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AI helps predict ulcerative colitis remission/activity, flare-ups
The AI tool predicted UC disease activity with 89% accuracy and inflammation at the biopsy site with 80% accuracy. Its ability to stratify risk of UC flare was on par with human pathologists.
“This tool in the near future will speed up, simplify, and standardize histological assessment of ulcerative colitis and provide the clinician with accurate prognostic information in real time,” co–lead author Marietta Iacucci, MD, PhD, from the University of Birmingham (England), and University College Cork (Ireland), said in an interview.
“The tool needs to be refined and further validated before it is ready for daily clinical practice. That work is ongoing now,” Dr. Iacucci said.
The researchers describe their advanced AI-based computer-aided detection tool in a study published online in Gastroenterology.
‘Strong’ performance
They used 535 digitized biopsies from 273 patients with UC (mean age, 48 years; 41% women) to develop and test the tool. They used a subset of 118 to train it to distinguish remission from activity, 42 to calibrate it, and 375 to test it. An additional 154 biopsies from 58 patients with UC were used to externally validate the tool.
The model also was tested to predict the corresponding endoscopic assessment and occurrence of flares at 12 months.
UC disease activity was defined by three different histologic indices: the Robarts Histopathology Index (RHI), the Nancy Histological Index (NHI), and the newly developed PICaSSO Histologic Remission Index (PHRI).
The AI tool had “strong diagnostic performance to detect disease activity” (PHRI > 0) with an overall area under the receiver operating characteristic curve of 0.87 and sensitivity and specificity of 89% and 85%, respectively.
The researchers note that, while the AI tool was trained for the PHRI, its sensitivity for RHI and NHI histologic remission/activity was also high (94% and 89%, respectively).
Despite the different mix of severity grades, the AI model “maintained a good diagnostic performance, proving its applicability outside the original development setting,” they reported.
The AI tool could also predict the presence of endoscopic inflammation in the biopsy area with about 80% accuracy.
“Though imperfect, this result is consistent with human-assessed correlation between endoscopy and histology,” the researchers noted.
The model predicted the corresponding endoscopic remission/activity with 79% and 82% accuracy for UCEIS and PICaSSO, respectively.
The hazard ratios for disease flare-up between the AI system and pathologists assessed by PHRI was similar (4.64 and 3.56, respectively), “demonstrating the ability of the computer to stratify the risk of flare comparably well to pathologists,” they added.
Both histology and outcome prediction were confirmed in the external validation cohort.
The AI system delivered results in an average of 9.8 seconds per slide.
Potential ‘game changer’
UC is a “complex condition to predict, and developing machine learning–derived systems to make this diagnostic job quicker and more accurate could be a game changer,” Dr. Iacucci said in a news release.
With refinement, the AI tool will have an impact on both clinical trials and daily practice, the researchers wrote. In clinical practice, histological reporting remains “largely descriptive and nonstandard, thus would greatly benefit from a quick and objective assessment. Similarly, clinical trials in UC could efficiently overcome costly central readings.”
Assessing and measuring improvement in endoscopy and histology are difficult parts of treating UC, said David Hudesman, MD, codirector of the Inflammatory Bowel Disease Center at New York University Langone Health.
“We do not know how much improvement is associated with improved long-term outcomes,” Dr. Hudesman said in an interview. “For example, does a patient need complete healing or is 50% better enough?” Dr. Hudesman was not involved with the current research.
“This study showed that AI can predict – with good accuracy – endoscopy and histology scores, as well as 1-year patient outcomes. If this is validated in larger studies, AI can help determine if we should adjust/change therapies or continue, which is very important,” he said.
This research was supported by the National Institute for Health Research Birmingham Biomedical Research Centre. Dr. Iacucci and Dr. Hudesman reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
The AI tool predicted UC disease activity with 89% accuracy and inflammation at the biopsy site with 80% accuracy. Its ability to stratify risk of UC flare was on par with human pathologists.
“This tool in the near future will speed up, simplify, and standardize histological assessment of ulcerative colitis and provide the clinician with accurate prognostic information in real time,” co–lead author Marietta Iacucci, MD, PhD, from the University of Birmingham (England), and University College Cork (Ireland), said in an interview.
“The tool needs to be refined and further validated before it is ready for daily clinical practice. That work is ongoing now,” Dr. Iacucci said.
The researchers describe their advanced AI-based computer-aided detection tool in a study published online in Gastroenterology.
‘Strong’ performance
They used 535 digitized biopsies from 273 patients with UC (mean age, 48 years; 41% women) to develop and test the tool. They used a subset of 118 to train it to distinguish remission from activity, 42 to calibrate it, and 375 to test it. An additional 154 biopsies from 58 patients with UC were used to externally validate the tool.
The model also was tested to predict the corresponding endoscopic assessment and occurrence of flares at 12 months.
UC disease activity was defined by three different histologic indices: the Robarts Histopathology Index (RHI), the Nancy Histological Index (NHI), and the newly developed PICaSSO Histologic Remission Index (PHRI).
The AI tool had “strong diagnostic performance to detect disease activity” (PHRI > 0) with an overall area under the receiver operating characteristic curve of 0.87 and sensitivity and specificity of 89% and 85%, respectively.
The researchers note that, while the AI tool was trained for the PHRI, its sensitivity for RHI and NHI histologic remission/activity was also high (94% and 89%, respectively).
Despite the different mix of severity grades, the AI model “maintained a good diagnostic performance, proving its applicability outside the original development setting,” they reported.
The AI tool could also predict the presence of endoscopic inflammation in the biopsy area with about 80% accuracy.
“Though imperfect, this result is consistent with human-assessed correlation between endoscopy and histology,” the researchers noted.
The model predicted the corresponding endoscopic remission/activity with 79% and 82% accuracy for UCEIS and PICaSSO, respectively.
The hazard ratios for disease flare-up between the AI system and pathologists assessed by PHRI was similar (4.64 and 3.56, respectively), “demonstrating the ability of the computer to stratify the risk of flare comparably well to pathologists,” they added.
Both histology and outcome prediction were confirmed in the external validation cohort.
The AI system delivered results in an average of 9.8 seconds per slide.
Potential ‘game changer’
UC is a “complex condition to predict, and developing machine learning–derived systems to make this diagnostic job quicker and more accurate could be a game changer,” Dr. Iacucci said in a news release.
With refinement, the AI tool will have an impact on both clinical trials and daily practice, the researchers wrote. In clinical practice, histological reporting remains “largely descriptive and nonstandard, thus would greatly benefit from a quick and objective assessment. Similarly, clinical trials in UC could efficiently overcome costly central readings.”
Assessing and measuring improvement in endoscopy and histology are difficult parts of treating UC, said David Hudesman, MD, codirector of the Inflammatory Bowel Disease Center at New York University Langone Health.
“We do not know how much improvement is associated with improved long-term outcomes,” Dr. Hudesman said in an interview. “For example, does a patient need complete healing or is 50% better enough?” Dr. Hudesman was not involved with the current research.
“This study showed that AI can predict – with good accuracy – endoscopy and histology scores, as well as 1-year patient outcomes. If this is validated in larger studies, AI can help determine if we should adjust/change therapies or continue, which is very important,” he said.
This research was supported by the National Institute for Health Research Birmingham Biomedical Research Centre. Dr. Iacucci and Dr. Hudesman reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
The AI tool predicted UC disease activity with 89% accuracy and inflammation at the biopsy site with 80% accuracy. Its ability to stratify risk of UC flare was on par with human pathologists.
“This tool in the near future will speed up, simplify, and standardize histological assessment of ulcerative colitis and provide the clinician with accurate prognostic information in real time,” co–lead author Marietta Iacucci, MD, PhD, from the University of Birmingham (England), and University College Cork (Ireland), said in an interview.
“The tool needs to be refined and further validated before it is ready for daily clinical practice. That work is ongoing now,” Dr. Iacucci said.
The researchers describe their advanced AI-based computer-aided detection tool in a study published online in Gastroenterology.
‘Strong’ performance
They used 535 digitized biopsies from 273 patients with UC (mean age, 48 years; 41% women) to develop and test the tool. They used a subset of 118 to train it to distinguish remission from activity, 42 to calibrate it, and 375 to test it. An additional 154 biopsies from 58 patients with UC were used to externally validate the tool.
The model also was tested to predict the corresponding endoscopic assessment and occurrence of flares at 12 months.
UC disease activity was defined by three different histologic indices: the Robarts Histopathology Index (RHI), the Nancy Histological Index (NHI), and the newly developed PICaSSO Histologic Remission Index (PHRI).
The AI tool had “strong diagnostic performance to detect disease activity” (PHRI > 0) with an overall area under the receiver operating characteristic curve of 0.87 and sensitivity and specificity of 89% and 85%, respectively.
The researchers note that, while the AI tool was trained for the PHRI, its sensitivity for RHI and NHI histologic remission/activity was also high (94% and 89%, respectively).
Despite the different mix of severity grades, the AI model “maintained a good diagnostic performance, proving its applicability outside the original development setting,” they reported.
The AI tool could also predict the presence of endoscopic inflammation in the biopsy area with about 80% accuracy.
“Though imperfect, this result is consistent with human-assessed correlation between endoscopy and histology,” the researchers noted.
The model predicted the corresponding endoscopic remission/activity with 79% and 82% accuracy for UCEIS and PICaSSO, respectively.
The hazard ratios for disease flare-up between the AI system and pathologists assessed by PHRI was similar (4.64 and 3.56, respectively), “demonstrating the ability of the computer to stratify the risk of flare comparably well to pathologists,” they added.
Both histology and outcome prediction were confirmed in the external validation cohort.
The AI system delivered results in an average of 9.8 seconds per slide.
Potential ‘game changer’
UC is a “complex condition to predict, and developing machine learning–derived systems to make this diagnostic job quicker and more accurate could be a game changer,” Dr. Iacucci said in a news release.
With refinement, the AI tool will have an impact on both clinical trials and daily practice, the researchers wrote. In clinical practice, histological reporting remains “largely descriptive and nonstandard, thus would greatly benefit from a quick and objective assessment. Similarly, clinical trials in UC could efficiently overcome costly central readings.”
Assessing and measuring improvement in endoscopy and histology are difficult parts of treating UC, said David Hudesman, MD, codirector of the Inflammatory Bowel Disease Center at New York University Langone Health.
“We do not know how much improvement is associated with improved long-term outcomes,” Dr. Hudesman said in an interview. “For example, does a patient need complete healing or is 50% better enough?” Dr. Hudesman was not involved with the current research.
“This study showed that AI can predict – with good accuracy – endoscopy and histology scores, as well as 1-year patient outcomes. If this is validated in larger studies, AI can help determine if we should adjust/change therapies or continue, which is very important,” he said.
This research was supported by the National Institute for Health Research Birmingham Biomedical Research Centre. Dr. Iacucci and Dr. Hudesman reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM GASTROENTEROLOGY
Patient-based mouse MVID model hints at mechanism
Researchers have identified a novel mutation in a patient with microvillus inclusion disease (MVID) and rapidly developed a specific mouse model to find insights into the disease process.
MVID is characterized by severe diarrhea, generally beginning within a few hours of birth. The condition is caused by inactivating mutations in the gene myosin VB (MYO5B). Affected individuals usually require lifetime use of total parenteral nutrition or small-bowel transplantation.
More than 100 MYO5B mutations have been identified in MVID patients, most of whom inherit two unique mutant alleles. This can lead to variability in phenotypes, which single-mutation animal models have been unable to mimic. Generally, patients have atrophy of microvilli on enterocytes as well as inclusion bodies within enterocytes that contain microvilli.
In the study, published in Cellular and Molecular Gastroenterology and Hepatology, researchers describe genetic sequencing of MYO5B mutations in a patient and both parents. One mutation is predicted to lead to protein truncation (c.1821delG), and the other (c.1555G>A) appeared to be inherited from the patient’s mother. The patient suffered from severe diarrhea after birth and was intermittently feeding intolerant.
The researchers conducted a range of diagnostic tests and biopsies. One particularly interesting finding was expression of the A-kinase anchoring protein 350 in the vicinity of the inclusion, wrote Andreanna Burman and her coauthors at Vanderbilt University, Nashville, Tenn. This protein takes part in a protein-mediating scaffolding pathway, suggesting that it could play a role in the development of the inclusions.
The researchers used multiplexed immunofluorescence (MxIF) staining of a biopsy of the duodenum to look for expression of a range of proteins. They found a striking decrease in enterocytes that express glucose transporter 2, implying that malabsorption might be due at least in part to enterocytes that fail to mature.
The patient also had internalization of apical nutrient transporters, which has been reported in other MVID patients. The researchers also developed a mouse model that incorporated the patient’s novel compound heterozygous genotype, which they cross-bred to produce a tamoxifen-inducible mouse model.
After the tamoxifen injection, the patient-mimicking animals exhibited a severe watery diarrhea, losing 19% of their body weight by day 4. The animals’ intestines showed a similar phenotype to that of the patient.
The apical sodium transporters sodium-glucose cotransporter 1 (SGLT1), apical sodium-dependent bile transporter, and NHE3 were internalized away from the apical membrane of the enterocytes in the patient-mimicking model animals. This structural difference may explain the limited absorption of sodium and water and the resultant watery diarrhea. The researchers also noted disruption of the actinin-4+ terminal web structure, as well as increased SGLT1 localization with lysosome-associated membrane protein 1+ lysosomes within the mouse model enterocytes. This association may indicate degradation of mislocalized proteins, the authors noted, which has also been seen in expanded RAB7+ vesicles within MVID patient tissues.
Other signs pointed to the expansion of immature cells in the upper crypt and lower villus, as well as faster shedding of enterocytes in the villus than in control animals. Scanning electron microscope images also showed immature and disorganized microvilli in the enterocytes of the patient-mimicking mice.
Taken together, “these findings are consistent with a deficit in enterocyte maturation in Myo5b(G519R) mice and in the patient with the MYO5B(G519R) mutation,” the authors wrote.
The authors suggest that their approach could be used more generally to quickly create mouse models of patient-specific monogenic congenital disorders.
The authors disclosed no conflicts of interest. The research was funded by the National Foundation of Science, National Institutes of Health, Vanderbilt Digestive Diseases Research Center Pilot and Feasibility grant, an American Physiological Society John F. Perkins, Jr. Research Career Enhancement Award, and a gift from the Christine Volpe Fund.
Genetically engineered mouse models (GEMMs) have offered tremendous insight into the genetics, biology, and pathobiology of the gastrointestinal tract. Yet, in the past, the time necessary to generate these GEMMs has presented challenges for modeling human diseases. With the ongoing identification of disease-associated polymorphisms or mutations, including through approaches like genomewide association studies (GWAS), defining the function of these specific genetic alterations in disease pathogenesis is of great importance.
Overall, this study demonstrates the value of both patient-mimicking mouse models and multiplexed staining to define the molecular mechanisms of congenital diseases in vivo.
Dr. Jonathan P. Katz is associate professor of medicine, department of medicine, gastroenterology division, University of Pennsylvania Perelman School of Medicine, Philadelphia. He has no relevant conflicts of interest.
Genetically engineered mouse models (GEMMs) have offered tremendous insight into the genetics, biology, and pathobiology of the gastrointestinal tract. Yet, in the past, the time necessary to generate these GEMMs has presented challenges for modeling human diseases. With the ongoing identification of disease-associated polymorphisms or mutations, including through approaches like genomewide association studies (GWAS), defining the function of these specific genetic alterations in disease pathogenesis is of great importance.
Overall, this study demonstrates the value of both patient-mimicking mouse models and multiplexed staining to define the molecular mechanisms of congenital diseases in vivo.
Dr. Jonathan P. Katz is associate professor of medicine, department of medicine, gastroenterology division, University of Pennsylvania Perelman School of Medicine, Philadelphia. He has no relevant conflicts of interest.
Genetically engineered mouse models (GEMMs) have offered tremendous insight into the genetics, biology, and pathobiology of the gastrointestinal tract. Yet, in the past, the time necessary to generate these GEMMs has presented challenges for modeling human diseases. With the ongoing identification of disease-associated polymorphisms or mutations, including through approaches like genomewide association studies (GWAS), defining the function of these specific genetic alterations in disease pathogenesis is of great importance.
Overall, this study demonstrates the value of both patient-mimicking mouse models and multiplexed staining to define the molecular mechanisms of congenital diseases in vivo.
Dr. Jonathan P. Katz is associate professor of medicine, department of medicine, gastroenterology division, University of Pennsylvania Perelman School of Medicine, Philadelphia. He has no relevant conflicts of interest.
Researchers have identified a novel mutation in a patient with microvillus inclusion disease (MVID) and rapidly developed a specific mouse model to find insights into the disease process.
MVID is characterized by severe diarrhea, generally beginning within a few hours of birth. The condition is caused by inactivating mutations in the gene myosin VB (MYO5B). Affected individuals usually require lifetime use of total parenteral nutrition or small-bowel transplantation.
More than 100 MYO5B mutations have been identified in MVID patients, most of whom inherit two unique mutant alleles. This can lead to variability in phenotypes, which single-mutation animal models have been unable to mimic. Generally, patients have atrophy of microvilli on enterocytes as well as inclusion bodies within enterocytes that contain microvilli.
In the study, published in Cellular and Molecular Gastroenterology and Hepatology, researchers describe genetic sequencing of MYO5B mutations in a patient and both parents. One mutation is predicted to lead to protein truncation (c.1821delG), and the other (c.1555G>A) appeared to be inherited from the patient’s mother. The patient suffered from severe diarrhea after birth and was intermittently feeding intolerant.
The researchers conducted a range of diagnostic tests and biopsies. One particularly interesting finding was expression of the A-kinase anchoring protein 350 in the vicinity of the inclusion, wrote Andreanna Burman and her coauthors at Vanderbilt University, Nashville, Tenn. This protein takes part in a protein-mediating scaffolding pathway, suggesting that it could play a role in the development of the inclusions.
The researchers used multiplexed immunofluorescence (MxIF) staining of a biopsy of the duodenum to look for expression of a range of proteins. They found a striking decrease in enterocytes that express glucose transporter 2, implying that malabsorption might be due at least in part to enterocytes that fail to mature.
The patient also had internalization of apical nutrient transporters, which has been reported in other MVID patients. The researchers also developed a mouse model that incorporated the patient’s novel compound heterozygous genotype, which they cross-bred to produce a tamoxifen-inducible mouse model.
After the tamoxifen injection, the patient-mimicking animals exhibited a severe watery diarrhea, losing 19% of their body weight by day 4. The animals’ intestines showed a similar phenotype to that of the patient.
The apical sodium transporters sodium-glucose cotransporter 1 (SGLT1), apical sodium-dependent bile transporter, and NHE3 were internalized away from the apical membrane of the enterocytes in the patient-mimicking model animals. This structural difference may explain the limited absorption of sodium and water and the resultant watery diarrhea. The researchers also noted disruption of the actinin-4+ terminal web structure, as well as increased SGLT1 localization with lysosome-associated membrane protein 1+ lysosomes within the mouse model enterocytes. This association may indicate degradation of mislocalized proteins, the authors noted, which has also been seen in expanded RAB7+ vesicles within MVID patient tissues.
Other signs pointed to the expansion of immature cells in the upper crypt and lower villus, as well as faster shedding of enterocytes in the villus than in control animals. Scanning electron microscope images also showed immature and disorganized microvilli in the enterocytes of the patient-mimicking mice.
Taken together, “these findings are consistent with a deficit in enterocyte maturation in Myo5b(G519R) mice and in the patient with the MYO5B(G519R) mutation,” the authors wrote.
The authors suggest that their approach could be used more generally to quickly create mouse models of patient-specific monogenic congenital disorders.
The authors disclosed no conflicts of interest. The research was funded by the National Foundation of Science, National Institutes of Health, Vanderbilt Digestive Diseases Research Center Pilot and Feasibility grant, an American Physiological Society John F. Perkins, Jr. Research Career Enhancement Award, and a gift from the Christine Volpe Fund.
Researchers have identified a novel mutation in a patient with microvillus inclusion disease (MVID) and rapidly developed a specific mouse model to find insights into the disease process.
MVID is characterized by severe diarrhea, generally beginning within a few hours of birth. The condition is caused by inactivating mutations in the gene myosin VB (MYO5B). Affected individuals usually require lifetime use of total parenteral nutrition or small-bowel transplantation.
More than 100 MYO5B mutations have been identified in MVID patients, most of whom inherit two unique mutant alleles. This can lead to variability in phenotypes, which single-mutation animal models have been unable to mimic. Generally, patients have atrophy of microvilli on enterocytes as well as inclusion bodies within enterocytes that contain microvilli.
In the study, published in Cellular and Molecular Gastroenterology and Hepatology, researchers describe genetic sequencing of MYO5B mutations in a patient and both parents. One mutation is predicted to lead to protein truncation (c.1821delG), and the other (c.1555G>A) appeared to be inherited from the patient’s mother. The patient suffered from severe diarrhea after birth and was intermittently feeding intolerant.
The researchers conducted a range of diagnostic tests and biopsies. One particularly interesting finding was expression of the A-kinase anchoring protein 350 in the vicinity of the inclusion, wrote Andreanna Burman and her coauthors at Vanderbilt University, Nashville, Tenn. This protein takes part in a protein-mediating scaffolding pathway, suggesting that it could play a role in the development of the inclusions.
The researchers used multiplexed immunofluorescence (MxIF) staining of a biopsy of the duodenum to look for expression of a range of proteins. They found a striking decrease in enterocytes that express glucose transporter 2, implying that malabsorption might be due at least in part to enterocytes that fail to mature.
The patient also had internalization of apical nutrient transporters, which has been reported in other MVID patients. The researchers also developed a mouse model that incorporated the patient’s novel compound heterozygous genotype, which they cross-bred to produce a tamoxifen-inducible mouse model.
After the tamoxifen injection, the patient-mimicking animals exhibited a severe watery diarrhea, losing 19% of their body weight by day 4. The animals’ intestines showed a similar phenotype to that of the patient.
The apical sodium transporters sodium-glucose cotransporter 1 (SGLT1), apical sodium-dependent bile transporter, and NHE3 were internalized away from the apical membrane of the enterocytes in the patient-mimicking model animals. This structural difference may explain the limited absorption of sodium and water and the resultant watery diarrhea. The researchers also noted disruption of the actinin-4+ terminal web structure, as well as increased SGLT1 localization with lysosome-associated membrane protein 1+ lysosomes within the mouse model enterocytes. This association may indicate degradation of mislocalized proteins, the authors noted, which has also been seen in expanded RAB7+ vesicles within MVID patient tissues.
Other signs pointed to the expansion of immature cells in the upper crypt and lower villus, as well as faster shedding of enterocytes in the villus than in control animals. Scanning electron microscope images also showed immature and disorganized microvilli in the enterocytes of the patient-mimicking mice.
Taken together, “these findings are consistent with a deficit in enterocyte maturation in Myo5b(G519R) mice and in the patient with the MYO5B(G519R) mutation,” the authors wrote.
The authors suggest that their approach could be used more generally to quickly create mouse models of patient-specific monogenic congenital disorders.
The authors disclosed no conflicts of interest. The research was funded by the National Foundation of Science, National Institutes of Health, Vanderbilt Digestive Diseases Research Center Pilot and Feasibility grant, an American Physiological Society John F. Perkins, Jr. Research Career Enhancement Award, and a gift from the Christine Volpe Fund.
FROM CELLULAR AND MOLECULAR GASTROENTEROLOGY AND HEPATOLOGY
TMEM16A, TMEM16F play crucial role in Paneth cell secretion
To defend the gut from microbes and pathogens, Paneth cells rely on TMEM16A, a calcium-activated chloride channel, and TMEM16F, a phospholipid scramblase, according to a new study published in Gastro Hep Advances.
The Paneth cells in mice missing TMEM16A or TMEM16F showed defects in signaling and release of secretary factors, researchers reported.
Inhibiting or activating TMEM16A and TMEM16F is likely to affect microbial content and immune functions in the small intestine, concluded Rainer Schreiber, Dr. rer. nat., of the Institute of Physiology at Universität Regensburg, Germany, and colleagues.
“Many small molecules and numerous natural or herbal compounds have been identified that either inhibit or activate TMEM16A or TMEM16F,” they wrote. “Some of these compounds may turn out to be useful therapeutics in inflammatory bowel disease, intestinal allergies, or abnormal colonization of the gut.”
Paneth cells play a central role in intestinal innate immune response, the authors wrote. Located at the base of small intestinal crypts and occasionally found in the proximal colon, these cells have defensive functions, such as protecting stem cells in response to invading microbes and eradicating ingested pathogens from intestinal crypts. Through secretion, they also regulate the composition and number of commensal intestinal bacteria. In inflammatory bowel disease, the Paneth cell zone expands due to an increase in cell size and cell number.
In previous studies, cholinergic stimulation provided enhanced protection in animals orally infected with virulent Salmonella enterica. However, the mechanisms of luminal stimulation of Paneth cell secretion in response to bacteria or lipopolysaccharide are unclear. Recent reports show that TMEM16A (also known as anoctamin 1, or ANO1) and TMEM16F (anoctamin 6, or ANO6) control intracellular calcium (Ca2+) signaling and that high local Ca2+ levels support exocytosis in intestinal cells.
The researchers analyzed the roles of the two molecules in Paneth cell secretion using mice with intestinal epithelial-specific knockout of TMEM16A or TMEM16F. They examined tissue structures and Paneth cells in the mice, as well as Paneth cell exocytosis in small intestinal organoids in vitro. They also compared Ca2+ signals between wild-type and knockout mice and analyzed bacterial colonization and intestinal apoptosis.
In wild-type mice, TMEM16A was detected at the apical pole of crypt epithelial cells, while TMEM16F was located predominantly at the basolateral side. Notably, TMEM16A was also located in intestinal smooth muscle cells.
Compared with wild-type mice, the TMEM16 knockout mice had pronounced accumulation of lysozyme in jejunal Paneth cells. This suggests a defect in Paneth cell secretion in the absence of TMEM16A and TMEM16F, the authors wrote.
Previous studies had found an accumulation of mucus in intestinal goblet cells in mice with tissue-specific knockout of TMEM16A and TMEM16F. In this study, a more detailed analysis of mucus using periodic acid-Schiff staining of duodenum, jejunum, and ileum confirmed those results and demonstrated enhanced mucus in the small intestine of knockout mice. This suggests that a lack of TMEM16A or TMEM16F causes a broad secretion defect in secretory cells, including Paneth cells, the authors wrote.
Because granules of Paneth cells contain antimicrobial peptides, cytokines, and other factors that control proliferation or epithelial cell death, the researchers analyzed the presence of Gram-positive and Gram-negative bacteria in the jejunum and ileum. Compared to wild-type mice, the number of bacteria was higher in the ileum of both TMEM16A and TMEM16F knockout mice and in the jejunum of TMEM16F knockout mice, suggesting reduced antimicrobial activity in the absence of TMEM16 proteins.
The researchers also compared regulated cell death of intestinal epithelial cells in jejuna of wild-type and knockout mice. They found largely reduced cell death in both TMEM16A and TMEM16F knockout mice.
“Intestinal inflammatory diseases such as Crohn’s disease, necrotizing enterocolitis, and intestinal microbiota dysbiosis have been related to abnormal Paneth cell physiology,” the authors wrote. “The present findings may therefore provide the basis for a novel anti-inflammatory therapy for intestinal diseases and may improve our understanding of the molecular mechanism of some of the currently available drugs.”
The study was supported by the Deutsche Forschungsgemeinschaft funding program. The authors disclosed no conflicts of interest.
To defend the gut from microbes and pathogens, Paneth cells rely on TMEM16A, a calcium-activated chloride channel, and TMEM16F, a phospholipid scramblase, according to a new study published in Gastro Hep Advances.
The Paneth cells in mice missing TMEM16A or TMEM16F showed defects in signaling and release of secretary factors, researchers reported.
Inhibiting or activating TMEM16A and TMEM16F is likely to affect microbial content and immune functions in the small intestine, concluded Rainer Schreiber, Dr. rer. nat., of the Institute of Physiology at Universität Regensburg, Germany, and colleagues.
“Many small molecules and numerous natural or herbal compounds have been identified that either inhibit or activate TMEM16A or TMEM16F,” they wrote. “Some of these compounds may turn out to be useful therapeutics in inflammatory bowel disease, intestinal allergies, or abnormal colonization of the gut.”
Paneth cells play a central role in intestinal innate immune response, the authors wrote. Located at the base of small intestinal crypts and occasionally found in the proximal colon, these cells have defensive functions, such as protecting stem cells in response to invading microbes and eradicating ingested pathogens from intestinal crypts. Through secretion, they also regulate the composition and number of commensal intestinal bacteria. In inflammatory bowel disease, the Paneth cell zone expands due to an increase in cell size and cell number.
In previous studies, cholinergic stimulation provided enhanced protection in animals orally infected with virulent Salmonella enterica. However, the mechanisms of luminal stimulation of Paneth cell secretion in response to bacteria or lipopolysaccharide are unclear. Recent reports show that TMEM16A (also known as anoctamin 1, or ANO1) and TMEM16F (anoctamin 6, or ANO6) control intracellular calcium (Ca2+) signaling and that high local Ca2+ levels support exocytosis in intestinal cells.
The researchers analyzed the roles of the two molecules in Paneth cell secretion using mice with intestinal epithelial-specific knockout of TMEM16A or TMEM16F. They examined tissue structures and Paneth cells in the mice, as well as Paneth cell exocytosis in small intestinal organoids in vitro. They also compared Ca2+ signals between wild-type and knockout mice and analyzed bacterial colonization and intestinal apoptosis.
In wild-type mice, TMEM16A was detected at the apical pole of crypt epithelial cells, while TMEM16F was located predominantly at the basolateral side. Notably, TMEM16A was also located in intestinal smooth muscle cells.
Compared with wild-type mice, the TMEM16 knockout mice had pronounced accumulation of lysozyme in jejunal Paneth cells. This suggests a defect in Paneth cell secretion in the absence of TMEM16A and TMEM16F, the authors wrote.
Previous studies had found an accumulation of mucus in intestinal goblet cells in mice with tissue-specific knockout of TMEM16A and TMEM16F. In this study, a more detailed analysis of mucus using periodic acid-Schiff staining of duodenum, jejunum, and ileum confirmed those results and demonstrated enhanced mucus in the small intestine of knockout mice. This suggests that a lack of TMEM16A or TMEM16F causes a broad secretion defect in secretory cells, including Paneth cells, the authors wrote.
Because granules of Paneth cells contain antimicrobial peptides, cytokines, and other factors that control proliferation or epithelial cell death, the researchers analyzed the presence of Gram-positive and Gram-negative bacteria in the jejunum and ileum. Compared to wild-type mice, the number of bacteria was higher in the ileum of both TMEM16A and TMEM16F knockout mice and in the jejunum of TMEM16F knockout mice, suggesting reduced antimicrobial activity in the absence of TMEM16 proteins.
The researchers also compared regulated cell death of intestinal epithelial cells in jejuna of wild-type and knockout mice. They found largely reduced cell death in both TMEM16A and TMEM16F knockout mice.
“Intestinal inflammatory diseases such as Crohn’s disease, necrotizing enterocolitis, and intestinal microbiota dysbiosis have been related to abnormal Paneth cell physiology,” the authors wrote. “The present findings may therefore provide the basis for a novel anti-inflammatory therapy for intestinal diseases and may improve our understanding of the molecular mechanism of some of the currently available drugs.”
The study was supported by the Deutsche Forschungsgemeinschaft funding program. The authors disclosed no conflicts of interest.
To defend the gut from microbes and pathogens, Paneth cells rely on TMEM16A, a calcium-activated chloride channel, and TMEM16F, a phospholipid scramblase, according to a new study published in Gastro Hep Advances.
The Paneth cells in mice missing TMEM16A or TMEM16F showed defects in signaling and release of secretary factors, researchers reported.
Inhibiting or activating TMEM16A and TMEM16F is likely to affect microbial content and immune functions in the small intestine, concluded Rainer Schreiber, Dr. rer. nat., of the Institute of Physiology at Universität Regensburg, Germany, and colleagues.
“Many small molecules and numerous natural or herbal compounds have been identified that either inhibit or activate TMEM16A or TMEM16F,” they wrote. “Some of these compounds may turn out to be useful therapeutics in inflammatory bowel disease, intestinal allergies, or abnormal colonization of the gut.”
Paneth cells play a central role in intestinal innate immune response, the authors wrote. Located at the base of small intestinal crypts and occasionally found in the proximal colon, these cells have defensive functions, such as protecting stem cells in response to invading microbes and eradicating ingested pathogens from intestinal crypts. Through secretion, they also regulate the composition and number of commensal intestinal bacteria. In inflammatory bowel disease, the Paneth cell zone expands due to an increase in cell size and cell number.
In previous studies, cholinergic stimulation provided enhanced protection in animals orally infected with virulent Salmonella enterica. However, the mechanisms of luminal stimulation of Paneth cell secretion in response to bacteria or lipopolysaccharide are unclear. Recent reports show that TMEM16A (also known as anoctamin 1, or ANO1) and TMEM16F (anoctamin 6, or ANO6) control intracellular calcium (Ca2+) signaling and that high local Ca2+ levels support exocytosis in intestinal cells.
The researchers analyzed the roles of the two molecules in Paneth cell secretion using mice with intestinal epithelial-specific knockout of TMEM16A or TMEM16F. They examined tissue structures and Paneth cells in the mice, as well as Paneth cell exocytosis in small intestinal organoids in vitro. They also compared Ca2+ signals between wild-type and knockout mice and analyzed bacterial colonization and intestinal apoptosis.
In wild-type mice, TMEM16A was detected at the apical pole of crypt epithelial cells, while TMEM16F was located predominantly at the basolateral side. Notably, TMEM16A was also located in intestinal smooth muscle cells.
Compared with wild-type mice, the TMEM16 knockout mice had pronounced accumulation of lysozyme in jejunal Paneth cells. This suggests a defect in Paneth cell secretion in the absence of TMEM16A and TMEM16F, the authors wrote.
Previous studies had found an accumulation of mucus in intestinal goblet cells in mice with tissue-specific knockout of TMEM16A and TMEM16F. In this study, a more detailed analysis of mucus using periodic acid-Schiff staining of duodenum, jejunum, and ileum confirmed those results and demonstrated enhanced mucus in the small intestine of knockout mice. This suggests that a lack of TMEM16A or TMEM16F causes a broad secretion defect in secretory cells, including Paneth cells, the authors wrote.
Because granules of Paneth cells contain antimicrobial peptides, cytokines, and other factors that control proliferation or epithelial cell death, the researchers analyzed the presence of Gram-positive and Gram-negative bacteria in the jejunum and ileum. Compared to wild-type mice, the number of bacteria was higher in the ileum of both TMEM16A and TMEM16F knockout mice and in the jejunum of TMEM16F knockout mice, suggesting reduced antimicrobial activity in the absence of TMEM16 proteins.
The researchers also compared regulated cell death of intestinal epithelial cells in jejuna of wild-type and knockout mice. They found largely reduced cell death in both TMEM16A and TMEM16F knockout mice.
“Intestinal inflammatory diseases such as Crohn’s disease, necrotizing enterocolitis, and intestinal microbiota dysbiosis have been related to abnormal Paneth cell physiology,” the authors wrote. “The present findings may therefore provide the basis for a novel anti-inflammatory therapy for intestinal diseases and may improve our understanding of the molecular mechanism of some of the currently available drugs.”
The study was supported by the Deutsche Forschungsgemeinschaft funding program. The authors disclosed no conflicts of interest.
FROM GASTRO HEP ADVANCES
Review explores the boundaries of endoscopic resection for esophageal adenocarcinoma
A growing body of evidence shows that deeper and larger tumors can be safely removed with endoscopy instead of surgery when individual patient risk is taken into account, according to a review by Eva P.D. Verheij, a doctoral candidate at Amsterdam University Medical Center, and colleagues.
“Management of patients with superficial esophageal adenocarcinoma (EAC) is becoming less invasive and more patient-tailored,” the researchers wrote in Techniques and Innovations in Gastrointestinal Endoscopy. “In the future, watchful waiting may be a valid alternative to surgery in selected cases.”
The investigators examined new advances that have been made in the management of superficial esophageal adenocarcinomas by endoscopy, and they address how guidelines may be falling short in light of newly published evidence.
Surgery is usually the first choice for the management of advanced esophageal adenocarcinoma. “Endoscopic treatment has become the cornerstone for early cancer confined to the mucosa,” the authors wrote.
“For low-risk submucosal EAC, which only invades the superficial submucosa (sm1, i.e. less than 500 mcm) without any other risk factors, endoscopic treatment as an alternative to surgery is gaining acceptance because multiple studies have demonstrated a very low risk of lymph node metastases (less than 2% for these lesions),” the investigators wrote. Although surgical resection with lymphadenectomy is currently the recommended treatment for cases with deep submucosal invasion, poor differentiation, or lymphovascular invasion, the investigators suggested that even these tumors may be within an endoscopist’s reach.
While the rate of lymph node metastasis for such patients has been reported to be as high as 46%, more recent endoscopic studies show a metastasis rate range of up to 20% after 23-63 months of follow-up.
“One possible explanation for the discrepancy in lymph node metastases rates between surgical and endoscopic studies could be the different preparation of slides for histopathological assessment,” the investigators wrote. “In general, the cuts in surgical specimen are made with wider intervals (±5 mm) than the cuts in endoscopic resection specimens (2-3 mm), with additional cuts in case of submucosal invasion. The hypothesis is that this wider interval may result in missing the area with the deepest tumor infiltration. This could result in an underdiagnosis of the actual invasion depth, and therefore an overestimation of the associated lymph node metastases risk.” A study published in August 2022 in Gastrointestinal Endoscopy found an annual metastases risk of 6.9% in patients with high-risk T1a EAC.
“Given its invasiveness and associated morbidity and mortality, esophagectomy may be overtreatment in those patients who will not develop lymph node metastases,” the investigators wrote. “Given the technical advances in endoscopy that enable us to radically remove large EACs, and to perform more meticulous follow-up, it might be time to swing the pendulum and only send those patients for surgery who have an indisputable indication for surgery, instead of performing esophagectomy as a prophylactic treatment.”
To truly find the limits of endoscopic resection for EAC, however, more research is needed.
“Ongoing studies are necessary to evaluate the lymph node metastases risk on an individual basis, using presence of histological risk factors. By predicting the risk of lymph node metastases, and considering patients’ wishes and condition, one might decide to perform esophagectomy or watchful waiting with strict endoscopic follow-up. In high-risk cases, we may use sentinel node navigated surgery in the future as an extra safety check before deciding on optimal management,” the authors wrote.
The investigators disclosed relationships Medtronic, C2 Therapeutics/Pentax Medical, MicroTech, and Aqua Medical.
Barrett’s esophagus (BE) is the only known precursor lesion to esophageal adenocarcinoma, a cancer with rising incidence and stage-dependent survival. Early detection of BE-related neoplasia provides the opportunity to intervene through endoscopic eradication therapy and avoid the morbidity associated with esophagectomy. Verheji and colleagues, a group from a robust BE expert center in the Netherlands, provide a comprehensive and detailed overview of the role of endoscopic therapy for superficial esophageal adenocarcinoma (EAC), which is gaining popularity. In this review, they nicely highlight the benefits of this approach as a minimally invasive, organ-preserving, safe, and effective treatment option.
Jennifer M. Kolb, MD, MS, is assistant professor of medicine, Vatche and Tamar Manoukian Division of Digestive Diseases University of California, Los Angeles. She also is affiliated with VA Greater Los Angeles Health Care System. She has no relevant conflicts of interest.
Barrett’s esophagus (BE) is the only known precursor lesion to esophageal adenocarcinoma, a cancer with rising incidence and stage-dependent survival. Early detection of BE-related neoplasia provides the opportunity to intervene through endoscopic eradication therapy and avoid the morbidity associated with esophagectomy. Verheji and colleagues, a group from a robust BE expert center in the Netherlands, provide a comprehensive and detailed overview of the role of endoscopic therapy for superficial esophageal adenocarcinoma (EAC), which is gaining popularity. In this review, they nicely highlight the benefits of this approach as a minimally invasive, organ-preserving, safe, and effective treatment option.
Jennifer M. Kolb, MD, MS, is assistant professor of medicine, Vatche and Tamar Manoukian Division of Digestive Diseases University of California, Los Angeles. She also is affiliated with VA Greater Los Angeles Health Care System. She has no relevant conflicts of interest.
Barrett’s esophagus (BE) is the only known precursor lesion to esophageal adenocarcinoma, a cancer with rising incidence and stage-dependent survival. Early detection of BE-related neoplasia provides the opportunity to intervene through endoscopic eradication therapy and avoid the morbidity associated with esophagectomy. Verheji and colleagues, a group from a robust BE expert center in the Netherlands, provide a comprehensive and detailed overview of the role of endoscopic therapy for superficial esophageal adenocarcinoma (EAC), which is gaining popularity. In this review, they nicely highlight the benefits of this approach as a minimally invasive, organ-preserving, safe, and effective treatment option.
Jennifer M. Kolb, MD, MS, is assistant professor of medicine, Vatche and Tamar Manoukian Division of Digestive Diseases University of California, Los Angeles. She also is affiliated with VA Greater Los Angeles Health Care System. She has no relevant conflicts of interest.
A growing body of evidence shows that deeper and larger tumors can be safely removed with endoscopy instead of surgery when individual patient risk is taken into account, according to a review by Eva P.D. Verheij, a doctoral candidate at Amsterdam University Medical Center, and colleagues.
“Management of patients with superficial esophageal adenocarcinoma (EAC) is becoming less invasive and more patient-tailored,” the researchers wrote in Techniques and Innovations in Gastrointestinal Endoscopy. “In the future, watchful waiting may be a valid alternative to surgery in selected cases.”
The investigators examined new advances that have been made in the management of superficial esophageal adenocarcinomas by endoscopy, and they address how guidelines may be falling short in light of newly published evidence.
Surgery is usually the first choice for the management of advanced esophageal adenocarcinoma. “Endoscopic treatment has become the cornerstone for early cancer confined to the mucosa,” the authors wrote.
“For low-risk submucosal EAC, which only invades the superficial submucosa (sm1, i.e. less than 500 mcm) without any other risk factors, endoscopic treatment as an alternative to surgery is gaining acceptance because multiple studies have demonstrated a very low risk of lymph node metastases (less than 2% for these lesions),” the investigators wrote. Although surgical resection with lymphadenectomy is currently the recommended treatment for cases with deep submucosal invasion, poor differentiation, or lymphovascular invasion, the investigators suggested that even these tumors may be within an endoscopist’s reach.
While the rate of lymph node metastasis for such patients has been reported to be as high as 46%, more recent endoscopic studies show a metastasis rate range of up to 20% after 23-63 months of follow-up.
“One possible explanation for the discrepancy in lymph node metastases rates between surgical and endoscopic studies could be the different preparation of slides for histopathological assessment,” the investigators wrote. “In general, the cuts in surgical specimen are made with wider intervals (±5 mm) than the cuts in endoscopic resection specimens (2-3 mm), with additional cuts in case of submucosal invasion. The hypothesis is that this wider interval may result in missing the area with the deepest tumor infiltration. This could result in an underdiagnosis of the actual invasion depth, and therefore an overestimation of the associated lymph node metastases risk.” A study published in August 2022 in Gastrointestinal Endoscopy found an annual metastases risk of 6.9% in patients with high-risk T1a EAC.
“Given its invasiveness and associated morbidity and mortality, esophagectomy may be overtreatment in those patients who will not develop lymph node metastases,” the investigators wrote. “Given the technical advances in endoscopy that enable us to radically remove large EACs, and to perform more meticulous follow-up, it might be time to swing the pendulum and only send those patients for surgery who have an indisputable indication for surgery, instead of performing esophagectomy as a prophylactic treatment.”
To truly find the limits of endoscopic resection for EAC, however, more research is needed.
“Ongoing studies are necessary to evaluate the lymph node metastases risk on an individual basis, using presence of histological risk factors. By predicting the risk of lymph node metastases, and considering patients’ wishes and condition, one might decide to perform esophagectomy or watchful waiting with strict endoscopic follow-up. In high-risk cases, we may use sentinel node navigated surgery in the future as an extra safety check before deciding on optimal management,” the authors wrote.
The investigators disclosed relationships Medtronic, C2 Therapeutics/Pentax Medical, MicroTech, and Aqua Medical.
A growing body of evidence shows that deeper and larger tumors can be safely removed with endoscopy instead of surgery when individual patient risk is taken into account, according to a review by Eva P.D. Verheij, a doctoral candidate at Amsterdam University Medical Center, and colleagues.
“Management of patients with superficial esophageal adenocarcinoma (EAC) is becoming less invasive and more patient-tailored,” the researchers wrote in Techniques and Innovations in Gastrointestinal Endoscopy. “In the future, watchful waiting may be a valid alternative to surgery in selected cases.”
The investigators examined new advances that have been made in the management of superficial esophageal adenocarcinomas by endoscopy, and they address how guidelines may be falling short in light of newly published evidence.
Surgery is usually the first choice for the management of advanced esophageal adenocarcinoma. “Endoscopic treatment has become the cornerstone for early cancer confined to the mucosa,” the authors wrote.
“For low-risk submucosal EAC, which only invades the superficial submucosa (sm1, i.e. less than 500 mcm) without any other risk factors, endoscopic treatment as an alternative to surgery is gaining acceptance because multiple studies have demonstrated a very low risk of lymph node metastases (less than 2% for these lesions),” the investigators wrote. Although surgical resection with lymphadenectomy is currently the recommended treatment for cases with deep submucosal invasion, poor differentiation, or lymphovascular invasion, the investigators suggested that even these tumors may be within an endoscopist’s reach.
While the rate of lymph node metastasis for such patients has been reported to be as high as 46%, more recent endoscopic studies show a metastasis rate range of up to 20% after 23-63 months of follow-up.
“One possible explanation for the discrepancy in lymph node metastases rates between surgical and endoscopic studies could be the different preparation of slides for histopathological assessment,” the investigators wrote. “In general, the cuts in surgical specimen are made with wider intervals (±5 mm) than the cuts in endoscopic resection specimens (2-3 mm), with additional cuts in case of submucosal invasion. The hypothesis is that this wider interval may result in missing the area with the deepest tumor infiltration. This could result in an underdiagnosis of the actual invasion depth, and therefore an overestimation of the associated lymph node metastases risk.” A study published in August 2022 in Gastrointestinal Endoscopy found an annual metastases risk of 6.9% in patients with high-risk T1a EAC.
“Given its invasiveness and associated morbidity and mortality, esophagectomy may be overtreatment in those patients who will not develop lymph node metastases,” the investigators wrote. “Given the technical advances in endoscopy that enable us to radically remove large EACs, and to perform more meticulous follow-up, it might be time to swing the pendulum and only send those patients for surgery who have an indisputable indication for surgery, instead of performing esophagectomy as a prophylactic treatment.”
To truly find the limits of endoscopic resection for EAC, however, more research is needed.
“Ongoing studies are necessary to evaluate the lymph node metastases risk on an individual basis, using presence of histological risk factors. By predicting the risk of lymph node metastases, and considering patients’ wishes and condition, one might decide to perform esophagectomy or watchful waiting with strict endoscopic follow-up. In high-risk cases, we may use sentinel node navigated surgery in the future as an extra safety check before deciding on optimal management,” the authors wrote.
The investigators disclosed relationships Medtronic, C2 Therapeutics/Pentax Medical, MicroTech, and Aqua Medical.
FROM TECHNIQUES AND INNOVATIONS IN GASTROINTESTINAL ENDOSCOPY
An earlier hep B biomarker for clinical outcomes?
Low serum levels of the hepatitis B core-related antigen (HBcrAg) could be an early biomarker of a functional cure of a hepatitis B infection, according to new findings from a retrospective study.
A drop in HBcrAg predicted the seroclearance of hepatitis B surface antigen (HBsAg), the widely accepted measure of optimal liver-related outcomes in patient care and clinical trials, long before HBsAg levels actually fell.
“In a large retrospective cohort study of chronic hepatitis B patients, we found lower levels of HBcrAg were associated with higher probability of clearing HBsAg,” wrote Tai-Chung Tseng and coauthors at National Taiwan University Hospital in Taipei. “Reduction of HBcrAg developed 10 years before decline of HBsAg in patients with high HBsAg levels at baseline.”
Nearly 300 million people worldwide are estimated to be positive for the HBsAg antigen, a marker of active hepatitis B virus (HBV) infection. Chronic HBV puts individuals at greater risk of cirrhosis, hepatocellular carcinoma (HCC), and other liver complications.
Seroclearance of HBsAg is generally regarded as signaling a functional cure, because it is associated with low viral activity and good clinical outcomes. Patients with low HBsAg levels may transition to complete clearance, while those with levels of 1,000 IU/mL or higher rarely achieve clearance either spontaneously or through treatment.
As with HBsAg, higher serum levels of HBcrAg have been linked to a raised risk of adverse events, including increased viral activity and heightened risk of developing hepatitis B e antigen-negative hepatitis, cirrhosis, and HCC. Lower HBcrAg levels are associated with a greater likelihood of HBsAg seroclearance in chronic hepatitis B patients who discontinued antiviral therapy.
In a study published in Gastroenterology, researchers conducted a retrospective Taiwanese cohort study of 2,614 untreated patients with hepatitis B who underwent long-term follow-up at National Taiwan University Hospital. The median age was 38.2 years, and 60.6% were men. At baseline, 14.8% had HBsAg levels of less than 100 IU/mL, and 47.7% had HBcrAg levels less than 10,000 IU/mL. Most (77.5%) were infected with HBV genotype B. From stored serum samples, the researchers quantified levels of HBV DNA, HBsAg, and HBcrAg and evaluated the relationships with spontaneous HBsAg seroclearance.
Over an average follow-up of about 12 years, 465 patients cleared HBsAg, an incidence of 1.43% per year. Researchers stratified patients by levels of viral markers. Compared to those with the highest HBcrAg levels (> 100,000 IU/mL), lower levels of HBcrAg were associated with greater likelihood of HBsAg clearance.
Specifically, intermediate levels (10,000-99,999 IU/mL) were associated with nearly double the chance of HBsAg clearance (hazard ratio [HR], 1.95; 95% confidence interval [CI], 1.44-2.65), and the lowest levels (< 10,000 IU/mL) were associated with just over triple the chance of clearance (HR, 3.15; 95% CI, 2.45-4.05). These associations held up with multivariable analyses, and HBV DNA levels were not significantly associated with HBsAg clearance.
“Not surprisingly, HBsAg levels still serve as a better predictor than the other two biomarkers,” the authors wrote. “Notably, the HBsAg levels are more like a short-term predictor” (within 5 years).
For patients with higher HBsAg levels (> 1,000 IU/mL), it took a median of 16 years to achieve HBsAg clearance. A subanalysis of the 1,539 patients with HbsAg levels > 1,000 IU/mL found that only HBcrAg levels below 10,000 IU/mL predicted HBsAg seroclearance versus 100,000 U/mL or higher (adjusted HR, 1.95; 95% CI, 1.16-3.27).
HBsAg levels began to decline later, often between 5 and 9 years before HBsAg seroclearance occurs. However, HBcrAg levels became undetectable 10-14 years before HBsAg seroclearance. Among patients achieving undetectable levels of HBcrAg, the annual HBsAg seroclearance rate was higher in the second decade of follow-up than in the first decade (3.75% versus 0.97%).
HBcrAg levels reflect the transcriptional activity of covalently closed circular DNA (cccDNA), the authors noted, while HBsAg can come from cccDNA and HBV-DNA integrated into the host genome. Several novel hepatitis B therapies in development target cccDNA transcription, but it isn’t known if the strategy will result in HBsAg clearance.
In the discussion section, the authors speculated about the possible pathology and treatment implications for several chronic hepatitis B scenarios. For example, the finding that HBcrAg clearance usually precedes HBsAg clearance suggests that reduction of cccDNA transcription is a requirement for curing hepatitis B, the authors speculate, but it also suggests that add-on treatment may need to target HBsAg transcribed from the integrated viral genome for a functional cure.
The researchers noted several study limitations, including that the cohort included only Asians largely with HBV genotypes B or C and that “further validation from Caucasian patients infected with genotypes types A or D is mandatory.”
Tai-Chung Tseng disclosed financial conflicts with Fujirebio, Bristol-Myers Squibb, and Gilead Sciences. The remaining authors had no conflicts of interest. The study received grant support from several institutions, including National Taiwan University Hospital.
Current hepatitis B virus (HBV) therapies do not eliminate the covalently closed circular DNA (cccDNA), and a single cccDNA can cause a infection. Hepatitis B core-related antigen (HBcrAg) has shown positive correlation with serum and hepatic HBV-DNA levels and cccDNA even in patients receiving antivirals for HBV. This is demonstrated by Tseng et al., where undetectable levels of HBcrAg predicted seroclearance of HBsAg by 10-14 years. This and past studies have shown HBcrAg to be a good predictor for cccDNA transcriptional activity, allowing health care providers to predict functional loss of HBsAg, flare-ups, treatment response, and when to conclude treatment.
Clinically, HBcrAg could be monitored in chronic HBV infection while patients are receiving treatment. A rise in HBcrAg has the ability to predict HBV flares, while a decrease in HBcrAg can forecast seroclearance of HBsAg. If there is undetectable level of HBsAg with detectable HBcrAg, it can mean the relapse of HBsAg+, and oral treatment could be continued. HBsAg and HBcrAg also can be used to determine when to stop treatment, especially with nucleos(t)ide analogs (NAs). The Mayo Clinic laboratories recently opened HBcrAg testing for patients with chronic HBV.
With emerging medications, HBV cure may be possible with multiple therapies. Hepatic cccDNA turnover may be halted by inhibiting capsid assembly and secretion, relaxed-circular DNA (rcDNA) nuclear delivery or conversion to cccDNA, and formation of viral RNAs. Since HBcrAg is a good indicator of cccDNA transcriptional activity, it should be used to determine the effectiveness of these new therapies in clinical trials.
Katerina Roma, DO, is with the department of internal medicine, Kirk Kerkorian School of Medicine at the University of Nevada, Las Vegas. Robert Gish, MD, is medical director of the Hepatitis B Foundation in Doylestown, Pa. They have no financial conflicts.
Current hepatitis B virus (HBV) therapies do not eliminate the covalently closed circular DNA (cccDNA), and a single cccDNA can cause a infection. Hepatitis B core-related antigen (HBcrAg) has shown positive correlation with serum and hepatic HBV-DNA levels and cccDNA even in patients receiving antivirals for HBV. This is demonstrated by Tseng et al., where undetectable levels of HBcrAg predicted seroclearance of HBsAg by 10-14 years. This and past studies have shown HBcrAg to be a good predictor for cccDNA transcriptional activity, allowing health care providers to predict functional loss of HBsAg, flare-ups, treatment response, and when to conclude treatment.
Clinically, HBcrAg could be monitored in chronic HBV infection while patients are receiving treatment. A rise in HBcrAg has the ability to predict HBV flares, while a decrease in HBcrAg can forecast seroclearance of HBsAg. If there is undetectable level of HBsAg with detectable HBcrAg, it can mean the relapse of HBsAg+, and oral treatment could be continued. HBsAg and HBcrAg also can be used to determine when to stop treatment, especially with nucleos(t)ide analogs (NAs). The Mayo Clinic laboratories recently opened HBcrAg testing for patients with chronic HBV.
With emerging medications, HBV cure may be possible with multiple therapies. Hepatic cccDNA turnover may be halted by inhibiting capsid assembly and secretion, relaxed-circular DNA (rcDNA) nuclear delivery or conversion to cccDNA, and formation of viral RNAs. Since HBcrAg is a good indicator of cccDNA transcriptional activity, it should be used to determine the effectiveness of these new therapies in clinical trials.
Katerina Roma, DO, is with the department of internal medicine, Kirk Kerkorian School of Medicine at the University of Nevada, Las Vegas. Robert Gish, MD, is medical director of the Hepatitis B Foundation in Doylestown, Pa. They have no financial conflicts.
Current hepatitis B virus (HBV) therapies do not eliminate the covalently closed circular DNA (cccDNA), and a single cccDNA can cause a infection. Hepatitis B core-related antigen (HBcrAg) has shown positive correlation with serum and hepatic HBV-DNA levels and cccDNA even in patients receiving antivirals for HBV. This is demonstrated by Tseng et al., where undetectable levels of HBcrAg predicted seroclearance of HBsAg by 10-14 years. This and past studies have shown HBcrAg to be a good predictor for cccDNA transcriptional activity, allowing health care providers to predict functional loss of HBsAg, flare-ups, treatment response, and when to conclude treatment.
Clinically, HBcrAg could be monitored in chronic HBV infection while patients are receiving treatment. A rise in HBcrAg has the ability to predict HBV flares, while a decrease in HBcrAg can forecast seroclearance of HBsAg. If there is undetectable level of HBsAg with detectable HBcrAg, it can mean the relapse of HBsAg+, and oral treatment could be continued. HBsAg and HBcrAg also can be used to determine when to stop treatment, especially with nucleos(t)ide analogs (NAs). The Mayo Clinic laboratories recently opened HBcrAg testing for patients with chronic HBV.
With emerging medications, HBV cure may be possible with multiple therapies. Hepatic cccDNA turnover may be halted by inhibiting capsid assembly and secretion, relaxed-circular DNA (rcDNA) nuclear delivery or conversion to cccDNA, and formation of viral RNAs. Since HBcrAg is a good indicator of cccDNA transcriptional activity, it should be used to determine the effectiveness of these new therapies in clinical trials.
Katerina Roma, DO, is with the department of internal medicine, Kirk Kerkorian School of Medicine at the University of Nevada, Las Vegas. Robert Gish, MD, is medical director of the Hepatitis B Foundation in Doylestown, Pa. They have no financial conflicts.
Low serum levels of the hepatitis B core-related antigen (HBcrAg) could be an early biomarker of a functional cure of a hepatitis B infection, according to new findings from a retrospective study.
A drop in HBcrAg predicted the seroclearance of hepatitis B surface antigen (HBsAg), the widely accepted measure of optimal liver-related outcomes in patient care and clinical trials, long before HBsAg levels actually fell.
“In a large retrospective cohort study of chronic hepatitis B patients, we found lower levels of HBcrAg were associated with higher probability of clearing HBsAg,” wrote Tai-Chung Tseng and coauthors at National Taiwan University Hospital in Taipei. “Reduction of HBcrAg developed 10 years before decline of HBsAg in patients with high HBsAg levels at baseline.”
Nearly 300 million people worldwide are estimated to be positive for the HBsAg antigen, a marker of active hepatitis B virus (HBV) infection. Chronic HBV puts individuals at greater risk of cirrhosis, hepatocellular carcinoma (HCC), and other liver complications.
Seroclearance of HBsAg is generally regarded as signaling a functional cure, because it is associated with low viral activity and good clinical outcomes. Patients with low HBsAg levels may transition to complete clearance, while those with levels of 1,000 IU/mL or higher rarely achieve clearance either spontaneously or through treatment.
As with HBsAg, higher serum levels of HBcrAg have been linked to a raised risk of adverse events, including increased viral activity and heightened risk of developing hepatitis B e antigen-negative hepatitis, cirrhosis, and HCC. Lower HBcrAg levels are associated with a greater likelihood of HBsAg seroclearance in chronic hepatitis B patients who discontinued antiviral therapy.
In a study published in Gastroenterology, researchers conducted a retrospective Taiwanese cohort study of 2,614 untreated patients with hepatitis B who underwent long-term follow-up at National Taiwan University Hospital. The median age was 38.2 years, and 60.6% were men. At baseline, 14.8% had HBsAg levels of less than 100 IU/mL, and 47.7% had HBcrAg levels less than 10,000 IU/mL. Most (77.5%) were infected with HBV genotype B. From stored serum samples, the researchers quantified levels of HBV DNA, HBsAg, and HBcrAg and evaluated the relationships with spontaneous HBsAg seroclearance.
Over an average follow-up of about 12 years, 465 patients cleared HBsAg, an incidence of 1.43% per year. Researchers stratified patients by levels of viral markers. Compared to those with the highest HBcrAg levels (> 100,000 IU/mL), lower levels of HBcrAg were associated with greater likelihood of HBsAg clearance.
Specifically, intermediate levels (10,000-99,999 IU/mL) were associated with nearly double the chance of HBsAg clearance (hazard ratio [HR], 1.95; 95% confidence interval [CI], 1.44-2.65), and the lowest levels (< 10,000 IU/mL) were associated with just over triple the chance of clearance (HR, 3.15; 95% CI, 2.45-4.05). These associations held up with multivariable analyses, and HBV DNA levels were not significantly associated with HBsAg clearance.
“Not surprisingly, HBsAg levels still serve as a better predictor than the other two biomarkers,” the authors wrote. “Notably, the HBsAg levels are more like a short-term predictor” (within 5 years).
For patients with higher HBsAg levels (> 1,000 IU/mL), it took a median of 16 years to achieve HBsAg clearance. A subanalysis of the 1,539 patients with HbsAg levels > 1,000 IU/mL found that only HBcrAg levels below 10,000 IU/mL predicted HBsAg seroclearance versus 100,000 U/mL or higher (adjusted HR, 1.95; 95% CI, 1.16-3.27).
HBsAg levels began to decline later, often between 5 and 9 years before HBsAg seroclearance occurs. However, HBcrAg levels became undetectable 10-14 years before HBsAg seroclearance. Among patients achieving undetectable levels of HBcrAg, the annual HBsAg seroclearance rate was higher in the second decade of follow-up than in the first decade (3.75% versus 0.97%).
HBcrAg levels reflect the transcriptional activity of covalently closed circular DNA (cccDNA), the authors noted, while HBsAg can come from cccDNA and HBV-DNA integrated into the host genome. Several novel hepatitis B therapies in development target cccDNA transcription, but it isn’t known if the strategy will result in HBsAg clearance.
In the discussion section, the authors speculated about the possible pathology and treatment implications for several chronic hepatitis B scenarios. For example, the finding that HBcrAg clearance usually precedes HBsAg clearance suggests that reduction of cccDNA transcription is a requirement for curing hepatitis B, the authors speculate, but it also suggests that add-on treatment may need to target HBsAg transcribed from the integrated viral genome for a functional cure.
The researchers noted several study limitations, including that the cohort included only Asians largely with HBV genotypes B or C and that “further validation from Caucasian patients infected with genotypes types A or D is mandatory.”
Tai-Chung Tseng disclosed financial conflicts with Fujirebio, Bristol-Myers Squibb, and Gilead Sciences. The remaining authors had no conflicts of interest. The study received grant support from several institutions, including National Taiwan University Hospital.
Low serum levels of the hepatitis B core-related antigen (HBcrAg) could be an early biomarker of a functional cure of a hepatitis B infection, according to new findings from a retrospective study.
A drop in HBcrAg predicted the seroclearance of hepatitis B surface antigen (HBsAg), the widely accepted measure of optimal liver-related outcomes in patient care and clinical trials, long before HBsAg levels actually fell.
“In a large retrospective cohort study of chronic hepatitis B patients, we found lower levels of HBcrAg were associated with higher probability of clearing HBsAg,” wrote Tai-Chung Tseng and coauthors at National Taiwan University Hospital in Taipei. “Reduction of HBcrAg developed 10 years before decline of HBsAg in patients with high HBsAg levels at baseline.”
Nearly 300 million people worldwide are estimated to be positive for the HBsAg antigen, a marker of active hepatitis B virus (HBV) infection. Chronic HBV puts individuals at greater risk of cirrhosis, hepatocellular carcinoma (HCC), and other liver complications.
Seroclearance of HBsAg is generally regarded as signaling a functional cure, because it is associated with low viral activity and good clinical outcomes. Patients with low HBsAg levels may transition to complete clearance, while those with levels of 1,000 IU/mL or higher rarely achieve clearance either spontaneously or through treatment.
As with HBsAg, higher serum levels of HBcrAg have been linked to a raised risk of adverse events, including increased viral activity and heightened risk of developing hepatitis B e antigen-negative hepatitis, cirrhosis, and HCC. Lower HBcrAg levels are associated with a greater likelihood of HBsAg seroclearance in chronic hepatitis B patients who discontinued antiviral therapy.
In a study published in Gastroenterology, researchers conducted a retrospective Taiwanese cohort study of 2,614 untreated patients with hepatitis B who underwent long-term follow-up at National Taiwan University Hospital. The median age was 38.2 years, and 60.6% were men. At baseline, 14.8% had HBsAg levels of less than 100 IU/mL, and 47.7% had HBcrAg levels less than 10,000 IU/mL. Most (77.5%) were infected with HBV genotype B. From stored serum samples, the researchers quantified levels of HBV DNA, HBsAg, and HBcrAg and evaluated the relationships with spontaneous HBsAg seroclearance.
Over an average follow-up of about 12 years, 465 patients cleared HBsAg, an incidence of 1.43% per year. Researchers stratified patients by levels of viral markers. Compared to those with the highest HBcrAg levels (> 100,000 IU/mL), lower levels of HBcrAg were associated with greater likelihood of HBsAg clearance.
Specifically, intermediate levels (10,000-99,999 IU/mL) were associated with nearly double the chance of HBsAg clearance (hazard ratio [HR], 1.95; 95% confidence interval [CI], 1.44-2.65), and the lowest levels (< 10,000 IU/mL) were associated with just over triple the chance of clearance (HR, 3.15; 95% CI, 2.45-4.05). These associations held up with multivariable analyses, and HBV DNA levels were not significantly associated with HBsAg clearance.
“Not surprisingly, HBsAg levels still serve as a better predictor than the other two biomarkers,” the authors wrote. “Notably, the HBsAg levels are more like a short-term predictor” (within 5 years).
For patients with higher HBsAg levels (> 1,000 IU/mL), it took a median of 16 years to achieve HBsAg clearance. A subanalysis of the 1,539 patients with HbsAg levels > 1,000 IU/mL found that only HBcrAg levels below 10,000 IU/mL predicted HBsAg seroclearance versus 100,000 U/mL or higher (adjusted HR, 1.95; 95% CI, 1.16-3.27).
HBsAg levels began to decline later, often between 5 and 9 years before HBsAg seroclearance occurs. However, HBcrAg levels became undetectable 10-14 years before HBsAg seroclearance. Among patients achieving undetectable levels of HBcrAg, the annual HBsAg seroclearance rate was higher in the second decade of follow-up than in the first decade (3.75% versus 0.97%).
HBcrAg levels reflect the transcriptional activity of covalently closed circular DNA (cccDNA), the authors noted, while HBsAg can come from cccDNA and HBV-DNA integrated into the host genome. Several novel hepatitis B therapies in development target cccDNA transcription, but it isn’t known if the strategy will result in HBsAg clearance.
In the discussion section, the authors speculated about the possible pathology and treatment implications for several chronic hepatitis B scenarios. For example, the finding that HBcrAg clearance usually precedes HBsAg clearance suggests that reduction of cccDNA transcription is a requirement for curing hepatitis B, the authors speculate, but it also suggests that add-on treatment may need to target HBsAg transcribed from the integrated viral genome for a functional cure.
The researchers noted several study limitations, including that the cohort included only Asians largely with HBV genotypes B or C and that “further validation from Caucasian patients infected with genotypes types A or D is mandatory.”
Tai-Chung Tseng disclosed financial conflicts with Fujirebio, Bristol-Myers Squibb, and Gilead Sciences. The remaining authors had no conflicts of interest. The study received grant support from several institutions, including National Taiwan University Hospital.
FROM GASTROENTEROLOGY
Celiac disease appears to double COVID-19 hospitalization risk
, a single-center U.S. study shows.
Vaccination against COVID-19 reduced the risk for hospitalization by almost half for both groups, however, the study finds.
“To our knowledge this is the first study that demonstrated a vaccination effect on mitigation of the risk of hospitalization in celiac disease patients with COVID-19 infection,” write Alberto Rubio-Tapia, MD, director, Celiac Disease Program, Digestive Disease and Surgery Institute, Cleveland Clinic Foundation, and colleagues.
Despite the increased risk for hospitalization among patients with celiac disease, there were no significant differences between those with and without the condition with respect to intensive care unit requirement, mortality, or thrombosis, the researchers found.
The findings suggest that celiac disease patients with COVID-19 are “not inherently at greater risk for more severe outcomes,” they wrote.
The study was published online in Clinical Gastroenterology and Hepatology.
Comparing outcomes
Although it has been shown that patients with celiac disease have increased susceptibility to viral illnesses, research to date has found similar COVID-19 incidence and outcomes, including hospitalization, between patients with celiac disease and the general population, the researchers wrote.
However, the impact of COVID-19 vaccination is less clear, so the researchers set out to compare the frequency of COVID-19–related outcomes between patients with and without celiac disease before and after vaccination.
Through an analysis of patient medical records, researchers found 171,763 patients diagnosed and treated for COVID-19 at their institution between March 1, 2020, and Jan 1, 2022. Of them, 110 adults had biopsy-proven celiac disease.
The median time from biopsy diagnosis of celiac disease to COVID-19 was 217 months, 66.3% of patients were documented to be following a gluten-free diet, and tissue transglutaminase IgA was positive in 46.2% at the time of COVID-19.
The celiac group was matched by age, ethnicity, sex, and date of COVID-19 diagnosis with a control group of 220 adults without a clinical diagnosis of celiac disease. The two cohorts had similar rates of comorbid obesity, type 2 diabetes, preexisting lung disease, and tobacco use.
Patients with celiac disease were significantly more likely to be hospitalized for COVID-19 than were the control participants, at 24% vs. 11% (hazard ratio, 2.1; P = .009), the researchers wrote.
However, hospitalized patients with celiac disease were less likely to require supplementary oxygen than were the control participants, at 63% vs. 84%.
Vaccination rates for COVID-19 were similar between the two groups, at 64.5% among patients with celiac disease and 70% in the control group. Vaccination was associated with a lower risk for hospitalization on multivariate analysis (HR, 0.53; P = .026).
There was no significant difference in hospitalization rates between vaccinated patients with celiac disease and vaccinated patients in the control group (odds ratio, 1.12; P = .79), the team reported.
The secondary outcomes of ICU requirement, mortality, and thrombosis were minimal in both groups, the researchers wrote.
Vaccination’s importance
The different findings regarding hospitalization risk among patients with celiac disease between this study and previous research are likely due to earlier studies not accounting for vaccination status, the researchers wrote.
“This study shows significantly different rates of hospitalization among patients with [celiac disease] depending on their vaccination status, with strong evidence for mitigation of hospitalization risk through vaccination,” they added.
“Vaccination against COVID-19 should be strongly recommended in patients with celiac disease,” the researchers concluded.
No funding was declared. Dr. Rubio-Tapia reported a relationship with Takeda. No other financial relationships were declared.
A version of this article first appeared on Medscape.com.
AGA offers guidance on celiac disease to help patients maintain a gluten-free diet in the AGA GI Patient Center: www.gastro.org/celiac .
, a single-center U.S. study shows.
Vaccination against COVID-19 reduced the risk for hospitalization by almost half for both groups, however, the study finds.
“To our knowledge this is the first study that demonstrated a vaccination effect on mitigation of the risk of hospitalization in celiac disease patients with COVID-19 infection,” write Alberto Rubio-Tapia, MD, director, Celiac Disease Program, Digestive Disease and Surgery Institute, Cleveland Clinic Foundation, and colleagues.
Despite the increased risk for hospitalization among patients with celiac disease, there were no significant differences between those with and without the condition with respect to intensive care unit requirement, mortality, or thrombosis, the researchers found.
The findings suggest that celiac disease patients with COVID-19 are “not inherently at greater risk for more severe outcomes,” they wrote.
The study was published online in Clinical Gastroenterology and Hepatology.
Comparing outcomes
Although it has been shown that patients with celiac disease have increased susceptibility to viral illnesses, research to date has found similar COVID-19 incidence and outcomes, including hospitalization, between patients with celiac disease and the general population, the researchers wrote.
However, the impact of COVID-19 vaccination is less clear, so the researchers set out to compare the frequency of COVID-19–related outcomes between patients with and without celiac disease before and after vaccination.
Through an analysis of patient medical records, researchers found 171,763 patients diagnosed and treated for COVID-19 at their institution between March 1, 2020, and Jan 1, 2022. Of them, 110 adults had biopsy-proven celiac disease.
The median time from biopsy diagnosis of celiac disease to COVID-19 was 217 months, 66.3% of patients were documented to be following a gluten-free diet, and tissue transglutaminase IgA was positive in 46.2% at the time of COVID-19.
The celiac group was matched by age, ethnicity, sex, and date of COVID-19 diagnosis with a control group of 220 adults without a clinical diagnosis of celiac disease. The two cohorts had similar rates of comorbid obesity, type 2 diabetes, preexisting lung disease, and tobacco use.
Patients with celiac disease were significantly more likely to be hospitalized for COVID-19 than were the control participants, at 24% vs. 11% (hazard ratio, 2.1; P = .009), the researchers wrote.
However, hospitalized patients with celiac disease were less likely to require supplementary oxygen than were the control participants, at 63% vs. 84%.
Vaccination rates for COVID-19 were similar between the two groups, at 64.5% among patients with celiac disease and 70% in the control group. Vaccination was associated with a lower risk for hospitalization on multivariate analysis (HR, 0.53; P = .026).
There was no significant difference in hospitalization rates between vaccinated patients with celiac disease and vaccinated patients in the control group (odds ratio, 1.12; P = .79), the team reported.
The secondary outcomes of ICU requirement, mortality, and thrombosis were minimal in both groups, the researchers wrote.
Vaccination’s importance
The different findings regarding hospitalization risk among patients with celiac disease between this study and previous research are likely due to earlier studies not accounting for vaccination status, the researchers wrote.
“This study shows significantly different rates of hospitalization among patients with [celiac disease] depending on their vaccination status, with strong evidence for mitigation of hospitalization risk through vaccination,” they added.
“Vaccination against COVID-19 should be strongly recommended in patients with celiac disease,” the researchers concluded.
No funding was declared. Dr. Rubio-Tapia reported a relationship with Takeda. No other financial relationships were declared.
A version of this article first appeared on Medscape.com.
AGA offers guidance on celiac disease to help patients maintain a gluten-free diet in the AGA GI Patient Center: www.gastro.org/celiac .
, a single-center U.S. study shows.
Vaccination against COVID-19 reduced the risk for hospitalization by almost half for both groups, however, the study finds.
“To our knowledge this is the first study that demonstrated a vaccination effect on mitigation of the risk of hospitalization in celiac disease patients with COVID-19 infection,” write Alberto Rubio-Tapia, MD, director, Celiac Disease Program, Digestive Disease and Surgery Institute, Cleveland Clinic Foundation, and colleagues.
Despite the increased risk for hospitalization among patients with celiac disease, there were no significant differences between those with and without the condition with respect to intensive care unit requirement, mortality, or thrombosis, the researchers found.
The findings suggest that celiac disease patients with COVID-19 are “not inherently at greater risk for more severe outcomes,” they wrote.
The study was published online in Clinical Gastroenterology and Hepatology.
Comparing outcomes
Although it has been shown that patients with celiac disease have increased susceptibility to viral illnesses, research to date has found similar COVID-19 incidence and outcomes, including hospitalization, between patients with celiac disease and the general population, the researchers wrote.
However, the impact of COVID-19 vaccination is less clear, so the researchers set out to compare the frequency of COVID-19–related outcomes between patients with and without celiac disease before and after vaccination.
Through an analysis of patient medical records, researchers found 171,763 patients diagnosed and treated for COVID-19 at their institution between March 1, 2020, and Jan 1, 2022. Of them, 110 adults had biopsy-proven celiac disease.
The median time from biopsy diagnosis of celiac disease to COVID-19 was 217 months, 66.3% of patients were documented to be following a gluten-free diet, and tissue transglutaminase IgA was positive in 46.2% at the time of COVID-19.
The celiac group was matched by age, ethnicity, sex, and date of COVID-19 diagnosis with a control group of 220 adults without a clinical diagnosis of celiac disease. The two cohorts had similar rates of comorbid obesity, type 2 diabetes, preexisting lung disease, and tobacco use.
Patients with celiac disease were significantly more likely to be hospitalized for COVID-19 than were the control participants, at 24% vs. 11% (hazard ratio, 2.1; P = .009), the researchers wrote.
However, hospitalized patients with celiac disease were less likely to require supplementary oxygen than were the control participants, at 63% vs. 84%.
Vaccination rates for COVID-19 were similar between the two groups, at 64.5% among patients with celiac disease and 70% in the control group. Vaccination was associated with a lower risk for hospitalization on multivariate analysis (HR, 0.53; P = .026).
There was no significant difference in hospitalization rates between vaccinated patients with celiac disease and vaccinated patients in the control group (odds ratio, 1.12; P = .79), the team reported.
The secondary outcomes of ICU requirement, mortality, and thrombosis were minimal in both groups, the researchers wrote.
Vaccination’s importance
The different findings regarding hospitalization risk among patients with celiac disease between this study and previous research are likely due to earlier studies not accounting for vaccination status, the researchers wrote.
“This study shows significantly different rates of hospitalization among patients with [celiac disease] depending on their vaccination status, with strong evidence for mitigation of hospitalization risk through vaccination,” they added.
“Vaccination against COVID-19 should be strongly recommended in patients with celiac disease,” the researchers concluded.
No funding was declared. Dr. Rubio-Tapia reported a relationship with Takeda. No other financial relationships were declared.
A version of this article first appeared on Medscape.com.
AGA offers guidance on celiac disease to help patients maintain a gluten-free diet in the AGA GI Patient Center: www.gastro.org/celiac .
FROM CLINICAL GASTROENTEROLOGY AND HEPATOLOGY
AGA clinical practice update: Telemedicine in gastroenterology
moving forward, according to a new clinical practice update from the American Gastroenterological Association.
The postpandemic era must balance patient and provider preferences, medical needs, quality of care, regulatory requirements, and reimbursement rules, Ziad Gellad, MD, associate professor of medicine in the gastroenterology division at Duke University, Durham, N.C., and colleagues wrote.
“Spurred by the COVID-19 pandemic, telehealth, and specifically telemedicine, has become an integral part of outpatient gastrointestinal care in the United States,” the authors wrote.
Dr. Gellad and colleagues penned a clinical practice update based on recently published studies and the experiences of the authors, who are active gastroenterologists and hepatologists with extensive experience using telemedicine in clinical practice.
First, the group addressed patient preferences for telemedicine in gastroenterology based on emerging data. During the past 2 years, studies in both the United States and Australia found that most patients voiced ongoing interest and willingness to use video visits, as well as satisfaction with their medical concerns being addressed via telemedicine. They also reported significantly decreased absenteeism, as compared with face-to-face visits.
At the same time, patient preferences may vary based on age, race, and other factors. For instance, younger adults, those with higher incomes, and Hispanic and Latino patients appear to be more likely to prefer video visits than older adults, those with lower incomes, and White or Black patients. In gastroenterology, specific telemedicine studies, especially among patients with inflammatory bowel disease (IBD) or chronic liver disease, older patients, Black patients, and those with Medicaid or Medicare insurance were more likely to complete a phone-based visit rather than a video visit.
Even still, barriers exist for some patients, which should be recognized, the authors wrote. Studies have found racial and socioeconomic disparities in accessing telemedicine, including video visits. When possible, ambulatory practices, institutions, and health systems should provide technical solutions and individual support to help patients overcome these barriers.
So far, telemedicine appears to be better suited for stable chronic conditions rather than acute illnesses, which are more likely to require a follow-up in-person visit or ED care. At the gastrointestinal level, patients being evaluated for liver transplantation via telemedicine had a reduced time from referral to evaluation by a hepatologist and to transplant listing, and liver transplant recipients had lower readmission rates, improved physical function, and better general health. Among studies of IBD patients, telemedicine led to similar quality of care metrics and higher IBD-specific quality of life.
At this time, decisions about using telemedicine for patients with digestive diseases remain nuanced, the authors wrote. In general, those with stable conditions, such as gastroesophageal reflux, irritable bowel syndrome, IBD, chronic constipation, chronic liver disease, and chronic pancreatitis, appear to be good candidates for telemedicine. Patients who are considering a change in therapy and wish to schedule a visit for additional information may also use telemedicine.
In addition, those who live in remote areas could be appropriate candidates for telemedicine as long as they have access, particularly for video visits. Among these patients, studies have shown that telemedicine can be appropriate for patients with IBD and the transition of care from pediatric to adult gastroenterologists. Ultimately, the decision depends on several factors, including the practice setting, geography, and complexity of care.
Many times, the main barrier to virtual care is the regulatory requirement to be licensed in the state where the patient lives. Although these requirements were eased during the COVID-19 pandemic, many restrictions have now returned in most states. Some practices may now support their clinicians in obtaining licenses for surrounding states, but ultimately, some regulatory compromise will be needed to continue multistate telemedicine without additional licensure, the authors wrote.
Reimbursement rules have also remained a barrier. Despite some changes during the pandemic, reimbursement will likely shift in the future, and additional documentation requirements are suggested. For instance, it’s important to document patient consent to telemedicine, the method of telemedicine (whether a secure two-way interactive video or phone call), patient location, provider location, a listing of all clinical participants’ roles and actions, and other individuals (such as trainees) present at the visit.
Finally, the clinical workflow for telemedicine should include a few additional steps, the authors wrote. Office staff should connect with patients before the visit to address any technical issues and ensure a proper connection, set up any assistive services such as an interpreter, complete previsit questionnaires via secure messaging, and conduct standard practices such as medication review. Postvisit instructions should then be sent through a secure portal or mail.
Moving forward, additional studies are needed to verify long-term outcomes associated with telemedicine, as well as the optimal ratio of in-person versus telemedicine visits for various disease states, the authors wrote.
“Telemedicine is accepted by both patients and providers, and is associated with certain key advantages, including reducing patient travel time and cost and work absenteeism,” they wrote. However, “gastroenterology providers need to be cognizant of certain patient and illness barriers to telemedicine and adhere to best practices to ensure high-quality gastrointestinal virtual care.”
The clinical practice update received no funding support. Dr. Gellad disclosed financial relationships with Higgs Boson, Inc.; Merck & Co; and Novo Nordisk. Author Seth Crockett is a consultant for IngenioRx and has received research funding from Freenome, Guardant, and Exact Sciences. Raymond Cross disclosed financial relationships with AbbvVie, BMS, Fzata, Janssen, Magellan Health, Pfizer, and Takeda and has received support from the Crohn's and Colitis Foundation, IBD Education Group, and CorEvitas.
moving forward, according to a new clinical practice update from the American Gastroenterological Association.
The postpandemic era must balance patient and provider preferences, medical needs, quality of care, regulatory requirements, and reimbursement rules, Ziad Gellad, MD, associate professor of medicine in the gastroenterology division at Duke University, Durham, N.C., and colleagues wrote.
“Spurred by the COVID-19 pandemic, telehealth, and specifically telemedicine, has become an integral part of outpatient gastrointestinal care in the United States,” the authors wrote.
Dr. Gellad and colleagues penned a clinical practice update based on recently published studies and the experiences of the authors, who are active gastroenterologists and hepatologists with extensive experience using telemedicine in clinical practice.
First, the group addressed patient preferences for telemedicine in gastroenterology based on emerging data. During the past 2 years, studies in both the United States and Australia found that most patients voiced ongoing interest and willingness to use video visits, as well as satisfaction with their medical concerns being addressed via telemedicine. They also reported significantly decreased absenteeism, as compared with face-to-face visits.
At the same time, patient preferences may vary based on age, race, and other factors. For instance, younger adults, those with higher incomes, and Hispanic and Latino patients appear to be more likely to prefer video visits than older adults, those with lower incomes, and White or Black patients. In gastroenterology, specific telemedicine studies, especially among patients with inflammatory bowel disease (IBD) or chronic liver disease, older patients, Black patients, and those with Medicaid or Medicare insurance were more likely to complete a phone-based visit rather than a video visit.
Even still, barriers exist for some patients, which should be recognized, the authors wrote. Studies have found racial and socioeconomic disparities in accessing telemedicine, including video visits. When possible, ambulatory practices, institutions, and health systems should provide technical solutions and individual support to help patients overcome these barriers.
So far, telemedicine appears to be better suited for stable chronic conditions rather than acute illnesses, which are more likely to require a follow-up in-person visit or ED care. At the gastrointestinal level, patients being evaluated for liver transplantation via telemedicine had a reduced time from referral to evaluation by a hepatologist and to transplant listing, and liver transplant recipients had lower readmission rates, improved physical function, and better general health. Among studies of IBD patients, telemedicine led to similar quality of care metrics and higher IBD-specific quality of life.
At this time, decisions about using telemedicine for patients with digestive diseases remain nuanced, the authors wrote. In general, those with stable conditions, such as gastroesophageal reflux, irritable bowel syndrome, IBD, chronic constipation, chronic liver disease, and chronic pancreatitis, appear to be good candidates for telemedicine. Patients who are considering a change in therapy and wish to schedule a visit for additional information may also use telemedicine.
In addition, those who live in remote areas could be appropriate candidates for telemedicine as long as they have access, particularly for video visits. Among these patients, studies have shown that telemedicine can be appropriate for patients with IBD and the transition of care from pediatric to adult gastroenterologists. Ultimately, the decision depends on several factors, including the practice setting, geography, and complexity of care.
Many times, the main barrier to virtual care is the regulatory requirement to be licensed in the state where the patient lives. Although these requirements were eased during the COVID-19 pandemic, many restrictions have now returned in most states. Some practices may now support their clinicians in obtaining licenses for surrounding states, but ultimately, some regulatory compromise will be needed to continue multistate telemedicine without additional licensure, the authors wrote.
Reimbursement rules have also remained a barrier. Despite some changes during the pandemic, reimbursement will likely shift in the future, and additional documentation requirements are suggested. For instance, it’s important to document patient consent to telemedicine, the method of telemedicine (whether a secure two-way interactive video or phone call), patient location, provider location, a listing of all clinical participants’ roles and actions, and other individuals (such as trainees) present at the visit.
Finally, the clinical workflow for telemedicine should include a few additional steps, the authors wrote. Office staff should connect with patients before the visit to address any technical issues and ensure a proper connection, set up any assistive services such as an interpreter, complete previsit questionnaires via secure messaging, and conduct standard practices such as medication review. Postvisit instructions should then be sent through a secure portal or mail.
Moving forward, additional studies are needed to verify long-term outcomes associated with telemedicine, as well as the optimal ratio of in-person versus telemedicine visits for various disease states, the authors wrote.
“Telemedicine is accepted by both patients and providers, and is associated with certain key advantages, including reducing patient travel time and cost and work absenteeism,” they wrote. However, “gastroenterology providers need to be cognizant of certain patient and illness barriers to telemedicine and adhere to best practices to ensure high-quality gastrointestinal virtual care.”
The clinical practice update received no funding support. Dr. Gellad disclosed financial relationships with Higgs Boson, Inc.; Merck & Co; and Novo Nordisk. Author Seth Crockett is a consultant for IngenioRx and has received research funding from Freenome, Guardant, and Exact Sciences. Raymond Cross disclosed financial relationships with AbbvVie, BMS, Fzata, Janssen, Magellan Health, Pfizer, and Takeda and has received support from the Crohn's and Colitis Foundation, IBD Education Group, and CorEvitas.
moving forward, according to a new clinical practice update from the American Gastroenterological Association.
The postpandemic era must balance patient and provider preferences, medical needs, quality of care, regulatory requirements, and reimbursement rules, Ziad Gellad, MD, associate professor of medicine in the gastroenterology division at Duke University, Durham, N.C., and colleagues wrote.
“Spurred by the COVID-19 pandemic, telehealth, and specifically telemedicine, has become an integral part of outpatient gastrointestinal care in the United States,” the authors wrote.
Dr. Gellad and colleagues penned a clinical practice update based on recently published studies and the experiences of the authors, who are active gastroenterologists and hepatologists with extensive experience using telemedicine in clinical practice.
First, the group addressed patient preferences for telemedicine in gastroenterology based on emerging data. During the past 2 years, studies in both the United States and Australia found that most patients voiced ongoing interest and willingness to use video visits, as well as satisfaction with their medical concerns being addressed via telemedicine. They also reported significantly decreased absenteeism, as compared with face-to-face visits.
At the same time, patient preferences may vary based on age, race, and other factors. For instance, younger adults, those with higher incomes, and Hispanic and Latino patients appear to be more likely to prefer video visits than older adults, those with lower incomes, and White or Black patients. In gastroenterology, specific telemedicine studies, especially among patients with inflammatory bowel disease (IBD) or chronic liver disease, older patients, Black patients, and those with Medicaid or Medicare insurance were more likely to complete a phone-based visit rather than a video visit.
Even still, barriers exist for some patients, which should be recognized, the authors wrote. Studies have found racial and socioeconomic disparities in accessing telemedicine, including video visits. When possible, ambulatory practices, institutions, and health systems should provide technical solutions and individual support to help patients overcome these barriers.
So far, telemedicine appears to be better suited for stable chronic conditions rather than acute illnesses, which are more likely to require a follow-up in-person visit or ED care. At the gastrointestinal level, patients being evaluated for liver transplantation via telemedicine had a reduced time from referral to evaluation by a hepatologist and to transplant listing, and liver transplant recipients had lower readmission rates, improved physical function, and better general health. Among studies of IBD patients, telemedicine led to similar quality of care metrics and higher IBD-specific quality of life.
At this time, decisions about using telemedicine for patients with digestive diseases remain nuanced, the authors wrote. In general, those with stable conditions, such as gastroesophageal reflux, irritable bowel syndrome, IBD, chronic constipation, chronic liver disease, and chronic pancreatitis, appear to be good candidates for telemedicine. Patients who are considering a change in therapy and wish to schedule a visit for additional information may also use telemedicine.
In addition, those who live in remote areas could be appropriate candidates for telemedicine as long as they have access, particularly for video visits. Among these patients, studies have shown that telemedicine can be appropriate for patients with IBD and the transition of care from pediatric to adult gastroenterologists. Ultimately, the decision depends on several factors, including the practice setting, geography, and complexity of care.
Many times, the main barrier to virtual care is the regulatory requirement to be licensed in the state where the patient lives. Although these requirements were eased during the COVID-19 pandemic, many restrictions have now returned in most states. Some practices may now support their clinicians in obtaining licenses for surrounding states, but ultimately, some regulatory compromise will be needed to continue multistate telemedicine without additional licensure, the authors wrote.
Reimbursement rules have also remained a barrier. Despite some changes during the pandemic, reimbursement will likely shift in the future, and additional documentation requirements are suggested. For instance, it’s important to document patient consent to telemedicine, the method of telemedicine (whether a secure two-way interactive video or phone call), patient location, provider location, a listing of all clinical participants’ roles and actions, and other individuals (such as trainees) present at the visit.
Finally, the clinical workflow for telemedicine should include a few additional steps, the authors wrote. Office staff should connect with patients before the visit to address any technical issues and ensure a proper connection, set up any assistive services such as an interpreter, complete previsit questionnaires via secure messaging, and conduct standard practices such as medication review. Postvisit instructions should then be sent through a secure portal or mail.
Moving forward, additional studies are needed to verify long-term outcomes associated with telemedicine, as well as the optimal ratio of in-person versus telemedicine visits for various disease states, the authors wrote.
“Telemedicine is accepted by both patients and providers, and is associated with certain key advantages, including reducing patient travel time and cost and work absenteeism,” they wrote. However, “gastroenterology providers need to be cognizant of certain patient and illness barriers to telemedicine and adhere to best practices to ensure high-quality gastrointestinal virtual care.”
The clinical practice update received no funding support. Dr. Gellad disclosed financial relationships with Higgs Boson, Inc.; Merck & Co; and Novo Nordisk. Author Seth Crockett is a consultant for IngenioRx and has received research funding from Freenome, Guardant, and Exact Sciences. Raymond Cross disclosed financial relationships with AbbvVie, BMS, Fzata, Janssen, Magellan Health, Pfizer, and Takeda and has received support from the Crohn's and Colitis Foundation, IBD Education Group, and CorEvitas.
FROM GASTROENTEROLOGY
Mortality increases substantially with fibrosis stage in NAFLD
The risks of all-cause and liver-related mortality increase substantially based on fibrosis stage in biopsy-confirmed nonalcoholic fatty liver disease (NAFLD), according to a study published in Clinical Gastroenterology and Hepatology.
In particular, patients with NAFLD and advanced fibrosis have a threefold higher risk of all-cause mortality and 10-fold higher risk of liver-related mortality, as compared with patients with NAFLD but not advanced fibrosis, Cheng Han Ng, with the National University of Singapore, and colleagues wrote.
they wrote. “In addition, these findings have important implications for clinical trial design and highlight the importance of developing therapeutics.”
Although previous studies have found higher risks of all-cause and liver-related mortality in patients with NAFLD with increasing fibrosis stages, they examined the risk of mortality in reference to stage 0 fibrosis and didn’t include comparisons across different stages of fibrosis. In addition, the studies typically used pooled risk ratios, didn’t account for time-to-event analysis, or incorporate the most recent data.
The study investigators conducted an updated time-to-event meta-analysis to understand the impact of fibrosis stage on all-cause and liver-related mortality in biopsy-confirmed NAFLD. In addition, they pooled the survival estimates of individual fibrosis stages based on reconstructed individual patient data and compared mortality between fibrosis stages.
In 14 included studies, 17,301 patients had biopsy-proven NAFLD, including 6,069 assessed for overall mortality and 3,421 for liver-related mortality. The studies were conducted in the United States, Canada, Sweden, Israel, Japan, and Hong Kong, with four multicenter studies across multiple regions. The median follow-up duration was 7.7 years, and the average age of patients was 50.5.
For nonadvanced fibrosis (F0-F2), the 1-, 3-, 5-, 8-, and 10-year all-cause mortality were 0.1%, 1.9%, 3.3%, 6%, and 7.7%, respectively. For clinically significant fibrosis (F2-F4), the rates were 0.3%, 8.4%, 14%, 23.7%, and 29.3%, respectively. For advanced fibrosis (F3-F4), the rates were 0.3%, 8.8%, 14.9%, 25.5%, and 32.2%, respectively. For cirrhosis (F4), the rates were 0.3%, 13%, 20.6%, 33.3%, and 41.5%, respectively.
Compared with F0 as a reference, there were no statistically significant differences in all-cause mortality for F1. However, the risk significantly increased for F2 (HR, 1.46; 95% confidence interval, 1.08-1.98; P 1⁄4 .01), F3 (HR, 1.96; 95% CI, 1.41-2.72; P < .01), and F4 (HR, 3.66; 95% CI, 2.65-5.05; P < .01). In addition, early fibrosis (F1-F2) resulted in a statistically significant increase in all-cause mortality, as did the presence of clinically significant fibrosis or advanced fibrosis.
Compared with non–clinically significant fibrosis (F0-F1), clinically significant fibrosis (F2-F4) resulted in a statistically significant increase in mortality (HR, 2.06; 95% CI, 1.52-2.81; P < .01).
Compared with nonadvanced fibrosis (F0-F2), advanced fibrosis (F3-F4) resulted in a significantly increased risk of mortality (HR, 3.32; 95% CI, 2.38-4.65; P < .01).
In a comparison between F3 and F4, F4 resulted in a statistically significant increase in mortality (HR, 2.67; 95% CI, 1.47-4.83; P < .01). In a sensitivity analysis with three studies including nonalcoholic steatohepatitis, patients with NASH had a significantly increased risk of mortality in F4 (HR, 5.08; 95% CI, 2.70-9.55; P < .01).
For liver-related mortality, F1 didn’t result in a statistically significant increase, as compared with F0. However, increased risks were found for F2 (HR, 4.07; 95% CI, 1.44-11.5; P < .01), F3 (HR, 7.59; 95% CI, 2.80-20.5; P < .01), and F4 (HR, 15.1; 95% CI, 5.27-43.4; P < .01). In addition, any fibrosis (F1-F4) resulted in an increased risk of mortality, early fibrosis resulted in a borderline nonsignificant increase, and clinically significant or advanced fibrosis led to an increased risk.
Compared with non–clinically significant fibrosis (F0-F1), clinically significant fibrosis (F2-F4) resulted in an increase in liver-related mortality (HR, 6.49; 95% CI, 3.30-12.8; P < .01).
Compared with nonadvanced fibrosis (F0-F2), advanced fibrosis (F3-F4) resulted in a statistically significant increase in liver-related mortality (HR, 10.4; 95% CI, 6.18-17.5; P < .01).
In a comparison between F3 and F4, F4 resulted in a significant increase in liver-related mortality (HR, 2.57; 95% CI, 1.22-5.42; P < .01).
Although the presence of F4 leads to the greatest risk of mortality, selection criteria in NASH clinical trials have predominately targeted patients with F0-F3, the authors wrote.
“NASH is currently the fastest growing cause for liver transplant and [transplant] remains the only known curative treatment for cirrhosis,” they wrote. “However, with the global shortage of suitable grafts for transplant and lack of viable treatment, our results highlight that there is an urgent need for an efficacious treatment for patients with NASH and F4.”
The researchers outlined several limitations of their study. The development of hepatocellular carcinoma and its effects on survival were outside the scope of the study, they wrote. Analysis of liver-related mortality by proportion was not conducted because of insufficient studies. Data were insufficient to perform subgroup analyses by gender, age, study design, medication use, and diagnostic modality for fibrosis stage.
The authors reported funding support from several national U.S. grants and disclosed consultant and advisory rules for numerous pharmaceutical companies.
Nonalcoholic fatty liver disease (NAFLD) is one of the most common liver diseases globally. This meta-analysis shows that all-cause mortality and liver-related mortality increase significantly and exponentially from fibrosis stage F2 onward. The findings have important implications for patients, care providers, health policy, and the NAFLD research agenda.
At the policy level, the significant increase in all-cause mortality even at early stages of NAFLD also highlights gaps in the need for coverage of well-established weight-loss treatments. While provisions of the Affordable Care Act have tried to reduce health disparities and improve access to weight-loss treatment, many health plans continue to limit or deny coverage for medications and bariatric surgery. Finally, the study emphasizes the urgency of conducting more research to establish successful treatments for individuals with advanced fibrosis, specifically those with cirrhosis.
Overall, the study provides valuable insights into mortality risks associated with different stages of fibrosis in NAFLD for all stakeholders in the NAFLD community.
Achita P. Desai, MD is an National Institutes of Health–funded clinician scientist, transplant hepatologist, and assistant professor in the division of gastroenterology and hepatology at Indiana University, Indianapolis. She reported no conflicts of interest.
Nonalcoholic fatty liver disease (NAFLD) is one of the most common liver diseases globally. This meta-analysis shows that all-cause mortality and liver-related mortality increase significantly and exponentially from fibrosis stage F2 onward. The findings have important implications for patients, care providers, health policy, and the NAFLD research agenda.
At the policy level, the significant increase in all-cause mortality even at early stages of NAFLD also highlights gaps in the need for coverage of well-established weight-loss treatments. While provisions of the Affordable Care Act have tried to reduce health disparities and improve access to weight-loss treatment, many health plans continue to limit or deny coverage for medications and bariatric surgery. Finally, the study emphasizes the urgency of conducting more research to establish successful treatments for individuals with advanced fibrosis, specifically those with cirrhosis.
Overall, the study provides valuable insights into mortality risks associated with different stages of fibrosis in NAFLD for all stakeholders in the NAFLD community.
Achita P. Desai, MD is an National Institutes of Health–funded clinician scientist, transplant hepatologist, and assistant professor in the division of gastroenterology and hepatology at Indiana University, Indianapolis. She reported no conflicts of interest.
Nonalcoholic fatty liver disease (NAFLD) is one of the most common liver diseases globally. This meta-analysis shows that all-cause mortality and liver-related mortality increase significantly and exponentially from fibrosis stage F2 onward. The findings have important implications for patients, care providers, health policy, and the NAFLD research agenda.
At the policy level, the significant increase in all-cause mortality even at early stages of NAFLD also highlights gaps in the need for coverage of well-established weight-loss treatments. While provisions of the Affordable Care Act have tried to reduce health disparities and improve access to weight-loss treatment, many health plans continue to limit or deny coverage for medications and bariatric surgery. Finally, the study emphasizes the urgency of conducting more research to establish successful treatments for individuals with advanced fibrosis, specifically those with cirrhosis.
Overall, the study provides valuable insights into mortality risks associated with different stages of fibrosis in NAFLD for all stakeholders in the NAFLD community.
Achita P. Desai, MD is an National Institutes of Health–funded clinician scientist, transplant hepatologist, and assistant professor in the division of gastroenterology and hepatology at Indiana University, Indianapolis. She reported no conflicts of interest.
The risks of all-cause and liver-related mortality increase substantially based on fibrosis stage in biopsy-confirmed nonalcoholic fatty liver disease (NAFLD), according to a study published in Clinical Gastroenterology and Hepatology.
In particular, patients with NAFLD and advanced fibrosis have a threefold higher risk of all-cause mortality and 10-fold higher risk of liver-related mortality, as compared with patients with NAFLD but not advanced fibrosis, Cheng Han Ng, with the National University of Singapore, and colleagues wrote.
they wrote. “In addition, these findings have important implications for clinical trial design and highlight the importance of developing therapeutics.”
Although previous studies have found higher risks of all-cause and liver-related mortality in patients with NAFLD with increasing fibrosis stages, they examined the risk of mortality in reference to stage 0 fibrosis and didn’t include comparisons across different stages of fibrosis. In addition, the studies typically used pooled risk ratios, didn’t account for time-to-event analysis, or incorporate the most recent data.
The study investigators conducted an updated time-to-event meta-analysis to understand the impact of fibrosis stage on all-cause and liver-related mortality in biopsy-confirmed NAFLD. In addition, they pooled the survival estimates of individual fibrosis stages based on reconstructed individual patient data and compared mortality between fibrosis stages.
In 14 included studies, 17,301 patients had biopsy-proven NAFLD, including 6,069 assessed for overall mortality and 3,421 for liver-related mortality. The studies were conducted in the United States, Canada, Sweden, Israel, Japan, and Hong Kong, with four multicenter studies across multiple regions. The median follow-up duration was 7.7 years, and the average age of patients was 50.5.
For nonadvanced fibrosis (F0-F2), the 1-, 3-, 5-, 8-, and 10-year all-cause mortality were 0.1%, 1.9%, 3.3%, 6%, and 7.7%, respectively. For clinically significant fibrosis (F2-F4), the rates were 0.3%, 8.4%, 14%, 23.7%, and 29.3%, respectively. For advanced fibrosis (F3-F4), the rates were 0.3%, 8.8%, 14.9%, 25.5%, and 32.2%, respectively. For cirrhosis (F4), the rates were 0.3%, 13%, 20.6%, 33.3%, and 41.5%, respectively.
Compared with F0 as a reference, there were no statistically significant differences in all-cause mortality for F1. However, the risk significantly increased for F2 (HR, 1.46; 95% confidence interval, 1.08-1.98; P 1⁄4 .01), F3 (HR, 1.96; 95% CI, 1.41-2.72; P < .01), and F4 (HR, 3.66; 95% CI, 2.65-5.05; P < .01). In addition, early fibrosis (F1-F2) resulted in a statistically significant increase in all-cause mortality, as did the presence of clinically significant fibrosis or advanced fibrosis.
Compared with non–clinically significant fibrosis (F0-F1), clinically significant fibrosis (F2-F4) resulted in a statistically significant increase in mortality (HR, 2.06; 95% CI, 1.52-2.81; P < .01).
Compared with nonadvanced fibrosis (F0-F2), advanced fibrosis (F3-F4) resulted in a significantly increased risk of mortality (HR, 3.32; 95% CI, 2.38-4.65; P < .01).
In a comparison between F3 and F4, F4 resulted in a statistically significant increase in mortality (HR, 2.67; 95% CI, 1.47-4.83; P < .01). In a sensitivity analysis with three studies including nonalcoholic steatohepatitis, patients with NASH had a significantly increased risk of mortality in F4 (HR, 5.08; 95% CI, 2.70-9.55; P < .01).
For liver-related mortality, F1 didn’t result in a statistically significant increase, as compared with F0. However, increased risks were found for F2 (HR, 4.07; 95% CI, 1.44-11.5; P < .01), F3 (HR, 7.59; 95% CI, 2.80-20.5; P < .01), and F4 (HR, 15.1; 95% CI, 5.27-43.4; P < .01). In addition, any fibrosis (F1-F4) resulted in an increased risk of mortality, early fibrosis resulted in a borderline nonsignificant increase, and clinically significant or advanced fibrosis led to an increased risk.
Compared with non–clinically significant fibrosis (F0-F1), clinically significant fibrosis (F2-F4) resulted in an increase in liver-related mortality (HR, 6.49; 95% CI, 3.30-12.8; P < .01).
Compared with nonadvanced fibrosis (F0-F2), advanced fibrosis (F3-F4) resulted in a statistically significant increase in liver-related mortality (HR, 10.4; 95% CI, 6.18-17.5; P < .01).
In a comparison between F3 and F4, F4 resulted in a significant increase in liver-related mortality (HR, 2.57; 95% CI, 1.22-5.42; P < .01).
Although the presence of F4 leads to the greatest risk of mortality, selection criteria in NASH clinical trials have predominately targeted patients with F0-F3, the authors wrote.
“NASH is currently the fastest growing cause for liver transplant and [transplant] remains the only known curative treatment for cirrhosis,” they wrote. “However, with the global shortage of suitable grafts for transplant and lack of viable treatment, our results highlight that there is an urgent need for an efficacious treatment for patients with NASH and F4.”
The researchers outlined several limitations of their study. The development of hepatocellular carcinoma and its effects on survival were outside the scope of the study, they wrote. Analysis of liver-related mortality by proportion was not conducted because of insufficient studies. Data were insufficient to perform subgroup analyses by gender, age, study design, medication use, and diagnostic modality for fibrosis stage.
The authors reported funding support from several national U.S. grants and disclosed consultant and advisory rules for numerous pharmaceutical companies.
The risks of all-cause and liver-related mortality increase substantially based on fibrosis stage in biopsy-confirmed nonalcoholic fatty liver disease (NAFLD), according to a study published in Clinical Gastroenterology and Hepatology.
In particular, patients with NAFLD and advanced fibrosis have a threefold higher risk of all-cause mortality and 10-fold higher risk of liver-related mortality, as compared with patients with NAFLD but not advanced fibrosis, Cheng Han Ng, with the National University of Singapore, and colleagues wrote.
they wrote. “In addition, these findings have important implications for clinical trial design and highlight the importance of developing therapeutics.”
Although previous studies have found higher risks of all-cause and liver-related mortality in patients with NAFLD with increasing fibrosis stages, they examined the risk of mortality in reference to stage 0 fibrosis and didn’t include comparisons across different stages of fibrosis. In addition, the studies typically used pooled risk ratios, didn’t account for time-to-event analysis, or incorporate the most recent data.
The study investigators conducted an updated time-to-event meta-analysis to understand the impact of fibrosis stage on all-cause and liver-related mortality in biopsy-confirmed NAFLD. In addition, they pooled the survival estimates of individual fibrosis stages based on reconstructed individual patient data and compared mortality between fibrosis stages.
In 14 included studies, 17,301 patients had biopsy-proven NAFLD, including 6,069 assessed for overall mortality and 3,421 for liver-related mortality. The studies were conducted in the United States, Canada, Sweden, Israel, Japan, and Hong Kong, with four multicenter studies across multiple regions. The median follow-up duration was 7.7 years, and the average age of patients was 50.5.
For nonadvanced fibrosis (F0-F2), the 1-, 3-, 5-, 8-, and 10-year all-cause mortality were 0.1%, 1.9%, 3.3%, 6%, and 7.7%, respectively. For clinically significant fibrosis (F2-F4), the rates were 0.3%, 8.4%, 14%, 23.7%, and 29.3%, respectively. For advanced fibrosis (F3-F4), the rates were 0.3%, 8.8%, 14.9%, 25.5%, and 32.2%, respectively. For cirrhosis (F4), the rates were 0.3%, 13%, 20.6%, 33.3%, and 41.5%, respectively.
Compared with F0 as a reference, there were no statistically significant differences in all-cause mortality for F1. However, the risk significantly increased for F2 (HR, 1.46; 95% confidence interval, 1.08-1.98; P 1⁄4 .01), F3 (HR, 1.96; 95% CI, 1.41-2.72; P < .01), and F4 (HR, 3.66; 95% CI, 2.65-5.05; P < .01). In addition, early fibrosis (F1-F2) resulted in a statistically significant increase in all-cause mortality, as did the presence of clinically significant fibrosis or advanced fibrosis.
Compared with non–clinically significant fibrosis (F0-F1), clinically significant fibrosis (F2-F4) resulted in a statistically significant increase in mortality (HR, 2.06; 95% CI, 1.52-2.81; P < .01).
Compared with nonadvanced fibrosis (F0-F2), advanced fibrosis (F3-F4) resulted in a significantly increased risk of mortality (HR, 3.32; 95% CI, 2.38-4.65; P < .01).
In a comparison between F3 and F4, F4 resulted in a statistically significant increase in mortality (HR, 2.67; 95% CI, 1.47-4.83; P < .01). In a sensitivity analysis with three studies including nonalcoholic steatohepatitis, patients with NASH had a significantly increased risk of mortality in F4 (HR, 5.08; 95% CI, 2.70-9.55; P < .01).
For liver-related mortality, F1 didn’t result in a statistically significant increase, as compared with F0. However, increased risks were found for F2 (HR, 4.07; 95% CI, 1.44-11.5; P < .01), F3 (HR, 7.59; 95% CI, 2.80-20.5; P < .01), and F4 (HR, 15.1; 95% CI, 5.27-43.4; P < .01). In addition, any fibrosis (F1-F4) resulted in an increased risk of mortality, early fibrosis resulted in a borderline nonsignificant increase, and clinically significant or advanced fibrosis led to an increased risk.
Compared with non–clinically significant fibrosis (F0-F1), clinically significant fibrosis (F2-F4) resulted in an increase in liver-related mortality (HR, 6.49; 95% CI, 3.30-12.8; P < .01).
Compared with nonadvanced fibrosis (F0-F2), advanced fibrosis (F3-F4) resulted in a statistically significant increase in liver-related mortality (HR, 10.4; 95% CI, 6.18-17.5; P < .01).
In a comparison between F3 and F4, F4 resulted in a significant increase in liver-related mortality (HR, 2.57; 95% CI, 1.22-5.42; P < .01).
Although the presence of F4 leads to the greatest risk of mortality, selection criteria in NASH clinical trials have predominately targeted patients with F0-F3, the authors wrote.
“NASH is currently the fastest growing cause for liver transplant and [transplant] remains the only known curative treatment for cirrhosis,” they wrote. “However, with the global shortage of suitable grafts for transplant and lack of viable treatment, our results highlight that there is an urgent need for an efficacious treatment for patients with NASH and F4.”
The researchers outlined several limitations of their study. The development of hepatocellular carcinoma and its effects on survival were outside the scope of the study, they wrote. Analysis of liver-related mortality by proportion was not conducted because of insufficient studies. Data were insufficient to perform subgroup analyses by gender, age, study design, medication use, and diagnostic modality for fibrosis stage.
The authors reported funding support from several national U.S. grants and disclosed consultant and advisory rules for numerous pharmaceutical companies.
FROM CLINICAL GASTROENTEROLOGY AND HEPATOLOGY
Pancreatic cancer incidence increases among young women in U.S.
Between 2001 and 2018, there was a greater than 200% difference in the incidence trend between men and women for ages 15-34, wrote Yazan Abboud, MD, a postdoctoral research fellow in the pancreaticobiliary department of the Karsh Division of Gastroenterology and Hepatology at Cedars-Sinai Medical Center, Los Angeles, and colleagues.
“The exact cause of the trend among younger women is unclear and may be driven by sex-based disproportional exposure or response to known or yet-to-be-explored risk factors,” they wrote. “Future efforts should aim to elucidate the causes of such a trend with the goal to formulate possible preventive measures.”
Although previous studies have found increasing pancreatic cancer incidence rates, especially in younger women, the data haven’t been externally validated outside of the National Cancer Institute’s Surveillance Epidemiology and End Results (SEER) data, they wrote. In addition, there are limited data about the contributing factors, such as race, histopathological subtype, tumor location, and stage at diagnosis.
Using SEER-excluded data from the Centers for Disease Control and Prevention’s National Program of Cancer Registries (NPCR), Dr. Abboud and colleagues conducted a population-based time-trend analysis of pancreatic cancer incidence rates from 2001 to 2018 in younger adults under age 55, including the role of demographics and tumor characteristics. They analyzed age-adjusted incidence rates (aIR), mortality rates, annual percentage change (APC), and average annual percentage change (AAPC) for ages 55 and older and ages 55 and younger. In addition, the research team evaluated the impact of incidence trends on sex-specific mortality trends in younger adults using the CDC’s National Center of Health Statistics database.
Between 2001 and 2018, 748,132 patients were diagnosed with pancreatic cancer. After excluding SEER data, 454,611 patients met the inclusion criteria. About 48.9% were women.
The overall aIR of pancreatic cancer during that time was 12.18 per 100,000 people. Women had a significantly lower aIR, at 10.69 per 100,000, compared with men at 13.95 per 100,000.
In general, pancreatic cancer aIR significantly increased during that time (AAPC = 1.17%). Sex-specific trends increased among both women (AAPC = 1.27%) and men (AAPC = 1.14%), though they showed no significant difference and were parallel.
In ages 55 and older, 401,419 patients (49.7% women) were diagnosed with pancreatic cancer. The aIR significantly increased during the study period (AAPC = 1.11%), with sex-specific aIR increasing in both women (AAPC = 1.11%) and men (AAPC = 1.17%), without a significant difference.
However, a difference appeared in the 53,051 patients (42.9% women) who were ages 55 and younger. The aIR relatively increased (AAPC = 1.29%), with faster jumps in women (AAPC = 2.36%), compared with men (AAPC = .62%). There was an absolute significant difference of 1.74%.
The trends continued in breakdowns by age. For 50,599 patients (42.2% women) between ages 35 and 54, the aIR relatively increased (AAPC = 1.10%). Sex-specific aIR increased among women (AAPC = 2.09%) but remained stable among men (AAPC = 0.54%), with an absolute significant difference of 1.55%.
In the youngest cohort of 2,452 patients (57.3% women) between ages 15 and 34, aIR relatively increased (AAPC = 4.93). Sex-specific aIR also increased in both women (AAPC = 6.45%) and men (AAPC = 2.97%), with an absolute significant difference of 3.48%.
By race, although White women under age 55 experienced increasing aIR at a greater rate than men (AAPC difference = 1.59%), an even more dramatic increase was seen in Black women, as compared to counterpart men (AAPC difference = 2.23%). Sex-specific trends in people of other races were parallel.
Based on tumor characteristics in ages 55 and younger, the pancreatic ductal adenocarcinoma histopathological subtype had an AAPC difference of 0.89%, and a tumor location in the head-of-pancreas had an AAPC difference of 1.64%.
When evaluating tumors based on stage-at-diagnosis, the AAPC difference was nonsignificant in all subgroups. However, sex-specific trends differed in tumors diagnosed at localized stages, suggesting that aIR in women may be increasing at a greater rate than in men (AAPC difference = 1.64%).
Among 64,239 patients (39.3% women) who died from pancreatic cancer under age 55, the mortality rates were unchanged in women (AAPC = –0.09%) but declined in men (AAPC = –0.64%), with an absolute significant AAPC difference of 0.54%.
“Pancreatic cancer has a very poor overall survival, accounting for 7% of cancer-related deaths. The incidence of cancers, in general, is expected to rise as life expectancy increases in the United States,” said Danny Issa, MD, a gastroenterologist at the University of California, Los Angeles, who wasn’t involved with this study.
“Recently, noncomparative studies showed a possible increase in the incidence of pancreatic cancer in younger White women and in older White men and women. These reports had limitations,” he said. “The findings of this study are monumental as they confirmed that age-adjusted incidence rates have been increasing at a higher rate in younger women compared to younger men.”
In addition, Dr. Issa said, the significant increases among Black women for adenocarcinoma and for cancers located in the head of the pancreas are notable and should be studied further.
“Over the past few decades, research studies have helped improve cancer treatment by uncovering risk factors and identifying the most affected (or protected) population,” he said. “Therefore, epidemiologic studies are crucial, especially for hard-to-treat cancers such as pancreatic cancer.”
The study was supported in part by a philanthropic grant from The Widjaja Family Fund for Pancreatic Cancer Research. The authors disclosed no conflicts of interest. Dr. Issa reported no relevant disclosures.
Between 2001 and 2018, there was a greater than 200% difference in the incidence trend between men and women for ages 15-34, wrote Yazan Abboud, MD, a postdoctoral research fellow in the pancreaticobiliary department of the Karsh Division of Gastroenterology and Hepatology at Cedars-Sinai Medical Center, Los Angeles, and colleagues.
“The exact cause of the trend among younger women is unclear and may be driven by sex-based disproportional exposure or response to known or yet-to-be-explored risk factors,” they wrote. “Future efforts should aim to elucidate the causes of such a trend with the goal to formulate possible preventive measures.”
Although previous studies have found increasing pancreatic cancer incidence rates, especially in younger women, the data haven’t been externally validated outside of the National Cancer Institute’s Surveillance Epidemiology and End Results (SEER) data, they wrote. In addition, there are limited data about the contributing factors, such as race, histopathological subtype, tumor location, and stage at diagnosis.
Using SEER-excluded data from the Centers for Disease Control and Prevention’s National Program of Cancer Registries (NPCR), Dr. Abboud and colleagues conducted a population-based time-trend analysis of pancreatic cancer incidence rates from 2001 to 2018 in younger adults under age 55, including the role of demographics and tumor characteristics. They analyzed age-adjusted incidence rates (aIR), mortality rates, annual percentage change (APC), and average annual percentage change (AAPC) for ages 55 and older and ages 55 and younger. In addition, the research team evaluated the impact of incidence trends on sex-specific mortality trends in younger adults using the CDC’s National Center of Health Statistics database.
Between 2001 and 2018, 748,132 patients were diagnosed with pancreatic cancer. After excluding SEER data, 454,611 patients met the inclusion criteria. About 48.9% were women.
The overall aIR of pancreatic cancer during that time was 12.18 per 100,000 people. Women had a significantly lower aIR, at 10.69 per 100,000, compared with men at 13.95 per 100,000.
In general, pancreatic cancer aIR significantly increased during that time (AAPC = 1.17%). Sex-specific trends increased among both women (AAPC = 1.27%) and men (AAPC = 1.14%), though they showed no significant difference and were parallel.
In ages 55 and older, 401,419 patients (49.7% women) were diagnosed with pancreatic cancer. The aIR significantly increased during the study period (AAPC = 1.11%), with sex-specific aIR increasing in both women (AAPC = 1.11%) and men (AAPC = 1.17%), without a significant difference.
However, a difference appeared in the 53,051 patients (42.9% women) who were ages 55 and younger. The aIR relatively increased (AAPC = 1.29%), with faster jumps in women (AAPC = 2.36%), compared with men (AAPC = .62%). There was an absolute significant difference of 1.74%.
The trends continued in breakdowns by age. For 50,599 patients (42.2% women) between ages 35 and 54, the aIR relatively increased (AAPC = 1.10%). Sex-specific aIR increased among women (AAPC = 2.09%) but remained stable among men (AAPC = 0.54%), with an absolute significant difference of 1.55%.
In the youngest cohort of 2,452 patients (57.3% women) between ages 15 and 34, aIR relatively increased (AAPC = 4.93). Sex-specific aIR also increased in both women (AAPC = 6.45%) and men (AAPC = 2.97%), with an absolute significant difference of 3.48%.
By race, although White women under age 55 experienced increasing aIR at a greater rate than men (AAPC difference = 1.59%), an even more dramatic increase was seen in Black women, as compared to counterpart men (AAPC difference = 2.23%). Sex-specific trends in people of other races were parallel.
Based on tumor characteristics in ages 55 and younger, the pancreatic ductal adenocarcinoma histopathological subtype had an AAPC difference of 0.89%, and a tumor location in the head-of-pancreas had an AAPC difference of 1.64%.
When evaluating tumors based on stage-at-diagnosis, the AAPC difference was nonsignificant in all subgroups. However, sex-specific trends differed in tumors diagnosed at localized stages, suggesting that aIR in women may be increasing at a greater rate than in men (AAPC difference = 1.64%).
Among 64,239 patients (39.3% women) who died from pancreatic cancer under age 55, the mortality rates were unchanged in women (AAPC = –0.09%) but declined in men (AAPC = –0.64%), with an absolute significant AAPC difference of 0.54%.
“Pancreatic cancer has a very poor overall survival, accounting for 7% of cancer-related deaths. The incidence of cancers, in general, is expected to rise as life expectancy increases in the United States,” said Danny Issa, MD, a gastroenterologist at the University of California, Los Angeles, who wasn’t involved with this study.
“Recently, noncomparative studies showed a possible increase in the incidence of pancreatic cancer in younger White women and in older White men and women. These reports had limitations,” he said. “The findings of this study are monumental as they confirmed that age-adjusted incidence rates have been increasing at a higher rate in younger women compared to younger men.”
In addition, Dr. Issa said, the significant increases among Black women for adenocarcinoma and for cancers located in the head of the pancreas are notable and should be studied further.
“Over the past few decades, research studies have helped improve cancer treatment by uncovering risk factors and identifying the most affected (or protected) population,” he said. “Therefore, epidemiologic studies are crucial, especially for hard-to-treat cancers such as pancreatic cancer.”
The study was supported in part by a philanthropic grant from The Widjaja Family Fund for Pancreatic Cancer Research. The authors disclosed no conflicts of interest. Dr. Issa reported no relevant disclosures.
Between 2001 and 2018, there was a greater than 200% difference in the incidence trend between men and women for ages 15-34, wrote Yazan Abboud, MD, a postdoctoral research fellow in the pancreaticobiliary department of the Karsh Division of Gastroenterology and Hepatology at Cedars-Sinai Medical Center, Los Angeles, and colleagues.
“The exact cause of the trend among younger women is unclear and may be driven by sex-based disproportional exposure or response to known or yet-to-be-explored risk factors,” they wrote. “Future efforts should aim to elucidate the causes of such a trend with the goal to formulate possible preventive measures.”
Although previous studies have found increasing pancreatic cancer incidence rates, especially in younger women, the data haven’t been externally validated outside of the National Cancer Institute’s Surveillance Epidemiology and End Results (SEER) data, they wrote. In addition, there are limited data about the contributing factors, such as race, histopathological subtype, tumor location, and stage at diagnosis.
Using SEER-excluded data from the Centers for Disease Control and Prevention’s National Program of Cancer Registries (NPCR), Dr. Abboud and colleagues conducted a population-based time-trend analysis of pancreatic cancer incidence rates from 2001 to 2018 in younger adults under age 55, including the role of demographics and tumor characteristics. They analyzed age-adjusted incidence rates (aIR), mortality rates, annual percentage change (APC), and average annual percentage change (AAPC) for ages 55 and older and ages 55 and younger. In addition, the research team evaluated the impact of incidence trends on sex-specific mortality trends in younger adults using the CDC’s National Center of Health Statistics database.
Between 2001 and 2018, 748,132 patients were diagnosed with pancreatic cancer. After excluding SEER data, 454,611 patients met the inclusion criteria. About 48.9% were women.
The overall aIR of pancreatic cancer during that time was 12.18 per 100,000 people. Women had a significantly lower aIR, at 10.69 per 100,000, compared with men at 13.95 per 100,000.
In general, pancreatic cancer aIR significantly increased during that time (AAPC = 1.17%). Sex-specific trends increased among both women (AAPC = 1.27%) and men (AAPC = 1.14%), though they showed no significant difference and were parallel.
In ages 55 and older, 401,419 patients (49.7% women) were diagnosed with pancreatic cancer. The aIR significantly increased during the study period (AAPC = 1.11%), with sex-specific aIR increasing in both women (AAPC = 1.11%) and men (AAPC = 1.17%), without a significant difference.
However, a difference appeared in the 53,051 patients (42.9% women) who were ages 55 and younger. The aIR relatively increased (AAPC = 1.29%), with faster jumps in women (AAPC = 2.36%), compared with men (AAPC = .62%). There was an absolute significant difference of 1.74%.
The trends continued in breakdowns by age. For 50,599 patients (42.2% women) between ages 35 and 54, the aIR relatively increased (AAPC = 1.10%). Sex-specific aIR increased among women (AAPC = 2.09%) but remained stable among men (AAPC = 0.54%), with an absolute significant difference of 1.55%.
In the youngest cohort of 2,452 patients (57.3% women) between ages 15 and 34, aIR relatively increased (AAPC = 4.93). Sex-specific aIR also increased in both women (AAPC = 6.45%) and men (AAPC = 2.97%), with an absolute significant difference of 3.48%.
By race, although White women under age 55 experienced increasing aIR at a greater rate than men (AAPC difference = 1.59%), an even more dramatic increase was seen in Black women, as compared to counterpart men (AAPC difference = 2.23%). Sex-specific trends in people of other races were parallel.
Based on tumor characteristics in ages 55 and younger, the pancreatic ductal adenocarcinoma histopathological subtype had an AAPC difference of 0.89%, and a tumor location in the head-of-pancreas had an AAPC difference of 1.64%.
When evaluating tumors based on stage-at-diagnosis, the AAPC difference was nonsignificant in all subgroups. However, sex-specific trends differed in tumors diagnosed at localized stages, suggesting that aIR in women may be increasing at a greater rate than in men (AAPC difference = 1.64%).
Among 64,239 patients (39.3% women) who died from pancreatic cancer under age 55, the mortality rates were unchanged in women (AAPC = –0.09%) but declined in men (AAPC = –0.64%), with an absolute significant AAPC difference of 0.54%.
“Pancreatic cancer has a very poor overall survival, accounting for 7% of cancer-related deaths. The incidence of cancers, in general, is expected to rise as life expectancy increases in the United States,” said Danny Issa, MD, a gastroenterologist at the University of California, Los Angeles, who wasn’t involved with this study.
“Recently, noncomparative studies showed a possible increase in the incidence of pancreatic cancer in younger White women and in older White men and women. These reports had limitations,” he said. “The findings of this study are monumental as they confirmed that age-adjusted incidence rates have been increasing at a higher rate in younger women compared to younger men.”
In addition, Dr. Issa said, the significant increases among Black women for adenocarcinoma and for cancers located in the head of the pancreas are notable and should be studied further.
“Over the past few decades, research studies have helped improve cancer treatment by uncovering risk factors and identifying the most affected (or protected) population,” he said. “Therefore, epidemiologic studies are crucial, especially for hard-to-treat cancers such as pancreatic cancer.”
The study was supported in part by a philanthropic grant from The Widjaja Family Fund for Pancreatic Cancer Research. The authors disclosed no conflicts of interest. Dr. Issa reported no relevant disclosures.
FROM GASTROENTEROLOGY
AGA guideline defines role of biomarkers in ulcerative colitis
The American Gastroenterological Association (AGA) has released a new clinical practice guideline defining the role of biomarkers in monitoring and managing ulcerative colitis (UC).
, reported lead guideline panelist Siddharth Singh, MD, of University of California San Diego, La Jolla, Calif., and colleagues.
“[I]n routine clinical practice, repeated endoscopic assessment is invasive, expensive, and may be impractical,” the panelists wrote. Their report is in Gastroenterology. “There is an important need for understanding how noninvasive biomarkers may serve as accurate and reliable surrogates for endoscopic assessment of inflammation and whether they can be more readily implemented in a UC care pathway.”
After reviewing relevant randomized controlled trials and observational studies, Dr. Singh and colleagues issued seven conditional recommendations, three of which concern patients in symptomatic remission, and four of which apply to patients with symptomatically active UC.
“The key take-home message is that the routine measurement of noninvasive biomarkers in addition to assessment of patient reported symptoms is critical in evaluating the disease burden of UC,” said Jordan E. Axelrad, MD, MPH, director of clinical and translational research at NYU Langone Health’s Inflammatory Bowel Disease Center, New York. “Many of these recommendations regarding the assessment of disease activity beyond symptoms alone are widely accepted, particularity at tertiary IBD centers; however, this guideline serves to formalize and structure the recommendations, with appropriate test cutoff values, in a simple UC care pathway.”
Recommendations for patients in symptomatic remission
For patients in remission, the guideline advises monitoring both symptoms and biomarkers, with biomarkers measured every 6-12 months.
Asymptomatic patients with normal biomarkers can skip routine endoscopy to evaluate disease activity, according to the guideline, but those with abnormal fecal calprotectin, fecal lactoferrin, or serum C-reactive protein (CRP) are candidates for endoscopic assessment instead of empiric treatment adjustment. Patients may still need periodic colonoscopy for dysplasia surveillance.
“The most important pearl [from the guideline] is that fecal calprotectin less than 150 mcg/g, normal fecal lactoferrin, or normal CRP, can be used to rule out active inflammation in patients in symptomatic remission,” according to Dr. Axelrad.
The guideline suggests that the two fecal biomarkers “may be optimal for monitoring and may be particularly useful in patients where biomarkers have historically correlated with endoscopic disease activity.” In contrast, normal CRP may be insufficient to rule out moderate to severe endoscopic inflammation in patients who recently entered remission following treatment adjustment.
While abnormal biomarkers in asymptomatic patients are sufficient cause for endoscopy, the guideline also suggests that retesting in 3-6 months is a reasonable alternative. If biomarkers are again elevated, then endoscopic evaluation should be considered.
Recommendations for patients with symptomatically active disease
The recommendations for patients with symptomatically active UC follow a similar pathway. The guideline advises an evaluation strategy combining symptoms and biomarkers instead of symptoms alone.
For example, patients with moderate to severe symptoms suggestive of flare and elevated biomarkers are candidates for treatment adjustment without endoscopy.
Still, patient preferences should be considered, Dr. Singh and colleagues noted.
“Patients who place greater value in confirming inflammation, particularly when making significant treatment decisions (such as starting or switching immunosuppressive therapies), and lesser value on the inconvenience of endoscopy, may choose to pursue endoscopic evaluation before treatment adjustment,” they wrote.
For patients with mild symptoms, endoscopy is generally recommended, according to the guideline, unless the patient recently had moderate to severe symptoms and has improved after treatment adjustment; in that case, biomarkers can be used to fine-tune therapy without the need for endoscopy.
Again, providers should engage in shared-decision making, the guideline advises. Patients with mild symptoms but no biomarker results may reasonably elect to undergo endoscopy prior to testing biomarkers, while patients with mild symptoms and normal biomarkers may reasonably elect to retest biomarkers in 3-6 months.
Data remain insufficient to recommend biomarkers over endoscopy
Dr. Singh and colleagues concluded the guideline by highlighting an insufficient level of direct evidence necessary to recommend a biomarker-based treat-to-target strategy over endoscopy-based monitoring strategy, despite indirect evidence suggesting this may be the case.
“[T]here have not been any studies comparing a biomarker-based strategy with an endoscopy-based strategy for assessment and monitoring of endoscopic remission,” they wrote. “This was identified as a knowledge gap by the panel.”
The authors disclosed relationships with Pfizer, AbbVie, Lilly, and others. Dr. Axelrad disclosed relationships with Janssen, AbbVie, Pfizer, and others.
The American Gastroenterological Association (AGA) has released a new clinical practice guideline defining the role of biomarkers in monitoring and managing ulcerative colitis (UC).
, reported lead guideline panelist Siddharth Singh, MD, of University of California San Diego, La Jolla, Calif., and colleagues.
“[I]n routine clinical practice, repeated endoscopic assessment is invasive, expensive, and may be impractical,” the panelists wrote. Their report is in Gastroenterology. “There is an important need for understanding how noninvasive biomarkers may serve as accurate and reliable surrogates for endoscopic assessment of inflammation and whether they can be more readily implemented in a UC care pathway.”
After reviewing relevant randomized controlled trials and observational studies, Dr. Singh and colleagues issued seven conditional recommendations, three of which concern patients in symptomatic remission, and four of which apply to patients with symptomatically active UC.
“The key take-home message is that the routine measurement of noninvasive biomarkers in addition to assessment of patient reported symptoms is critical in evaluating the disease burden of UC,” said Jordan E. Axelrad, MD, MPH, director of clinical and translational research at NYU Langone Health’s Inflammatory Bowel Disease Center, New York. “Many of these recommendations regarding the assessment of disease activity beyond symptoms alone are widely accepted, particularity at tertiary IBD centers; however, this guideline serves to formalize and structure the recommendations, with appropriate test cutoff values, in a simple UC care pathway.”
Recommendations for patients in symptomatic remission
For patients in remission, the guideline advises monitoring both symptoms and biomarkers, with biomarkers measured every 6-12 months.
Asymptomatic patients with normal biomarkers can skip routine endoscopy to evaluate disease activity, according to the guideline, but those with abnormal fecal calprotectin, fecal lactoferrin, or serum C-reactive protein (CRP) are candidates for endoscopic assessment instead of empiric treatment adjustment. Patients may still need periodic colonoscopy for dysplasia surveillance.
“The most important pearl [from the guideline] is that fecal calprotectin less than 150 mcg/g, normal fecal lactoferrin, or normal CRP, can be used to rule out active inflammation in patients in symptomatic remission,” according to Dr. Axelrad.
The guideline suggests that the two fecal biomarkers “may be optimal for monitoring and may be particularly useful in patients where biomarkers have historically correlated with endoscopic disease activity.” In contrast, normal CRP may be insufficient to rule out moderate to severe endoscopic inflammation in patients who recently entered remission following treatment adjustment.
While abnormal biomarkers in asymptomatic patients are sufficient cause for endoscopy, the guideline also suggests that retesting in 3-6 months is a reasonable alternative. If biomarkers are again elevated, then endoscopic evaluation should be considered.
Recommendations for patients with symptomatically active disease
The recommendations for patients with symptomatically active UC follow a similar pathway. The guideline advises an evaluation strategy combining symptoms and biomarkers instead of symptoms alone.
For example, patients with moderate to severe symptoms suggestive of flare and elevated biomarkers are candidates for treatment adjustment without endoscopy.
Still, patient preferences should be considered, Dr. Singh and colleagues noted.
“Patients who place greater value in confirming inflammation, particularly when making significant treatment decisions (such as starting or switching immunosuppressive therapies), and lesser value on the inconvenience of endoscopy, may choose to pursue endoscopic evaluation before treatment adjustment,” they wrote.
For patients with mild symptoms, endoscopy is generally recommended, according to the guideline, unless the patient recently had moderate to severe symptoms and has improved after treatment adjustment; in that case, biomarkers can be used to fine-tune therapy without the need for endoscopy.
Again, providers should engage in shared-decision making, the guideline advises. Patients with mild symptoms but no biomarker results may reasonably elect to undergo endoscopy prior to testing biomarkers, while patients with mild symptoms and normal biomarkers may reasonably elect to retest biomarkers in 3-6 months.
Data remain insufficient to recommend biomarkers over endoscopy
Dr. Singh and colleagues concluded the guideline by highlighting an insufficient level of direct evidence necessary to recommend a biomarker-based treat-to-target strategy over endoscopy-based monitoring strategy, despite indirect evidence suggesting this may be the case.
“[T]here have not been any studies comparing a biomarker-based strategy with an endoscopy-based strategy for assessment and monitoring of endoscopic remission,” they wrote. “This was identified as a knowledge gap by the panel.”
The authors disclosed relationships with Pfizer, AbbVie, Lilly, and others. Dr. Axelrad disclosed relationships with Janssen, AbbVie, Pfizer, and others.
The American Gastroenterological Association (AGA) has released a new clinical practice guideline defining the role of biomarkers in monitoring and managing ulcerative colitis (UC).
, reported lead guideline panelist Siddharth Singh, MD, of University of California San Diego, La Jolla, Calif., and colleagues.
“[I]n routine clinical practice, repeated endoscopic assessment is invasive, expensive, and may be impractical,” the panelists wrote. Their report is in Gastroenterology. “There is an important need for understanding how noninvasive biomarkers may serve as accurate and reliable surrogates for endoscopic assessment of inflammation and whether they can be more readily implemented in a UC care pathway.”
After reviewing relevant randomized controlled trials and observational studies, Dr. Singh and colleagues issued seven conditional recommendations, three of which concern patients in symptomatic remission, and four of which apply to patients with symptomatically active UC.
“The key take-home message is that the routine measurement of noninvasive biomarkers in addition to assessment of patient reported symptoms is critical in evaluating the disease burden of UC,” said Jordan E. Axelrad, MD, MPH, director of clinical and translational research at NYU Langone Health’s Inflammatory Bowel Disease Center, New York. “Many of these recommendations regarding the assessment of disease activity beyond symptoms alone are widely accepted, particularity at tertiary IBD centers; however, this guideline serves to formalize and structure the recommendations, with appropriate test cutoff values, in a simple UC care pathway.”
Recommendations for patients in symptomatic remission
For patients in remission, the guideline advises monitoring both symptoms and biomarkers, with biomarkers measured every 6-12 months.
Asymptomatic patients with normal biomarkers can skip routine endoscopy to evaluate disease activity, according to the guideline, but those with abnormal fecal calprotectin, fecal lactoferrin, or serum C-reactive protein (CRP) are candidates for endoscopic assessment instead of empiric treatment adjustment. Patients may still need periodic colonoscopy for dysplasia surveillance.
“The most important pearl [from the guideline] is that fecal calprotectin less than 150 mcg/g, normal fecal lactoferrin, or normal CRP, can be used to rule out active inflammation in patients in symptomatic remission,” according to Dr. Axelrad.
The guideline suggests that the two fecal biomarkers “may be optimal for monitoring and may be particularly useful in patients where biomarkers have historically correlated with endoscopic disease activity.” In contrast, normal CRP may be insufficient to rule out moderate to severe endoscopic inflammation in patients who recently entered remission following treatment adjustment.
While abnormal biomarkers in asymptomatic patients are sufficient cause for endoscopy, the guideline also suggests that retesting in 3-6 months is a reasonable alternative. If biomarkers are again elevated, then endoscopic evaluation should be considered.
Recommendations for patients with symptomatically active disease
The recommendations for patients with symptomatically active UC follow a similar pathway. The guideline advises an evaluation strategy combining symptoms and biomarkers instead of symptoms alone.
For example, patients with moderate to severe symptoms suggestive of flare and elevated biomarkers are candidates for treatment adjustment without endoscopy.
Still, patient preferences should be considered, Dr. Singh and colleagues noted.
“Patients who place greater value in confirming inflammation, particularly when making significant treatment decisions (such as starting or switching immunosuppressive therapies), and lesser value on the inconvenience of endoscopy, may choose to pursue endoscopic evaluation before treatment adjustment,” they wrote.
For patients with mild symptoms, endoscopy is generally recommended, according to the guideline, unless the patient recently had moderate to severe symptoms and has improved after treatment adjustment; in that case, biomarkers can be used to fine-tune therapy without the need for endoscopy.
Again, providers should engage in shared-decision making, the guideline advises. Patients with mild symptoms but no biomarker results may reasonably elect to undergo endoscopy prior to testing biomarkers, while patients with mild symptoms and normal biomarkers may reasonably elect to retest biomarkers in 3-6 months.
Data remain insufficient to recommend biomarkers over endoscopy
Dr. Singh and colleagues concluded the guideline by highlighting an insufficient level of direct evidence necessary to recommend a biomarker-based treat-to-target strategy over endoscopy-based monitoring strategy, despite indirect evidence suggesting this may be the case.
“[T]here have not been any studies comparing a biomarker-based strategy with an endoscopy-based strategy for assessment and monitoring of endoscopic remission,” they wrote. “This was identified as a knowledge gap by the panel.”
The authors disclosed relationships with Pfizer, AbbVie, Lilly, and others. Dr. Axelrad disclosed relationships with Janssen, AbbVie, Pfizer, and others.
FROM GASTROENTEROLOGY