The Journal of Family Practice

More than one-third of American adults and approximately 17% of children and adolescents between the ages of 2 and 19 years are obese.^1,2 Poor diet coupled with a sedentary lifestyle is the highest ranked cause of non-communicable disease and a leading cause of preventable death, according to the National Research Council.³

Bariatric surgery (BS) is a viable therapeutic option for obese patients who do not respond to conventional lifestyle interventions for losing weight. There are multiple gastrointestinal (GI) procedures available that are classified as either malabsorptive (Roux-en-Y gastric bypass [RYGB] and biliopancreatic diversion [BPD] with or without duodenal switch) or restrictive (laparoscopic adjustable gastric banding [LAGB] and vertical sleeve gastrectomy [VSG]).

Approximately half of the 196,000 bariatric procedures performed in the United States in 2015 were of the sleeve variety, another 23% were RYGB, and the remaining percentage was divided among the other types.⁴ Postoperative risks include nutritional deficiencies, decreased bone mineral density (BMD), dumping syndrome (when food rapidly dumps from the stomach to the intestine), and gastroesophageal reflux disease (GERD) with possible ulceration.

Despite these potential complications, a systematic review and meta-analysis found that obese people who underwent BS (gastric banding or gastric bypass) had significantly reduced risks of global, non-cardiovascular (CV), and CV mortality compared with obese controls.⁵ Helping patients to realize these benefits requires that the entire health care team—especially the family physician—is aware of the special considerations for this population.

Patients undergoing bariatric surgery require routine lifetime screening for nutritional deficiencies.

To that end, this article reviews the details of diagnosing and managing post-surgical complications. It also addresses issues unique to managing certain subpopulations, such as post-BS patients who require revision surgery or who want to pursue body contouring surgery; adolescents who undergo BS surgery; and women who want to get pregnant postoperatively.

Monitor patients for these post-surgery complications

Postoperative BS follow-up varies depending on location, surgeon preference, and availability of multidisciplinary resources. At our institution, patients have a minimum of 3 follow-up visits with their surgeon (during hospitalization and 2 weeks and 2 months postoperatively). This is followed by visits with Endocrinology 6 months after surgery and annually thereafter. Given the variability of follow-up, family physicians should coordinate with specialists where appropriate and be aware of postoperative complications and monitoring since it is likely they will have the most frequent contact with these patients.

Nutritional deficiencies are common and require lifelong screening

Nutritional deficiencies are the most common complications of malabsorptive BS. Guidelines from the Endocrine Society, as well as guidelines from the American Association of Clinical Endocrinologists (AACE), The Obesity Society (TOS), and the American Society for Metabolic and Bariatric Surgery (ASMBS), recommend routine lifetime screening for deficiencies after surgery.^6,7 Complete blood cell count, electrolytes, glucose, creatinine, and liver function tests should be obtained at one, 3, 6, 12, 18, and 24 months following surgery and annually thereafter.⁶

Multiple factors contribute to nutritional and micronutrient deficiencies, including reduced oral intake of food, decreased GI absorption, food intolerance, nausea/vomiting, and nonadherence with dietary supplements.⁸ Oral supplementation should be in chewable, powder, or liquid form because pill and capsule absorption may be altered.^8,9 Over-the-counter multivitamins may not contain the requisite daily doses recommended after BS.⁹ Patients and physicians should evaluate supplements together to ensure appropriate nutritional and micronutrient supplementation (TABLE 1^6,8-11).

Bone mineral density can start to decrease soon after surgery

Studies evaluating BMD after BS have produced variable findings. In obese patients, dual-energy x-ray absorptiometry (DEXA) measurements may not be accurate due to adipose tissue artifact and table weight limits. In addition, limited data exist on the incidence of fractures after BS. Of 2 notable studies, only one, a population-based study involving 258 Minnesota residents who underwent a first bariatric surgery between 1985 and 2004, demonstrated a significantly increased incidence of fractures.^12,13

In addition, studies show bone turnover markers, including C-terminal telopeptide, increase as early as 3 months after BS.¹⁴ Several guidelines recommend routine BMD screening after BS (TABLE 2).^6,7 The mechanism of bone demineralization is likely multifactorial—a function of the magnitude of the weight loss and skeletal unloading, calcium and vitamin D deficiencies, and associated secondary hyperparathyroidism.¹⁵ Treatment for secondary hyperparathyroidism is adequate supplementation with vitamin D and calcium.

Optimal dosing for vitamin D has not been determined. One recent systematic review suggests routine prophylaxis with at least 2000 international units (IU)/d and found the greatest improvement for known deficiency with doses of 1500-9100 IU/d following malabsorptive surgeries.¹¹ After laparoscopic sleeve gastrectomy, at least 1000 IU/d vitamin D is recommended.¹¹

Overall, high variability exists among patients, and an individualized approach for dosing is recommended.¹¹ Vitamin D levels should be monitored 2 and 4 weeks after initiation of treatment and every 3 months thereafter.¹¹ Normal levels of serum calcium, 25-OH vitamin D, bone-specific alkaline phosphatase, and 24-hour urinary calcium excretion indicate adequate calcium and vitamin D supplementation.⁶

Dumping syndrome can lead to hypoglycemia

Dumping syndrome is a common complication following BS, with prevalence ranging from 25% to 75%, depending upon the type of procedure performed.^16,17 There are 2 types: early and late. Early dumping syndrome occurs within 30 minutes of eating. Symptoms are related to the robust release of gastrointestinal hormones caused by rapid gastric emptying. Symptoms include nausea, abdominal pain, diarrhea, flushing, hypotension, and tachycardia.

Late dumping is characterized as postprandial hypoglycemia occurring one to 3 hours after eating. Late dumping is likely caused by a combination of changes within the pancreatic beta cells and abnormal insulin response to glucose.^16-18 Rapid gastric emptying leads to rapid release of glucose in the gut, which, in turn, leads to brisk insulin secretion. Since glucose is absorbed faster than insulin’s half-life, the resulting (relatively) high levels of insulin may cause hypoglycemia.^16-18

Sigstad’s scoring system can be used to confirm suspected cases of dumping syndrome (TABLE 3^16,17,19). A diagnosis can also be made with an oral glucose challenge in which pulse, blood pressure, glucose, and hematocrit are measured after ingestion of 50 g glucose. The test is positive if heart rate increases by 10 beats per minute, hematocrit increases by 3% 30 minutes after ingestion, or glucose falls below 60 mg/dL 2 to 3 hours after ingestion.¹⁷

First-line treatment of dumping syndrome consists of dietary modifications. The goal is to slow the rate of gastric emptying by eating smaller, more frequent meals; separating beverages from food; decreasing carbohydrates; and increasing fiber and protein content.

If results are suboptimal after dietary changes, medications can be prescribed including acarbose to prevent postprandial hypoglycemia; anticholinergics such as dicyclomine to slow gastric emptying; and somatostatin to decrease gastric emptying and inhibit GI hormone release.¹⁷ Lastly, for resistant and severe postprandial hypoglycemia, a few patients have undergone pancreatectomy, but only about 65% experienced improvement in symptoms and 12% developed diabetes post-surgically.²⁰

Gout attacks may initially increase, but then decrease

BS affects the incidence of gout attacks in patients with a history of gout. One comparative study of approximately 150 patients demonstrated that those with a history of gout had significantly more gout attacks in the first month after BS compared with obese patients with a history of gout undergoing other upper GI surgeries.²¹ There was no difference between malabsorptive and restrictive procedures. But after the first month, BS patients had significantly fewer gout attacks and lower uric acid levels than their obese counterparts.²¹

Protein rich diets, catabolism potentiated by aggressive caloric restriction following BS, and dehydration contribute to the initial increase. Therefore, patients who have had at least one gout attack in the year prior to surgery or who are on hypouricemic medication may benefit from at least one month of prophylactic therapy (eg, allopurinol and colchicine) after surgery.

GERD and ulceration: How to respond

Obesity is a known risk factor for GERD, but the effect of BS on GERD is uncertain and seems to vary with the procedure performed. RYGB decreases GERD and is, therefore, used as both a secondary treatment in those not responding to medications and a revision treatment for fundoplication and other types of BSs. Sleeve gastrectomy and adjustable gastric banding have mixed effects on GERD. A systematic review by de Jong et al revealed a decreased prevalence of reflux symptoms and GERD medication use after LAGB; however, during longer follow-up, 15% of previously unaffected patients reported experiencing GERD.²² The 2011 International Sleeve Gastrectomy Expert Panel Consensus Statement retrospectively noted a postoperative incidence of GERD as high as 31%.²³

BS patients with GERD should be treated with a proton pump inhibitor. If this fails, refer patients to a gastroenterologist for further evaluation.²⁴

Ulcers after BS may be an indication for revision surgery. Data are mixed regarding increased risk of marginal ulceration from nonsteroidal anti-inflammatory drug (NSAID) use, but NSAIDs have been linked to an increased risk of anastomotic leakage.^25-28 Thus, it seems prudent to avoid NSAIDs in people who have undergone BS.

Keeping watch over psychiatric comorbidities

A recent meta-analysis by Dawes et al²⁹ showed that about 23% of patients pursuing BS have a comorbid mood disorder. Specifically, the preoperative prevalence of depression (19%) and binge-eating disorder (17%) were found to be higher than rates in the general population.²⁹ The meta-analysis found improvement in the prevalence of depression with fewer symptoms and less antidepressant medication use in the first 3 years after surgery and a decrease in the rate of binge-eating disorder, although there were fewer supporting data for the latter. These findings were observed with both restrictive and malabsorptive procedures.

The data are mixed regarding rates of alcohol abuse and suicide. Further research is necessary in this field. Patients who have had BS should receive ongoing psychiatric and psychological care from a multidisciplinary team as a matter of course.

Will a second surgery be needed?

Revision surgery. In 2015, about 14% of the almost 200,000 BSs performed were revisions.⁴ Revision surgery is indicated in BS patients with weight regain, recurrent comorbid diseases (eg, diabetes, hypertension), or complications of primary BS. Restrictive procedures have a higher revision rate than malabsorptive procedures, primarily due to a higher rate of weight regain.^6,30

Because revision surgery is associated with more complications and possibly longer hospital stays than primary BS, it should be performed by a bariatric surgeon with extensive experience.^30,31 Restrictive revisions are typically converted to malabsorptive procedures. Cost is a limiting factor as many patients’ insurance coverage is limited to one BS per lifetime.

Body contouring. Body contouring surgery (BCS) can improve physical and mental well-being and may be a protective factor for weight regain after bariatric surgery.³² Despite its desirability—particularly to women, adolescents, and those with large decreases in body mass index (BMI)—few patients can afford BCS since it is rarely covered by insurance.

Complications of BCS vary, but are most commonly infection and wound dehiscence. This is, in part, due to poorer wound healing in BS patients compared to those with nonsurgical massive weight loss. The cause of poor wound healing is thought to be secondary to nutritional deficiencies and the catabolic state induced by post-surgical weight loss. Recommendations for BCS include weight stability for more than one year after BS, age >16 years, excess skin causing significant functional impairment, non-smoking status, and presence of good social support.³³

Bariatric surgery in adolescents is on the rise

Children in the highest body mass index quartile have more than twice the death rate of those in the lowest BMI quartile.³⁴ Thus, it is not surprising that the rate of BS in adolescents is increasing.⁷ BS in this age group is successful for weight loss and improvement of comorbid conditions, with relatively low complication rates.³⁵ Options include malabsorptive and restrictive procedures, although gastric banding has not been approved by the US Food and Drug Administration for patients under the age of 18 years.

Monitor vitamin D levels 2 and 4 weeks after initiation of treatment and every 3 months thereafter.After BS, adolescent girls should be counseled regarding the possibility of pregnancy (restoration of fertility) and appropriate contraception. Adolescent patients require nutritional supplementation after BS as indicated in TABLE 1.^6,8-11

When determining which adolescents to refer for BS, we recommend the following criteria: ^35-38

• failure of a minimum 6-month trial of a staged treatment approach, as recommended by Barlow et al,³⁶ including diet, exercise, and pharmacologic treatment
• BMI ≥35 with type 2 diabetes or severe sleep apnea (apnea hypopnea index [AHI] >15)³⁷
• BMI ≥40 with mild sleep apnea (AHI >5), hypertension, or pre-diabetes³⁷
• Tanner stage IV or V
• at least 95% skeletal growth (for malabsorptive surgery).³⁷ This can be determined using an estimated adult height from mid-parental height formula and assessing growth plate closure with hand radiographs for bone age
• appropriate maturity level permitting adherence
• good psychological support
• a multidisciplinary team for postoperative and long-term follow-up care.

Planning for the future: Exploring the possibility of pregnancy

Obesity is the primary cause of maternal and fetal morbidity during pregnancy. It is associated with increased rates of early miscarriage, congenital defects, macrosomia, and fetal death. Maternal risks of obesity include: gestational hypertension, gestational diabetes mellitus (GDM), and pre-eclampsia. Obese mothers also have a higher incidence of failed induction, caesarean section, and breastfeeding failure.^10,39 Given that half of all BSs are performed in women of reproductive age, this population deserves special consideration.¹⁰

A recent meta-analysis by Galazis et al⁴⁰ concluded that BS performed prior to pregnancy led to decreased rates of preeclampsia, GDM, large neonates, preterm birth, and neonatal intensive care unit admission. Perinatal mortality did not increase after BS. However, BS led to higher rates of maternal anemia. There was no significant difference between groups in incidence of cesarean section.

The post BS female patient should be advised to use a reliable form of contraception for a minimum of 12 to 18 months after surgery.^6,10,39 Involve high-risk obstetric specialists during pregnancies. Diet should be supplemented as indicated in TABLE 1.^6,8-11

CORRESPONDENCE
Amy Rothberg, MD, PhD, Domino’s Farms, Lobby G, Suite 1500, 24 Frank Lloyd Wright Drive, Ann Arbor, MI 48106; [email protected].

More than one-third of American adults and approximately 17% of children and adolescents between the ages of 2 and 19 years are obese.^1,2 Poor diet coupled with a sedentary lifestyle is the highest ranked cause of non-communicable disease and a leading cause of preventable death, according to the National Research Council.³

Bariatric surgery (BS) is a viable therapeutic option for obese patients who do not respond to conventional lifestyle interventions for losing weight. There are multiple gastrointestinal (GI) procedures available that are classified as either malabsorptive (Roux-en-Y gastric bypass [RYGB] and biliopancreatic diversion [BPD] with or without duodenal switch) or restrictive (laparoscopic adjustable gastric banding [LAGB] and vertical sleeve gastrectomy [VSG]).

Approximately half of the 196,000 bariatric procedures performed in the United States in 2015 were of the sleeve variety, another 23% were RYGB, and the remaining percentage was divided among the other types.⁴ Postoperative risks include nutritional deficiencies, decreased bone mineral density (BMD), dumping syndrome (when food rapidly dumps from the stomach to the intestine), and gastroesophageal reflux disease (GERD) with possible ulceration.

Despite these potential complications, a systematic review and meta-analysis found that obese people who underwent BS (gastric banding or gastric bypass) had significantly reduced risks of global, non-cardiovascular (CV), and CV mortality compared with obese controls.⁵ Helping patients to realize these benefits requires that the entire health care team—especially the family physician—is aware of the special considerations for this population.

Patients undergoing bariatric surgery require routine lifetime screening for nutritional deficiencies.

To that end, this article reviews the details of diagnosing and managing post-surgical complications. It also addresses issues unique to managing certain subpopulations, such as post-BS patients who require revision surgery or who want to pursue body contouring surgery; adolescents who undergo BS surgery; and women who want to get pregnant postoperatively.

Monitor patients for these post-surgery complications

Postoperative BS follow-up varies depending on location, surgeon preference, and availability of multidisciplinary resources. At our institution, patients have a minimum of 3 follow-up visits with their surgeon (during hospitalization and 2 weeks and 2 months postoperatively). This is followed by visits with Endocrinology 6 months after surgery and annually thereafter. Given the variability of follow-up, family physicians should coordinate with specialists where appropriate and be aware of postoperative complications and monitoring since it is likely they will have the most frequent contact with these patients.

Nutritional deficiencies are common and require lifelong screening

Nutritional deficiencies are the most common complications of malabsorptive BS. Guidelines from the Endocrine Society, as well as guidelines from the American Association of Clinical Endocrinologists (AACE), The Obesity Society (TOS), and the American Society for Metabolic and Bariatric Surgery (ASMBS), recommend routine lifetime screening for deficiencies after surgery.^6,7 Complete blood cell count, electrolytes, glucose, creatinine, and liver function tests should be obtained at one, 3, 6, 12, 18, and 24 months following surgery and annually thereafter.⁶

Multiple factors contribute to nutritional and micronutrient deficiencies, including reduced oral intake of food, decreased GI absorption, food intolerance, nausea/vomiting, and nonadherence with dietary supplements.⁸ Oral supplementation should be in chewable, powder, or liquid form because pill and capsule absorption may be altered.^8,9 Over-the-counter multivitamins may not contain the requisite daily doses recommended after BS.⁹ Patients and physicians should evaluate supplements together to ensure appropriate nutritional and micronutrient supplementation (TABLE 1^6,8-11).

Bone mineral density can start to decrease soon after surgery

Studies evaluating BMD after BS have produced variable findings. In obese patients, dual-energy x-ray absorptiometry (DEXA) measurements may not be accurate due to adipose tissue artifact and table weight limits. In addition, limited data exist on the incidence of fractures after BS. Of 2 notable studies, only one, a population-based study involving 258 Minnesota residents who underwent a first bariatric surgery between 1985 and 2004, demonstrated a significantly increased incidence of fractures.^12,13

In addition, studies show bone turnover markers, including C-terminal telopeptide, increase as early as 3 months after BS.¹⁴ Several guidelines recommend routine BMD screening after BS (TABLE 2).^6,7 The mechanism of bone demineralization is likely multifactorial—a function of the magnitude of the weight loss and skeletal unloading, calcium and vitamin D deficiencies, and associated secondary hyperparathyroidism.¹⁵ Treatment for secondary hyperparathyroidism is adequate supplementation with vitamin D and calcium.

Optimal dosing for vitamin D has not been determined. One recent systematic review suggests routine prophylaxis with at least 2000 international units (IU)/d and found the greatest improvement for known deficiency with doses of 1500-9100 IU/d following malabsorptive surgeries.¹¹ After laparoscopic sleeve gastrectomy, at least 1000 IU/d vitamin D is recommended.¹¹

Overall, high variability exists among patients, and an individualized approach for dosing is recommended.¹¹ Vitamin D levels should be monitored 2 and 4 weeks after initiation of treatment and every 3 months thereafter.¹¹ Normal levels of serum calcium, 25-OH vitamin D, bone-specific alkaline phosphatase, and 24-hour urinary calcium excretion indicate adequate calcium and vitamin D supplementation.⁶

Dumping syndrome can lead to hypoglycemia

Dumping syndrome is a common complication following BS, with prevalence ranging from 25% to 75%, depending upon the type of procedure performed.^16,17 There are 2 types: early and late. Early dumping syndrome occurs within 30 minutes of eating. Symptoms are related to the robust release of gastrointestinal hormones caused by rapid gastric emptying. Symptoms include nausea, abdominal pain, diarrhea, flushing, hypotension, and tachycardia.

Late dumping is characterized as postprandial hypoglycemia occurring one to 3 hours after eating. Late dumping is likely caused by a combination of changes within the pancreatic beta cells and abnormal insulin response to glucose.^16-18 Rapid gastric emptying leads to rapid release of glucose in the gut, which, in turn, leads to brisk insulin secretion. Since glucose is absorbed faster than insulin’s half-life, the resulting (relatively) high levels of insulin may cause hypoglycemia.^16-18

Sigstad’s scoring system can be used to confirm suspected cases of dumping syndrome (TABLE 3^16,17,19). A diagnosis can also be made with an oral glucose challenge in which pulse, blood pressure, glucose, and hematocrit are measured after ingestion of 50 g glucose. The test is positive if heart rate increases by 10 beats per minute, hematocrit increases by 3% 30 minutes after ingestion, or glucose falls below 60 mg/dL 2 to 3 hours after ingestion.¹⁷

First-line treatment of dumping syndrome consists of dietary modifications. The goal is to slow the rate of gastric emptying by eating smaller, more frequent meals; separating beverages from food; decreasing carbohydrates; and increasing fiber and protein content.

If results are suboptimal after dietary changes, medications can be prescribed including acarbose to prevent postprandial hypoglycemia; anticholinergics such as dicyclomine to slow gastric emptying; and somatostatin to decrease gastric emptying and inhibit GI hormone release.¹⁷ Lastly, for resistant and severe postprandial hypoglycemia, a few patients have undergone pancreatectomy, but only about 65% experienced improvement in symptoms and 12% developed diabetes post-surgically.²⁰

Gout attacks may initially increase, but then decrease

BS affects the incidence of gout attacks in patients with a history of gout. One comparative study of approximately 150 patients demonstrated that those with a history of gout had significantly more gout attacks in the first month after BS compared with obese patients with a history of gout undergoing other upper GI surgeries.²¹ There was no difference between malabsorptive and restrictive procedures. But after the first month, BS patients had significantly fewer gout attacks and lower uric acid levels than their obese counterparts.²¹

Protein rich diets, catabolism potentiated by aggressive caloric restriction following BS, and dehydration contribute to the initial increase. Therefore, patients who have had at least one gout attack in the year prior to surgery or who are on hypouricemic medication may benefit from at least one month of prophylactic therapy (eg, allopurinol and colchicine) after surgery.

GERD and ulceration: How to respond

Obesity is a known risk factor for GERD, but the effect of BS on GERD is uncertain and seems to vary with the procedure performed. RYGB decreases GERD and is, therefore, used as both a secondary treatment in those not responding to medications and a revision treatment for fundoplication and other types of BSs. Sleeve gastrectomy and adjustable gastric banding have mixed effects on GERD. A systematic review by de Jong et al revealed a decreased prevalence of reflux symptoms and GERD medication use after LAGB; however, during longer follow-up, 15% of previously unaffected patients reported experiencing GERD.²² The 2011 International Sleeve Gastrectomy Expert Panel Consensus Statement retrospectively noted a postoperative incidence of GERD as high as 31%.²³

BS patients with GERD should be treated with a proton pump inhibitor. If this fails, refer patients to a gastroenterologist for further evaluation.²⁴

Ulcers after BS may be an indication for revision surgery. Data are mixed regarding increased risk of marginal ulceration from nonsteroidal anti-inflammatory drug (NSAID) use, but NSAIDs have been linked to an increased risk of anastomotic leakage.^25-28 Thus, it seems prudent to avoid NSAIDs in people who have undergone BS.

Keeping watch over psychiatric comorbidities

A recent meta-analysis by Dawes et al²⁹ showed that about 23% of patients pursuing BS have a comorbid mood disorder. Specifically, the preoperative prevalence of depression (19%) and binge-eating disorder (17%) were found to be higher than rates in the general population.²⁹ The meta-analysis found improvement in the prevalence of depression with fewer symptoms and less antidepressant medication use in the first 3 years after surgery and a decrease in the rate of binge-eating disorder, although there were fewer supporting data for the latter. These findings were observed with both restrictive and malabsorptive procedures.

The data are mixed regarding rates of alcohol abuse and suicide. Further research is necessary in this field. Patients who have had BS should receive ongoing psychiatric and psychological care from a multidisciplinary team as a matter of course.

Will a second surgery be needed?

Revision surgery. In 2015, about 14% of the almost 200,000 BSs performed were revisions.⁴ Revision surgery is indicated in BS patients with weight regain, recurrent comorbid diseases (eg, diabetes, hypertension), or complications of primary BS. Restrictive procedures have a higher revision rate than malabsorptive procedures, primarily due to a higher rate of weight regain.^6,30

Because revision surgery is associated with more complications and possibly longer hospital stays than primary BS, it should be performed by a bariatric surgeon with extensive experience.^30,31 Restrictive revisions are typically converted to malabsorptive procedures. Cost is a limiting factor as many patients’ insurance coverage is limited to one BS per lifetime.

Body contouring. Body contouring surgery (BCS) can improve physical and mental well-being and may be a protective factor for weight regain after bariatric surgery.³² Despite its desirability—particularly to women, adolescents, and those with large decreases in body mass index (BMI)—few patients can afford BCS since it is rarely covered by insurance.

Complications of BCS vary, but are most commonly infection and wound dehiscence. This is, in part, due to poorer wound healing in BS patients compared to those with nonsurgical massive weight loss. The cause of poor wound healing is thought to be secondary to nutritional deficiencies and the catabolic state induced by post-surgical weight loss. Recommendations for BCS include weight stability for more than one year after BS, age >16 years, excess skin causing significant functional impairment, non-smoking status, and presence of good social support.³³

Bariatric surgery in adolescents is on the rise

Children in the highest body mass index quartile have more than twice the death rate of those in the lowest BMI quartile.³⁴ Thus, it is not surprising that the rate of BS in adolescents is increasing.⁷ BS in this age group is successful for weight loss and improvement of comorbid conditions, with relatively low complication rates.³⁵ Options include malabsorptive and restrictive procedures, although gastric banding has not been approved by the US Food and Drug Administration for patients under the age of 18 years.

Monitor vitamin D levels 2 and 4 weeks after initiation of treatment and every 3 months thereafter.After BS, adolescent girls should be counseled regarding the possibility of pregnancy (restoration of fertility) and appropriate contraception. Adolescent patients require nutritional supplementation after BS as indicated in TABLE 1.^6,8-11

When determining which adolescents to refer for BS, we recommend the following criteria: ^35-38

• failure of a minimum 6-month trial of a staged treatment approach, as recommended by Barlow et al,³⁶ including diet, exercise, and pharmacologic treatment
• BMI ≥35 with type 2 diabetes or severe sleep apnea (apnea hypopnea index [AHI] >15)³⁷
• BMI ≥40 with mild sleep apnea (AHI >5), hypertension, or pre-diabetes³⁷
• Tanner stage IV or V
• at least 95% skeletal growth (for malabsorptive surgery).³⁷ This can be determined using an estimated adult height from mid-parental height formula and assessing growth plate closure with hand radiographs for bone age
• appropriate maturity level permitting adherence
• good psychological support
• a multidisciplinary team for postoperative and long-term follow-up care.

Planning for the future: Exploring the possibility of pregnancy

Obesity is the primary cause of maternal and fetal morbidity during pregnancy. It is associated with increased rates of early miscarriage, congenital defects, macrosomia, and fetal death. Maternal risks of obesity include: gestational hypertension, gestational diabetes mellitus (GDM), and pre-eclampsia. Obese mothers also have a higher incidence of failed induction, caesarean section, and breastfeeding failure.^10,39 Given that half of all BSs are performed in women of reproductive age, this population deserves special consideration.¹⁰

A recent meta-analysis by Galazis et al⁴⁰ concluded that BS performed prior to pregnancy led to decreased rates of preeclampsia, GDM, large neonates, preterm birth, and neonatal intensive care unit admission. Perinatal mortality did not increase after BS. However, BS led to higher rates of maternal anemia. There was no significant difference between groups in incidence of cesarean section.

The post BS female patient should be advised to use a reliable form of contraception for a minimum of 12 to 18 months after surgery.^6,10,39 Involve high-risk obstetric specialists during pregnancies. Diet should be supplemented as indicated in TABLE 1.^6,8-11

CORRESPONDENCE
Amy Rothberg, MD, PhD, Domino’s Farms, Lobby G, Suite 1500, 24 Frank Lloyd Wright Drive, Ann Arbor, MI 48106; [email protected].

More than one-third of American adults and approximately 17% of children and adolescents between the ages of 2 and 19 years are obese.^1,2 Poor diet coupled with a sedentary lifestyle is the highest ranked cause of non-communicable disease and a leading cause of preventable death, according to the National Research Council.³

Bariatric surgery (BS) is a viable therapeutic option for obese patients who do not respond to conventional lifestyle interventions for losing weight. There are multiple gastrointestinal (GI) procedures available that are classified as either malabsorptive (Roux-en-Y gastric bypass [RYGB] and biliopancreatic diversion [BPD] with or without duodenal switch) or restrictive (laparoscopic adjustable gastric banding [LAGB] and vertical sleeve gastrectomy [VSG]).

Approximately half of the 196,000 bariatric procedures performed in the United States in 2015 were of the sleeve variety, another 23% were RYGB, and the remaining percentage was divided among the other types.⁴ Postoperative risks include nutritional deficiencies, decreased bone mineral density (BMD), dumping syndrome (when food rapidly dumps from the stomach to the intestine), and gastroesophageal reflux disease (GERD) with possible ulceration.

Despite these potential complications, a systematic review and meta-analysis found that obese people who underwent BS (gastric banding or gastric bypass) had significantly reduced risks of global, non-cardiovascular (CV), and CV mortality compared with obese controls.⁵ Helping patients to realize these benefits requires that the entire health care team—especially the family physician—is aware of the special considerations for this population.

Patients undergoing bariatric surgery require routine lifetime screening for nutritional deficiencies.

To that end, this article reviews the details of diagnosing and managing post-surgical complications. It also addresses issues unique to managing certain subpopulations, such as post-BS patients who require revision surgery or who want to pursue body contouring surgery; adolescents who undergo BS surgery; and women who want to get pregnant postoperatively.

Monitor patients for these post-surgery complications

Postoperative BS follow-up varies depending on location, surgeon preference, and availability of multidisciplinary resources. At our institution, patients have a minimum of 3 follow-up visits with their surgeon (during hospitalization and 2 weeks and 2 months postoperatively). This is followed by visits with Endocrinology 6 months after surgery and annually thereafter. Given the variability of follow-up, family physicians should coordinate with specialists where appropriate and be aware of postoperative complications and monitoring since it is likely they will have the most frequent contact with these patients.

Nutritional deficiencies are common and require lifelong screening

Nutritional deficiencies are the most common complications of malabsorptive BS. Guidelines from the Endocrine Society, as well as guidelines from the American Association of Clinical Endocrinologists (AACE), The Obesity Society (TOS), and the American Society for Metabolic and Bariatric Surgery (ASMBS), recommend routine lifetime screening for deficiencies after surgery.^6,7 Complete blood cell count, electrolytes, glucose, creatinine, and liver function tests should be obtained at one, 3, 6, 12, 18, and 24 months following surgery and annually thereafter.⁶

Multiple factors contribute to nutritional and micronutrient deficiencies, including reduced oral intake of food, decreased GI absorption, food intolerance, nausea/vomiting, and nonadherence with dietary supplements.⁸ Oral supplementation should be in chewable, powder, or liquid form because pill and capsule absorption may be altered.^8,9 Over-the-counter multivitamins may not contain the requisite daily doses recommended after BS.⁹ Patients and physicians should evaluate supplements together to ensure appropriate nutritional and micronutrient supplementation (TABLE 1^6,8-11).

Bone mineral density can start to decrease soon after surgery

Studies evaluating BMD after BS have produced variable findings. In obese patients, dual-energy x-ray absorptiometry (DEXA) measurements may not be accurate due to adipose tissue artifact and table weight limits. In addition, limited data exist on the incidence of fractures after BS. Of 2 notable studies, only one, a population-based study involving 258 Minnesota residents who underwent a first bariatric surgery between 1985 and 2004, demonstrated a significantly increased incidence of fractures.^12,13

In addition, studies show bone turnover markers, including C-terminal telopeptide, increase as early as 3 months after BS.¹⁴ Several guidelines recommend routine BMD screening after BS (TABLE 2).^6,7 The mechanism of bone demineralization is likely multifactorial—a function of the magnitude of the weight loss and skeletal unloading, calcium and vitamin D deficiencies, and associated secondary hyperparathyroidism.¹⁵ Treatment for secondary hyperparathyroidism is adequate supplementation with vitamin D and calcium.

Optimal dosing for vitamin D has not been determined. One recent systematic review suggests routine prophylaxis with at least 2000 international units (IU)/d and found the greatest improvement for known deficiency with doses of 1500-9100 IU/d following malabsorptive surgeries.¹¹ After laparoscopic sleeve gastrectomy, at least 1000 IU/d vitamin D is recommended.¹¹

Overall, high variability exists among patients, and an individualized approach for dosing is recommended.¹¹ Vitamin D levels should be monitored 2 and 4 weeks after initiation of treatment and every 3 months thereafter.¹¹ Normal levels of serum calcium, 25-OH vitamin D, bone-specific alkaline phosphatase, and 24-hour urinary calcium excretion indicate adequate calcium and vitamin D supplementation.⁶

Dumping syndrome can lead to hypoglycemia

Dumping syndrome is a common complication following BS, with prevalence ranging from 25% to 75%, depending upon the type of procedure performed.^16,17 There are 2 types: early and late. Early dumping syndrome occurs within 30 minutes of eating. Symptoms are related to the robust release of gastrointestinal hormones caused by rapid gastric emptying. Symptoms include nausea, abdominal pain, diarrhea, flushing, hypotension, and tachycardia.

Late dumping is characterized as postprandial hypoglycemia occurring one to 3 hours after eating. Late dumping is likely caused by a combination of changes within the pancreatic beta cells and abnormal insulin response to glucose.^16-18 Rapid gastric emptying leads to rapid release of glucose in the gut, which, in turn, leads to brisk insulin secretion. Since glucose is absorbed faster than insulin’s half-life, the resulting (relatively) high levels of insulin may cause hypoglycemia.^16-18

Sigstad’s scoring system can be used to confirm suspected cases of dumping syndrome (TABLE 3^16,17,19). A diagnosis can also be made with an oral glucose challenge in which pulse, blood pressure, glucose, and hematocrit are measured after ingestion of 50 g glucose. The test is positive if heart rate increases by 10 beats per minute, hematocrit increases by 3% 30 minutes after ingestion, or glucose falls below 60 mg/dL 2 to 3 hours after ingestion.¹⁷

First-line treatment of dumping syndrome consists of dietary modifications. The goal is to slow the rate of gastric emptying by eating smaller, more frequent meals; separating beverages from food; decreasing carbohydrates; and increasing fiber and protein content.

If results are suboptimal after dietary changes, medications can be prescribed including acarbose to prevent postprandial hypoglycemia; anticholinergics such as dicyclomine to slow gastric emptying; and somatostatin to decrease gastric emptying and inhibit GI hormone release.¹⁷ Lastly, for resistant and severe postprandial hypoglycemia, a few patients have undergone pancreatectomy, but only about 65% experienced improvement in symptoms and 12% developed diabetes post-surgically.²⁰

Gout attacks may initially increase, but then decrease

BS affects the incidence of gout attacks in patients with a history of gout. One comparative study of approximately 150 patients demonstrated that those with a history of gout had significantly more gout attacks in the first month after BS compared with obese patients with a history of gout undergoing other upper GI surgeries.²¹ There was no difference between malabsorptive and restrictive procedures. But after the first month, BS patients had significantly fewer gout attacks and lower uric acid levels than their obese counterparts.²¹

Protein rich diets, catabolism potentiated by aggressive caloric restriction following BS, and dehydration contribute to the initial increase. Therefore, patients who have had at least one gout attack in the year prior to surgery or who are on hypouricemic medication may benefit from at least one month of prophylactic therapy (eg, allopurinol and colchicine) after surgery.

GERD and ulceration: How to respond

Obesity is a known risk factor for GERD, but the effect of BS on GERD is uncertain and seems to vary with the procedure performed. RYGB decreases GERD and is, therefore, used as both a secondary treatment in those not responding to medications and a revision treatment for fundoplication and other types of BSs. Sleeve gastrectomy and adjustable gastric banding have mixed effects on GERD. A systematic review by de Jong et al revealed a decreased prevalence of reflux symptoms and GERD medication use after LAGB; however, during longer follow-up, 15% of previously unaffected patients reported experiencing GERD.²² The 2011 International Sleeve Gastrectomy Expert Panel Consensus Statement retrospectively noted a postoperative incidence of GERD as high as 31%.²³

BS patients with GERD should be treated with a proton pump inhibitor. If this fails, refer patients to a gastroenterologist for further evaluation.²⁴

Ulcers after BS may be an indication for revision surgery. Data are mixed regarding increased risk of marginal ulceration from nonsteroidal anti-inflammatory drug (NSAID) use, but NSAIDs have been linked to an increased risk of anastomotic leakage.^25-28 Thus, it seems prudent to avoid NSAIDs in people who have undergone BS.

Keeping watch over psychiatric comorbidities

A recent meta-analysis by Dawes et al²⁹ showed that about 23% of patients pursuing BS have a comorbid mood disorder. Specifically, the preoperative prevalence of depression (19%) and binge-eating disorder (17%) were found to be higher than rates in the general population.²⁹ The meta-analysis found improvement in the prevalence of depression with fewer symptoms and less antidepressant medication use in the first 3 years after surgery and a decrease in the rate of binge-eating disorder, although there were fewer supporting data for the latter. These findings were observed with both restrictive and malabsorptive procedures.

The data are mixed regarding rates of alcohol abuse and suicide. Further research is necessary in this field. Patients who have had BS should receive ongoing psychiatric and psychological care from a multidisciplinary team as a matter of course.

Will a second surgery be needed?

Revision surgery. In 2015, about 14% of the almost 200,000 BSs performed were revisions.⁴ Revision surgery is indicated in BS patients with weight regain, recurrent comorbid diseases (eg, diabetes, hypertension), or complications of primary BS. Restrictive procedures have a higher revision rate than malabsorptive procedures, primarily due to a higher rate of weight regain.^6,30

Because revision surgery is associated with more complications and possibly longer hospital stays than primary BS, it should be performed by a bariatric surgeon with extensive experience.^30,31 Restrictive revisions are typically converted to malabsorptive procedures. Cost is a limiting factor as many patients’ insurance coverage is limited to one BS per lifetime.

Body contouring. Body contouring surgery (BCS) can improve physical and mental well-being and may be a protective factor for weight regain after bariatric surgery.³² Despite its desirability—particularly to women, adolescents, and those with large decreases in body mass index (BMI)—few patients can afford BCS since it is rarely covered by insurance.

Complications of BCS vary, but are most commonly infection and wound dehiscence. This is, in part, due to poorer wound healing in BS patients compared to those with nonsurgical massive weight loss. The cause of poor wound healing is thought to be secondary to nutritional deficiencies and the catabolic state induced by post-surgical weight loss. Recommendations for BCS include weight stability for more than one year after BS, age >16 years, excess skin causing significant functional impairment, non-smoking status, and presence of good social support.³³

Bariatric surgery in adolescents is on the rise

Children in the highest body mass index quartile have more than twice the death rate of those in the lowest BMI quartile.³⁴ Thus, it is not surprising that the rate of BS in adolescents is increasing.⁷ BS in this age group is successful for weight loss and improvement of comorbid conditions, with relatively low complication rates.³⁵ Options include malabsorptive and restrictive procedures, although gastric banding has not been approved by the US Food and Drug Administration for patients under the age of 18 years.

Monitor vitamin D levels 2 and 4 weeks after initiation of treatment and every 3 months thereafter.After BS, adolescent girls should be counseled regarding the possibility of pregnancy (restoration of fertility) and appropriate contraception. Adolescent patients require nutritional supplementation after BS as indicated in TABLE 1.^6,8-11

When determining which adolescents to refer for BS, we recommend the following criteria: ^35-38

• failure of a minimum 6-month trial of a staged treatment approach, as recommended by Barlow et al,³⁶ including diet, exercise, and pharmacologic treatment
• BMI ≥35 with type 2 diabetes or severe sleep apnea (apnea hypopnea index [AHI] >15)³⁷
• BMI ≥40 with mild sleep apnea (AHI >5), hypertension, or pre-diabetes³⁷
• Tanner stage IV or V
• at least 95% skeletal growth (for malabsorptive surgery).³⁷ This can be determined using an estimated adult height from mid-parental height formula and assessing growth plate closure with hand radiographs for bone age
• appropriate maturity level permitting adherence
• good psychological support
• a multidisciplinary team for postoperative and long-term follow-up care.

Planning for the future: Exploring the possibility of pregnancy

Obesity is the primary cause of maternal and fetal morbidity during pregnancy. It is associated with increased rates of early miscarriage, congenital defects, macrosomia, and fetal death. Maternal risks of obesity include: gestational hypertension, gestational diabetes mellitus (GDM), and pre-eclampsia. Obese mothers also have a higher incidence of failed induction, caesarean section, and breastfeeding failure.^10,39 Given that half of all BSs are performed in women of reproductive age, this population deserves special consideration.¹⁰

A recent meta-analysis by Galazis et al⁴⁰ concluded that BS performed prior to pregnancy led to decreased rates of preeclampsia, GDM, large neonates, preterm birth, and neonatal intensive care unit admission. Perinatal mortality did not increase after BS. However, BS led to higher rates of maternal anemia. There was no significant difference between groups in incidence of cesarean section.

The post BS female patient should be advised to use a reliable form of contraception for a minimum of 12 to 18 months after surgery.^6,10,39 Involve high-risk obstetric specialists during pregnancies. Diet should be supplemented as indicated in TABLE 1.^6,8-11

CORRESPONDENCE
Amy Rothberg, MD, PhD, Domino’s Farms, Lobby G, Suite 1500, 24 Frank Lloyd Wright Drive, Ann Arbor, MI 48106; [email protected].

ILLUSTRATIVE CASE

A 34-year-old woman presents to your office for unbearable sweating. She notes that the sweating occurs nearly daily on her hands, face, and in her axillary regions, causing social embarrassment. She has tried multiple antiperspirants to no avail. Is there anything she can take to reduce the sweating?

Hyperhidrosis is a common, self-limiting problem affecting 2% to 3% of the population in the United States.² Patients may complain of localized sweating of the hands, feet, face, or underarms or more systemic, generalized sweating in multiple locations. Either way, patients always note a significant impact on their quality of life.

Treatment of hyperhidrosis has traditionally focused on topical therapies to the affected areas. Research has shown that localized treatment with antiperspirants containing aluminum salt is effective by both subjective report and objective measurements at reducing sweating—particularly in the axilla, hands, and feet.^3,4 Additionally, a systematic review of observational and experimental studies found topical glycopyrrolate to be efficacious for craniofacial hyperhidrosis with minimal adverse effects.⁵ The availability of low-cost prescription and over-the-counter aluminum-based antiperspirant agents makes topicals the first-line choice.

More invasive treatments are available for hyperhidrosis that is refractory to topicals. In a double-blind, randomized controlled trial, researchers injected either botulinum toxin type A (BTX-A) 50 U or placebo in patients with bilateral primary axillary hyperhidrosis.⁶ Of the 207 patients who received treatment injections, 96.1% had at least a 50% reduction of axillary sweating at 4 weeks after one injection, as measured by gravimetric assessment. The BTX-A injections also produced a prolonged effect; mean duration between injections was 30.6 weeks.

Other invasive treatments include iontophoresis, surgery, and laser therapy; however, these methods are not suitable for body-wide application and are, thus, not appropriate for patients with generalized hyperhidrosis.

Oxybutynin is the first oral agent to emerge as a treatment option for hyperhidrosis. This cholinergic antagonist had historically been used to treat overactive bladder. As a cholinergic antagonist, oxybutynin not only reduces urinary frequency, but also decreases secretions in various locations and, thus, can cause dry mouth and reduce perspiration.

In one prospective placebo-controlled trial, 50 patients with generalized hyperhidrosis were randomized to receive either oxybutynin titrated from 2.5 mg orally once daily to 5 mg orally twice daily or placebo for 6 weeks.⁷ Seventeen (73.9%) patients receiving oxybutynin for palmar or axillary hyperhidrosis reported moderate to “great” resolution of their symptoms compared with 6 (27.3%) patients in the placebo group. Dry mouth was reported in 34.8% of patients receiving oxybutynin vs 9.1% of those who received placebo (P=.038); however, no patients dropped out of the study due to this adverse effect.⁷

STUDY SUMMARY

This multicenter, randomized controlled trial compared oxybutynin to placebo in 62 adults with localized or generalized hyperhidrosis from 12 outpatient dermatology practices in France. It is the first study to include patients with a localized, as well as a generalized form of the condition.

Patients were included if they were >18 years of age, enrolled in the National Health Insurance system in France, and reported a Hyperhidrosis Disease Severity Scale (HDSS) score ≥2. The HDSS is a validated, one-question tool (“How would you rate the severity of your sweating?”). Patients provide a score of 1 (no perceptible sweating and no interference with everyday life) to 4 (intolerable sweating with constant interference with everyday life).⁸ Patients were excluded if they had any contraindications to the use of an anticholinergic medication.

This trial used a relatively low dose of oxybutynin, which produced significant benefit while minimizing anticholinergic adverse effects.

Patients randomized to oxybutynin took 2.5 mg/d orally initially and increased gradually over 8 days until reaching an effective dose that was not more than 7.5 mg/d. They then continued at that dose for 6 weeks. The primary outcome was improvement on the HDSS by one or more points measured at the beginning of the trial and at 6 weeks. Secondary outcomes included change in quality of life, as measured by the Dermatology Life Quality Index (DLQI) and reported adverse effects. The DLQI is a dermatology-specific quality-of-life measure consisting of 10 questions. Scores range from 0 (where their disease has no impact on their quality of life) to 30 (maximum impact of their disease on their quality of life).⁹

Improved HDSS and DLQI scores. Most patients (83%) in the study had generalized hyperhidrosis. Patients were in their mid-thirties. Sixty percent of the patients in the oxybutynin group had an improvement of one point or more on the 4-point HDSS compared to 27% in the placebo group (P<.01). DLQI scores improved by 6.9 points in the oxybutynin group and 2.3 points in the placebo group (P<.01).

The most common adverse effect was dry mouth, which occurred in 13 patients (43%) in the oxybutynin group and in 3 patients (11%) in the placebo group (P<.01); it did not cause any patients to drop out of the study. The second most common adverse effect was blurred vision, which only occurred in the oxybutynin group (4 patients; 13%).

WHAT'S NEW

This is the first randomized controlled trial to demonstrate the efficacy of an oral agent for generalized primary hyperhidrosis. This trial used a relatively low dose of oxybutynin, which produced significant benefit while minimizing anticholinergic adverse effects.

CAVEATS

There are many situations for which anticholinergic medications are inappropriate, including use by geriatric patients and those with gastrointestinal disorders, urinary retention, or glaucoma.

CHALLENGES TO IMPLEMENTATION

Few if any challenges exist to the utilization of oxybutynin; inexpensive generic versions are widely available.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

ILLUSTRATIVE CASE

A 34-year-old woman presents to your office for unbearable sweating. She notes that the sweating occurs nearly daily on her hands, face, and in her axillary regions, causing social embarrassment. She has tried multiple antiperspirants to no avail. Is there anything she can take to reduce the sweating?

Hyperhidrosis is a common, self-limiting problem affecting 2% to 3% of the population in the United States.² Patients may complain of localized sweating of the hands, feet, face, or underarms or more systemic, generalized sweating in multiple locations. Either way, patients always note a significant impact on their quality of life.

Treatment of hyperhidrosis has traditionally focused on topical therapies to the affected areas. Research has shown that localized treatment with antiperspirants containing aluminum salt is effective by both subjective report and objective measurements at reducing sweating—particularly in the axilla, hands, and feet.^3,4 Additionally, a systematic review of observational and experimental studies found topical glycopyrrolate to be efficacious for craniofacial hyperhidrosis with minimal adverse effects.⁵ The availability of low-cost prescription and over-the-counter aluminum-based antiperspirant agents makes topicals the first-line choice.

More invasive treatments are available for hyperhidrosis that is refractory to topicals. In a double-blind, randomized controlled trial, researchers injected either botulinum toxin type A (BTX-A) 50 U or placebo in patients with bilateral primary axillary hyperhidrosis.⁶ Of the 207 patients who received treatment injections, 96.1% had at least a 50% reduction of axillary sweating at 4 weeks after one injection, as measured by gravimetric assessment. The BTX-A injections also produced a prolonged effect; mean duration between injections was 30.6 weeks.

Other invasive treatments include iontophoresis, surgery, and laser therapy; however, these methods are not suitable for body-wide application and are, thus, not appropriate for patients with generalized hyperhidrosis.

Oxybutynin is the first oral agent to emerge as a treatment option for hyperhidrosis. This cholinergic antagonist had historically been used to treat overactive bladder. As a cholinergic antagonist, oxybutynin not only reduces urinary frequency, but also decreases secretions in various locations and, thus, can cause dry mouth and reduce perspiration.

In one prospective placebo-controlled trial, 50 patients with generalized hyperhidrosis were randomized to receive either oxybutynin titrated from 2.5 mg orally once daily to 5 mg orally twice daily or placebo for 6 weeks.⁷ Seventeen (73.9%) patients receiving oxybutynin for palmar or axillary hyperhidrosis reported moderate to “great” resolution of their symptoms compared with 6 (27.3%) patients in the placebo group. Dry mouth was reported in 34.8% of patients receiving oxybutynin vs 9.1% of those who received placebo (P=.038); however, no patients dropped out of the study due to this adverse effect.⁷

STUDY SUMMARY

This multicenter, randomized controlled trial compared oxybutynin to placebo in 62 adults with localized or generalized hyperhidrosis from 12 outpatient dermatology practices in France. It is the first study to include patients with a localized, as well as a generalized form of the condition.

Patients were included if they were >18 years of age, enrolled in the National Health Insurance system in France, and reported a Hyperhidrosis Disease Severity Scale (HDSS) score ≥2. The HDSS is a validated, one-question tool (“How would you rate the severity of your sweating?”). Patients provide a score of 1 (no perceptible sweating and no interference with everyday life) to 4 (intolerable sweating with constant interference with everyday life).⁸ Patients were excluded if they had any contraindications to the use of an anticholinergic medication.

This trial used a relatively low dose of oxybutynin, which produced significant benefit while minimizing anticholinergic adverse effects.

Patients randomized to oxybutynin took 2.5 mg/d orally initially and increased gradually over 8 days until reaching an effective dose that was not more than 7.5 mg/d. They then continued at that dose for 6 weeks. The primary outcome was improvement on the HDSS by one or more points measured at the beginning of the trial and at 6 weeks. Secondary outcomes included change in quality of life, as measured by the Dermatology Life Quality Index (DLQI) and reported adverse effects. The DLQI is a dermatology-specific quality-of-life measure consisting of 10 questions. Scores range from 0 (where their disease has no impact on their quality of life) to 30 (maximum impact of their disease on their quality of life).⁹

Improved HDSS and DLQI scores. Most patients (83%) in the study had generalized hyperhidrosis. Patients were in their mid-thirties. Sixty percent of the patients in the oxybutynin group had an improvement of one point or more on the 4-point HDSS compared to 27% in the placebo group (P<.01). DLQI scores improved by 6.9 points in the oxybutynin group and 2.3 points in the placebo group (P<.01).

The most common adverse effect was dry mouth, which occurred in 13 patients (43%) in the oxybutynin group and in 3 patients (11%) in the placebo group (P<.01); it did not cause any patients to drop out of the study. The second most common adverse effect was blurred vision, which only occurred in the oxybutynin group (4 patients; 13%).

WHAT'S NEW

This is the first randomized controlled trial to demonstrate the efficacy of an oral agent for generalized primary hyperhidrosis. This trial used a relatively low dose of oxybutynin, which produced significant benefit while minimizing anticholinergic adverse effects.

CAVEATS

There are many situations for which anticholinergic medications are inappropriate, including use by geriatric patients and those with gastrointestinal disorders, urinary retention, or glaucoma.

CHALLENGES TO IMPLEMENTATION

Few if any challenges exist to the utilization of oxybutynin; inexpensive generic versions are widely available.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

ILLUSTRATIVE CASE

A 34-year-old woman presents to your office for unbearable sweating. She notes that the sweating occurs nearly daily on her hands, face, and in her axillary regions, causing social embarrassment. She has tried multiple antiperspirants to no avail. Is there anything she can take to reduce the sweating?

Hyperhidrosis is a common, self-limiting problem affecting 2% to 3% of the population in the United States.² Patients may complain of localized sweating of the hands, feet, face, or underarms or more systemic, generalized sweating in multiple locations. Either way, patients always note a significant impact on their quality of life.

Treatment of hyperhidrosis has traditionally focused on topical therapies to the affected areas. Research has shown that localized treatment with antiperspirants containing aluminum salt is effective by both subjective report and objective measurements at reducing sweating—particularly in the axilla, hands, and feet.^3,4 Additionally, a systematic review of observational and experimental studies found topical glycopyrrolate to be efficacious for craniofacial hyperhidrosis with minimal adverse effects.⁵ The availability of low-cost prescription and over-the-counter aluminum-based antiperspirant agents makes topicals the first-line choice.

More invasive treatments are available for hyperhidrosis that is refractory to topicals. In a double-blind, randomized controlled trial, researchers injected either botulinum toxin type A (BTX-A) 50 U or placebo in patients with bilateral primary axillary hyperhidrosis.⁶ Of the 207 patients who received treatment injections, 96.1% had at least a 50% reduction of axillary sweating at 4 weeks after one injection, as measured by gravimetric assessment. The BTX-A injections also produced a prolonged effect; mean duration between injections was 30.6 weeks.

Other invasive treatments include iontophoresis, surgery, and laser therapy; however, these methods are not suitable for body-wide application and are, thus, not appropriate for patients with generalized hyperhidrosis.

Oxybutynin is the first oral agent to emerge as a treatment option for hyperhidrosis. This cholinergic antagonist had historically been used to treat overactive bladder. As a cholinergic antagonist, oxybutynin not only reduces urinary frequency, but also decreases secretions in various locations and, thus, can cause dry mouth and reduce perspiration.

In one prospective placebo-controlled trial, 50 patients with generalized hyperhidrosis were randomized to receive either oxybutynin titrated from 2.5 mg orally once daily to 5 mg orally twice daily or placebo for 6 weeks.⁷ Seventeen (73.9%) patients receiving oxybutynin for palmar or axillary hyperhidrosis reported moderate to “great” resolution of their symptoms compared with 6 (27.3%) patients in the placebo group. Dry mouth was reported in 34.8% of patients receiving oxybutynin vs 9.1% of those who received placebo (P=.038); however, no patients dropped out of the study due to this adverse effect.⁷

STUDY SUMMARY

This multicenter, randomized controlled trial compared oxybutynin to placebo in 62 adults with localized or generalized hyperhidrosis from 12 outpatient dermatology practices in France. It is the first study to include patients with a localized, as well as a generalized form of the condition.

Patients were included if they were >18 years of age, enrolled in the National Health Insurance system in France, and reported a Hyperhidrosis Disease Severity Scale (HDSS) score ≥2. The HDSS is a validated, one-question tool (“How would you rate the severity of your sweating?”). Patients provide a score of 1 (no perceptible sweating and no interference with everyday life) to 4 (intolerable sweating with constant interference with everyday life).⁸ Patients were excluded if they had any contraindications to the use of an anticholinergic medication.

This trial used a relatively low dose of oxybutynin, which produced significant benefit while minimizing anticholinergic adverse effects.

Patients randomized to oxybutynin took 2.5 mg/d orally initially and increased gradually over 8 days until reaching an effective dose that was not more than 7.5 mg/d. They then continued at that dose for 6 weeks. The primary outcome was improvement on the HDSS by one or more points measured at the beginning of the trial and at 6 weeks. Secondary outcomes included change in quality of life, as measured by the Dermatology Life Quality Index (DLQI) and reported adverse effects. The DLQI is a dermatology-specific quality-of-life measure consisting of 10 questions. Scores range from 0 (where their disease has no impact on their quality of life) to 30 (maximum impact of their disease on their quality of life).⁹

Improved HDSS and DLQI scores. Most patients (83%) in the study had generalized hyperhidrosis. Patients were in their mid-thirties. Sixty percent of the patients in the oxybutynin group had an improvement of one point or more on the 4-point HDSS compared to 27% in the placebo group (P<.01). DLQI scores improved by 6.9 points in the oxybutynin group and 2.3 points in the placebo group (P<.01).

The most common adverse effect was dry mouth, which occurred in 13 patients (43%) in the oxybutynin group and in 3 patients (11%) in the placebo group (P<.01); it did not cause any patients to drop out of the study. The second most common adverse effect was blurred vision, which only occurred in the oxybutynin group (4 patients; 13%).

WHAT'S NEW

This is the first randomized controlled trial to demonstrate the efficacy of an oral agent for generalized primary hyperhidrosis. This trial used a relatively low dose of oxybutynin, which produced significant benefit while minimizing anticholinergic adverse effects.

CAVEATS

There are many situations for which anticholinergic medications are inappropriate, including use by geriatric patients and those with gastrointestinal disorders, urinary retention, or glaucoma.

CHALLENGES TO IMPLEMENTATION

Few if any challenges exist to the utilization of oxybutynin; inexpensive generic versions are widely available.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

A 63-year-old woman with a 3-year history of osteoporosis presented to our clinic with a 2-week history of severe right hip pain. She had been taking a bisphosphonate—oral ibandronate sodium, 150 mg, once monthly—for about 6 years. The postmenopausal patient had a history of degenerative disc disease and lumbar back pain, but no known history of recent trauma or falls.

A clinical exam revealed full passive and active range of motion; however, she had pain with weight bearing. A full metabolic panel revealed no significant abnormalities. A leg length discrepancy was noted, so a bone length study was ordered. Anteroposterior x-rays of the bilateral lower extremities demonstrated a focal convexity along the lateral cortical junction of the proximal right femur (FIGURE).

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

Dx: Bisphosphonate-associated proximal insufficiency fracture

Based on the patient’s clinical history and x-ray findings, we determined that the patient had sustained a bisphosphonate-associated proximal femoral insufficiency fracture. Insufficiency fractures arise from normal physi­­ologic stress on abnormal bone. They commonly occur in conditions that impair normal bone physiology and remodeling, such as osteoporosis, renal insufficiency, rheumatoid arthritis, and diabetes.¹

Could a bisphosphonate be to blame? Bisphosphonate therapy has been associated with significant benefits, including increased bone mineral density (BMD), decreased incidence of fracture, and improved mortality.^2-4 But it’s been postulated that the global suppression of bone turnover caused by these drugs may also impair the bone remodeling process.⁵ Some case reports have suggested an association between chronic bisphosphonate use and atypical insufficiency fractures. These atypical femur fractures are characterized by their location (along the diaphysis in the region distal to the lesser trochanter), the patient’s history (there may be minimal to no trauma), and the potential for “beaking” (localized periosteal or endosteal thickening of the lateral cortex).^6,7

Bisphosphonate therapy has been associated with significant benefits, but it’s been suggested that these drugs may impair the bone remodeling process.

Several large, population-based, case-control studies have found a temporal relationship between bisphosphonate therapy and a statistically significant increased risk of subtrochanteric fractures.^8-10 These studies do note, however, that the absolute risk of insufficiency fracture is very low, and that the benefits of bisphosphonate therapy greatly outweigh the risks. A 2013 meta-analysis came to the same conclusion.¹¹

Treatment options include PT, surgical intervention

When an insufficiency fracture is identified in a patient taking a bisphosphonate, the medication should be discontinued and a consultation with Endocrinology should be arranged. Nonsurgical management ranges from physical therapy to alternative medication regimens, such as teriparatide—a recombinant human parathyroid hormone used to restore bone quality. A variety of surgical stabilization options are also available.⁶

In contrast to typical subtrochanteric fractures, about half of patients with atypical insufficiency fractures demonstrate poor fracture healing that requires surgical intervention.¹² Complete fractures almost always require surgery, while incomplete subtrochanteric femur fractures can usually be managed conservatively by altering pharmacologic prophylaxis (interval dosing or discontinuation of the bisphosphonate and initiation of an alternative therapy like teriparatide) in conjunction with routine radiologic surveillance. Internal fixation may be considered for cases of persistent pain or those that progress to an unstable fracture.¹³

Our patient declined surgical intervention. We switched her monthly ibandronate dosage to a periodic dosing schedule (6 months on, followed by 6 months off) and advised her to rest and take nonsteroidal anti-inflammatory drugs when needed. While consensus guidelines exist for the management of osteoporosis (see Osteoporosis: Assessing your patient’s risk), there is still debate over the optimal length of bisphosphonate therapy and the impact of drug holidays; a recent review in The BMJ discusses bisphosphonate use in detail.⁵

Follow-up x-rays 14 months later revealed that the insufficiency fracture had healed with a bony callus.

CORRESPONDENCE
Joseph S. McMonagle, MD, Eastern Virginia Medical School, Department of Radiology, P.O. Box 1980, Norfolk, VA; [email protected].

A 63-year-old woman with a 3-year history of osteoporosis presented to our clinic with a 2-week history of severe right hip pain. She had been taking a bisphosphonate—oral ibandronate sodium, 150 mg, once monthly—for about 6 years. The postmenopausal patient had a history of degenerative disc disease and lumbar back pain, but no known history of recent trauma or falls.

A clinical exam revealed full passive and active range of motion; however, she had pain with weight bearing. A full metabolic panel revealed no significant abnormalities. A leg length discrepancy was noted, so a bone length study was ordered. Anteroposterior x-rays of the bilateral lower extremities demonstrated a focal convexity along the lateral cortical junction of the proximal right femur (FIGURE).

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

Dx: Bisphosphonate-associated proximal insufficiency fracture

Based on the patient’s clinical history and x-ray findings, we determined that the patient had sustained a bisphosphonate-associated proximal femoral insufficiency fracture. Insufficiency fractures arise from normal physi­­ologic stress on abnormal bone. They commonly occur in conditions that impair normal bone physiology and remodeling, such as osteoporosis, renal insufficiency, rheumatoid arthritis, and diabetes.¹

Could a bisphosphonate be to blame? Bisphosphonate therapy has been associated with significant benefits, including increased bone mineral density (BMD), decreased incidence of fracture, and improved mortality.^2-4 But it’s been postulated that the global suppression of bone turnover caused by these drugs may also impair the bone remodeling process.⁵ Some case reports have suggested an association between chronic bisphosphonate use and atypical insufficiency fractures. These atypical femur fractures are characterized by their location (along the diaphysis in the region distal to the lesser trochanter), the patient’s history (there may be minimal to no trauma), and the potential for “beaking” (localized periosteal or endosteal thickening of the lateral cortex).^6,7

Bisphosphonate therapy has been associated with significant benefits, but it’s been suggested that these drugs may impair the bone remodeling process.

Several large, population-based, case-control studies have found a temporal relationship between bisphosphonate therapy and a statistically significant increased risk of subtrochanteric fractures.^8-10 These studies do note, however, that the absolute risk of insufficiency fracture is very low, and that the benefits of bisphosphonate therapy greatly outweigh the risks. A 2013 meta-analysis came to the same conclusion.¹¹

Treatment options include PT, surgical intervention

When an insufficiency fracture is identified in a patient taking a bisphosphonate, the medication should be discontinued and a consultation with Endocrinology should be arranged. Nonsurgical management ranges from physical therapy to alternative medication regimens, such as teriparatide—a recombinant human parathyroid hormone used to restore bone quality. A variety of surgical stabilization options are also available.⁶

In contrast to typical subtrochanteric fractures, about half of patients with atypical insufficiency fractures demonstrate poor fracture healing that requires surgical intervention.¹² Complete fractures almost always require surgery, while incomplete subtrochanteric femur fractures can usually be managed conservatively by altering pharmacologic prophylaxis (interval dosing or discontinuation of the bisphosphonate and initiation of an alternative therapy like teriparatide) in conjunction with routine radiologic surveillance. Internal fixation may be considered for cases of persistent pain or those that progress to an unstable fracture.¹³

Our patient declined surgical intervention. We switched her monthly ibandronate dosage to a periodic dosing schedule (6 months on, followed by 6 months off) and advised her to rest and take nonsteroidal anti-inflammatory drugs when needed. While consensus guidelines exist for the management of osteoporosis (see Osteoporosis: Assessing your patient’s risk), there is still debate over the optimal length of bisphosphonate therapy and the impact of drug holidays; a recent review in The BMJ discusses bisphosphonate use in detail.⁵

Follow-up x-rays 14 months later revealed that the insufficiency fracture had healed with a bony callus.

CORRESPONDENCE
Joseph S. McMonagle, MD, Eastern Virginia Medical School, Department of Radiology, P.O. Box 1980, Norfolk, VA; [email protected].

A 63-year-old woman with a 3-year history of osteoporosis presented to our clinic with a 2-week history of severe right hip pain. She had been taking a bisphosphonate—oral ibandronate sodium, 150 mg, once monthly—for about 6 years. The postmenopausal patient had a history of degenerative disc disease and lumbar back pain, but no known history of recent trauma or falls.

A clinical exam revealed full passive and active range of motion; however, she had pain with weight bearing. A full metabolic panel revealed no significant abnormalities. A leg length discrepancy was noted, so a bone length study was ordered. Anteroposterior x-rays of the bilateral lower extremities demonstrated a focal convexity along the lateral cortical junction of the proximal right femur (FIGURE).

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

Dx: Bisphosphonate-associated proximal insufficiency fracture

Based on the patient’s clinical history and x-ray findings, we determined that the patient had sustained a bisphosphonate-associated proximal femoral insufficiency fracture. Insufficiency fractures arise from normal physi­­ologic stress on abnormal bone. They commonly occur in conditions that impair normal bone physiology and remodeling, such as osteoporosis, renal insufficiency, rheumatoid arthritis, and diabetes.¹

Could a bisphosphonate be to blame? Bisphosphonate therapy has been associated with significant benefits, including increased bone mineral density (BMD), decreased incidence of fracture, and improved mortality.^2-4 But it’s been postulated that the global suppression of bone turnover caused by these drugs may also impair the bone remodeling process.⁵ Some case reports have suggested an association between chronic bisphosphonate use and atypical insufficiency fractures. These atypical femur fractures are characterized by their location (along the diaphysis in the region distal to the lesser trochanter), the patient’s history (there may be minimal to no trauma), and the potential for “beaking” (localized periosteal or endosteal thickening of the lateral cortex).^6,7

Bisphosphonate therapy has been associated with significant benefits, but it’s been suggested that these drugs may impair the bone remodeling process.

Several large, population-based, case-control studies have found a temporal relationship between bisphosphonate therapy and a statistically significant increased risk of subtrochanteric fractures.^8-10 These studies do note, however, that the absolute risk of insufficiency fracture is very low, and that the benefits of bisphosphonate therapy greatly outweigh the risks. A 2013 meta-analysis came to the same conclusion.¹¹

Treatment options include PT, surgical intervention

When an insufficiency fracture is identified in a patient taking a bisphosphonate, the medication should be discontinued and a consultation with Endocrinology should be arranged. Nonsurgical management ranges from physical therapy to alternative medication regimens, such as teriparatide—a recombinant human parathyroid hormone used to restore bone quality. A variety of surgical stabilization options are also available.⁶

In contrast to typical subtrochanteric fractures, about half of patients with atypical insufficiency fractures demonstrate poor fracture healing that requires surgical intervention.¹² Complete fractures almost always require surgery, while incomplete subtrochanteric femur fractures can usually be managed conservatively by altering pharmacologic prophylaxis (interval dosing or discontinuation of the bisphosphonate and initiation of an alternative therapy like teriparatide) in conjunction with routine radiologic surveillance. Internal fixation may be considered for cases of persistent pain or those that progress to an unstable fracture.¹³

Our patient declined surgical intervention. We switched her monthly ibandronate dosage to a periodic dosing schedule (6 months on, followed by 6 months off) and advised her to rest and take nonsteroidal anti-inflammatory drugs when needed. While consensus guidelines exist for the management of osteoporosis (see Osteoporosis: Assessing your patient’s risk), there is still debate over the optimal length of bisphosphonate therapy and the impact of drug holidays; a recent review in The BMJ discusses bisphosphonate use in detail.⁵

Follow-up x-rays 14 months later revealed that the insufficiency fracture had healed with a bony callus.

CORRESPONDENCE
Joseph S. McMonagle, MD, Eastern Virginia Medical School, Department of Radiology, P.O. Box 1980, Norfolk, VA; [email protected].

THE CASE

A 23-year-old woman seeks medical attention at the request of her boyfriend because she’s been “miserable” for 3 weeks. In the examination room, she slouches in the chair and says her mood is low, her grades have dropped, and she no longer enjoys social gatherings or her other usual activities. She has no thoughts of suicide, no weight loss, and no somatic symptoms.

She says she is generally healthy, does not take any regular medications, and has never been pregnant. When asked about previous similar episodes, she admits to feeling this way about 3 times a year for one to 2 months at a time. She has tried different antidepressants, which haven’t helped much and have made her irritable and interfered with sleep.

When asked about mania or hypomania, she says there are short periods, roughly a couple of weeks 2 or 3 times a year, when she will get a lot of work done and can get by with little sleep. She has never gone on “spending sprees,” though, or indulged in any other unusual or dangerous behavior. And she has never been hospitalized for symptoms.

HOW WOULD YOU PROCEED WITH THIS PATIENT?

Bipolar disorders, over time, typically cause fluctuations in mood, activity, and energy level. If disorders go untreated, a patient’s behavior may cause considerable damage to relationships, finances, and reputations. And for some patients, the disorder can take the ultimate toll, resulting in death by suicide or accident.

Subtypes of bipolar disorder differ in the timing and severity of manic (or hypomanic) and depressive symptoms or episodes. Type I is the classic manic-depressive illness; type II is characterized by chronic treatment-resistant depression punctuated by hypomanic episodes; and cyclothymia leads to chronic fluctuations in mood. The diagnostic category “bipolar disorder not otherwise specified” applies to patients who meet some, but not all, of the criteria for other bipolar disorder subtypes.¹

Prevalence. As with other mood symptoms or disorders, patients with bipolar disorder are often seen first in primary care due, in part, to barriers to obtaining psychiatric care or to avoidance of the perceived stigma in seeking such care.² In a systematic review of patients who were interviewed randomly in primary care settings, 0.5% to 4.3% met criteria for bipolar disorder.³ The average age of onset for bipolar disorder is 15 to 19 years.⁴ In the United States, the prevalence of bipolar disorder type I is 1%; type II is 1.1%.³

The cause of bipolar disorder is unknown, but familial predisposition, biopsychosocial factors, and environment all seem to play a role. Children of parents with bipolar disorder have a 4% to 15% chance of receiving the same diagnosis, compared with children of parents without bipolar disorder, whose risk is only as high as 2%.^5,6

Clinical presentation varies

When patients with bipolar disorder are first seen in the office, their state may be depression, mania, hypomania, or even euthymia. Keep in mind that the first 3 aberrations may indicate other disorders, either psychiatric (TABLE 1)^1,4 or medical (eg, hyperthyroidism, delirium).

Verify a true depressive episode

Symptoms must last for 2 weeks and include anhedonia or depressed mood, as well as some combination of changes in sleep, increased feelings of guilt, poor concentration, changes in appetite, loss of energy, psychomotor agitation or retardation, or suicidal thoughts.¹

Know the criteria for mania

True mania is a distinct period of abnormally and persistently elevated, expansive, or irritable mood, accompanied by abnormally and persistently increased activity or energy, and lasting at least one week for most of the day, nearly every day (or any duration if hospitalization is necessary).

During that time, the patient must also exhibit at least 3 or more of the following symptoms (not counting irritability, if present): ¹

• distractibility,
• insomnia,
• grandiosity,
• flights of ideas,
• increased goal-directed activity or agitation,
• rapid/pressured speech, or
• reckless behaviors.

How hypomania differs from mania. The symptoms of hypomania are less severe than those of mania—eg, social functioning is less impaired or is even normal, and there is no need for hospitalization. Patients may feel they have been much more productive than usual or have needed less sleep to engage in daily activities. Hypomania may be present but not reported by patients who perceive nothing wrong.^1,4

Rule out alternate diagnoses and apply DSM-5 criteria

There are no objective tests to confirm a diagnosis of bipolar disorder. If you suspect bipolar disorder, focus your clinical evaluation on ruling out competing mental health or medical diagnoses, and on determining whether the patient’s history meets criteria for a bipolar disorder as described in the Diagnostic and Statistical Manual of Mental Disorders (DSM-5).¹

Explore the patient’s psychiatric history (including hospitalizations, medications, and electroconvulsive therapy), general medical history, family history of psychiatric disorders (including suicide), and social history (including substance use and abuse). And carefully observe mental status. Confirming a diagnosis of bipolar disorder may take multiple visits, but strongly suggestive symptoms could warrant empirical treatment.

Helpful scales. The Patient Health Questionnaire (PHQ-9; https://www.uspreventiveservicestaskforce.org/Home/GetFileByID/218) and the Beck Depression Inventory (http://www.hr.ucdavis.edu/asap/pdf_files/Beck_Depression_Inventory.pdf) are useful for ruling out depressive disorders. Other scales are available, but they cannot confirm bipolar disorder. Laboratory testing selected according to patient symptoms (TABLE 2⁴) can help rule out alternative diagnoses, but are also useful for establishing a baseline for medications.

Pharmacologic treatment: Match agents to symptoms

When treating bipolar disorder, choose a drug that targets a patient’s specific symptoms (TABLE 3).^7-10 In primary care, the most commonly-used treatments for bipolar disorder type II are lamotrigine, valproic acid, and lithium.¹¹

When to refer

Many cases of bipolar disorder type II can be managed successfully in a primary care practice, as can some cases of stable bipolar disorder type I. Psychiatric consultation may be most beneficial if the patient has recently attempted suicide or has suicidal ideation, has symptoms refractory to treatment, has poor medication adherence, or is misusing medications.

In primary care, up to 4% of patients randomly interviewed met criteria for bipolar disorder.

Even when patients are co-managed with psychiatric consultation, family physicians often ensure patients’ medication adherence, help patients understand their illness, manage overall health-related behaviors (including getting sufficient sleep), and make sure patients follow up as needed with their psychiatrist. Often, once patients have achieved equilibrium on mood-stabilizing (or other) medications, you can manage them and monitor medications with further consultation only as needed for clinical deterioration or other issues. Cognitive behavioral therapy may be useful as adjunctive treatment, particularly when patients are in active treatment.¹²

› CASE

This case is typical for many patients with depressed mood. A few key features in the patient’s history suggest bipolar disorder type II:

• depression that has been refractory to treatment
• multiple failed drug treatments, with mood-related adverse effects
• hypomania perceived as a “productive time,” and not as a problem
• absence of overt manic symptoms.

The patient was given a diagnosis of bipolar disorder type II with current depressed mood and no evidence of acute mania. She was started on valproic acid 250 mg po tid. She reported an initial improvement in mood but stopped the medication after one month because it caused intolerable drowsiness. She was then prescribed lamotrigine progressing gradually in 2-week intervals from 25 mg to 100 mg daily. She tolerated the medication well, and after 3 months of treatment, her mood symptoms improved and she had no further episodes of depressed mood.

CORRESPONDENCE
Michael Jason Wells, MD, Department of Family and Geriatric Medicine, University of Louisville School of Medicine, 201 Abraham Flexner Way, Suite 690, Louisville, KY 40202; [email protected].

THE CASE

A 23-year-old woman seeks medical attention at the request of her boyfriend because she’s been “miserable” for 3 weeks. In the examination room, she slouches in the chair and says her mood is low, her grades have dropped, and she no longer enjoys social gatherings or her other usual activities. She has no thoughts of suicide, no weight loss, and no somatic symptoms.

She says she is generally healthy, does not take any regular medications, and has never been pregnant. When asked about previous similar episodes, she admits to feeling this way about 3 times a year for one to 2 months at a time. She has tried different antidepressants, which haven’t helped much and have made her irritable and interfered with sleep.

When asked about mania or hypomania, she says there are short periods, roughly a couple of weeks 2 or 3 times a year, when she will get a lot of work done and can get by with little sleep. She has never gone on “spending sprees,” though, or indulged in any other unusual or dangerous behavior. And she has never been hospitalized for symptoms.

HOW WOULD YOU PROCEED WITH THIS PATIENT?

Bipolar disorders, over time, typically cause fluctuations in mood, activity, and energy level. If disorders go untreated, a patient’s behavior may cause considerable damage to relationships, finances, and reputations. And for some patients, the disorder can take the ultimate toll, resulting in death by suicide or accident.

Subtypes of bipolar disorder differ in the timing and severity of manic (or hypomanic) and depressive symptoms or episodes. Type I is the classic manic-depressive illness; type II is characterized by chronic treatment-resistant depression punctuated by hypomanic episodes; and cyclothymia leads to chronic fluctuations in mood. The diagnostic category “bipolar disorder not otherwise specified” applies to patients who meet some, but not all, of the criteria for other bipolar disorder subtypes.¹

Prevalence. As with other mood symptoms or disorders, patients with bipolar disorder are often seen first in primary care due, in part, to barriers to obtaining psychiatric care or to avoidance of the perceived stigma in seeking such care.² In a systematic review of patients who were interviewed randomly in primary care settings, 0.5% to 4.3% met criteria for bipolar disorder.³ The average age of onset for bipolar disorder is 15 to 19 years.⁴ In the United States, the prevalence of bipolar disorder type I is 1%; type II is 1.1%.³

The cause of bipolar disorder is unknown, but familial predisposition, biopsychosocial factors, and environment all seem to play a role. Children of parents with bipolar disorder have a 4% to 15% chance of receiving the same diagnosis, compared with children of parents without bipolar disorder, whose risk is only as high as 2%.^5,6

Clinical presentation varies

When patients with bipolar disorder are first seen in the office, their state may be depression, mania, hypomania, or even euthymia. Keep in mind that the first 3 aberrations may indicate other disorders, either psychiatric (TABLE 1)^1,4 or medical (eg, hyperthyroidism, delirium).

Verify a true depressive episode

Symptoms must last for 2 weeks and include anhedonia or depressed mood, as well as some combination of changes in sleep, increased feelings of guilt, poor concentration, changes in appetite, loss of energy, psychomotor agitation or retardation, or suicidal thoughts.¹

Know the criteria for mania

True mania is a distinct period of abnormally and persistently elevated, expansive, or irritable mood, accompanied by abnormally and persistently increased activity or energy, and lasting at least one week for most of the day, nearly every day (or any duration if hospitalization is necessary).

During that time, the patient must also exhibit at least 3 or more of the following symptoms (not counting irritability, if present): ¹

• distractibility,
• insomnia,
• grandiosity,
• flights of ideas,
• increased goal-directed activity or agitation,
• rapid/pressured speech, or
• reckless behaviors.

How hypomania differs from mania. The symptoms of hypomania are less severe than those of mania—eg, social functioning is less impaired or is even normal, and there is no need for hospitalization. Patients may feel they have been much more productive than usual or have needed less sleep to engage in daily activities. Hypomania may be present but not reported by patients who perceive nothing wrong.^1,4

Rule out alternate diagnoses and apply DSM-5 criteria

There are no objective tests to confirm a diagnosis of bipolar disorder. If you suspect bipolar disorder, focus your clinical evaluation on ruling out competing mental health or medical diagnoses, and on determining whether the patient’s history meets criteria for a bipolar disorder as described in the Diagnostic and Statistical Manual of Mental Disorders (DSM-5).¹

Explore the patient’s psychiatric history (including hospitalizations, medications, and electroconvulsive therapy), general medical history, family history of psychiatric disorders (including suicide), and social history (including substance use and abuse). And carefully observe mental status. Confirming a diagnosis of bipolar disorder may take multiple visits, but strongly suggestive symptoms could warrant empirical treatment.

Helpful scales. The Patient Health Questionnaire (PHQ-9; https://www.uspreventiveservicestaskforce.org/Home/GetFileByID/218) and the Beck Depression Inventory (http://www.hr.ucdavis.edu/asap/pdf_files/Beck_Depression_Inventory.pdf) are useful for ruling out depressive disorders. Other scales are available, but they cannot confirm bipolar disorder. Laboratory testing selected according to patient symptoms (TABLE 2⁴) can help rule out alternative diagnoses, but are also useful for establishing a baseline for medications.

Pharmacologic treatment: Match agents to symptoms

When treating bipolar disorder, choose a drug that targets a patient’s specific symptoms (TABLE 3).^7-10 In primary care, the most commonly-used treatments for bipolar disorder type II are lamotrigine, valproic acid, and lithium.¹¹

When to refer

Many cases of bipolar disorder type II can be managed successfully in a primary care practice, as can some cases of stable bipolar disorder type I. Psychiatric consultation may be most beneficial if the patient has recently attempted suicide or has suicidal ideation, has symptoms refractory to treatment, has poor medication adherence, or is misusing medications.

In primary care, up to 4% of patients randomly interviewed met criteria for bipolar disorder.

Even when patients are co-managed with psychiatric consultation, family physicians often ensure patients’ medication adherence, help patients understand their illness, manage overall health-related behaviors (including getting sufficient sleep), and make sure patients follow up as needed with their psychiatrist. Often, once patients have achieved equilibrium on mood-stabilizing (or other) medications, you can manage them and monitor medications with further consultation only as needed for clinical deterioration or other issues. Cognitive behavioral therapy may be useful as adjunctive treatment, particularly when patients are in active treatment.¹²

› CASE

This case is typical for many patients with depressed mood. A few key features in the patient’s history suggest bipolar disorder type II:

• depression that has been refractory to treatment
• multiple failed drug treatments, with mood-related adverse effects
• hypomania perceived as a “productive time,” and not as a problem
• absence of overt manic symptoms.

The patient was given a diagnosis of bipolar disorder type II with current depressed mood and no evidence of acute mania. She was started on valproic acid 250 mg po tid. She reported an initial improvement in mood but stopped the medication after one month because it caused intolerable drowsiness. She was then prescribed lamotrigine progressing gradually in 2-week intervals from 25 mg to 100 mg daily. She tolerated the medication well, and after 3 months of treatment, her mood symptoms improved and she had no further episodes of depressed mood.

CORRESPONDENCE
Michael Jason Wells, MD, Department of Family and Geriatric Medicine, University of Louisville School of Medicine, 201 Abraham Flexner Way, Suite 690, Louisville, KY 40202; [email protected].

THE CASE

A 23-year-old woman seeks medical attention at the request of her boyfriend because she’s been “miserable” for 3 weeks. In the examination room, she slouches in the chair and says her mood is low, her grades have dropped, and she no longer enjoys social gatherings or her other usual activities. She has no thoughts of suicide, no weight loss, and no somatic symptoms.

She says she is generally healthy, does not take any regular medications, and has never been pregnant. When asked about previous similar episodes, she admits to feeling this way about 3 times a year for one to 2 months at a time. She has tried different antidepressants, which haven’t helped much and have made her irritable and interfered with sleep.

When asked about mania or hypomania, she says there are short periods, roughly a couple of weeks 2 or 3 times a year, when she will get a lot of work done and can get by with little sleep. She has never gone on “spending sprees,” though, or indulged in any other unusual or dangerous behavior. And she has never been hospitalized for symptoms.

HOW WOULD YOU PROCEED WITH THIS PATIENT?

Bipolar disorders, over time, typically cause fluctuations in mood, activity, and energy level. If disorders go untreated, a patient’s behavior may cause considerable damage to relationships, finances, and reputations. And for some patients, the disorder can take the ultimate toll, resulting in death by suicide or accident.

Subtypes of bipolar disorder differ in the timing and severity of manic (or hypomanic) and depressive symptoms or episodes. Type I is the classic manic-depressive illness; type II is characterized by chronic treatment-resistant depression punctuated by hypomanic episodes; and cyclothymia leads to chronic fluctuations in mood. The diagnostic category “bipolar disorder not otherwise specified” applies to patients who meet some, but not all, of the criteria for other bipolar disorder subtypes.¹

Prevalence. As with other mood symptoms or disorders, patients with bipolar disorder are often seen first in primary care due, in part, to barriers to obtaining psychiatric care or to avoidance of the perceived stigma in seeking such care.² In a systematic review of patients who were interviewed randomly in primary care settings, 0.5% to 4.3% met criteria for bipolar disorder.³ The average age of onset for bipolar disorder is 15 to 19 years.⁴ In the United States, the prevalence of bipolar disorder type I is 1%; type II is 1.1%.³

The cause of bipolar disorder is unknown, but familial predisposition, biopsychosocial factors, and environment all seem to play a role. Children of parents with bipolar disorder have a 4% to 15% chance of receiving the same diagnosis, compared with children of parents without bipolar disorder, whose risk is only as high as 2%.^5,6

Clinical presentation varies

When patients with bipolar disorder are first seen in the office, their state may be depression, mania, hypomania, or even euthymia. Keep in mind that the first 3 aberrations may indicate other disorders, either psychiatric (TABLE 1)^1,4 or medical (eg, hyperthyroidism, delirium).

Verify a true depressive episode

Symptoms must last for 2 weeks and include anhedonia or depressed mood, as well as some combination of changes in sleep, increased feelings of guilt, poor concentration, changes in appetite, loss of energy, psychomotor agitation or retardation, or suicidal thoughts.¹

Know the criteria for mania

True mania is a distinct period of abnormally and persistently elevated, expansive, or irritable mood, accompanied by abnormally and persistently increased activity or energy, and lasting at least one week for most of the day, nearly every day (or any duration if hospitalization is necessary).

During that time, the patient must also exhibit at least 3 or more of the following symptoms (not counting irritability, if present): ¹

• distractibility,
• insomnia,
• grandiosity,
• flights of ideas,
• increased goal-directed activity or agitation,
• rapid/pressured speech, or
• reckless behaviors.

How hypomania differs from mania. The symptoms of hypomania are less severe than those of mania—eg, social functioning is less impaired or is even normal, and there is no need for hospitalization. Patients may feel they have been much more productive than usual or have needed less sleep to engage in daily activities. Hypomania may be present but not reported by patients who perceive nothing wrong.^1,4

Rule out alternate diagnoses and apply DSM-5 criteria

There are no objective tests to confirm a diagnosis of bipolar disorder. If you suspect bipolar disorder, focus your clinical evaluation on ruling out competing mental health or medical diagnoses, and on determining whether the patient’s history meets criteria for a bipolar disorder as described in the Diagnostic and Statistical Manual of Mental Disorders (DSM-5).¹

Explore the patient’s psychiatric history (including hospitalizations, medications, and electroconvulsive therapy), general medical history, family history of psychiatric disorders (including suicide), and social history (including substance use and abuse). And carefully observe mental status. Confirming a diagnosis of bipolar disorder may take multiple visits, but strongly suggestive symptoms could warrant empirical treatment.

Helpful scales. The Patient Health Questionnaire (PHQ-9; https://www.uspreventiveservicestaskforce.org/Home/GetFileByID/218) and the Beck Depression Inventory (http://www.hr.ucdavis.edu/asap/pdf_files/Beck_Depression_Inventory.pdf) are useful for ruling out depressive disorders. Other scales are available, but they cannot confirm bipolar disorder. Laboratory testing selected according to patient symptoms (TABLE 2⁴) can help rule out alternative diagnoses, but are also useful for establishing a baseline for medications.

Pharmacologic treatment: Match agents to symptoms

When treating bipolar disorder, choose a drug that targets a patient’s specific symptoms (TABLE 3).^7-10 In primary care, the most commonly-used treatments for bipolar disorder type II are lamotrigine, valproic acid, and lithium.¹¹

When to refer

Many cases of bipolar disorder type II can be managed successfully in a primary care practice, as can some cases of stable bipolar disorder type I. Psychiatric consultation may be most beneficial if the patient has recently attempted suicide or has suicidal ideation, has symptoms refractory to treatment, has poor medication adherence, or is misusing medications.

In primary care, up to 4% of patients randomly interviewed met criteria for bipolar disorder.

Even when patients are co-managed with psychiatric consultation, family physicians often ensure patients’ medication adherence, help patients understand their illness, manage overall health-related behaviors (including getting sufficient sleep), and make sure patients follow up as needed with their psychiatrist. Often, once patients have achieved equilibrium on mood-stabilizing (or other) medications, you can manage them and monitor medications with further consultation only as needed for clinical deterioration or other issues. Cognitive behavioral therapy may be useful as adjunctive treatment, particularly when patients are in active treatment.¹²

› CASE

This case is typical for many patients with depressed mood. A few key features in the patient’s history suggest bipolar disorder type II:

• depression that has been refractory to treatment
• multiple failed drug treatments, with mood-related adverse effects
• hypomania perceived as a “productive time,” and not as a problem
• absence of overt manic symptoms.

The patient was given a diagnosis of bipolar disorder type II with current depressed mood and no evidence of acute mania. She was started on valproic acid 250 mg po tid. She reported an initial improvement in mood but stopped the medication after one month because it caused intolerable drowsiness. She was then prescribed lamotrigine progressing gradually in 2-week intervals from 25 mg to 100 mg daily. She tolerated the medication well, and after 3 months of treatment, her mood symptoms improved and she had no further episodes of depressed mood.

CORRESPONDENCE
Michael Jason Wells, MD, Department of Family and Geriatric Medicine, University of Louisville School of Medicine, 201 Abraham Flexner Way, Suite 690, Louisville, KY 40202; [email protected].

CASE › Amber S,* a 33-year-old woman who works on the production line at a bread factory, sought care at my health center with a several month history of non-bloody diarrhea that was increasing in frequency and urgency and was accompanied by painful abdominal bloating and cramping. She said that these symptoms were negatively impacting her interpersonal relationships, as well as her productivity at work. She reported that “almost everything” she ate upset her stomach and “goes right through her,” including fruits, vegetables, and meat, as well as greasy fast food. She had researched her symptoms on the Internet and was worried that she might have something serious like inflammatory bowel disease or cancer.

Irritable bowel syndrome (IBS) is a common functional gastrointestinal disorder (FGID) that negatively impacts the quality of life (QOL) of millions of people worldwide.¹ In fact, one study of 179 people with IBS found that 76% of survey respondents reported some degree of IBS-related impairment in at least 5 domains of daily life: daily activities, comorbid psychiatric diagnoses, symptom severity, QOL, and symptom-specific cognitive affective factors related to IBS.²

Estimating prevalence and incidence is a formidable challenge given various diagnostic criteria, the influence of population selection, inclusion or exclusion of non-GI comorbidities, and various cultural influences.³ That said, it’s estimated that IBS impacts approximately 11% of the world’s population, and approximately 30% of these individuals seek treatment.^1,4 While there are no significant differences in GI symptoms between those who consult physicians and those who do not, those who do seek treatment report higher pain scores, greater levels of anxiety, and a greater reduction in QOL.⁵

All ages affected. IBS has been reported in patients of all ages, including children and the elderly, with no definable difference reported in the frequency of subtypes (diarrhea- or constipation-predominant).

This article reviews the latest explanations, diagnostic criteria, and treatment guidelines for this challenging condition so that you can offer your patients confident care without needless testing or referral.

[polldaddy:9755564]

A lack of consensus among practicing physicians

Historically, IBS has been regarded by many primary care physicians (PCPs) as a diagnosis of exclusion. Lab tests would be ordered, nothing significant would be found, and the patient would be referred to the gastroenterologist for a definitive diagnosis.

Perceptions and misconceptions about IBS continue to abound to this day. Many are neither completely right nor wrong partly because so many triggers for IBS exist and partly because of the heretofore lack of simple, standardized criteria to diagnose the condition. Other factors contributing to the confusion are that the diagnosis of IBS is purely symptom-based and that proposals of its pathophysiology have traditionally been complex.

It is presumed that IBS shares common pathophysiologic mechanisms—including visceral hypersensitivity—with syndromes like functional dyspepsia.For example, a 2006 survey-based study of PCPs and gastroenterologists found that PCPs were less likely than gastroenterologists to believe that IBS was related to prior physical or sexual abuse, previous infection, or learned behavior, but were more likely to associate dietary factors or a linkable genetic etiology with IBS.⁶ Both sets of beliefs, however, may be considered correct.

Similarly, a 2009 qualitative study conducted in the Netherlands found that general practitioners (GPs) considered smoking, caffeine, diet, “hasty lifestyle,” and lack of exercise as potential triggers for IBS symptoms, while PCPs in the United Kingdom considered diet, infection, and travel to be possible triggers.⁷ Again, all play a role.

While GPs reported that patients should take responsibility for managing their IBS and for minimizing its impact on their daily lives, they admitted limited awareness of the extent to which IBS affected their patients’ daily living.⁷

A 2013 survey-based study in England determined that GPs understand the relationship between IBS and psychological symptoms including anxiety and stress, and posited that the majority of patients could be managed within primary care without referral for psychological interventions.⁸ Moreover, they reported that a dedicated risk assessment tool for patients with IBS would be helpful to stratify severity of disease. The study concluded that the reluctance of GPs to refer patients for evidence-based psychological treatments may prevent them from obtaining appropriate services and care.

Newer explanatory model shines light on IBS

A newer explanation that is based on 3 main hypotheses is elucidating the true nature of IBS and providing a pragmatic model for the clinical setting (FIGURE 1).⁹ According to the model, IBS entails the following 3 elements, which combined lead to the symptoms of IBS:

• Altered or abnormal peripheral regulation of gut function (including sensory and secretory mechanisms)
• Altered brain-gut signaling (including visceral hypersensitivity)
• Psychological distress.

It is reasonable to consider that epigenetic changes may underlie the etiology and pathophysiology of IBS and could increase one’s susceptibility to developing the disorder. Additionally, it is presumed that IBS shares common pathophysiologic mechanisms, including visceral hypersensitivity, with other associated functional syndromes, such as functional dyspepsia.

New criteria make diagnosis on symptoms alone easier

In addition to a new explanatory model, clear criteria for diagnosing the disorder now exist, which should make it easier for PCPs to make the diagnosis without additional testing or referral. The 2016 Rome IV criteria³ provide guidelines for diagnosing the various subtypes of IBS including IBS-D (diarrhea predominant), IBS-C (constipation predominant), and IBS-M (mixed subtypes). A laboratory evaluation is really only needed for patients who fall outside the criteria or who have alarm symptoms, which include:

• age >50 years at onset of symptoms,

• new onset of constipation in the elderly,

• rectal bleeding,
• unexplained weight loss or anemia,
• family history of organic GI disease, and
• a palpable abdominal or rectal mass.

These symptoms should prompt referral to a gastroenterologist. Once alarm symptoms have been excluded, the diagnosis of IBS is based upon the presence of characteristic symptoms and changes in stool habits (FIGURE 2^3,10).

Patterns of migration. Over time, patients may migrate between subtypes, most commonly from IBS-C or IBS-D to IBS-M; switching between IBS-C and IBS-D occurs less commonly.¹¹ Patients who meet criteria for IBS but whose bowel habits and symptoms cannot be grouped into any of these 3 categories are considered to have IBS unclassified. The Bristol Stool Form Scale (available at: https://www.niddk.nih.gov/health-information/health-communication-programs/bowel-control-awareness-campaign/Documents/Bristol_Stool_Form_Scale_508.pdf) should be used to gauge and track stool consistency.

A novel diagnostic test for IBS has been validated for differentiating patients with IBS-D from those with inflammatory bowel disease (IBD).¹² The test focused on the beliefs that cytolethal distending toxin B (CdtB) is produced by bacteria that cause acute viral gastroenteritis (eg, norovirus, rotavirus), and that host antibodies to CdtB cross-react with the protein vinculin in the host gut, producing an “IBS-like phenotype.”

Additional treatment options for diarrhea-predominant IBS include antidepressants (tricyclics or SSRIs) and antispasmodics, such as dicyclomine and hyoscyamine.In a 2015 large-scale multicenter trial, both anti-CdtB and anti-vinculin antibodies were found to be significantly elevated in subjects with IBS-D compared to non-IBS subjects,¹² providing evidence to support the long-held belief that viral gastroenteritis is often at the root of IBS.

Treatment aims to decrease symptoms and improve QOL

Treatment of IBS is directed at decreasing symptoms of abdominal pain and discomfort, bloating, diarrhea, and constipation while improving QOL. Therapeutic options for treatment of each symptom are listed in FIGURE 3,^13,14 including several that are commonly used and have moderate efficacy, but are not currently approved by the US Food and Drug Administration for this purpose.

Current evidence-based pharmacologic guidelines from the American Gastroenterological Association (AGA) can be found at: https://www.guideline.gov/summaries/summary/49122?osrc=12. Figure 3^13,14 provides a few additional options not included in the AGA guidelines and presents the information in a simple schematic.

Pharmacologic therapies for IBS-D

Eluxadoline is a novel mixed mu opioid receptor agonist and delta opioid receptor antagonist developed for the treatment of IBS-D. It normalizes GI transit and defecation under conditions of environmental stress or post-inflammatory altered GI function.¹⁵ A 2016 study involving almost 2500 patients found that eluxadoline was significantly better than placebo at decreasing abdominal pain and improving stool consistency on the same day for at least half of a 26-week period.¹³ The most common adverse effects were nausea, constipation, and abdominal pain. Pancreatitis occurred rarely.

Rifaximin. Because GI flora play a central role in the pathophysiology of IBS, researchers have found that rifaximin, a minimally absorbed antibiotic, is a potentially important player in treatment. Two double-blind, placebo-controlled trials (TARGET 1 and TARGET 2) found that after 4 weeks of treatment, patients experienced significant improvement in global IBS symptoms including bloating, abdominal pain, and stool consistency on rifaximin vs placebo (40.7% vs 31.7%; P<.001 in the 2 studies combined).¹⁶ The incidence of adverse effects (headache, upper respiratory infection, nausea, abdominal pain, diarrhea, and urinary tract infection) was comparable to that with placebo.

Alosetron. Research has shown this selective 5-HT3 receptor antagonist to improve all IBS QOL measures, restriction of daily activities, and patient satisfaction significantly more than placebo in women.¹⁷ While initial use of alosetron in 2000 was widespread, the rare serious adverse event of ischemic colitis led to its withdrawal from the US market within a few months.¹⁸ Alosetron returned to the market in 2002 with restricted marketing (to treat only women with severe diarrhea-predominant IBS). (See Lotronex [alosetron hydrochloride] full prescribing information available at: https://lotronex.com/hcp/index.html.) Data from a 9-year risk management program subsequently found a cumulative incidence rate for ischemic colitis of 1.03 cases per 1000 patient/years.¹⁹

Current evidence suggests that targeted carbohydrate and gluten exclusion plays a role in the treatment and symptomatic improvement of patients with IBS.Other possible options include various antidepressants (tricyclics such as amitriptyline, imipramine, and nortriptyline; or selective serotonin reuptake inhibitors [SSRIs] such as citalopram, fluoxetine, and paroxetine) and antispasmodics such as dicyclomine and hyoscyamine.

Pharmacologic therapies for IBS-C

Linaclotide is a guanylate cyclase-C agonist with an indication for treatment of IBS-C. A double-blind, parallel-group, placebo-controlled trial found that the percentage of patients who experienced a decrease in abdominal pain was nearly 25%, with statistically significant improvements in bloating, straining, and stool consistency over a 26-week period.²⁰ In a report on 2 phase 3 trials, researchers found that linaclotide improved global symptom scores and significantly decreased abdominal bloating and fullness, pain, cramping, and discomfort vs placebo. Diarrhea was the most commonly reported adverse event in patients with severe abdominal symptoms (18.8%-21%).²¹

Lubiprostone is a prostaglandin E1 analogue that activates type-2-chloride channels on the apical membrane of epithelial cells in the intestine. In a combined analysis of 2 phase 3 randomized trials, lubiprostone was administered twice daily for 12 weeks vs placebo and patients were asked to describe how they felt after the trial period. Survey responders reported significant improvements in global IBS-C symptoms (17.9% vs 10.1%; P=.001).²² A meta-analysis of studies on lubiprostone found that diarrhea, nausea, and abdominal pain were the most common adverse effects, but their occurrence was not that much greater than with placebo.²³

Diet and probiotics can play a significant role

The role of dietary components in the treatment of IBS is gaining increasing attention. Such components can have a direct effect on gastric and intestinal motility, visceral sensation, immune activation, brain-gut interactions, and the microbiome. Current evidence suggests that targeted carbohydrate and gluten exclusion plays a favorable role in the treatment and symptomatic improvement of patients with IBS.²⁴

A 2014 study conducted in Australia showed that a diet low in FODMAPs (fermentable oligosaccharides, disaccharides, monosaccharides, and polyols), which is characterized by avoiding foods containing gluten and those that are high in fructose, reduced overall GI symptom scores (including scores involving abdominal bloating, pain, and flatus) in patients with IBS compared to those consuming a normal Australian diet.²⁵ The International Foundation for Functional Gastrointestinal Disorders’ Web site provides a detailed guide to low FODMAP foods and can be found at: http://www.aboutibs.org/low-fodmap-diet.html.

Probiotics are now commonly used in the symptomatic treatment of many upper and lower GI disorders. While much anecdotal evidence exists to support their benefit, there is a paucity of large-scale and rigorous research to provide substantial outcomes-based evidence. The theory for their use is that they support regulation of the gut microbiome, which in turn improves the imbalance between the intestinal microbiome and a dysfunctional intestinal barrier.

Probiotics are now used in the symptomatic treatment of many upper and lower GI disorders.A 2014 randomized, double-blind, placebo-controlled trial involving multispecies probiotics (a mixture of Bifidobacterium longum, B. bifidum, B. lactis, Lactobacillus acidophilus, L. rhamnosus, and Streptococcus thermophilus) found that patients who received probiotics had significantly reduced symptoms of IBS after 4 weeks compared with placebo, and modest improvement in abdominal pain and discomfort as well as bloating.²⁶ One study involving 122 patients from 2011 found that B. bifidum MIMBb75 reduced the global assessment of IBS symptoms by -88 points (95% CI, -1.07 to -0.69) when compared with only -0.16 (95% CI, -.32 to 0.00) points in the placebo group (P<.0001).²⁷ MIMBb75 also significantly improved the IBS symptoms of pain/discomfort, distension/bloating, urgency, and digestive disorder. And one randomized, double-blind, placebo-controlled study involving 67 patients found that QOL scores improved two-fold when patients took Saccharomyces boulardii (15.4% vs 7.0%; P<.05).²⁸

Dried plums or prunes have been used successfully for decades for the symptomatic treatment of constipation. A single-blinded, randomized, cross-over study compared prunes 50 g/d to psyllium fiber 11 g/d and found that prunes were more efficacious (P<.05) with spontaneous bowel movements and stool consistency scores.²⁹

Peppermint oil has been studied as an alternative therapy for symptoms of IBS, but efficacy and tolerability are concerns. A meta-analysis of randomized controlled trials with a minimum duration of 2 weeks found that compared with placebo, peppermint oil provided improvement in abdominal pain, bloating, and global symptoms, but some patients reported transient heartburn.³⁰ A 4-week, randomized, double-blind, placebo-controlled clinical trial sponsored by IM HealthScience found a novel oral formulation of triple-enteric-coated sustained-release peppermint oil microspheres caused less heartburn than was reported in the previous study, but still significantly improved abdominal symptoms and lessened pain on defecation and fecal urgency.³¹

CASE › Suspecting IBS-D, the FP ordered a complete blood count, tissue transglutaminase antibodies, and a stool culture, all of which were unremarkable. Ms. S has been trying to follow a low FODMAP diet and has been taking some over-the-counter probiotics with only minimal relief of abdominal bloating and cramping and no improvement in stool consistency. Her FP started her on eluxadoline 100 mg twice daily with food. After 12 weeks of therapy, she reports significant improvement in global IBS symptoms and nearly complete resolution of her diarrhea.

*Amber S is a real patient in my practice. Her name has been changed to protect her identity.

CORRESPONDENCE
Joel J. Heidelbaugh, MD, FAAFP, FACG, Ypsilanti Health Center, 200 Arnet Suite 200, Ypsilanti, MI 48198; [email protected].