated care among all providers is needed for optimal maternal and fetal outcomes.23,24 A gastroenterologist, ideally an IBD specialist, should follow the patient throughout pregnancy, seeing the patient at least once during the first or second trimester and as needed during pregnancy.16 A high-risk obstetrician or maternal-fetal medicine specialist should be involved early in pregnancy, as well. Open communication among all disciplines ensures that a common message is conveyed to the patient.16,24 A nutritionist, mental health provider, and lactation specialist knowledgeable about IBD drugs may be of assistance, as well.16
Disease activity
While women with IBD are at increased risk of spontaneous abortion, preterm birth, and labor complications, this risk is mitigated by controlling disease activity.25 The risk of preterm birth, small-for-gestational-age birth, and delivery via C-section is much higher in women with moderate-to-high disease activity, compared with those with low disease activity.26 The presence of active perianal disease mandates C-section over vaginal delivery. Fourth-degree lacerations following vaginal delivery are most common among those patients with perianal disease.26,27 Stillbirths were shown to be increased only in those with active IBD when compared with non-IBD comparators and inactive IBD.28-31;11
Noninvasive methods for disease monitoring are preferred in pregnancy, but serum markers such as erythrocyte sedimentation rate and C-reactive protein may not be reliable in the pregnant patient (Figure).32 Fecal calprotectin does rise in correlation with disease activity, but exact thresholds have not been validated in pregnancy.33,34
An unsedated, unprepped flexible sigmoidoscopy can be safely performed throughout pregnancy.35 When there is a strong indication, a complete colonoscopy can be performed in the pregnant patient as well.36 Current American Society for Gastrointestinal Endoscopy (ASGE) guidelines suggest placing the patient in the left lateral tilt position to avoid decreased maternal and placental perfusion via compression of the aorta or inferior vena cava and performing endoscopy during the second trimester, although trimester-specific timing is not always feasible by indication.37
Medication use and safety
IBD medications are a priority topic of concern among pregnant patients or those considering conception.38 Comprehensive data from the PIANO (Pregnancy in Inflammatory Bowel Disease and Neonatal Outcomes) registry has shown that most IBD drugs do not result in adverse pregnancy outcomes and should be continued.39 The use of biologics and thiopurines, either in combination or alone, is not related to an increased risk of congenital malformations, spontaneous abortion, preterm birth, low birth weight, or infections during the child’s first year of life.7,39 Developmental milestones also remain unaffected.39 Here, we will discuss safety considerations during pregnancy (see Table).
5-aminosalycylic acid. 5-aminosalicylic acid (5-ASA) agents are generally low risk during pregnancy and should be continued.40-41 Sulfasalazine does interfere with folate metabolism, but by increasing folic acid supplementation to 2 grams per day, sulfasalazine can be continued throughout pregnancy, as well.42
Corticosteroids. Intrapartum corticosteroid use is associated with an increased risk of gestational diabetes and adrenal insufficiency when used long term.43-45 Short-term use may, however, be necessary to control an acute flare. The lowest dose for the shortest duration possible is recommended. Because of its high first-pass metabolism, budesonide is considered low risk in pregnancy.
Methotrexate. Methotrexate needs to be stopped at least 3 months prior to conception and should be avoided throughout pregnancy. Use during pregnancy can result in spontaneous abortions, as well as embryotoxicity.46
Thiopurines (6-mercaptopurine and azathioprine). Patients who are taking thiopurines prior to conception to maintain remission can continue to do so. Data on thiopurines from the PIANO registry has shown no increase in spontaneous abortions, congenital malformations, low birth weight, preterm birth, rates of infection in the child, or developmental delays.47-51
Calcineurin inhibitors (cyclosporine and tacrolimus). Calcineurin inhibitors are reserved for the management of acute severe UC. Safety data on calcineurin inhibitors is conflicting, and there is not enough information at this time to identify risk during pregnancy. Cyclosporine can be used for salvage therapy if absolutely needed, and there are case reports of its successful using during pregnancy.16,52
Biologic therapies. With the exception of certolizumab, all of the currently used biologics are actively transported across the placenta.39,53,54 Intrapartum use of biologic therapies does not worsen pregnancy or neonatal outcomes, including the risk for intensive care unit admission, infections, and developmental milestones.39,47
While drug concentrations may vary slightly during pregnancy, these changes are not substantial enough to warrant more frequent monitoring or dose adjustments, and prepregnancy weight should be used for dosing.55,56
Antitumor necrosis factor agents used in IBD include infliximab, adalimumab, certolizumab, and golimumab.57 All are low risk for pregnant patients and their offspring. Dosage timings can be adjusted, but not stopped, to minimize exposure to the child; however, it cannot be adjusted for certolizumab pegol because of its lack of placental transfer.58-59
Natalizumab and vedolizumab are integrin receptor antagonists and are also low risk in pregnancy.57;60-62;39
Ustekinumab, an interleukin-12/23 antagonist, can be found in infant serum and cord blood, as well. Health outcomes are similar in the exposed mother and child, however, compared with those of the general population.39;63-64
Small molecule drugs. Unlike monoclonal antibodies, which do not cross the placenta in large amounts until early in the second trimester, small molecules can cross in the first trimester during the critical period of organogenesis.
The two small molecule agents currently approved for use in UC are tofacitinib, a janus kinase inhibitor, and ozanimod, a sphingosine-1-phosphate receptor agonist.65-66 Further data are still needed to make recommendations on the use of tofacitinib and ozanimod in pregnancy. At this time, we recommend weighing the risks (unknown risk to human pregnancy) vs. benefits (controlled disease activity with clear risk of harm to mother and baby from flare) in the individual patient before counseling on use in pregnancy.
Delivery
Mode of delivery
The mode of delivery should be determined by the obstetrician. C-section is recommended for patients with active perianal disease or, in some cases, a history of ileal pouch anal anastomosis (IPAA).67-68 Vaginal delivery in the setting of perianal disease has been shown to increase the risk of fourth-degree laceration and anal sphincter dysfunction in the future.26-27 Anorectal motility may be impacted by IPAA construction and vaginal delivery independently of each other. It is therefore suggested that vaginal delivery be avoided in patients with a history of IPAA to avoid compounding the risk. Some studies do not show clear harm from vaginal delivery in the setting of IPAA, however, and informed decision making among all stakeholders should be had.27;69-70
Anticoagulation
The incidence of venous thromboembolism (VTE) is elevated in patients with IBD during pregnancy, and up to 12 weeks postpartum, compared with pregnant patients without IBD.71-72 VTE for prophylaxis is indicated in the pregnant patient while hospitalized and potentially thereafter depending on the patient’s risk factors, which may include obesity, prior personal history of VTE, heart failure, and prolonged immobility. Unfractionated heparin, low molecular weight heparin, and warfarin are safe for breastfeeding women.16,73
Postpartum care of mother
There is a risk of postpartum flare, occurring in about one third of patients in the first 6 months postpartum.74-75 De-escalating therapy during delivery or immediately postpartum is a predictor of a postpartum flare.75 If no infection is present and the timing interval is appropriate, biologic therapies should be continued and can be resumed 24 hours after a vaginal delivery and 48 hours after a C-section.16,76
NSAIDs and opioids can be used for pain relief but should be avoided in the long-term to prevent flares (NSAIDs) and infant sedation (associated with opioids) when used while breastfeeding.77 The LactMed database is an excellent resource for clarification on risk of medication use while breastfeeding.78
In particular, contraception should be addressed postpartum. Exogenous estrogen use increases the risk of VTE, which is already increased in IBD; nonestrogen containing, long-acting reversible contraception is preferred.79-80 Progestin-only implants or intrauterine devices may be used first line. The efficacy of oral contraceptives is theoretically reduced in those with rapid bowel transit, active small bowel inflammation, and prior small bowel resection, so adding another form of contraception is recommended.16,81
Source: American Gastroenterological Association
Postdelivery care of baby
Breastfeeding
Guidelines regarding medication use during breastfeeding are similar to those in pregnancy (see Table). Breastfeeding on biologics and thiopurines can continue without interruption in the child. Thiopurine concentrations in breast milk are low or undetectable.82,78 TNF receptor antagonists, anti-integrin therapies, and ustekinumab are found in low to undetectable levels in breast milk, as well.78
On the other hand, the active metabolite of methotrexate is detectable in breast milk and most sources recommend not breastfeeding on methotrexate. At doses used in IBD (15-25 milligrams per week), some experts have suggested avoiding breastfeeding for 24 hours following a dose.57,78 It is the practice of this author to recommend not breastfeeding at all on methotrexate.
5-ASA therapies are low risk for breastfeeding, but alternatives to sulfasalazine are preferred. The sulfapyridine metabolite transfers to breast milk and may cause hemolysis in infants born with a glucose-6-phosphate dehydrogenase deficiency.78
With regards to calcineurin inhibitors, tacrolimus appears in breast milk in low quantities, while cyclosporine levels are variable. Data from the National Transplantation Pregnancy Registry suggest that these medications can be used at the time of breastfeeding with close monitoring.78
There is not enough data on small molecule therapies at this time to support breastfeeding safety, and it is our practice to not recommend breastfeeding in this scenario.
The transfer of steroids to the child via breast milk does occur but at subtherapeutic levels.16 Budesonide has high first pass metabolism and is low risk during breastfeeding.83-84 As far as is known, IBD maintenance medications do not suppress lactation. The use of intravenous corticosteroids can, however, temporarily decrease milk production.16,85
Vaccines
Vaccination of infants can proceed as indicated by the Center for Disease Control and Prevention guidelines, with one exception. If the child’s mother was exposed to any biologic agents (not including certolizumab) during the third trimester, any live vaccines should be withheld in the first 6 months of life. In the United States, this restriction currently only applies to the rotavirus vaccine, which is administered starting at the age of 2 months.16,86 Notably, inadvertent administration of the rotavirus vaccine in the biologic-exposed child does not appear to result in any adverse effects.87 Immunity is achieved even if the child is exposed to IBD therapies through breast milk.88
Developmental milestones
Infant exposure to biologics and thiopurines has not been shown to result in any developmental delays. The PIANO study measured developmental milestones at 48 months from birth and found no differences when compared with validated population norms.39 A separate study observing childhood development up to 7 years of age in patients born to mothers with IBD found similar cognitive scores and motor development when compared with those born to mothers without IBD.89
Conclusion
Women considering conception should be optimized prior to pregnancy and maintained on appropriate medications throughout pregnancy and lactation to achieve a healthy pregnancy for both mother and baby. To date, biologics and thiopurines are not associated with adverse pregnancy outcomes. More data are needed for small molecules.
Dr. Chugh is an advanced inflammatory bowel disease fellow in the division of gastroenterology at the University of California San Francisco. Dr. Mahadevan is professor of medicine and codirector at the Center for Colitis and Crohn’s Disease in the division of gastroenterology at the University of California San Francisco. Dr. Mahadevan has potential conflicts related to AbbVie, Janssen, BMS, Takeda, Pfizer, Lilly, Gilead, Arena, and Prometheus Biosciences.
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Definitive diverticular hemorrhage: Diagnosis and management
Diverticular hemorrhage is the most common cause of colonic bleeding, accounting for 20%-65% of cases of severe lower intestinal bleeding in adults.1 Urgent colonoscopy after purging the colon of blood, clots, and stool is the most accurate method of diagnosing and guiding treatment of definitive diverticular hemorrhage.2-5 The diagnosis of definitive diverticular hemorrhage depends upon identification of some stigmata of recent hemorrhage (SRH) in a single diverticulum (TIC), which can include active arterial bleeding, oozing, non-bleeding visible vessel, adherent clot, or flat spot.2-4 Although other approaches, such as nuclear medicine scans and angiography of various types (CT, MRI, or standard angiography), for the early diagnosis of patients with severe hematochezia are utilized in many medical centers, only active bleeding can be detected by these techniques. However, as subsequently discussed, this SRH is documented in only 26% of definitive diverticular bleeds found on urgent colonoscopy, so diagnostic yields of these techniques will be low.2-5
The diagnosis of patients with severe hematochezia and diverticulosis, as well as triage of all of them to specific medical, endoscopic, radiologic, or surgical management, is facilitated by an urgent endoscopic approach.2-5 Patients who are diagnosed with definitive diverticular hemorrhage on colonoscopy represent about 30% of all true TIC bleeds when urgent colonoscopy is the management approach.2-5 That is because approximately 50% of all patients with colon diverticulosis and first presentation of severe hematochezia have incidental diverticulosis; they have colonic diverticulosis, but another site of bleeding is identified as the cause of hemorrhage in the gastrointestinal tract.2-4 Presumptive diverticular hemorrhage is diagnosed when colonic diverticulosis without TIC stigmata are found but no other GI bleeding source is found on colonoscopy, anoscopy, enteroscopy, or capsule endoscopy.2-5 In our experience with urgent colonoscopy, the presumptive diverticular bleed group accounts for about 70% of patients with documented diverticular hemorrhage (e.g., not including incidental diverticulosis bleeds but combining subgroups of patients with either definitive or presumptive TIC diagnoses as documented TIC hemorrhage).
Clinical presentation
Patients with diverticular hemorrhage present with severe, painless large volume hematochezia. Hematochezia may be self-limited and spontaneously resolve in 75%-80% of all patients but with high rebleeding rates up to 40%.5-7 Of all patients with diverticulosis, only about 3%-5% develop diverticular hemorrhage.8 Risk factors for diverticular hemorrhage include medications (e.g., nonsteroidal anti-inflammatory drugs – NSAIDs, antiplatelet drugs, and anticoagulants) and other clinical factors, such as older age, low-fiber diet, and chronic constipation.9,10 On urgent colonoscopy, more than 70% of diverticulosis in U.S. patients are located anatomically in the descending colon or more distally. In contrast, about 60% of definitive diverticular hemorrhage cases in our experience had diverticula with stigmata identified at or proximal to the splenic flexure.2,4,11
Pathophysiology
Colonic diverticula are herniations of mucosa and submucosa with colonic arteries that penetrate the muscular wall. Bleeding can occur when there is asymmetric rupture of the vasa recta at either the base of the diverticulum or the neck.4 Thinning of the mucosa on the luminal surface (such as that resulting from impacted fecaliths and stool) can cause injury to the site of the penetrating vessels, resulting in hemorrhage.12
Initial management
Patients with acute, severe hematochezia should be triaged to an inpatient setting with a monitored bed. Admission to an intensive care unit should be considered for patients with hemodynamic instability, persistent bleeding, and/or significant comorbidities. Patients with TIC hemorrhage often require resuscitation with crystalloids and packed red blood cell transfusions for hemoglobin less than 8 g/dl.4 Unlike upper GI hemorrhage, which has been extensively reported on, data regarding a more restrictive transfusion threshold, compared with a liberal transfusion threshold, in lower intestinal bleeding are very limited. Correction of underlying coagulopathies is recommended but should be individualized, particularly in those patients on antithrombotic agents or with underlying bleeding disorders.
Urgent diagnosis and hemostasis
Urgent colonoscopy within 24 hours is the most accurate way to make a diagnosis of definitive diverticular hemorrhage and to effectively and safely treat them.2-4,10,11 For patients with severe hematochezia, when the colonoscopy is either not available in a medical center or does not reveal the source of bleeding, nuclear scintigraphy or angiography (CT, MRI, or interventional radiology [IR]) are recommended. CT angiography may be particularly helpful to diagnose patients with hemodynamic instability who are suspected to have active TIC bleeding and are not able to complete a bowel preparation. However, these imaging techniques require active bleeding at the time of the study to be diagnostic. This SRH is also uncommon for definitive diverticular hemorrhage, so the diagnostic yield is usually quite low.2-5,10,11 An additional limitation of scintigraphy and CT or MRI angiography is that, if active bleeding is found, some other type of treatment, such as colonoscopy, IR angiography, or surgery, will be required for definitive hemostasis.
For urgent colonoscopy, adequate colon preparation with a large volume preparation (6-8 liters of polyethylene glycol-based solution) is recommended to clear stool, blood, and clots to allow endoscopic visualization and localization of the bleeding source. Use of a nasogastric tube should be considered if the patient is unable to drink enough prep.2-4,13 Additionally, administration of a prokinetic agent, such as Metoclopramide, may improve gastric emptying and tolerance of the prep. During colonoscopy, careful inspection of the colonic mucosa during insertion and withdrawal is important since lesions may bleed intermittently and SRH can be missed. An adult or pediatric colonoscope with a large working channel (at least 3.3 mm) is recommended to facilitate suctioning of blood clots and stool, as well as allow the passage of endoscopic hemostasis accessories. Targeted water-jet irrigation, an expert colonoscopist, a cap attachment, and adequate colon preparation are all predictors for improved diagnosis of definitive diverticular hemorrhage.4,14
SRH in definitive TIC bleeds all have a high risk of TIC rebleeding,2-4,10,11 including active bleeding, nonbleeding visible vessel, adherent clot, and a flat spot (See Figure).
Based on CURE Hemostasis Group data of 118 definitive TIC bleeds, 26% had active bleeding, 24% had a nonbleeding visible vessel, 37% had an adherent clot, and 13% had a flat spot (with underlying arterial blood flow by Doppler probe monitoring).4 Approximately 50% of the SRH were found in the neck of the TIC and 50% at the base, with actively bleeding cases more often from the base. In CURE Doppler endoscopic probe studies, 90% of all stigmata had an underlying arterial blood flow detected with the Doppler probe.4,10 The Doppler probe is reported to be very useful for risk stratification and to confirm obliteration of the arterial blood flow underlying SRH for definitive hemostasis.4,10
Endoscopic treatment
Given high rates of rebleeding with medical management alone, definitive TIC hemorrhage can be effectively and safely treated with endoscopic therapies once SRH are localized.4,10 Endoscopic therapies that have been reported in the literature include electrocoagulation, hemoclip, band ligation, and over-the-scope clip. Four-quadrant injection of 1:20,000 epinephrine around the SRH can improve visualization of SRH and provide temporary control of bleeding, but it should be combined with other modalities because of risk of rebleeding with epinephrine alone.15 Results from studies reporting rates of both early rebleeding (occurring within 30 days) and late rebleeding (occurring after 30 days) are listed in the Table. 
Multipolar electrocoagulation (MPEC), which utilizes a focal electric current to generate heat, can coaptively coagulate small TIC arteries.16 For SRH in the neck of TIC, MPEC is effective for coaptive coagulation at a power of 12-15 watts in 1-2 second pulses with moderate laterally applied tamponade pressure. MPEC should be avoided for treating SRH at the TIC base because of lack of muscularis propria and higher risk of perforation.
Hemoclip therapy has been reported to be safe and efficacious in treatment of definitive TIC hemorrhage, by causing mechanical hemostasis with occlusion of the bleeding artery.16 Hemoclips are recommended to treat stigmata in the base of TICs and should be targeted on either side of visible vessel in order to occlude the artery underneath it.4,10 With a cap on the tip of the colonoscope, suctioning can evert TICs, allowing more precise placement of hemoclip on SRH in the base of the TIC.17 Hemoclip retention rates vary with different models and can range from less than 7 days to more than 4 weeks. Hemoclips can also mark the site if early rebleeding occurs; then, reintervention (e.g., repeat endoscopy or angioembolization) is facilitated.
Another treatment is endoscopic band ligation, which provides mechanical hemostasis. Endoscopic band ligation has been reported to be efficacious for TIC hemorrhage.18 Suctioning the TIC with the SRH into the distal cap and deploying a band leads to obliteration of vessels and potentially necrosis and disappearance of banded TIC.16 This technique carries a risk of perforation because of the thin walls of TICs. This risk may be higher for right-sided colon lesions since an exvivo colon specimen study reported serosal entrapment and inclusion of muscularis propria postband ligation, both of which may result in ischemia of intestinal wall and delayed perforation.19
Over-the-scope clip (OTSC) has been reported in case series for treatment of definitive TIC hemorrhage. With a distal cap and large clip, suctioning can evert TICs and facilitate deployment over the SRH.20,21 OTSC can grasp an entire TIC with the SRH and obliterate the arterial blood flow with a single clip.20,21 No complications have been reported yet for treatment of TIC hemorrhage. However, the OTSC system is relatively expensive when compared with other modalities.
After endoscopic treatment is performed, four-quadrant spot tattooing is recommended adjacent to the TIC with the SRH. This step will facilitate localization and treatment in the case of TIC rebleeding.4,10
Outcomes following endoscopic treatment
Following endoscopic treatment, patients should be monitored for early and late rebleeding. In a pooled analysis of case series composed of 847 patients with TIC bleeding, among the 137 patients in which endoscopic hemostasis was initially achieved, early rebleeding occurred in 8% and late rebleeding occurred in 12% of patients.22 Risk factors for TIC rebleeding within 30 days were residual arterial blood flow following hemostasis and early reinitiation of antiplatelet agents.
Remote treatment of TIC hemorrhage distant from the SRH is a significant risk factor for early TIC rebleeding.4, 10 For example, using hemoclips to close the mouth of a TIC when active bleeding or an SRH is located in the TIC base often fails because arterial flow remains open in the base and the artery is larger there.4,10 This example highlights the importance of focal obliteration of arterial blood flow underlying SRH in order to achieve definitive hemostasis.4,10
Salvage treatments
For TIC hemorrhage that is not controlled by endoscopic therapy, transcatheter arterial embolization (TAE) is recommended. If bleeding rate is high enough (at least 0.5 milliliters per minute) to be detected by angiography, TAE can serve as an effective method of diagnosis and immediate hemostasis.23 However, the most common major complication of embolization is intestinal ischemia. The incidence of intestinal ischemia has been reported as high as 10%, with highest risk with embolization of at least three vasa recta.24
Surgery is also recommended if TIC hemorrhage cannot be controlled with endoscopic therapy or TAE. Segmental colectomy is recommended if the bleeding site can be localized before surgery with colonoscopy or angiography resulting from significantly lower perioperative morbidity than subtotal colectomy.25 However, subtotal colectomy may be necessary if preoperative localization of bleeding is unsuccessful.
There are very few reports of short- or long-term results that compare endoscopy, TAE, and surgery for management of TIC bleeding. However, a recent retrospective study reported better outcomes with endoscopic treatment of definitive TIC bleeding.26 Patients who underwent endoscopic treatment had fewer RBC transfusions, shorter hospitalizations, and lower rates of postprocedure complications.
Management after cessation of hemorrhage
Medical management is important following an episode of TIC hemorrhage. A mainstay is daily fiber supplementation every morning and stool softener in the evening. Furthermore, patients are advised to drink an extra liter of fluids (not containing alcohol or caffeine) daily. By reducing colon transit time and increasing stool weight, these measures can help control constipation and prevent future complications of TIC disease.27
Patients with recurrent TIC hemorrhage should undergo evaluation for elective surgery, provided they are appropriate surgical candidates. If preoperative localization of bleeding site is successful, segmental colectomy is preferred. Segmental resection is associated with significantly decreased rebleeding rate, with lower rates of morbidity compared with subtotal colectomy.32
Chronic NSAIDs, aspirin, and antiplatelet drugs are risk factors for recurrent TIC hemorrhage, and avoiding these medications is recommended if possible.33,34 Although anticoagulants have shown to be associated with increased risk of all-cause gastrointestinal bleeding, these agents have not been shown to increase risk of recurrent TIC hemorrhage in recent large retrospective studies. Since antiplatelet and anticoagulation agents serve to reduce risk of thromboembolic events, the clinician who recommended these medications should be consulted after a TIC bleed to re-evaluate whether these medications can be discontinued or reduced in dose.
Conclusion
The most effective way to diagnose and treat definitive TIC hemorrhage is to perform an urgent colonoscopy within 24 hours to identify and treat TIC SRH. This procedure requires thoroughly cleansing the colon first, as well as an experienced colonoscopist who can identify and treat TIC SRH to obliterate arterial blood flow underneath SRH and achieve definitive TIC hemostasis. Other approaches to early diagnosis include nuclear medicine scintigraphy or angiography (CT, MRI, or IR). However, these techniques can only detect active bleeding which is documented in only 26% of colonoscopically diagnosed definitive TIC hemorrhages. So, the expected diagnostic yield of these tests will be low. When urgent colonoscopy fails to make a diagnosis or TIC bleeding continues, TAE and/or surgery are recommended. After definitive hemostasis of TIC hemorrhage and for long term management, control of constipation and discontinuation of chronic NSAIDs and antiplatelet drugs (if possible) are recommended to prevent recurrent TIC hemorrhage.
Dr. Cusumano and Dr. Paiji are fellow physicians in the Vatche and Tamar Manoukian Division of Digestive Diseases at University of California Los Angeles. Dr. Jensen is a professor of medicine in Vatche and Tamar Manoukian Division of Digestive Diseases and is with the CURE Digestive Diseases Research Center at the VA Greater Los Angeles Healthcare System, Calif. All authors declare that they have no competing interests or disclosures.
References
1. Longstreth GF. Am J Gastroenterol. 1997;92(3):419-24.
2. Jensen DM et al. The New England Journal of Medicine. 2000;342(2):78-82.
3. Jensen DM et al. Techniques in Gastrointestinal Endoscopy. 2001;3(4):192-8.
4. Jensen DM. Am J Gastroenterol. 2018;113(11):1570-3.
5. Zuckerman GR et al. Gastrointestinal Endoscopy. 1999;49(2):228-38.
6. Stollman N et al. Lancet. 2004;363(9409):631-9.
7. McGuire HH et al. Ann Surg. 1994;220(5):653-6.
8. McGuire HH et al. Ann Surg. 1972;175(6):847-55.
9. Strate LL et al. Clinical gastroenterology and hepatol. 2008;6(9):1004-10.
10. Jensen DM et al. Gastrointestinal endoscopy. 2016;83(2):416-23.
11. Jensen DM et al. Gastrointest Endosc Clin N Am. 1997;7(3):477-98.
12. Maykel JA et al. Clin Colon Rectal Surg. 2004;17(3):195-204.
13. Green BT et al. Am J Gastroenterol. 2005;100(11):2395-402.
14. Niikura R et al. Journal of Clinical Gastroenterol. 2015;49(3):e24-30.
15. Bloomfeld RS et al. Am J Gastroenterol. 2001;96(8):2367-72.
16. Parsi MA,et al. VideoGIE. 2019;4(7):285-99.
17. Kaltenbach T et al. Clinical Gastroenterology and Hepatol. 2012;10(2):131-7.
18. Nakano K et al. Endosc Int Open. 2015;3(5):E529-33.
19. Barker KB et al. Gastrointestinal Endoscopy. 2005;62(2):224-7.
20. Kaltenbach T et al. Gastrointest Endosc Clin N Am. 2020;30(1):13-23.
21. Yamazaki K et al. VideoGIE. 2020;5(6):252-4.
22. Strate LL et al. Clinical Gastroenterology and Hepatol. 2010;8(4):333-43.
23. Evangelista et al. J Vasc Interv Radiol. 2000;11(5):601-6.
24. Kodani M et al. J Vasc Interv Radiol. 2016;27(6):824-30.
25. Mohammed et al. Clin Colon Rectal Surg. 2018;31(4):243-50.
26. Wongpongsalee T et al. Gastrointestinal Endoscopy. 2020;91(6):AB471-2.
27. Böhm SK. Viszeralmedizin. 2015;31(2):84-94.
28. Prakash C et al. Endoscopy. 1999;31(6):460-3.
29. Yen EF et al. Digestive Diseases and Sciences. 2008;53(9):2480-5.
30. Ishii N et al. Gastrointestinal Endoscopy. 2012;75(2):382-7.
31. Nagata N et al. Gastrointestinal Endoscopy. 2018;88(5):841-53.e4.
32. Parkes BM et al. Am Surg. 1993;59(10):676-8.
33. Vajravelu RK et al. Gastroenterology. 2018;155(5):1416-27.
34. Oakland K et al. Clin Gastroenterol Hepatol. 2019;17(7):1276-84.e3.
35. Yamada A et al. Dis Colon Rectum. 2008;51(1):116-20.
36. Coleman CI et al. Int J Clin Pract. 2012;66(1):53-63.
37. Holster IL et al. Gastroenterology. 2013;145(1):105-12.e15.
Diverticular hemorrhage is the most common cause of colonic bleeding, accounting for 20%-65% of cases of severe lower intestinal bleeding in adults.1 Urgent colonoscopy after purging the colon of blood, clots, and stool is the most accurate method of diagnosing and guiding treatment of definitive diverticular hemorrhage.2-5 The diagnosis of definitive diverticular hemorrhage depends upon identification of some stigmata of recent hemorrhage (SRH) in a single diverticulum (TIC), which can include active arterial bleeding, oozing, non-bleeding visible vessel, adherent clot, or flat spot.2-4 Although other approaches, such as nuclear medicine scans and angiography of various types (CT, MRI, or standard angiography), for the early diagnosis of patients with severe hematochezia are utilized in many medical centers, only active bleeding can be detected by these techniques. However, as subsequently discussed, this SRH is documented in only 26% of definitive diverticular bleeds found on urgent colonoscopy, so diagnostic yields of these techniques will be low.2-5
The diagnosis of patients with severe hematochezia and diverticulosis, as well as triage of all of them to specific medical, endoscopic, radiologic, or surgical management, is facilitated by an urgent endoscopic approach.2-5 Patients who are diagnosed with definitive diverticular hemorrhage on colonoscopy represent about 30% of all true TIC bleeds when urgent colonoscopy is the management approach.2-5 That is because approximately 50% of all patients with colon diverticulosis and first presentation of severe hematochezia have incidental diverticulosis; they have colonic diverticulosis, but another site of bleeding is identified as the cause of hemorrhage in the gastrointestinal tract.2-4 Presumptive diverticular hemorrhage is diagnosed when colonic diverticulosis without TIC stigmata are found but no other GI bleeding source is found on colonoscopy, anoscopy, enteroscopy, or capsule endoscopy.2-5 In our experience with urgent colonoscopy, the presumptive diverticular bleed group accounts for about 70% of patients with documented diverticular hemorrhage (e.g., not including incidental diverticulosis bleeds but combining subgroups of patients with either definitive or presumptive TIC diagnoses as documented TIC hemorrhage).
Clinical presentation
Patients with diverticular hemorrhage present with severe, painless large volume hematochezia. Hematochezia may be self-limited and spontaneously resolve in 75%-80% of all patients but with high rebleeding rates up to 40%.5-7 Of all patients with diverticulosis, only about 3%-5% develop diverticular hemorrhage.8 Risk factors for diverticular hemorrhage include medications (e.g., nonsteroidal anti-inflammatory drugs – NSAIDs, antiplatelet drugs, and anticoagulants) and other clinical factors, such as older age, low-fiber diet, and chronic constipation.9,10 On urgent colonoscopy, more than 70% of diverticulosis in U.S. patients are located anatomically in the descending colon or more distally. In contrast, about 60% of definitive diverticular hemorrhage cases in our experience had diverticula with stigmata identified at or proximal to the splenic flexure.2,4,11
Pathophysiology
Colonic diverticula are herniations of mucosa and submucosa with colonic arteries that penetrate the muscular wall. Bleeding can occur when there is asymmetric rupture of the vasa recta at either the base of the diverticulum or the neck.4 Thinning of the mucosa on the luminal surface (such as that resulting from impacted fecaliths and stool) can cause injury to the site of the penetrating vessels, resulting in hemorrhage.12
Initial management
Patients with acute, severe hematochezia should be triaged to an inpatient setting with a monitored bed. Admission to an intensive care unit should be considered for patients with hemodynamic instability, persistent bleeding, and/or significant comorbidities. Patients with TIC hemorrhage often require resuscitation with crystalloids and packed red blood cell transfusions for hemoglobin less than 8 g/dl.4 Unlike upper GI hemorrhage, which has been extensively reported on, data regarding a more restrictive transfusion threshold, compared with a liberal transfusion threshold, in lower intestinal bleeding are very limited. Correction of underlying coagulopathies is recommended but should be individualized, particularly in those patients on antithrombotic agents or with underlying bleeding disorders.
Urgent diagnosis and hemostasis
Urgent colonoscopy within 24 hours is the most accurate way to make a diagnosis of definitive diverticular hemorrhage and to effectively and safely treat them.2-4,10,11 For patients with severe hematochezia, when the colonoscopy is either not available in a medical center or does not reveal the source of bleeding, nuclear scintigraphy or angiography (CT, MRI, or interventional radiology [IR]) are recommended. CT angiography may be particularly helpful to diagnose patients with hemodynamic instability who are suspected to have active TIC bleeding and are not able to complete a bowel preparation. However, these imaging techniques require active bleeding at the time of the study to be diagnostic. This SRH is also uncommon for definitive diverticular hemorrhage, so the diagnostic yield is usually quite low.2-5,10,11 An additional limitation of scintigraphy and CT or MRI angiography is that, if active bleeding is found, some other type of treatment, such as colonoscopy, IR angiography, or surgery, will be required for definitive hemostasis.
For urgent colonoscopy, adequate colon preparation with a large volume preparation (6-8 liters of polyethylene glycol-based solution) is recommended to clear stool, blood, and clots to allow endoscopic visualization and localization of the bleeding source. Use of a nasogastric tube should be considered if the patient is unable to drink enough prep.2-4,13 Additionally, administration of a prokinetic agent, such as Metoclopramide, may improve gastric emptying and tolerance of the prep. During colonoscopy, careful inspection of the colonic mucosa during insertion and withdrawal is important since lesions may bleed intermittently and SRH can be missed. An adult or pediatric colonoscope with a large working channel (at least 3.3 mm) is recommended to facilitate suctioning of blood clots and stool, as well as allow the passage of endoscopic hemostasis accessories. Targeted water-jet irrigation, an expert colonoscopist, a cap attachment, and adequate colon preparation are all predictors for improved diagnosis of definitive diverticular hemorrhage.4,14
SRH in definitive TIC bleeds all have a high risk of TIC rebleeding,2-4,10,11 including active bleeding, nonbleeding visible vessel, adherent clot, and a flat spot (See Figure).
Based on CURE Hemostasis Group data of 118 definitive TIC bleeds, 26% had active bleeding, 24% had a nonbleeding visible vessel, 37% had an adherent clot, and 13% had a flat spot (with underlying arterial blood flow by Doppler probe monitoring).4 Approximately 50% of the SRH were found in the neck of the TIC and 50% at the base, with actively bleeding cases more often from the base. In CURE Doppler endoscopic probe studies, 90% of all stigmata had an underlying arterial blood flow detected with the Doppler probe.4,10 The Doppler probe is reported to be very useful for risk stratification and to confirm obliteration of the arterial blood flow underlying SRH for definitive hemostasis.4,10
Endoscopic treatment
Given high rates of rebleeding with medical management alone, definitive TIC hemorrhage can be effectively and safely treated with endoscopic therapies once SRH are localized.4,10 Endoscopic therapies that have been reported in the literature include electrocoagulation, hemoclip, band ligation, and over-the-scope clip. Four-quadrant injection of 1:20,000 epinephrine around the SRH can improve visualization of SRH and provide temporary control of bleeding, but it should be combined with other modalities because of risk of rebleeding with epinephrine alone.15 Results from studies reporting rates of both early rebleeding (occurring within 30 days) and late rebleeding (occurring after 30 days) are listed in the Table.
Multipolar electrocoagulation (MPEC), which utilizes a focal electric current to generate heat, can coaptively coagulate small TIC arteries.16 For SRH in the neck of TIC, MPEC is effective for coaptive coagulation at a power of 12-15 watts in 1-2 second pulses with moderate laterally applied tamponade pressure. MPEC should be avoided for treating SRH at the TIC base because of lack of muscularis propria and higher risk of perforation.
Hemoclip therapy has been reported to be safe and efficacious in treatment of definitive TIC hemorrhage, by causing mechanical hemostasis with occlusion of the bleeding artery.16 Hemoclips are recommended to treat stigmata in the base of TICs and should be targeted on either side of visible vessel in order to occlude the artery underneath it.4,10 With a cap on the tip of the colonoscope, suctioning can evert TICs, allowing more precise placement of hemoclip on SRH in the base of the TIC.17 Hemoclip retention rates vary with different models and can range from less than 7 days to more than 4 weeks. Hemoclips can also mark the site if early rebleeding occurs; then, reintervention (e.g., repeat endoscopy or angioembolization) is facilitated.
Another treatment is endoscopic band ligation, which provides mechanical hemostasis. Endoscopic band ligation has been reported to be efficacious for TIC hemorrhage.18 Suctioning the TIC with the SRH into the distal cap and deploying a band leads to obliteration of vessels and potentially necrosis and disappearance of banded TIC.16 This technique carries a risk of perforation because of the thin walls of TICs. This risk may be higher for right-sided colon lesions since an exvivo colon specimen study reported serosal entrapment and inclusion of muscularis propria postband ligation, both of which may result in ischemia of intestinal wall and delayed perforation.19
Over-the-scope clip (OTSC) has been reported in case series for treatment of definitive TIC hemorrhage. With a distal cap and large clip, suctioning can evert TICs and facilitate deployment over the SRH.20,21 OTSC can grasp an entire TIC with the SRH and obliterate the arterial blood flow with a single clip.20,21 No complications have been reported yet for treatment of TIC hemorrhage. However, the OTSC system is relatively expensive when compared with other modalities.
After endoscopic treatment is performed, four-quadrant spot tattooing is recommended adjacent to the TIC with the SRH. This step will facilitate localization and treatment in the case of TIC rebleeding.4,10
Outcomes following endoscopic treatment
Following endoscopic treatment, patients should be monitored for early and late rebleeding. In a pooled analysis of case series composed of 847 patients with TIC bleeding, among the 137 patients in which endoscopic hemostasis was initially achieved, early rebleeding occurred in 8% and late rebleeding occurred in 12% of patients.22 Risk factors for TIC rebleeding within 30 days were residual arterial blood flow following hemostasis and early reinitiation of antiplatelet agents.
Remote treatment of TIC hemorrhage distant from the SRH is a significant risk factor for early TIC rebleeding.4, 10 For example, using hemoclips to close the mouth of a TIC when active bleeding or an SRH is located in the TIC base often fails because arterial flow remains open in the base and the artery is larger there.4,10 This example highlights the importance of focal obliteration of arterial blood flow underlying SRH in order to achieve definitive hemostasis.4,10
Salvage treatments
For TIC hemorrhage that is not controlled by endoscopic therapy, transcatheter arterial embolization (TAE) is recommended. If bleeding rate is high enough (at least 0.5 milliliters per minute) to be detected by angiography, TAE can serve as an effective method of diagnosis and immediate hemostasis.23 However, the most common major complication of embolization is intestinal ischemia. The incidence of intestinal ischemia has been reported as high as 10%, with highest risk with embolization of at least three vasa recta.24
Surgery is also recommended if TIC hemorrhage cannot be controlled with endoscopic therapy or TAE. Segmental colectomy is recommended if the bleeding site can be localized before surgery with colonoscopy or angiography resulting from significantly lower perioperative morbidity than subtotal colectomy.25 However, subtotal colectomy may be necessary if preoperative localization of bleeding is unsuccessful.
There are very few reports of short- or long-term results that compare endoscopy, TAE, and surgery for management of TIC bleeding. However, a recent retrospective study reported better outcomes with endoscopic treatment of definitive TIC bleeding.26 Patients who underwent endoscopic treatment had fewer RBC transfusions, shorter hospitalizations, and lower rates of postprocedure complications.
Management after cessation of hemorrhage
Medical management is important following an episode of TIC hemorrhage. A mainstay is daily fiber supplementation every morning and stool softener in the evening. Furthermore, patients are advised to drink an extra liter of fluids (not containing alcohol or caffeine) daily. By reducing colon transit time and increasing stool weight, these measures can help control constipation and prevent future complications of TIC disease.27
Patients with recurrent TIC hemorrhage should undergo evaluation for elective surgery, provided they are appropriate surgical candidates. If preoperative localization of bleeding site is successful, segmental colectomy is preferred. Segmental resection is associated with significantly decreased rebleeding rate, with lower rates of morbidity compared with subtotal colectomy.32
Chronic NSAIDs, aspirin, and antiplatelet drugs are risk factors for recurrent TIC hemorrhage, and avoiding these medications is recommended if possible.33,34 Although anticoagulants have shown to be associated with increased risk of all-cause gastrointestinal bleeding, these agents have not been shown to increase risk of recurrent TIC hemorrhage in recent large retrospective studies. Since antiplatelet and anticoagulation agents serve to reduce risk of thromboembolic events, the clinician who recommended these medications should be consulted after a TIC bleed to re-evaluate whether these medications can be discontinued or reduced in dose.
Conclusion
The most effective way to diagnose and treat definitive TIC hemorrhage is to perform an urgent colonoscopy within 24 hours to identify and treat TIC SRH. This procedure requires thoroughly cleansing the colon first, as well as an experienced colonoscopist who can identify and treat TIC SRH to obliterate arterial blood flow underneath SRH and achieve definitive TIC hemostasis. Other approaches to early diagnosis include nuclear medicine scintigraphy or angiography (CT, MRI, or IR). However, these techniques can only detect active bleeding which is documented in only 26% of colonoscopically diagnosed definitive TIC hemorrhages. So, the expected diagnostic yield of these tests will be low. When urgent colonoscopy fails to make a diagnosis or TIC bleeding continues, TAE and/or surgery are recommended. After definitive hemostasis of TIC hemorrhage and for long term management, control of constipation and discontinuation of chronic NSAIDs and antiplatelet drugs (if possible) are recommended to prevent recurrent TIC hemorrhage.
Dr. Cusumano and Dr. Paiji are fellow physicians in the Vatche and Tamar Manoukian Division of Digestive Diseases at University of California Los Angeles. Dr. Jensen is a professor of medicine in Vatche and Tamar Manoukian Division of Digestive Diseases and is with the CURE Digestive Diseases Research Center at the VA Greater Los Angeles Healthcare System, Calif. All authors declare that they have no competing interests or disclosures.
References
1. Longstreth GF. Am J Gastroenterol. 1997;92(3):419-24.
2. Jensen DM et al. The New England Journal of Medicine. 2000;342(2):78-82.
3. Jensen DM et al. Techniques in Gastrointestinal Endoscopy. 2001;3(4):192-8.
4. Jensen DM. Am J Gastroenterol. 2018;113(11):1570-3.
5. Zuckerman GR et al. Gastrointestinal Endoscopy. 1999;49(2):228-38.
6. Stollman N et al. Lancet. 2004;363(9409):631-9.
7. McGuire HH et al. Ann Surg. 1994;220(5):653-6.
8. McGuire HH et al. Ann Surg. 1972;175(6):847-55.
9. Strate LL et al. Clinical gastroenterology and hepatol. 2008;6(9):1004-10.
10. Jensen DM et al. Gastrointestinal endoscopy. 2016;83(2):416-23.
11. Jensen DM et al. Gastrointest Endosc Clin N Am. 1997;7(3):477-98.
12. Maykel JA et al. Clin Colon Rectal Surg. 2004;17(3):195-204.
13. Green BT et al. Am J Gastroenterol. 2005;100(11):2395-402.
14. Niikura R et al. Journal of Clinical Gastroenterol. 2015;49(3):e24-30.
15. Bloomfeld RS et al. Am J Gastroenterol. 2001;96(8):2367-72.
16. Parsi MA,et al. VideoGIE. 2019;4(7):285-99.
17. Kaltenbach T et al. Clinical Gastroenterology and Hepatol. 2012;10(2):131-7.
18. Nakano K et al. Endosc Int Open. 2015;3(5):E529-33.
19. Barker KB et al. Gastrointestinal Endoscopy. 2005;62(2):224-7.
20. Kaltenbach T et al. Gastrointest Endosc Clin N Am. 2020;30(1):13-23.
21. Yamazaki K et al. VideoGIE. 2020;5(6):252-4.
22. Strate LL et al. Clinical Gastroenterology and Hepatol. 2010;8(4):333-43.
23. Evangelista et al. J Vasc Interv Radiol. 2000;11(5):601-6.
24. Kodani M et al. J Vasc Interv Radiol. 2016;27(6):824-30.
25. Mohammed et al. Clin Colon Rectal Surg. 2018;31(4):243-50.
26. Wongpongsalee T et al. Gastrointestinal Endoscopy. 2020;91(6):AB471-2.
27. Böhm SK. Viszeralmedizin. 2015;31(2):84-94.
28. Prakash C et al. Endoscopy. 1999;31(6):460-3.
29. Yen EF et al. Digestive Diseases and Sciences. 2008;53(9):2480-5.
30. Ishii N et al. Gastrointestinal Endoscopy. 2012;75(2):382-7.
31. Nagata N et al. Gastrointestinal Endoscopy. 2018;88(5):841-53.e4.
32. Parkes BM et al. Am Surg. 1993;59(10):676-8.
33. Vajravelu RK et al. Gastroenterology. 2018;155(5):1416-27.
34. Oakland K et al. Clin Gastroenterol Hepatol. 2019;17(7):1276-84.e3.
35. Yamada A et al. Dis Colon Rectum. 2008;51(1):116-20.
36. Coleman CI et al. Int J Clin Pract. 2012;66(1):53-63.
37. Holster IL et al. Gastroenterology. 2013;145(1):105-12.e15.
Diverticular hemorrhage is the most common cause of colonic bleeding, accounting for 20%-65% of cases of severe lower intestinal bleeding in adults.1 Urgent colonoscopy after purging the colon of blood, clots, and stool is the most accurate method of diagnosing and guiding treatment of definitive diverticular hemorrhage.2-5 The diagnosis of definitive diverticular hemorrhage depends upon identification of some stigmata of recent hemorrhage (SRH) in a single diverticulum (TIC), which can include active arterial bleeding, oozing, non-bleeding visible vessel, adherent clot, or flat spot.2-4 Although other approaches, such as nuclear medicine scans and angiography of various types (CT, MRI, or standard angiography), for the early diagnosis of patients with severe hematochezia are utilized in many medical centers, only active bleeding can be detected by these techniques. However, as subsequently discussed, this SRH is documented in only 26% of definitive diverticular bleeds found on urgent colonoscopy, so diagnostic yields of these techniques will be low.2-5
The diagnosis of patients with severe hematochezia and diverticulosis, as well as triage of all of them to specific medical, endoscopic, radiologic, or surgical management, is facilitated by an urgent endoscopic approach.2-5 Patients who are diagnosed with definitive diverticular hemorrhage on colonoscopy represent about 30% of all true TIC bleeds when urgent colonoscopy is the management approach.2-5 That is because approximately 50% of all patients with colon diverticulosis and first presentation of severe hematochezia have incidental diverticulosis; they have colonic diverticulosis, but another site of bleeding is identified as the cause of hemorrhage in the gastrointestinal tract.2-4 Presumptive diverticular hemorrhage is diagnosed when colonic diverticulosis without TIC stigmata are found but no other GI bleeding source is found on colonoscopy, anoscopy, enteroscopy, or capsule endoscopy.2-5 In our experience with urgent colonoscopy, the presumptive diverticular bleed group accounts for about 70% of patients with documented diverticular hemorrhage (e.g., not including incidental diverticulosis bleeds but combining subgroups of patients with either definitive or presumptive TIC diagnoses as documented TIC hemorrhage).
Clinical presentation
Patients with diverticular hemorrhage present with severe, painless large volume hematochezia. Hematochezia may be self-limited and spontaneously resolve in 75%-80% of all patients but with high rebleeding rates up to 40%.5-7 Of all patients with diverticulosis, only about 3%-5% develop diverticular hemorrhage.8 Risk factors for diverticular hemorrhage include medications (e.g., nonsteroidal anti-inflammatory drugs – NSAIDs, antiplatelet drugs, and anticoagulants) and other clinical factors, such as older age, low-fiber diet, and chronic constipation.9,10 On urgent colonoscopy, more than 70% of diverticulosis in U.S. patients are located anatomically in the descending colon or more distally. In contrast, about 60% of definitive diverticular hemorrhage cases in our experience had diverticula with stigmata identified at or proximal to the splenic flexure.2,4,11
Pathophysiology
Colonic diverticula are herniations of mucosa and submucosa with colonic arteries that penetrate the muscular wall. Bleeding can occur when there is asymmetric rupture of the vasa recta at either the base of the diverticulum or the neck.4 Thinning of the mucosa on the luminal surface (such as that resulting from impacted fecaliths and stool) can cause injury to the site of the penetrating vessels, resulting in hemorrhage.12
Initial management
Patients with acute, severe hematochezia should be triaged to an inpatient setting with a monitored bed. Admission to an intensive care unit should be considered for patients with hemodynamic instability, persistent bleeding, and/or significant comorbidities. Patients with TIC hemorrhage often require resuscitation with crystalloids and packed red blood cell transfusions for hemoglobin less than 8 g/dl.4 Unlike upper GI hemorrhage, which has been extensively reported on, data regarding a more restrictive transfusion threshold, compared with a liberal transfusion threshold, in lower intestinal bleeding are very limited. Correction of underlying coagulopathies is recommended but should be individualized, particularly in those patients on antithrombotic agents or with underlying bleeding disorders.
Urgent diagnosis and hemostasis
Urgent colonoscopy within 24 hours is the most accurate way to make a diagnosis of definitive diverticular hemorrhage and to effectively and safely treat them.2-4,10,11 For patients with severe hematochezia, when the colonoscopy is either not available in a medical center or does not reveal the source of bleeding, nuclear scintigraphy or angiography (CT, MRI, or interventional radiology [IR]) are recommended. CT angiography may be particularly helpful to diagnose patients with hemodynamic instability who are suspected to have active TIC bleeding and are not able to complete a bowel preparation. However, these imaging techniques require active bleeding at the time of the study to be diagnostic. This SRH is also uncommon for definitive diverticular hemorrhage, so the diagnostic yield is usually quite low.2-5,10,11 An additional limitation of scintigraphy and CT or MRI angiography is that, if active bleeding is found, some other type of treatment, such as colonoscopy, IR angiography, or surgery, will be required for definitive hemostasis.
For urgent colonoscopy, adequate colon preparation with a large volume preparation (6-8 liters of polyethylene glycol-based solution) is recommended to clear stool, blood, and clots to allow endoscopic visualization and localization of the bleeding source. Use of a nasogastric tube should be considered if the patient is unable to drink enough prep.2-4,13 Additionally, administration of a prokinetic agent, such as Metoclopramide, may improve gastric emptying and tolerance of the prep. During colonoscopy, careful inspection of the colonic mucosa during insertion and withdrawal is important since lesions may bleed intermittently and SRH can be missed. An adult or pediatric colonoscope with a large working channel (at least 3.3 mm) is recommended to facilitate suctioning of blood clots and stool, as well as allow the passage of endoscopic hemostasis accessories. Targeted water-jet irrigation, an expert colonoscopist, a cap attachment, and adequate colon preparation are all predictors for improved diagnosis of definitive diverticular hemorrhage.4,14
SRH in definitive TIC bleeds all have a high risk of TIC rebleeding,2-4,10,11 including active bleeding, nonbleeding visible vessel, adherent clot, and a flat spot (See Figure).
Based on CURE Hemostasis Group data of 118 definitive TIC bleeds, 26% had active bleeding, 24% had a nonbleeding visible vessel, 37% had an adherent clot, and 13% had a flat spot (with underlying arterial blood flow by Doppler probe monitoring).4 Approximately 50% of the SRH were found in the neck of the TIC and 50% at the base, with actively bleeding cases more often from the base. In CURE Doppler endoscopic probe studies, 90% of all stigmata had an underlying arterial blood flow detected with the Doppler probe.4,10 The Doppler probe is reported to be very useful for risk stratification and to confirm obliteration of the arterial blood flow underlying SRH for definitive hemostasis.4,10
Endoscopic treatment
Given high rates of rebleeding with medical management alone, definitive TIC hemorrhage can be effectively and safely treated with endoscopic therapies once SRH are localized.4,10 Endoscopic therapies that have been reported in the literature include electrocoagulation, hemoclip, band ligation, and over-the-scope clip. Four-quadrant injection of 1:20,000 epinephrine around the SRH can improve visualization of SRH and provide temporary control of bleeding, but it should be combined with other modalities because of risk of rebleeding with epinephrine alone.15 Results from studies reporting rates of both early rebleeding (occurring within 30 days) and late rebleeding (occurring after 30 days) are listed in the Table.
Multipolar electrocoagulation (MPEC), which utilizes a focal electric current to generate heat, can coaptively coagulate small TIC arteries.16 For SRH in the neck of TIC, MPEC is effective for coaptive coagulation at a power of 12-15 watts in 1-2 second pulses with moderate laterally applied tamponade pressure. MPEC should be avoided for treating SRH at the TIC base because of lack of muscularis propria and higher risk of perforation.
Hemoclip therapy has been reported to be safe and efficacious in treatment of definitive TIC hemorrhage, by causing mechanical hemostasis with occlusion of the bleeding artery.16 Hemoclips are recommended to treat stigmata in the base of TICs and should be targeted on either side of visible vessel in order to occlude the artery underneath it.4,10 With a cap on the tip of the colonoscope, suctioning can evert TICs, allowing more precise placement of hemoclip on SRH in the base of the TIC.17 Hemoclip retention rates vary with different models and can range from less than 7 days to more than 4 weeks. Hemoclips can also mark the site if early rebleeding occurs; then, reintervention (e.g., repeat endoscopy or angioembolization) is facilitated.
Another treatment is endoscopic band ligation, which provides mechanical hemostasis. Endoscopic band ligation has been reported to be efficacious for TIC hemorrhage.18 Suctioning the TIC with the SRH into the distal cap and deploying a band leads to obliteration of vessels and potentially necrosis and disappearance of banded TIC.16 This technique carries a risk of perforation because of the thin walls of TICs. This risk may be higher for right-sided colon lesions since an exvivo colon specimen study reported serosal entrapment and inclusion of muscularis propria postband ligation, both of which may result in ischemia of intestinal wall and delayed perforation.19
Over-the-scope clip (OTSC) has been reported in case series for treatment of definitive TIC hemorrhage. With a distal cap and large clip, suctioning can evert TICs and facilitate deployment over the SRH.20,21 OTSC can grasp an entire TIC with the SRH and obliterate the arterial blood flow with a single clip.20,21 No complications have been reported yet for treatment of TIC hemorrhage. However, the OTSC system is relatively expensive when compared with other modalities.
After endoscopic treatment is performed, four-quadrant spot tattooing is recommended adjacent to the TIC with the SRH. This step will facilitate localization and treatment in the case of TIC rebleeding.4,10
Outcomes following endoscopic treatment
Following endoscopic treatment, patients should be monitored for early and late rebleeding. In a pooled analysis of case series composed of 847 patients with TIC bleeding, among the 137 patients in which endoscopic hemostasis was initially achieved, early rebleeding occurred in 8% and late rebleeding occurred in 12% of patients.22 Risk factors for TIC rebleeding within 30 days were residual arterial blood flow following hemostasis and early reinitiation of antiplatelet agents.
Remote treatment of TIC hemorrhage distant from the SRH is a significant risk factor for early TIC rebleeding.4, 10 For example, using hemoclips to close the mouth of a TIC when active bleeding or an SRH is located in the TIC base often fails because arterial flow remains open in the base and the artery is larger there.4,10 This example highlights the importance of focal obliteration of arterial blood flow underlying SRH in order to achieve definitive hemostasis.4,10
Salvage treatments
For TIC hemorrhage that is not controlled by endoscopic therapy, transcatheter arterial embolization (TAE) is recommended. If bleeding rate is high enough (at least 0.5 milliliters per minute) to be detected by angiography, TAE can serve as an effective method of diagnosis and immediate hemostasis.23 However, the most common major complication of embolization is intestinal ischemia. The incidence of intestinal ischemia has been reported as high as 10%, with highest risk with embolization of at least three vasa recta.24
Surgery is also recommended if TIC hemorrhage cannot be controlled with endoscopic therapy or TAE. Segmental colectomy is recommended if the bleeding site can be localized before surgery with colonoscopy or angiography resulting from significantly lower perioperative morbidity than subtotal colectomy.25 However, subtotal colectomy may be necessary if preoperative localization of bleeding is unsuccessful.
There are very few reports of short- or long-term results that compare endoscopy, TAE, and surgery for management of TIC bleeding. However, a recent retrospective study reported better outcomes with endoscopic treatment of definitive TIC bleeding.26 Patients who underwent endoscopic treatment had fewer RBC transfusions, shorter hospitalizations, and lower rates of postprocedure complications.
Management after cessation of hemorrhage
Medical management is important following an episode of TIC hemorrhage. A mainstay is daily fiber supplementation every morning and stool softener in the evening. Furthermore, patients are advised to drink an extra liter of fluids (not containing alcohol or caffeine) daily. By reducing colon transit time and increasing stool weight, these measures can help control constipation and prevent future complications of TIC disease.27
Patients with recurrent TIC hemorrhage should undergo evaluation for elective surgery, provided they are appropriate surgical candidates. If preoperative localization of bleeding site is successful, segmental colectomy is preferred. Segmental resection is associated with significantly decreased rebleeding rate, with lower rates of morbidity compared with subtotal colectomy.32
Chronic NSAIDs, aspirin, and antiplatelet drugs are risk factors for recurrent TIC hemorrhage, and avoiding these medications is recommended if possible.33,34 Although anticoagulants have shown to be associated with increased risk of all-cause gastrointestinal bleeding, these agents have not been shown to increase risk of recurrent TIC hemorrhage in recent large retrospective studies. Since antiplatelet and anticoagulation agents serve to reduce risk of thromboembolic events, the clinician who recommended these medications should be consulted after a TIC bleed to re-evaluate whether these medications can be discontinued or reduced in dose.
Conclusion
The most effective way to diagnose and treat definitive TIC hemorrhage is to perform an urgent colonoscopy within 24 hours to identify and treat TIC SRH. This procedure requires thoroughly cleansing the colon first, as well as an experienced colonoscopist who can identify and treat TIC SRH to obliterate arterial blood flow underneath SRH and achieve definitive TIC hemostasis. Other approaches to early diagnosis include nuclear medicine scintigraphy or angiography (CT, MRI, or IR). However, these techniques can only detect active bleeding which is documented in only 26% of colonoscopically diagnosed definitive TIC hemorrhages. So, the expected diagnostic yield of these tests will be low. When urgent colonoscopy fails to make a diagnosis or TIC bleeding continues, TAE and/or surgery are recommended. After definitive hemostasis of TIC hemorrhage and for long term management, control of constipation and discontinuation of chronic NSAIDs and antiplatelet drugs (if possible) are recommended to prevent recurrent TIC hemorrhage.
Dr. Cusumano and Dr. Paiji are fellow physicians in the Vatche and Tamar Manoukian Division of Digestive Diseases at University of California Los Angeles. Dr. Jensen is a professor of medicine in Vatche and Tamar Manoukian Division of Digestive Diseases and is with the CURE Digestive Diseases Research Center at the VA Greater Los Angeles Healthcare System, Calif. All authors declare that they have no competing interests or disclosures.
References
1. Longstreth GF. Am J Gastroenterol. 1997;92(3):419-24.
2. Jensen DM et al. The New England Journal of Medicine. 2000;342(2):78-82.
3. Jensen DM et al. Techniques in Gastrointestinal Endoscopy. 2001;3(4):192-8.
4. Jensen DM. Am J Gastroenterol. 2018;113(11):1570-3.
5. Zuckerman GR et al. Gastrointestinal Endoscopy. 1999;49(2):228-38.
6. Stollman N et al. Lancet. 2004;363(9409):631-9.
7. McGuire HH et al. Ann Surg. 1994;220(5):653-6.
8. McGuire HH et al. Ann Surg. 1972;175(6):847-55.
9. Strate LL et al. Clinical gastroenterology and hepatol. 2008;6(9):1004-10.
10. Jensen DM et al. Gastrointestinal endoscopy. 2016;83(2):416-23.
11. Jensen DM et al. Gastrointest Endosc Clin N Am. 1997;7(3):477-98.
12. Maykel JA et al. Clin Colon Rectal Surg. 2004;17(3):195-204.
13. Green BT et al. Am J Gastroenterol. 2005;100(11):2395-402.
14. Niikura R et al. Journal of Clinical Gastroenterol. 2015;49(3):e24-30.
15. Bloomfeld RS et al. Am J Gastroenterol. 2001;96(8):2367-72.
16. Parsi MA,et al. VideoGIE. 2019;4(7):285-99.
17. Kaltenbach T et al. Clinical Gastroenterology and Hepatol. 2012;10(2):131-7.
18. Nakano K et al. Endosc Int Open. 2015;3(5):E529-33.
19. Barker KB et al. Gastrointestinal Endoscopy. 2005;62(2):224-7.
20. Kaltenbach T et al. Gastrointest Endosc Clin N Am. 2020;30(1):13-23.
21. Yamazaki K et al. VideoGIE. 2020;5(6):252-4.
22. Strate LL et al. Clinical Gastroenterology and Hepatol. 2010;8(4):333-43.
23. Evangelista et al. J Vasc Interv Radiol. 2000;11(5):601-6.
24. Kodani M et al. J Vasc Interv Radiol. 2016;27(6):824-30.
25. Mohammed et al. Clin Colon Rectal Surg. 2018;31(4):243-50.
26. Wongpongsalee T et al. Gastrointestinal Endoscopy. 2020;91(6):AB471-2.
27. Böhm SK. Viszeralmedizin. 2015;31(2):84-94.
28. Prakash C et al. Endoscopy. 1999;31(6):460-3.
29. Yen EF et al. Digestive Diseases and Sciences. 2008;53(9):2480-5.
30. Ishii N et al. Gastrointestinal Endoscopy. 2012;75(2):382-7.
31. Nagata N et al. Gastrointestinal Endoscopy. 2018;88(5):841-53.e4.
32. Parkes BM et al. Am Surg. 1993;59(10):676-8.
33. Vajravelu RK et al. Gastroenterology. 2018;155(5):1416-27.
34. Oakland K et al. Clin Gastroenterol Hepatol. 2019;17(7):1276-84.e3.
35. Yamada A et al. Dis Colon Rectum. 2008;51(1):116-20.
36. Coleman CI et al. Int J Clin Pract. 2012;66(1):53-63.
37. Holster IL et al. Gastroenterology. 2013;145(1):105-12.e15.
Microscopic colitis: A common, yet often overlooked, cause of chronic diarrhea
Microscopic colitis is an inflammatory disease of the colon and a frequent cause of chronic or recurrent watery diarrhea, particularly in older persons. MC consists of two subtypes, collagenous colitis (CC) and lymphocytic colitis (LC). While the primary symptom is diarrhea, other signs and symptoms such as abdominal pain, weight loss, and dehydration or electrolyte abnormalities may also be present depending on disease severity.1 In MC, the colonic mucosa usually appears normal on colonoscopy, and the diagnosis is made by histologic findings of intraepithelial lymphocytosis with (CC) or without (LC) a prominent subepithelial collagen band. The management approaches to CC and LC are similar and should be directed based on the severity of symptoms.2 We review the epidemiology, risk factors, pathophysiology, diagnosis, and clinical management for this condition, as well as novel therapeutic approaches.
Epidemiology
Although the incidence of MC increased in the late twentieth century, more recently, it has stabilized with an estimated incidence varying from 1 to 25 per 100,000 person-years.3-5 A recent meta-analysis revealed a pooled incidence of 4.85 per 100,000 persons for LC and 4.14 per 100,000 persons for CC.6 Proposed explanations for the rising incidence in the late twentieth century include improved clinical awareness of the disease, possible increased use of drugs associated with MC, and increased performance of diagnostic colonoscopies for chronic diarrhea. Since MC is now well-recognized, the recent plateau in incidence rates may reflect decreased detection bias.
The prevalence of MC ranges from 10%-20% in patients undergoing colonoscopy for chronic watery diarrhea.6,7 The prevalence of LC is approximately 63.1 cases per 100,000 person-years and, for CC, is 49.2 cases per 100,000 person-years.6-8 Recent studies have demonstrated increasing prevalence of MC likely resulting from an aging population.9,10
Risk stratification
Female gender, increasing age, concomitant autoimmune disease, and the use of certain drugs, including NSAIDs, proton pump inhibitors (PPIs), statins, and selective serotonin reuptake inhibitors (SSRIs), have been associated with an increased risk of MC.11,12 Autoimmune disorders, including celiac disease (CD), rheumatoid arthritis, hypothyroidism, and hyperthyroidism, are more common in patients with MC. The association with CD, in particular, is clinically important, as CD is associated with a 50-70 times greater risk of MC, and 2%-9% of patients with MC have CD.13,14
Several medications have been associated with MC. In a British multicenter prospective study, MC was associated with the use of NSAIDs, PPIs, and SSRIs;15 however, recent studies have questioned the association of MC with some of these medications, which might worsen diarrhea but not actually cause MC.16
An additional risk factor for MC is smoking. A recent meta-analysis demonstrated that current and former smokers had an increased risk of MC (odds ratio, 2.99; 95% confidence interval, 2.15-4.15 and OR, 1.63; 95% CI, 1.37-1.94, respectively), compared with nonsmokers.17 Smokers develop MC at a younger age, and smoking is associated with increased disease severity and decreased likelihood of attaining remission.18,19
Pathogenesis
The pathogenesis of MC remains largely unknown, although there are several hypotheses. The leading proposed mechanisms include reaction to luminal antigens, dysregulated collagen metabolism, genetic predisposition, autoimmunity, and bile acid malabsorption.
MC may be caused by abnormal epithelial barrier function, leading to increased permeability and reaction to luminal antigens, including dietary antigens, certain drugs, and bacterial products, 20,21 which themselves lead to the immune dysregulation and intestinal inflammation seen in MC. This mechanism may explain the association of several drugs with MC. Histological changes resembling LC are reported in patients with CD who consume gluten; however, large population-based studies have not found specific dietary associations with the development of MC.22
Another potential mechanism of MC is dysregulated collagen deposition. Collagen accumulation in the subepithelial layer in CC may result from increased levels of fibroblast growth factor, transforming growth factor–beta and vascular endothelial growth factor.23 Nonetheless, studies have not found an association between the severity of diarrhea in patients with CC and the thickness of the subepithelial collagen band.
Thirdly, autoimmunity and genetic predisposition have been postulated in the pathogenesis of MC. As previously discussed, MC is associated with several autoimmune diseases and predominantly occurs in women, a distinctive feature of autoimmune disorders. Several studies have demonstrated an association between MC and HLA-DQ2 and -DQ3 haplotypes,24 as well as potential polymorphisms in the serotonin transporter gene promoter.25 It is important to note, however, that only a few familial cases of MC have been reported to date.26
Lastly, bile acid malabsorption may play a role in the etiology of MC. Histologic findings of inflammation, along with villous atrophy and collagen deposition, have been reported in the ileum of patients with MC;27,28 however, because patients with MC without bile acid malabsorption may also respond to bile acid binders such as cholestyramine, these findings unlikely to be the sole mechanism explaining the development of the disease.
Despite the different proposed mechanisms for the pathogenesis of MC, no definite conclusions can be drawn because of the limited size of these studies and their often conflicting results.
Clinical features
Clinicians should suspect MC in patients with chronic or recurrent watery diarrhea, particularly in older persons. Other risk factors include female gender, use of certain culprit medications, smoking, and presence of other autoimmune diseases. The clinical manifestations of MC subtypes LC and CC are similar with no significant clinical differences.1,2 In addition to diarrhea, patients with MC may have abdominal pain, fatigue, and dehydration or electrolyte abnormalities depending on disease severity. Patients may also present with fecal urgency, incontinence, and nocturnal stools. Quality of life is often reduced in these patients, predominantly in those with severe or refractory symptoms.29,30 The natural course of MC is highly variable, with some patients achieving spontaneous resolution after one episode and others developing chronic symptoms.
Diagnosis
The differential diagnosis of chronic watery diarrhea is broad and includes malabsorption/maldigestion, inflammatory bowel disease (IBD), irritable bowel syndrome, and medication side effects. In addition, although gastrointestinal infections typically cause acute or subacute diarrhea, some can present with chronic diarrhea. Malabsorption/maldigestion may occur because of CD, lactose intolerance, and pancreatic insufficiency, among other conditions. A thorough history, regarding recent antibiotic and medication use, travel, and immunosuppression, should be obtained in patients with chronic diarrhea. Additionally, laboratory and endoscopic evaluation with random biopsies of the colon can further help differentiate these diseases from MC. A few studies suggest fecal calprotectin may be used to differentiate MC from other noninflammatory conditions such as irritable bowel syndrome, as well as to monitor disease activity. This test is not expected to distinguish MC from other inflammatory causes of diarrhea, such as IBD, and therefore, its role in clinical practice is uncertain.31
The diagnosis of MC is made by biopsy of the colonic mucosa demonstrating characteristic pathologic features.32 Unlike in diseases such as Crohn’s disease or ulcerative colitis, the colon usually appears normal in MC, although mild nonspecific changes, such as erythema or edema, may be visualized. There is no consensus on the ideal location to obtain biopsies for MC or whether biopsies from both the left and the right colon are required.2,33 The procedure of choice for the diagnosis of MC is colonoscopy with random biopsies taken throughout the colon. More limited evaluation by flexible sigmoidoscopy with biopsies may miss cases of MC as inflammation and collagen thickening are not necessarily uniform throughout the colon; however, in a patient that has undergone a recent colonoscopy for colon cancer screening without colon biopsies, a flexible sigmoidoscopy may be a reasonable next test for evaluation of MC, provided biopsies are obtained above the rectosigmoid colon.34
The MC subtypes are differentiated based on histology. The hallmark of LC is less than 20 intraepithelial lymphocytes per 100 surface epithelial cells (normal, less than 5) (Figure 1A). CC is characterized by a thickened subepithelial collagen band greater than 7-10 micrometers (normal, less than 5) (Figure 1B). For a subgroup of patients with milder abnormalities that do not meet these histological criteria, the terms “microscopic colitis, not otherwise specified” or “microscopic colitis, incomplete” may be used.35 These patients often respond to standard treatments for MC. There is an additional subset of patients with biopsy demonstrating features of both CC and LC simultaneously, as well as patients transitioning from one MC subtype to another over time.32,35
Management approach
The first step in management of patients with MC includes stopping culprit medications if there is a temporal relationship between the initiation of the medication and the onset of diarrhea, as well as encouraging smoking cessation. These steps alone, however, are unlikely to achieve clinical remission in most patients. A stepwise pharmacological approach is used in the management of MC based on disease severity (Figure 2). For patients with mild symptoms, antidiarrheal medications, such as loperamide, may be helpful.36 Long-term use of loperamide at therapeutic doses no greater than 16 mg daily appears to be safe if required to maintain symptom response. For those with persistent symptoms despite antidiarrheal medications, bismuth subsalicylate at three 262 mg tablets three times daily for 6-8 weeks can be considered. Long-term use of bismuth subsalicylate is not advised, especially at this dose, because of possible neurotoxicity.37
For patients refractory to the above treatments or those with moderate-to-severe symptoms, an 8-week course of budesonide at 9 mg daily is the first-line treatment.38 The dose was tapered before discontinuation in some studies but not in others. Both strategies appear effective. A recent meta-analysis of nine randomized trials demonstrated pooled ORs of 7.34 (95% CI, 4.08-13.19) and 8.35 (95% CI, 4.14-16.85) for response to budesonide induction and maintenance, respectively.39
Cholestyramine is another medication considered in the management of MC and warrants further investigation. To date, no randomized clinical trials have been conducted to evaluate bile acid sequestrants in MC, but they should be considered before placing patients on immunosuppressive medications. Some providers use mesalamine in this setting, although mesalamine is inferior to budesonide in the induction of clinical remission in MC.40
Despite high rates of response to budesonide, relapse after discontinuation is frequent (60%-80%), and time to relapse is variable41,42 The American Gastroenterological Association recommends budesonide for maintenance of remission in patients with recurrence following discontinuation of induction therapy. The lowest effective dose that maintains resolution of symptoms should be prescribed, ideally at 6 mg daily or lower.38 Although budesonide has a greater first-pass metabolism, compared with other glucocorticoids, patients should be monitored for possible side effects including hypertension, diabetes, and osteoporosis, as well as ophthalmologic disease, including cataracts and glaucoma.
For those who are intolerant to budesonide or have refractory symptoms, concomitant disorders such as CD that may be contributing to symptoms must be excluded. Immunosuppressive medications – such as thiopurines and biologic agents, including tumor necrosis factor–alpha inhibitors or vedolizumab – may be considered in refractory cases.43,44 Of note, there are limited studies evaluating the use of these medications for MC. Lastly, surgeries including ileostomy with or without colectomy have been performed in the most severe cases for resistant disease that has failed numerous pharmacological therapies.45
Patients should be counseled that, while symptoms from MC can be quite bothersome and disabling, there appears to be a normal life expectancy and no association between MC and colon cancer, unlike with other inflammatory conditions of the colon such as IBD.46,47
Conclusion and future outlook
As a common cause of chronic watery diarrhea, MC will be commonly encountered in primary care and gastroenterology practices. The diagnosis should be suspected in patients presenting with chronic or recurrent watery diarrhea, especially with female gender, autoimmune disease, and increasing age. The management of MC requires an algorithmic approach directed by symptom severity, with a subgroup of patients requiring maintenance therapy for relapsing symptoms. The care of patients with MC will continue to evolve in the future. Further work is needed to explore long-term safety outcomes with budesonide and the role of immunomodulators and newer biologic agents for patients with complex, refractory disease.
Dr. Tome is with the department of internal medicine at the Mayo Clinic, Rochester, Minn. Dr. Kamboj, and Dr. Pardi are with the division of gastroenterology and hepatology at the Mayo Clinic. Dr. Pardi has grant funding from Pfizer, Vedanta, Seres, Finch, Applied Molecular Transport, and Takeda and has consulted for Vedanta and Otsuka. The other authors have no conflicts of interest to report.
References
1. Nyhlin N et al. Aliment Pharmacol Ther. 2014;39:963-72.
2. Miehlke S et al. United European Gastroenterol J. 2020;20-8.
3. Pardi DS et al. Gut. 2007;56:504-8.
4. Fernández-Bañares F et al. J Crohn’s Colitis.2016;10(7):805-11.
5. Gentile NM et al. Clin Gastroenterol Hepatol. 2014;12(5):838-42.
6. Tong J et al. Am J Gastroenterol. 2015;110:265-76.
7. Olesen M et al. Gut. 2004;53(3):346-50.
8. Bergman D et al. Aliment Pharmacol Ther. 2019;49(11):1395-400.
9. Guagnozzi D et al. Dig Liver Dis. 2012;44(5):384-8.
10. Münch A et al. J Crohns Colitis. 2012;6(9):932-45.
11. Macaigne G et al. Am J Gastroenterol. 2014; 09(9):1461-70.
12. Verhaegh BP et al. Aliment Pharmacol Ther. 2016;43(9):1004-13.
13. Stewart M et al. Aliment Pharmacol Ther. 2011;33(12):1340-9.
14. Green PHR et al. Clin Gastroenterol Hepatol. 2009;7(11):1210-6.
15. Masclee GM et al. Am J Gastroenterol. 2015;110:749-59.
16. Zylberberg H et al. Ailment Pharmacol Ther. 2021 Jun;53(11)1209-15.
17. Jaruvongvanich V et al. Inflamm Bowel Dis. 2019;25(4):672-8.
18. Fernández-Bañares F et al. Inflamm Bowel Dis. 2013; 19(7):1470-6.
19. Yen EF et al. Inflamm Bowel Dis. 2012;18(10):1835-41.
20. Barmeyer C et al. J Gastroenterol. 2017;52(10):1090-100.
21. Morgan DM et al. Clin Gastroenterol Hepatol. 2020;18(4):984-6.
22. Larsson JK et al. Eur J Clin Nutr. 2016;70:1309-17.
23. Madisch A et al.. Inflamm Bowel Dis. 2011;17(11):2295-8.
24. Stahl E et al. Gastroenterology. 2020;159(2):549-61.
25. Sikander A et al. Dig Dis Sci. 2015; 60:887-94.
26. Abdo AA et al. Can J Gastroenterol. 2001;15(5):341-3.
27. Fernandez-Bañares F et al. Dig Dis Sci.2001;46(10):2231-8.
28. Lyutakov I et al. Eur J Gastroenterol Hepatol. 2021;1;33(3):380-7.
29. Hjortswang H et al. Dig Liver Dis. 2011 Feb;43(2):102-9.
30. Cotter TG= et al. Gut. 2018;67(3):441-6.
31. Von Arnim U et al. Clin Exp Gastroenterol. 2016;9:97-103.
32. Langner C et al. Histopathology. 2015;66:613-26.
33. ASGE Standards of Practice Committee and Sharaf RN et al. Gastrointest Endosc. 2013;78:216-24.
34. Macaigne G et al. Clin Res Hepatol Gastroenterol. 2017;41(3):333-40.
35. Bjørnbak C et al. Aliment Pharmacol Ther. 2011;34(10):1225-34.
36. Pardi DS et al. Gastroenterology. 2016;150(1):247-74.
37. Masannat Y and Nazer E. West Virginia Med J. 2013;109(3):32-4.
38. Nguyen GC et al. Gastroenterology. 2016; 150(1):242-6.
39. Sebastian S et al. Eur J Gastroenterol Hepatol. 2019 Aug;31(8):919-27.
40. Miehlke S et al. Gastroenterology. 2014;146(5):1222-30.
41. Gentile NM et al. Am J Gastroenterol. 2013;108:256-9.
42. Münch A et al. Gut. 2016; 65(1):47-56.
43. Cotter TG et al. Aliment Pharmacol Ther. 2017; 46(2):169-74.
44. Esteve M et al. J Crohns Colitis. 2011;5(6):612-8.
45. Cottreau J et al. Clin J Gastroenterol. 2016;9:140-4.
46. Kamboj AK et al. Program No. P1876. ACG 2018 Annual Scientific Meeting Abstracts. Philadelphia, Pennsylvania: American College of Gastroenterology.
47. Yen EF et al. Dig Dis Sci. 2012;57:161-9.
Microscopic colitis is an inflammatory disease of the colon and a frequent cause of chronic or recurrent watery diarrhea, particularly in older persons. MC consists of two subtypes, collagenous colitis (CC) and lymphocytic colitis (LC). While the primary symptom is diarrhea, other signs and symptoms such as abdominal pain, weight loss, and dehydration or electrolyte abnormalities may also be present depending on disease severity.1 In MC, the colonic mucosa usually appears normal on colonoscopy, and the diagnosis is made by histologic findings of intraepithelial lymphocytosis with (CC) or without (LC) a prominent subepithelial collagen band. The management approaches to CC and LC are similar and should be directed based on the severity of symptoms.2 We review the epidemiology, risk factors, pathophysiology, diagnosis, and clinical management for this condition, as well as novel therapeutic approaches.
Epidemiology
Although the incidence of MC increased in the late twentieth century, more recently, it has stabilized with an estimated incidence varying from 1 to 25 per 100,000 person-years.3-5 A recent meta-analysis revealed a pooled incidence of 4.85 per 100,000 persons for LC and 4.14 per 100,000 persons for CC.6 Proposed explanations for the rising incidence in the late twentieth century include improved clinical awareness of the disease, possible increased use of drugs associated with MC, and increased performance of diagnostic colonoscopies for chronic diarrhea. Since MC is now well-recognized, the recent plateau in incidence rates may reflect decreased detection bias.
The prevalence of MC ranges from 10%-20% in patients undergoing colonoscopy for chronic watery diarrhea.6,7 The prevalence of LC is approximately 63.1 cases per 100,000 person-years and, for CC, is 49.2 cases per 100,000 person-years.6-8 Recent studies have demonstrated increasing prevalence of MC likely resulting from an aging population.9,10
Risk stratification
Female gender, increasing age, concomitant autoimmune disease, and the use of certain drugs, including NSAIDs, proton pump inhibitors (PPIs), statins, and selective serotonin reuptake inhibitors (SSRIs), have been associated with an increased risk of MC.11,12 Autoimmune disorders, including celiac disease (CD), rheumatoid arthritis, hypothyroidism, and hyperthyroidism, are more common in patients with MC. The association with CD, in particular, is clinically important, as CD is associated with a 50-70 times greater risk of MC, and 2%-9% of patients with MC have CD.13,14
Several medications have been associated with MC. In a British multicenter prospective study, MC was associated with the use of NSAIDs, PPIs, and SSRIs;15 however, recent studies have questioned the association of MC with some of these medications, which might worsen diarrhea but not actually cause MC.16
An additional risk factor for MC is smoking. A recent meta-analysis demonstrated that current and former smokers had an increased risk of MC (odds ratio, 2.99; 95% confidence interval, 2.15-4.15 and OR, 1.63; 95% CI, 1.37-1.94, respectively), compared with nonsmokers.17 Smokers develop MC at a younger age, and smoking is associated with increased disease severity and decreased likelihood of attaining remission.18,19
Pathogenesis
The pathogenesis of MC remains largely unknown, although there are several hypotheses. The leading proposed mechanisms include reaction to luminal antigens, dysregulated collagen metabolism, genetic predisposition, autoimmunity, and bile acid malabsorption.
MC may be caused by abnormal epithelial barrier function, leading to increased permeability and reaction to luminal antigens, including dietary antigens, certain drugs, and bacterial products, 20,21 which themselves lead to the immune dysregulation and intestinal inflammation seen in MC. This mechanism may explain the association of several drugs with MC. Histological changes resembling LC are reported in patients with CD who consume gluten; however, large population-based studies have not found specific dietary associations with the development of MC.22
Another potential mechanism of MC is dysregulated collagen deposition. Collagen accumulation in the subepithelial layer in CC may result from increased levels of fibroblast growth factor, transforming growth factor–beta and vascular endothelial growth factor.23 Nonetheless, studies have not found an association between the severity of diarrhea in patients with CC and the thickness of the subepithelial collagen band.
Thirdly, autoimmunity and genetic predisposition have been postulated in the pathogenesis of MC. As previously discussed, MC is associated with several autoimmune diseases and predominantly occurs in women, a distinctive feature of autoimmune disorders. Several studies have demonstrated an association between MC and HLA-DQ2 and -DQ3 haplotypes,24 as well as potential polymorphisms in the serotonin transporter gene promoter.25 It is important to note, however, that only a few familial cases of MC have been reported to date.26
Lastly, bile acid malabsorption may play a role in the etiology of MC. Histologic findings of inflammation, along with villous atrophy and collagen deposition, have been reported in the ileum of patients with MC;27,28 however, because patients with MC without bile acid malabsorption may also respond to bile acid binders such as cholestyramine, these findings unlikely to be the sole mechanism explaining the development of the disease.
Despite the different proposed mechanisms for the pathogenesis of MC, no definite conclusions can be drawn because of the limited size of these studies and their often conflicting results.
Clinical features
Clinicians should suspect MC in patients with chronic or recurrent watery diarrhea, particularly in older persons. Other risk factors include female gender, use of certain culprit medications, smoking, and presence of other autoimmune diseases. The clinical manifestations of MC subtypes LC and CC are similar with no significant clinical differences.1,2 In addition to diarrhea, patients with MC may have abdominal pain, fatigue, and dehydration or electrolyte abnormalities depending on disease severity. Patients may also present with fecal urgency, incontinence, and nocturnal stools. Quality of life is often reduced in these patients, predominantly in those with severe or refractory symptoms.29,30 The natural course of MC is highly variable, with some patients achieving spontaneous resolution after one episode and others developing chronic symptoms.
Diagnosis
The differential diagnosis of chronic watery diarrhea is broad and includes malabsorption/maldigestion, inflammatory bowel disease (IBD), irritable bowel syndrome, and medication side effects. In addition, although gastrointestinal infections typically cause acute or subacute diarrhea, some can present with chronic diarrhea. Malabsorption/maldigestion may occur because of CD, lactose intolerance, and pancreatic insufficiency, among other conditions. A thorough history, regarding recent antibiotic and medication use, travel, and immunosuppression, should be obtained in patients with chronic diarrhea. Additionally, laboratory and endoscopic evaluation with random biopsies of the colon can further help differentiate these diseases from MC. A few studies suggest fecal calprotectin may be used to differentiate MC from other noninflammatory conditions such as irritable bowel syndrome, as well as to monitor disease activity. This test is not expected to distinguish MC from other inflammatory causes of diarrhea, such as IBD, and therefore, its role in clinical practice is uncertain.31
The diagnosis of MC is made by biopsy of the colonic mucosa demonstrating characteristic pathologic features.32 Unlike in diseases such as Crohn’s disease or ulcerative colitis, the colon usually appears normal in MC, although mild nonspecific changes, such as erythema or edema, may be visualized. There is no consensus on the ideal location to obtain biopsies for MC or whether biopsies from both the left and the right colon are required.2,33 The procedure of choice for the diagnosis of MC is colonoscopy with random biopsies taken throughout the colon. More limited evaluation by flexible sigmoidoscopy with biopsies may miss cases of MC as inflammation and collagen thickening are not necessarily uniform throughout the colon; however, in a patient that has undergone a recent colonoscopy for colon cancer screening without colon biopsies, a flexible sigmoidoscopy may be a reasonable next test for evaluation of MC, provided biopsies are obtained above the rectosigmoid colon.34
The MC subtypes are differentiated based on histology. The hallmark of LC is less than 20 intraepithelial lymphocytes per 100 surface epithelial cells (normal, less than 5) (Figure 1A). CC is characterized by a thickened subepithelial collagen band greater than 7-10 micrometers (normal, less than 5) (Figure 1B). For a subgroup of patients with milder abnormalities that do not meet these histological criteria, the terms “microscopic colitis, not otherwise specified” or “microscopic colitis, incomplete” may be used.35 These patients often respond to standard treatments for MC. There is an additional subset of patients with biopsy demonstrating features of both CC and LC simultaneously, as well as patients transitioning from one MC subtype to another over time.32,35
Management approach
The first step in management of patients with MC includes stopping culprit medications if there is a temporal relationship between the initiation of the medication and the onset of diarrhea, as well as encouraging smoking cessation. These steps alone, however, are unlikely to achieve clinical remission in most patients. A stepwise pharmacological approach is used in the management of MC based on disease severity (Figure 2). For patients with mild symptoms, antidiarrheal medications, such as loperamide, may be helpful.36 Long-term use of loperamide at therapeutic doses no greater than 16 mg daily appears to be safe if required to maintain symptom response. For those with persistent symptoms despite antidiarrheal medications, bismuth subsalicylate at three 262 mg tablets three times daily for 6-8 weeks can be considered. Long-term use of bismuth subsalicylate is not advised, especially at this dose, because of possible neurotoxicity.37
For patients refractory to the above treatments or those with moderate-to-severe symptoms, an 8-week course of budesonide at 9 mg daily is the first-line treatment.38 The dose was tapered before discontinuation in some studies but not in others. Both strategies appear effective. A recent meta-analysis of nine randomized trials demonstrated pooled ORs of 7.34 (95% CI, 4.08-13.19) and 8.35 (95% CI, 4.14-16.85) for response to budesonide induction and maintenance, respectively.39
Cholestyramine is another medication considered in the management of MC and warrants further investigation. To date, no randomized clinical trials have been conducted to evaluate bile acid sequestrants in MC, but they should be considered before placing patients on immunosuppressive medications. Some providers use mesalamine in this setting, although mesalamine is inferior to budesonide in the induction of clinical remission in MC.40
Despite high rates of response to budesonide, relapse after discontinuation is frequent (60%-80%), and time to relapse is variable41,42 The American Gastroenterological Association recommends budesonide for maintenance of remission in patients with recurrence following discontinuation of induction therapy. The lowest effective dose that maintains resolution of symptoms should be prescribed, ideally at 6 mg daily or lower.38 Although budesonide has a greater first-pass metabolism, compared with other glucocorticoids, patients should be monitored for possible side effects including hypertension, diabetes, and osteoporosis, as well as ophthalmologic disease, including cataracts and glaucoma.
For those who are intolerant to budesonide or have refractory symptoms, concomitant disorders such as CD that may be contributing to symptoms must be excluded. Immunosuppressive medications – such as thiopurines and biologic agents, including tumor necrosis factor–alpha inhibitors or vedolizumab – may be considered in refractory cases.43,44 Of note, there are limited studies evaluating the use of these medications for MC. Lastly, surgeries including ileostomy with or without colectomy have been performed in the most severe cases for resistant disease that has failed numerous pharmacological therapies.45
Patients should be counseled that, while symptoms from MC can be quite bothersome and disabling, there appears to be a normal life expectancy and no association between MC and colon cancer, unlike with other inflammatory conditions of the colon such as IBD.46,47
Conclusion and future outlook
As a common cause of chronic watery diarrhea, MC will be commonly encountered in primary care and gastroenterology practices. The diagnosis should be suspected in patients presenting with chronic or recurrent watery diarrhea, especially with female gender, autoimmune disease, and increasing age. The management of MC requires an algorithmic approach directed by symptom severity, with a subgroup of patients requiring maintenance therapy for relapsing symptoms. The care of patients with MC will continue to evolve in the future. Further work is needed to explore long-term safety outcomes with budesonide and the role of immunomodulators and newer biologic agents for patients with complex, refractory disease.
Dr. Tome is with the department of internal medicine at the Mayo Clinic, Rochester, Minn. Dr. Kamboj, and Dr. Pardi are with the division of gastroenterology and hepatology at the Mayo Clinic. Dr. Pardi has grant funding from Pfizer, Vedanta, Seres, Finch, Applied Molecular Transport, and Takeda and has consulted for Vedanta and Otsuka. The other authors have no conflicts of interest to report.
References
1. Nyhlin N et al. Aliment Pharmacol Ther. 2014;39:963-72.
2. Miehlke S et al. United European Gastroenterol J. 2020;20-8.
3. Pardi DS et al. Gut. 2007;56:504-8.
4. Fernández-Bañares F et al. J Crohn’s Colitis.2016;10(7):805-11.
5. Gentile NM et al. Clin Gastroenterol Hepatol. 2014;12(5):838-42.
6. Tong J et al. Am J Gastroenterol. 2015;110:265-76.
7. Olesen M et al. Gut. 2004;53(3):346-50.
8. Bergman D et al. Aliment Pharmacol Ther. 2019;49(11):1395-400.
9. Guagnozzi D et al. Dig Liver Dis. 2012;44(5):384-8.
10. Münch A et al. J Crohns Colitis. 2012;6(9):932-45.
11. Macaigne G et al. Am J Gastroenterol. 2014; 09(9):1461-70.
12. Verhaegh BP et al. Aliment Pharmacol Ther. 2016;43(9):1004-13.
13. Stewart M et al. Aliment Pharmacol Ther. 2011;33(12):1340-9.
14. Green PHR et al. Clin Gastroenterol Hepatol. 2009;7(11):1210-6.
15. Masclee GM et al. Am J Gastroenterol. 2015;110:749-59.
16. Zylberberg H et al. Ailment Pharmacol Ther. 2021 Jun;53(11)1209-15.
17. Jaruvongvanich V et al. Inflamm Bowel Dis. 2019;25(4):672-8.
18. Fernández-Bañares F et al. Inflamm Bowel Dis. 2013; 19(7):1470-6.
19. Yen EF et al. Inflamm Bowel Dis. 2012;18(10):1835-41.
20. Barmeyer C et al. J Gastroenterol. 2017;52(10):1090-100.
21. Morgan DM et al. Clin Gastroenterol Hepatol. 2020;18(4):984-6.
22. Larsson JK et al. Eur J Clin Nutr. 2016;70:1309-17.
23. Madisch A et al.. Inflamm Bowel Dis. 2011;17(11):2295-8.
24. Stahl E et al. Gastroenterology. 2020;159(2):549-61.
25. Sikander A et al. Dig Dis Sci. 2015; 60:887-94.
26. Abdo AA et al. Can J Gastroenterol. 2001;15(5):341-3.
27. Fernandez-Bañares F et al. Dig Dis Sci.2001;46(10):2231-8.
28. Lyutakov I et al. Eur J Gastroenterol Hepatol. 2021;1;33(3):380-7.
29. Hjortswang H et al. Dig Liver Dis. 2011 Feb;43(2):102-9.
30. Cotter TG= et al. Gut. 2018;67(3):441-6.
31. Von Arnim U et al. Clin Exp Gastroenterol. 2016;9:97-103.
32. Langner C et al. Histopathology. 2015;66:613-26.
33. ASGE Standards of Practice Committee and Sharaf RN et al. Gastrointest Endosc. 2013;78:216-24.
34. Macaigne G et al. Clin Res Hepatol Gastroenterol. 2017;41(3):333-40.
35. Bjørnbak C et al. Aliment Pharmacol Ther. 2011;34(10):1225-34.
36. Pardi DS et al. Gastroenterology. 2016;150(1):247-74.
37. Masannat Y and Nazer E. West Virginia Med J. 2013;109(3):32-4.
38. Nguyen GC et al. Gastroenterology. 2016; 150(1):242-6.
39. Sebastian S et al. Eur J Gastroenterol Hepatol. 2019 Aug;31(8):919-27.
40. Miehlke S et al. Gastroenterology. 2014;146(5):1222-30.
41. Gentile NM et al. Am J Gastroenterol. 2013;108:256-9.
42. Münch A et al. Gut. 2016; 65(1):47-56.
43. Cotter TG et al. Aliment Pharmacol Ther. 2017; 46(2):169-74.
44. Esteve M et al. J Crohns Colitis. 2011;5(6):612-8.
45. Cottreau J et al. Clin J Gastroenterol. 2016;9:140-4.
46. Kamboj AK et al. Program No. P1876. ACG 2018 Annual Scientific Meeting Abstracts. Philadelphia, Pennsylvania: American College of Gastroenterology.
47. Yen EF et al. Dig Dis Sci. 2012;57:161-9.
Microscopic colitis is an inflammatory disease of the colon and a frequent cause of chronic or recurrent watery diarrhea, particularly in older persons. MC consists of two subtypes, collagenous colitis (CC) and lymphocytic colitis (LC). While the primary symptom is diarrhea, other signs and symptoms such as abdominal pain, weight loss, and dehydration or electrolyte abnormalities may also be present depending on disease severity.1 In MC, the colonic mucosa usually appears normal on colonoscopy, and the diagnosis is made by histologic findings of intraepithelial lymphocytosis with (CC) or without (LC) a prominent subepithelial collagen band. The management approaches to CC and LC are similar and should be directed based on the severity of symptoms.2 We review the epidemiology, risk factors, pathophysiology, diagnosis, and clinical management for this condition, as well as novel therapeutic approaches.
Epidemiology
Although the incidence of MC increased in the late twentieth century, more recently, it has stabilized with an estimated incidence varying from 1 to 25 per 100,000 person-years.3-5 A recent meta-analysis revealed a pooled incidence of 4.85 per 100,000 persons for LC and 4.14 per 100,000 persons for CC.6 Proposed explanations for the rising incidence in the late twentieth century include improved clinical awareness of the disease, possible increased use of drugs associated with MC, and increased performance of diagnostic colonoscopies for chronic diarrhea. Since MC is now well-recognized, the recent plateau in incidence rates may reflect decreased detection bias.
The prevalence of MC ranges from 10%-20% in patients undergoing colonoscopy for chronic watery diarrhea.6,7 The prevalence of LC is approximately 63.1 cases per 100,000 person-years and, for CC, is 49.2 cases per 100,000 person-years.6-8 Recent studies have demonstrated increasing prevalence of MC likely resulting from an aging population.9,10
Risk stratification
Female gender, increasing age, concomitant autoimmune disease, and the use of certain drugs, including NSAIDs, proton pump inhibitors (PPIs), statins, and selective serotonin reuptake inhibitors (SSRIs), have been associated with an increased risk of MC.11,12 Autoimmune disorders, including celiac disease (CD), rheumatoid arthritis, hypothyroidism, and hyperthyroidism, are more common in patients with MC. The association with CD, in particular, is clinically important, as CD is associated with a 50-70 times greater risk of MC, and 2%-9% of patients with MC have CD.13,14
Several medications have been associated with MC. In a British multicenter prospective study, MC was associated with the use of NSAIDs, PPIs, and SSRIs;15 however, recent studies have questioned the association of MC with some of these medications, which might worsen diarrhea but not actually cause MC.16
An additional risk factor for MC is smoking. A recent meta-analysis demonstrated that current and former smokers had an increased risk of MC (odds ratio, 2.99; 95% confidence interval, 2.15-4.15 and OR, 1.63; 95% CI, 1.37-1.94, respectively), compared with nonsmokers.17 Smokers develop MC at a younger age, and smoking is associated with increased disease severity and decreased likelihood of attaining remission.18,19
Pathogenesis
The pathogenesis of MC remains largely unknown, although there are several hypotheses. The leading proposed mechanisms include reaction to luminal antigens, dysregulated collagen metabolism, genetic predisposition, autoimmunity, and bile acid malabsorption.
MC may be caused by abnormal epithelial barrier function, leading to increased permeability and reaction to luminal antigens, including dietary antigens, certain drugs, and bacterial products, 20,21 which themselves lead to the immune dysregulation and intestinal inflammation seen in MC. This mechanism may explain the association of several drugs with MC. Histological changes resembling LC are reported in patients with CD who consume gluten; however, large population-based studies have not found specific dietary associations with the development of MC.22
Another potential mechanism of MC is dysregulated collagen deposition. Collagen accumulation in the subepithelial layer in CC may result from increased levels of fibroblast growth factor, transforming growth factor–beta and vascular endothelial growth factor.23 Nonetheless, studies have not found an association between the severity of diarrhea in patients with CC and the thickness of the subepithelial collagen band.
Thirdly, autoimmunity and genetic predisposition have been postulated in the pathogenesis of MC. As previously discussed, MC is associated with several autoimmune diseases and predominantly occurs in women, a distinctive feature of autoimmune disorders. Several studies have demonstrated an association between MC and HLA-DQ2 and -DQ3 haplotypes,24 as well as potential polymorphisms in the serotonin transporter gene promoter.25 It is important to note, however, that only a few familial cases of MC have been reported to date.26
Lastly, bile acid malabsorption may play a role in the etiology of MC. Histologic findings of inflammation, along with villous atrophy and collagen deposition, have been reported in the ileum of patients with MC;27,28 however, because patients with MC without bile acid malabsorption may also respond to bile acid binders such as cholestyramine, these findings unlikely to be the sole mechanism explaining the development of the disease.
Despite the different proposed mechanisms for the pathogenesis of MC, no definite conclusions can be drawn because of the limited size of these studies and their often conflicting results.
Clinical features
Clinicians should suspect MC in patients with chronic or recurrent watery diarrhea, particularly in older persons. Other risk factors include female gender, use of certain culprit medications, smoking, and presence of other autoimmune diseases. The clinical manifestations of MC subtypes LC and CC are similar with no significant clinical differences.1,2 In addition to diarrhea, patients with MC may have abdominal pain, fatigue, and dehydration or electrolyte abnormalities depending on disease severity. Patients may also present with fecal urgency, incontinence, and nocturnal stools. Quality of life is often reduced in these patients, predominantly in those with severe or refractory symptoms.29,30 The natural course of MC is highly variable, with some patients achieving spontaneous resolution after one episode and others developing chronic symptoms.
Diagnosis
The differential diagnosis of chronic watery diarrhea is broad and includes malabsorption/maldigestion, inflammatory bowel disease (IBD), irritable bowel syndrome, and medication side effects. In addition, although gastrointestinal infections typically cause acute or subacute diarrhea, some can present with chronic diarrhea. Malabsorption/maldigestion may occur because of CD, lactose intolerance, and pancreatic insufficiency, among other conditions. A thorough history, regarding recent antibiotic and medication use, travel, and immunosuppression, should be obtained in patients with chronic diarrhea. Additionally, laboratory and endoscopic evaluation with random biopsies of the colon can further help differentiate these diseases from MC. A few studies suggest fecal calprotectin may be used to differentiate MC from other noninflammatory conditions such as irritable bowel syndrome, as well as to monitor disease activity. This test is not expected to distinguish MC from other inflammatory causes of diarrhea, such as IBD, and therefore, its role in clinical practice is uncertain.31
The diagnosis of MC is made by biopsy of the colonic mucosa demonstrating characteristic pathologic features.32 Unlike in diseases such as Crohn’s disease or ulcerative colitis, the colon usually appears normal in MC, although mild nonspecific changes, such as erythema or edema, may be visualized. There is no consensus on the ideal location to obtain biopsies for MC or whether biopsies from both the left and the right colon are required.2,33 The procedure of choice for the diagnosis of MC is colonoscopy with random biopsies taken throughout the colon. More limited evaluation by flexible sigmoidoscopy with biopsies may miss cases of MC as inflammation and collagen thickening are not necessarily uniform throughout the colon; however, in a patient that has undergone a recent colonoscopy for colon cancer screening without colon biopsies, a flexible sigmoidoscopy may be a reasonable next test for evaluation of MC, provided biopsies are obtained above the rectosigmoid colon.34
The MC subtypes are differentiated based on histology. The hallmark of LC is less than 20 intraepithelial lymphocytes per 100 surface epithelial cells (normal, less than 5) (Figure 1A). CC is characterized by a thickened subepithelial collagen band greater than 7-10 micrometers (normal, less than 5) (Figure 1B). For a subgroup of patients with milder abnormalities that do not meet these histological criteria, the terms “microscopic colitis, not otherwise specified” or “microscopic colitis, incomplete” may be used.35 These patients often respond to standard treatments for MC. There is an additional subset of patients with biopsy demonstrating features of both CC and LC simultaneously, as well as patients transitioning from one MC subtype to another over time.32,35
Management approach
The first step in management of patients with MC includes stopping culprit medications if there is a temporal relationship between the initiation of the medication and the onset of diarrhea, as well as encouraging smoking cessation. These steps alone, however, are unlikely to achieve clinical remission in most patients. A stepwise pharmacological approach is used in the management of MC based on disease severity (Figure 2). For patients with mild symptoms, antidiarrheal medications, such as loperamide, may be helpful.36 Long-term use of loperamide at therapeutic doses no greater than 16 mg daily appears to be safe if required to maintain symptom response. For those with persistent symptoms despite antidiarrheal medications, bismuth subsalicylate at three 262 mg tablets three times daily for 6-8 weeks can be considered. Long-term use of bismuth subsalicylate is not advised, especially at this dose, because of possible neurotoxicity.37
For patients refractory to the above treatments or those with moderate-to-severe symptoms, an 8-week course of budesonide at 9 mg daily is the first-line treatment.38 The dose was tapered before discontinuation in some studies but not in others. Both strategies appear effective. A recent meta-analysis of nine randomized trials demonstrated pooled ORs of 7.34 (95% CI, 4.08-13.19) and 8.35 (95% CI, 4.14-16.85) for response to budesonide induction and maintenance, respectively.39
Cholestyramine is another medication considered in the management of MC and warrants further investigation. To date, no randomized clinical trials have been conducted to evaluate bile acid sequestrants in MC, but they should be considered before placing patients on immunosuppressive medications. Some providers use mesalamine in this setting, although mesalamine is inferior to budesonide in the induction of clinical remission in MC.40
Despite high rates of response to budesonide, relapse after discontinuation is frequent (60%-80%), and time to relapse is variable41,42 The American Gastroenterological Association recommends budesonide for maintenance of remission in patients with recurrence following discontinuation of induction therapy. The lowest effective dose that maintains resolution of symptoms should be prescribed, ideally at 6 mg daily or lower.38 Although budesonide has a greater first-pass metabolism, compared with other glucocorticoids, patients should be monitored for possible side effects including hypertension, diabetes, and osteoporosis, as well as ophthalmologic disease, including cataracts and glaucoma.
For those who are intolerant to budesonide or have refractory symptoms, concomitant disorders such as CD that may be contributing to symptoms must be excluded. Immunosuppressive medications – such as thiopurines and biologic agents, including tumor necrosis factor–alpha inhibitors or vedolizumab – may be considered in refractory cases.43,44 Of note, there are limited studies evaluating the use of these medications for MC. Lastly, surgeries including ileostomy with or without colectomy have been performed in the most severe cases for resistant disease that has failed numerous pharmacological therapies.45
Patients should be counseled that, while symptoms from MC can be quite bothersome and disabling, there appears to be a normal life expectancy and no association between MC and colon cancer, unlike with other inflammatory conditions of the colon such as IBD.46,47
Conclusion and future outlook
As a common cause of chronic watery diarrhea, MC will be commonly encountered in primary care and gastroenterology practices. The diagnosis should be suspected in patients presenting with chronic or recurrent watery diarrhea, especially with female gender, autoimmune disease, and increasing age. The management of MC requires an algorithmic approach directed by symptom severity, with a subgroup of patients requiring maintenance therapy for relapsing symptoms. The care of patients with MC will continue to evolve in the future. Further work is needed to explore long-term safety outcomes with budesonide and the role of immunomodulators and newer biologic agents for patients with complex, refractory disease.
Dr. Tome is with the department of internal medicine at the Mayo Clinic, Rochester, Minn. Dr. Kamboj, and Dr. Pardi are with the division of gastroenterology and hepatology at the Mayo Clinic. Dr. Pardi has grant funding from Pfizer, Vedanta, Seres, Finch, Applied Molecular Transport, and Takeda and has consulted for Vedanta and Otsuka. The other authors have no conflicts of interest to report.
References
1. Nyhlin N et al. Aliment Pharmacol Ther. 2014;39:963-72.
2. Miehlke S et al. United European Gastroenterol J. 2020;20-8.
3. Pardi DS et al. Gut. 2007;56:504-8.
4. Fernández-Bañares F et al. J Crohn’s Colitis.2016;10(7):805-11.
5. Gentile NM et al. Clin Gastroenterol Hepatol. 2014;12(5):838-42.
6. Tong J et al. Am J Gastroenterol. 2015;110:265-76.
7. Olesen M et al. Gut. 2004;53(3):346-50.
8. Bergman D et al. Aliment Pharmacol Ther. 2019;49(11):1395-400.
9. Guagnozzi D et al. Dig Liver Dis. 2012;44(5):384-8.
10. Münch A et al. J Crohns Colitis. 2012;6(9):932-45.
11. Macaigne G et al. Am J Gastroenterol. 2014; 09(9):1461-70.
12. Verhaegh BP et al. Aliment Pharmacol Ther. 2016;43(9):1004-13.
13. Stewart M et al. Aliment Pharmacol Ther. 2011;33(12):1340-9.
14. Green PHR et al. Clin Gastroenterol Hepatol. 2009;7(11):1210-6.
15. Masclee GM et al. Am J Gastroenterol. 2015;110:749-59.
16. Zylberberg H et al. Ailment Pharmacol Ther. 2021 Jun;53(11)1209-15.
17. Jaruvongvanich V et al. Inflamm Bowel Dis. 2019;25(4):672-8.
18. Fernández-Bañares F et al. Inflamm Bowel Dis. 2013; 19(7):1470-6.
19. Yen EF et al. Inflamm Bowel Dis. 2012;18(10):1835-41.
20. Barmeyer C et al. J Gastroenterol. 2017;52(10):1090-100.
21. Morgan DM et al. Clin Gastroenterol Hepatol. 2020;18(4):984-6.
22. Larsson JK et al. Eur J Clin Nutr. 2016;70:1309-17.
23. Madisch A et al.. Inflamm Bowel Dis. 2011;17(11):2295-8.
24. Stahl E et al. Gastroenterology. 2020;159(2):549-61.
25. Sikander A et al. Dig Dis Sci. 2015; 60:887-94.
26. Abdo AA et al. Can J Gastroenterol. 2001;15(5):341-3.
27. Fernandez-Bañares F et al. Dig Dis Sci.2001;46(10):2231-8.
28. Lyutakov I et al. Eur J Gastroenterol Hepatol. 2021;1;33(3):380-7.
29. Hjortswang H et al. Dig Liver Dis. 2011 Feb;43(2):102-9.
30. Cotter TG= et al. Gut. 2018;67(3):441-6.
31. Von Arnim U et al. Clin Exp Gastroenterol. 2016;9:97-103.
32. Langner C et al. Histopathology. 2015;66:613-26.
33. ASGE Standards of Practice Committee and Sharaf RN et al. Gastrointest Endosc. 2013;78:216-24.
34. Macaigne G et al. Clin Res Hepatol Gastroenterol. 2017;41(3):333-40.
35. Bjørnbak C et al. Aliment Pharmacol Ther. 2011;34(10):1225-34.
36. Pardi DS et al. Gastroenterology. 2016;150(1):247-74.
37. Masannat Y and Nazer E. West Virginia Med J. 2013;109(3):32-4.
38. Nguyen GC et al. Gastroenterology. 2016; 150(1):242-6.
39. Sebastian S et al. Eur J Gastroenterol Hepatol. 2019 Aug;31(8):919-27.
40. Miehlke S et al. Gastroenterology. 2014;146(5):1222-30.
41. Gentile NM et al. Am J Gastroenterol. 2013;108:256-9.
42. Münch A et al. Gut. 2016; 65(1):47-56.
43. Cotter TG et al. Aliment Pharmacol Ther. 2017; 46(2):169-74.
44. Esteve M et al. J Crohns Colitis. 2011;5(6):612-8.
45. Cottreau J et al. Clin J Gastroenterol. 2016;9:140-4.
46. Kamboj AK et al. Program No. P1876. ACG 2018 Annual Scientific Meeting Abstracts. Philadelphia, Pennsylvania: American College of Gastroenterology.
47. Yen EF et al. Dig Dis Sci. 2012;57:161-9.
Dyssynergic defecation
Introduction
About 40% of the population experiences lower GI symptoms suggestive of gastrointestinal motility disorders.1,2 The global prevalence of chronic constipation is 18%, and the condition includes multiple overlapping subtypes.3 Evacuation disorders affect over half (59%) of patients and include dyssynergic defecation (DD).4 The inability to coordinate the abdominal, rectal, pelvic floor, and anal/puborectalis muscles to evacuate stools causes DD.5 The etiology of DD remains unclear and is often misdiagnosed. Clinically, the symptoms of DD overlap with other lower GI disorders, often leading to unnecessary and invasive procedures.2 We describe the clinical characteristics, diagnostic tools, treatment options, and evidence-based approach for the management of DD.
Clinical presentation
Over two-thirds of patients with DD acquire this disorder during adulthood, and one-third have symptoms from childhood.6 Though there is not usually an inciting event, 29% of patients report that symptoms began after events such as pregnancy or back injury,6 and opioid users have higher prevalence and severity of DD.7
Over 80% of patients report excessive straining, feelings of incomplete evacuation, and hard stools, and 50% report sensation of anal blockage or use of digital maneuvers.2 Other symptoms include infrequent bowel movements, abdominal pain, anal pain, and stool leakage.2 Evaluation of DD includes obtaining a detailed history utilizing the Bristol Stool Form Scale;8 however, patients’ recall of stool habit is often inaccurate, which results in suboptimal care.9,10 Prospective stool diaries can help to provide more objective assessment of patients’ symptoms, eliminate recall bias, and provide more reliable information. Several useful questionnaires are available for clinical and research purposes to characterize lower-GI symptoms, including the Constipation Scoring System,11 Patient Assessment of Constipation Symptoms (PAC-SYM),12 and Patient Assessment of Constipation Quality of Life (PAC-QOL).2,13 The Constipation Stool digital app enhances accuracy of data capture and offers a reliable and user-friendly method for recording bowel symptoms for patients, clinicians, and clinical investigators.14
Diagnosis
The diagnosis of DD requires careful physical and digital rectal examination together with anorectal manometry and a balloon expulsion test. Defecography and colonic transit studies provide additional assessment.
Physical examination
Abdominal examination should include palpation for stool in the colon and identification of abdominal mass or fecal impaction.2A high-quality digital rectal examination can help to identify patients who could benefit from physiological testing to confirm and treat DD.15 Rectal examination is performed by placing examiner’s lubricated gloved right index finger in a patient’s rectum, with the examiner’s left hand on patient’s abdomen, and asking the patient to push and bear down as if defecating.15 The contraction of the abdominal muscles is felt using the left hand, while the anal sphincter relaxation and degree of perineal descent are felt using the right-hand index finger.15 A diagnosis of dyssynergia is suspected if the digital rectal examination reveals two or more of the following abnormalities: inability to contract abdominal muscles (lack of push effort), inability to relax or paradoxical contraction of the anal sphincter and/or puborectalis, or absence of perineal descent.15 Digital rectal examination has good sensitivity (75%), specificity (87%), and positive predictive value (97%) for DD.16
High resolution anorectal manometry
Anorectal manometry (ARM) is the preferred method for the evaluation of defecatory disorders.17,18 ARM is best performed using the high-resolution anorectal manometry (HRAM) systems19 that consist of a flexible probe – 0.5-cm diameter with multiple circumferential sensors along the anal canal – and another two sensors inside a rectal balloon.18 It provides a topographic and waveform display of manometric pressure data (Figure). The 3D high-definition ARM probe is a rigid 1-cm probe that provides 3D topographic profiles.18 ARM is typically performed in both the left lateral position and in a more physiological seated position.20,21 There is considerable variation amongst different institutions on how to perform HRAM, and a recent International Anorectal Physiology Working Group (IAPWG) has provided consensus recommendations for performing this test.22 The procedure for performing HRAM is reviewed elsewhere, but the key elements are summarized below.18
Push maneuver: On HRAM, after the assessment of resting and squeeze anal sphincter pressures, the patient is asked to push or bear down as if to defecate while lying in left lateral decubitus position. The best of two attempts that closely mimics a normal bearing down maneuver is used for categorizing patient’s defecatory pattern.18 In patients with DD, at least four distinct dyssynergia phenotypes have been recognized (Figure),23 though recent studies suggest eight patterns.24 Defecation index (maximum rectal pressure/minimum residual anal pressure when bearing down) greater than 1.2 is considered normal.18
Simulated defecation on commode: The subject is asked to attempt defecation while seated on a commode with intrarectal balloon filled with 60 cc of air, and both the defecation pattern(s) and defecation index are calculated. A lack of coordinated push effort is highly suggestive of DD.21
Rectoanal Inhibitory Reflex (RAIR): RAIR describes the reflex relaxation of the internal anal sphincter after rectal distension. RAIR is dependent on intact autonomic ganglia and myenteric plexus25and is mediated by the release of nitric oxide and vasoactive intestinal peptide.26 The absence of RAIR suggests Hirschsprung disease.22.27.28
Rectal sensory testing: Intermittent balloon distension of the rectum with incremental volumes of air induces a range of rectal sensations that include first sensation, desire to defecate, urgency to defecate, and maximum tolerable volume. Rectal hyposensitivity is diagnosed when two or more sensory thresholds are higher than those seen in normal subjects29.30 and likely results from disruption of afferent gut-brain pathways, cortical perception/rectal wall dysfunction, or both.29 Rectal hyposensitivity affects 40% of patients with constipation30and is associated with DD but not delayed colonic transit.31 Rectal hyposensitivity may also be seen in patients with diabetes or fecal incontinence.18 About two-thirds of patients with rectal hyposensitivity have rectal hypercompliance, and some have megarectum.32 Some patients with DD have coexisting irritable bowel syndrome (IBS) and may have rectal hypersensitivity.18,33 Rectal compliance is measured alongside rectal sensitivity analysis by plotting a graph between the change in intraballoon volume (mL) and change in intrarectal pressures (mm Hg) during incremental balloon distensions.18.34 Rectal hypercompliance may be seen in megarectum and dyssynergic defecation.34,35 Rectal hypocompliance may be seen in patients with inflammatory bowel disease, postpelvic radiation, chronic ischemia, and advanced age.18
Balloon expulsion test: This test is performed by placing a plastic probe with a balloon in the rectum and filling it with 50 cc of warm water. Patients are given 5 minutes to expel the balloon while sitting on a commode. Balloon expulsion time of more than 1 minute suggests a diagnosis of DD,21 although 2 minutes provides a higher level of agreement with manometric findings.36 Balloon type and body position can influence the results.37 Inability to expel the balloon with normal manometric findings is considered an inconclusive finding per the recent London Classification (i.e., it may be associated with generation of anorectal symptoms, but the clinical relevance of this finding is unclear as it may also be seen in healthy subjects).22
Defecography
Defecography is a dynamic fluoroscopic study performed in the sitting position after injecting 150 mL of barium paste into the patient’s rectum. Defecography provides useful information about structural changes (e.g., rectoceles, enteroceles, rectal prolapse, and intussusception), DD, and descending perineum syndrome.38 Methodological differences, radiation exposure, and poor interobserver agreement have limited its wider use; therefore, anorectal manometry and the balloon expulsion test are recommended for the initial evaluation of DD.39 Magnetic resonance defecography may be more useful.17,38
Colonic transit studies
Colonic transit study can be assessed using radiopaque markers, wireless motility capsule, or scintigraphy. Wireless motility capsule and scintigraphy have the advantage of determining gastric, small bowel, and whole gut transit times as well. About two-thirds of patients with DD have slow transit constipation (STC),6 which improves after treatment of DD.40 Hence, in patients with chronic constipation, evaluation and management of DD is recommended first. If symptoms persist, then consider colonic transit assessment.41 Given the overlapping nature of the conditions, documentation of STC at the outset could facilitate treatment of both.
Diagnostic criteria for DD
Patients should fulfill the following criteria for diagnosis of DD:42,43
- Fulfill symptom(s) diagnostic criteria for functional constipation and/or constipation-predominant IBS.
- Demonstrate dyssynergic pattern (Types I-IV; Figure) during attempted defecation on manometry recordings.
- Meet one or more of the following criteria:
- Inability to expel an artificial stool (50 mL water-filled balloon) within 1 minute.
- Inability to evacuate or retention of 50% or more of barium during defecography. (Some institutions use a prolonged colonic transit time: greater than 5 markers or 20% or higher marker retention on a plain abdominal x-Ray at 120 hours after ingestion of one radio-opaque marker capsule containing 24 radio-opaque markers.)
Treatment of DD
The treatment modalities for DD depend on several factors: patient’s age, comorbidities, underlying pathophysiology, and patient expectations. Treatment options include standard management of constipation, but biofeedback therapy is the mainstay.
Standard management
Medications that cause or worsen constipation should be avoided. The patient should consume adequate fluid and exercise regularly. Patients should receive instructions for timed toilet training (twice daily, 30 minutes after meals). Patients should push at about 50%-70% of their ability for no longer than 5 minutes and avoid postponing defecation or use of digital maneuvers to facilitate defecation.42 The patients should take 25 g of soluble fiber (e.g., psyllium) daily. Of note, the benefits of fiber can take days to weeks44 and may be limited in patients with STC and DD.45 Medications including laxatives and intestinal secretagogues (lubiprostone, linaclotide, plecanatide), and enterokinetic agents (prucalopride) can be used as adjunct therapy for management of DD.42 Their use is titrated during and after biofeedback therapy and may decrease after successful treatment.46
Biofeedback therapy
Biofeedback therapy involves operant conditioning techniques using either a solid state anorectal manometry system, electromyography, simulated balloon, or home biofeedback training devices.42,47 The goals of biofeedback therapy are to correct the abdominal pelvic muscle discoordination during defecation and improve rectal sensation to stool if impaired. Biofeedback therapy involves patient education and active training (typically six sessions, 1-2 weeks apart, with each about 30-60 minutes long), followed by a reinforcement stage (three sessions at 3, 6, and 12 months), though there are variations in training protocols.42
The success of biofeedback therapy depends on the patient’s motivation and the therapist’s skills.42 Compared with standard therapy (diet, exercise, pharmacotherapy), biofeedback therapy provides sustained improvement of bowel symptoms and anorectal function. Up to 70%-80% of DD patients show significant improvement of symptoms in randomized controlled trials (Table).48-52 Biofeedback therapy may also improve dyspeptic symptoms.53 Patients with harder stool consistency, greater willingness to participate, lower baseline bowel satisfaction, lower baseline anal sphincter relaxation, and prolonged balloon expulsion time, as well as patients who used digital maneuvers for defection, more commonly respond to biofeedback therapy.54,55 Longstanding laxative use has been associated with decreased response to biofeedback therapy.56 In patients with rectal hyposensitivity, barostat-assisted sensory training is more effective than a hand-held syringe technique.30 In patients with constipation predominant IBS and rectal hyposensitivity, sensory adaption training is more efficacious and better tolerated than escitalopram.30 Biofeedback therapy was afforded a grade A recommendation for treatment of DD by the American and European Societies of Neurogastroenterology and Motility.57
The access to office-based biofeedback therapy may be limited because of costs and low availability. The time required to attend multiple sessions may be burdensome for some patients, especially if they are taking time off from work. A recent study showed that patients with higher level of education may be less likely to adhere to biofeedback therapy.58 Recently, home biofeedback was shown to be noninferior to office biofeedback and was more cost-effective, which provides an alternative option for treating more patients.59
Endoscopic/surgical options
Other less effective treatment options for DD include botulinum toxin injection and myectomy.60-62 Botulinum toxin injection appears to have mixed effects with less than 50% of patients reporting symptomatic improvement, and it may cause fecal incontinence.60,63
Conclusion
DD is a common yet poorly recognized cause of constipation. Its clinical presentation overlaps with other lower-GI disorders. Its diagnosis requires detailed history, digital rectal examination, prospective stool diaries, anorectal manometry, and balloon expulsion tests. Biofeedback therapy offers excellent and sustained symptomatic improvement; however, access to office-based biofeedback is limited, and there is an urgent need for home-based biofeedback therapy programs.59
Dr. Rao is J. Harold Harrison Distinguished University Chair, professor of medicine, director of neurogastroenterology/motility, and director of digestive health at the Digestive Health Clinical Research Center Augusta (Georgia) University. He is supported by National Institutes of Health grants R01DK121003-02 and U01DK115572. Dr. Jehangir is a gastroenterology and Hepatology Fellow at the Digestive Health Clinical Research Center at Augusta University. They reported having no conflicts of interest.
References
1. Peery AF, et al. Gastroenterology. 2012;143(5):1179-1187.e3 .
2. Curtin B, et al. J Neurogastroenterol Motil. 2020 30;26(4):423-36.
3. Suares NC & Ford AC. Am J Gastroenterol. 2011 Sep;106(9):1582-91.
4. Mertz H, et al. Am J Gastroenterol. 1999;94(3):609-15.
5. Rao SS, et al. Am J Gastroenterol. 1998;93(7):1042-50.
6. Rao SSC, et al. J Clin Gastroenterol. 2004;38(8):680-5.
7. Nojkov B, et al. Am J Gastroenterol. 2019;114(11):1772-7.
8. Heaton KW, et al. Gut. 1992;33(6):818-24.
9. Prichard DO & Bharucha AE. 2018 Oct 15;7:F1000 Faculty Rev-1640.
10. Ashraf W, et al. Am J Gastroenterol. 1996;91(1):26-32.
11. Agachan F, et al.. Dis Colon Rectum. 1996;39(6):681-5.
12. Frank L, et al. Scand J Gastroenterol. 1999;34(9):870-7.
13. Marquis P, et al. Scand J Gastroenterol. 2005;40(5):540-51.
14. Yan Y, et al. Gastroenterology. 2020;158(6):S-400.
15. Rao SSC. Am J Gastroenterol. 2018;113(5):635-8.
16. Tantiphlachiva K, et al. Digital rectal examination is a useful tool for identifying patients with dyssynergia. Clin Gastroenterol Hepatol. 2010;8(11):955-60.
17. Carrington EV, et al. Nat Rev Gastroenterol Hepatol. 2018;15(5):309-23.
18. Tetangco EP, et al. Performing and analyzing high-resolution anorectal manometry. NeuroGastroLatam Rev. 2018;2:120-32.
19. Lee YY, et al. Curr Gastroenterol Rep. 2013;15(12):360.
20. Sharma M, et al. Neurogastroenterol Motil. 2020;32(10):e13910.
21. Rao SSC, et al.. Am J Gastroenterol. 2006;101(12):2790-6.
22. Carrington EV, et al. Neurogastroenterol Motil. 2020;32(1):e13679.
23. Rao SSC. Gastroenterol Clin North Am. 2008;37(3):569-86, viii.
24. Rao SSC, et al. Gastroenterology. 2016;150(4):S158-9.
25. Guinet A, et al. Int J Colorectal Dis. 2011;26(4):507-13.
26. Rattan S, et al. Gastroenterology. 1992;103(1):43-50.
27. Remes-Troche JM & Rao SSC. 2008;2(3):323-35.
28. Zaafouri H, et al..Int J Surgery. 2015. 2(1):9-17.
29. Remes-Troche JM, et al. Dis Colon Rectum. 2010;53(7):1047-54.
30. Rao SSC, et al. Gastroenterology. 2013;144(5):S-363.
31. Yu T, et al. Medicine (Baltimore). 2016;95(19):e3667.
32. Gladman MA, et al. Neurogastroenterol Motil. 2009;21(5):508-16, e4-5.
33. Lee KJ, et al. Digestion. 2006;73(2-3):133-41 .
34. Rao SSC, et al. Neurogastroenterol Motil. 2002;14(5):553-9.
35. Coss-Adame E, et al.. Clin Gastroenterol Hepatol. 2015;13(6):1143-1150.e1.
36. Chiarioni G, et al. Clin Gastroenterol Hepatol. 2014;12(12):2049-54.
37. Gu G, et al. Gastroenterology. 2018;154(6):S-545–S-546.
38. Savoye-Collet C, et al.. Gastroenterol Clin North Am. 2008;37(3):553-67, viii.
39. Videlock EJ, et al. Neurogastroenterol Motil. 2013;25(6):509-20.
40. Rao SSC, et al. Neurogastroenterol Motil. 2004;16(5):589-96.
41. Wald A, et al. Am J Gastroenterol. 2014;109(8):1141-57 ; (Quiz) 1058.
42. Rao SSC & Patcharatrakul T. J Neurogastroenterol Motil. 2016;22(3):423-35.
43. Rao SS, et al. Functional Anorectal Disorders. Gastroenterology. 2016. S0016-5085(16)00175-X.
44. Bharucha AE, et al.. Gastroenterology. 2013;144(1):218-38.
45. Voderholzer WA, et al. Am J Gastroenterol. 1997;92(1):95-8.
46. Lee HJ, et al. Neurogastroenterol Motil. 2015;27(6):787-95.
47. Simón MA & Bueno AM. J Clin Gastroenterol. 2017;51(10):e90-4.
48. Chiarioni G,et al.. Gastroenterology. 2006;130(3):657-64.
49. Heymen S, et al.. Dis Colon Rectum. 2007;50(4):428-41.
50. Rao SSC, et al. Clin Gastroenterol Hepatol. 2007;5(3):331-8.
51. Rao SSC, et al. Am J Gastroenterol. 2010;105(4):890-6.
52. Patcharatrakul T, et al. Biofeedback therapy. In Clinical and basic neurogastroenterology and motility. India: Stacy Masucci; 2020:517-32.
53. Huaman J-W, et al. Clin Gastroenterol Hepatol. 2020;18(11):2463-2470.e1.
54. Patcharatrakul T, et al. Clin Gastroenterol Hepatol. 2018;16(5):715-21.
55. Chaudhry A, et al. Gastroenterology. 2020;158(6):S-382–S-383.
56. Shim LSE, et al. Aliment Pharmacol Ther. 2011;33(11):1245-51.
57. Rao SSC, et al. Neurogastroenterol Motil. 2015;27(5):594-609.
58. Jangsirikul S, et al. Gastroenterology. 2020;158(6):S-383.
59. Rao SSC, et al. Am J Gastroenterol. 2019;114(6):938-44.
60. Ron Y, et al.. Dis Colon Rectum. 2001;44(12):1821-6.
61. Podzemny V, et al. World J Gastroenterol. 2015;21(4):1053-60.
62. Faried M, et al. J Gastrointest Surg. 2010;14(8):1235-43.
63. Hallan RI, et al. Lancet. 1988;2(8613):714-7.
Introduction
About 40% of the population experiences lower GI symptoms suggestive of gastrointestinal motility disorders.1,2 The global prevalence of chronic constipation is 18%, and the condition includes multiple overlapping subtypes.3 Evacuation disorders affect over half (59%) of patients and include dyssynergic defecation (DD).4 The inability to coordinate the abdominal, rectal, pelvic floor, and anal/puborectalis muscles to evacuate stools causes DD.5 The etiology of DD remains unclear and is often misdiagnosed. Clinically, the symptoms of DD overlap with other lower GI disorders, often leading to unnecessary and invasive procedures.2 We describe the clinical characteristics, diagnostic tools, treatment options, and evidence-based approach for the management of DD.
Clinical presentation
Over two-thirds of patients with DD acquire this disorder during adulthood, and one-third have symptoms from childhood.6 Though there is not usually an inciting event, 29% of patients report that symptoms began after events such as pregnancy or back injury,6 and opioid users have higher prevalence and severity of DD.7
Over 80% of patients report excessive straining, feelings of incomplete evacuation, and hard stools, and 50% report sensation of anal blockage or use of digital maneuvers.2 Other symptoms include infrequent bowel movements, abdominal pain, anal pain, and stool leakage.2 Evaluation of DD includes obtaining a detailed history utilizing the Bristol Stool Form Scale;8 however, patients’ recall of stool habit is often inaccurate, which results in suboptimal care.9,10 Prospective stool diaries can help to provide more objective assessment of patients’ symptoms, eliminate recall bias, and provide more reliable information. Several useful questionnaires are available for clinical and research purposes to characterize lower-GI symptoms, including the Constipation Scoring System,11 Patient Assessment of Constipation Symptoms (PAC-SYM),12 and Patient Assessment of Constipation Quality of Life (PAC-QOL).2,13 The Constipation Stool digital app enhances accuracy of data capture and offers a reliable and user-friendly method for recording bowel symptoms for patients, clinicians, and clinical investigators.14
Diagnosis
The diagnosis of DD requires careful physical and digital rectal examination together with anorectal manometry and a balloon expulsion test. Defecography and colonic transit studies provide additional assessment.
Physical examination
Abdominal examination should include palpation for stool in the colon and identification of abdominal mass or fecal impaction.2A high-quality digital rectal examination can help to identify patients who could benefit from physiological testing to confirm and treat DD.15 Rectal examination is performed by placing examiner’s lubricated gloved right index finger in a patient’s rectum, with the examiner’s left hand on patient’s abdomen, and asking the patient to push and bear down as if defecating.15 The contraction of the abdominal muscles is felt using the left hand, while the anal sphincter relaxation and degree of perineal descent are felt using the right-hand index finger.15 A diagnosis of dyssynergia is suspected if the digital rectal examination reveals two or more of the following abnormalities: inability to contract abdominal muscles (lack of push effort), inability to relax or paradoxical contraction of the anal sphincter and/or puborectalis, or absence of perineal descent.15 Digital rectal examination has good sensitivity (75%), specificity (87%), and positive predictive value (97%) for DD.16
High resolution anorectal manometry
Anorectal manometry (ARM) is the preferred method for the evaluation of defecatory disorders.17,18 ARM is best performed using the high-resolution anorectal manometry (HRAM) systems19 that consist of a flexible probe – 0.5-cm diameter with multiple circumferential sensors along the anal canal – and another two sensors inside a rectal balloon.18 It provides a topographic and waveform display of manometric pressure data (Figure). The 3D high-definition ARM probe is a rigid 1-cm probe that provides 3D topographic profiles.18 ARM is typically performed in both the left lateral position and in a more physiological seated position.20,21 There is considerable variation amongst different institutions on how to perform HRAM, and a recent International Anorectal Physiology Working Group (IAPWG) has provided consensus recommendations for performing this test.22 The procedure for performing HRAM is reviewed elsewhere, but the key elements are summarized below.18
Push maneuver: On HRAM, after the assessment of resting and squeeze anal sphincter pressures, the patient is asked to push or bear down as if to defecate while lying in left lateral decubitus position. The best of two attempts that closely mimics a normal bearing down maneuver is used for categorizing patient’s defecatory pattern.18 In patients with DD, at least four distinct dyssynergia phenotypes have been recognized (Figure),23 though recent studies suggest eight patterns.24 Defecation index (maximum rectal pressure/minimum residual anal pressure when bearing down) greater than 1.2 is considered normal.18
Simulated defecation on commode: The subject is asked to attempt defecation while seated on a commode with intrarectal balloon filled with 60 cc of air, and both the defecation pattern(s) and defecation index are calculated. A lack of coordinated push effort is highly suggestive of DD.21
Rectoanal Inhibitory Reflex (RAIR): RAIR describes the reflex relaxation of the internal anal sphincter after rectal distension. RAIR is dependent on intact autonomic ganglia and myenteric plexus25and is mediated by the release of nitric oxide and vasoactive intestinal peptide.26 The absence of RAIR suggests Hirschsprung disease.22.27.28
Rectal sensory testing: Intermittent balloon distension of the rectum with incremental volumes of air induces a range of rectal sensations that include first sensation, desire to defecate, urgency to defecate, and maximum tolerable volume. Rectal hyposensitivity is diagnosed when two or more sensory thresholds are higher than those seen in normal subjects29.30 and likely results from disruption of afferent gut-brain pathways, cortical perception/rectal wall dysfunction, or both.29 Rectal hyposensitivity affects 40% of patients with constipation30and is associated with DD but not delayed colonic transit.31 Rectal hyposensitivity may also be seen in patients with diabetes or fecal incontinence.18 About two-thirds of patients with rectal hyposensitivity have rectal hypercompliance, and some have megarectum.32 Some patients with DD have coexisting irritable bowel syndrome (IBS) and may have rectal hypersensitivity.18,33 Rectal compliance is measured alongside rectal sensitivity analysis by plotting a graph between the change in intraballoon volume (mL) and change in intrarectal pressures (mm Hg) during incremental balloon distensions.18.34 Rectal hypercompliance may be seen in megarectum and dyssynergic defecation.34,35 Rectal hypocompliance may be seen in patients with inflammatory bowel disease, postpelvic radiation, chronic ischemia, and advanced age.18
Balloon expulsion test: This test is performed by placing a plastic probe with a balloon in the rectum and filling it with 50 cc of warm water. Patients are given 5 minutes to expel the balloon while sitting on a commode. Balloon expulsion time of more than 1 minute suggests a diagnosis of DD,21 although 2 minutes provides a higher level of agreement with manometric findings.36 Balloon type and body position can influence the results.37 Inability to expel the balloon with normal manometric findings is considered an inconclusive finding per the recent London Classification (i.e., it may be associated with generation of anorectal symptoms, but the clinical relevance of this finding is unclear as it may also be seen in healthy subjects).22
Defecography
Defecography is a dynamic fluoroscopic study performed in the sitting position after injecting 150 mL of barium paste into the patient’s rectum. Defecography provides useful information about structural changes (e.g., rectoceles, enteroceles, rectal prolapse, and intussusception), DD, and descending perineum syndrome.38 Methodological differences, radiation exposure, and poor interobserver agreement have limited its wider use; therefore, anorectal manometry and the balloon expulsion test are recommended for the initial evaluation of DD.39 Magnetic resonance defecography may be more useful.17,38
Colonic transit studies
Colonic transit study can be assessed using radiopaque markers, wireless motility capsule, or scintigraphy. Wireless motility capsule and scintigraphy have the advantage of determining gastric, small bowel, and whole gut transit times as well. About two-thirds of patients with DD have slow transit constipation (STC),6 which improves after treatment of DD.40 Hence, in patients with chronic constipation, evaluation and management of DD is recommended first. If symptoms persist, then consider colonic transit assessment.41 Given the overlapping nature of the conditions, documentation of STC at the outset could facilitate treatment of both.
Diagnostic criteria for DD
Patients should fulfill the following criteria for diagnosis of DD:42,43
- Fulfill symptom(s) diagnostic criteria for functional constipation and/or constipation-predominant IBS.
- Demonstrate dyssynergic pattern (Types I-IV; Figure) during attempted defecation on manometry recordings.
- Meet one or more of the following criteria:
- Inability to expel an artificial stool (50 mL water-filled balloon) within 1 minute.
- Inability to evacuate or retention of 50% or more of barium during defecography. (Some institutions use a prolonged colonic transit time: greater than 5 markers or 20% or higher marker retention on a plain abdominal x-Ray at 120 hours after ingestion of one radio-opaque marker capsule containing 24 radio-opaque markers.)
Treatment of DD
The treatment modalities for DD depend on several factors: patient’s age, comorbidities, underlying pathophysiology, and patient expectations. Treatment options include standard management of constipation, but biofeedback therapy is the mainstay.
Standard management
Medications that cause or worsen constipation should be avoided. The patient should consume adequate fluid and exercise regularly. Patients should receive instructions for timed toilet training (twice daily, 30 minutes after meals). Patients should push at about 50%-70% of their ability for no longer than 5 minutes and avoid postponing defecation or use of digital maneuvers to facilitate defecation.42 The patients should take 25 g of soluble fiber (e.g., psyllium) daily. Of note, the benefits of fiber can take days to weeks44 and may be limited in patients with STC and DD.45 Medications including laxatives and intestinal secretagogues (lubiprostone, linaclotide, plecanatide), and enterokinetic agents (prucalopride) can be used as adjunct therapy for management of DD.42 Their use is titrated during and after biofeedback therapy and may decrease after successful treatment.46
Biofeedback therapy
Biofeedback therapy involves operant conditioning techniques using either a solid state anorectal manometry system, electromyography, simulated balloon, or home biofeedback training devices.42,47 The goals of biofeedback therapy are to correct the abdominal pelvic muscle discoordination during defecation and improve rectal sensation to stool if impaired. Biofeedback therapy involves patient education and active training (typically six sessions, 1-2 weeks apart, with each about 30-60 minutes long), followed by a reinforcement stage (three sessions at 3, 6, and 12 months), though there are variations in training protocols.42
The success of biofeedback therapy depends on the patient’s motivation and the therapist’s skills.42 Compared with standard therapy (diet, exercise, pharmacotherapy), biofeedback therapy provides sustained improvement of bowel symptoms and anorectal function. Up to 70%-80% of DD patients show significant improvement of symptoms in randomized controlled trials (Table).48-52 Biofeedback therapy may also improve dyspeptic symptoms.53 Patients with harder stool consistency, greater willingness to participate, lower baseline bowel satisfaction, lower baseline anal sphincter relaxation, and prolonged balloon expulsion time, as well as patients who used digital maneuvers for defection, more commonly respond to biofeedback therapy.54,55 Longstanding laxative use has been associated with decreased response to biofeedback therapy.56 In patients with rectal hyposensitivity, barostat-assisted sensory training is more effective than a hand-held syringe technique.30 In patients with constipation predominant IBS and rectal hyposensitivity, sensory adaption training is more efficacious and better tolerated than escitalopram.30 Biofeedback therapy was afforded a grade A recommendation for treatment of DD by the American and European Societies of Neurogastroenterology and Motility.57
The access to office-based biofeedback therapy may be limited because of costs and low availability. The time required to attend multiple sessions may be burdensome for some patients, especially if they are taking time off from work. A recent study showed that patients with higher level of education may be less likely to adhere to biofeedback therapy.58 Recently, home biofeedback was shown to be noninferior to office biofeedback and was more cost-effective, which provides an alternative option for treating more patients.59
Endoscopic/surgical options
Other less effective treatment options for DD include botulinum toxin injection and myectomy.60-62 Botulinum toxin injection appears to have mixed effects with less than 50% of patients reporting symptomatic improvement, and it may cause fecal incontinence.60,63
Conclusion
DD is a common yet poorly recognized cause of constipation. Its clinical presentation overlaps with other lower-GI disorders. Its diagnosis requires detailed history, digital rectal examination, prospective stool diaries, anorectal manometry, and balloon expulsion tests. Biofeedback therapy offers excellent and sustained symptomatic improvement; however, access to office-based biofeedback is limited, and there is an urgent need for home-based biofeedback therapy programs.59
Dr. Rao is J. Harold Harrison Distinguished University Chair, professor of medicine, director of neurogastroenterology/motility, and director of digestive health at the Digestive Health Clinical Research Center Augusta (Georgia) University. He is supported by National Institutes of Health grants R01DK121003-02 and U01DK115572. Dr. Jehangir is a gastroenterology and Hepatology Fellow at the Digestive Health Clinical Research Center at Augusta University. They reported having no conflicts of interest.
References
1. Peery AF, et al. Gastroenterology. 2012;143(5):1179-1187.e3 .
2. Curtin B, et al. J Neurogastroenterol Motil. 2020 30;26(4):423-36.
3. Suares NC & Ford AC. Am J Gastroenterol. 2011 Sep;106(9):1582-91.
4. Mertz H, et al. Am J Gastroenterol. 1999;94(3):609-15.
5. Rao SS, et al. Am J Gastroenterol. 1998;93(7):1042-50.
6. Rao SSC, et al. J Clin Gastroenterol. 2004;38(8):680-5.
7. Nojkov B, et al. Am J Gastroenterol. 2019;114(11):1772-7.
8. Heaton KW, et al. Gut. 1992;33(6):818-24.
9. Prichard DO & Bharucha AE. 2018 Oct 15;7:F1000 Faculty Rev-1640.
10. Ashraf W, et al. Am J Gastroenterol. 1996;91(1):26-32.
11. Agachan F, et al.. Dis Colon Rectum. 1996;39(6):681-5.
12. Frank L, et al. Scand J Gastroenterol. 1999;34(9):870-7.
13. Marquis P, et al. Scand J Gastroenterol. 2005;40(5):540-51.
14. Yan Y, et al. Gastroenterology. 2020;158(6):S-400.
15. Rao SSC. Am J Gastroenterol. 2018;113(5):635-8.
16. Tantiphlachiva K, et al. Digital rectal examination is a useful tool for identifying patients with dyssynergia. Clin Gastroenterol Hepatol. 2010;8(11):955-60.
17. Carrington EV, et al. Nat Rev Gastroenterol Hepatol. 2018;15(5):309-23.
18. Tetangco EP, et al. Performing and analyzing high-resolution anorectal manometry. NeuroGastroLatam Rev. 2018;2:120-32.
19. Lee YY, et al. Curr Gastroenterol Rep. 2013;15(12):360.
20. Sharma M, et al. Neurogastroenterol Motil. 2020;32(10):e13910.
21. Rao SSC, et al.. Am J Gastroenterol. 2006;101(12):2790-6.
22. Carrington EV, et al. Neurogastroenterol Motil. 2020;32(1):e13679.
23. Rao SSC. Gastroenterol Clin North Am. 2008;37(3):569-86, viii.
24. Rao SSC, et al. Gastroenterology. 2016;150(4):S158-9.
25. Guinet A, et al. Int J Colorectal Dis. 2011;26(4):507-13.
26. Rattan S, et al. Gastroenterology. 1992;103(1):43-50.
27. Remes-Troche JM & Rao SSC. 2008;2(3):323-35.
28. Zaafouri H, et al..Int J Surgery. 2015. 2(1):9-17.
29. Remes-Troche JM, et al. Dis Colon Rectum. 2010;53(7):1047-54.
30. Rao SSC, et al. Gastroenterology. 2013;144(5):S-363.
31. Yu T, et al. Medicine (Baltimore). 2016;95(19):e3667.
32. Gladman MA, et al. Neurogastroenterol Motil. 2009;21(5):508-16, e4-5.
33. Lee KJ, et al. Digestion. 2006;73(2-3):133-41 .
34. Rao SSC, et al. Neurogastroenterol Motil. 2002;14(5):553-9.
35. Coss-Adame E, et al.. Clin Gastroenterol Hepatol. 2015;13(6):1143-1150.e1.
36. Chiarioni G, et al. Clin Gastroenterol Hepatol. 2014;12(12):2049-54.
37. Gu G, et al. Gastroenterology. 2018;154(6):S-545–S-546.
38. Savoye-Collet C, et al.. Gastroenterol Clin North Am. 2008;37(3):553-67, viii.
39. Videlock EJ, et al. Neurogastroenterol Motil. 2013;25(6):509-20.
40. Rao SSC, et al. Neurogastroenterol Motil. 2004;16(5):589-96.
41. Wald A, et al. Am J Gastroenterol. 2014;109(8):1141-57 ; (Quiz) 1058.
42. Rao SSC & Patcharatrakul T. J Neurogastroenterol Motil. 2016;22(3):423-35.
43. Rao SS, et al. Functional Anorectal Disorders. Gastroenterology. 2016. S0016-5085(16)00175-X.
44. Bharucha AE, et al.. Gastroenterology. 2013;144(1):218-38.
45. Voderholzer WA, et al. Am J Gastroenterol. 1997;92(1):95-8.
46. Lee HJ, et al. Neurogastroenterol Motil. 2015;27(6):787-95.
47. Simón MA & Bueno AM. J Clin Gastroenterol. 2017;51(10):e90-4.
48. Chiarioni G,et al.. Gastroenterology. 2006;130(3):657-64.
49. Heymen S, et al.. Dis Colon Rectum. 2007;50(4):428-41.
50. Rao SSC, et al. Clin Gastroenterol Hepatol. 2007;5(3):331-8.
51. Rao SSC, et al. Am J Gastroenterol. 2010;105(4):890-6.
52. Patcharatrakul T, et al. Biofeedback therapy. In Clinical and basic neurogastroenterology and motility. India: Stacy Masucci; 2020:517-32.
53. Huaman J-W, et al. Clin Gastroenterol Hepatol. 2020;18(11):2463-2470.e1.
54. Patcharatrakul T, et al. Clin Gastroenterol Hepatol. 2018;16(5):715-21.
55. Chaudhry A, et al. Gastroenterology. 2020;158(6):S-382–S-383.
56. Shim LSE, et al. Aliment Pharmacol Ther. 2011;33(11):1245-51.
57. Rao SSC, et al. Neurogastroenterol Motil. 2015;27(5):594-609.
58. Jangsirikul S, et al. Gastroenterology. 2020;158(6):S-383.
59. Rao SSC, et al. Am J Gastroenterol. 2019;114(6):938-44.
60. Ron Y, et al.. Dis Colon Rectum. 2001;44(12):1821-6.
61. Podzemny V, et al. World J Gastroenterol. 2015;21(4):1053-60.
62. Faried M, et al. J Gastrointest Surg. 2010;14(8):1235-43.
63. Hallan RI, et al. Lancet. 1988;2(8613):714-7.
Introduction
About 40% of the population experiences lower GI symptoms suggestive of gastrointestinal motility disorders.1,2 The global prevalence of chronic constipation is 18%, and the condition includes multiple overlapping subtypes.3 Evacuation disorders affect over half (59%) of patients and include dyssynergic defecation (DD).4 The inability to coordinate the abdominal, rectal, pelvic floor, and anal/puborectalis muscles to evacuate stools causes DD.5 The etiology of DD remains unclear and is often misdiagnosed. Clinically, the symptoms of DD overlap with other lower GI disorders, often leading to unnecessary and invasive procedures.2 We describe the clinical characteristics, diagnostic tools, treatment options, and evidence-based approach for the management of DD.
Clinical presentation
Over two-thirds of patients with DD acquire this disorder during adulthood, and one-third have symptoms from childhood.6 Though there is not usually an inciting event, 29% of patients report that symptoms began after events such as pregnancy or back injury,6 and opioid users have higher prevalence and severity of DD.7
Over 80% of patients report excessive straining, feelings of incomplete evacuation, and hard stools, and 50% report sensation of anal blockage or use of digital maneuvers.2 Other symptoms include infrequent bowel movements, abdominal pain, anal pain, and stool leakage.2 Evaluation of DD includes obtaining a detailed history utilizing the Bristol Stool Form Scale;8 however, patients’ recall of stool habit is often inaccurate, which results in suboptimal care.9,10 Prospective stool diaries can help to provide more objective assessment of patients’ symptoms, eliminate recall bias, and provide more reliable information. Several useful questionnaires are available for clinical and research purposes to characterize lower-GI symptoms, including the Constipation Scoring System,11 Patient Assessment of Constipation Symptoms (PAC-SYM),12 and Patient Assessment of Constipation Quality of Life (PAC-QOL).2,13 The Constipation Stool digital app enhances accuracy of data capture and offers a reliable and user-friendly method for recording bowel symptoms for patients, clinicians, and clinical investigators.14
Diagnosis
The diagnosis of DD requires careful physical and digital rectal examination together with anorectal manometry and a balloon expulsion test. Defecography and colonic transit studies provide additional assessment.
Physical examination
Abdominal examination should include palpation for stool in the colon and identification of abdominal mass or fecal impaction.2A high-quality digital rectal examination can help to identify patients who could benefit from physiological testing to confirm and treat DD.15 Rectal examination is performed by placing examiner’s lubricated gloved right index finger in a patient’s rectum, with the examiner’s left hand on patient’s abdomen, and asking the patient to push and bear down as if defecating.15 The contraction of the abdominal muscles is felt using the left hand, while the anal sphincter relaxation and degree of perineal descent are felt using the right-hand index finger.15 A diagnosis of dyssynergia is suspected if the digital rectal examination reveals two or more of the following abnormalities: inability to contract abdominal muscles (lack of push effort), inability to relax or paradoxical contraction of the anal sphincter and/or puborectalis, or absence of perineal descent.15 Digital rectal examination has good sensitivity (75%), specificity (87%), and positive predictive value (97%) for DD.16
High resolution anorectal manometry
Anorectal manometry (ARM) is the preferred method for the evaluation of defecatory disorders.17,18 ARM is best performed using the high-resolution anorectal manometry (HRAM) systems19 that consist of a flexible probe – 0.5-cm diameter with multiple circumferential sensors along the anal canal – and another two sensors inside a rectal balloon.18 It provides a topographic and waveform display of manometric pressure data (Figure). The 3D high-definition ARM probe is a rigid 1-cm probe that provides 3D topographic profiles.18 ARM is typically performed in both the left lateral position and in a more physiological seated position.20,21 There is considerable variation amongst different institutions on how to perform HRAM, and a recent International Anorectal Physiology Working Group (IAPWG) has provided consensus recommendations for performing this test.22 The procedure for performing HRAM is reviewed elsewhere, but the key elements are summarized below.18
Push maneuver: On HRAM, after the assessment of resting and squeeze anal sphincter pressures, the patient is asked to push or bear down as if to defecate while lying in left lateral decubitus position. The best of two attempts that closely mimics a normal bearing down maneuver is used for categorizing patient’s defecatory pattern.18 In patients with DD, at least four distinct dyssynergia phenotypes have been recognized (Figure),23 though recent studies suggest eight patterns.24 Defecation index (maximum rectal pressure/minimum residual anal pressure when bearing down) greater than 1.2 is considered normal.18
Simulated defecation on commode: The subject is asked to attempt defecation while seated on a commode with intrarectal balloon filled with 60 cc of air, and both the defecation pattern(s) and defecation index are calculated. A lack of coordinated push effort is highly suggestive of DD.21
Rectoanal Inhibitory Reflex (RAIR): RAIR describes the reflex relaxation of the internal anal sphincter after rectal distension. RAIR is dependent on intact autonomic ganglia and myenteric plexus25and is mediated by the release of nitric oxide and vasoactive intestinal peptide.26 The absence of RAIR suggests Hirschsprung disease.22.27.28
Rectal sensory testing: Intermittent balloon distension of the rectum with incremental volumes of air induces a range of rectal sensations that include first sensation, desire to defecate, urgency to defecate, and maximum tolerable volume. Rectal hyposensitivity is diagnosed when two or more sensory thresholds are higher than those seen in normal subjects29.30 and likely results from disruption of afferent gut-brain pathways, cortical perception/rectal wall dysfunction, or both.29 Rectal hyposensitivity affects 40% of patients with constipation30and is associated with DD but not delayed colonic transit.31 Rectal hyposensitivity may also be seen in patients with diabetes or fecal incontinence.18 About two-thirds of patients with rectal hyposensitivity have rectal hypercompliance, and some have megarectum.32 Some patients with DD have coexisting irritable bowel syndrome (IBS) and may have rectal hypersensitivity.18,33 Rectal compliance is measured alongside rectal sensitivity analysis by plotting a graph between the change in intraballoon volume (mL) and change in intrarectal pressures (mm Hg) during incremental balloon distensions.18.34 Rectal hypercompliance may be seen in megarectum and dyssynergic defecation.34,35 Rectal hypocompliance may be seen in patients with inflammatory bowel disease, postpelvic radiation, chronic ischemia, and advanced age.18
Balloon expulsion test: This test is performed by placing a plastic probe with a balloon in the rectum and filling it with 50 cc of warm water. Patients are given 5 minutes to expel the balloon while sitting on a commode. Balloon expulsion time of more than 1 minute suggests a diagnosis of DD,21 although 2 minutes provides a higher level of agreement with manometric findings.36 Balloon type and body position can influence the results.37 Inability to expel the balloon with normal manometric findings is considered an inconclusive finding per the recent London Classification (i.e., it may be associated with generation of anorectal symptoms, but the clinical relevance of this finding is unclear as it may also be seen in healthy subjects).22
Defecography
Defecography is a dynamic fluoroscopic study performed in the sitting position after injecting 150 mL of barium paste into the patient’s rectum. Defecography provides useful information about structural changes (e.g., rectoceles, enteroceles, rectal prolapse, and intussusception), DD, and descending perineum syndrome.38 Methodological differences, radiation exposure, and poor interobserver agreement have limited its wider use; therefore, anorectal manometry and the balloon expulsion test are recommended for the initial evaluation of DD.39 Magnetic resonance defecography may be more useful.17,38
Colonic transit studies
Colonic transit study can be assessed using radiopaque markers, wireless motility capsule, or scintigraphy. Wireless motility capsule and scintigraphy have the advantage of determining gastric, small bowel, and whole gut transit times as well. About two-thirds of patients with DD have slow transit constipation (STC),6 which improves after treatment of DD.40 Hence, in patients with chronic constipation, evaluation and management of DD is recommended first. If symptoms persist, then consider colonic transit assessment.41 Given the overlapping nature of the conditions, documentation of STC at the outset could facilitate treatment of both.
Diagnostic criteria for DD
Patients should fulfill the following criteria for diagnosis of DD:42,43
- Fulfill symptom(s) diagnostic criteria for functional constipation and/or constipation-predominant IBS.
- Demonstrate dyssynergic pattern (Types I-IV; Figure) during attempted defecation on manometry recordings.
- Meet one or more of the following criteria:
- Inability to expel an artificial stool (50 mL water-filled balloon) within 1 minute.
- Inability to evacuate or retention of 50% or more of barium during defecography. (Some institutions use a prolonged colonic transit time: greater than 5 markers or 20% or higher marker retention on a plain abdominal x-Ray at 120 hours after ingestion of one radio-opaque marker capsule containing 24 radio-opaque markers.)
Treatment of DD
The treatment modalities for DD depend on several factors: patient’s age, comorbidities, underlying pathophysiology, and patient expectations. Treatment options include standard management of constipation, but biofeedback therapy is the mainstay.
Standard management
Medications that cause or worsen constipation should be avoided. The patient should consume adequate fluid and exercise regularly. Patients should receive instructions for timed toilet training (twice daily, 30 minutes after meals). Patients should push at about 50%-70% of their ability for no longer than 5 minutes and avoid postponing defecation or use of digital maneuvers to facilitate defecation.42 The patients should take 25 g of soluble fiber (e.g., psyllium) daily. Of note, the benefits of fiber can take days to weeks44 and may be limited in patients with STC and DD.45 Medications including laxatives and intestinal secretagogues (lubiprostone, linaclotide, plecanatide), and enterokinetic agents (prucalopride) can be used as adjunct therapy for management of DD.42 Their use is titrated during and after biofeedback therapy and may decrease after successful treatment.46
Biofeedback therapy
Biofeedback therapy involves operant conditioning techniques using either a solid state anorectal manometry system, electromyography, simulated balloon, or home biofeedback training devices.42,47 The goals of biofeedback therapy are to correct the abdominal pelvic muscle discoordination during defecation and improve rectal sensation to stool if impaired. Biofeedback therapy involves patient education and active training (typically six sessions, 1-2 weeks apart, with each about 30-60 minutes long), followed by a reinforcement stage (three sessions at 3, 6, and 12 months), though there are variations in training protocols.42
The success of biofeedback therapy depends on the patient’s motivation and the therapist’s skills.42 Compared with standard therapy (diet, exercise, pharmacotherapy), biofeedback therapy provides sustained improvement of bowel symptoms and anorectal function. Up to 70%-80% of DD patients show significant improvement of symptoms in randomized controlled trials (Table).48-52 Biofeedback therapy may also improve dyspeptic symptoms.53 Patients with harder stool consistency, greater willingness to participate, lower baseline bowel satisfaction, lower baseline anal sphincter relaxation, and prolonged balloon expulsion time, as well as patients who used digital maneuvers for defection, more commonly respond to biofeedback therapy.54,55 Longstanding laxative use has been associated with decreased response to biofeedback therapy.56 In patients with rectal hyposensitivity, barostat-assisted sensory training is more effective than a hand-held syringe technique.30 In patients with constipation predominant IBS and rectal hyposensitivity, sensory adaption training is more efficacious and better tolerated than escitalopram.30 Biofeedback therapy was afforded a grade A recommendation for treatment of DD by the American and European Societies of Neurogastroenterology and Motility.57
The access to office-based biofeedback therapy may be limited because of costs and low availability. The time required to attend multiple sessions may be burdensome for some patients, especially if they are taking time off from work. A recent study showed that patients with higher level of education may be less likely to adhere to biofeedback therapy.58 Recently, home biofeedback was shown to be noninferior to office biofeedback and was more cost-effective, which provides an alternative option for treating more patients.59
Endoscopic/surgical options
Other less effective treatment options for DD include botulinum toxin injection and myectomy.60-62 Botulinum toxin injection appears to have mixed effects with less than 50% of patients reporting symptomatic improvement, and it may cause fecal incontinence.60,63
Conclusion
DD is a common yet poorly recognized cause of constipation. Its clinical presentation overlaps with other lower-GI disorders. Its diagnosis requires detailed history, digital rectal examination, prospective stool diaries, anorectal manometry, and balloon expulsion tests. Biofeedback therapy offers excellent and sustained symptomatic improvement; however, access to office-based biofeedback is limited, and there is an urgent need for home-based biofeedback therapy programs.59
Dr. Rao is J. Harold Harrison Distinguished University Chair, professor of medicine, director of neurogastroenterology/motility, and director of digestive health at the Digestive Health Clinical Research Center Augusta (Georgia) University. He is supported by National Institutes of Health grants R01DK121003-02 and U01DK115572. Dr. Jehangir is a gastroenterology and Hepatology Fellow at the Digestive Health Clinical Research Center at Augusta University. They reported having no conflicts of interest.
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Update on feeding tubes: Indications and troubleshooting complications
Introduction
Gastroenterologists are in a unique position to manage individuals with feeding tubes as their training underscores principles in digestion, absorption, nutrition support, and enteral tube placement. Adequate management of individuals with feeding tubes and, importantly, the complications that arise from feeding tube use and placement require a basic understanding of intestinal anatomy and physiology. Therefore, gastroenterologists are well suited to both place and manage individuals with feeding tubes in the long term.
Indications for tube feeding
When deciding on the appropriate route for artificial nutrition support, the first decision to be made is enteral access versus parenteral nutrition support. Enteral nutrition confers multiple benefits, including preservation of the mucosal lining, reductions in complicated infections, decreased costs, and improved patient compliance. All attempts at adequate enteral access should be made before deciding on the use of parenteral nutrition. Following the clinical decision to pursue artificial means of nutrition support and enteral access, the next common decision is the anticipated duration of nutrition support. Generally, the oral or nasal tubes are used for short durations (i.e., less than 4 weeks) with percutaneous placement into the stomach or small intestine for longer-term feeding (i.e., percutaneous endoscopic gastrostomy [PEG] or percutaneous endoscopic jejunostomy [PEJ]).
The most general indication for nutrition support is an inability to maintain adequate nutritional needs with oral intake alone. General categories of inadequate oral intake include neurologic disorders, malignancy, and gastrointestinal conditions affecting digestion and absorption (Table 1). Absolute and relative contraindications to PEG placement are listed in Table 2. If an endoscopic placement is not possible, alternative means of placement (i.e., surgery or interventional radiology) can be considered to avoid the consequences of prolonged malnutrition. In-hospital mortality following PEG placement has decreased 40% over the last 10 years, which can be attributed to improved patient selection, enhanced discharge practices, and exclusion of patients with the highest comorbidity and mortality rates, like those with advanced dementia or terminal cancer.1
PEG placement in patients with dementia is controversial, with previous studies not demonstrating improved outcomes and association with high mortality rates,2 so the practice is currently not recommended by the American Geriatrics Society in individuals with advanced dementia.3 However, a large Japanese study showed that careful selection of patients with mild dementia to undergo gastrostomy increased independence fourfold; therefore, multidisciplinary involvement is often necessary in the decision to pursue artificial means of nutrition support in this population.4
The recent coronavirus disease 2019 (COVID-19) pandemic has placed additional strains on endoscopic placement and has highlighted the effect of the severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) on GI symptoms. A recent meta-analysis showed an overall incidence of GI symptoms of 17.6% in the following conditions in decreasing order of prevalence: anorexia, diarrhea, nausea, vomiting, and abdominal discomfort.5 In addition, the prolonged ventilatory requirements among a subset of individuals with the most severe COVID-19 results in extended periods of nutrition support via enteral tube placements. In individuals with ICU-acquired weakness and discharge to long-term care facilities, the placement of percutaneous endoscopic tubes may be required, although with the additional consideration of the need for an aerosolizing procedure. Delay of placement has been advocated, in addition to appropriate personal protective equipment, in order to ensure safe placement for the endoscopy staff.6
Types of feeding tubes
After deciding to feed a patient enterally and determining the anticipated duration of enteral support, the next decision is to determine the most appropriate location of feeding delivery: into the stomach or the small bowel. Gastric feeding is advantageous most commonly because of its increased capacity, allowing for larger volumes to be delivered over shorter durations. However, in the setting of postsurgical anatomy, gastroparesis, or obstructing tumors/pancreatic inflammation, distal delivery of tube feeds may be required into the jejunum. Additionally, percutaneous tubes placed into the stomach can have extenders into the small bowel (GJ tubes) to allow for feeding into the small bowel and decompression or delivery of medications into the stomach.
In general, gastric feeding is preferred over small bowel feeding as PEG tubes are more stable and have fewer complications than either PEG-J or direct PEJ tubes. Gastrostomy tubes are generally shorter and larger in diameter making them less likely to clog. PEG-J tubes have separate lumens for gastric and small intestinal access, but the smaller-bore jejunal extension tubes are more likely to clog or become dislodged. While direct PEJ is shown to have higher rates of tube patency and decreased rates of endoscopic re-intervention, compared with PEG-J,7 one limitation of a direct PEJ is difficulty in placement and site selection, which can be performed with a pediatric colonoscope or balloon enteroscopy system. Most commonly, this procedure is performed under general anesthesia.
In the case of a critically ill patient in the ICU, it is recommended to start enteral nutrition within 24-48 hours of arrival to avoid complications of prolonged calorie deficits. Nasally inserted feeding tubes (e.g., Cortrak, Avanos Medical Devices, Alpharetta, Ga.) are most commonly used at the bedside and can be placed blindly using electromagnetic image guidance, radiographically, or endoscopy. However, the small caliber of nasoenteric tubes comes with the common complication of clogging, which can be overcome with slightly larger bore gastric feeding tubes. If gastric feeding is not tolerated (e.g., in the case of vomiting, witnessed aspiration), small bowel feeding should be initiated and can be a more durable form of enteral feeding with fewer interruptions as feedings do not need to be held for procedures or symptomatic gastric intolerance. In clinical areas of question, or if there is a concern for intolerance of enteral feeding, a short trial with nasogastric or nasojejunal tube placement should be performed before a more definitive percutaneous placement.
With respect to percutaneous tubes, important characteristics to choose are the size (diameter in French units), type of internal retention device, and external appearance of the tube (standard or low profile). All percutaneous tubes contain an external retention device (i.e., bumper) that fits against the skin and an internal retention device that is either a balloon or plastic dome or funnel that prevents the tube from becoming dislodged. Balloon retention tubes require replacement every 3-6 months, while nonballoon tubes generally require replacement annually in order to prevent the plastic from cracking, which can make removal complicated. Low-profile tubes have an external cap, which, when opened, allows for extension tubing to be securely attached while in use and detached while not in use. Low-profile tubes are often preferred among younger, active patients and those with adequate dexterity to allow for attachment of the external extension tubing. These tubes are most often inserted as a replacement for an initially endoscopically placed tube, although one-step systems for initial placement are available. The size of the low-profile tube is chosen based on the size of the existing PEG tube and by measuring the length of the stoma tract using specialized measuring devices.8 Patients and caregivers can also be trained to replace balloon-type tubes on their own to limit complications of displaced or cracked tubes. Low-profile tubes are commercially available for both gastric placement and gastric placement with extension into the small bowel, which often requires fluoroscopy for secure placement.
All percutaneous enteral tubes are being transitioned to the ENfit connector system, which prevents connections from the enteral system to nonenteral systems (namely intravenous lines, chest tubes) and vice versa. Tubing misconnections have been rarely reported, and the EnFIT system is designed to prevent such misadventures that have resulted in serious complications and even mortality.9 Adapter devices are available that may be required for patients with feeding tubes who have not been transitioned yet. Most commonly with new tube placements and replacements, patients and providers will have to become familiar with the new syringes and feeding bags required with EnFIT connectors.
Gastrostomy placement can be considered a higher-risk endoscopic procedure. One complicating factor is the increased use of antiplatelet and anticoagulant therapies in individuals with a history of neurologic insults. The American Society for Gastrointestinal Endoscopy (ASGE) guidelines recommend that coumadin be held 5 days before the procedure and bridged with heparin if the patient is at high risk of thromboembolic complications. For patients on dual anti-platelet therapy, thienopyridines like clopidogrel are often stopped 5-7 days prior to procedure with continuation of aspirin,10 but there are more recent data that PEG insertion is safe with continued use of DAPT.11 Direct-acting anticoagulants (DOACs) are often stopped 24-48 hours prior to procedure and then restarted 48 hours after tube placement, but this is dependent on the half-life of the specific DOAC and the patient’s renal function. Patients with decreased creatinine clearance may need to hold the DOAC up to 3-4 days prior to the procedure. In this situation, referring to ASGE guidelines and consultation with a hematologist or managing anti-coagulation clinic is advised.10
Troubleshooting complications
Nasoenteric tubes: One of the most common and irritating complications with nasoenteric feeding tubes is clogging. To prevent clogging, the tube should be flushed frequently.12 At least 30 mL of free water should be used to flush the tube every 4-8 hours for continuous feedings or before and after bolus feeding. Additionally, 15-30 mL of water should be given with each separate medication administration, and if possible, medication administration via small-bore small bowel feeding tubes should be avoided.12 Water flushing is especially important with small-caliber tubes and pumps that deliver both feeding and water flushes. It is available for small bowel feeding in order to allow for programmed water delivery.
Warm water flushes can also help unclog the tube,12 and additional pharmacologic and mechanical devices have been promoted for clogged tubes. One common technique is mixing pancreatic enzymes (Viokase) with a crushed 325-mg tablet of nonenteric coated sodium bicarbonate and 5 mL of water to create a solution that has the alkaline properties allowing for both pancreatic enzyme activation and clog dissolution. Additionally, an endoscopic retrograde cholangiopancreatography (ERCP) catheter can be placed into longer feeding tubes to directly infuse the activated agent to the site of the clog.13 If water and enzymes are not successful in unclogging the tube, commercially available brushes can help remove clogs. The TubeClear® system (Actuated Medical, Bellefonte, Penna) has a single-use stem that is connected to AC power to create a jackhammerlike movement to remove clogs in longer nasoenteral and gastrojejunal tubes.
PEG tubes (short-term complications): Procedural and immediate postprocedural complications include bleeding, aspiration, pneumoperitoneum, and perforation. Pneumoperitoneum occurs in approximately 50% of cases and is generally clinically insignificant. The risk of pneumoperitoneum can be reduced by using CO2 insufflation.14 If the patient develops systemic signs of infection or peritoneal signs, CT scan with oral contrast is warranted for further evaluation and to assess for inadvertent perforation of overlying bowel or dislodged tube. Aspiration during or following endoscopy is another common complication of PEG placement and risk factors include over-sedation, supine positioning, advanced age, and neurologic dysfunction. This risk can be mitigated by avoiding over-sedation, immediately aspirating gastric contents when the stomach is reached, and avoiding excessive insufflation.15 In addition, elevating the head of the bed during the procedure and dedicating an assistant to perform oral suctioning during the entire procedure is recommended.
PEG tubes (long-term complications): More delayed complications of PEG insertion include wound infection, buried bumper syndrome, tumor seeding, peristomal leakage, and tube dislodgement. The prevalence of wound infection is 5%- 25%,16 and randomized controlled trials have demonstrated the efficacy of a single dose of an IV antibiotic (i.e., cephalosporin) in those not already receiving a broad spectrum antibiotic and administered prophylactically before tube placement.17 The significance of this reduction is such that antibiotic administration before tube placement should be considered a quality measure for the procedure. A small amount of redness around the tube site (less than 5 mm) is typical, but extension of erythema, warmth, tenderness, purulent drainage, or systemic symptoms is consistent with infection and warrants additional antibiotic administration. Minor infections can be treated with local antiseptics and oral antibiotics, and early intervention is important to prevent need for hospital admission, systemic antibiotics, and even surgical debridement.
Peristomal leakage is reported in approximately 1%-2% of patients.18 Photographs of the site can be very useful in evaluating and managing peristomal leakage and infections. Interventions include reducing gastric secretions with proton pump inhibitors and management of the skin with barrier creams, such as zinc oxide (Calmoseptine®) ointment. Placement of a larger-diameter tube only enlarges the stoma track and worsens the leakage. In such cases, thorough evaluations for delayed gastric emptying (gastroparesis), distal obstruction, or constipation should be performed and managed accordingly. Opiates are common contributors to constipation and delayed gastric emptying and often require reduction in use or directed antagonist therapy to reduce leaking. Continuous feeding over bolus feedings and delivering nutrition distally into the small bowel (PEG-J placement) can improve leaking from gastrostomy tubes. Additional means of management include stabilizing the tube by replacing a traditional tube with a low-profile tube or using right-angle external bumpers. If all measures fail, removing the tube and allowing for stomal closure can be attempted,16 although this option often requires parenteral nutrition support to prevent prolonged periods of inadequate nutrition.
Buried bumper syndrome (BBS) occurs in 1.5%-8.8% of PEG placements and is a common late complication of PEG placement, although early reports have been described.18 The development of BBS occurs when the internal bumper migrates from the gastric lumen through and into the stomach or abdominal wall. It occurs more frequently with solid nonballoon retention tubes and is caused by excessive compression of the external bumper against the skin and abdominal wall. Patients with BBS usually present with an immobile catheter, resistance with feeds (because of a closure of the stomach wall around the internal portion of the gastrostomy tube), abdominal pain, or peristomal leakage. Physicians should be aware of and assess tubes for BBS, in particular when replacing an immobile tube (cannot be pushed into the free stomach lumen) or when there is difficulty in flushing water into the tube. This complication can be easily prevented by allowing a minimum of 0.5-1.0 cm (1 finger breadth) between the external bumper and the abdominal wall. In particular, patients and caregivers should be warned that if the patient gains significant amounts of weight, the outer bumper will need to be loosened. Once BBS is diagnosed, the PEG tube requires removal and replacement as it can cause bleeding, infection, or fasciitis. The general steps to replacement include endoscopic removal of the existing tube and replacement of new PEG in the existing tract as long as the BBS is not severe. In most cases a replacement tube can be pulled into place using the pull-PEG technique at the same gastrostomy site as long as the stoma tract can be cannulated with a wire after the existing tube is removed.
Similar to nasoenteric tubes, PEG tubes can become clogged, although this complication is infrequent. The primary steps for prevention include adequately flushing with water before and after feeds and ensuring that all medications are liquid or well crushed and dissolved before instilling. Timely tube replacement also ensures that the internal portions of the gastrostomy tube remain free of debris. Management is similar to that of unclogging nasoenteral tubes, as discussed above, and specific commercial declogging devices for PEG tubes include the Bionix Declogger® (Bionix Development Corp., Toledo, Ohio) and the Bard® PEG cleaning brush (Bard Peripheral Vascular Inc., Tempe, Ariz.). The Bionix system has a plastic stem with a screw and thread design that will remove clogs in 14-24 French PEG tubes, while the Bard brush has a flexible nylon stem with soft bristles at the end to prevent mucosal injury and can be used for prophylaxis against clogs, as well as removing clogs themselves.12
Lastly, a rare but important complication of PEG placement is tumor seeding of the PEG site in patients with active head and neck or upper gastrointestinal cancer.19 The presumed mechanism is shearing of tumor cells as the PEG is pulled through the upper aerodigestive tract and through the wall of the stomach, as prior studies have demonstrated frequent seeding of tubes and incision sites as shown by brushing the tube for malignant cells after tube placement.20 It is important to recognize this complication and not misdiagnose it as granulation tissue, infection, or bleeding as the spread of the cancer generally portends a poor prognosis. Therefore, it is best to use a PEG insertion technique that does not involve pulling or pushing the PEG through the upper aerodigestive tract in patients with active cancer and instead place tubes via an external approach by colleagues in interventional radiology or via direct surgical placement.
Conclusion
Gastroenterologists occupy a unique role in evaluation, diagnosis, and management of patients requiring enteral feeding. In addition, they are best equipped to place, prevent, and manage complications of tube feeding. For this reason, it is imperative that gastroenterologists familiarize themselves with indications for enteral tubes and types of enteral tubes available, as well as the identification and management of common complications. Comprehensive understanding of these concepts will augment the practicing gastroenterologist’s ability to manage patients requiring enteral nutrition support with confidence.
References
1. Stein DJ et al. Dig Dis Sci. 2020 Jun 19. doi: 10.1007/s10620-020-06396-y.
2. American Geriatrics Society Ethics Committee and Clinical Practice and Models of Care Committee. J Am Geriatr Soc. 2014;62(8):1590-3.
3. Dietrich CG, Schoppmeyer K. World J Gastroenterol. 2020;26(20):2464-71.
4. Suzuki Y et al. T Gastroenterology Res.2012 Feb;5(1):10-20.
5. Cheung KS et al. Gastroenterology. 2020 Jul;159(1):81-95.
6. Micic D et al. Am J Gastroenterol. 2020 Sep;115(9):1367-70.
7. Fan AC et al. Gastrointest Endosc. 2002;56(6):890-4.
8. Tang SJ. Video J Encycl GI Endosc. 2014;2(2):70-3.
9. Guenter P, Lyman B. Nutr Clin Pract. 2016;31(6):769-72.
10. Acosta RD et al. Gastrointest Endosc. 2016;83(1):3-16.
11. Richter JA et al. Gastrointest Endosc. 2011;74(1):22-34.
12. Boullata JI et al. JPEN. 2017;41(1):15-103.
13. McClave SA. Tech Gastrointest Endosc. 2021;3(1):62-8.
14. Murphy CJ et al. Endosc Int Open. 2016;4(3):E292. doi: 10.1053/tgie.2001.19915.
15. Lynch CR et al. Pract Gastroenterology. 2004;28:66-77.
16. Hucl T et al. Best Pract Res Clin Gastroenterol. 2016;30(5):769-81. doi: 10.1016/j.bpg.2016.10.002.
17. Jafri NS et al. Aliment Pharmacol & Therapeut. 2007;25(6):647-56. doi: 10.1111/j.1365-2036.2007.03247.x.
18. Blumenstein I et al. World J Gastroenterol. 2014;20(26):8505-24. doi: 10.3748/wjg.v20.i26.8505.
19. Fung E et al. Surgical Endosc. 2017;31(9):3623-7. doi: 10.1007/s00464-016-5394-8.
20. Ellrichmann M et al. Endoscopy. 2013;45(07):526-31. doi: 10.1055/s-0033-1344023.
Dr. Toy is with the department of internal medicine at the University of Utah, Salt Lake City. Dr. Fang is with the division of gastroenterology and hepatology at the University of Utah.
Introduction
Gastroenterologists are in a unique position to manage individuals with feeding tubes as their training underscores principles in digestion, absorption, nutrition support, and enteral tube placement. Adequate management of individuals with feeding tubes and, importantly, the complications that arise from feeding tube use and placement require a basic understanding of intestinal anatomy and physiology. Therefore, gastroenterologists are well suited to both place and manage individuals with feeding tubes in the long term.
Indications for tube feeding
When deciding on the appropriate route for artificial nutrition support, the first decision to be made is enteral access versus parenteral nutrition support. Enteral nutrition confers multiple benefits, including preservation of the mucosal lining, reductions in complicated infections, decreased costs, and improved patient compliance. All attempts at adequate enteral access should be made before deciding on the use of parenteral nutrition. Following the clinical decision to pursue artificial means of nutrition support and enteral access, the next common decision is the anticipated duration of nutrition support. Generally, the oral or nasal tubes are used for short durations (i.e., less than 4 weeks) with percutaneous placement into the stomach or small intestine for longer-term feeding (i.e., percutaneous endoscopic gastrostomy [PEG] or percutaneous endoscopic jejunostomy [PEJ]).
The most general indication for nutrition support is an inability to maintain adequate nutritional needs with oral intake alone. General categories of inadequate oral intake include neurologic disorders, malignancy, and gastrointestinal conditions affecting digestion and absorption (Table 1). Absolute and relative contraindications to PEG placement are listed in Table 2. If an endoscopic placement is not possible, alternative means of placement (i.e., surgery or interventional radiology) can be considered to avoid the consequences of prolonged malnutrition. In-hospital mortality following PEG placement has decreased 40% over the last 10 years, which can be attributed to improved patient selection, enhanced discharge practices, and exclusion of patients with the highest comorbidity and mortality rates, like those with advanced dementia or terminal cancer.1
PEG placement in patients with dementia is controversial, with previous studies not demonstrating improved outcomes and association with high mortality rates,2 so the practice is currently not recommended by the American Geriatrics Society in individuals with advanced dementia.3 However, a large Japanese study showed that careful selection of patients with mild dementia to undergo gastrostomy increased independence fourfold; therefore, multidisciplinary involvement is often necessary in the decision to pursue artificial means of nutrition support in this population.4
The recent coronavirus disease 2019 (COVID-19) pandemic has placed additional strains on endoscopic placement and has highlighted the effect of the severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) on GI symptoms. A recent meta-analysis showed an overall incidence of GI symptoms of 17.6% in the following conditions in decreasing order of prevalence: anorexia, diarrhea, nausea, vomiting, and abdominal discomfort.5 In addition, the prolonged ventilatory requirements among a subset of individuals with the most severe COVID-19 results in extended periods of nutrition support via enteral tube placements. In individuals with ICU-acquired weakness and discharge to long-term care facilities, the placement of percutaneous endoscopic tubes may be required, although with the additional consideration of the need for an aerosolizing procedure. Delay of placement has been advocated, in addition to appropriate personal protective equipment, in order to ensure safe placement for the endoscopy staff.6
Types of feeding tubes
After deciding to feed a patient enterally and determining the anticipated duration of enteral support, the next decision is to determine the most appropriate location of feeding delivery: into the stomach or the small bowel. Gastric feeding is advantageous most commonly because of its increased capacity, allowing for larger volumes to be delivered over shorter durations. However, in the setting of postsurgical anatomy, gastroparesis, or obstructing tumors/pancreatic inflammation, distal delivery of tube feeds may be required into the jejunum. Additionally, percutaneous tubes placed into the stomach can have extenders into the small bowel (GJ tubes) to allow for feeding into the small bowel and decompression or delivery of medications into the stomach.
In general, gastric feeding is preferred over small bowel feeding as PEG tubes are more stable and have fewer complications than either PEG-J or direct PEJ tubes. Gastrostomy tubes are generally shorter and larger in diameter making them less likely to clog. PEG-J tubes have separate lumens for gastric and small intestinal access, but the smaller-bore jejunal extension tubes are more likely to clog or become dislodged. While direct PEJ is shown to have higher rates of tube patency and decreased rates of endoscopic re-intervention, compared with PEG-J,7 one limitation of a direct PEJ is difficulty in placement and site selection, which can be performed with a pediatric colonoscope or balloon enteroscopy system. Most commonly, this procedure is performed under general anesthesia.
In the case of a critically ill patient in the ICU, it is recommended to start enteral nutrition within 24-48 hours of arrival to avoid complications of prolonged calorie deficits. Nasally inserted feeding tubes (e.g., Cortrak, Avanos Medical Devices, Alpharetta, Ga.) are most commonly used at the bedside and can be placed blindly using electromagnetic image guidance, radiographically, or endoscopy. However, the small caliber of nasoenteric tubes comes with the common complication of clogging, which can be overcome with slightly larger bore gastric feeding tubes. If gastric feeding is not tolerated (e.g., in the case of vomiting, witnessed aspiration), small bowel feeding should be initiated and can be a more durable form of enteral feeding with fewer interruptions as feedings do not need to be held for procedures or symptomatic gastric intolerance. In clinical areas of question, or if there is a concern for intolerance of enteral feeding, a short trial with nasogastric or nasojejunal tube placement should be performed before a more definitive percutaneous placement.
With respect to percutaneous tubes, important characteristics to choose are the size (diameter in French units), type of internal retention device, and external appearance of the tube (standard or low profile). All percutaneous tubes contain an external retention device (i.e., bumper) that fits against the skin and an internal retention device that is either a balloon or plastic dome or funnel that prevents the tube from becoming dislodged. Balloon retention tubes require replacement every 3-6 months, while nonballoon tubes generally require replacement annually in order to prevent the plastic from cracking, which can make removal complicated. Low-profile tubes have an external cap, which, when opened, allows for extension tubing to be securely attached while in use and detached while not in use. Low-profile tubes are often preferred among younger, active patients and those with adequate dexterity to allow for attachment of the external extension tubing. These tubes are most often inserted as a replacement for an initially endoscopically placed tube, although one-step systems for initial placement are available. The size of the low-profile tube is chosen based on the size of the existing PEG tube and by measuring the length of the stoma tract using specialized measuring devices.8 Patients and caregivers can also be trained to replace balloon-type tubes on their own to limit complications of displaced or cracked tubes. Low-profile tubes are commercially available for both gastric placement and gastric placement with extension into the small bowel, which often requires fluoroscopy for secure placement.
All percutaneous enteral tubes are being transitioned to the ENfit connector system, which prevents connections from the enteral system to nonenteral systems (namely intravenous lines, chest tubes) and vice versa. Tubing misconnections have been rarely reported, and the EnFIT system is designed to prevent such misadventures that have resulted in serious complications and even mortality.9 Adapter devices are available that may be required for patients with feeding tubes who have not been transitioned yet. Most commonly with new tube placements and replacements, patients and providers will have to become familiar with the new syringes and feeding bags required with EnFIT connectors.
Gastrostomy placement can be considered a higher-risk endoscopic procedure. One complicating factor is the increased use of antiplatelet and anticoagulant therapies in individuals with a history of neurologic insults. The American Society for Gastrointestinal Endoscopy (ASGE) guidelines recommend that coumadin be held 5 days before the procedure and bridged with heparin if the patient is at high risk of thromboembolic complications. For patients on dual anti-platelet therapy, thienopyridines like clopidogrel are often stopped 5-7 days prior to procedure with continuation of aspirin,10 but there are more recent data that PEG insertion is safe with continued use of DAPT.11 Direct-acting anticoagulants (DOACs) are often stopped 24-48 hours prior to procedure and then restarted 48 hours after tube placement, but this is dependent on the half-life of the specific DOAC and the patient’s renal function. Patients with decreased creatinine clearance may need to hold the DOAC up to 3-4 days prior to the procedure. In this situation, referring to ASGE guidelines and consultation with a hematologist or managing anti-coagulation clinic is advised.10
Troubleshooting complications
Nasoenteric tubes: One of the most common and irritating complications with nasoenteric feeding tubes is clogging. To prevent clogging, the tube should be flushed frequently.12 At least 30 mL of free water should be used to flush the tube every 4-8 hours for continuous feedings or before and after bolus feeding. Additionally, 15-30 mL of water should be given with each separate medication administration, and if possible, medication administration via small-bore small bowel feeding tubes should be avoided.12 Water flushing is especially important with small-caliber tubes and pumps that deliver both feeding and water flushes. It is available for small bowel feeding in order to allow for programmed water delivery.
Warm water flushes can also help unclog the tube,12 and additional pharmacologic and mechanical devices have been promoted for clogged tubes. One common technique is mixing pancreatic enzymes (Viokase) with a crushed 325-mg tablet of nonenteric coated sodium bicarbonate and 5 mL of water to create a solution that has the alkaline properties allowing for both pancreatic enzyme activation and clog dissolution. Additionally, an endoscopic retrograde cholangiopancreatography (ERCP) catheter can be placed into longer feeding tubes to directly infuse the activated agent to the site of the clog.13 If water and enzymes are not successful in unclogging the tube, commercially available brushes can help remove clogs. The TubeClear® system (Actuated Medical, Bellefonte, Penna) has a single-use stem that is connected to AC power to create a jackhammerlike movement to remove clogs in longer nasoenteral and gastrojejunal tubes.
PEG tubes (short-term complications): Procedural and immediate postprocedural complications include bleeding, aspiration, pneumoperitoneum, and perforation. Pneumoperitoneum occurs in approximately 50% of cases and is generally clinically insignificant. The risk of pneumoperitoneum can be reduced by using CO2 insufflation.14 If the patient develops systemic signs of infection or peritoneal signs, CT scan with oral contrast is warranted for further evaluation and to assess for inadvertent perforation of overlying bowel or dislodged tube. Aspiration during or following endoscopy is another common complication of PEG placement and risk factors include over-sedation, supine positioning, advanced age, and neurologic dysfunction. This risk can be mitigated by avoiding over-sedation, immediately aspirating gastric contents when the stomach is reached, and avoiding excessive insufflation.15 In addition, elevating the head of the bed during the procedure and dedicating an assistant to perform oral suctioning during the entire procedure is recommended.
PEG tubes (long-term complications): More delayed complications of PEG insertion include wound infection, buried bumper syndrome, tumor seeding, peristomal leakage, and tube dislodgement. The prevalence of wound infection is 5%- 25%,16 and randomized controlled trials have demonstrated the efficacy of a single dose of an IV antibiotic (i.e., cephalosporin) in those not already receiving a broad spectrum antibiotic and administered prophylactically before tube placement.17 The significance of this reduction is such that antibiotic administration before tube placement should be considered a quality measure for the procedure. A small amount of redness around the tube site (less than 5 mm) is typical, but extension of erythema, warmth, tenderness, purulent drainage, or systemic symptoms is consistent with infection and warrants additional antibiotic administration. Minor infections can be treated with local antiseptics and oral antibiotics, and early intervention is important to prevent need for hospital admission, systemic antibiotics, and even surgical debridement.
Peristomal leakage is reported in approximately 1%-2% of patients.18 Photographs of the site can be very useful in evaluating and managing peristomal leakage and infections. Interventions include reducing gastric secretions with proton pump inhibitors and management of the skin with barrier creams, such as zinc oxide (Calmoseptine®) ointment. Placement of a larger-diameter tube only enlarges the stoma track and worsens the leakage. In such cases, thorough evaluations for delayed gastric emptying (gastroparesis), distal obstruction, or constipation should be performed and managed accordingly. Opiates are common contributors to constipation and delayed gastric emptying and often require reduction in use or directed antagonist therapy to reduce leaking. Continuous feeding over bolus feedings and delivering nutrition distally into the small bowel (PEG-J placement) can improve leaking from gastrostomy tubes. Additional means of management include stabilizing the tube by replacing a traditional tube with a low-profile tube or using right-angle external bumpers. If all measures fail, removing the tube and allowing for stomal closure can be attempted,16 although this option often requires parenteral nutrition support to prevent prolonged periods of inadequate nutrition.
Buried bumper syndrome (BBS) occurs in 1.5%-8.8% of PEG placements and is a common late complication of PEG placement, although early reports have been described.18 The development of BBS occurs when the internal bumper migrates from the gastric lumen through and into the stomach or abdominal wall. It occurs more frequently with solid nonballoon retention tubes and is caused by excessive compression of the external bumper against the skin and abdominal wall. Patients with BBS usually present with an immobile catheter, resistance with feeds (because of a closure of the stomach wall around the internal portion of the gastrostomy tube), abdominal pain, or peristomal leakage. Physicians should be aware of and assess tubes for BBS, in particular when replacing an immobile tube (cannot be pushed into the free stomach lumen) or when there is difficulty in flushing water into the tube. This complication can be easily prevented by allowing a minimum of 0.5-1.0 cm (1 finger breadth) between the external bumper and the abdominal wall. In particular, patients and caregivers should be warned that if the patient gains significant amounts of weight, the outer bumper will need to be loosened. Once BBS is diagnosed, the PEG tube requires removal and replacement as it can cause bleeding, infection, or fasciitis. The general steps to replacement include endoscopic removal of the existing tube and replacement of new PEG in the existing tract as long as the BBS is not severe. In most cases a replacement tube can be pulled into place using the pull-PEG technique at the same gastrostomy site as long as the stoma tract can be cannulated with a wire after the existing tube is removed.
Similar to nasoenteric tubes, PEG tubes can become clogged, although this complication is infrequent. The primary steps for prevention include adequately flushing with water before and after feeds and ensuring that all medications are liquid or well crushed and dissolved before instilling. Timely tube replacement also ensures that the internal portions of the gastrostomy tube remain free of debris. Management is similar to that of unclogging nasoenteral tubes, as discussed above, and specific commercial declogging devices for PEG tubes include the Bionix Declogger® (Bionix Development Corp., Toledo, Ohio) and the Bard® PEG cleaning brush (Bard Peripheral Vascular Inc., Tempe, Ariz.). The Bionix system has a plastic stem with a screw and thread design that will remove clogs in 14-24 French PEG tubes, while the Bard brush has a flexible nylon stem with soft bristles at the end to prevent mucosal injury and can be used for prophylaxis against clogs, as well as removing clogs themselves.12
Lastly, a rare but important complication of PEG placement is tumor seeding of the PEG site in patients with active head and neck or upper gastrointestinal cancer.19 The presumed mechanism is shearing of tumor cells as the PEG is pulled through the upper aerodigestive tract and through the wall of the stomach, as prior studies have demonstrated frequent seeding of tubes and incision sites as shown by brushing the tube for malignant cells after tube placement.20 It is important to recognize this complication and not misdiagnose it as granulation tissue, infection, or bleeding as the spread of the cancer generally portends a poor prognosis. Therefore, it is best to use a PEG insertion technique that does not involve pulling or pushing the PEG through the upper aerodigestive tract in patients with active cancer and instead place tubes via an external approach by colleagues in interventional radiology or via direct surgical placement.
Conclusion
Gastroenterologists occupy a unique role in evaluation, diagnosis, and management of patients requiring enteral feeding. In addition, they are best equipped to place, prevent, and manage complications of tube feeding. For this reason, it is imperative that gastroenterologists familiarize themselves with indications for enteral tubes and types of enteral tubes available, as well as the identification and management of common complications. Comprehensive understanding of these concepts will augment the practicing gastroenterologist’s ability to manage patients requiring enteral nutrition support with confidence.
References
1. Stein DJ et al. Dig Dis Sci. 2020 Jun 19. doi: 10.1007/s10620-020-06396-y.
2. American Geriatrics Society Ethics Committee and Clinical Practice and Models of Care Committee. J Am Geriatr Soc. 2014;62(8):1590-3.
3. Dietrich CG, Schoppmeyer K. World J Gastroenterol. 2020;26(20):2464-71.
4. Suzuki Y et al. T Gastroenterology Res.2012 Feb;5(1):10-20.
5. Cheung KS et al. Gastroenterology. 2020 Jul;159(1):81-95.
6. Micic D et al. Am J Gastroenterol. 2020 Sep;115(9):1367-70.
7. Fan AC et al. Gastrointest Endosc. 2002;56(6):890-4.
8. Tang SJ. Video J Encycl GI Endosc. 2014;2(2):70-3.
9. Guenter P, Lyman B. Nutr Clin Pract. 2016;31(6):769-72.
10. Acosta RD et al. Gastrointest Endosc. 2016;83(1):3-16.
11. Richter JA et al. Gastrointest Endosc. 2011;74(1):22-34.
12. Boullata JI et al. JPEN. 2017;41(1):15-103.
13. McClave SA. Tech Gastrointest Endosc. 2021;3(1):62-8.
14. Murphy CJ et al. Endosc Int Open. 2016;4(3):E292. doi: 10.1053/tgie.2001.19915.
15. Lynch CR et al. Pract Gastroenterology. 2004;28:66-77.
16. Hucl T et al. Best Pract Res Clin Gastroenterol. 2016;30(5):769-81. doi: 10.1016/j.bpg.2016.10.002.
17. Jafri NS et al. Aliment Pharmacol & Therapeut. 2007;25(6):647-56. doi: 10.1111/j.1365-2036.2007.03247.x.
18. Blumenstein I et al. World J Gastroenterol. 2014;20(26):8505-24. doi: 10.3748/wjg.v20.i26.8505.
19. Fung E et al. Surgical Endosc. 2017;31(9):3623-7. doi: 10.1007/s00464-016-5394-8.
20. Ellrichmann M et al. Endoscopy. 2013;45(07):526-31. doi: 10.1055/s-0033-1344023.
Dr. Toy is with the department of internal medicine at the University of Utah, Salt Lake City. Dr. Fang is with the division of gastroenterology and hepatology at the University of Utah.
Introduction
Gastroenterologists are in a unique position to manage individuals with feeding tubes as their training underscores principles in digestion, absorption, nutrition support, and enteral tube placement. Adequate management of individuals with feeding tubes and, importantly, the complications that arise from feeding tube use and placement require a basic understanding of intestinal anatomy and physiology. Therefore, gastroenterologists are well suited to both place and manage individuals with feeding tubes in the long term.
Indications for tube feeding
When deciding on the appropriate route for artificial nutrition support, the first decision to be made is enteral access versus parenteral nutrition support. Enteral nutrition confers multiple benefits, including preservation of the mucosal lining, reductions in complicated infections, decreased costs, and improved patient compliance. All attempts at adequate enteral access should be made before deciding on the use of parenteral nutrition. Following the clinical decision to pursue artificial means of nutrition support and enteral access, the next common decision is the anticipated duration of nutrition support. Generally, the oral or nasal tubes are used for short durations (i.e., less than 4 weeks) with percutaneous placement into the stomach or small intestine for longer-term feeding (i.e., percutaneous endoscopic gastrostomy [PEG] or percutaneous endoscopic jejunostomy [PEJ]).
The most general indication for nutrition support is an inability to maintain adequate nutritional needs with oral intake alone. General categories of inadequate oral intake include neurologic disorders, malignancy, and gastrointestinal conditions affecting digestion and absorption (Table 1). Absolute and relative contraindications to PEG placement are listed in Table 2. If an endoscopic placement is not possible, alternative means of placement (i.e., surgery or interventional radiology) can be considered to avoid the consequences of prolonged malnutrition. In-hospital mortality following PEG placement has decreased 40% over the last 10 years, which can be attributed to improved patient selection, enhanced discharge practices, and exclusion of patients with the highest comorbidity and mortality rates, like those with advanced dementia or terminal cancer.1
PEG placement in patients with dementia is controversial, with previous studies not demonstrating improved outcomes and association with high mortality rates,2 so the practice is currently not recommended by the American Geriatrics Society in individuals with advanced dementia.3 However, a large Japanese study showed that careful selection of patients with mild dementia to undergo gastrostomy increased independence fourfold; therefore, multidisciplinary involvement is often necessary in the decision to pursue artificial means of nutrition support in this population.4
The recent coronavirus disease 2019 (COVID-19) pandemic has placed additional strains on endoscopic placement and has highlighted the effect of the severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) on GI symptoms. A recent meta-analysis showed an overall incidence of GI symptoms of 17.6% in the following conditions in decreasing order of prevalence: anorexia, diarrhea, nausea, vomiting, and abdominal discomfort.5 In addition, the prolonged ventilatory requirements among a subset of individuals with the most severe COVID-19 results in extended periods of nutrition support via enteral tube placements. In individuals with ICU-acquired weakness and discharge to long-term care facilities, the placement of percutaneous endoscopic tubes may be required, although with the additional consideration of the need for an aerosolizing procedure. Delay of placement has been advocated, in addition to appropriate personal protective equipment, in order to ensure safe placement for the endoscopy staff.6
Types of feeding tubes
After deciding to feed a patient enterally and determining the anticipated duration of enteral support, the next decision is to determine the most appropriate location of feeding delivery: into the stomach or the small bowel. Gastric feeding is advantageous most commonly because of its increased capacity, allowing for larger volumes to be delivered over shorter durations. However, in the setting of postsurgical anatomy, gastroparesis, or obstructing tumors/pancreatic inflammation, distal delivery of tube feeds may be required into the jejunum. Additionally, percutaneous tubes placed into the stomach can have extenders into the small bowel (GJ tubes) to allow for feeding into the small bowel and decompression or delivery of medications into the stomach.
In general, gastric feeding is preferred over small bowel feeding as PEG tubes are more stable and have fewer complications than either PEG-J or direct PEJ tubes. Gastrostomy tubes are generally shorter and larger in diameter making them less likely to clog. PEG-J tubes have separate lumens for gastric and small intestinal access, but the smaller-bore jejunal extension tubes are more likely to clog or become dislodged. While direct PEJ is shown to have higher rates of tube patency and decreased rates of endoscopic re-intervention, compared with PEG-J,7 one limitation of a direct PEJ is difficulty in placement and site selection, which can be performed with a pediatric colonoscope or balloon enteroscopy system. Most commonly, this procedure is performed under general anesthesia.
In the case of a critically ill patient in the ICU, it is recommended to start enteral nutrition within 24-48 hours of arrival to avoid complications of prolonged calorie deficits. Nasally inserted feeding tubes (e.g., Cortrak, Avanos Medical Devices, Alpharetta, Ga.) are most commonly used at the bedside and can be placed blindly using electromagnetic image guidance, radiographically, or endoscopy. However, the small caliber of nasoenteric tubes comes with the common complication of clogging, which can be overcome with slightly larger bore gastric feeding tubes. If gastric feeding is not tolerated (e.g., in the case of vomiting, witnessed aspiration), small bowel feeding should be initiated and can be a more durable form of enteral feeding with fewer interruptions as feedings do not need to be held for procedures or symptomatic gastric intolerance. In clinical areas of question, or if there is a concern for intolerance of enteral feeding, a short trial with nasogastric or nasojejunal tube placement should be performed before a more definitive percutaneous placement.
With respect to percutaneous tubes, important characteristics to choose are the size (diameter in French units), type of internal retention device, and external appearance of the tube (standard or low profile). All percutaneous tubes contain an external retention device (i.e., bumper) that fits against the skin and an internal retention device that is either a balloon or plastic dome or funnel that prevents the tube from becoming dislodged. Balloon retention tubes require replacement every 3-6 months, while nonballoon tubes generally require replacement annually in order to prevent the plastic from cracking, which can make removal complicated. Low-profile tubes have an external cap, which, when opened, allows for extension tubing to be securely attached while in use and detached while not in use. Low-profile tubes are often preferred among younger, active patients and those with adequate dexterity to allow for attachment of the external extension tubing. These tubes are most often inserted as a replacement for an initially endoscopically placed tube, although one-step systems for initial placement are available. The size of the low-profile tube is chosen based on the size of the existing PEG tube and by measuring the length of the stoma tract using specialized measuring devices.8 Patients and caregivers can also be trained to replace balloon-type tubes on their own to limit complications of displaced or cracked tubes. Low-profile tubes are commercially available for both gastric placement and gastric placement with extension into the small bowel, which often requires fluoroscopy for secure placement.
All percutaneous enteral tubes are being transitioned to the ENfit connector system, which prevents connections from the enteral system to nonenteral systems (namely intravenous lines, chest tubes) and vice versa. Tubing misconnections have been rarely reported, and the EnFIT system is designed to prevent such misadventures that have resulted in serious complications and even mortality.9 Adapter devices are available that may be required for patients with feeding tubes who have not been transitioned yet. Most commonly with new tube placements and replacements, patients and providers will have to become familiar with the new syringes and feeding bags required with EnFIT connectors.
Gastrostomy placement can be considered a higher-risk endoscopic procedure. One complicating factor is the increased use of antiplatelet and anticoagulant therapies in individuals with a history of neurologic insults. The American Society for Gastrointestinal Endoscopy (ASGE) guidelines recommend that coumadin be held 5 days before the procedure and bridged with heparin if the patient is at high risk of thromboembolic complications. For patients on dual anti-platelet therapy, thienopyridines like clopidogrel are often stopped 5-7 days prior to procedure with continuation of aspirin,10 but there are more recent data that PEG insertion is safe with continued use of DAPT.11 Direct-acting anticoagulants (DOACs) are often stopped 24-48 hours prior to procedure and then restarted 48 hours after tube placement, but this is dependent on the half-life of the specific DOAC and the patient’s renal function. Patients with decreased creatinine clearance may need to hold the DOAC up to 3-4 days prior to the procedure. In this situation, referring to ASGE guidelines and consultation with a hematologist or managing anti-coagulation clinic is advised.10
Troubleshooting complications
Nasoenteric tubes: One of the most common and irritating complications with nasoenteric feeding tubes is clogging. To prevent clogging, the tube should be flushed frequently.12 At least 30 mL of free water should be used to flush the tube every 4-8 hours for continuous feedings or before and after bolus feeding. Additionally, 15-30 mL of water should be given with each separate medication administration, and if possible, medication administration via small-bore small bowel feeding tubes should be avoided.12 Water flushing is especially important with small-caliber tubes and pumps that deliver both feeding and water flushes. It is available for small bowel feeding in order to allow for programmed water delivery.
Warm water flushes can also help unclog the tube,12 and additional pharmacologic and mechanical devices have been promoted for clogged tubes. One common technique is mixing pancreatic enzymes (Viokase) with a crushed 325-mg tablet of nonenteric coated sodium bicarbonate and 5 mL of water to create a solution that has the alkaline properties allowing for both pancreatic enzyme activation and clog dissolution. Additionally, an endoscopic retrograde cholangiopancreatography (ERCP) catheter can be placed into longer feeding tubes to directly infuse the activated agent to the site of the clog.13 If water and enzymes are not successful in unclogging the tube, commercially available brushes can help remove clogs. The TubeClear® system (Actuated Medical, Bellefonte, Penna) has a single-use stem that is connected to AC power to create a jackhammerlike movement to remove clogs in longer nasoenteral and gastrojejunal tubes.
PEG tubes (short-term complications): Procedural and immediate postprocedural complications include bleeding, aspiration, pneumoperitoneum, and perforation. Pneumoperitoneum occurs in approximately 50% of cases and is generally clinically insignificant. The risk of pneumoperitoneum can be reduced by using CO2 insufflation.14 If the patient develops systemic signs of infection or peritoneal signs, CT scan with oral contrast is warranted for further evaluation and to assess for inadvertent perforation of overlying bowel or dislodged tube. Aspiration during or following endoscopy is another common complication of PEG placement and risk factors include over-sedation, supine positioning, advanced age, and neurologic dysfunction. This risk can be mitigated by avoiding over-sedation, immediately aspirating gastric contents when the stomach is reached, and avoiding excessive insufflation.15 In addition, elevating the head of the bed during the procedure and dedicating an assistant to perform oral suctioning during the entire procedure is recommended.
PEG tubes (long-term complications): More delayed complications of PEG insertion include wound infection, buried bumper syndrome, tumor seeding, peristomal leakage, and tube dislodgement. The prevalence of wound infection is 5%- 25%,16 and randomized controlled trials have demonstrated the efficacy of a single dose of an IV antibiotic (i.e., cephalosporin) in those not already receiving a broad spectrum antibiotic and administered prophylactically before tube placement.17 The significance of this reduction is such that antibiotic administration before tube placement should be considered a quality measure for the procedure. A small amount of redness around the tube site (less than 5 mm) is typical, but extension of erythema, warmth, tenderness, purulent drainage, or systemic symptoms is consistent with infection and warrants additional antibiotic administration. Minor infections can be treated with local antiseptics and oral antibiotics, and early intervention is important to prevent need for hospital admission, systemic antibiotics, and even surgical debridement.
Peristomal leakage is reported in approximately 1%-2% of patients.18 Photographs of the site can be very useful in evaluating and managing peristomal leakage and infections. Interventions include reducing gastric secretions with proton pump inhibitors and management of the skin with barrier creams, such as zinc oxide (Calmoseptine®) ointment. Placement of a larger-diameter tube only enlarges the stoma track and worsens the leakage. In such cases, thorough evaluations for delayed gastric emptying (gastroparesis), distal obstruction, or constipation should be performed and managed accordingly. Opiates are common contributors to constipation and delayed gastric emptying and often require reduction in use or directed antagonist therapy to reduce leaking. Continuous feeding over bolus feedings and delivering nutrition distally into the small bowel (PEG-J placement) can improve leaking from gastrostomy tubes. Additional means of management include stabilizing the tube by replacing a traditional tube with a low-profile tube or using right-angle external bumpers. If all measures fail, removing the tube and allowing for stomal closure can be attempted,16 although this option often requires parenteral nutrition support to prevent prolonged periods of inadequate nutrition.
Buried bumper syndrome (BBS) occurs in 1.5%-8.8% of PEG placements and is a common late complication of PEG placement, although early reports have been described.18 The development of BBS occurs when the internal bumper migrates from the gastric lumen through and into the stomach or abdominal wall. It occurs more frequently with solid nonballoon retention tubes and is caused by excessive compression of the external bumper against the skin and abdominal wall. Patients with BBS usually present with an immobile catheter, resistance with feeds (because of a closure of the stomach wall around the internal portion of the gastrostomy tube), abdominal pain, or peristomal leakage. Physicians should be aware of and assess tubes for BBS, in particular when replacing an immobile tube (cannot be pushed into the free stomach lumen) or when there is difficulty in flushing water into the tube. This complication can be easily prevented by allowing a minimum of 0.5-1.0 cm (1 finger breadth) between the external bumper and the abdominal wall. In particular, patients and caregivers should be warned that if the patient gains significant amounts of weight, the outer bumper will need to be loosened. Once BBS is diagnosed, the PEG tube requires removal and replacement as it can cause bleeding, infection, or fasciitis. The general steps to replacement include endoscopic removal of the existing tube and replacement of new PEG in the existing tract as long as the BBS is not severe. In most cases a replacement tube can be pulled into place using the pull-PEG technique at the same gastrostomy site as long as the stoma tract can be cannulated with a wire after the existing tube is removed.
Similar to nasoenteric tubes, PEG tubes can become clogged, although this complication is infrequent. The primary steps for prevention include adequately flushing with water before and after feeds and ensuring that all medications are liquid or well crushed and dissolved before instilling. Timely tube replacement also ensures that the internal portions of the gastrostomy tube remain free of debris. Management is similar to that of unclogging nasoenteral tubes, as discussed above, and specific commercial declogging devices for PEG tubes include the Bionix Declogger® (Bionix Development Corp., Toledo, Ohio) and the Bard® PEG cleaning brush (Bard Peripheral Vascular Inc., Tempe, Ariz.). The Bionix system has a plastic stem with a screw and thread design that will remove clogs in 14-24 French PEG tubes, while the Bard brush has a flexible nylon stem with soft bristles at the end to prevent mucosal injury and can be used for prophylaxis against clogs, as well as removing clogs themselves.12
Lastly, a rare but important complication of PEG placement is tumor seeding of the PEG site in patients with active head and neck or upper gastrointestinal cancer.19 The presumed mechanism is shearing of tumor cells as the PEG is pulled through the upper aerodigestive tract and through the wall of the stomach, as prior studies have demonstrated frequent seeding of tubes and incision sites as shown by brushing the tube for malignant cells after tube placement.20 It is important to recognize this complication and not misdiagnose it as granulation tissue, infection, or bleeding as the spread of the cancer generally portends a poor prognosis. Therefore, it is best to use a PEG insertion technique that does not involve pulling or pushing the PEG through the upper aerodigestive tract in patients with active cancer and instead place tubes via an external approach by colleagues in interventional radiology or via direct surgical placement.
Conclusion
Gastroenterologists occupy a unique role in evaluation, diagnosis, and management of patients requiring enteral feeding. In addition, they are best equipped to place, prevent, and manage complications of tube feeding. For this reason, it is imperative that gastroenterologists familiarize themselves with indications for enteral tubes and types of enteral tubes available, as well as the identification and management of common complications. Comprehensive understanding of these concepts will augment the practicing gastroenterologist’s ability to manage patients requiring enteral nutrition support with confidence.
References
1. Stein DJ et al. Dig Dis Sci. 2020 Jun 19. doi: 10.1007/s10620-020-06396-y.
2. American Geriatrics Society Ethics Committee and Clinical Practice and Models of Care Committee. J Am Geriatr Soc. 2014;62(8):1590-3.
3. Dietrich CG, Schoppmeyer K. World J Gastroenterol. 2020;26(20):2464-71.
4. Suzuki Y et al. T Gastroenterology Res.2012 Feb;5(1):10-20.
5. Cheung KS et al. Gastroenterology. 2020 Jul;159(1):81-95.
6. Micic D et al. Am J Gastroenterol. 2020 Sep;115(9):1367-70.
7. Fan AC et al. Gastrointest Endosc. 2002;56(6):890-4.
8. Tang SJ. Video J Encycl GI Endosc. 2014;2(2):70-3.
9. Guenter P, Lyman B. Nutr Clin Pract. 2016;31(6):769-72.
10. Acosta RD et al. Gastrointest Endosc. 2016;83(1):3-16.
11. Richter JA et al. Gastrointest Endosc. 2011;74(1):22-34.
12. Boullata JI et al. JPEN. 2017;41(1):15-103.
13. McClave SA. Tech Gastrointest Endosc. 2021;3(1):62-8.
14. Murphy CJ et al. Endosc Int Open. 2016;4(3):E292. doi: 10.1053/tgie.2001.19915.
15. Lynch CR et al. Pract Gastroenterology. 2004;28:66-77.
16. Hucl T et al. Best Pract Res Clin Gastroenterol. 2016;30(5):769-81. doi: 10.1016/j.bpg.2016.10.002.
17. Jafri NS et al. Aliment Pharmacol & Therapeut. 2007;25(6):647-56. doi: 10.1111/j.1365-2036.2007.03247.x.
18. Blumenstein I et al. World J Gastroenterol. 2014;20(26):8505-24. doi: 10.3748/wjg.v20.i26.8505.
19. Fung E et al. Surgical Endosc. 2017;31(9):3623-7. doi: 10.1007/s00464-016-5394-8.
20. Ellrichmann M et al. Endoscopy. 2013;45(07):526-31. doi: 10.1055/s-0033-1344023.
Dr. Toy is with the department of internal medicine at the University of Utah, Salt Lake City. Dr. Fang is with the division of gastroenterology and hepatology at the University of Utah.
Role of gastroenterologists in the U.S. in the management of gastric cancer
Introduction
Although gastric cancer is one of the most common causes of cancer death in the world, the burden of gastric cancer in the United States tends to be underestimated relative to that of other cancers of the digestive system. In fact, the 5-year survival rate from gastric cancer remains poor (~32%)1 in the United States, and this is largely because gastric cancers are not diagnosed at an early stage when curative therapeutic options are available. Cumulative epidemiologic data consistently demonstrate that the incidence of gastric cancer in the United States varies according to ethnicity, immigrant status, and country of origin. It is important for practicing gastroenterologists in the United States to recognize individual risk profiles and identify people at higher risk for gastric cancer. Hereditary diffuse gastric cancer is an inherited form of diffuse-type gastric cancer and has pathogenic variants in the E-cadherin gene that are inherited in an autosomal dominant pattern. The lifetime risk of gastric cancer in individuals with HDGC is very high, and prophylactic total gastrectomy is usually advised. This article focuses on intestinal type cancer.
Epidemiology
Gastric cancer (proximal and distal gastric cancer combined) is the fifth most frequently diagnosed cancer and the third most common cause of cancer death worldwide, with 1,033,701 new cases and 782,685 deaths in 2018.2 Gastric cancer is subcategorized based on location (proximal [i.e., esophagogastric junctional, gastric cardia] and distal) and histology (intestinal and diffuse type), and each subtype is considered to have a distinct pathogenesis. Distal intestinal type gastric cancer is most commonly encountered in clinical practice. In this article, gastric cancer will signify distal intestinal type gastric cancer unless it is otherwise noted. In general, incidence rates are about twofold higher in men than in women. There is marked geographic variation in incidence rates, and the age-standardized incidence rates in eastern Asia (32.1 and 13.2, per 100,000) are approximately six times higher than those in northern America (5.6 and 2.8, per 100,000) in both men and women, respectively.2 Recent studies evaluating global trends in the incidence and mortality of gastric cancer have demonstrated decreases worldwide.3-5 However, the degree of decrease in the incidence and mortality of gastric cancer varies substantially across geographic regions, reflecting the heterogeneous distribution of risk profiles. A comprehensive analysis of a U.S. population registry demonstrated a linear decrease in the incidence of gastric cancer in the United States (0.94% decrease per year between 2001 and 2015),6 though the annual percent change in the gastric cancer mortality in the United States was lower (around 2% decrease per year between 1980 and 2011) than in other countries.3Several population-based studies conducted in the United States have demonstrated that the incidence of gastric cancer varied by ethnicity, immigrant status, and country of origin, and the highest incidence was observed among Asian immigrants.7,8 A comprehensive meta-analysis examining the risk of gastric cancer in immigrants from high-incidence regions to low-incidence regions found a persistently higher risk of gastric cancer and related mortality among immigrants.9 These results indicate that there are important risk factors such as environmental and dietary factors in addition to the traditionally considered risk factors including male gender, age, family history, and tobacco use. A survey conducted in an ethnically and culturally diverse U.S. city showed that gastroenterology providers demonstrated knowledge deficiencies in identifying and managing patients with increased risk of gastric cancer.10 Recognizing individualized risk profiles in higher-risk groups (e.g., immigrants from higher-incidence/prevalence regions) is important for optimizing management of gastric cancer in the United States.
Assessment and management of modifiable risk factors
Helicobacter pylori, a group 1 carcinogen, is the most well-recognized risk factor for gastric cancer, particularly noncardia gastric cancer.11 Since a landmark longitudinal follow-up study in Japan demonstrated that people with H. pylori infection are more likely to develop gastric cancer than those without H. pylori infection,12 accumulating evidence largely from Asian countries has shown that eradication of H. pylori is associated with a reduced incidence of gastric cancer regardless of baseline risk.13 There are also data on the protective effect for gastric cancer of H. pylori eradication in asymptomatic individuals. Another meta-analysis of six international randomized control trials demonstrated a 34% relative risk reduction of gastric cancer occurrence in asymptomatic people (relative risk of developing gastric cancer was 0.66 in those who received eradication therapy compared with those with placebo or no treatment, 95% CI, 0.46-0.95).14 A U.S. practice guideline published after these meta-analyses recommends that all patients with a positive test indicating active infection with H. pylori should be offered treatment and testing to prove eradication,15 though the recommendation was not purely intended to reduce the gastric cancer risk in U.S. population. Subsequently, a Department of Veterans Affairs cohort study added valuable insights from a U.S. experience to the body of evidence from other countries with higher prevalence. In this study of more than 370,000 patients with a history of H. pylori infection, the detection and successful eradication of H. pylori was associated with a 76% lower incidence of gastric cancer compared with people without H. pylori treatment.16 This study also provided insight into H. pylori treatment practice patterns. Of patients with a positive H. pylori test result (stool antigen, urea breath test, or pathology), approximately 75% were prescribed an eradication regimen and only 21% of those underwent eradication tests. A low rate (24%) of eradication testing was subsequently reported by the same group among U.S. patients regardless of gastric cancer risk profiles.17 The lesson from the aforementioned study is that treatment and eradication of H. pylori even among asymptomatic U.S. patients reduces the risk of subsequent gastric cancer. However, it may be difficult to generalize the results of this study given the nature of the Veterans Affairs cohort, and more data are required to justify the implementation of nationwide preventive H. pylori screening in the general U.S. population.
Smoking has been recognized as the other important risk factor. A study from the European prospective multicenter cohort demonstrated a significant association of cigarette smoking and gastric cancer risk (HR for ever-smokers 1.45 [95% CI, 1.08-1.94], current-smokers in males 1.73 [95% CI, 1.06-2.83], and current smokers in females 1.87 [95% CI, 1.12-3.12], respectively) after adjustment for educational level, dietary consumption profiles, alcohol intake, and body mass index (BMI).18 A subsequent meta-analysis provided solid evidence of smoking as the important behavioral risk factor for gastric cancer.19 Smoking also predisposed to the development of proximal gastric cancer.20 Along with other cancers in the digestive system such as in the esophagus, colon and rectum, liver, gallbladder, and pancreas, a significant association of BMI and the risk of proximal gastric cancer (RR of the highest BMI category compared with normal BMI, 1.8 [95% CI, 1.3-2.5]) was reported, with positive dose-response relationships; however, the association was not sufficient for distal gastric cancer.21 There is also evidence to show a trend of greater alcohol consumption (>45 grams per day [about 3 drinks a day]) associated with the increased risk of gastric cancer.21 It has been thought that salt and salt-preserved food increase the risk of gastric cancer. It should be noted that the observational studies showing the associations were published from Asian countries where such foods were a substantial part of traditional diets (e.g., salted vegetables in Japan) and the incidence of gastric cancer is high. There is also a speculation that preserved foods may have been eaten in more underserved, low socioeconomic regions where refrigeration was not available and prevalence of H. pylori infection was higher. Except for documented inherited form of gastric cancer (e.g., HDGC or hereditary cancer syndromes), most gastric cancers are considered sporadic. A recent randomized study published from South Korea investigated a cohort of higher-risk asymptomatic patients with family history significant for gastric cancer. This study of 1,676 subjects with a median follow-up of 9.2 years showed that successful eradication of H. pylori in the first-degree relatives of those with gastric cancer significantly reduced the risk (HR 0.45 [95% CI, 0.21-0.94]) of developing gastric cancer.22 As previously discussed, in the United States where the prevalence of H. pylori and the incidence of gastric cancer are both lower than in some Asian countries, routine screening of asymptomatic individuals for H. pylori is not justified yet. There may be a role for screening individuals who are first-generation immigrants from areas of high gastric cancer incidence and also have a first-degree relative with gastric cancer.
Who should we consider high risk and offer screening EGD?
With available evidence to date, screening for gastric cancer in a general U.S. population is not recommended. However, it is important to acknowledge the aforementioned varying incidence of gastric cancer in the United States among ethnicity, immigrant status, and country of origin. Immigrants from high-incidence regions maintain a higher risk of gastric cancer and related mortality even after migration to lower-incidence regions. The latter comprehensive study estimated that as many as 12.7 million people (29.4% of total U.S. immigrant population) have emigrated from higher-incidence regions including East Asian and some Central American countries.9 Indeed, an opportunistic nationwide gastric cancer screening program has been implemented in South Korea (beginning at age 40, biannually)23 and Japan (beginning at age 50, biannually).24 Two decision-analytic simulation studies have provided insight into the uncertainty about the cost effectiveness for potential targeted gastric cancer screening in higher-risk populations in the United States. One study demonstrated that esophagogastroduodenoscopy (EGD) screening for otherwise asymptomatic Asian American people (as well as Hispanics and non-Hispanic Blacks) at the time of screening colonoscopy at 50 years of age with continued endoscopic surveillance every 3 years was cost effective, only if gastric intestinal metaplasia (GIM) or more advanced lesions were diagnosed at the index screening EGD.25 Previous studies analyzing the cost effectiveness for gastric cancer screening in the United States had the limitation of not stratifying according to race or ethnicity, or accounting for patients diagnosed with GIM. Subsequently, the same research group extended this model analysis and has published additional findings that this strategy is cost effective for each of the most prevalent Asian American ethnicities (Chinese, Filipino, Southeast Asian, Vietnamese, Korean, and Japanese Americans) in the United States irrespective of sex.26 Although the authors raised a limitation that additional risk factors such as family history, tobacco use, or persistent H. pylori infection were not considered in the model because data regarding differentiated noncardia gastric cancer risk among Asian American ethnicities based on these risk factors are not available.
These two model analytic studies added valuable insights to the body of evidence that subsequent EGDs after the one-time bundled EGD is cost effective for higher-risk asymptomatic people in the United States, if the index screening EGD with gastric mucosal biopsies demonstrates at least GIM. Further population-based research to elucidate risk stratification among higher-risk people will provide a schema that could standardize management and resource allocation as well as increase the cost effectiveness of a gastric cancer screening program in the United States. The degree of risk of developing gastric cancer in autoimmune gastritis varies among the reported studies.27-29 Although the benefit of endoscopic screening in patients with autoimmune gastritis has not been established, a single endoscopic evaluation should be recommended soon after the diagnosis of autoimmune gastritis in order to identify prevalent neoplastic lesions.30
Practical consideration when we perform EGD for early gastric cancer screening
Identification of higher-risk patients should alert an endoscopist to observe mucosa with greater care with a lower threshold to biopsy any suspicious lesions. Preprocedural risk stratification for each individual before performing diagnostic EGD will improve early gastric cancer detection. While we perform EGD, detecting precursor lesions (atrophic gastritis and GIM) is as important as diagnosing an early gastric cancer. Screening and management of patients with precursor lesions (i.e., atrophic gastritis and GIM) is beyond the scope of this article, and this was published in a previous issue of the New Gastroenterologist. It is important to first grossly survey the entire gastric mucosa using high-definition while light (HDWL) endoscopy and screen for any focal irregular (raised or depressed) mucosal lesions. These lesions are often erythematous and should be examined carefully. Use of mucolytic and/or deforming agents (e.g., N-acetylcysteine or simethicone) is recommended for the improvement of visual clarity of gastric mucosa.31 Simethicone is widely used in the United States for colonoscopy and should also be available at the time of EGD for better gastric mucosal visibility. If irregular mucosal lesions are noted, this area should also be examined under narrowband imaging (NBI) in addition to HDWL. According to a simplified classification consisting of mucosal and vascular irregularity, NBI provides better mucosal surface morphology for diagnosis of early gastric cancer compared with HDWL, and a thorough examination of the surface characteristics is a prerequisite.32 This classification was further validated in a randomized control trial, and NBI increased sensitivity for the diagnosis of neoplasia compared with HDWL (92 % vs. 74 %).33 The majority of institutions in the United States have a newer-generation NBI (Olympus America, EVIS EXERA III video system, GIF-HQ190), which provides brighter endoscopic images to better characterize gastric neoplastic lesions. Once we recognize an area suspicious for neoplasia, we should describe the macroscopic features according to a classification system.
The Paris classification, one of the most widely recognized classification systems among U.S. gastroenterologists, is recommended for gastric neoplastic lesions.34Gastric neoplastic lesions with a “superficial” endoscopic appearance are classified as subtypes of “type 0.” The term “type 0” was chosen to distinguish the classification of “superficial” lesions from the Borrmann classification for “advanced” gastric tumors, which includes types 1 to 4. In the classification, a neoplastic lesion is called “superficial” when its endoscopic appearance suggests that the depth of penetration in the digestive wall is not more than into the submucosa (i.e., there is no infiltration of the muscularis propria). The distinctive characters of polypoid and nonpolypoid lesions are summarized in Table 1. Endoscopic submucosal dissection (ESD) has steadily gained acceptance for the treatment of early gastric cancer in the United States. The American Gastroenterological Association recommended in the 2019 institutional updated clinical practice guideline that ESD should be considered the first-line therapy for visible, endoscopically resectable, superficial gastric neoplasia.35 This recommendation is further supported by the published data on efficacy and safety of ESD for early gastric neoplasia in a large multicenter cohort in the United States.36 For all suspicious lesions, irrespective of pathological neoplastic confirmation, referral to an experienced center for further evaluation and endoscopic management should be considered. Lastly, all patients with early gastric cancer should be evaluated for H. pylori infection and treated if the test is positive. Eradication of H. pylori is associated with a lower rate of metachronous gastric cancer,37 and treatment of H. pylori as secondary prevention is also recommended.
Conclusion
As summarized above, cumulative epidemiologic data consistently demonstrate that the incidence of gastric cancer in the U.S. varies according to ethnicity, immigrant status, and country of origin. New gastroenterologists will need to recognize individual risk profiles and identify people at higher risk for gastric cancer. Risk stratification before performing endoscopic evaluation will improve early gastric cancer detection and make noninvasive, effective therapies an option.
References
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13. Lee YC et al. Gastroenterology. 2016;150:1113-24.
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15. Chey W et al. Am J Gastroenterol. 2017;112:212-39.
16. Kumar S et al. Gastroenterology. 2020;158:527-36.
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22. Choi IJ et al. N Engl J Med. 2020;382:427-36.
23. Kim BJ et al. World J Gastroenterol. 2013;19:736-41.
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26. Shah SC et al. Clin Gastroenterol Hepatol. 2020 Jul 21:S1542-3565(20)30993-9. doi: 10.1016/j.cgh.2020.07.031.
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31. Chiu PWY et al. Gut. 2019;68:186-97.
32. Pimentel-Nunes P et al. Endoscopy. 2012;44:236-46.
33. Pimentel-Nunes P et al. Endoscopy. 2016;48:723-30.
34. Participants in the Paris Workshop. Gastrointest Endosc. 2003;58:S3-43.
35. Draganov PV et al. Clin Gastroenterol Hepatol. 2019;17:16-25.
36. Ngamruengphong S et al. Clin Gastroenterol Hepatol. 2020 Jun 18;S1542-3565(20)30834-X. Online ahead of print.
37. Choi IJ et al. N Engl J Med. 2018;378:1085-95.
Dr. Tomizawa is a clinical assistant professor of medicine in the division of gastroenterology, University of Washington, Seattle.
Introduction
Although gastric cancer is one of the most common causes of cancer death in the world, the burden of gastric cancer in the United States tends to be underestimated relative to that of other cancers of the digestive system. In fact, the 5-year survival rate from gastric cancer remains poor (~32%)1 in the United States, and this is largely because gastric cancers are not diagnosed at an early stage when curative therapeutic options are available. Cumulative epidemiologic data consistently demonstrate that the incidence of gastric cancer in the United States varies according to ethnicity, immigrant status, and country of origin. It is important for practicing gastroenterologists in the United States to recognize individual risk profiles and identify people at higher risk for gastric cancer. Hereditary diffuse gastric cancer is an inherited form of diffuse-type gastric cancer and has pathogenic variants in the E-cadherin gene that are inherited in an autosomal dominant pattern. The lifetime risk of gastric cancer in individuals with HDGC is very high, and prophylactic total gastrectomy is usually advised. This article focuses on intestinal type cancer.
Epidemiology
Gastric cancer (proximal and distal gastric cancer combined) is the fifth most frequently diagnosed cancer and the third most common cause of cancer death worldwide, with 1,033,701 new cases and 782,685 deaths in 2018.2 Gastric cancer is subcategorized based on location (proximal [i.e., esophagogastric junctional, gastric cardia] and distal) and histology (intestinal and diffuse type), and each subtype is considered to have a distinct pathogenesis. Distal intestinal type gastric cancer is most commonly encountered in clinical practice. In this article, gastric cancer will signify distal intestinal type gastric cancer unless it is otherwise noted. In general, incidence rates are about twofold higher in men than in women. There is marked geographic variation in incidence rates, and the age-standardized incidence rates in eastern Asia (32.1 and 13.2, per 100,000) are approximately six times higher than those in northern America (5.6 and 2.8, per 100,000) in both men and women, respectively.2 Recent studies evaluating global trends in the incidence and mortality of gastric cancer have demonstrated decreases worldwide.3-5 However, the degree of decrease in the incidence and mortality of gastric cancer varies substantially across geographic regions, reflecting the heterogeneous distribution of risk profiles. A comprehensive analysis of a U.S. population registry demonstrated a linear decrease in the incidence of gastric cancer in the United States (0.94% decrease per year between 2001 and 2015),6 though the annual percent change in the gastric cancer mortality in the United States was lower (around 2% decrease per year between 1980 and 2011) than in other countries.3Several population-based studies conducted in the United States have demonstrated that the incidence of gastric cancer varied by ethnicity, immigrant status, and country of origin, and the highest incidence was observed among Asian immigrants.7,8 A comprehensive meta-analysis examining the risk of gastric cancer in immigrants from high-incidence regions to low-incidence regions found a persistently higher risk of gastric cancer and related mortality among immigrants.9 These results indicate that there are important risk factors such as environmental and dietary factors in addition to the traditionally considered risk factors including male gender, age, family history, and tobacco use. A survey conducted in an ethnically and culturally diverse U.S. city showed that gastroenterology providers demonstrated knowledge deficiencies in identifying and managing patients with increased risk of gastric cancer.10 Recognizing individualized risk profiles in higher-risk groups (e.g., immigrants from higher-incidence/prevalence regions) is important for optimizing management of gastric cancer in the United States.
Assessment and management of modifiable risk factors
Helicobacter pylori, a group 1 carcinogen, is the most well-recognized risk factor for gastric cancer, particularly noncardia gastric cancer.11 Since a landmark longitudinal follow-up study in Japan demonstrated that people with H. pylori infection are more likely to develop gastric cancer than those without H. pylori infection,12 accumulating evidence largely from Asian countries has shown that eradication of H. pylori is associated with a reduced incidence of gastric cancer regardless of baseline risk.13 There are also data on the protective effect for gastric cancer of H. pylori eradication in asymptomatic individuals. Another meta-analysis of six international randomized control trials demonstrated a 34% relative risk reduction of gastric cancer occurrence in asymptomatic people (relative risk of developing gastric cancer was 0.66 in those who received eradication therapy compared with those with placebo or no treatment, 95% CI, 0.46-0.95).14 A U.S. practice guideline published after these meta-analyses recommends that all patients with a positive test indicating active infection with H. pylori should be offered treatment and testing to prove eradication,15 though the recommendation was not purely intended to reduce the gastric cancer risk in U.S. population. Subsequently, a Department of Veterans Affairs cohort study added valuable insights from a U.S. experience to the body of evidence from other countries with higher prevalence. In this study of more than 370,000 patients with a history of H. pylori infection, the detection and successful eradication of H. pylori was associated with a 76% lower incidence of gastric cancer compared with people without H. pylori treatment.16 This study also provided insight into H. pylori treatment practice patterns. Of patients with a positive H. pylori test result (stool antigen, urea breath test, or pathology), approximately 75% were prescribed an eradication regimen and only 21% of those underwent eradication tests. A low rate (24%) of eradication testing was subsequently reported by the same group among U.S. patients regardless of gastric cancer risk profiles.17 The lesson from the aforementioned study is that treatment and eradication of H. pylori even among asymptomatic U.S. patients reduces the risk of subsequent gastric cancer. However, it may be difficult to generalize the results of this study given the nature of the Veterans Affairs cohort, and more data are required to justify the implementation of nationwide preventive H. pylori screening in the general U.S. population.
Smoking has been recognized as the other important risk factor. A study from the European prospective multicenter cohort demonstrated a significant association of cigarette smoking and gastric cancer risk (HR for ever-smokers 1.45 [95% CI, 1.08-1.94], current-smokers in males 1.73 [95% CI, 1.06-2.83], and current smokers in females 1.87 [95% CI, 1.12-3.12], respectively) after adjustment for educational level, dietary consumption profiles, alcohol intake, and body mass index (BMI).18 A subsequent meta-analysis provided solid evidence of smoking as the important behavioral risk factor for gastric cancer.19 Smoking also predisposed to the development of proximal gastric cancer.20 Along with other cancers in the digestive system such as in the esophagus, colon and rectum, liver, gallbladder, and pancreas, a significant association of BMI and the risk of proximal gastric cancer (RR of the highest BMI category compared with normal BMI, 1.8 [95% CI, 1.3-2.5]) was reported, with positive dose-response relationships; however, the association was not sufficient for distal gastric cancer.21 There is also evidence to show a trend of greater alcohol consumption (>45 grams per day [about 3 drinks a day]) associated with the increased risk of gastric cancer.21 It has been thought that salt and salt-preserved food increase the risk of gastric cancer. It should be noted that the observational studies showing the associations were published from Asian countries where such foods were a substantial part of traditional diets (e.g., salted vegetables in Japan) and the incidence of gastric cancer is high. There is also a speculation that preserved foods may have been eaten in more underserved, low socioeconomic regions where refrigeration was not available and prevalence of H. pylori infection was higher. Except for documented inherited form of gastric cancer (e.g., HDGC or hereditary cancer syndromes), most gastric cancers are considered sporadic. A recent randomized study published from South Korea investigated a cohort of higher-risk asymptomatic patients with family history significant for gastric cancer. This study of 1,676 subjects with a median follow-up of 9.2 years showed that successful eradication of H. pylori in the first-degree relatives of those with gastric cancer significantly reduced the risk (HR 0.45 [95% CI, 0.21-0.94]) of developing gastric cancer.22 As previously discussed, in the United States where the prevalence of H. pylori and the incidence of gastric cancer are both lower than in some Asian countries, routine screening of asymptomatic individuals for H. pylori is not justified yet. There may be a role for screening individuals who are first-generation immigrants from areas of high gastric cancer incidence and also have a first-degree relative with gastric cancer.
Who should we consider high risk and offer screening EGD?
With available evidence to date, screening for gastric cancer in a general U.S. population is not recommended. However, it is important to acknowledge the aforementioned varying incidence of gastric cancer in the United States among ethnicity, immigrant status, and country of origin. Immigrants from high-incidence regions maintain a higher risk of gastric cancer and related mortality even after migration to lower-incidence regions. The latter comprehensive study estimated that as many as 12.7 million people (29.4% of total U.S. immigrant population) have emigrated from higher-incidence regions including East Asian and some Central American countries.9 Indeed, an opportunistic nationwide gastric cancer screening program has been implemented in South Korea (beginning at age 40, biannually)23 and Japan (beginning at age 50, biannually).24 Two decision-analytic simulation studies have provided insight into the uncertainty about the cost effectiveness for potential targeted gastric cancer screening in higher-risk populations in the United States. One study demonstrated that esophagogastroduodenoscopy (EGD) screening for otherwise asymptomatic Asian American people (as well as Hispanics and non-Hispanic Blacks) at the time of screening colonoscopy at 50 years of age with continued endoscopic surveillance every 3 years was cost effective, only if gastric intestinal metaplasia (GIM) or more advanced lesions were diagnosed at the index screening EGD.25 Previous studies analyzing the cost effectiveness for gastric cancer screening in the United States had the limitation of not stratifying according to race or ethnicity, or accounting for patients diagnosed with GIM. Subsequently, the same research group extended this model analysis and has published additional findings that this strategy is cost effective for each of the most prevalent Asian American ethnicities (Chinese, Filipino, Southeast Asian, Vietnamese, Korean, and Japanese Americans) in the United States irrespective of sex.26 Although the authors raised a limitation that additional risk factors such as family history, tobacco use, or persistent H. pylori infection were not considered in the model because data regarding differentiated noncardia gastric cancer risk among Asian American ethnicities based on these risk factors are not available.
These two model analytic studies added valuable insights to the body of evidence that subsequent EGDs after the one-time bundled EGD is cost effective for higher-risk asymptomatic people in the United States, if the index screening EGD with gastric mucosal biopsies demonstrates at least GIM. Further population-based research to elucidate risk stratification among higher-risk people will provide a schema that could standardize management and resource allocation as well as increase the cost effectiveness of a gastric cancer screening program in the United States. The degree of risk of developing gastric cancer in autoimmune gastritis varies among the reported studies.27-29 Although the benefit of endoscopic screening in patients with autoimmune gastritis has not been established, a single endoscopic evaluation should be recommended soon after the diagnosis of autoimmune gastritis in order to identify prevalent neoplastic lesions.30
Practical consideration when we perform EGD for early gastric cancer screening
Identification of higher-risk patients should alert an endoscopist to observe mucosa with greater care with a lower threshold to biopsy any suspicious lesions. Preprocedural risk stratification for each individual before performing diagnostic EGD will improve early gastric cancer detection. While we perform EGD, detecting precursor lesions (atrophic gastritis and GIM) is as important as diagnosing an early gastric cancer. Screening and management of patients with precursor lesions (i.e., atrophic gastritis and GIM) is beyond the scope of this article, and this was published in a previous issue of the New Gastroenterologist. It is important to first grossly survey the entire gastric mucosa using high-definition while light (HDWL) endoscopy and screen for any focal irregular (raised or depressed) mucosal lesions. These lesions are often erythematous and should be examined carefully. Use of mucolytic and/or deforming agents (e.g., N-acetylcysteine or simethicone) is recommended for the improvement of visual clarity of gastric mucosa.31 Simethicone is widely used in the United States for colonoscopy and should also be available at the time of EGD for better gastric mucosal visibility. If irregular mucosal lesions are noted, this area should also be examined under narrowband imaging (NBI) in addition to HDWL. According to a simplified classification consisting of mucosal and vascular irregularity, NBI provides better mucosal surface morphology for diagnosis of early gastric cancer compared with HDWL, and a thorough examination of the surface characteristics is a prerequisite.32 This classification was further validated in a randomized control trial, and NBI increased sensitivity for the diagnosis of neoplasia compared with HDWL (92 % vs. 74 %).33 The majority of institutions in the United States have a newer-generation NBI (Olympus America, EVIS EXERA III video system, GIF-HQ190), which provides brighter endoscopic images to better characterize gastric neoplastic lesions. Once we recognize an area suspicious for neoplasia, we should describe the macroscopic features according to a classification system.
The Paris classification, one of the most widely recognized classification systems among U.S. gastroenterologists, is recommended for gastric neoplastic lesions.34Gastric neoplastic lesions with a “superficial” endoscopic appearance are classified as subtypes of “type 0.” The term “type 0” was chosen to distinguish the classification of “superficial” lesions from the Borrmann classification for “advanced” gastric tumors, which includes types 1 to 4. In the classification, a neoplastic lesion is called “superficial” when its endoscopic appearance suggests that the depth of penetration in the digestive wall is not more than into the submucosa (i.e., there is no infiltration of the muscularis propria). The distinctive characters of polypoid and nonpolypoid lesions are summarized in Table 1. Endoscopic submucosal dissection (ESD) has steadily gained acceptance for the treatment of early gastric cancer in the United States. The American Gastroenterological Association recommended in the 2019 institutional updated clinical practice guideline that ESD should be considered the first-line therapy for visible, endoscopically resectable, superficial gastric neoplasia.35 This recommendation is further supported by the published data on efficacy and safety of ESD for early gastric neoplasia in a large multicenter cohort in the United States.36 For all suspicious lesions, irrespective of pathological neoplastic confirmation, referral to an experienced center for further evaluation and endoscopic management should be considered. Lastly, all patients with early gastric cancer should be evaluated for H. pylori infection and treated if the test is positive. Eradication of H. pylori is associated with a lower rate of metachronous gastric cancer,37 and treatment of H. pylori as secondary prevention is also recommended.
Conclusion
As summarized above, cumulative epidemiologic data consistently demonstrate that the incidence of gastric cancer in the U.S. varies according to ethnicity, immigrant status, and country of origin. New gastroenterologists will need to recognize individual risk profiles and identify people at higher risk for gastric cancer. Risk stratification before performing endoscopic evaluation will improve early gastric cancer detection and make noninvasive, effective therapies an option.
References
1. Surveillance, Epidemiology, and End Results Program cancer statistics. https://seer.cancer.gov/statfacts/html/stomach.html.
2. Bray F et al. Ca Cancer J Clin. 2018;68:394-424.
3. Ferro A et al. Eur J Cancer. 2014;50:1330-44.
4. Luo G et al. Int J Cancer. 2017;141:1333-44.
5. Arnold M et al. Eur J Cancer. 2015;51:1164-87.
6. Thrift AP, El-Serag HB. Clin Gastroenterol Hepatol. 2020;18:534-42.
7. Kim Y et al. Epidemiol Health. 2015;37:e2015066.
8. Kamineni A et al. Cancer Causes Control. 1999;10:77-83.
9. Pabla BS et al. Clin Gastroenterol Hepatol. 2020;18:347-59.
10. Shah SC et al. Knowledge Gaps among Physicians Caring for Multiethnic Populations at Increased Gastric Cancer Risk. Gut Liver. 2018 Jan 15;12(1):38-45.
11. International Agency for Research on Cancer. Monographs on the Identification of Carcinogenic Hazards to Humans. IARC. July 7, 2019. 12. Uemura N et al. N Engl J Med. 2001;345:784-9.
13. Lee YC et al. Gastroenterology. 2016;150:1113-24.
14. Ford AC et al. BMJ. 2014;348:g3174.
15. Chey W et al. Am J Gastroenterol. 2017;112:212-39.
16. Kumar S et al. Gastroenterology. 2020;158:527-36.
17. Kumar S et al. Clin Gastroenterol Hepatol. 2020 Apr 6;S1542-3565(20)30436-5.
18. González CA et al. Int J Cancer. 2003;107:629-34.
19. Ladeiras-Lopes R et al. Cancer Causes Control. 2008;19:689-701.
20. Cavaleiro-Pinto M et al. Cancer Causes Control. 2011;22:375-87.
21. Lauby-Secretan B et al. N Engl J Med. 2016;375:794-8.
22. Choi IJ et al. N Engl J Med. 2020;382:427-36.
23. Kim BJ et al. World J Gastroenterol. 2013;19:736-41.
24. Hamashima C. Jpn J Clin Oncol. 2018;48:278–86.
25. Saumoy M et al. Gastroenterology. 2018;155:648-60.
26. Shah SC et al. Clin Gastroenterol Hepatol. 2020 Jul 21:S1542-3565(20)30993-9. doi: 10.1016/j.cgh.2020.07.031.
27. Brinton LA et al. Br J Cancer. 1989;59:810-3.
28. Hsing AW et al. Cancer. 1993;71:745-50.
29. Schafer LW et al. Mayo Clin Proc. 1985;60:444-8.
30. American Society for Gastrointestinal Endoscopy Standards of Practice Committee. Gastrointest Endosc. 2015;82:1-8.
31. Chiu PWY et al. Gut. 2019;68:186-97.
32. Pimentel-Nunes P et al. Endoscopy. 2012;44:236-46.
33. Pimentel-Nunes P et al. Endoscopy. 2016;48:723-30.
34. Participants in the Paris Workshop. Gastrointest Endosc. 2003;58:S3-43.
35. Draganov PV et al. Clin Gastroenterol Hepatol. 2019;17:16-25.
36. Ngamruengphong S et al. Clin Gastroenterol Hepatol. 2020 Jun 18;S1542-3565(20)30834-X. Online ahead of print.
37. Choi IJ et al. N Engl J Med. 2018;378:1085-95.
Dr. Tomizawa is a clinical assistant professor of medicine in the division of gastroenterology, University of Washington, Seattle.
Introduction
Although gastric cancer is one of the most common causes of cancer death in the world, the burden of gastric cancer in the United States tends to be underestimated relative to that of other cancers of the digestive system. In fact, the 5-year survival rate from gastric cancer remains poor (~32%)1 in the United States, and this is largely because gastric cancers are not diagnosed at an early stage when curative therapeutic options are available. Cumulative epidemiologic data consistently demonstrate that the incidence of gastric cancer in the United States varies according to ethnicity, immigrant status, and country of origin. It is important for practicing gastroenterologists in the United States to recognize individual risk profiles and identify people at higher risk for gastric cancer. Hereditary diffuse gastric cancer is an inherited form of diffuse-type gastric cancer and has pathogenic variants in the E-cadherin gene that are inherited in an autosomal dominant pattern. The lifetime risk of gastric cancer in individuals with HDGC is very high, and prophylactic total gastrectomy is usually advised. This article focuses on intestinal type cancer.
Epidemiology
Gastric cancer (proximal and distal gastric cancer combined) is the fifth most frequently diagnosed cancer and the third most common cause of cancer death worldwide, with 1,033,701 new cases and 782,685 deaths in 2018.2 Gastric cancer is subcategorized based on location (proximal [i.e., esophagogastric junctional, gastric cardia] and distal) and histology (intestinal and diffuse type), and each subtype is considered to have a distinct pathogenesis. Distal intestinal type gastric cancer is most commonly encountered in clinical practice. In this article, gastric cancer will signify distal intestinal type gastric cancer unless it is otherwise noted. In general, incidence rates are about twofold higher in men than in women. There is marked geographic variation in incidence rates, and the age-standardized incidence rates in eastern Asia (32.1 and 13.2, per 100,000) are approximately six times higher than those in northern America (5.6 and 2.8, per 100,000) in both men and women, respectively.2 Recent studies evaluating global trends in the incidence and mortality of gastric cancer have demonstrated decreases worldwide.3-5 However, the degree of decrease in the incidence and mortality of gastric cancer varies substantially across geographic regions, reflecting the heterogeneous distribution of risk profiles. A comprehensive analysis of a U.S. population registry demonstrated a linear decrease in the incidence of gastric cancer in the United States (0.94% decrease per year between 2001 and 2015),6 though the annual percent change in the gastric cancer mortality in the United States was lower (around 2% decrease per year between 1980 and 2011) than in other countries.3Several population-based studies conducted in the United States have demonstrated that the incidence of gastric cancer varied by ethnicity, immigrant status, and country of origin, and the highest incidence was observed among Asian immigrants.7,8 A comprehensive meta-analysis examining the risk of gastric cancer in immigrants from high-incidence regions to low-incidence regions found a persistently higher risk of gastric cancer and related mortality among immigrants.9 These results indicate that there are important risk factors such as environmental and dietary factors in addition to the traditionally considered risk factors including male gender, age, family history, and tobacco use. A survey conducted in an ethnically and culturally diverse U.S. city showed that gastroenterology providers demonstrated knowledge deficiencies in identifying and managing patients with increased risk of gastric cancer.10 Recognizing individualized risk profiles in higher-risk groups (e.g., immigrants from higher-incidence/prevalence regions) is important for optimizing management of gastric cancer in the United States.
Assessment and management of modifiable risk factors
Helicobacter pylori, a group 1 carcinogen, is the most well-recognized risk factor for gastric cancer, particularly noncardia gastric cancer.11 Since a landmark longitudinal follow-up study in Japan demonstrated that people with H. pylori infection are more likely to develop gastric cancer than those without H. pylori infection,12 accumulating evidence largely from Asian countries has shown that eradication of H. pylori is associated with a reduced incidence of gastric cancer regardless of baseline risk.13 There are also data on the protective effect for gastric cancer of H. pylori eradication in asymptomatic individuals. Another meta-analysis of six international randomized control trials demonstrated a 34% relative risk reduction of gastric cancer occurrence in asymptomatic people (relative risk of developing gastric cancer was 0.66 in those who received eradication therapy compared with those with placebo or no treatment, 95% CI, 0.46-0.95).14 A U.S. practice guideline published after these meta-analyses recommends that all patients with a positive test indicating active infection with H. pylori should be offered treatment and testing to prove eradication,15 though the recommendation was not purely intended to reduce the gastric cancer risk in U.S. population. Subsequently, a Department of Veterans Affairs cohort study added valuable insights from a U.S. experience to the body of evidence from other countries with higher prevalence. In this study of more than 370,000 patients with a history of H. pylori infection, the detection and successful eradication of H. pylori was associated with a 76% lower incidence of gastric cancer compared with people without H. pylori treatment.16 This study also provided insight into H. pylori treatment practice patterns. Of patients with a positive H. pylori test result (stool antigen, urea breath test, or pathology), approximately 75% were prescribed an eradication regimen and only 21% of those underwent eradication tests. A low rate (24%) of eradication testing was subsequently reported by the same group among U.S. patients regardless of gastric cancer risk profiles.17 The lesson from the aforementioned study is that treatment and eradication of H. pylori even among asymptomatic U.S. patients reduces the risk of subsequent gastric cancer. However, it may be difficult to generalize the results of this study given the nature of the Veterans Affairs cohort, and more data are required to justify the implementation of nationwide preventive H. pylori screening in the general U.S. population.
Smoking has been recognized as the other important risk factor. A study from the European prospective multicenter cohort demonstrated a significant association of cigarette smoking and gastric cancer risk (HR for ever-smokers 1.45 [95% CI, 1.08-1.94], current-smokers in males 1.73 [95% CI, 1.06-2.83], and current smokers in females 1.87 [95% CI, 1.12-3.12], respectively) after adjustment for educational level, dietary consumption profiles, alcohol intake, and body mass index (BMI).18 A subsequent meta-analysis provided solid evidence of smoking as the important behavioral risk factor for gastric cancer.19 Smoking also predisposed to the development of proximal gastric cancer.20 Along with other cancers in the digestive system such as in the esophagus, colon and rectum, liver, gallbladder, and pancreas, a significant association of BMI and the risk of proximal gastric cancer (RR of the highest BMI category compared with normal BMI, 1.8 [95% CI, 1.3-2.5]) was reported, with positive dose-response relationships; however, the association was not sufficient for distal gastric cancer.21 There is also evidence to show a trend of greater alcohol consumption (>45 grams per day [about 3 drinks a day]) associated with the increased risk of gastric cancer.21 It has been thought that salt and salt-preserved food increase the risk of gastric cancer. It should be noted that the observational studies showing the associations were published from Asian countries where such foods were a substantial part of traditional diets (e.g., salted vegetables in Japan) and the incidence of gastric cancer is high. There is also a speculation that preserved foods may have been eaten in more underserved, low socioeconomic regions where refrigeration was not available and prevalence of H. pylori infection was higher. Except for documented inherited form of gastric cancer (e.g., HDGC or hereditary cancer syndromes), most gastric cancers are considered sporadic. A recent randomized study published from South Korea investigated a cohort of higher-risk asymptomatic patients with family history significant for gastric cancer. This study of 1,676 subjects with a median follow-up of 9.2 years showed that successful eradication of H. pylori in the first-degree relatives of those with gastric cancer significantly reduced the risk (HR 0.45 [95% CI, 0.21-0.94]) of developing gastric cancer.22 As previously discussed, in the United States where the prevalence of H. pylori and the incidence of gastric cancer are both lower than in some Asian countries, routine screening of asymptomatic individuals for H. pylori is not justified yet. There may be a role for screening individuals who are first-generation immigrants from areas of high gastric cancer incidence and also have a first-degree relative with gastric cancer.
Who should we consider high risk and offer screening EGD?
With available evidence to date, screening for gastric cancer in a general U.S. population is not recommended. However, it is important to acknowledge the aforementioned varying incidence of gastric cancer in the United States among ethnicity, immigrant status, and country of origin. Immigrants from high-incidence regions maintain a higher risk of gastric cancer and related mortality even after migration to lower-incidence regions. The latter comprehensive study estimated that as many as 12.7 million people (29.4% of total U.S. immigrant population) have emigrated from higher-incidence regions including East Asian and some Central American countries.9 Indeed, an opportunistic nationwide gastric cancer screening program has been implemented in South Korea (beginning at age 40, biannually)23 and Japan (beginning at age 50, biannually).24 Two decision-analytic simulation studies have provided insight into the uncertainty about the cost effectiveness for potential targeted gastric cancer screening in higher-risk populations in the United States. One study demonstrated that esophagogastroduodenoscopy (EGD) screening for otherwise asymptomatic Asian American people (as well as Hispanics and non-Hispanic Blacks) at the time of screening colonoscopy at 50 years of age with continued endoscopic surveillance every 3 years was cost effective, only if gastric intestinal metaplasia (GIM) or more advanced lesions were diagnosed at the index screening EGD.25 Previous studies analyzing the cost effectiveness for gastric cancer screening in the United States had the limitation of not stratifying according to race or ethnicity, or accounting for patients diagnosed with GIM. Subsequently, the same research group extended this model analysis and has published additional findings that this strategy is cost effective for each of the most prevalent Asian American ethnicities (Chinese, Filipino, Southeast Asian, Vietnamese, Korean, and Japanese Americans) in the United States irrespective of sex.26 Although the authors raised a limitation that additional risk factors such as family history, tobacco use, or persistent H. pylori infection were not considered in the model because data regarding differentiated noncardia gastric cancer risk among Asian American ethnicities based on these risk factors are not available.
These two model analytic studies added valuable insights to the body of evidence that subsequent EGDs after the one-time bundled EGD is cost effective for higher-risk asymptomatic people in the United States, if the index screening EGD with gastric mucosal biopsies demonstrates at least GIM. Further population-based research to elucidate risk stratification among higher-risk people will provide a schema that could standardize management and resource allocation as well as increase the cost effectiveness of a gastric cancer screening program in the United States. The degree of risk of developing gastric cancer in autoimmune gastritis varies among the reported studies.27-29 Although the benefit of endoscopic screening in patients with autoimmune gastritis has not been established, a single endoscopic evaluation should be recommended soon after the diagnosis of autoimmune gastritis in order to identify prevalent neoplastic lesions.30
Practical consideration when we perform EGD for early gastric cancer screening
Identification of higher-risk patients should alert an endoscopist to observe mucosa with greater care with a lower threshold to biopsy any suspicious lesions. Preprocedural risk stratification for each individual before performing diagnostic EGD will improve early gastric cancer detection. While we perform EGD, detecting precursor lesions (atrophic gastritis and GIM) is as important as diagnosing an early gastric cancer. Screening and management of patients with precursor lesions (i.e., atrophic gastritis and GIM) is beyond the scope of this article, and this was published in a previous issue of the New Gastroenterologist. It is important to first grossly survey the entire gastric mucosa using high-definition while light (HDWL) endoscopy and screen for any focal irregular (raised or depressed) mucosal lesions. These lesions are often erythematous and should be examined carefully. Use of mucolytic and/or deforming agents (e.g., N-acetylcysteine or simethicone) is recommended for the improvement of visual clarity of gastric mucosa.31 Simethicone is widely used in the United States for colonoscopy and should also be available at the time of EGD for better gastric mucosal visibility. If irregular mucosal lesions are noted, this area should also be examined under narrowband imaging (NBI) in addition to HDWL. According to a simplified classification consisting of mucosal and vascular irregularity, NBI provides better mucosal surface morphology for diagnosis of early gastric cancer compared with HDWL, and a thorough examination of the surface characteristics is a prerequisite.32 This classification was further validated in a randomized control trial, and NBI increased sensitivity for the diagnosis of neoplasia compared with HDWL (92 % vs. 74 %).33 The majority of institutions in the United States have a newer-generation NBI (Olympus America, EVIS EXERA III video system, GIF-HQ190), which provides brighter endoscopic images to better characterize gastric neoplastic lesions. Once we recognize an area suspicious for neoplasia, we should describe the macroscopic features according to a classification system.
The Paris classification, one of the most widely recognized classification systems among U.S. gastroenterologists, is recommended for gastric neoplastic lesions.34Gastric neoplastic lesions with a “superficial” endoscopic appearance are classified as subtypes of “type 0.” The term “type 0” was chosen to distinguish the classification of “superficial” lesions from the Borrmann classification for “advanced” gastric tumors, which includes types 1 to 4. In the classification, a neoplastic lesion is called “superficial” when its endoscopic appearance suggests that the depth of penetration in the digestive wall is not more than into the submucosa (i.e., there is no infiltration of the muscularis propria). The distinctive characters of polypoid and nonpolypoid lesions are summarized in Table 1. Endoscopic submucosal dissection (ESD) has steadily gained acceptance for the treatment of early gastric cancer in the United States. The American Gastroenterological Association recommended in the 2019 institutional updated clinical practice guideline that ESD should be considered the first-line therapy for visible, endoscopically resectable, superficial gastric neoplasia.35 This recommendation is further supported by the published data on efficacy and safety of ESD for early gastric neoplasia in a large multicenter cohort in the United States.36 For all suspicious lesions, irrespective of pathological neoplastic confirmation, referral to an experienced center for further evaluation and endoscopic management should be considered. Lastly, all patients with early gastric cancer should be evaluated for H. pylori infection and treated if the test is positive. Eradication of H. pylori is associated with a lower rate of metachronous gastric cancer,37 and treatment of H. pylori as secondary prevention is also recommended.
Conclusion
As summarized above, cumulative epidemiologic data consistently demonstrate that the incidence of gastric cancer in the U.S. varies according to ethnicity, immigrant status, and country of origin. New gastroenterologists will need to recognize individual risk profiles and identify people at higher risk for gastric cancer. Risk stratification before performing endoscopic evaluation will improve early gastric cancer detection and make noninvasive, effective therapies an option.
References
1. Surveillance, Epidemiology, and End Results Program cancer statistics. https://seer.cancer.gov/statfacts/html/stomach.html.
2. Bray F et al. Ca Cancer J Clin. 2018;68:394-424.
3. Ferro A et al. Eur J Cancer. 2014;50:1330-44.
4. Luo G et al. Int J Cancer. 2017;141:1333-44.
5. Arnold M et al. Eur J Cancer. 2015;51:1164-87.
6. Thrift AP, El-Serag HB. Clin Gastroenterol Hepatol. 2020;18:534-42.
7. Kim Y et al. Epidemiol Health. 2015;37:e2015066.
8. Kamineni A et al. Cancer Causes Control. 1999;10:77-83.
9. Pabla BS et al. Clin Gastroenterol Hepatol. 2020;18:347-59.
10. Shah SC et al. Knowledge Gaps among Physicians Caring for Multiethnic Populations at Increased Gastric Cancer Risk. Gut Liver. 2018 Jan 15;12(1):38-45.
11. International Agency for Research on Cancer. Monographs on the Identification of Carcinogenic Hazards to Humans. IARC. July 7, 2019. 12. Uemura N et al. N Engl J Med. 2001;345:784-9.
13. Lee YC et al. Gastroenterology. 2016;150:1113-24.
14. Ford AC et al. BMJ. 2014;348:g3174.
15. Chey W et al. Am J Gastroenterol. 2017;112:212-39.
16. Kumar S et al. Gastroenterology. 2020;158:527-36.
17. Kumar S et al. Clin Gastroenterol Hepatol. 2020 Apr 6;S1542-3565(20)30436-5.
18. González CA et al. Int J Cancer. 2003;107:629-34.
19. Ladeiras-Lopes R et al. Cancer Causes Control. 2008;19:689-701.
20. Cavaleiro-Pinto M et al. Cancer Causes Control. 2011;22:375-87.
21. Lauby-Secretan B et al. N Engl J Med. 2016;375:794-8.
22. Choi IJ et al. N Engl J Med. 2020;382:427-36.
23. Kim BJ et al. World J Gastroenterol. 2013;19:736-41.
24. Hamashima C. Jpn J Clin Oncol. 2018;48:278–86.
25. Saumoy M et al. Gastroenterology. 2018;155:648-60.
26. Shah SC et al. Clin Gastroenterol Hepatol. 2020 Jul 21:S1542-3565(20)30993-9. doi: 10.1016/j.cgh.2020.07.031.
27. Brinton LA et al. Br J Cancer. 1989;59:810-3.
28. Hsing AW et al. Cancer. 1993;71:745-50.
29. Schafer LW et al. Mayo Clin Proc. 1985;60:444-8.
30. American Society for Gastrointestinal Endoscopy Standards of Practice Committee. Gastrointest Endosc. 2015;82:1-8.
31. Chiu PWY et al. Gut. 2019;68:186-97.
32. Pimentel-Nunes P et al. Endoscopy. 2012;44:236-46.
33. Pimentel-Nunes P et al. Endoscopy. 2016;48:723-30.
34. Participants in the Paris Workshop. Gastrointest Endosc. 2003;58:S3-43.
35. Draganov PV et al. Clin Gastroenterol Hepatol. 2019;17:16-25.
36. Ngamruengphong S et al. Clin Gastroenterol Hepatol. 2020 Jun 18;S1542-3565(20)30834-X. Online ahead of print.
37. Choi IJ et al. N Engl J Med. 2018;378:1085-95.
Dr. Tomizawa is a clinical assistant professor of medicine in the division of gastroenterology, University of Washington, Seattle.
Eosinophilic esophagitis: Frequently asked questions (and answers) for the early-career gastroenterologist
Introduction
Eosinophilic esophagitis (EoE) has transformed over the past 3 decades from a rarely encountered entity to one of the most common causes of dysphagia in adults.1 Given the marked rise in prevalence, the early-career gastroenterologist will undoubtedly be involved with managing this disease.2 The typical presentation includes a young, atopic male presenting with dysphagia in the outpatient setting or, more acutely, with a food impaction when on call. As every fellow is keenly aware, the calls often come late at night as patients commonly have meat impactions while consuming dinner. Current management focuses on symptomatic, histologic, and endoscopic improvement with medication, dietary, and mechanical (i.e., dilation) modalities.
EoE is defined by the presence of esophageal dysfunction and esophageal eosinophilic inflammation with ≥15 eosinophils/high-powered field (eos/hpf) required for the diagnosis. With better understanding of the pathogenesis of EoE involving the complex interaction of environmental, host, and genetic factors, advancements have been made as it relates to the diagnostic criteria, endoscopic evaluation, and therapeutic options. In this article, we review the current management of adult patients with EoE and offer practical guidance to key questions for the young gastroenterologist as well as insights into future areas of interest.
What should I consider when diagnosing EoE?
Symptoms are central to the diagnosis and clinical presentation of EoE. In assessing symptoms, clinicians should be aware of adaptive “IMPACT” strategies patients often subconsciously develop in response to their chronic and progressive condition: Imbibing fluids with meals, modifying foods by cutting or pureeing, prolonging meal times, avoiding harder texture foods, chewing excessively, and turning away tablets/pills.3 Failure to query such adaptive behaviors may lead to an underestimation of disease activity and severity.
An important aspect to confirming the diagnosis of EoE is to exclude other causes of esophageal eosinophilia. Gastroesophageal reflux disease (GERD) is known to cause esophageal eosinophilia and historically has been viewed as a distinct disease process. In fact, initial guidelines included lack of response to a proton pump inhibitor (PPI) trial or normal esophageal pH monitoring as diagnostic criteria.4 However, as experience was garnered, it became clear that PPI therapy was effective at improving inflammation in 30%-50% of patients with clinical presentations and histologic features consistent with EoE. As such, the concept of PPI–responsive esophageal eosinophilia (PPI-REE) was introduced in 2011.5 Further investigation then highlighted that PPI-REE and EoE had nearly identical clinical, endoscopic, and histologic features as well as eosinophil biomarker and gene expression profiles. Hence, recent international guidelines no longer necessitate a PPI trial to establish a diagnosis of EoE.6
The young gastroenterologist should also be mindful of other issues related to the initial diagnosis of EoE. EoE may present concomitantly with other disease entities including GERD, “extra-esophageal” eosinophilic gastrointestinal diseases, concomitant IgE-mediated food allergy, hypereosinophilic syndromes, connective tissue disorders, autoimmune diseases, celiac disease, and inflammatory bowel disease.3 It has been speculated that some of these disorders share common aspects of genetic and environmental predisposing factors as well as shared pathogenesis. Careful history taking should include a full review of atopic conditions and GI-related symptoms and endoscopy should carefully inspect not only the esophagus, but also gastric and duodenal mucosa. The endoscopic features almost always reveal edema, rings, exudates, furrows, and strictures and can be assessed using the EoE Endoscopic Reference Scoring system (EREFS).7 EREFS allows for systematic identification of abnormalities that can inform decisions regarding treatment efficacy and decisions on the need for esophageal dilation. When the esophageal mucosa is evaluated for biopsies, furrows and exudates should be targeted, if present, and multiple biopsies (minimum of five to six) should be taken throughout the esophagus given the patchy nature of the disease.
How do I choose an initial therapy?
The choice of initial therapy considers patient preferences, medication availability, disease severity, impact on quality of life, and need for repeated endoscopies. While there are many novel agents currently being investigated in phase 2 and 3 clinical trials, the current mainstays of treatment include PPI therapy, topical steroids, dietary therapy, and dilation. Of note, there have been no head-to-head trials comparing these different modalities. A recent systematic review reported that PPIs can induce histologic remission in 42% of patients.8 The ease of use and availability of PPI therapy make this an attractive first choice for patients. Pooled estimates show that topical steroids can induce remission in 66% of patients.8 It is important to note that there is currently no Food and Drug Administration–approved formulation of steroids for the treatment of EoE. As such, there are several practical aspects to consider when instructing patients to use agents not designed for esophageal delivery (Figure 1).
Source: Dr. Patel, Dr. Hirano
Lack of insurance coverage for topical steroids can make cost of a prescription a deterrent to use. While topical steroids are well tolerated, concerns for candidiasis and adrenal insufficiency are being monitored in prospective, long-term clinical trials. Concomitant use of steroids with PPI would be appropriate for EoE patients with coexisting GERD (severe heartburn, erosive esophagitis, Barrett’s esophagus). In addition, we often combine steroids with PPI therapy for EoE patients who demonstrate a convincing but incomplete response to PPI monotherapy (i.e., reduction of baseline inflammation from 75 eos/hpf to 20 eos/hpf).
Diet therapy is a popular choice for management of EoE by patients, given the ability to remove food triggers that initiate the immune dysregulation and to avoid chronic medication use. Three dietary options have been described including an elemental, amino acid–based diet which eliminates all common food allergens, allergy testing–directed elimination diet, and an empiric elimination diet. Though elemental diets have shown the most efficacy, practical aspects of implementing, maintaining, and identifying triggers restrict their adoption by most patients and clinicians.9 Allergy-directed elimination diets, where allergens are eliminated based on office-based allergy testing, initially seemed promising, though studies have shown limited histologic remission, compared with other diet therapies as well as the inability to identify true food triggers. Advancement of office-based testing to identify food triggers is needed to streamline this dietary approach. In the adult patient, the empiric elimination diet remains an attractive choice of the available dietary therapies. In this dietary approach, which has shown efficacy in both children and adults, the most common food allergens (milk, wheat, soy, egg, nuts, and seafood) are eliminated.9
How do I make dietary therapy work in clinical practice?
Before dietary therapy is initiated, it is important that your practice is situated to support this approach and that patients fully understand the process. A multidisciplinary approach optimizes dietary therapy. Dietitians provide expert guidance on eliminating trigger foods, maintaining nutrition, and avoiding inadvertent cross-contamination. Patient questions may include the safety of consumption of non–cow-based cheese/milk, alcoholic beverages, wheat alternatives, and restaurant food. Allergists address concerns for a concomitant IgE food allergy based on a clinical history or previous testing. Patients should be informed that identifying a food trigger often takes several months and multiple endoscopies. Clinicians should be aware of potential food cost and accessibility issues as well as the reported, albeit uncommon, development of de novo IgE-mediated food allergy during reintroduction. Timing of diet therapy is also a factor in success. Patients should avoid starting diets during major holidays, family celebrations, college years, and busy travel months.
Particularly empiric elimination diets, frequently used in adults, several approaches have been described (Figure 2).
Source: Dr. Patel, Dr. Hirano
Initially, a step-down approach was described, with patients pursuing a six-food elimination diet (SFED), which eliminates the six most common triggers: milk, wheat, soy/legumes, egg, nuts, and seafood. Once in histologic remission, patients then systematically reintroduce foods in order to identify a causative trigger. Given that many patients have only one or two identified food triggers, other approaches were created including a single-food elimination diet eliminating milk, the two-food elimination diet (TFED) eliminating milk and wheat, and the four-food elimination diet (FFED) eliminating milk, wheat, soy/legumes, and eggs. A novel step-up approach has also now been described where patients start with the TFED and progress to the FFED and then potentially SFED based on histologic response.10 This approach has the potential to more readily identify triggers, decrease diagnostic time, and reduce endoscopic interventions. There are pros and cons to each elimination diet approach that should be discussed with patients. Many patients may find a one- or two-food elimination diet more feasible than a full SFED.
What should I consider when performing dilation?
Esophageal dilation is frequently used to address the fibrostenotic complications of EoE that do not as readily respond to PPI, steroid, or diet therapy. The majority of patients note symptomatic improvement following dilation, though dilation alone does not address the inflammatory component of disease.8 With a conservative approach, the complication rates of esophageal dilation in EoE are similar to that of benign, esophageal strictures. Endoscopists should be aware that endoscopy alone can miss strictures and consider both practical and technical aspects when performing dilations (Table 1).11,12
When should an allergist be consulted?
The role of the allergist in the management of patients with EoE varies by patient and practice. IgE serologic or skin testing have limited accuracy in identifying food triggers for EoE. Nevertheless, the majority of patients with EoE have an atopic condition which may include asthma, allergic rhinitis, atopic dermatitis, or IgE-mediated food allergy. Although EoE is thought to primarily occur from an immune response to ingested oral allergens, aeroallergens may exacerbate disease as evidenced by the seasonal variation in EoE symptoms in some patients. The allergist provides treatment for these “extraesophageal” atopic conditions which may, in turn, have synergistic effects on the treatment of EoE. Furthermore, allergists may prescribe biologic therapies that are FDA approved for the treatment of atopic dermatitis, asthma, and allergic rhinitis. While not approved for EoE, several of these agents have shown efficacy in phase 2 clinical trials in EoE. In some practice settings, allergists primarily manage EoE patients with the assistance of gastroenterologists for periodic endoscopic activity assessment.
What are the key aspects of maintenance therapy?
The goals of treatment focus on symptomatic, histologic, and endoscopic improvement, and the prevention of future or ongoing fibrostenotic complications.2 Because of the adaptive eating behaviors discussed above, symptom response may not reliably correlate with histologic and/or endoscopic improvement. Moreover, dysphagia is related to strictures that often do not resolve in spite of resolution of mucosal inflammation. As such, histology and endoscopy are more objective and reliable targets of a successful response to therapy. Though studies have used variable esophageal density levels for response, using a cutoff of <15 eos/hpf as a therapeutic endpoint is reasonable for both initial response to therapy and long-term monitoring.13 We advocate for standardization of reporting endoscopic findings to better track change over time using the EREFS scoring system.7 While inflammatory features improve, the fibrostenotic features may persist despite improvement in histology. Dilation is often performed in these situations, especially for symptomatic individuals.
During clinical follow-up, the frequency of monitoring as it relates to symptom and endoscopic assessment is not well defined. It is reasonable to repeat endoscopic intervention following changes in therapy (i.e., reduction in steroid dosing or reintroduction of putative food triggers) or in symptoms.13 It is unclear if patients benefit from repeated endoscopies at set intervals without symptom change and after histologic response has been confirmed. In our practice, endoscopies are often considered on an annual basis. This interval is increased for patients with demonstrated stability of disease.
For patients who opt for dietary therapy and have one or two food triggers identified, long-term maintenance therapy can be straightforward with ongoing food avoidance. Limited data exist regarding long-term effectiveness of dietary therapy but loss of initial response has been reported that is often attributed to problems with adherence. Use of “diet holidays” or “planned cheats” to allow for intermittent consumption of trigger foods, often under the cover of short-term use of steroids, may improve the long-term feasibility of diet approaches.
In the recent American Gastroenterological Association guidelines, continuation of swallowed, topical steroids is recommended following remission with short-term treatment. The recurrence of both symptoms and inflammation following medication withdrawal supports this practice. Furthermore, natural history studies demonstrate progression of esophageal strictures with untreated disease.
There are no clear guidelines for long-term dosage and use of PPI or topical steroid therapy. Our practice is to down-titrate the dose of PPI or steroid following remission with short-term therapy, often starting with a reduction from twice a day to daily dosing. Although topical steroid therapy has fewer side effects, compared with systemic steroids, patients should be aware of the potential for adrenal suppression especially in an atopic population who may be exposed to multiple forms of topical steroids. Shared decision-making between patients and providers is recommended to determine comfort level with long-term use of prescription medications and dosage.
What’s on the horizon?
Several areas of development are underway to better assess and manage EoE. Novel histologic scoring tools now assess characteristics on pathology beyond eosinophil density, office-based testing modalities have been developed to assess inflammatory activity and thereby obviate the need for endoscopy, new technology can provide measures of esophageal remodeling and provide assessment of disease severity, and several biologic agents are being studied that target specific allergic mediators of the immune response in EoE.3,14-18 These novel tools, technologies, and therapies will undoubtedly change the management approach to EoE. Referral of patients into ongoing clinical trials will help inform advances in the field.
Conclusion
As an increasingly prevalent disease with a high degree of upper GI morbidity, EoE has transitioned from a rare entity to a commonly encountered disease. The new gastroenterologist will confront both straightforward as well as complex patients with EoE, and we offer several practical aspects on management. In the years ahead, the care of patients with EoE will continue to evolve to a more streamlined, effective, and personalized approach.
References
1. Kidambi T et al. World J Gastroenterol. 2012;18:4335-41.
2. Dellon ES et al. Gastroenterology. 2018;154:319-32 e3.
3. Hirano I et al. Gastroenterology. 2020;158:840-51.
4. Furuta GT et al. Gastroenterology. 2007;133:1342-63.
5. Liacouras CA et al. J Allergy Clin Immunol. 2011;128:3-20 e6; quiz 1-2.
6. Dellon ES et al. Gastroenterology. 2018;155:1022-33 e10.
7. Hirano I et al. Gut. 2013;62:489-95.
8. Rank MA et al. Gastroenterology. 2020;158:1789-810 e15.
9. Arias A et al. Gastroenterology. 2014;146:1639-48.
10. Molina-Infante J et al. J Allergy Clin Immunol. 2018;141:1365-72.
11. Gentile N et al. Aliment Pharmacol Ther. 2014;40:1333-40.
12. Hirano I. Gastroenterology. 2018;155:601-6.
13. Hirano I et al. Gastroenterology. 2020;158:1776-86.
14. Collins MH et al. Dis Esophagus. 2017;30:1-8.
15. Furuta GT et al. Gut. 2013;62:1395-405.
16. Katzka DA et al. Clin Gastroenterol Hepatol. 2015;13:77-83 e2.
17. Kwiatek MA et al. Gastroenterology. 2011;140:82-90.
18. Nicodeme F et al. Clin Gastroenterol Hepatol. 2013;11:1101-7 e1.
Introduction
Eosinophilic esophagitis (EoE) has transformed over the past 3 decades from a rarely encountered entity to one of the most common causes of dysphagia in adults.1 Given the marked rise in prevalence, the early-career gastroenterologist will undoubtedly be involved with managing this disease.2 The typical presentation includes a young, atopic male presenting with dysphagia in the outpatient setting or, more acutely, with a food impaction when on call. As every fellow is keenly aware, the calls often come late at night as patients commonly have meat impactions while consuming dinner. Current management focuses on symptomatic, histologic, and endoscopic improvement with medication, dietary, and mechanical (i.e., dilation) modalities.
EoE is defined by the presence of esophageal dysfunction and esophageal eosinophilic inflammation with ≥15 eosinophils/high-powered field (eos/hpf) required for the diagnosis. With better understanding of the pathogenesis of EoE involving the complex interaction of environmental, host, and genetic factors, advancements have been made as it relates to the diagnostic criteria, endoscopic evaluation, and therapeutic options. In this article, we review the current management of adult patients with EoE and offer practical guidance to key questions for the young gastroenterologist as well as insights into future areas of interest.
What should I consider when diagnosing EoE?
Symptoms are central to the diagnosis and clinical presentation of EoE. In assessing symptoms, clinicians should be aware of adaptive “IMPACT” strategies patients often subconsciously develop in response to their chronic and progressive condition: Imbibing fluids with meals, modifying foods by cutting or pureeing, prolonging meal times, avoiding harder texture foods, chewing excessively, and turning away tablets/pills.3 Failure to query such adaptive behaviors may lead to an underestimation of disease activity and severity.
An important aspect to confirming the diagnosis of EoE is to exclude other causes of esophageal eosinophilia. Gastroesophageal reflux disease (GERD) is known to cause esophageal eosinophilia and historically has been viewed as a distinct disease process. In fact, initial guidelines included lack of response to a proton pump inhibitor (PPI) trial or normal esophageal pH monitoring as diagnostic criteria.4 However, as experience was garnered, it became clear that PPI therapy was effective at improving inflammation in 30%-50% of patients with clinical presentations and histologic features consistent with EoE. As such, the concept of PPI–responsive esophageal eosinophilia (PPI-REE) was introduced in 2011.5 Further investigation then highlighted that PPI-REE and EoE had nearly identical clinical, endoscopic, and histologic features as well as eosinophil biomarker and gene expression profiles. Hence, recent international guidelines no longer necessitate a PPI trial to establish a diagnosis of EoE.6
The young gastroenterologist should also be mindful of other issues related to the initial diagnosis of EoE. EoE may present concomitantly with other disease entities including GERD, “extra-esophageal” eosinophilic gastrointestinal diseases, concomitant IgE-mediated food allergy, hypereosinophilic syndromes, connective tissue disorders, autoimmune diseases, celiac disease, and inflammatory bowel disease.3 It has been speculated that some of these disorders share common aspects of genetic and environmental predisposing factors as well as shared pathogenesis. Careful history taking should include a full review of atopic conditions and GI-related symptoms and endoscopy should carefully inspect not only the esophagus, but also gastric and duodenal mucosa. The endoscopic features almost always reveal edema, rings, exudates, furrows, and strictures and can be assessed using the EoE Endoscopic Reference Scoring system (EREFS).7 EREFS allows for systematic identification of abnormalities that can inform decisions regarding treatment efficacy and decisions on the need for esophageal dilation. When the esophageal mucosa is evaluated for biopsies, furrows and exudates should be targeted, if present, and multiple biopsies (minimum of five to six) should be taken throughout the esophagus given the patchy nature of the disease.
How do I choose an initial therapy?
The choice of initial therapy considers patient preferences, medication availability, disease severity, impact on quality of life, and need for repeated endoscopies. While there are many novel agents currently being investigated in phase 2 and 3 clinical trials, the current mainstays of treatment include PPI therapy, topical steroids, dietary therapy, and dilation. Of note, there have been no head-to-head trials comparing these different modalities. A recent systematic review reported that PPIs can induce histologic remission in 42% of patients.8 The ease of use and availability of PPI therapy make this an attractive first choice for patients. Pooled estimates show that topical steroids can induce remission in 66% of patients.8 It is important to note that there is currently no Food and Drug Administration–approved formulation of steroids for the treatment of EoE. As such, there are several practical aspects to consider when instructing patients to use agents not designed for esophageal delivery (Figure 1).
Source: Dr. Patel, Dr. Hirano
Lack of insurance coverage for topical steroids can make cost of a prescription a deterrent to use. While topical steroids are well tolerated, concerns for candidiasis and adrenal insufficiency are being monitored in prospective, long-term clinical trials. Concomitant use of steroids with PPI would be appropriate for EoE patients with coexisting GERD (severe heartburn, erosive esophagitis, Barrett’s esophagus). In addition, we often combine steroids with PPI therapy for EoE patients who demonstrate a convincing but incomplete response to PPI monotherapy (i.e., reduction of baseline inflammation from 75 eos/hpf to 20 eos/hpf).
Diet therapy is a popular choice for management of EoE by patients, given the ability to remove food triggers that initiate the immune dysregulation and to avoid chronic medication use. Three dietary options have been described including an elemental, amino acid–based diet which eliminates all common food allergens, allergy testing–directed elimination diet, and an empiric elimination diet. Though elemental diets have shown the most efficacy, practical aspects of implementing, maintaining, and identifying triggers restrict their adoption by most patients and clinicians.9 Allergy-directed elimination diets, where allergens are eliminated based on office-based allergy testing, initially seemed promising, though studies have shown limited histologic remission, compared with other diet therapies as well as the inability to identify true food triggers. Advancement of office-based testing to identify food triggers is needed to streamline this dietary approach. In the adult patient, the empiric elimination diet remains an attractive choice of the available dietary therapies. In this dietary approach, which has shown efficacy in both children and adults, the most common food allergens (milk, wheat, soy, egg, nuts, and seafood) are eliminated.9
How do I make dietary therapy work in clinical practice?
Before dietary therapy is initiated, it is important that your practice is situated to support this approach and that patients fully understand the process. A multidisciplinary approach optimizes dietary therapy. Dietitians provide expert guidance on eliminating trigger foods, maintaining nutrition, and avoiding inadvertent cross-contamination. Patient questions may include the safety of consumption of non–cow-based cheese/milk, alcoholic beverages, wheat alternatives, and restaurant food. Allergists address concerns for a concomitant IgE food allergy based on a clinical history or previous testing. Patients should be informed that identifying a food trigger often takes several months and multiple endoscopies. Clinicians should be aware of potential food cost and accessibility issues as well as the reported, albeit uncommon, development of de novo IgE-mediated food allergy during reintroduction. Timing of diet therapy is also a factor in success. Patients should avoid starting diets during major holidays, family celebrations, college years, and busy travel months.
Particularly empiric elimination diets, frequently used in adults, several approaches have been described (Figure 2).
Source: Dr. Patel, Dr. Hirano
Initially, a step-down approach was described, with patients pursuing a six-food elimination diet (SFED), which eliminates the six most common triggers: milk, wheat, soy/legumes, egg, nuts, and seafood. Once in histologic remission, patients then systematically reintroduce foods in order to identify a causative trigger. Given that many patients have only one or two identified food triggers, other approaches were created including a single-food elimination diet eliminating milk, the two-food elimination diet (TFED) eliminating milk and wheat, and the four-food elimination diet (FFED) eliminating milk, wheat, soy/legumes, and eggs. A novel step-up approach has also now been described where patients start with the TFED and progress to the FFED and then potentially SFED based on histologic response.10 This approach has the potential to more readily identify triggers, decrease diagnostic time, and reduce endoscopic interventions. There are pros and cons to each elimination diet approach that should be discussed with patients. Many patients may find a one- or two-food elimination diet more feasible than a full SFED.
What should I consider when performing dilation?
Esophageal dilation is frequently used to address the fibrostenotic complications of EoE that do not as readily respond to PPI, steroid, or diet therapy. The majority of patients note symptomatic improvement following dilation, though dilation alone does not address the inflammatory component of disease.8 With a conservative approach, the complication rates of esophageal dilation in EoE are similar to that of benign, esophageal strictures. Endoscopists should be aware that endoscopy alone can miss strictures and consider both practical and technical aspects when performing dilations (Table 1).11,12
When should an allergist be consulted?
The role of the allergist in the management of patients with EoE varies by patient and practice. IgE serologic or skin testing have limited accuracy in identifying food triggers for EoE. Nevertheless, the majority of patients with EoE have an atopic condition which may include asthma, allergic rhinitis, atopic dermatitis, or IgE-mediated food allergy. Although EoE is thought to primarily occur from an immune response to ingested oral allergens, aeroallergens may exacerbate disease as evidenced by the seasonal variation in EoE symptoms in some patients. The allergist provides treatment for these “extraesophageal” atopic conditions which may, in turn, have synergistic effects on the treatment of EoE. Furthermore, allergists may prescribe biologic therapies that are FDA approved for the treatment of atopic dermatitis, asthma, and allergic rhinitis. While not approved for EoE, several of these agents have shown efficacy in phase 2 clinical trials in EoE. In some practice settings, allergists primarily manage EoE patients with the assistance of gastroenterologists for periodic endoscopic activity assessment.
What are the key aspects of maintenance therapy?
The goals of treatment focus on symptomatic, histologic, and endoscopic improvement, and the prevention of future or ongoing fibrostenotic complications.2 Because of the adaptive eating behaviors discussed above, symptom response may not reliably correlate with histologic and/or endoscopic improvement. Moreover, dysphagia is related to strictures that often do not resolve in spite of resolution of mucosal inflammation. As such, histology and endoscopy are more objective and reliable targets of a successful response to therapy. Though studies have used variable esophageal density levels for response, using a cutoff of <15 eos/hpf as a therapeutic endpoint is reasonable for both initial response to therapy and long-term monitoring.13 We advocate for standardization of reporting endoscopic findings to better track change over time using the EREFS scoring system.7 While inflammatory features improve, the fibrostenotic features may persist despite improvement in histology. Dilation is often performed in these situations, especially for symptomatic individuals.
During clinical follow-up, the frequency of monitoring as it relates to symptom and endoscopic assessment is not well defined. It is reasonable to repeat endoscopic intervention following changes in therapy (i.e., reduction in steroid dosing or reintroduction of putative food triggers) or in symptoms.13 It is unclear if patients benefit from repeated endoscopies at set intervals without symptom change and after histologic response has been confirmed. In our practice, endoscopies are often considered on an annual basis. This interval is increased for patients with demonstrated stability of disease.
For patients who opt for dietary therapy and have one or two food triggers identified, long-term maintenance therapy can be straightforward with ongoing food avoidance. Limited data exist regarding long-term effectiveness of dietary therapy but loss of initial response has been reported that is often attributed to problems with adherence. Use of “diet holidays” or “planned cheats” to allow for intermittent consumption of trigger foods, often under the cover of short-term use of steroids, may improve the long-term feasibility of diet approaches.
In the recent American Gastroenterological Association guidelines, continuation of swallowed, topical steroids is recommended following remission with short-term treatment. The recurrence of both symptoms and inflammation following medication withdrawal supports this practice. Furthermore, natural history studies demonstrate progression of esophageal strictures with untreated disease.
There are no clear guidelines for long-term dosage and use of PPI or topical steroid therapy. Our practice is to down-titrate the dose of PPI or steroid following remission with short-term therapy, often starting with a reduction from twice a day to daily dosing. Although topical steroid therapy has fewer side effects, compared with systemic steroids, patients should be aware of the potential for adrenal suppression especially in an atopic population who may be exposed to multiple forms of topical steroids. Shared decision-making between patients and providers is recommended to determine comfort level with long-term use of prescription medications and dosage.
What’s on the horizon?
Several areas of development are underway to better assess and manage EoE. Novel histologic scoring tools now assess characteristics on pathology beyond eosinophil density, office-based testing modalities have been developed to assess inflammatory activity and thereby obviate the need for endoscopy, new technology can provide measures of esophageal remodeling and provide assessment of disease severity, and several biologic agents are being studied that target specific allergic mediators of the immune response in EoE.3,14-18 These novel tools, technologies, and therapies will undoubtedly change the management approach to EoE. Referral of patients into ongoing clinical trials will help inform advances in the field.
Conclusion
As an increasingly prevalent disease with a high degree of upper GI morbidity, EoE has transitioned from a rare entity to a commonly encountered disease. The new gastroenterologist will confront both straightforward as well as complex patients with EoE, and we offer several practical aspects on management. In the years ahead, the care of patients with EoE will continue to evolve to a more streamlined, effective, and personalized approach.
References
1. Kidambi T et al. World J Gastroenterol. 2012;18:4335-41.
2. Dellon ES et al. Gastroenterology. 2018;154:319-32 e3.
3. Hirano I et al. Gastroenterology. 2020;158:840-51.
4. Furuta GT et al. Gastroenterology. 2007;133:1342-63.
5. Liacouras CA et al. J Allergy Clin Immunol. 2011;128:3-20 e6; quiz 1-2.
6. Dellon ES et al. Gastroenterology. 2018;155:1022-33 e10.
7. Hirano I et al. Gut. 2013;62:489-95.
8. Rank MA et al. Gastroenterology. 2020;158:1789-810 e15.
9. Arias A et al. Gastroenterology. 2014;146:1639-48.
10. Molina-Infante J et al. J Allergy Clin Immunol. 2018;141:1365-72.
11. Gentile N et al. Aliment Pharmacol Ther. 2014;40:1333-40.
12. Hirano I. Gastroenterology. 2018;155:601-6.
13. Hirano I et al. Gastroenterology. 2020;158:1776-86.
14. Collins MH et al. Dis Esophagus. 2017;30:1-8.
15. Furuta GT et al. Gut. 2013;62:1395-405.
16. Katzka DA et al. Clin Gastroenterol Hepatol. 2015;13:77-83 e2.
17. Kwiatek MA et al. Gastroenterology. 2011;140:82-90.
18. Nicodeme F et al. Clin Gastroenterol Hepatol. 2013;11:1101-7 e1.
Introduction
Eosinophilic esophagitis (EoE) has transformed over the past 3 decades from a rarely encountered entity to one of the most common causes of dysphagia in adults.1 Given the marked rise in prevalence, the early-career gastroenterologist will undoubtedly be involved with managing this disease.2 The typical presentation includes a young, atopic male presenting with dysphagia in the outpatient setting or, more acutely, with a food impaction when on call. As every fellow is keenly aware, the calls often come late at night as patients commonly have meat impactions while consuming dinner. Current management focuses on symptomatic, histologic, and endoscopic improvement with medication, dietary, and mechanical (i.e., dilation) modalities.
EoE is defined by the presence of esophageal dysfunction and esophageal eosinophilic inflammation with ≥15 eosinophils/high-powered field (eos/hpf) required for the diagnosis. With better understanding of the pathogenesis of EoE involving the complex interaction of environmental, host, and genetic factors, advancements have been made as it relates to the diagnostic criteria, endoscopic evaluation, and therapeutic options. In this article, we review the current management of adult patients with EoE and offer practical guidance to key questions for the young gastroenterologist as well as insights into future areas of interest.
What should I consider when diagnosing EoE?
Symptoms are central to the diagnosis and clinical presentation of EoE. In assessing symptoms, clinicians should be aware of adaptive “IMPACT” strategies patients often subconsciously develop in response to their chronic and progressive condition: Imbibing fluids with meals, modifying foods by cutting or pureeing, prolonging meal times, avoiding harder texture foods, chewing excessively, and turning away tablets/pills.3 Failure to query such adaptive behaviors may lead to an underestimation of disease activity and severity.
An important aspect to confirming the diagnosis of EoE is to exclude other causes of esophageal eosinophilia. Gastroesophageal reflux disease (GERD) is known to cause esophageal eosinophilia and historically has been viewed as a distinct disease process. In fact, initial guidelines included lack of response to a proton pump inhibitor (PPI) trial or normal esophageal pH monitoring as diagnostic criteria.4 However, as experience was garnered, it became clear that PPI therapy was effective at improving inflammation in 30%-50% of patients with clinical presentations and histologic features consistent with EoE. As such, the concept of PPI–responsive esophageal eosinophilia (PPI-REE) was introduced in 2011.5 Further investigation then highlighted that PPI-REE and EoE had nearly identical clinical, endoscopic, and histologic features as well as eosinophil biomarker and gene expression profiles. Hence, recent international guidelines no longer necessitate a PPI trial to establish a diagnosis of EoE.6
The young gastroenterologist should also be mindful of other issues related to the initial diagnosis of EoE. EoE may present concomitantly with other disease entities including GERD, “extra-esophageal” eosinophilic gastrointestinal diseases, concomitant IgE-mediated food allergy, hypereosinophilic syndromes, connective tissue disorders, autoimmune diseases, celiac disease, and inflammatory bowel disease.3 It has been speculated that some of these disorders share common aspects of genetic and environmental predisposing factors as well as shared pathogenesis. Careful history taking should include a full review of atopic conditions and GI-related symptoms and endoscopy should carefully inspect not only the esophagus, but also gastric and duodenal mucosa. The endoscopic features almost always reveal edema, rings, exudates, furrows, and strictures and can be assessed using the EoE Endoscopic Reference Scoring system (EREFS).7 EREFS allows for systematic identification of abnormalities that can inform decisions regarding treatment efficacy and decisions on the need for esophageal dilation. When the esophageal mucosa is evaluated for biopsies, furrows and exudates should be targeted, if present, and multiple biopsies (minimum of five to six) should be taken throughout the esophagus given the patchy nature of the disease.
How do I choose an initial therapy?
The choice of initial therapy considers patient preferences, medication availability, disease severity, impact on quality of life, and need for repeated endoscopies. While there are many novel agents currently being investigated in phase 2 and 3 clinical trials, the current mainstays of treatment include PPI therapy, topical steroids, dietary therapy, and dilation. Of note, there have been no head-to-head trials comparing these different modalities. A recent systematic review reported that PPIs can induce histologic remission in 42% of patients.8 The ease of use and availability of PPI therapy make this an attractive first choice for patients. Pooled estimates show that topical steroids can induce remission in 66% of patients.8 It is important to note that there is currently no Food and Drug Administration–approved formulation of steroids for the treatment of EoE. As such, there are several practical aspects to consider when instructing patients to use agents not designed for esophageal delivery (Figure 1).
Source: Dr. Patel, Dr. Hirano
Lack of insurance coverage for topical steroids can make cost of a prescription a deterrent to use. While topical steroids are well tolerated, concerns for candidiasis and adrenal insufficiency are being monitored in prospective, long-term clinical trials. Concomitant use of steroids with PPI would be appropriate for EoE patients with coexisting GERD (severe heartburn, erosive esophagitis, Barrett’s esophagus). In addition, we often combine steroids with PPI therapy for EoE patients who demonstrate a convincing but incomplete response to PPI monotherapy (i.e., reduction of baseline inflammation from 75 eos/hpf to 20 eos/hpf).
Diet therapy is a popular choice for management of EoE by patients, given the ability to remove food triggers that initiate the immune dysregulation and to avoid chronic medication use. Three dietary options have been described including an elemental, amino acid–based diet which eliminates all common food allergens, allergy testing–directed elimination diet, and an empiric elimination diet. Though elemental diets have shown the most efficacy, practical aspects of implementing, maintaining, and identifying triggers restrict their adoption by most patients and clinicians.9 Allergy-directed elimination diets, where allergens are eliminated based on office-based allergy testing, initially seemed promising, though studies have shown limited histologic remission, compared with other diet therapies as well as the inability to identify true food triggers. Advancement of office-based testing to identify food triggers is needed to streamline this dietary approach. In the adult patient, the empiric elimination diet remains an attractive choice of the available dietary therapies. In this dietary approach, which has shown efficacy in both children and adults, the most common food allergens (milk, wheat, soy, egg, nuts, and seafood) are eliminated.9
How do I make dietary therapy work in clinical practice?
Before dietary therapy is initiated, it is important that your practice is situated to support this approach and that patients fully understand the process. A multidisciplinary approach optimizes dietary therapy. Dietitians provide expert guidance on eliminating trigger foods, maintaining nutrition, and avoiding inadvertent cross-contamination. Patient questions may include the safety of consumption of non–cow-based cheese/milk, alcoholic beverages, wheat alternatives, and restaurant food. Allergists address concerns for a concomitant IgE food allergy based on a clinical history or previous testing. Patients should be informed that identifying a food trigger often takes several months and multiple endoscopies. Clinicians should be aware of potential food cost and accessibility issues as well as the reported, albeit uncommon, development of de novo IgE-mediated food allergy during reintroduction. Timing of diet therapy is also a factor in success. Patients should avoid starting diets during major holidays, family celebrations, college years, and busy travel months.
Particularly empiric elimination diets, frequently used in adults, several approaches have been described (Figure 2).
Source: Dr. Patel, Dr. Hirano
Initially, a step-down approach was described, with patients pursuing a six-food elimination diet (SFED), which eliminates the six most common triggers: milk, wheat, soy/legumes, egg, nuts, and seafood. Once in histologic remission, patients then systematically reintroduce foods in order to identify a causative trigger. Given that many patients have only one or two identified food triggers, other approaches were created including a single-food elimination diet eliminating milk, the two-food elimination diet (TFED) eliminating milk and wheat, and the four-food elimination diet (FFED) eliminating milk, wheat, soy/legumes, and eggs. A novel step-up approach has also now been described where patients start with the TFED and progress to the FFED and then potentially SFED based on histologic response.10 This approach has the potential to more readily identify triggers, decrease diagnostic time, and reduce endoscopic interventions. There are pros and cons to each elimination diet approach that should be discussed with patients. Many patients may find a one- or two-food elimination diet more feasible than a full SFED.
What should I consider when performing dilation?
Esophageal dilation is frequently used to address the fibrostenotic complications of EoE that do not as readily respond to PPI, steroid, or diet therapy. The majority of patients note symptomatic improvement following dilation, though dilation alone does not address the inflammatory component of disease.8 With a conservative approach, the complication rates of esophageal dilation in EoE are similar to that of benign, esophageal strictures. Endoscopists should be aware that endoscopy alone can miss strictures and consider both practical and technical aspects when performing dilations (Table 1).11,12
When should an allergist be consulted?
The role of the allergist in the management of patients with EoE varies by patient and practice. IgE serologic or skin testing have limited accuracy in identifying food triggers for EoE. Nevertheless, the majority of patients with EoE have an atopic condition which may include asthma, allergic rhinitis, atopic dermatitis, or IgE-mediated food allergy. Although EoE is thought to primarily occur from an immune response to ingested oral allergens, aeroallergens may exacerbate disease as evidenced by the seasonal variation in EoE symptoms in some patients. The allergist provides treatment for these “extraesophageal” atopic conditions which may, in turn, have synergistic effects on the treatment of EoE. Furthermore, allergists may prescribe biologic therapies that are FDA approved for the treatment of atopic dermatitis, asthma, and allergic rhinitis. While not approved for EoE, several of these agents have shown efficacy in phase 2 clinical trials in EoE. In some practice settings, allergists primarily manage EoE patients with the assistance of gastroenterologists for periodic endoscopic activity assessment.
What are the key aspects of maintenance therapy?
The goals of treatment focus on symptomatic, histologic, and endoscopic improvement, and the prevention of future or ongoing fibrostenotic complications.2 Because of the adaptive eating behaviors discussed above, symptom response may not reliably correlate with histologic and/or endoscopic improvement. Moreover, dysphagia is related to strictures that often do not resolve in spite of resolution of mucosal inflammation. As such, histology and endoscopy are more objective and reliable targets of a successful response to therapy. Though studies have used variable esophageal density levels for response, using a cutoff of <15 eos/hpf as a therapeutic endpoint is reasonable for both initial response to therapy and long-term monitoring.13 We advocate for standardization of reporting endoscopic findings to better track change over time using the EREFS scoring system.7 While inflammatory features improve, the fibrostenotic features may persist despite improvement in histology. Dilation is often performed in these situations, especially for symptomatic individuals.
During clinical follow-up, the frequency of monitoring as it relates to symptom and endoscopic assessment is not well defined. It is reasonable to repeat endoscopic intervention following changes in therapy (i.e., reduction in steroid dosing or reintroduction of putative food triggers) or in symptoms.13 It is unclear if patients benefit from repeated endoscopies at set intervals without symptom change and after histologic response has been confirmed. In our practice, endoscopies are often considered on an annual basis. This interval is increased for patients with demonstrated stability of disease.
For patients who opt for dietary therapy and have one or two food triggers identified, long-term maintenance therapy can be straightforward with ongoing food avoidance. Limited data exist regarding long-term effectiveness of dietary therapy but loss of initial response has been reported that is often attributed to problems with adherence. Use of “diet holidays” or “planned cheats” to allow for intermittent consumption of trigger foods, often under the cover of short-term use of steroids, may improve the long-term feasibility of diet approaches.
In the recent American Gastroenterological Association guidelines, continuation of swallowed, topical steroids is recommended following remission with short-term treatment. The recurrence of both symptoms and inflammation following medication withdrawal supports this practice. Furthermore, natural history studies demonstrate progression of esophageal strictures with untreated disease.
There are no clear guidelines for long-term dosage and use of PPI or topical steroid therapy. Our practice is to down-titrate the dose of PPI or steroid following remission with short-term therapy, often starting with a reduction from twice a day to daily dosing. Although topical steroid therapy has fewer side effects, compared with systemic steroids, patients should be aware of the potential for adrenal suppression especially in an atopic population who may be exposed to multiple forms of topical steroids. Shared decision-making between patients and providers is recommended to determine comfort level with long-term use of prescription medications and dosage.
What’s on the horizon?
Several areas of development are underway to better assess and manage EoE. Novel histologic scoring tools now assess characteristics on pathology beyond eosinophil density, office-based testing modalities have been developed to assess inflammatory activity and thereby obviate the need for endoscopy, new technology can provide measures of esophageal remodeling and provide assessment of disease severity, and several biologic agents are being studied that target specific allergic mediators of the immune response in EoE.3,14-18 These novel tools, technologies, and therapies will undoubtedly change the management approach to EoE. Referral of patients into ongoing clinical trials will help inform advances in the field.
Conclusion
As an increasingly prevalent disease with a high degree of upper GI morbidity, EoE has transitioned from a rare entity to a commonly encountered disease. The new gastroenterologist will confront both straightforward as well as complex patients with EoE, and we offer several practical aspects on management. In the years ahead, the care of patients with EoE will continue to evolve to a more streamlined, effective, and personalized approach.
References
1. Kidambi T et al. World J Gastroenterol. 2012;18:4335-41.
2. Dellon ES et al. Gastroenterology. 2018;154:319-32 e3.
3. Hirano I et al. Gastroenterology. 2020;158:840-51.
4. Furuta GT et al. Gastroenterology. 2007;133:1342-63.
5. Liacouras CA et al. J Allergy Clin Immunol. 2011;128:3-20 e6; quiz 1-2.
6. Dellon ES et al. Gastroenterology. 2018;155:1022-33 e10.
7. Hirano I et al. Gut. 2013;62:489-95.
8. Rank MA et al. Gastroenterology. 2020;158:1789-810 e15.
9. Arias A et al. Gastroenterology. 2014;146:1639-48.
10. Molina-Infante J et al. J Allergy Clin Immunol. 2018;141:1365-72.
11. Gentile N et al. Aliment Pharmacol Ther. 2014;40:1333-40.
12. Hirano I. Gastroenterology. 2018;155:601-6.
13. Hirano I et al. Gastroenterology. 2020;158:1776-86.
14. Collins MH et al. Dis Esophagus. 2017;30:1-8.
15. Furuta GT et al. Gut. 2013;62:1395-405.
16. Katzka DA et al. Clin Gastroenterol Hepatol. 2015;13:77-83 e2.
17. Kwiatek MA et al. Gastroenterology. 2011;140:82-90.
18. Nicodeme F et al. Clin Gastroenterol Hepatol. 2013;11:1101-7 e1.
Cyclic vomiting syndrome: A GI primer
Introduction
Cyclic vomiting syndrome (CVS) is a chronic disorder of gut-brain interaction (DGBI) and is characterized by recurrent episodes of severe nausea, vomiting, and often, abdominal pain. Patients are usually asymptomatic in between episodes.1 CVS was considered a pediatric disease but is now known to be as common in adults. The prevalence of CVS in adults was 2% in a recent population-based study.2 Patients are predominantly white. Both males and females are affected with some studies showing a female preponderance. The mean age of onset is 5 years in children and 35 years in adults.3
The etiology of CVS is not known, but various hypotheses have been proposed. Zaki et al. showed that two mitochondrial DNA polymorphisms 16519T and 3010A were associated with a 17-fold increased odds of having CVS in children.4 These polymorphisms were not associated with CVS in adults.5 Alterations in the brain-gut axis also have been shown in CVS. Functional neuroimaging studies demonstrate that patients with CVS displayed increased connectivity between insula and salience networks with concomitant decrease in connectivity to somatosensory networks.6 Recent data also indicate that the endocannabinoid system (ECS) and the hypothalamic-pituitary-adrenal axis are implicated in CVS with an increase in serum endocannabinoid concentration during an episode.7 The same study also showed a significant increase in salivary cortisol in CVS patients who used cannabis. Further, single nucleotide polymorphisms (SNPs) in the gene that encodes for the cannabinoid receptor type 1 (CB1R) are implicated in CVS.8 The CB1R is part of the ECS and is densely expressed in brain areas involved in emesis, such as the dorsal vagal complex consisting of the area postrema (AP), nucleus of the solitary tract (NTS), and also the dorsal motor nucleus of the vagus.9 Wasilewski et al. showed an increased risk of CVS among individuals with AG and GG genotypes of CNR1 rs806380 (P less than .01), whereas the CC genotype of CNR1 rs806368 was associated with a decreased risk of CVS (P less than .05).8 CB1R agonists – endocannabinoids and tetrahydrocannabinol (THC) – have acute antiemetic and anxiolytic effects.9-11 The apparent paradoxical effects of cannabis in this patient population are yet to be explained and need further study.
Diagnosis and clinical features of CVS
Figure 1: Phases of Cyclic Vomiting Syndrome12
Adapted from Fleisher DR, Gornowicz B, Adams K, Burch R, Feldman EJ. Cyclic Vomiting Syndrome in 41 adults: The illness, the patients, and problems of management. BMC Med 2005;3:20. This work is licensed under the Creative Commons Attribution 4.0 International License https://creativecommons.org/licenses/by/4.0/, which permits unrestricted use, distribution, modification, and reproduction in any medium.
CVS consists of four phases which include the a) prodromal phase, b) the episodic phase, c) recovery phase, and d) the interepisodic phase; and was first described by David Fleisher.12 The phases of CVS are important for clinicians and patients alike as they have therapeutic implications. The administration of abortive medications during a prodrome can terminate an episode. The phases of CVS are shown above.
Most patients (~ 93%) have a prodromal phase. Symptoms during this phase can include nausea, abdominal pain, diaphoresis, fatigue, weakness, hot flashes, chills, shivering, increased thirst, loss of appetite, burping, lightheadedness, and paresthesia.13 Some patients report a sense of impending doom and many have symptoms consistent with panic. If untreated, this progresses to the emetic phase and patients have unrelenting nausea, retching, vomiting, and other symptoms. During an episode, patients may vomit up to 20 times per hour and the episode may last several hours to days. During this phase, patients are sometimes described as being in a “conscious coma” and exhibit lethargy, listlessness, withdrawal, and sometimes disorientation.14,15 The emetic phase is followed by the recovery phase, during which symptoms subside and patients are able to resume oral intake. Patients are usually asymptomatic between episodes but ~ 30% can have interepisodic nausea and dyspepsia. In some patients, episodes become progressively longer and the interepisodic phase is considerably shortened and patients have a “coalescence of symptoms.”12 It is important to elicit a thorough history in all patients with vomiting in order to make an accurate diagnosis of CVS since coalescence of symptoms only occurs over a period of time. Episodes often are triggered by psychological stress, both positive and negative. Common triggers can include positive events such as birthdays, holidays, and negative ones like examinations, the death of a loved one, etc. Sleep deprivation and physical exhaustion also can trigger an episode.12 
CVS remains a clinical diagnosis since there are no biomarkers. While there is a lack of data on the optimal work-up in these patients, experts recommend an upper endoscopy or upper GI series in order to rule out alternative gastric and intestinal pathology (e.g., malrotation with volvulus).16 Of note, a gastric-emptying study is not recommended as part of the routine work-up as per recent guidelines because of the poor specificity of this test in establishing a diagnosis of CVS.16 Biochemical testing including a complete blood count, serum electrolytes, serum glucose, liver panel, and urinalysis is also warranted. Any additional testing is indicated when clinical features suggest an alternative diagnosis. For instance, neurologic symptoms might warrant a cranial MRI to exclude an intracerebral tumor or other lesions of the brain.
The severity and unpredictable nature of symptoms makes it difficult for some patients to attend school or work; one study found that 32% of patients with CVS were completely disabled.12 Despite increasing awareness of this disorder, patients often are misdiagnosed. The prevalence of CVS in an outpatient gastroenterology clinic in the United Kingdom was 11% and was markedly underdiagnosed in the community.17 Only 5% of patients who were subsequently diagnosed with CVS were initially diagnosed accurately by their referring physician despite meeting criteria for the disorder.17 A subset of patients with CVS even undergo futile surgeries.13 Fleisher et al. noted that 30% of a 41-patient cohort underwent cholecystectomy for CVS symptoms without any improvement in disease.12 Prompt diagnosis and appropriate therapy is essential to improve patient outcomes and improve quality of life.
CVS is associated with various comorbidities such as migraine, anxiety, depression and dysautonomia, which can further impair quality of life.18,19 Approximately 70% of CVS patients report a personal or family history of migraine. Anxiety and depression affects nearly half of patients with CVS.13 Cannabis use is significantly more prevalent among patients with CVS than patients without CVS.20
Role of cannabis in CVS
The role of cannabis in the pathogenesis of symptoms in CVS is controversial. While cannabis has antiemetic properties, there is a strong link between its use and CVS. The use of cannabis has increased over the past decade with increasing legalization.21 Several studies have shown that 40%-80% of patients with CVS use cannabis.22,23 Following this, cannabinoid hyperemesis syndrome (CHS) was coined as a separate entity based on this statistical association, though there are no data to support the notion that cannabis causes vomiting.24,25 CHS has clinical features that are indistinguishable from CVS except for the chronic heavy cannabis use. A peculiar bathing behavior called “compulsive hot-water bathing” has been described and was thought to be pathognomonic of cannabis use.26 During an episode, patients will take multiple hot showers/baths, which temporarily alleviate their symptoms. Many patients even report running out of hot water and sometimes check into a hotel for a continuous supply of hot water. A small number of patients may sustain burns from the hot-water bathing. However, studies show that this hot-water bathing behavior also is seen in about 50% of patents with CVS who do not use cannabis.22
CHS is now defined by Rome IV criteria, which include episodes of nausea and vomiting similar to CVS preceded by chronic, heavy cannabis use. Patients must have complete resolution of symptoms following cessation.1 A recent systematic review of 376 cases of purported CHS showed that only 59 (15.7%) met Rome IV criteria for this disorder.27 This is because of considerable heterogeneity in how the diagnosis of CHS was made and the lack of standard diagnostic criteria at the time. Some cases of CHS were diagnosed merely based on an association of vomiting, hot-water bathing, and cannabis use.28 Only a minority of patients (71,19%) had a duration of follow-up more than 4 weeks, which would make it impossible to establish a diagnosis of CHS. A period of at least a year or a duration of time that spans at least three episodes is generally recommended to determine if abstinence from cannabis causes a true resolution of symptoms.27 Whether CHS is a separate entity or a subtype of CVS remains to be determined. The paradoxical effects of cannabis may happen because of the use of highly potent cannabis products that are currently in use. A complete discussion of the role of cannabis in CVS is beyond the scope of this article, and the reader is referred to a recent systematic review and discussion.27
Treatment
CVS should be treated based on a biopsychosocial model with a multidisciplinary team that includes a gastroenterologist with knowledge of CVS, primary care physician, psychologist, psychiatrist, and sleep specialist if needed.16 Initiating prophylactic treatment is based on the severity of disease. An algorithm for the treatment of CVS based on severity of symptoms is shown below.
Figure 2. Adapted and reprinted by permission from the Licensor: Springer Nature, Current Treatment Options in Gastroenterology, Bhandari S, Venkatesan T. Novel Treatments for Cyclic Vomiting Syndrome: Beyond Ondansetron and Amitriptyline, 14:495-506, Copyright 2016.
Patients who have mild disease (defined as fewer than four episodes/year, episodes lasting up to 2 days, quick recovery from episodes, or episodes not requiring ED care or hospitalization) are usually prescribed abortive medications.16 These medications are best administered during the prodromal phase and can prevent progression to the emetic phase. Medications used for aborting episodes include sumatriptan (20 mg intranasal or 6 mg subcutaneous), ondansetron (8 mg sublingual), and diphenhydramine (25-50 mg).30,31 This combination can help abort symptoms and potentially avoid ED visits or hospitalizations. Patients with moderate-to-severe CVS are offered prophylactic therapy in addition to abortive therapy.16
Recent guidelines recommend tricyclic antidepressants (TCAs) as the first-line agent in the prophylaxis of CVS episodes. Data from 14 studies determined that 70% (413/600) of patients responded partially or completely to TCAs.16 An open-label study of 46 patients by Hejazi et al. noted a decline in the number of CVS episodes from 17 to 3, in the duration of a CVS episode from 6 to 2 days, and in the number of ED visits/ hospitalizations from 15 to 3.3.32Amitriptyline should be started at 25 mg at night and titrated up by 10-25 mg each week to minimize emergence of side effects. The mean effective dose is 75-100 mg or 1.0-1.5 mg/kg. An EKG should be checked at baseline and during titration to monitor the QT interval. Unfortunately, side effects from TCAs are quite common and include cognitive impairment, drowsiness, dryness of mouth, weight gain, constipation, and mood changes, which may warrant dose reduction or discontinuation. Antiepileptics such as topiramate, mitochondrial supplements such as Coenzyme Q10 and riboflavin are alternative prophylactic agents in CVS.33 Aprepitant, a newer NK1 receptor antagonist has been found to be effective in refractory CVS.34 In addition to pharmacotherapy, addressing comorbid conditions such as anxiety and depression and counseling patients to abstain from heavy cannabis use is also important to achieve good health care outcomes.
In summary, CVS is a common, chronic functional GI disorder with episodic nausea, vomiting, and often, abdominal pain. Symptoms can be disabling, and prompt diagnosis and therapy is important. CVS is associated with multiple comorbid conditions such as migraine, anxiety and depression, and a biopsychosocial model of care is essential. Medications such as amitriptyline are effective in the prophylaxis of CVS, but side effects hamper their use. Recent recommendations for management of CVS have been published.16 Cannabis is frequently used by patients for symptom relief but use of high potency products may cause worsening of symptoms or unmask symptoms in genetically predisposed individuals.23 Studies to elucidate the pathophysiology of CVS should help in the development of better therapies.
Dr. Mooers is PGY-2, an internal medicine resident in the department of medicine, Medical College of Wisconsin, Milwaukee; Dr. Venkatesan is professor of medicine, division of gastroenterology and hepatology, department of medicine, Medical College of Wisconsin, Milwaukee. The authors have no conflicts to disclose.
References
1. Stanghellini V et al. Gastroenterology. 2016;150:1380-92.
2. Aziz I et al. Clin Gastroenterol Hepatol. 2019 Apr;17(5):878-86.
3. Kovacic K et al. Curr Gastroenterol Rep. 2018;20(10):46.
4. Zaki EA et al. Cephalalgia. 2009;29:719-28.
5. Venkatesan T et al. BMC Gastroenterol. 2014;14:181.
6. Ellingsen DM et al. Neurogastroenterol Motil. 2017;29 (6)e13004 9.
7. Venkatesan T et al. Neurogastroenterol Motil. 2016;28:1409-18.
8. Wasilewski A et al. Am J Gastroenterol. 2017;112:933-9.
9. van Sickle MD et al. Am J Physiol Gastrointest Liver Physiol 2003;285:G566-76.
10. Parker LA et al. Br J Pharmacol. 2011;163:1411-22.
11. van Sickle MD et al. Gastroenterology. 2001;121:767-74.
12. Fleisher DR et al. BMC Med. 2005;3:20.
13. Kumar N et al. BMC Gastroenterol. 2012;12:52.
14. Li BU et al. J Pediatr Gastroenterol Nutr. 2008;47:379-93.
15. Bhandari S et al. Clin Auton Res. 2018 Apr;28(2):203-9.
16. Venkatesan T et al. Neurogastroenterol Motil. 2019;31 Suppl 2:e13604. doi: 10.1111/nmo.13604.
17. Sagar RC et al. Neurogastroenterol Motil. 2018;30. doi: 10.1111/nmo.13174.
18. Taranukha T et al. Neurogastroenterol Motil. 2018 Apr;30(4):e13245. doi: 10.1111/nmo.13245.
19. Bhandari S and Venkatesan T. Dig Dis Sci. 2017;62:2035-44.
20. Choung RS et al. Neurogastroenterol Motil. 2012;24:20-6, e21. doi: 10.1111/j.1365-2982.2011.01791.x.
21. Bhandari S et al. Intern Med J. 2019 May;49(5):649-55.
22. Venkatesan T et al. Exp Brain Res. 2014; 232:2563-70.
23. Venkatesan T et al. Clin Gastroenterol Hepatol. 2019 Jul 25. doi: 10.1016/j.cgh.2019.07.039.
24. Simonetto DA et al. Mayo Clin Proc. 2012;87:114-9.
25. Wallace EA et al. South Med J. 2011;104:659-64.
26. Allen JH et al. Gut. 2004;53:1566-70.
27. Venkatesan T et al. Neurogastroenterol Motil. 2019;31 Suppl 2:e13606. doi: 10.1111/nmo.13606.
28. Habboushe J et al. Basic Clin Pharmacol Toxicol. 2018;122:660-2.
29. Bhandari S and Venkatesan T. Curr Treat Options Gastroenterol. 2016;14:495-506.
30. Hikita T et al. Cephalalgia. 2011;31:504-7.
31. Fuseau E et al. Clin Pharmacokinet 2002;41:801-11.
32. Hejazi RA et al. J Clin Gastroenterol. 2010;44:18-21.
33. Sezer OB and Sezer T. J Neurogastroenterol Motil. 2016;22:656-60.
34. Cristofori F et al. Aliment Pharmacol Ther. 2014;40:309-17.
Introduction
Cyclic vomiting syndrome (CVS) is a chronic disorder of gut-brain interaction (DGBI) and is characterized by recurrent episodes of severe nausea, vomiting, and often, abdominal pain. Patients are usually asymptomatic in between episodes.1 CVS was considered a pediatric disease but is now known to be as common in adults. The prevalence of CVS in adults was 2% in a recent population-based study.2 Patients are predominantly white. Both males and females are affected with some studies showing a female preponderance. The mean age of onset is 5 years in children and 35 years in adults.3
The etiology of CVS is not known, but various hypotheses have been proposed. Zaki et al. showed that two mitochondrial DNA polymorphisms 16519T and 3010A were associated with a 17-fold increased odds of having CVS in children.4 These polymorphisms were not associated with CVS in adults.5 Alterations in the brain-gut axis also have been shown in CVS. Functional neuroimaging studies demonstrate that patients with CVS displayed increased connectivity between insula and salience networks with concomitant decrease in connectivity to somatosensory networks.6 Recent data also indicate that the endocannabinoid system (ECS) and the hypothalamic-pituitary-adrenal axis are implicated in CVS with an increase in serum endocannabinoid concentration during an episode.7 The same study also showed a significant increase in salivary cortisol in CVS patients who used cannabis. Further, single nucleotide polymorphisms (SNPs) in the gene that encodes for the cannabinoid receptor type 1 (CB1R) are implicated in CVS.8 The CB1R is part of the ECS and is densely expressed in brain areas involved in emesis, such as the dorsal vagal complex consisting of the area postrema (AP), nucleus of the solitary tract (NTS), and also the dorsal motor nucleus of the vagus.9 Wasilewski et al. showed an increased risk of CVS among individuals with AG and GG genotypes of CNR1 rs806380 (P less than .01), whereas the CC genotype of CNR1 rs806368 was associated with a decreased risk of CVS (P less than .05).8 CB1R agonists – endocannabinoids and tetrahydrocannabinol (THC) – have acute antiemetic and anxiolytic effects.9-11 The apparent paradoxical effects of cannabis in this patient population are yet to be explained and need further study.
Diagnosis and clinical features of CVS
Figure 1: Phases of Cyclic Vomiting Syndrome12
Adapted from Fleisher DR, Gornowicz B, Adams K, Burch R, Feldman EJ. Cyclic Vomiting Syndrome in 41 adults: The illness, the patients, and problems of management. BMC Med 2005;3:20. This work is licensed under the Creative Commons Attribution 4.0 International License https://creativecommons.org/licenses/by/4.0/, which permits unrestricted use, distribution, modification, and reproduction in any medium.
CVS consists of four phases which include the a) prodromal phase, b) the episodic phase, c) recovery phase, and d) the interepisodic phase; and was first described by David Fleisher.12 The phases of CVS are important for clinicians and patients alike as they have therapeutic implications. The administration of abortive medications during a prodrome can terminate an episode. The phases of CVS are shown above.
Most patients (~ 93%) have a prodromal phase. Symptoms during this phase can include nausea, abdominal pain, diaphoresis, fatigue, weakness, hot flashes, chills, shivering, increased thirst, loss of appetite, burping, lightheadedness, and paresthesia.13 Some patients report a sense of impending doom and many have symptoms consistent with panic. If untreated, this progresses to the emetic phase and patients have unrelenting nausea, retching, vomiting, and other symptoms. During an episode, patients may vomit up to 20 times per hour and the episode may last several hours to days. During this phase, patients are sometimes described as being in a “conscious coma” and exhibit lethargy, listlessness, withdrawal, and sometimes disorientation.14,15 The emetic phase is followed by the recovery phase, during which symptoms subside and patients are able to resume oral intake. Patients are usually asymptomatic between episodes but ~ 30% can have interepisodic nausea and dyspepsia. In some patients, episodes become progressively longer and the interepisodic phase is considerably shortened and patients have a “coalescence of symptoms.”12 It is important to elicit a thorough history in all patients with vomiting in order to make an accurate diagnosis of CVS since coalescence of symptoms only occurs over a period of time. Episodes often are triggered by psychological stress, both positive and negative. Common triggers can include positive events such as birthdays, holidays, and negative ones like examinations, the death of a loved one, etc. Sleep deprivation and physical exhaustion also can trigger an episode.12
CVS remains a clinical diagnosis since there are no biomarkers. While there is a lack of data on the optimal work-up in these patients, experts recommend an upper endoscopy or upper GI series in order to rule out alternative gastric and intestinal pathology (e.g., malrotation with volvulus).16 Of note, a gastric-emptying study is not recommended as part of the routine work-up as per recent guidelines because of the poor specificity of this test in establishing a diagnosis of CVS.16 Biochemical testing including a complete blood count, serum electrolytes, serum glucose, liver panel, and urinalysis is also warranted. Any additional testing is indicated when clinical features suggest an alternative diagnosis. For instance, neurologic symptoms might warrant a cranial MRI to exclude an intracerebral tumor or other lesions of the brain.
The severity and unpredictable nature of symptoms makes it difficult for some patients to attend school or work; one study found that 32% of patients with CVS were completely disabled.12 Despite increasing awareness of this disorder, patients often are misdiagnosed. The prevalence of CVS in an outpatient gastroenterology clinic in the United Kingdom was 11% and was markedly underdiagnosed in the community.17 Only 5% of patients who were subsequently diagnosed with CVS were initially diagnosed accurately by their referring physician despite meeting criteria for the disorder.17 A subset of patients with CVS even undergo futile surgeries.13 Fleisher et al. noted that 30% of a 41-patient cohort underwent cholecystectomy for CVS symptoms without any improvement in disease.12 Prompt diagnosis and appropriate therapy is essential to improve patient outcomes and improve quality of life.
CVS is associated with various comorbidities such as migraine, anxiety, depression and dysautonomia, which can further impair quality of life.18,19 Approximately 70% of CVS patients report a personal or family history of migraine. Anxiety and depression affects nearly half of patients with CVS.13 Cannabis use is significantly more prevalent among patients with CVS than patients without CVS.20
Role of cannabis in CVS
The role of cannabis in the pathogenesis of symptoms in CVS is controversial. While cannabis has antiemetic properties, there is a strong link between its use and CVS. The use of cannabis has increased over the past decade with increasing legalization.21 Several studies have shown that 40%-80% of patients with CVS use cannabis.22,23 Following this, cannabinoid hyperemesis syndrome (CHS) was coined as a separate entity based on this statistical association, though there are no data to support the notion that cannabis causes vomiting.24,25 CHS has clinical features that are indistinguishable from CVS except for the chronic heavy cannabis use. A peculiar bathing behavior called “compulsive hot-water bathing” has been described and was thought to be pathognomonic of cannabis use.26 During an episode, patients will take multiple hot showers/baths, which temporarily alleviate their symptoms. Many patients even report running out of hot water and sometimes check into a hotel for a continuous supply of hot water. A small number of patients may sustain burns from the hot-water bathing. However, studies show that this hot-water bathing behavior also is seen in about 50% of patents with CVS who do not use cannabis.22
CHS is now defined by Rome IV criteria, which include episodes of nausea and vomiting similar to CVS preceded by chronic, heavy cannabis use. Patients must have complete resolution of symptoms following cessation.1 A recent systematic review of 376 cases of purported CHS showed that only 59 (15.7%) met Rome IV criteria for this disorder.27 This is because of considerable heterogeneity in how the diagnosis of CHS was made and the lack of standard diagnostic criteria at the time. Some cases of CHS were diagnosed merely based on an association of vomiting, hot-water bathing, and cannabis use.28 Only a minority of patients (71,19%) had a duration of follow-up more than 4 weeks, which would make it impossible to establish a diagnosis of CHS. A period of at least a year or a duration of time that spans at least three episodes is generally recommended to determine if abstinence from cannabis causes a true resolution of symptoms.27 Whether CHS is a separate entity or a subtype of CVS remains to be determined. The paradoxical effects of cannabis may happen because of the use of highly potent cannabis products that are currently in use. A complete discussion of the role of cannabis in CVS is beyond the scope of this article, and the reader is referred to a recent systematic review and discussion.27
Treatment
CVS should be treated based on a biopsychosocial model with a multidisciplinary team that includes a gastroenterologist with knowledge of CVS, primary care physician, psychologist, psychiatrist, and sleep specialist if needed.16 Initiating prophylactic treatment is based on the severity of disease. An algorithm for the treatment of CVS based on severity of symptoms is shown below.
Figure 2. Adapted and reprinted by permission from the Licensor: Springer Nature, Current Treatment Options in Gastroenterology, Bhandari S, Venkatesan T. Novel Treatments for Cyclic Vomiting Syndrome: Beyond Ondansetron and Amitriptyline, 14:495-506, Copyright 2016.
Patients who have mild disease (defined as fewer than four episodes/year, episodes lasting up to 2 days, quick recovery from episodes, or episodes not requiring ED care or hospitalization) are usually prescribed abortive medications.16 These medications are best administered during the prodromal phase and can prevent progression to the emetic phase. Medications used for aborting episodes include sumatriptan (20 mg intranasal or 6 mg subcutaneous), ondansetron (8 mg sublingual), and diphenhydramine (25-50 mg).30,31 This combination can help abort symptoms and potentially avoid ED visits or hospitalizations. Patients with moderate-to-severe CVS are offered prophylactic therapy in addition to abortive therapy.16
Recent guidelines recommend tricyclic antidepressants (TCAs) as the first-line agent in the prophylaxis of CVS episodes. Data from 14 studies determined that 70% (413/600) of patients responded partially or completely to TCAs.16 An open-label study of 46 patients by Hejazi et al. noted a decline in the number of CVS episodes from 17 to 3, in the duration of a CVS episode from 6 to 2 days, and in the number of ED visits/ hospitalizations from 15 to 3.3.32Amitriptyline should be started at 25 mg at night and titrated up by 10-25 mg each week to minimize emergence of side effects. The mean effective dose is 75-100 mg or 1.0-1.5 mg/kg. An EKG should be checked at baseline and during titration to monitor the QT interval. Unfortunately, side effects from TCAs are quite common and include cognitive impairment, drowsiness, dryness of mouth, weight gain, constipation, and mood changes, which may warrant dose reduction or discontinuation. Antiepileptics such as topiramate, mitochondrial supplements such as Coenzyme Q10 and riboflavin are alternative prophylactic agents in CVS.33 Aprepitant, a newer NK1 receptor antagonist has been found to be effective in refractory CVS.34 In addition to pharmacotherapy, addressing comorbid conditions such as anxiety and depression and counseling patients to abstain from heavy cannabis use is also important to achieve good health care outcomes.
In summary, CVS is a common, chronic functional GI disorder with episodic nausea, vomiting, and often, abdominal pain. Symptoms can be disabling, and prompt diagnosis and therapy is important. CVS is associated with multiple comorbid conditions such as migraine, anxiety and depression, and a biopsychosocial model of care is essential. Medications such as amitriptyline are effective in the prophylaxis of CVS, but side effects hamper their use. Recent recommendations for management of CVS have been published.16 Cannabis is frequently used by patients for symptom relief but use of high potency products may cause worsening of symptoms or unmask symptoms in genetically predisposed individuals.23 Studies to elucidate the pathophysiology of CVS should help in the development of better therapies.
Dr. Mooers is PGY-2, an internal medicine resident in the department of medicine, Medical College of Wisconsin, Milwaukee; Dr. Venkatesan is professor of medicine, division of gastroenterology and hepatology, department of medicine, Medical College of Wisconsin, Milwaukee. The authors have no conflicts to disclose.
References
1. Stanghellini V et al. Gastroenterology. 2016;150:1380-92.
2. Aziz I et al. Clin Gastroenterol Hepatol. 2019 Apr;17(5):878-86.
3. Kovacic K et al. Curr Gastroenterol Rep. 2018;20(10):46.
4. Zaki EA et al. Cephalalgia. 2009;29:719-28.
5. Venkatesan T et al. BMC Gastroenterol. 2014;14:181.
6. Ellingsen DM et al. Neurogastroenterol Motil. 2017;29 (6)e13004 9.
7. Venkatesan T et al. Neurogastroenterol Motil. 2016;28:1409-18.
8. Wasilewski A et al. Am J Gastroenterol. 2017;112:933-9.
9. van Sickle MD et al. Am J Physiol Gastrointest Liver Physiol 2003;285:G566-76.
10. Parker LA et al. Br J Pharmacol. 2011;163:1411-22.
11. van Sickle MD et al. Gastroenterology. 2001;121:767-74.
12. Fleisher DR et al. BMC Med. 2005;3:20.
13. Kumar N et al. BMC Gastroenterol. 2012;12:52.
14. Li BU et al. J Pediatr Gastroenterol Nutr. 2008;47:379-93.
15. Bhandari S et al. Clin Auton Res. 2018 Apr;28(2):203-9.
16. Venkatesan T et al. Neurogastroenterol Motil. 2019;31 Suppl 2:e13604. doi: 10.1111/nmo.13604.
17. Sagar RC et al. Neurogastroenterol Motil. 2018;30. doi: 10.1111/nmo.13174.
18. Taranukha T et al. Neurogastroenterol Motil. 2018 Apr;30(4):e13245. doi: 10.1111/nmo.13245.
19. Bhandari S and Venkatesan T. Dig Dis Sci. 2017;62:2035-44.
20. Choung RS et al. Neurogastroenterol Motil. 2012;24:20-6, e21. doi: 10.1111/j.1365-2982.2011.01791.x.
21. Bhandari S et al. Intern Med J. 2019 May;49(5):649-55.
22. Venkatesan T et al. Exp Brain Res. 2014; 232:2563-70.
23. Venkatesan T et al. Clin Gastroenterol Hepatol. 2019 Jul 25. doi: 10.1016/j.cgh.2019.07.039.
24. Simonetto DA et al. Mayo Clin Proc. 2012;87:114-9.
25. Wallace EA et al. South Med J. 2011;104:659-64.
26. Allen JH et al. Gut. 2004;53:1566-70.
27. Venkatesan T et al. Neurogastroenterol Motil. 2019;31 Suppl 2:e13606. doi: 10.1111/nmo.13606.
28. Habboushe J et al. Basic Clin Pharmacol Toxicol. 2018;122:660-2.
29. Bhandari S and Venkatesan T. Curr Treat Options Gastroenterol. 2016;14:495-506.
30. Hikita T et al. Cephalalgia. 2011;31:504-7.
31. Fuseau E et al. Clin Pharmacokinet 2002;41:801-11.
32. Hejazi RA et al. J Clin Gastroenterol. 2010;44:18-21.
33. Sezer OB and Sezer T. J Neurogastroenterol Motil. 2016;22:656-60.
34. Cristofori F et al. Aliment Pharmacol Ther. 2014;40:309-17.
Introduction
Cyclic vomiting syndrome (CVS) is a chronic disorder of gut-brain interaction (DGBI) and is characterized by recurrent episodes of severe nausea, vomiting, and often, abdominal pain. Patients are usually asymptomatic in between episodes.1 CVS was considered a pediatric disease but is now known to be as common in adults. The prevalence of CVS in adults was 2% in a recent population-based study.2 Patients are predominantly white. Both males and females are affected with some studies showing a female preponderance. The mean age of onset is 5 years in children and 35 years in adults.3
The etiology of CVS is not known, but various hypotheses have been proposed. Zaki et al. showed that two mitochondrial DNA polymorphisms 16519T and 3010A were associated with a 17-fold increased odds of having CVS in children.4 These polymorphisms were not associated with CVS in adults.5 Alterations in the brain-gut axis also have been shown in CVS. Functional neuroimaging studies demonstrate that patients with CVS displayed increased connectivity between insula and salience networks with concomitant decrease in connectivity to somatosensory networks.6 Recent data also indicate that the endocannabinoid system (ECS) and the hypothalamic-pituitary-adrenal axis are implicated in CVS with an increase in serum endocannabinoid concentration during an episode.7 The same study also showed a significant increase in salivary cortisol in CVS patients who used cannabis. Further, single nucleotide polymorphisms (SNPs) in the gene that encodes for the cannabinoid receptor type 1 (CB1R) are implicated in CVS.8 The CB1R is part of the ECS and is densely expressed in brain areas involved in emesis, such as the dorsal vagal complex consisting of the area postrema (AP), nucleus of the solitary tract (NTS), and also the dorsal motor nucleus of the vagus.9 Wasilewski et al. showed an increased risk of CVS among individuals with AG and GG genotypes of CNR1 rs806380 (P less than .01), whereas the CC genotype of CNR1 rs806368 was associated with a decreased risk of CVS (P less than .05).8 CB1R agonists – endocannabinoids and tetrahydrocannabinol (THC) – have acute antiemetic and anxiolytic effects.9-11 The apparent paradoxical effects of cannabis in this patient population are yet to be explained and need further study.
Diagnosis and clinical features of CVS
Figure 1: Phases of Cyclic Vomiting Syndrome12
Adapted from Fleisher DR, Gornowicz B, Adams K, Burch R, Feldman EJ. Cyclic Vomiting Syndrome in 41 adults: The illness, the patients, and problems of management. BMC Med 2005;3:20. This work is licensed under the Creative Commons Attribution 4.0 International License https://creativecommons.org/licenses/by/4.0/, which permits unrestricted use, distribution, modification, and reproduction in any medium.
CVS consists of four phases which include the a) prodromal phase, b) the episodic phase, c) recovery phase, and d) the interepisodic phase; and was first described by David Fleisher.12 The phases of CVS are important for clinicians and patients alike as they have therapeutic implications. The administration of abortive medications during a prodrome can terminate an episode. The phases of CVS are shown above.
Most patients (~ 93%) have a prodromal phase. Symptoms during this phase can include nausea, abdominal pain, diaphoresis, fatigue, weakness, hot flashes, chills, shivering, increased thirst, loss of appetite, burping, lightheadedness, and paresthesia.13 Some patients report a sense of impending doom and many have symptoms consistent with panic. If untreated, this progresses to the emetic phase and patients have unrelenting nausea, retching, vomiting, and other symptoms. During an episode, patients may vomit up to 20 times per hour and the episode may last several hours to days. During this phase, patients are sometimes described as being in a “conscious coma” and exhibit lethargy, listlessness, withdrawal, and sometimes disorientation.14,15 The emetic phase is followed by the recovery phase, during which symptoms subside and patients are able to resume oral intake. Patients are usually asymptomatic between episodes but ~ 30% can have interepisodic nausea and dyspepsia. In some patients, episodes become progressively longer and the interepisodic phase is considerably shortened and patients have a “coalescence of symptoms.”12 It is important to elicit a thorough history in all patients with vomiting in order to make an accurate diagnosis of CVS since coalescence of symptoms only occurs over a period of time. Episodes often are triggered by psychological stress, both positive and negative. Common triggers can include positive events such as birthdays, holidays, and negative ones like examinations, the death of a loved one, etc. Sleep deprivation and physical exhaustion also can trigger an episode.12
CVS remains a clinical diagnosis since there are no biomarkers. While there is a lack of data on the optimal work-up in these patients, experts recommend an upper endoscopy or upper GI series in order to rule out alternative gastric and intestinal pathology (e.g., malrotation with volvulus).16 Of note, a gastric-emptying study is not recommended as part of the routine work-up as per recent guidelines because of the poor specificity of this test in establishing a diagnosis of CVS.16 Biochemical testing including a complete blood count, serum electrolytes, serum glucose, liver panel, and urinalysis is also warranted. Any additional testing is indicated when clinical features suggest an alternative diagnosis. For instance, neurologic symptoms might warrant a cranial MRI to exclude an intracerebral tumor or other lesions of the brain.
The severity and unpredictable nature of symptoms makes it difficult for some patients to attend school or work; one study found that 32% of patients with CVS were completely disabled.12 Despite increasing awareness of this disorder, patients often are misdiagnosed. The prevalence of CVS in an outpatient gastroenterology clinic in the United Kingdom was 11% and was markedly underdiagnosed in the community.17 Only 5% of patients who were subsequently diagnosed with CVS were initially diagnosed accurately by their referring physician despite meeting criteria for the disorder.17 A subset of patients with CVS even undergo futile surgeries.13 Fleisher et al. noted that 30% of a 41-patient cohort underwent cholecystectomy for CVS symptoms without any improvement in disease.12 Prompt diagnosis and appropriate therapy is essential to improve patient outcomes and improve quality of life.
CVS is associated with various comorbidities such as migraine, anxiety, depression and dysautonomia, which can further impair quality of life.18,19 Approximately 70% of CVS patients report a personal or family history of migraine. Anxiety and depression affects nearly half of patients with CVS.13 Cannabis use is significantly more prevalent among patients with CVS than patients without CVS.20
Role of cannabis in CVS
The role of cannabis in the pathogenesis of symptoms in CVS is controversial. While cannabis has antiemetic properties, there is a strong link between its use and CVS. The use of cannabis has increased over the past decade with increasing legalization.21 Several studies have shown that 40%-80% of patients with CVS use cannabis.22,23 Following this, cannabinoid hyperemesis syndrome (CHS) was coined as a separate entity based on this statistical association, though there are no data to support the notion that cannabis causes vomiting.24,25 CHS has clinical features that are indistinguishable from CVS except for the chronic heavy cannabis use. A peculiar bathing behavior called “compulsive hot-water bathing” has been described and was thought to be pathognomonic of cannabis use.26 During an episode, patients will take multiple hot showers/baths, which temporarily alleviate their symptoms. Many patients even report running out of hot water and sometimes check into a hotel for a continuous supply of hot water. A small number of patients may sustain burns from the hot-water bathing. However, studies show that this hot-water bathing behavior also is seen in about 50% of patents with CVS who do not use cannabis.22
CHS is now defined by Rome IV criteria, which include episodes of nausea and vomiting similar to CVS preceded by chronic, heavy cannabis use. Patients must have complete resolution of symptoms following cessation.1 A recent systematic review of 376 cases of purported CHS showed that only 59 (15.7%) met Rome IV criteria for this disorder.27 This is because of considerable heterogeneity in how the diagnosis of CHS was made and the lack of standard diagnostic criteria at the time. Some cases of CHS were diagnosed merely based on an association of vomiting, hot-water bathing, and cannabis use.28 Only a minority of patients (71,19%) had a duration of follow-up more than 4 weeks, which would make it impossible to establish a diagnosis of CHS. A period of at least a year or a duration of time that spans at least three episodes is generally recommended to determine if abstinence from cannabis causes a true resolution of symptoms.27 Whether CHS is a separate entity or a subtype of CVS remains to be determined. The paradoxical effects of cannabis may happen because of the use of highly potent cannabis products that are currently in use. A complete discussion of the role of cannabis in CVS is beyond the scope of this article, and the reader is referred to a recent systematic review and discussion.27
Treatment
CVS should be treated based on a biopsychosocial model with a multidisciplinary team that includes a gastroenterologist with knowledge of CVS, primary care physician, psychologist, psychiatrist, and sleep specialist if needed.16 Initiating prophylactic treatment is based on the severity of disease. An algorithm for the treatment of CVS based on severity of symptoms is shown below.
Figure 2. Adapted and reprinted by permission from the Licensor: Springer Nature, Current Treatment Options in Gastroenterology, Bhandari S, Venkatesan T. Novel Treatments for Cyclic Vomiting Syndrome: Beyond Ondansetron and Amitriptyline, 14:495-506, Copyright 2016.
Patients who have mild disease (defined as fewer than four episodes/year, episodes lasting up to 2 days, quick recovery from episodes, or episodes not requiring ED care or hospitalization) are usually prescribed abortive medications.16 These medications are best administered during the prodromal phase and can prevent progression to the emetic phase. Medications used for aborting episodes include sumatriptan (20 mg intranasal or 6 mg subcutaneous), ondansetron (8 mg sublingual), and diphenhydramine (25-50 mg).30,31 This combination can help abort symptoms and potentially avoid ED visits or hospitalizations. Patients with moderate-to-severe CVS are offered prophylactic therapy in addition to abortive therapy.16
Recent guidelines recommend tricyclic antidepressants (TCAs) as the first-line agent in the prophylaxis of CVS episodes. Data from 14 studies determined that 70% (413/600) of patients responded partially or completely to TCAs.16 An open-label study of 46 patients by Hejazi et al. noted a decline in the number of CVS episodes from 17 to 3, in the duration of a CVS episode from 6 to 2 days, and in the number of ED visits/ hospitalizations from 15 to 3.3.32Amitriptyline should be started at 25 mg at night and titrated up by 10-25 mg each week to minimize emergence of side effects. The mean effective dose is 75-100 mg or 1.0-1.5 mg/kg. An EKG should be checked at baseline and during titration to monitor the QT interval. Unfortunately, side effects from TCAs are quite common and include cognitive impairment, drowsiness, dryness of mouth, weight gain, constipation, and mood changes, which may warrant dose reduction or discontinuation. Antiepileptics such as topiramate, mitochondrial supplements such as Coenzyme Q10 and riboflavin are alternative prophylactic agents in CVS.33 Aprepitant, a newer NK1 receptor antagonist has been found to be effective in refractory CVS.34 In addition to pharmacotherapy, addressing comorbid conditions such as anxiety and depression and counseling patients to abstain from heavy cannabis use is also important to achieve good health care outcomes.
In summary, CVS is a common, chronic functional GI disorder with episodic nausea, vomiting, and often, abdominal pain. Symptoms can be disabling, and prompt diagnosis and therapy is important. CVS is associated with multiple comorbid conditions such as migraine, anxiety and depression, and a biopsychosocial model of care is essential. Medications such as amitriptyline are effective in the prophylaxis of CVS, but side effects hamper their use. Recent recommendations for management of CVS have been published.16 Cannabis is frequently used by patients for symptom relief but use of high potency products may cause worsening of symptoms or unmask symptoms in genetically predisposed individuals.23 Studies to elucidate the pathophysiology of CVS should help in the development of better therapies.
Dr. Mooers is PGY-2, an internal medicine resident in the department of medicine, Medical College of Wisconsin, Milwaukee; Dr. Venkatesan is professor of medicine, division of gastroenterology and hepatology, department of medicine, Medical College of Wisconsin, Milwaukee. The authors have no conflicts to disclose.
References
1. Stanghellini V et al. Gastroenterology. 2016;150:1380-92.
2. Aziz I et al. Clin Gastroenterol Hepatol. 2019 Apr;17(5):878-86.
3. Kovacic K et al. Curr Gastroenterol Rep. 2018;20(10):46.
4. Zaki EA et al. Cephalalgia. 2009;29:719-28.
5. Venkatesan T et al. BMC Gastroenterol. 2014;14:181.
6. Ellingsen DM et al. Neurogastroenterol Motil. 2017;29 (6)e13004 9.
7. Venkatesan T et al. Neurogastroenterol Motil. 2016;28:1409-18.
8. Wasilewski A et al. Am J Gastroenterol. 2017;112:933-9.
9. van Sickle MD et al. Am J Physiol Gastrointest Liver Physiol 2003;285:G566-76.
10. Parker LA et al. Br J Pharmacol. 2011;163:1411-22.
11. van Sickle MD et al. Gastroenterology. 2001;121:767-74.
12. Fleisher DR et al. BMC Med. 2005;3:20.
13. Kumar N et al. BMC Gastroenterol. 2012;12:52.
14. Li BU et al. J Pediatr Gastroenterol Nutr. 2008;47:379-93.
15. Bhandari S et al. Clin Auton Res. 2018 Apr;28(2):203-9.
16. Venkatesan T et al. Neurogastroenterol Motil. 2019;31 Suppl 2:e13604. doi: 10.1111/nmo.13604.
17. Sagar RC et al. Neurogastroenterol Motil. 2018;30. doi: 10.1111/nmo.13174.
18. Taranukha T et al. Neurogastroenterol Motil. 2018 Apr;30(4):e13245. doi: 10.1111/nmo.13245.
19. Bhandari S and Venkatesan T. Dig Dis Sci. 2017;62:2035-44.
20. Choung RS et al. Neurogastroenterol Motil. 2012;24:20-6, e21. doi: 10.1111/j.1365-2982.2011.01791.x.
21. Bhandari S et al. Intern Med J. 2019 May;49(5):649-55.
22. Venkatesan T et al. Exp Brain Res. 2014; 232:2563-70.
23. Venkatesan T et al. Clin Gastroenterol Hepatol. 2019 Jul 25. doi: 10.1016/j.cgh.2019.07.039.
24. Simonetto DA et al. Mayo Clin Proc. 2012;87:114-9.
25. Wallace EA et al. South Med J. 2011;104:659-64.
26. Allen JH et al. Gut. 2004;53:1566-70.
27. Venkatesan T et al. Neurogastroenterol Motil. 2019;31 Suppl 2:e13606. doi: 10.1111/nmo.13606.
28. Habboushe J et al. Basic Clin Pharmacol Toxicol. 2018;122:660-2.
29. Bhandari S and Venkatesan T. Curr Treat Options Gastroenterol. 2016;14:495-506.
30. Hikita T et al. Cephalalgia. 2011;31:504-7.
31. Fuseau E et al. Clin Pharmacokinet 2002;41:801-11.
32. Hejazi RA et al. J Clin Gastroenterol. 2010;44:18-21.
33. Sezer OB and Sezer T. J Neurogastroenterol Motil. 2016;22:656-60.
34. Cristofori F et al. Aliment Pharmacol Ther. 2014;40:309-17.
Colorectal polyps and cancer – when to refer to genetics
Introduction
Genetic predisposition to colorectal polyps and colorectal cancer (CRC) is more common than previously recognized. Approximately 5%-10% of all individuals diagnosed with CRC have a known genetic association. However, among those with early-onset CRC (diagnosed at age less than 50 years), recent studies show that up to 20% have an associated genetic mutation.1,2 In addition, the risk of CRC in patients with certain hereditary syndromes, such as familial adenomatous polyposis (FAP), approaches 80%-90% without timely management.3 This overall high risk of CRC and extracolonic malignancies in patients with a hereditary syndrome, along with the rising rates of early-onset CRC, underscores the importance of early diagnosis and management of a hereditary condition.
Despite increasing awareness of hereditary polyposis and nonpolyposis syndromes, referral rates for genetic counseling and testing remain low.4 As gastroenterologists we have several unique opportunities, in clinic and in endoscopy, to identify patients at risk for hereditary syndromes.
Risk stratification
Personal and family history
Reviewing personal medical history and family history in detail should be a routine part of our practice. This is often when initial signs of a potential hereditary syndrome can be detected. For example, if a patient reports a personal or family history of colorectal polyps or CRC, additional information that becomes important includes age at time of diagnosis, polyp burden (number and histologic subtype), presence of inflammatory bowel disease, and history of any extracolonic malignancies. Patients with multiple colorectal polyps (e.g. more than 10-20 adenomas or more than 2 hamartomas) and those with CRC diagnosed at a young age (younger than 50 years) should be considered candidates for genetic evaluation.5
Lynch syndrome (LS), an autosomal dominant condition caused by loss of DNA mismatch repair (MMR) genes, is the most common hereditary CRC syndrome, accounting for 2%-4% of all CRCs.3,6 Extracolonic LS-associated cancers to keep in mind while reviewing personal and family histories include those involving the gastrointestinal (GI) tract such as gastric, pancreatic, biliary tract, and small intestine cancers, and also non-GI tract cancers including endometrial, ovarian, urinary tract, and renal cancers along with brain tumors, and skin lesions including sebaceous adenomas, sebaceous carcinomas, and keratoacanthomas. Notably, after CRC, endometrial cancer is the second most common cancer among women with LS. Prior diagnosis of endometrial cancer should also prompt additional history-taking and evaluation for LS.
As the National Comprehensive Cancer Network (NCCN) highlights in its recent guidelines, several key findings in family history that should prompt referral to genetics for evaluation and testing for LS include: one or more first-degree relatives (FDR) with CRC or endometrial cancer diagnosed at less than 50 years of age, one or more FDR with CRC or endometrial cancer and another synchronous or metachronous LS-related cancer, two or more FDR or second-degree relatives (SDR) with LS-related cancer (including at least one diagnosed at age less than 50 years), and three or more FDR or SDR with LS-related cancers (regardless of age).5
Comprehensive assessment of family history should include all cancer diagnoses in first- and second-degree relatives, including age at diagnosis and cancer type, as well as ethnicity, as these inform the likelihood that the patient harbors a germline pathogenic variant associated with cancer predisposition.5 Given the difficulty of eliciting this level of detail, the family histories elicited in clinical settings are often limited or incomplete. Unknown family history should not be mistaken for unremarkable family history. Alternatively, if family history is unimpressive, this is not necessarily reassuring, as there can be variability in disease penetrance, including autosomal recessive syndromes that may skip generations, and de novo mutations do occur. In fact, among individuals with early-onset CRC diagnosed at age less than 50, only half of mutation carriers reported a family history of CRC in an FDR.2 Thus, individuals with concerning personal histories should undergo a genetic evaluation even if family history is not concerning.
Polyp phenotype
In addition to personal and family history, colon polyp history (including number, size, and histology) can provide important clues to identifying individuals with genetic predisposition to CRC. Table 1 highlights hereditary syndromes and polyp phenotypes associated with increased CRC risk. Based on consensus guidelines, individuals with a history of greater than 10-20 adenomas, 2 or more hamartomas, or 5 or more sessile serrated polyps should be referred for genetic testing.5,7 Serrated polyposis syndrome (SPS) is diagnosed based on at least one of the following criteria: 1) 5 or more serrated polyps, all at least 5 mm in size, proximal to the rectum including at least 2 that are 10 mm or larger in size, or 2) more than 20 serrated polyps distributed throughout the colon with at least 5 proximal to the rectum.8 Pathogenic germline variants in RNF43, a tumor suppressor gene, have been associated with SPS in rare families; however, in most cases genetic testing is uninformative and further genetic and environmental discovery studies are needed to determine the underlying cause.8,9
Risk prediction models
Models have been developed that integrate family history and phenotype data to help identify patients who may be at risk for LS. The Amsterdam criteria (more than 3 relatives with LS-associated cancers, more than 2 generations involving LS-associated cancers, and more than 1 cancer diagnosed before the age of 50; “3:2:1” criteria) were initially developed for research purposes to identify individuals who were likely to be carriers of mutations of LS based on CRC and later revised to include extracolonic malignancies (Amsterdam II).11 However, they have limited sensitivity for identifying high-risk patients. Similarly, the Bethesda guidelines have also been modified and revised to identify patients at risk for LS whose tumors should be tested with microsatellite instability (MSI), but also with limited sensitivity.12
Several risk prediction models have been developed that perform better than the Amsterdam criteria or Bethesda guidelines for determining which patients should be referred for genetic testing for LS. These include MMRPredict, MMRpro, and PREMM5.13-16 These models use clinical data (personal and family history of cancer and tumor phenotypes) to calculate the probability of a germline mutation in one of the mismatch repair (MMR) genes associated with LS. The current threshold at which to refer a patient for genetic counseling and testing is a predicted probability of 5% or greater using any one of these models, though some have proposed lowering the threshold to 2.5%.16,17
Universal tumor testing
Because of the limitations of relying on clinical family history, such as with the Amsterdam criteria and the Bethesda guidelines,18,19 as of 2014 the NCCN recommended universal tumor screening for DNA MMR deficiency associated with LS. This approach, also known as “universal testing,” has been shown to be cost effective and more sensitive in identifying at-risk patients than clinical criteria alone.20,21 Specifically, the NCCN recommends that tumor specimens of all patients diagnosed with CRC undergo testing for microsatellite instability (MSI) or loss of MMR proteins (MLH1, MSH2, MSH6, PMS2) expression by immunohistochemistry (IHC).5 Loss of MMR proteins or MSI-high findings should prompt a referral to genetics for counseling and consideration of testing for germline mutations. Universal testing of CRC and endometrial cancers is considered the most reliable way to screen patients for LS.
Universal testing by MSI or IHC may be performed on premalignant or malignant lesions. However, it is important to recognize that DNA MMR deficiency testing may not be as reliable when applied to colorectal polyps. Using data from three cancer registries (Dana-Farber Cancer Institute, University of Michigan, MD Anderson Cancer Center), Yurgelun and colleagues investigated the yield of MSI and IHC in colorectal polyps removed from patients with known LS.22 Overall, high-level MSI was found in only 41% of Lynch-associated adenomas and loss of MMR protein expression was evident in only 50%. While adenomas 8 mm in size or greater were more likely to have MSI-high or loss of MMR protein expression compared with those less than 8 mm in size, MMR-deficiency phenotype was less reliable in smaller adenomas. Consequently, results of MSI and/or IHC should therefore be interpreted with caution and in the context of the specimen upon which they are performed.
Considerations for clinical genetic testing
Genetic testing for cancer susceptibility should include informed consent and counseling for patients regarding potential risks and benefits. Clinicians ordering genetic testing should have the expertise necessary to interpret test results, which may be positive (pathogenic or likely pathogenic germline variant identified), or negative (no variants identified), or may yield one or more variants of uncertain clinical significance. Individuals found to carry a pathogenic or likely pathogenic germline variant associated with cancer susceptibility should be referred for additional genetic counseling and may require additional expert consultation for management of extracolonic cancer risks. It is important that individuals diagnosed with a hereditary cancer syndrome be informed that this diagnosis has implications for family members, who may also be at risk for the condition and may benefit from genetic testing.
Practical considerations
Given the difficulty in obtaining a detailed family history while in clinic or in endoscopy, several studies have investigated strategies that may be integrated into practice to identify high-risk patients without substantial burden on providers or patients. Kastrinos and colleagues identified the following three high-yield questions as part of a CRC Risk Assessment Tool that can be used while performing a precolonoscopy assessment: 1) Do you have a first-degree relative with CRC or LS-related cancer diagnosed before age 50?; 2) Have you had CRC or polyps diagnosed prior to age 50?; and 3) Do you have three or more relatives with CRC? The authors found that these three questions alone identified 77% of high-risk individuals.23 In addition, implementation of family history screening instruments using standardized surveys or self-administered risk prediction models at the time of colonoscopy have been shown to improve ascertainment of high-risk patients.24,25 Such strategies may become increasingly easier to implement with integration into patients’ electronic medical records.
Conclusions
Hereditary CRC syndromes are becoming increasingly important to identify, especially in an era where we are seeing rising rates of early-onset CRC. Early identification of high-risk features (Table 2) can lead to timely diagnosis with the goal to implement preventive strategies for screening and/or surveillance, ideally prior to development of cancers.
As gastroenterologists, we have several unique opportunities to identify these individuals and must maintain a high level of suspicion with careful attention when obtaining personal and family history details in clinic and in endoscopy.
Dr. Maratt is assistant professor, Indiana University, Richard L. Roudebush VA Medical Center, Indianapolis. Dr. Stoffel is assistant professor, University of Michigan; director of Cancer Genetic Clinic, Rogel Cancer Center, Ann Arbor. They have no conflicts of interest.
References
1. Pearlman R et al. JAMA Oncol. 2017;3(4):464-71.
2. Stoffel EM et al. Gastroenterology. 2018;154(4):897-905.
3. Kanth P et al. Am J Gastroenterol. 2017;112:1509-25.
4. Brennan B et al. Ther Adv Gastroenterol. 2017;10:361-71.
5. National Comprehensive Cancer Network. Available at: nccn.org.
6. Lynch HT et al. Nat Rev Cancer. 2015;15:181-94.
7. Syngal S et al. Am J Gastroenterol. 2015;110:223-62.
8. Mankaney G et al. Clin Gastroenterol Hepatol. 2020:(in press)
9. Yan HHN et al. Gut 2017;66:1645-56.
10. Ma H et al. Pathology. 2018;50:49-59.
11. Vasen H et al. Gastroenterology 1999;116:1453-6.
12. Umar A et al. J Natl Cancer Inst. 2004;96:261-8.
13. Kastrinos F et al. J Natl Cancer Inst. 2015;108(2):1-9.
14. Chen S et al. JAMA. 2006;296(12):1479-87.
15. Barnetson RA et al. N Engl J Med. 2006;354(26):2751-63.
16. Kastrinos F et al. J Clin Oncol. 2017;35:2165-72.
17. Kastrinos F et al. Fam Cancer. 2018;17:567-67.
18. Cohen SA et al. Annu Rev Genomics Hum Genet. 2019;20:293-307.
19. Matloff J et al. J Natl Compr Canc Netw. 2013;11:1380-5.
20. Ladabaum U et al. Ann Intern Med. 2011;155(2):69-79.
21. Hampel H et al. N Engl J Med. 2005;352(18):1851-60.
22. Yurgelun MB et al. Cancer Prev Res. 2012;5:574-82.
23. Kastrinos F et al. Am J Gastroenterol. 2009;104:1508-18.
24. Luba DG et al. Clin Gastroenterol Hepatol. 2018;16:49-58.
25. Guivatchian T et al. Gastrointest Endosc. 2017;86:684-91.
Introduction
Genetic predisposition to colorectal polyps and colorectal cancer (CRC) is more common than previously recognized. Approximately 5%-10% of all individuals diagnosed with CRC have a known genetic association. However, among those with early-onset CRC (diagnosed at age less than 50 years), recent studies show that up to 20% have an associated genetic mutation.1,2 In addition, the risk of CRC in patients with certain hereditary syndromes, such as familial adenomatous polyposis (FAP), approaches 80%-90% without timely management.3 This overall high risk of CRC and extracolonic malignancies in patients with a hereditary syndrome, along with the rising rates of early-onset CRC, underscores the importance of early diagnosis and management of a hereditary condition.
Despite increasing awareness of hereditary polyposis and nonpolyposis syndromes, referral rates for genetic counseling and testing remain low.4 As gastroenterologists we have several unique opportunities, in clinic and in endoscopy, to identify patients at risk for hereditary syndromes.
Risk stratification
Personal and family history
Reviewing personal medical history and family history in detail should be a routine part of our practice. This is often when initial signs of a potential hereditary syndrome can be detected. For example, if a patient reports a personal or family history of colorectal polyps or CRC, additional information that becomes important includes age at time of diagnosis, polyp burden (number and histologic subtype), presence of inflammatory bowel disease, and history of any extracolonic malignancies. Patients with multiple colorectal polyps (e.g. more than 10-20 adenomas or more than 2 hamartomas) and those with CRC diagnosed at a young age (younger than 50 years) should be considered candidates for genetic evaluation.5
Lynch syndrome (LS), an autosomal dominant condition caused by loss of DNA mismatch repair (MMR) genes, is the most common hereditary CRC syndrome, accounting for 2%-4% of all CRCs.3,6 Extracolonic LS-associated cancers to keep in mind while reviewing personal and family histories include those involving the gastrointestinal (GI) tract such as gastric, pancreatic, biliary tract, and small intestine cancers, and also non-GI tract cancers including endometrial, ovarian, urinary tract, and renal cancers along with brain tumors, and skin lesions including sebaceous adenomas, sebaceous carcinomas, and keratoacanthomas. Notably, after CRC, endometrial cancer is the second most common cancer among women with LS. Prior diagnosis of endometrial cancer should also prompt additional history-taking and evaluation for LS.
As the National Comprehensive Cancer Network (NCCN) highlights in its recent guidelines, several key findings in family history that should prompt referral to genetics for evaluation and testing for LS include: one or more first-degree relatives (FDR) with CRC or endometrial cancer diagnosed at less than 50 years of age, one or more FDR with CRC or endometrial cancer and another synchronous or metachronous LS-related cancer, two or more FDR or second-degree relatives (SDR) with LS-related cancer (including at least one diagnosed at age less than 50 years), and three or more FDR or SDR with LS-related cancers (regardless of age).5
Comprehensive assessment of family history should include all cancer diagnoses in first- and second-degree relatives, including age at diagnosis and cancer type, as well as ethnicity, as these inform the likelihood that the patient harbors a germline pathogenic variant associated with cancer predisposition.5 Given the difficulty of eliciting this level of detail, the family histories elicited in clinical settings are often limited or incomplete. Unknown family history should not be mistaken for unremarkable family history. Alternatively, if family history is unimpressive, this is not necessarily reassuring, as there can be variability in disease penetrance, including autosomal recessive syndromes that may skip generations, and de novo mutations do occur. In fact, among individuals with early-onset CRC diagnosed at age less than 50, only half of mutation carriers reported a family history of CRC in an FDR.2 Thus, individuals with concerning personal histories should undergo a genetic evaluation even if family history is not concerning.
Polyp phenotype
In addition to personal and family history, colon polyp history (including number, size, and histology) can provide important clues to identifying individuals with genetic predisposition to CRC. Table 1 highlights hereditary syndromes and polyp phenotypes associated with increased CRC risk. Based on consensus guidelines, individuals with a history of greater than 10-20 adenomas, 2 or more hamartomas, or 5 or more sessile serrated polyps should be referred for genetic testing.5,7 Serrated polyposis syndrome (SPS) is diagnosed based on at least one of the following criteria: 1) 5 or more serrated polyps, all at least 5 mm in size, proximal to the rectum including at least 2 that are 10 mm or larger in size, or 2) more than 20 serrated polyps distributed throughout the colon with at least 5 proximal to the rectum.8 Pathogenic germline variants in RNF43, a tumor suppressor gene, have been associated with SPS in rare families; however, in most cases genetic testing is uninformative and further genetic and environmental discovery studies are needed to determine the underlying cause.8,9
Risk prediction models
Models have been developed that integrate family history and phenotype data to help identify patients who may be at risk for LS. The Amsterdam criteria (more than 3 relatives with LS-associated cancers, more than 2 generations involving LS-associated cancers, and more than 1 cancer diagnosed before the age of 50; “3:2:1” criteria) were initially developed for research purposes to identify individuals who were likely to be carriers of mutations of LS based on CRC and later revised to include extracolonic malignancies (Amsterdam II).11 However, they have limited sensitivity for identifying high-risk patients. Similarly, the Bethesda guidelines have also been modified and revised to identify patients at risk for LS whose tumors should be tested with microsatellite instability (MSI), but also with limited sensitivity.12
Several risk prediction models have been developed that perform better than the Amsterdam criteria or Bethesda guidelines for determining which patients should be referred for genetic testing for LS. These include MMRPredict, MMRpro, and PREMM5.13-16 These models use clinical data (personal and family history of cancer and tumor phenotypes) to calculate the probability of a germline mutation in one of the mismatch repair (MMR) genes associated with LS. The current threshold at which to refer a patient for genetic counseling and testing is a predicted probability of 5% or greater using any one of these models, though some have proposed lowering the threshold to 2.5%.16,17
Universal tumor testing
Because of the limitations of relying on clinical family history, such as with the Amsterdam criteria and the Bethesda guidelines,18,19 as of 2014 the NCCN recommended universal tumor screening for DNA MMR deficiency associated with LS. This approach, also known as “universal testing,” has been shown to be cost effective and more sensitive in identifying at-risk patients than clinical criteria alone.20,21 Specifically, the NCCN recommends that tumor specimens of all patients diagnosed with CRC undergo testing for microsatellite instability (MSI) or loss of MMR proteins (MLH1, MSH2, MSH6, PMS2) expression by immunohistochemistry (IHC).5 Loss of MMR proteins or MSI-high findings should prompt a referral to genetics for counseling and consideration of testing for germline mutations. Universal testing of CRC and endometrial cancers is considered the most reliable way to screen patients for LS.
Universal testing by MSI or IHC may be performed on premalignant or malignant lesions. However, it is important to recognize that DNA MMR deficiency testing may not be as reliable when applied to colorectal polyps. Using data from three cancer registries (Dana-Farber Cancer Institute, University of Michigan, MD Anderson Cancer Center), Yurgelun and colleagues investigated the yield of MSI and IHC in colorectal polyps removed from patients with known LS.22 Overall, high-level MSI was found in only 41% of Lynch-associated adenomas and loss of MMR protein expression was evident in only 50%. While adenomas 8 mm in size or greater were more likely to have MSI-high or loss of MMR protein expression compared with those less than 8 mm in size, MMR-deficiency phenotype was less reliable in smaller adenomas. Consequently, results of MSI and/or IHC should therefore be interpreted with caution and in the context of the specimen upon which they are performed.
Considerations for clinical genetic testing
Genetic testing for cancer susceptibility should include informed consent and counseling for patients regarding potential risks and benefits. Clinicians ordering genetic testing should have the expertise necessary to interpret test results, which may be positive (pathogenic or likely pathogenic germline variant identified), or negative (no variants identified), or may yield one or more variants of uncertain clinical significance. Individuals found to carry a pathogenic or likely pathogenic germline variant associated with cancer susceptibility should be referred for additional genetic counseling and may require additional expert consultation for management of extracolonic cancer risks. It is important that individuals diagnosed with a hereditary cancer syndrome be informed that this diagnosis has implications for family members, who may also be at risk for the condition and may benefit from genetic testing.
Practical considerations
Given the difficulty in obtaining a detailed family history while in clinic or in endoscopy, several studies have investigated strategies that may be integrated into practice to identify high-risk patients without substantial burden on providers or patients. Kastrinos and colleagues identified the following three high-yield questions as part of a CRC Risk Assessment Tool that can be used while performing a precolonoscopy assessment: 1) Do you have a first-degree relative with CRC or LS-related cancer diagnosed before age 50?; 2) Have you had CRC or polyps diagnosed prior to age 50?; and 3) Do you have three or more relatives with CRC? The authors found that these three questions alone identified 77% of high-risk individuals.23 In addition, implementation of family history screening instruments using standardized surveys or self-administered risk prediction models at the time of colonoscopy have been shown to improve ascertainment of high-risk patients.24,25 Such strategies may become increasingly easier to implement with integration into patients’ electronic medical records.
Conclusions
Hereditary CRC syndromes are becoming increasingly important to identify, especially in an era where we are seeing rising rates of early-onset CRC. Early identification of high-risk features (Table 2) can lead to timely diagnosis with the goal to implement preventive strategies for screening and/or surveillance, ideally prior to development of cancers.
As gastroenterologists, we have several unique opportunities to identify these individuals and must maintain a high level of suspicion with careful attention when obtaining personal and family history details in clinic and in endoscopy.
Dr. Maratt is assistant professor, Indiana University, Richard L. Roudebush VA Medical Center, Indianapolis. Dr. Stoffel is assistant professor, University of Michigan; director of Cancer Genetic Clinic, Rogel Cancer Center, Ann Arbor. They have no conflicts of interest.
References
1. Pearlman R et al. JAMA Oncol. 2017;3(4):464-71.
2. Stoffel EM et al. Gastroenterology. 2018;154(4):897-905.
3. Kanth P et al. Am J Gastroenterol. 2017;112:1509-25.
4. Brennan B et al. Ther Adv Gastroenterol. 2017;10:361-71.
5. National Comprehensive Cancer Network. Available at: nccn.org.
6. Lynch HT et al. Nat Rev Cancer. 2015;15:181-94.
7. Syngal S et al. Am J Gastroenterol. 2015;110:223-62.
8. Mankaney G et al. Clin Gastroenterol Hepatol. 2020:(in press)
9. Yan HHN et al. Gut 2017;66:1645-56.
10. Ma H et al. Pathology. 2018;50:49-59.
11. Vasen H et al. Gastroenterology 1999;116:1453-6.
12. Umar A et al. J Natl Cancer Inst. 2004;96:261-8.
13. Kastrinos F et al. J Natl Cancer Inst. 2015;108(2):1-9.
14. Chen S et al. JAMA. 2006;296(12):1479-87.
15. Barnetson RA et al. N Engl J Med. 2006;354(26):2751-63.
16. Kastrinos F et al. J Clin Oncol. 2017;35:2165-72.
17. Kastrinos F et al. Fam Cancer. 2018;17:567-67.
18. Cohen SA et al. Annu Rev Genomics Hum Genet. 2019;20:293-307.
19. Matloff J et al. J Natl Compr Canc Netw. 2013;11:1380-5.
20. Ladabaum U et al. Ann Intern Med. 2011;155(2):69-79.
21. Hampel H et al. N Engl J Med. 2005;352(18):1851-60.
22. Yurgelun MB et al. Cancer Prev Res. 2012;5:574-82.
23. Kastrinos F et al. Am J Gastroenterol. 2009;104:1508-18.
24. Luba DG et al. Clin Gastroenterol Hepatol. 2018;16:49-58.
25. Guivatchian T et al. Gastrointest Endosc. 2017;86:684-91.
Introduction
Genetic predisposition to colorectal polyps and colorectal cancer (CRC) is more common than previously recognized. Approximately 5%-10% of all individuals diagnosed with CRC have a known genetic association. However, among those with early-onset CRC (diagnosed at age less than 50 years), recent studies show that up to 20% have an associated genetic mutation.1,2 In addition, the risk of CRC in patients with certain hereditary syndromes, such as familial adenomatous polyposis (FAP), approaches 80%-90% without timely management.3 This overall high risk of CRC and extracolonic malignancies in patients with a hereditary syndrome, along with the rising rates of early-onset CRC, underscores the importance of early diagnosis and management of a hereditary condition.
Despite increasing awareness of hereditary polyposis and nonpolyposis syndromes, referral rates for genetic counseling and testing remain low.4 As gastroenterologists we have several unique opportunities, in clinic and in endoscopy, to identify patients at risk for hereditary syndromes.
Risk stratification
Personal and family history
Reviewing personal medical history and family history in detail should be a routine part of our practice. This is often when initial signs of a potential hereditary syndrome can be detected. For example, if a patient reports a personal or family history of colorectal polyps or CRC, additional information that becomes important includes age at time of diagnosis, polyp burden (number and histologic subtype), presence of inflammatory bowel disease, and history of any extracolonic malignancies. Patients with multiple colorectal polyps (e.g. more than 10-20 adenomas or more than 2 hamartomas) and those with CRC diagnosed at a young age (younger than 50 years) should be considered candidates for genetic evaluation.5
Lynch syndrome (LS), an autosomal dominant condition caused by loss of DNA mismatch repair (MMR) genes, is the most common hereditary CRC syndrome, accounting for 2%-4% of all CRCs.3,6 Extracolonic LS-associated cancers to keep in mind while reviewing personal and family histories include those involving the gastrointestinal (GI) tract such as gastric, pancreatic, biliary tract, and small intestine cancers, and also non-GI tract cancers including endometrial, ovarian, urinary tract, and renal cancers along with brain tumors, and skin lesions including sebaceous adenomas, sebaceous carcinomas, and keratoacanthomas. Notably, after CRC, endometrial cancer is the second most common cancer among women with LS. Prior diagnosis of endometrial cancer should also prompt additional history-taking and evaluation for LS.
As the National Comprehensive Cancer Network (NCCN) highlights in its recent guidelines, several key findings in family history that should prompt referral to genetics for evaluation and testing for LS include: one or more first-degree relatives (FDR) with CRC or endometrial cancer diagnosed at less than 50 years of age, one or more FDR with CRC or endometrial cancer and another synchronous or metachronous LS-related cancer, two or more FDR or second-degree relatives (SDR) with LS-related cancer (including at least one diagnosed at age less than 50 years), and three or more FDR or SDR with LS-related cancers (regardless of age).5
Comprehensive assessment of family history should include all cancer diagnoses in first- and second-degree relatives, including age at diagnosis and cancer type, as well as ethnicity, as these inform the likelihood that the patient harbors a germline pathogenic variant associated with cancer predisposition.5 Given the difficulty of eliciting this level of detail, the family histories elicited in clinical settings are often limited or incomplete. Unknown family history should not be mistaken for unremarkable family history. Alternatively, if family history is unimpressive, this is not necessarily reassuring, as there can be variability in disease penetrance, including autosomal recessive syndromes that may skip generations, and de novo mutations do occur. In fact, among individuals with early-onset CRC diagnosed at age less than 50, only half of mutation carriers reported a family history of CRC in an FDR.2 Thus, individuals with concerning personal histories should undergo a genetic evaluation even if family history is not concerning.
Polyp phenotype
In addition to personal and family history, colon polyp history (including number, size, and histology) can provide important clues to identifying individuals with genetic predisposition to CRC. Table 1 highlights hereditary syndromes and polyp phenotypes associated with increased CRC risk. Based on consensus guidelines, individuals with a history of greater than 10-20 adenomas, 2 or more hamartomas, or 5 or more sessile serrated polyps should be referred for genetic testing.5,7 Serrated polyposis syndrome (SPS) is diagnosed based on at least one of the following criteria: 1) 5 or more serrated polyps, all at least 5 mm in size, proximal to the rectum including at least 2 that are 10 mm or larger in size, or 2) more than 20 serrated polyps distributed throughout the colon with at least 5 proximal to the rectum.8 Pathogenic germline variants in RNF43, a tumor suppressor gene, have been associated with SPS in rare families; however, in most cases genetic testing is uninformative and further genetic and environmental discovery studies are needed to determine the underlying cause.8,9
Risk prediction models
Models have been developed that integrate family history and phenotype data to help identify patients who may be at risk for LS. The Amsterdam criteria (more than 3 relatives with LS-associated cancers, more than 2 generations involving LS-associated cancers, and more than 1 cancer diagnosed before the age of 50; “3:2:1” criteria) were initially developed for research purposes to identify individuals who were likely to be carriers of mutations of LS based on CRC and later revised to include extracolonic malignancies (Amsterdam II).11 However, they have limited sensitivity for identifying high-risk patients. Similarly, the Bethesda guidelines have also been modified and revised to identify patients at risk for LS whose tumors should be tested with microsatellite instability (MSI), but also with limited sensitivity.12
Several risk prediction models have been developed that perform better than the Amsterdam criteria or Bethesda guidelines for determining which patients should be referred for genetic testing for LS. These include MMRPredict, MMRpro, and PREMM5.13-16 These models use clinical data (personal and family history of cancer and tumor phenotypes) to calculate the probability of a germline mutation in one of the mismatch repair (MMR) genes associated with LS. The current threshold at which to refer a patient for genetic counseling and testing is a predicted probability of 5% or greater using any one of these models, though some have proposed lowering the threshold to 2.5%.16,17
Universal tumor testing
Because of the limitations of relying on clinical family history, such as with the Amsterdam criteria and the Bethesda guidelines,18,19 as of 2014 the NCCN recommended universal tumor screening for DNA MMR deficiency associated with LS. This approach, also known as “universal testing,” has been shown to be cost effective and more sensitive in identifying at-risk patients than clinical criteria alone.20,21 Specifically, the NCCN recommends that tumor specimens of all patients diagnosed with CRC undergo testing for microsatellite instability (MSI) or loss of MMR proteins (MLH1, MSH2, MSH6, PMS2) expression by immunohistochemistry (IHC).5 Loss of MMR proteins or MSI-high findings should prompt a referral to genetics for counseling and consideration of testing for germline mutations. Universal testing of CRC and endometrial cancers is considered the most reliable way to screen patients for LS.
Universal testing by MSI or IHC may be performed on premalignant or malignant lesions. However, it is important to recognize that DNA MMR deficiency testing may not be as reliable when applied to colorectal polyps. Using data from three cancer registries (Dana-Farber Cancer Institute, University of Michigan, MD Anderson Cancer Center), Yurgelun and colleagues investigated the yield of MSI and IHC in colorectal polyps removed from patients with known LS.22 Overall, high-level MSI was found in only 41% of Lynch-associated adenomas and loss of MMR protein expression was evident in only 50%. While adenomas 8 mm in size or greater were more likely to have MSI-high or loss of MMR protein expression compared with those less than 8 mm in size, MMR-deficiency phenotype was less reliable in smaller adenomas. Consequently, results of MSI and/or IHC should therefore be interpreted with caution and in the context of the specimen upon which they are performed.
Considerations for clinical genetic testing
Genetic testing for cancer susceptibility should include informed consent and counseling for patients regarding potential risks and benefits. Clinicians ordering genetic testing should have the expertise necessary to interpret test results, which may be positive (pathogenic or likely pathogenic germline variant identified), or negative (no variants identified), or may yield one or more variants of uncertain clinical significance. Individuals found to carry a pathogenic or likely pathogenic germline variant associated with cancer susceptibility should be referred for additional genetic counseling and may require additional expert consultation for management of extracolonic cancer risks. It is important that individuals diagnosed with a hereditary cancer syndrome be informed that this diagnosis has implications for family members, who may also be at risk for the condition and may benefit from genetic testing.
Practical considerations
Given the difficulty in obtaining a detailed family history while in clinic or in endoscopy, several studies have investigated strategies that may be integrated into practice to identify high-risk patients without substantial burden on providers or patients. Kastrinos and colleagues identified the following three high-yield questions as part of a CRC Risk Assessment Tool that can be used while performing a precolonoscopy assessment: 1) Do you have a first-degree relative with CRC or LS-related cancer diagnosed before age 50?; 2) Have you had CRC or polyps diagnosed prior to age 50?; and 3) Do you have three or more relatives with CRC? The authors found that these three questions alone identified 77% of high-risk individuals.23 In addition, implementation of family history screening instruments using standardized surveys or self-administered risk prediction models at the time of colonoscopy have been shown to improve ascertainment of high-risk patients.24,25 Such strategies may become increasingly easier to implement with integration into patients’ electronic medical records.
Conclusions
Hereditary CRC syndromes are becoming increasingly important to identify, especially in an era where we are seeing rising rates of early-onset CRC. Early identification of high-risk features (Table 2) can lead to timely diagnosis with the goal to implement preventive strategies for screening and/or surveillance, ideally prior to development of cancers.
As gastroenterologists, we have several unique opportunities to identify these individuals and must maintain a high level of suspicion with careful attention when obtaining personal and family history details in clinic and in endoscopy.
Dr. Maratt is assistant professor, Indiana University, Richard L. Roudebush VA Medical Center, Indianapolis. Dr. Stoffel is assistant professor, University of Michigan; director of Cancer Genetic Clinic, Rogel Cancer Center, Ann Arbor. They have no conflicts of interest.
References
1. Pearlman R et al. JAMA Oncol. 2017;3(4):464-71.
2. Stoffel EM et al. Gastroenterology. 2018;154(4):897-905.
3. Kanth P et al. Am J Gastroenterol. 2017;112:1509-25.
4. Brennan B et al. Ther Adv Gastroenterol. 2017;10:361-71.
5. National Comprehensive Cancer Network. Available at: nccn.org.
6. Lynch HT et al. Nat Rev Cancer. 2015;15:181-94.
7. Syngal S et al. Am J Gastroenterol. 2015;110:223-62.
8. Mankaney G et al. Clin Gastroenterol Hepatol. 2020:(in press)
9. Yan HHN et al. Gut 2017;66:1645-56.
10. Ma H et al. Pathology. 2018;50:49-59.
11. Vasen H et al. Gastroenterology 1999;116:1453-6.
12. Umar A et al. J Natl Cancer Inst. 2004;96:261-8.
13. Kastrinos F et al. J Natl Cancer Inst. 2015;108(2):1-9.
14. Chen S et al. JAMA. 2006;296(12):1479-87.
15. Barnetson RA et al. N Engl J Med. 2006;354(26):2751-63.
16. Kastrinos F et al. J Clin Oncol. 2017;35:2165-72.
17. Kastrinos F et al. Fam Cancer. 2018;17:567-67.
18. Cohen SA et al. Annu Rev Genomics Hum Genet. 2019;20:293-307.
19. Matloff J et al. J Natl Compr Canc Netw. 2013;11:1380-5.
20. Ladabaum U et al. Ann Intern Med. 2011;155(2):69-79.
21. Hampel H et al. N Engl J Med. 2005;352(18):1851-60.
22. Yurgelun MB et al. Cancer Prev Res. 2012;5:574-82.
23. Kastrinos F et al. Am J Gastroenterol. 2009;104:1508-18.
24. Luba DG et al. Clin Gastroenterol Hepatol. 2018;16:49-58.
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