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Genomics data reveal promising PSC therapeutic target
, according to a study published in Gastro Hep Advances.
PSC is very rare, with an incidence of 0-1.3 cases per 100,000 people per year. Because up to 80% of patients with PSC also have inflammatory bowel disease (IBD), a link along the gut-liver axis is suspected. So far, scientists have not understood the causes of PSC, the main complications of which include biliary cirrhosis, bacterial cholangitis, and cholangiocarcinoma.
No treatment is currently available for PSC, but the findings of this genomics study suggest several targets that may be worth pursuing, particularly the gene NR0B2.
“The therapeutic targeting of NR0B2 may potentiate that of FXR [farnesoid X receptor] and enable action on early events of the disease and prevent its progression,” wrote Christophe Desterke, PhD, of the Paul-Brousse Hospital, the French National Institute of Health and Medical Research, and the University of Paris-Saclay in Villejuif, France, and his associates.
The researchers used an algorithmic tool to mine the MEDLINE/PubMed/NCBI database using the three key symptoms of PSC – biliary fibrosis, biliary inflammation, and biliary stasis – as their keywords. This approach allowed them to discover the genes and potential pathways related to PSC in published research text or in clinical, animal, and cellular models.
The researchers initially found 525 genes linked to PSC and then compared them to RNA data from liver biopsies taken from patients with liver disease from various causes. This process led to a ranking of the 10 best markers of PSC, based on the data-mining method and the genes’ association with one or more of the three PSC symptoms.
At the top of the list is NR1H4, also called FXR, which ranks most highly with biliary fibrosis and biliary stasis. NR1H4 is already a clear target for cholestatic and fatty liver diseases, the authors noted. The other genes, in descending order of relevance, are: ABCB4, ABCB11, TGFB1, IFNL3, PNPLA3, IL6, TLR4, GPBAR1, and IL17A. In addition, complications of PSC were significantly associated with upregulation of TNFRS12A, SOX9, ANXA2, MMP7, and LCN2.
Separately, investigation of the 525 initially identified genes in mouse models of PSC revealed that NR0B2 is also a key player in the pathogenesis of PSC.
"NR0B2 was upregulated in PSC livers independent of gender, age, and body mass index,” the authors reported. “Importantly, it was not dependent on the severity of PSC in the prognostic cohort, suggesting that this may be an early event during the disease.”
The researchers also found a possible pathway explaining the autoimmunity of PSC – the involvement of CD274, also known as the PDL1 immune checkpoint. The authors noted that the PDL1 inhibitor pembrolizumab has previously been reported as a cause of sclerosing cholangitis.
Further, the researchers discovered overexpression of FOXP3 in the livers of patients with PSC. Because FOXP3 determines what T-cell subtypes look like, the finding suggests that an “imbalance between Foxp3þ regulatory T cells and Th17 cells may be involved in IBD and PSC,” they wrote.
Also of note was the overexpression of SOX9 in the livers of patients with PSC whose profiles suggested the worst clinical prognoses.
Finally, the researchers identified three genes as potentially involved in development of cholangiocarcinoma: GSTA3, ID2 (which is overexpressed in biliary tract cancer), and especially TMEM45A, a protein in cells’ Golgi apparatus that is already known to be involved in the development of several other cancers.
The research was funded by the French National Institute of Health and Medical Research. The authors reported no conflicts of interest.
Primary sclerosing cholangitis (PSC) is a bile duct disease with few therapeutic options other than liver transplant, and thus its prognosis remains grim. Additionally, the factors that cause the disease are not well understood. Identifying the pathways and genes involved in PSC pathogenesis could help in the development of potential therapeutic targets.
In this report Desterke et al. mined public data sets to identify and define a PSC-specific network. Of the top genes in this list, NR0B2 stood out as a potential player in pathogenesis because of its involvement in regulating bile acid metabolism. The authors showed that upregulation of NR0B2 occurs early in the disease process and in patient tissues is independent of variables such as gender and sex. Interestingly, the authors showed that this upregulation occurs primarily in cholangiocytes, the cells lining the bile duct. Higher expression of NR0B2 results in reprogramming that alters the metabolic function of these cells and predisposes them to malignancy.
This study, which is the first to look at omics data for PSC, highlights the involvement of genes and pathways that were previously unrecognized in disease pathogenesis. By using data derived from human PSC liver biopsies and animal models of PSC, the authors were able to validate their findings across species, which strengthened their conclusions. This approach also showed that NR0B2 deregulation occurs primarily in cholangiocytes, suggesting that future therapies should be targeted to this cell type. These important findings will improve our understanding of this rare but clinically significant disease.
Kari Nejak-Bowen, PhD, MBA, is associate professor, department of pathology, University of Pittsburgh School of Medicine. She has no relevant conflicts of interest.
Primary sclerosing cholangitis (PSC) is a bile duct disease with few therapeutic options other than liver transplant, and thus its prognosis remains grim. Additionally, the factors that cause the disease are not well understood. Identifying the pathways and genes involved in PSC pathogenesis could help in the development of potential therapeutic targets.
In this report Desterke et al. mined public data sets to identify and define a PSC-specific network. Of the top genes in this list, NR0B2 stood out as a potential player in pathogenesis because of its involvement in regulating bile acid metabolism. The authors showed that upregulation of NR0B2 occurs early in the disease process and in patient tissues is independent of variables such as gender and sex. Interestingly, the authors showed that this upregulation occurs primarily in cholangiocytes, the cells lining the bile duct. Higher expression of NR0B2 results in reprogramming that alters the metabolic function of these cells and predisposes them to malignancy.
This study, which is the first to look at omics data for PSC, highlights the involvement of genes and pathways that were previously unrecognized in disease pathogenesis. By using data derived from human PSC liver biopsies and animal models of PSC, the authors were able to validate their findings across species, which strengthened their conclusions. This approach also showed that NR0B2 deregulation occurs primarily in cholangiocytes, suggesting that future therapies should be targeted to this cell type. These important findings will improve our understanding of this rare but clinically significant disease.
Kari Nejak-Bowen, PhD, MBA, is associate professor, department of pathology, University of Pittsburgh School of Medicine. She has no relevant conflicts of interest.
Primary sclerosing cholangitis (PSC) is a bile duct disease with few therapeutic options other than liver transplant, and thus its prognosis remains grim. Additionally, the factors that cause the disease are not well understood. Identifying the pathways and genes involved in PSC pathogenesis could help in the development of potential therapeutic targets.
In this report Desterke et al. mined public data sets to identify and define a PSC-specific network. Of the top genes in this list, NR0B2 stood out as a potential player in pathogenesis because of its involvement in regulating bile acid metabolism. The authors showed that upregulation of NR0B2 occurs early in the disease process and in patient tissues is independent of variables such as gender and sex. Interestingly, the authors showed that this upregulation occurs primarily in cholangiocytes, the cells lining the bile duct. Higher expression of NR0B2 results in reprogramming that alters the metabolic function of these cells and predisposes them to malignancy.
This study, which is the first to look at omics data for PSC, highlights the involvement of genes and pathways that were previously unrecognized in disease pathogenesis. By using data derived from human PSC liver biopsies and animal models of PSC, the authors were able to validate their findings across species, which strengthened their conclusions. This approach also showed that NR0B2 deregulation occurs primarily in cholangiocytes, suggesting that future therapies should be targeted to this cell type. These important findings will improve our understanding of this rare but clinically significant disease.
Kari Nejak-Bowen, PhD, MBA, is associate professor, department of pathology, University of Pittsburgh School of Medicine. She has no relevant conflicts of interest.
, according to a study published in Gastro Hep Advances.
PSC is very rare, with an incidence of 0-1.3 cases per 100,000 people per year. Because up to 80% of patients with PSC also have inflammatory bowel disease (IBD), a link along the gut-liver axis is suspected. So far, scientists have not understood the causes of PSC, the main complications of which include biliary cirrhosis, bacterial cholangitis, and cholangiocarcinoma.
No treatment is currently available for PSC, but the findings of this genomics study suggest several targets that may be worth pursuing, particularly the gene NR0B2.
“The therapeutic targeting of NR0B2 may potentiate that of FXR [farnesoid X receptor] and enable action on early events of the disease and prevent its progression,” wrote Christophe Desterke, PhD, of the Paul-Brousse Hospital, the French National Institute of Health and Medical Research, and the University of Paris-Saclay in Villejuif, France, and his associates.
The researchers used an algorithmic tool to mine the MEDLINE/PubMed/NCBI database using the three key symptoms of PSC – biliary fibrosis, biliary inflammation, and biliary stasis – as their keywords. This approach allowed them to discover the genes and potential pathways related to PSC in published research text or in clinical, animal, and cellular models.
The researchers initially found 525 genes linked to PSC and then compared them to RNA data from liver biopsies taken from patients with liver disease from various causes. This process led to a ranking of the 10 best markers of PSC, based on the data-mining method and the genes’ association with one or more of the three PSC symptoms.
At the top of the list is NR1H4, also called FXR, which ranks most highly with biliary fibrosis and biliary stasis. NR1H4 is already a clear target for cholestatic and fatty liver diseases, the authors noted. The other genes, in descending order of relevance, are: ABCB4, ABCB11, TGFB1, IFNL3, PNPLA3, IL6, TLR4, GPBAR1, and IL17A. In addition, complications of PSC were significantly associated with upregulation of TNFRS12A, SOX9, ANXA2, MMP7, and LCN2.
Separately, investigation of the 525 initially identified genes in mouse models of PSC revealed that NR0B2 is also a key player in the pathogenesis of PSC.
"NR0B2 was upregulated in PSC livers independent of gender, age, and body mass index,” the authors reported. “Importantly, it was not dependent on the severity of PSC in the prognostic cohort, suggesting that this may be an early event during the disease.”
The researchers also found a possible pathway explaining the autoimmunity of PSC – the involvement of CD274, also known as the PDL1 immune checkpoint. The authors noted that the PDL1 inhibitor pembrolizumab has previously been reported as a cause of sclerosing cholangitis.
Further, the researchers discovered overexpression of FOXP3 in the livers of patients with PSC. Because FOXP3 determines what T-cell subtypes look like, the finding suggests that an “imbalance between Foxp3þ regulatory T cells and Th17 cells may be involved in IBD and PSC,” they wrote.
Also of note was the overexpression of SOX9 in the livers of patients with PSC whose profiles suggested the worst clinical prognoses.
Finally, the researchers identified three genes as potentially involved in development of cholangiocarcinoma: GSTA3, ID2 (which is overexpressed in biliary tract cancer), and especially TMEM45A, a protein in cells’ Golgi apparatus that is already known to be involved in the development of several other cancers.
The research was funded by the French National Institute of Health and Medical Research. The authors reported no conflicts of interest.
, according to a study published in Gastro Hep Advances.
PSC is very rare, with an incidence of 0-1.3 cases per 100,000 people per year. Because up to 80% of patients with PSC also have inflammatory bowel disease (IBD), a link along the gut-liver axis is suspected. So far, scientists have not understood the causes of PSC, the main complications of which include biliary cirrhosis, bacterial cholangitis, and cholangiocarcinoma.
No treatment is currently available for PSC, but the findings of this genomics study suggest several targets that may be worth pursuing, particularly the gene NR0B2.
“The therapeutic targeting of NR0B2 may potentiate that of FXR [farnesoid X receptor] and enable action on early events of the disease and prevent its progression,” wrote Christophe Desterke, PhD, of the Paul-Brousse Hospital, the French National Institute of Health and Medical Research, and the University of Paris-Saclay in Villejuif, France, and his associates.
The researchers used an algorithmic tool to mine the MEDLINE/PubMed/NCBI database using the three key symptoms of PSC – biliary fibrosis, biliary inflammation, and biliary stasis – as their keywords. This approach allowed them to discover the genes and potential pathways related to PSC in published research text or in clinical, animal, and cellular models.
The researchers initially found 525 genes linked to PSC and then compared them to RNA data from liver biopsies taken from patients with liver disease from various causes. This process led to a ranking of the 10 best markers of PSC, based on the data-mining method and the genes’ association with one or more of the three PSC symptoms.
At the top of the list is NR1H4, also called FXR, which ranks most highly with biliary fibrosis and biliary stasis. NR1H4 is already a clear target for cholestatic and fatty liver diseases, the authors noted. The other genes, in descending order of relevance, are: ABCB4, ABCB11, TGFB1, IFNL3, PNPLA3, IL6, TLR4, GPBAR1, and IL17A. In addition, complications of PSC were significantly associated with upregulation of TNFRS12A, SOX9, ANXA2, MMP7, and LCN2.
Separately, investigation of the 525 initially identified genes in mouse models of PSC revealed that NR0B2 is also a key player in the pathogenesis of PSC.
"NR0B2 was upregulated in PSC livers independent of gender, age, and body mass index,” the authors reported. “Importantly, it was not dependent on the severity of PSC in the prognostic cohort, suggesting that this may be an early event during the disease.”
The researchers also found a possible pathway explaining the autoimmunity of PSC – the involvement of CD274, also known as the PDL1 immune checkpoint. The authors noted that the PDL1 inhibitor pembrolizumab has previously been reported as a cause of sclerosing cholangitis.
Further, the researchers discovered overexpression of FOXP3 in the livers of patients with PSC. Because FOXP3 determines what T-cell subtypes look like, the finding suggests that an “imbalance between Foxp3þ regulatory T cells and Th17 cells may be involved in IBD and PSC,” they wrote.
Also of note was the overexpression of SOX9 in the livers of patients with PSC whose profiles suggested the worst clinical prognoses.
Finally, the researchers identified three genes as potentially involved in development of cholangiocarcinoma: GSTA3, ID2 (which is overexpressed in biliary tract cancer), and especially TMEM45A, a protein in cells’ Golgi apparatus that is already known to be involved in the development of several other cancers.
The research was funded by the French National Institute of Health and Medical Research. The authors reported no conflicts of interest.
FROM GASTRO HEP ADVANCES
Proximal ADR could become important new quality metric
Measurement of the proximal adenoma detection rate may be an important new quality metric for screening colonoscopy, propose researchers in a study that found proportionately more adenomas detected in the right colon with increasing patient age.
As patients age, in fact, the rate of increase of proximal adenomas is far greater than for distal adenomas in both men and women and in all races, wrote Lawrence Kosinski, MD, founder and chief medical officer of Sonar MD in Chicago, and colleagues.
Adenoma detection rate (ADR), the proportion of screening colonoscopies performed by a physician that detect at least one histologically confirmed colorectal adenoma or adenocarcinoma, has become an accepted quality metric because of the association of high ADR with lower rates of postcolonoscopy colorectal cancer (CRC). ADR varies widely among endoscopists, however, which could be related to differences in adenoma detection in different parts of the colon.
the authors wrote. “These differences could be clinically important if CRC occurs after colonoscopy.” The study was published in Techniques and Innovations in Gastrointestinal Endoscopy .
Dr. Kosinski and colleagues analyzed retrospective claims data from all colonoscopies performed between 2016-2018 submitted to the Health Care Service Corporation, which is the exclusive Blue Cross Blue Shield licensee for Illinois, Texas, Oklahoma, New Mexico, and Montana. All 50 states were represented in the patient population, though Illinois and Texas accounted for 66% of the cases.
The research team limited the study group to include patients who underwent a screening colonoscopy, representing 30.9% of the total population. They further refined the data to include only screening colonoscopies performed by the 710 endoscopists with at least 100 screenings during the study period, representing 34.5% of the total patients. They also excluded 10,685 cases with family history because the high-risk patients could alter the results.
Using ICD-10 codes, the researchers identified the polyp detection locations and then calculated the ADR for the entire colon (T-ADR) and both the proximal (P-ADR) and distal (D-ADR) colon to determine differences in the ratio of P-ADR versus D-ADR by age, sex, and race. They were unable to determine whether the polyps were adenomas or sessile serrated lesions, so the ADR calculations include both.
The 182,296 screening colonoscopies included 93,164 women (51%) and 89,132 men (49%). About 79% of patients were aged 50-64 years, and 5.8% were under age 50. The dataset preceded the U.S. Preventive Services Task Force recommendation to initiate screening at age 45.
Overall, T-ADR was consistent with accepted norms in both men (25.99%) and women (19.72%). Compared with women, men had a 4.5% higher prevalence of proximal adenomas and a 2.5% higher prevalence of distal adenomas at any age. The small cohort of Native Americans (296 patients) had a numerically higher T-ADR, P-ADR, and D-ADR than other groups.
By age, T-ADR increased significantly with advancing age, from 0.13 in patients under age 40 to 0.39 in ages 70 and older. The increase was driven by a sharp rise in P-ADR, particularly after age 60. There was a relatively small increase in D-ADR after ages 45-49.
Notably, the P-ADR/D-ADR ratio increased from 1.2 in patients under age 40 to 2.65 in ages 75 and older in both men and women.
Since the experience of the endoscopist affects ADR, the research team also calculated the ADR data by the number of total colonoscopies by endoscopist per decile. T-ADR, P-ADR, and D-ADR were associated directly in a linear relationship with the number of total colonoscopies performed. The slope of the P-ADR trendline was 2.3 times higher than the slope of the D-ADR trendline, indicating a higher volume of procedures directly related to higher polyp detection – specifically the P-ADR.
“Our data demonstrate that it is feasible to measure P-ADR in clinical practice,” the authors wrote. “We propose that P-ADR be considered a quality metric for colonoscopy.”
In addition, because of considerable variation in ADR based on age and sex, calculated ADR should be normalized by the age and sex of the specific patient profile of each endoscopist so relevant benchmarks can be established based on practice demographics, they wrote. For example, an endoscopist with a practice that includes predominantly younger women would have a different benchmark than a colleague with an older male population.
“With appropriate use of gender and age adjustments to ADR, endoscopists in need of further education and mentoring can be identified,” they wrote.
The authors declared no funding for the study. One author reported advisory roles for several medical companies, and the remaining authors disclosed no conflicts.
“What gets measured gets managed” is a common mantra in quality improvement. Adenoma detection rate (ADR) is currently one measure of a “quality” colonoscopy and a metric that is studied to determine means for improvement. ADR is an imperfect measure as it does not necessarily reflect true risk of a postcolonoscopy cancer in all parts of the colon since many post colonoscopy cancers are found in the proximal colon. To try to better understand potential differences in polyps found in different segments of the colon, and to determine if this was a metric that could be measured, Kosinski and colleagues studied a large claims database to understand the potential difference in ADR in the proximal versus distal colon.
Sunanda Kane, MD, MSPH, is professor of medicine in the division of gastroenterology and hepatology at the Mayo Clinic, Rochester, Minn. Dr. Kane has no relevant conflicts of interest.
“What gets measured gets managed” is a common mantra in quality improvement. Adenoma detection rate (ADR) is currently one measure of a “quality” colonoscopy and a metric that is studied to determine means for improvement. ADR is an imperfect measure as it does not necessarily reflect true risk of a postcolonoscopy cancer in all parts of the colon since many post colonoscopy cancers are found in the proximal colon. To try to better understand potential differences in polyps found in different segments of the colon, and to determine if this was a metric that could be measured, Kosinski and colleagues studied a large claims database to understand the potential difference in ADR in the proximal versus distal colon.
Sunanda Kane, MD, MSPH, is professor of medicine in the division of gastroenterology and hepatology at the Mayo Clinic, Rochester, Minn. Dr. Kane has no relevant conflicts of interest.
“What gets measured gets managed” is a common mantra in quality improvement. Adenoma detection rate (ADR) is currently one measure of a “quality” colonoscopy and a metric that is studied to determine means for improvement. ADR is an imperfect measure as it does not necessarily reflect true risk of a postcolonoscopy cancer in all parts of the colon since many post colonoscopy cancers are found in the proximal colon. To try to better understand potential differences in polyps found in different segments of the colon, and to determine if this was a metric that could be measured, Kosinski and colleagues studied a large claims database to understand the potential difference in ADR in the proximal versus distal colon.
Sunanda Kane, MD, MSPH, is professor of medicine in the division of gastroenterology and hepatology at the Mayo Clinic, Rochester, Minn. Dr. Kane has no relevant conflicts of interest.
Measurement of the proximal adenoma detection rate may be an important new quality metric for screening colonoscopy, propose researchers in a study that found proportionately more adenomas detected in the right colon with increasing patient age.
As patients age, in fact, the rate of increase of proximal adenomas is far greater than for distal adenomas in both men and women and in all races, wrote Lawrence Kosinski, MD, founder and chief medical officer of Sonar MD in Chicago, and colleagues.
Adenoma detection rate (ADR), the proportion of screening colonoscopies performed by a physician that detect at least one histologically confirmed colorectal adenoma or adenocarcinoma, has become an accepted quality metric because of the association of high ADR with lower rates of postcolonoscopy colorectal cancer (CRC). ADR varies widely among endoscopists, however, which could be related to differences in adenoma detection in different parts of the colon.
the authors wrote. “These differences could be clinically important if CRC occurs after colonoscopy.” The study was published in Techniques and Innovations in Gastrointestinal Endoscopy .
Dr. Kosinski and colleagues analyzed retrospective claims data from all colonoscopies performed between 2016-2018 submitted to the Health Care Service Corporation, which is the exclusive Blue Cross Blue Shield licensee for Illinois, Texas, Oklahoma, New Mexico, and Montana. All 50 states were represented in the patient population, though Illinois and Texas accounted for 66% of the cases.
The research team limited the study group to include patients who underwent a screening colonoscopy, representing 30.9% of the total population. They further refined the data to include only screening colonoscopies performed by the 710 endoscopists with at least 100 screenings during the study period, representing 34.5% of the total patients. They also excluded 10,685 cases with family history because the high-risk patients could alter the results.
Using ICD-10 codes, the researchers identified the polyp detection locations and then calculated the ADR for the entire colon (T-ADR) and both the proximal (P-ADR) and distal (D-ADR) colon to determine differences in the ratio of P-ADR versus D-ADR by age, sex, and race. They were unable to determine whether the polyps were adenomas or sessile serrated lesions, so the ADR calculations include both.
The 182,296 screening colonoscopies included 93,164 women (51%) and 89,132 men (49%). About 79% of patients were aged 50-64 years, and 5.8% were under age 50. The dataset preceded the U.S. Preventive Services Task Force recommendation to initiate screening at age 45.
Overall, T-ADR was consistent with accepted norms in both men (25.99%) and women (19.72%). Compared with women, men had a 4.5% higher prevalence of proximal adenomas and a 2.5% higher prevalence of distal adenomas at any age. The small cohort of Native Americans (296 patients) had a numerically higher T-ADR, P-ADR, and D-ADR than other groups.
By age, T-ADR increased significantly with advancing age, from 0.13 in patients under age 40 to 0.39 in ages 70 and older. The increase was driven by a sharp rise in P-ADR, particularly after age 60. There was a relatively small increase in D-ADR after ages 45-49.
Notably, the P-ADR/D-ADR ratio increased from 1.2 in patients under age 40 to 2.65 in ages 75 and older in both men and women.
Since the experience of the endoscopist affects ADR, the research team also calculated the ADR data by the number of total colonoscopies by endoscopist per decile. T-ADR, P-ADR, and D-ADR were associated directly in a linear relationship with the number of total colonoscopies performed. The slope of the P-ADR trendline was 2.3 times higher than the slope of the D-ADR trendline, indicating a higher volume of procedures directly related to higher polyp detection – specifically the P-ADR.
“Our data demonstrate that it is feasible to measure P-ADR in clinical practice,” the authors wrote. “We propose that P-ADR be considered a quality metric for colonoscopy.”
In addition, because of considerable variation in ADR based on age and sex, calculated ADR should be normalized by the age and sex of the specific patient profile of each endoscopist so relevant benchmarks can be established based on practice demographics, they wrote. For example, an endoscopist with a practice that includes predominantly younger women would have a different benchmark than a colleague with an older male population.
“With appropriate use of gender and age adjustments to ADR, endoscopists in need of further education and mentoring can be identified,” they wrote.
The authors declared no funding for the study. One author reported advisory roles for several medical companies, and the remaining authors disclosed no conflicts.
Measurement of the proximal adenoma detection rate may be an important new quality metric for screening colonoscopy, propose researchers in a study that found proportionately more adenomas detected in the right colon with increasing patient age.
As patients age, in fact, the rate of increase of proximal adenomas is far greater than for distal adenomas in both men and women and in all races, wrote Lawrence Kosinski, MD, founder and chief medical officer of Sonar MD in Chicago, and colleagues.
Adenoma detection rate (ADR), the proportion of screening colonoscopies performed by a physician that detect at least one histologically confirmed colorectal adenoma or adenocarcinoma, has become an accepted quality metric because of the association of high ADR with lower rates of postcolonoscopy colorectal cancer (CRC). ADR varies widely among endoscopists, however, which could be related to differences in adenoma detection in different parts of the colon.
the authors wrote. “These differences could be clinically important if CRC occurs after colonoscopy.” The study was published in Techniques and Innovations in Gastrointestinal Endoscopy .
Dr. Kosinski and colleagues analyzed retrospective claims data from all colonoscopies performed between 2016-2018 submitted to the Health Care Service Corporation, which is the exclusive Blue Cross Blue Shield licensee for Illinois, Texas, Oklahoma, New Mexico, and Montana. All 50 states were represented in the patient population, though Illinois and Texas accounted for 66% of the cases.
The research team limited the study group to include patients who underwent a screening colonoscopy, representing 30.9% of the total population. They further refined the data to include only screening colonoscopies performed by the 710 endoscopists with at least 100 screenings during the study period, representing 34.5% of the total patients. They also excluded 10,685 cases with family history because the high-risk patients could alter the results.
Using ICD-10 codes, the researchers identified the polyp detection locations and then calculated the ADR for the entire colon (T-ADR) and both the proximal (P-ADR) and distal (D-ADR) colon to determine differences in the ratio of P-ADR versus D-ADR by age, sex, and race. They were unable to determine whether the polyps were adenomas or sessile serrated lesions, so the ADR calculations include both.
The 182,296 screening colonoscopies included 93,164 women (51%) and 89,132 men (49%). About 79% of patients were aged 50-64 years, and 5.8% were under age 50. The dataset preceded the U.S. Preventive Services Task Force recommendation to initiate screening at age 45.
Overall, T-ADR was consistent with accepted norms in both men (25.99%) and women (19.72%). Compared with women, men had a 4.5% higher prevalence of proximal adenomas and a 2.5% higher prevalence of distal adenomas at any age. The small cohort of Native Americans (296 patients) had a numerically higher T-ADR, P-ADR, and D-ADR than other groups.
By age, T-ADR increased significantly with advancing age, from 0.13 in patients under age 40 to 0.39 in ages 70 and older. The increase was driven by a sharp rise in P-ADR, particularly after age 60. There was a relatively small increase in D-ADR after ages 45-49.
Notably, the P-ADR/D-ADR ratio increased from 1.2 in patients under age 40 to 2.65 in ages 75 and older in both men and women.
Since the experience of the endoscopist affects ADR, the research team also calculated the ADR data by the number of total colonoscopies by endoscopist per decile. T-ADR, P-ADR, and D-ADR were associated directly in a linear relationship with the number of total colonoscopies performed. The slope of the P-ADR trendline was 2.3 times higher than the slope of the D-ADR trendline, indicating a higher volume of procedures directly related to higher polyp detection – specifically the P-ADR.
“Our data demonstrate that it is feasible to measure P-ADR in clinical practice,” the authors wrote. “We propose that P-ADR be considered a quality metric for colonoscopy.”
In addition, because of considerable variation in ADR based on age and sex, calculated ADR should be normalized by the age and sex of the specific patient profile of each endoscopist so relevant benchmarks can be established based on practice demographics, they wrote. For example, an endoscopist with a practice that includes predominantly younger women would have a different benchmark than a colleague with an older male population.
“With appropriate use of gender and age adjustments to ADR, endoscopists in need of further education and mentoring can be identified,” they wrote.
The authors declared no funding for the study. One author reported advisory roles for several medical companies, and the remaining authors disclosed no conflicts.
FROM TECHNIQUES AND INNOVATIONS IN GASTROINTESTINAL ENDOSCOPY
Genomic features may explain sex differences in HBV-associated HCC
In findings that point to a potential treatment strategy, researchers in China have discovered how two risk factors – male hormones and aflatoxin – may drive hepatocellular carcinoma (HCC). The liver cancer genetics and biology differ between men and women and help explain why aflatoxin exposure increases the risk of HCC in hepatitis B virus (HBV)–infected patients, particularly in men.
The researchers found evidence that androgen signaling increased aflatoxin metabolism and genotoxicity, reduced DNA repair capabilities, and quelled antitumor immunity, Chungui Xu, PhD, with the State Key Lab of Molecular Oncology at the National Cancer Center at Peking Union Medical College in Beijing, and colleagues wrote. The study was published in Cellular and Molecular Gastroenterology and Hepatology.
“Androgen signaling in the context of genotoxic stress repressed DNA damage repair,” the authors wrote. “The alteration caused more nuclear DNA leakage into cytosol to activate the cGAS-STING pathway, which increased T-cell infiltration into tumor mass and improved anti–programmed cell death protein 1 [PD-1] immunotherapy in HCCs.”
In the study, the researchers conducted genomic analyses of HCC tumor samples from people with HBV who were exposed to aflatoxin in Qidong, China, an area that until recently had some of the highest liver cancer rates in the world. In subsequent experiments in cell lines and mice, the team investigated how the genetic alterations and transcription dysfunctions reflected the combined carcinogenic effects of aflatoxin and HPV.
Dr. Xu and colleagues performed whole-genome, whole-exome, and RNA sequencing on tumor and matched nonneoplastic liver tissues from 101 HBV-related HCC patients (47 men and 54 women). The patients had received primary hepatectomy without systemic treatment or radiation therapy and were followed for 5 years. Aflatoxin exposure was confirmed by recording aflatoxin M1 in their urine 3-18 years before HCC diagnosis. For comparison, the research team analyzed 113 HBV-related HCC samples without aflatoxin exposure from the Cancer Genome Atlas database. They also looked at 181 Chinese HCC samples from the International Cancer Genome Consortium that had no record of aflatoxin exposure. They found no sex differences in mutation patterns for previously identified HCC driver genes, but the tumor mutation burden was higher in the Qidong set.
In the Qidong samples, the research team identified 71 genes with significantly different mutation frequencies by sex. Among those, 62 genes were associated more frequently with men, and 9 genes were associated with women. None of the genes have been reported previously as HCC drivers, although some have been found previously in other cancers, such as melanoma, lung cancer, and thyroid adenocarcinoma.
From whole-genome sequencing of 88 samples, the research team detected HBV integration in 37 samples and identified 110 breakpoints. No difference in HBV breakpoint numbers was detected between the sexes, though there were differences in somatic mutation profiles and in HBV integration, and only men had HBV breakpoints binding to androgen receptors.
From RNA sequencing of 87 samples, the research team identified 3,070 significantly differentially expressed genes between men and women. The transcription levels of estrogen receptor 1 and 2 were similar between the sexes, but men expressed higher androgen receptor levels.
The researchers then analyzed the variation in gene expression between the male and female gene sets to understand HCC transcriptional dysfunction. The samples from men showed different biological capabilities, with several signaling pathways related to HCC development and progression that were up-regulated. The male samples also showed repression of specific antitumor immunity.
Men’s HCC tumor samples expressed higher levels of aflatoxin metabolism-related genes, such as AHR and CYP1A1, but lower levels of GSTM1 genes.
Turning to cell lines, the researchers used HBV-positive HepG2.2.15 cells and PLC/PRF/5 cells to test sex hormones in the regulation of AHR and CYP1A1 and how their interactions affected aflatoxin B1 cytotoxicity. After aflatoxin treatment, the addition of testosterone to the cultures significantly enhanced the transcription levels of AHR and CYP1A1. The aflatoxin dose needed to cause cell death was reduced by half in the presence of testosterone.
DNA damage from aflatoxin activates DNA repair mechanisms, so the research team analyzed different repair pathways. In the male tumor samples, the most down-regulated pathway was NHEJ. The male samples expressed significantly lower levels of NHEJ factors than did the female samples, including XRCC4, MRE11, ATM, HRCC5, and NBN.
In cell lines, the researchers tested the effects of androgen alone and with aflatoxin on the regulation of NHEJ factors. The transcriptional levels of XRCC4, LIG4, and MRE11 were reduced significantly in cells treated with both aflatoxin and testosterone, compared with those treated with aflatoxin alone. Notably, the addition of 17beta-estradiol estrogen partially reversed the reduction of XRCC4 and MRE11 expression.
The tumor samples from men also showed different gene signatures of immune responses and inflammation from the samples from women. The genes related to interferon I signaling and response were up-regulated significantly in male samples but not in female samples. In addition, the samples from men showed repression of antigen-specific antitumor immunity. The research team detected significantly increased CD8+T-cell infiltration in tumor tissues of men but not women, as well as higher transcriptional levels of PD-1 and CTLA-4, which are two immune checkpoint proteins on T cells that keep them from attacking the tumor. The data indicate that androgen signaling in established HBV-related HCCs contribute to the development of an immunosuppressive microenvironment, the authors wrote, which could render the tumor sensitive to anti–PD-1 immunotherapy.
In mice, the researchers examined the impact of a favorable androgen pathway on anti–PD-1 treatment effects against hepatoma. They administered tamoxifen to block ER signaling in syngeneic tumor-bearing mice. In both male and female mice, tamoxifen enhanced the anti–PD-1 effects to eradicate the tumor quickly. They also administered flutamide to tumor-bearing mice to block the androgen pathway and found no significant difference in tumor growth in female mice, but in male mice, tumors grew faster in the flutamide-treated mice.
“Therapeutics that favor androgen signaling and/or blocking estrogen signaling may provide a new strategy to improve the efficacy of immune checkpoint inhibitors against HCC in combination with radiotherapy or chemotherapy that induced DNA damage,” the authors wrote. “The adjuvant effects of tamoxifen for favorable androgen signaling to boost the anti–PD-1 effect in HCC patients needs future study in a prospective HCC cohort.”
The study was supported by the National Natural Science Foundation Fund of China, Innovation Fund for Medical Sciences of Chinese Academy of Medical Sciences, State Key Project for Infectious Diseases, and Peking Union Medical College. The authors disclosed no conflicts.
To read an editorial that accompanied this study in Cellular and Molecular Gastroenterology and Hepatology, go to https://www.cmghjournal.org/article/S2352-345X(22)00234-X/fulltext.
In findings that point to a potential treatment strategy, researchers in China have discovered how two risk factors – male hormones and aflatoxin – may drive hepatocellular carcinoma (HCC). The liver cancer genetics and biology differ between men and women and help explain why aflatoxin exposure increases the risk of HCC in hepatitis B virus (HBV)–infected patients, particularly in men.
The researchers found evidence that androgen signaling increased aflatoxin metabolism and genotoxicity, reduced DNA repair capabilities, and quelled antitumor immunity, Chungui Xu, PhD, with the State Key Lab of Molecular Oncology at the National Cancer Center at Peking Union Medical College in Beijing, and colleagues wrote. The study was published in Cellular and Molecular Gastroenterology and Hepatology.
“Androgen signaling in the context of genotoxic stress repressed DNA damage repair,” the authors wrote. “The alteration caused more nuclear DNA leakage into cytosol to activate the cGAS-STING pathway, which increased T-cell infiltration into tumor mass and improved anti–programmed cell death protein 1 [PD-1] immunotherapy in HCCs.”
In the study, the researchers conducted genomic analyses of HCC tumor samples from people with HBV who were exposed to aflatoxin in Qidong, China, an area that until recently had some of the highest liver cancer rates in the world. In subsequent experiments in cell lines and mice, the team investigated how the genetic alterations and transcription dysfunctions reflected the combined carcinogenic effects of aflatoxin and HPV.
Dr. Xu and colleagues performed whole-genome, whole-exome, and RNA sequencing on tumor and matched nonneoplastic liver tissues from 101 HBV-related HCC patients (47 men and 54 women). The patients had received primary hepatectomy without systemic treatment or radiation therapy and were followed for 5 years. Aflatoxin exposure was confirmed by recording aflatoxin M1 in their urine 3-18 years before HCC diagnosis. For comparison, the research team analyzed 113 HBV-related HCC samples without aflatoxin exposure from the Cancer Genome Atlas database. They also looked at 181 Chinese HCC samples from the International Cancer Genome Consortium that had no record of aflatoxin exposure. They found no sex differences in mutation patterns for previously identified HCC driver genes, but the tumor mutation burden was higher in the Qidong set.
In the Qidong samples, the research team identified 71 genes with significantly different mutation frequencies by sex. Among those, 62 genes were associated more frequently with men, and 9 genes were associated with women. None of the genes have been reported previously as HCC drivers, although some have been found previously in other cancers, such as melanoma, lung cancer, and thyroid adenocarcinoma.
From whole-genome sequencing of 88 samples, the research team detected HBV integration in 37 samples and identified 110 breakpoints. No difference in HBV breakpoint numbers was detected between the sexes, though there were differences in somatic mutation profiles and in HBV integration, and only men had HBV breakpoints binding to androgen receptors.
From RNA sequencing of 87 samples, the research team identified 3,070 significantly differentially expressed genes between men and women. The transcription levels of estrogen receptor 1 and 2 were similar between the sexes, but men expressed higher androgen receptor levels.
The researchers then analyzed the variation in gene expression between the male and female gene sets to understand HCC transcriptional dysfunction. The samples from men showed different biological capabilities, with several signaling pathways related to HCC development and progression that were up-regulated. The male samples also showed repression of specific antitumor immunity.
Men’s HCC tumor samples expressed higher levels of aflatoxin metabolism-related genes, such as AHR and CYP1A1, but lower levels of GSTM1 genes.
Turning to cell lines, the researchers used HBV-positive HepG2.2.15 cells and PLC/PRF/5 cells to test sex hormones in the regulation of AHR and CYP1A1 and how their interactions affected aflatoxin B1 cytotoxicity. After aflatoxin treatment, the addition of testosterone to the cultures significantly enhanced the transcription levels of AHR and CYP1A1. The aflatoxin dose needed to cause cell death was reduced by half in the presence of testosterone.
DNA damage from aflatoxin activates DNA repair mechanisms, so the research team analyzed different repair pathways. In the male tumor samples, the most down-regulated pathway was NHEJ. The male samples expressed significantly lower levels of NHEJ factors than did the female samples, including XRCC4, MRE11, ATM, HRCC5, and NBN.
In cell lines, the researchers tested the effects of androgen alone and with aflatoxin on the regulation of NHEJ factors. The transcriptional levels of XRCC4, LIG4, and MRE11 were reduced significantly in cells treated with both aflatoxin and testosterone, compared with those treated with aflatoxin alone. Notably, the addition of 17beta-estradiol estrogen partially reversed the reduction of XRCC4 and MRE11 expression.
The tumor samples from men also showed different gene signatures of immune responses and inflammation from the samples from women. The genes related to interferon I signaling and response were up-regulated significantly in male samples but not in female samples. In addition, the samples from men showed repression of antigen-specific antitumor immunity. The research team detected significantly increased CD8+T-cell infiltration in tumor tissues of men but not women, as well as higher transcriptional levels of PD-1 and CTLA-4, which are two immune checkpoint proteins on T cells that keep them from attacking the tumor. The data indicate that androgen signaling in established HBV-related HCCs contribute to the development of an immunosuppressive microenvironment, the authors wrote, which could render the tumor sensitive to anti–PD-1 immunotherapy.
In mice, the researchers examined the impact of a favorable androgen pathway on anti–PD-1 treatment effects against hepatoma. They administered tamoxifen to block ER signaling in syngeneic tumor-bearing mice. In both male and female mice, tamoxifen enhanced the anti–PD-1 effects to eradicate the tumor quickly. They also administered flutamide to tumor-bearing mice to block the androgen pathway and found no significant difference in tumor growth in female mice, but in male mice, tumors grew faster in the flutamide-treated mice.
“Therapeutics that favor androgen signaling and/or blocking estrogen signaling may provide a new strategy to improve the efficacy of immune checkpoint inhibitors against HCC in combination with radiotherapy or chemotherapy that induced DNA damage,” the authors wrote. “The adjuvant effects of tamoxifen for favorable androgen signaling to boost the anti–PD-1 effect in HCC patients needs future study in a prospective HCC cohort.”
The study was supported by the National Natural Science Foundation Fund of China, Innovation Fund for Medical Sciences of Chinese Academy of Medical Sciences, State Key Project for Infectious Diseases, and Peking Union Medical College. The authors disclosed no conflicts.
To read an editorial that accompanied this study in Cellular and Molecular Gastroenterology and Hepatology, go to https://www.cmghjournal.org/article/S2352-345X(22)00234-X/fulltext.
In findings that point to a potential treatment strategy, researchers in China have discovered how two risk factors – male hormones and aflatoxin – may drive hepatocellular carcinoma (HCC). The liver cancer genetics and biology differ between men and women and help explain why aflatoxin exposure increases the risk of HCC in hepatitis B virus (HBV)–infected patients, particularly in men.
The researchers found evidence that androgen signaling increased aflatoxin metabolism and genotoxicity, reduced DNA repair capabilities, and quelled antitumor immunity, Chungui Xu, PhD, with the State Key Lab of Molecular Oncology at the National Cancer Center at Peking Union Medical College in Beijing, and colleagues wrote. The study was published in Cellular and Molecular Gastroenterology and Hepatology.
“Androgen signaling in the context of genotoxic stress repressed DNA damage repair,” the authors wrote. “The alteration caused more nuclear DNA leakage into cytosol to activate the cGAS-STING pathway, which increased T-cell infiltration into tumor mass and improved anti–programmed cell death protein 1 [PD-1] immunotherapy in HCCs.”
In the study, the researchers conducted genomic analyses of HCC tumor samples from people with HBV who were exposed to aflatoxin in Qidong, China, an area that until recently had some of the highest liver cancer rates in the world. In subsequent experiments in cell lines and mice, the team investigated how the genetic alterations and transcription dysfunctions reflected the combined carcinogenic effects of aflatoxin and HPV.
Dr. Xu and colleagues performed whole-genome, whole-exome, and RNA sequencing on tumor and matched nonneoplastic liver tissues from 101 HBV-related HCC patients (47 men and 54 women). The patients had received primary hepatectomy without systemic treatment or radiation therapy and were followed for 5 years. Aflatoxin exposure was confirmed by recording aflatoxin M1 in their urine 3-18 years before HCC diagnosis. For comparison, the research team analyzed 113 HBV-related HCC samples without aflatoxin exposure from the Cancer Genome Atlas database. They also looked at 181 Chinese HCC samples from the International Cancer Genome Consortium that had no record of aflatoxin exposure. They found no sex differences in mutation patterns for previously identified HCC driver genes, but the tumor mutation burden was higher in the Qidong set.
In the Qidong samples, the research team identified 71 genes with significantly different mutation frequencies by sex. Among those, 62 genes were associated more frequently with men, and 9 genes were associated with women. None of the genes have been reported previously as HCC drivers, although some have been found previously in other cancers, such as melanoma, lung cancer, and thyroid adenocarcinoma.
From whole-genome sequencing of 88 samples, the research team detected HBV integration in 37 samples and identified 110 breakpoints. No difference in HBV breakpoint numbers was detected between the sexes, though there were differences in somatic mutation profiles and in HBV integration, and only men had HBV breakpoints binding to androgen receptors.
From RNA sequencing of 87 samples, the research team identified 3,070 significantly differentially expressed genes between men and women. The transcription levels of estrogen receptor 1 and 2 were similar between the sexes, but men expressed higher androgen receptor levels.
The researchers then analyzed the variation in gene expression between the male and female gene sets to understand HCC transcriptional dysfunction. The samples from men showed different biological capabilities, with several signaling pathways related to HCC development and progression that were up-regulated. The male samples also showed repression of specific antitumor immunity.
Men’s HCC tumor samples expressed higher levels of aflatoxin metabolism-related genes, such as AHR and CYP1A1, but lower levels of GSTM1 genes.
Turning to cell lines, the researchers used HBV-positive HepG2.2.15 cells and PLC/PRF/5 cells to test sex hormones in the regulation of AHR and CYP1A1 and how their interactions affected aflatoxin B1 cytotoxicity. After aflatoxin treatment, the addition of testosterone to the cultures significantly enhanced the transcription levels of AHR and CYP1A1. The aflatoxin dose needed to cause cell death was reduced by half in the presence of testosterone.
DNA damage from aflatoxin activates DNA repair mechanisms, so the research team analyzed different repair pathways. In the male tumor samples, the most down-regulated pathway was NHEJ. The male samples expressed significantly lower levels of NHEJ factors than did the female samples, including XRCC4, MRE11, ATM, HRCC5, and NBN.
In cell lines, the researchers tested the effects of androgen alone and with aflatoxin on the regulation of NHEJ factors. The transcriptional levels of XRCC4, LIG4, and MRE11 were reduced significantly in cells treated with both aflatoxin and testosterone, compared with those treated with aflatoxin alone. Notably, the addition of 17beta-estradiol estrogen partially reversed the reduction of XRCC4 and MRE11 expression.
The tumor samples from men also showed different gene signatures of immune responses and inflammation from the samples from women. The genes related to interferon I signaling and response were up-regulated significantly in male samples but not in female samples. In addition, the samples from men showed repression of antigen-specific antitumor immunity. The research team detected significantly increased CD8+T-cell infiltration in tumor tissues of men but not women, as well as higher transcriptional levels of PD-1 and CTLA-4, which are two immune checkpoint proteins on T cells that keep them from attacking the tumor. The data indicate that androgen signaling in established HBV-related HCCs contribute to the development of an immunosuppressive microenvironment, the authors wrote, which could render the tumor sensitive to anti–PD-1 immunotherapy.
In mice, the researchers examined the impact of a favorable androgen pathway on anti–PD-1 treatment effects against hepatoma. They administered tamoxifen to block ER signaling in syngeneic tumor-bearing mice. In both male and female mice, tamoxifen enhanced the anti–PD-1 effects to eradicate the tumor quickly. They also administered flutamide to tumor-bearing mice to block the androgen pathway and found no significant difference in tumor growth in female mice, but in male mice, tumors grew faster in the flutamide-treated mice.
“Therapeutics that favor androgen signaling and/or blocking estrogen signaling may provide a new strategy to improve the efficacy of immune checkpoint inhibitors against HCC in combination with radiotherapy or chemotherapy that induced DNA damage,” the authors wrote. “The adjuvant effects of tamoxifen for favorable androgen signaling to boost the anti–PD-1 effect in HCC patients needs future study in a prospective HCC cohort.”
The study was supported by the National Natural Science Foundation Fund of China, Innovation Fund for Medical Sciences of Chinese Academy of Medical Sciences, State Key Project for Infectious Diseases, and Peking Union Medical College. The authors disclosed no conflicts.
To read an editorial that accompanied this study in Cellular and Molecular Gastroenterology and Hepatology, go to https://www.cmghjournal.org/article/S2352-345X(22)00234-X/fulltext.
FROM CELLULAR AND MOLECULAR GASTROENTEROLOGY AND HEPATOLOGY
Nonheavy alcohol use associated with liver fibrosis, NASH
according to a new report.
An analysis of current drinkers in the Framingham Heart Study found that a higher number of drinks per week and higher frequency of drinking were associated with increased odds of fibrosis among patients whose consumption fell below the threshold for heavy alcohol use.
“Although the detrimental effects of heavy alcohol use are well accepted, there is no consensus guideline on how to counsel patients about how nonheavy alcohol use may affect liver health,” Brooke Rice, MD, an internal medicine resident at Boston University, said in an interview.
“Current terminology classifies fatty liver disease as either alcoholic or nonalcoholic,” she said. “Our results call this strict categorization into question, suggesting that even nonheavy alcohol use should be considered as a factor contributing to more advanced nonalcoholic fatty liver disease [NAFLD] phenotypes.”
The study was published online in Clinical Gastroenterology and Hepatology.
Analyzing associations
NAFLD and alcohol-related liver disease, which are the most common causes of chronic liver disease worldwide, are histologically identical but distinguished by the presence of significant alcohol use, the study authors wrote.
Heavy alcohol use, based on guidelines from the American Association for the Study of Liver Diseases, is defined as more than 14 drinks per week for women or more than 21 drinks per week for men.
Although heavy alcohol use is consistently associated with cirrhosis and steatohepatitis, studies of nonheavy alcohol use have shown conflicting results, the authors wrote. However, evidence suggests that the pattern of alcohol consumption – particularly increased weekly drinking and binge drinking – may be an important predictor.
Dr. Rice and colleagues conducted a cross-sectional study of 2,629 current drinkers in the Framingham Heart Study who completed alcohol-use questionnaires and vibration-controlled transient elastography between April 2016 and April 2019. They analyzed the association between fibrosis and several alcohol-use measures, including total consumption and drinking patterns, among nonheavy alcohol users whose liver disease would be classified as “nonalcoholic” by current nomenclature.
The research team defined clinically significant fibrosis as a liver stiffness measurement of 8.2 kPa or higher. For at-risk NASH, the researchers used two FibroScan-AST (FAST) score thresholds – greater than 0.35 or 0.67 and higher. They also considered additional metabolic factors such as physical activity, body mass index, blood pressure, glucose measures, and metabolic syndrome.
Participants were asked to estimate the frequency of alcohol use (average number of drinking days per week during the past year) and the usual quantity of alcohol consumed (average number of drinks on a typical drinking day during the past year). Researchers multiplied the figures to estimate the average total number of drinks per week.
Among the 2,629 current drinkers (53% women, 47% men), the average age was 54 years, 7.2% had diabetes, and 26.9% met the criteria for metabolic syndrome. Participants drank about 3 days per week on average with a usual consumption of two drinks per drinking day, averaging a total weekly alcohol consumption of six drinks.
The average liver stiffness measurement was 5.6 kPa, and 8.2% had significant fibrosis.
At the FAST score threshold of 0.67 or greater, 1.9% of participants were likely to have at-risk NASH, with a higher prevalence in those with obesity (4.5%) or diabetes (9.5%). At the FAST score threshold of greater than 0.35, the prevalence of at-risk NASH was 12.4%, which was higher in those with obesity (26.3%) or diabetes (34.4%).
Overall, an increased total number of drinks per week and higher frequency of drinking days were associated with increased odds of fibrosis.
Almost 17.5% of participants engaged in risky weekly drinking, which was defined as 8 or more drinks per week for women and 15 or more drinks per week for men. Risky weekly drinking was also associated with higher odds of fibrosis.
After excluding 158 heavy drinkers, the prevalence of fibrosis was unchanged at 8%, and an increased total of drinks per week remained significantly associated with fibrosis.
In addition, multiple alcohol-use measures were positively associated with a FAST score greater than 0.35 and were similar after excluding heavy alcohol users. These measures include the number of drinks per week, the frequency of drinking days, and binge drinking.
“We showed that nonheavy alcohol use is associated with fibrosis and at-risk NASH, which are both predictors of long-term liver-related morbidity and mortality,” Dr. Rice said.
Implications for patient care
The findings have important implications for both NAFLD clinical trials and patient care, the study authors wrote. For instance, the U.S. Dietary Guidelines for Americans recommend limiting alcohol use to one drink per day for women and two drinks per day for men.
“Our results reinforce the importance of encouraging all patients to reduce alcohol intake as much as possible and to at least adhere to current U.S. Dietary Guidelines recommended limits,” Dr. Rice said. “Almost half of participants in our study consumed in excess of these limits, which strongly associated with at-risk NASH.”
Additional long-term studies are needed to determine the benefits of limiting alcohol consumption to reduce liver-related morbidity and mortality, the authors wrote.
The effect of alcohol consumption on liver health “has been controversial, since some studies have suggested that nonheavy alcohol use can even have some beneficial metabolic effects and has been associated with reduced risk of fatty liver disease, while other studies have found that nonheavy alcohol use is associated with increased risk for liver-related clinical outcomes,” Fredrik Åberg, MD, PhD, a hepatologist and liver transplant specialist at Helsinki University Hospital, said in an interview.
Dr. Åberg wasn’t involved with this study but has researched alcohol consumption and liver disease. Among non–heavy alcohol users, drinking more alcohol per week is associated with increased hospitalization for liver disease, hepatocellular carcinoma, and liver-related death, he and his colleagues have found.
“We concluded that the net effect of non-heavy drinking on the liver is harm,” he said. “Overall, this study by Rice and colleagues supports the recommendation that persons with mild liver disease should reduce their drinking, and persons with severe liver disease (cirrhosis and advanced fibrosis) should abstain from alcohol use.”
The study authors are supported in part by the National Institute of Diabetes and Digestive and Kidney Diseases, a Doris Duke Charitable Foundation Grant, a Gilead Sciences Research Scholars Award, the Boston University Department of Medicine Career Investment Award, and the Boston University Clinical Translational Science Institute. The Framingham Heart Study is supported in part by the National Heart, Lung, and Blood Institute. The authors and Dr. Åberg reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
according to a new report.
An analysis of current drinkers in the Framingham Heart Study found that a higher number of drinks per week and higher frequency of drinking were associated with increased odds of fibrosis among patients whose consumption fell below the threshold for heavy alcohol use.
“Although the detrimental effects of heavy alcohol use are well accepted, there is no consensus guideline on how to counsel patients about how nonheavy alcohol use may affect liver health,” Brooke Rice, MD, an internal medicine resident at Boston University, said in an interview.
“Current terminology classifies fatty liver disease as either alcoholic or nonalcoholic,” she said. “Our results call this strict categorization into question, suggesting that even nonheavy alcohol use should be considered as a factor contributing to more advanced nonalcoholic fatty liver disease [NAFLD] phenotypes.”
The study was published online in Clinical Gastroenterology and Hepatology.
Analyzing associations
NAFLD and alcohol-related liver disease, which are the most common causes of chronic liver disease worldwide, are histologically identical but distinguished by the presence of significant alcohol use, the study authors wrote.
Heavy alcohol use, based on guidelines from the American Association for the Study of Liver Diseases, is defined as more than 14 drinks per week for women or more than 21 drinks per week for men.
Although heavy alcohol use is consistently associated with cirrhosis and steatohepatitis, studies of nonheavy alcohol use have shown conflicting results, the authors wrote. However, evidence suggests that the pattern of alcohol consumption – particularly increased weekly drinking and binge drinking – may be an important predictor.
Dr. Rice and colleagues conducted a cross-sectional study of 2,629 current drinkers in the Framingham Heart Study who completed alcohol-use questionnaires and vibration-controlled transient elastography between April 2016 and April 2019. They analyzed the association between fibrosis and several alcohol-use measures, including total consumption and drinking patterns, among nonheavy alcohol users whose liver disease would be classified as “nonalcoholic” by current nomenclature.
The research team defined clinically significant fibrosis as a liver stiffness measurement of 8.2 kPa or higher. For at-risk NASH, the researchers used two FibroScan-AST (FAST) score thresholds – greater than 0.35 or 0.67 and higher. They also considered additional metabolic factors such as physical activity, body mass index, blood pressure, glucose measures, and metabolic syndrome.
Participants were asked to estimate the frequency of alcohol use (average number of drinking days per week during the past year) and the usual quantity of alcohol consumed (average number of drinks on a typical drinking day during the past year). Researchers multiplied the figures to estimate the average total number of drinks per week.
Among the 2,629 current drinkers (53% women, 47% men), the average age was 54 years, 7.2% had diabetes, and 26.9% met the criteria for metabolic syndrome. Participants drank about 3 days per week on average with a usual consumption of two drinks per drinking day, averaging a total weekly alcohol consumption of six drinks.
The average liver stiffness measurement was 5.6 kPa, and 8.2% had significant fibrosis.
At the FAST score threshold of 0.67 or greater, 1.9% of participants were likely to have at-risk NASH, with a higher prevalence in those with obesity (4.5%) or diabetes (9.5%). At the FAST score threshold of greater than 0.35, the prevalence of at-risk NASH was 12.4%, which was higher in those with obesity (26.3%) or diabetes (34.4%).
Overall, an increased total number of drinks per week and higher frequency of drinking days were associated with increased odds of fibrosis.
Almost 17.5% of participants engaged in risky weekly drinking, which was defined as 8 or more drinks per week for women and 15 or more drinks per week for men. Risky weekly drinking was also associated with higher odds of fibrosis.
After excluding 158 heavy drinkers, the prevalence of fibrosis was unchanged at 8%, and an increased total of drinks per week remained significantly associated with fibrosis.
In addition, multiple alcohol-use measures were positively associated with a FAST score greater than 0.35 and were similar after excluding heavy alcohol users. These measures include the number of drinks per week, the frequency of drinking days, and binge drinking.
“We showed that nonheavy alcohol use is associated with fibrosis and at-risk NASH, which are both predictors of long-term liver-related morbidity and mortality,” Dr. Rice said.
Implications for patient care
The findings have important implications for both NAFLD clinical trials and patient care, the study authors wrote. For instance, the U.S. Dietary Guidelines for Americans recommend limiting alcohol use to one drink per day for women and two drinks per day for men.
“Our results reinforce the importance of encouraging all patients to reduce alcohol intake as much as possible and to at least adhere to current U.S. Dietary Guidelines recommended limits,” Dr. Rice said. “Almost half of participants in our study consumed in excess of these limits, which strongly associated with at-risk NASH.”
Additional long-term studies are needed to determine the benefits of limiting alcohol consumption to reduce liver-related morbidity and mortality, the authors wrote.
The effect of alcohol consumption on liver health “has been controversial, since some studies have suggested that nonheavy alcohol use can even have some beneficial metabolic effects and has been associated with reduced risk of fatty liver disease, while other studies have found that nonheavy alcohol use is associated with increased risk for liver-related clinical outcomes,” Fredrik Åberg, MD, PhD, a hepatologist and liver transplant specialist at Helsinki University Hospital, said in an interview.
Dr. Åberg wasn’t involved with this study but has researched alcohol consumption and liver disease. Among non–heavy alcohol users, drinking more alcohol per week is associated with increased hospitalization for liver disease, hepatocellular carcinoma, and liver-related death, he and his colleagues have found.
“We concluded that the net effect of non-heavy drinking on the liver is harm,” he said. “Overall, this study by Rice and colleagues supports the recommendation that persons with mild liver disease should reduce their drinking, and persons with severe liver disease (cirrhosis and advanced fibrosis) should abstain from alcohol use.”
The study authors are supported in part by the National Institute of Diabetes and Digestive and Kidney Diseases, a Doris Duke Charitable Foundation Grant, a Gilead Sciences Research Scholars Award, the Boston University Department of Medicine Career Investment Award, and the Boston University Clinical Translational Science Institute. The Framingham Heart Study is supported in part by the National Heart, Lung, and Blood Institute. The authors and Dr. Åberg reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
according to a new report.
An analysis of current drinkers in the Framingham Heart Study found that a higher number of drinks per week and higher frequency of drinking were associated with increased odds of fibrosis among patients whose consumption fell below the threshold for heavy alcohol use.
“Although the detrimental effects of heavy alcohol use are well accepted, there is no consensus guideline on how to counsel patients about how nonheavy alcohol use may affect liver health,” Brooke Rice, MD, an internal medicine resident at Boston University, said in an interview.
“Current terminology classifies fatty liver disease as either alcoholic or nonalcoholic,” she said. “Our results call this strict categorization into question, suggesting that even nonheavy alcohol use should be considered as a factor contributing to more advanced nonalcoholic fatty liver disease [NAFLD] phenotypes.”
The study was published online in Clinical Gastroenterology and Hepatology.
Analyzing associations
NAFLD and alcohol-related liver disease, which are the most common causes of chronic liver disease worldwide, are histologically identical but distinguished by the presence of significant alcohol use, the study authors wrote.
Heavy alcohol use, based on guidelines from the American Association for the Study of Liver Diseases, is defined as more than 14 drinks per week for women or more than 21 drinks per week for men.
Although heavy alcohol use is consistently associated with cirrhosis and steatohepatitis, studies of nonheavy alcohol use have shown conflicting results, the authors wrote. However, evidence suggests that the pattern of alcohol consumption – particularly increased weekly drinking and binge drinking – may be an important predictor.
Dr. Rice and colleagues conducted a cross-sectional study of 2,629 current drinkers in the Framingham Heart Study who completed alcohol-use questionnaires and vibration-controlled transient elastography between April 2016 and April 2019. They analyzed the association between fibrosis and several alcohol-use measures, including total consumption and drinking patterns, among nonheavy alcohol users whose liver disease would be classified as “nonalcoholic” by current nomenclature.
The research team defined clinically significant fibrosis as a liver stiffness measurement of 8.2 kPa or higher. For at-risk NASH, the researchers used two FibroScan-AST (FAST) score thresholds – greater than 0.35 or 0.67 and higher. They also considered additional metabolic factors such as physical activity, body mass index, blood pressure, glucose measures, and metabolic syndrome.
Participants were asked to estimate the frequency of alcohol use (average number of drinking days per week during the past year) and the usual quantity of alcohol consumed (average number of drinks on a typical drinking day during the past year). Researchers multiplied the figures to estimate the average total number of drinks per week.
Among the 2,629 current drinkers (53% women, 47% men), the average age was 54 years, 7.2% had diabetes, and 26.9% met the criteria for metabolic syndrome. Participants drank about 3 days per week on average with a usual consumption of two drinks per drinking day, averaging a total weekly alcohol consumption of six drinks.
The average liver stiffness measurement was 5.6 kPa, and 8.2% had significant fibrosis.
At the FAST score threshold of 0.67 or greater, 1.9% of participants were likely to have at-risk NASH, with a higher prevalence in those with obesity (4.5%) or diabetes (9.5%). At the FAST score threshold of greater than 0.35, the prevalence of at-risk NASH was 12.4%, which was higher in those with obesity (26.3%) or diabetes (34.4%).
Overall, an increased total number of drinks per week and higher frequency of drinking days were associated with increased odds of fibrosis.
Almost 17.5% of participants engaged in risky weekly drinking, which was defined as 8 or more drinks per week for women and 15 or more drinks per week for men. Risky weekly drinking was also associated with higher odds of fibrosis.
After excluding 158 heavy drinkers, the prevalence of fibrosis was unchanged at 8%, and an increased total of drinks per week remained significantly associated with fibrosis.
In addition, multiple alcohol-use measures were positively associated with a FAST score greater than 0.35 and were similar after excluding heavy alcohol users. These measures include the number of drinks per week, the frequency of drinking days, and binge drinking.
“We showed that nonheavy alcohol use is associated with fibrosis and at-risk NASH, which are both predictors of long-term liver-related morbidity and mortality,” Dr. Rice said.
Implications for patient care
The findings have important implications for both NAFLD clinical trials and patient care, the study authors wrote. For instance, the U.S. Dietary Guidelines for Americans recommend limiting alcohol use to one drink per day for women and two drinks per day for men.
“Our results reinforce the importance of encouraging all patients to reduce alcohol intake as much as possible and to at least adhere to current U.S. Dietary Guidelines recommended limits,” Dr. Rice said. “Almost half of participants in our study consumed in excess of these limits, which strongly associated with at-risk NASH.”
Additional long-term studies are needed to determine the benefits of limiting alcohol consumption to reduce liver-related morbidity and mortality, the authors wrote.
The effect of alcohol consumption on liver health “has been controversial, since some studies have suggested that nonheavy alcohol use can even have some beneficial metabolic effects and has been associated with reduced risk of fatty liver disease, while other studies have found that nonheavy alcohol use is associated with increased risk for liver-related clinical outcomes,” Fredrik Åberg, MD, PhD, a hepatologist and liver transplant specialist at Helsinki University Hospital, said in an interview.
Dr. Åberg wasn’t involved with this study but has researched alcohol consumption and liver disease. Among non–heavy alcohol users, drinking more alcohol per week is associated with increased hospitalization for liver disease, hepatocellular carcinoma, and liver-related death, he and his colleagues have found.
“We concluded that the net effect of non-heavy drinking on the liver is harm,” he said. “Overall, this study by Rice and colleagues supports the recommendation that persons with mild liver disease should reduce their drinking, and persons with severe liver disease (cirrhosis and advanced fibrosis) should abstain from alcohol use.”
The study authors are supported in part by the National Institute of Diabetes and Digestive and Kidney Diseases, a Doris Duke Charitable Foundation Grant, a Gilead Sciences Research Scholars Award, the Boston University Department of Medicine Career Investment Award, and the Boston University Clinical Translational Science Institute. The Framingham Heart Study is supported in part by the National Heart, Lung, and Blood Institute. The authors and Dr. Åberg reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM CLINICAL GASTROENTEROLOGY AND HEPATOLOGY
Dietary interventions can support IBD treatment
For Crohn’s disease, a diet low in refined carbohydrates and a symptoms-guided diet appeared to help with remission, yet reduction of refined carbohydrates or red meat didn’t reduce the risk of relapse. For ulcerative colitis, solid food diets were similar to control measures.
“The Internet has a dizzying array of diet variants touted to benefit inflammation and IBD, which has led to much confusion among patients, and even clinicians, over what is truly effective or not,” Berkeley Limketkai, MD, PhD, director of clinical research at the Center for Inflammatory Bowel Disease at the University of California, Los Angeles, said in an interview.
“Even experiences shared by well-meaning individuals might not be generalizable to others,” he said. “The lack of clarity on what is or is not effective motivated us to perform this systematic review and meta-analysis.”
The study was published online in Clinical Gastroenterology and Hepatology.
Analyzing diets
Some nutritional therapies, such as exclusive enteral nutrition, have good evidence to support their use in the treatment of IBD, Dr. Limketkai said. However, patients often find maintaining a liquid diet difficult, particularly over a long period of time, so clinicians and patients have been interested in solid food diets as a treatment for IBD.
In 2019, Dr. Limketkai and colleagues conducted a systematic review and meta-analysis of randomized controlled trials focused on solid food diets for IBD that was published with the Cochrane Collaboration. At that time, the data were considered sparse, and the certainty of evidence was very low or low. Since then, several high-quality trials have been published.
For this study, Dr. Limketkai and colleagues conducted an updated review of 36 studies and a meta-analysis of 27 studies that compared a solid food diet with a control diet in patients with Crohn’s disease or ulcerative colitis. The intervention arm had to involve a well-defined diet, not merely a “usual” diet.
Among the studies, 12 evaluated dietary interventions for inducing clinical remission in patients with active Crohn’s disease, and 639 patients were involved. Overall, a low–refined carbohydrate diet was superior to a high-carbohydrate diet or a low-fiber diet. In addition, a symptoms-guided diet, which sequentially eliminated foods that aggravated a patient’s symptoms, was superior to conventional nutrition advice. However, the studies had serious imprecisions and very low certainty of evidence.
Compared with respective controls, a highly restrictive organic diet, a low-microparticle diet, and a low-calcium diet were ineffective at inducing remission of Crohn’s disease. Studies focused on immunoglobulin G-based measures were also inconsistent.
When comparing diets touted to benefit patients with Crohn’s disease, the Specific Carbohydrate Diet was similar to the Mediterranean diet and the whole-food diet, though the certainty of evidence was low. Partial enteral nutrition was similar to exclusive enteral nutrition, though there was substantial statistical heterogeneity between studies and very low certainty of evidence.
For maintenance of Crohn’s disease remission, researchers evaluated 14 studies that included 1,211 patients with inactive disease. Partial enteral nutrition appeared to reduce the risk of relapse, although evidence certainty was very low. In contrast, reducing red meat or refined carbohydrates did not lower the risk of relapse.
“These findings seemingly contradict our belief that red meat and refined carbohydrates have proinflammatory effects, although there are other studies that appear to show inconsistent, weak, or no association between consumption of unprocessed red meat and disease,” Dr. Limketkai said. “The caveat is that our findings are based on weak evidence, which may change as more studies are performed over time.”
For induction of remission in ulcerative colitis, researchers evaluated three studies that included 124 participants with active disease. When compared with participants’ usual diet, there was no benefit from a diet that excluded symptom-provoking foods, fried foods, refined carbohydrates, additives, preservatives, most condiments, spices, and beverages other than boiled water. Other studies found no benefit from eliminating cow milk protein or gluten.
For maintenance of ulcerative colitis remission, they looked at four studies that included 101 patients with inactive disease. Overall, there was no benefit from a carrageenan-free diet, anti-inflammatory diet, or cow milk protein elimination diet.
Helping patients
Although the certainty of evidence remains very low or low for most dietary trials in IBD, the emerging data suggest that nutrition plays an important role in IBD management and should be considered in the overall treatment plan for patients, the study authors wrote.
“Patients continue to look for ways to control their IBD, particularly with diet. Providers continue to struggle with making evidence-based recommendations about dietary interventions for IBD. This systematic review is a useful tool for providers to advise their patients,” James D. Lewis, MD, associate director of the inflammatory bowel diseases program at the University of Pennsylvania, Philadelphia, said in an interview.
Dr. Lewis, who wasn’t involved with this study, has researched dietary interventions for IBD. He and his colleagues have found that reducing red meat does not lower the rate of Crohn’s disease flares and that the Mediterranean diet and Specific Carbohydrate Diet appear to be similar for inducing clinical remission.
Based on this review, partial enteral nutrition could be an option for patients with Crohn’s disease, Dr. Lewis said.
“Partial enteral nutrition is much easier than exclusive enteral nutrition for patients,” he said. “However, there remains uncertainty as to whether the solid food component of a partial enteral nutrition approach impacts outcomes.”
As more dietary studies become available, the certainty of evidence could improve and lead to better recommendations for patients, Dr. Limketkai and colleagues wrote. They are conducting several studies focused on the concept of precision nutrition.
“While certain diets may be helpful and effective for IBD, different diets work differently in different people. This concept is no different than the fact that different IBD medications work differently in different individuals,” Dr. Limketkai said. “However, given the current state of evidence for dietary interventions in IBD, we still have a long path of research ahead of us.”
The study received no funding. The study authors reported no conflicts of interest. Dr. Lewis reported no relevant disclosures.
A version of this article first appeared on Medscape.com.
For Crohn’s disease, a diet low in refined carbohydrates and a symptoms-guided diet appeared to help with remission, yet reduction of refined carbohydrates or red meat didn’t reduce the risk of relapse. For ulcerative colitis, solid food diets were similar to control measures.
“The Internet has a dizzying array of diet variants touted to benefit inflammation and IBD, which has led to much confusion among patients, and even clinicians, over what is truly effective or not,” Berkeley Limketkai, MD, PhD, director of clinical research at the Center for Inflammatory Bowel Disease at the University of California, Los Angeles, said in an interview.
“Even experiences shared by well-meaning individuals might not be generalizable to others,” he said. “The lack of clarity on what is or is not effective motivated us to perform this systematic review and meta-analysis.”
The study was published online in Clinical Gastroenterology and Hepatology.
Analyzing diets
Some nutritional therapies, such as exclusive enteral nutrition, have good evidence to support their use in the treatment of IBD, Dr. Limketkai said. However, patients often find maintaining a liquid diet difficult, particularly over a long period of time, so clinicians and patients have been interested in solid food diets as a treatment for IBD.
In 2019, Dr. Limketkai and colleagues conducted a systematic review and meta-analysis of randomized controlled trials focused on solid food diets for IBD that was published with the Cochrane Collaboration. At that time, the data were considered sparse, and the certainty of evidence was very low or low. Since then, several high-quality trials have been published.
For this study, Dr. Limketkai and colleagues conducted an updated review of 36 studies and a meta-analysis of 27 studies that compared a solid food diet with a control diet in patients with Crohn’s disease or ulcerative colitis. The intervention arm had to involve a well-defined diet, not merely a “usual” diet.
Among the studies, 12 evaluated dietary interventions for inducing clinical remission in patients with active Crohn’s disease, and 639 patients were involved. Overall, a low–refined carbohydrate diet was superior to a high-carbohydrate diet or a low-fiber diet. In addition, a symptoms-guided diet, which sequentially eliminated foods that aggravated a patient’s symptoms, was superior to conventional nutrition advice. However, the studies had serious imprecisions and very low certainty of evidence.
Compared with respective controls, a highly restrictive organic diet, a low-microparticle diet, and a low-calcium diet were ineffective at inducing remission of Crohn’s disease. Studies focused on immunoglobulin G-based measures were also inconsistent.
When comparing diets touted to benefit patients with Crohn’s disease, the Specific Carbohydrate Diet was similar to the Mediterranean diet and the whole-food diet, though the certainty of evidence was low. Partial enteral nutrition was similar to exclusive enteral nutrition, though there was substantial statistical heterogeneity between studies and very low certainty of evidence.
For maintenance of Crohn’s disease remission, researchers evaluated 14 studies that included 1,211 patients with inactive disease. Partial enteral nutrition appeared to reduce the risk of relapse, although evidence certainty was very low. In contrast, reducing red meat or refined carbohydrates did not lower the risk of relapse.
“These findings seemingly contradict our belief that red meat and refined carbohydrates have proinflammatory effects, although there are other studies that appear to show inconsistent, weak, or no association between consumption of unprocessed red meat and disease,” Dr. Limketkai said. “The caveat is that our findings are based on weak evidence, which may change as more studies are performed over time.”
For induction of remission in ulcerative colitis, researchers evaluated three studies that included 124 participants with active disease. When compared with participants’ usual diet, there was no benefit from a diet that excluded symptom-provoking foods, fried foods, refined carbohydrates, additives, preservatives, most condiments, spices, and beverages other than boiled water. Other studies found no benefit from eliminating cow milk protein or gluten.
For maintenance of ulcerative colitis remission, they looked at four studies that included 101 patients with inactive disease. Overall, there was no benefit from a carrageenan-free diet, anti-inflammatory diet, or cow milk protein elimination diet.
Helping patients
Although the certainty of evidence remains very low or low for most dietary trials in IBD, the emerging data suggest that nutrition plays an important role in IBD management and should be considered in the overall treatment plan for patients, the study authors wrote.
“Patients continue to look for ways to control their IBD, particularly with diet. Providers continue to struggle with making evidence-based recommendations about dietary interventions for IBD. This systematic review is a useful tool for providers to advise their patients,” James D. Lewis, MD, associate director of the inflammatory bowel diseases program at the University of Pennsylvania, Philadelphia, said in an interview.
Dr. Lewis, who wasn’t involved with this study, has researched dietary interventions for IBD. He and his colleagues have found that reducing red meat does not lower the rate of Crohn’s disease flares and that the Mediterranean diet and Specific Carbohydrate Diet appear to be similar for inducing clinical remission.
Based on this review, partial enteral nutrition could be an option for patients with Crohn’s disease, Dr. Lewis said.
“Partial enteral nutrition is much easier than exclusive enteral nutrition for patients,” he said. “However, there remains uncertainty as to whether the solid food component of a partial enteral nutrition approach impacts outcomes.”
As more dietary studies become available, the certainty of evidence could improve and lead to better recommendations for patients, Dr. Limketkai and colleagues wrote. They are conducting several studies focused on the concept of precision nutrition.
“While certain diets may be helpful and effective for IBD, different diets work differently in different people. This concept is no different than the fact that different IBD medications work differently in different individuals,” Dr. Limketkai said. “However, given the current state of evidence for dietary interventions in IBD, we still have a long path of research ahead of us.”
The study received no funding. The study authors reported no conflicts of interest. Dr. Lewis reported no relevant disclosures.
A version of this article first appeared on Medscape.com.
For Crohn’s disease, a diet low in refined carbohydrates and a symptoms-guided diet appeared to help with remission, yet reduction of refined carbohydrates or red meat didn’t reduce the risk of relapse. For ulcerative colitis, solid food diets were similar to control measures.
“The Internet has a dizzying array of diet variants touted to benefit inflammation and IBD, which has led to much confusion among patients, and even clinicians, over what is truly effective or not,” Berkeley Limketkai, MD, PhD, director of clinical research at the Center for Inflammatory Bowel Disease at the University of California, Los Angeles, said in an interview.
“Even experiences shared by well-meaning individuals might not be generalizable to others,” he said. “The lack of clarity on what is or is not effective motivated us to perform this systematic review and meta-analysis.”
The study was published online in Clinical Gastroenterology and Hepatology.
Analyzing diets
Some nutritional therapies, such as exclusive enteral nutrition, have good evidence to support their use in the treatment of IBD, Dr. Limketkai said. However, patients often find maintaining a liquid diet difficult, particularly over a long period of time, so clinicians and patients have been interested in solid food diets as a treatment for IBD.
In 2019, Dr. Limketkai and colleagues conducted a systematic review and meta-analysis of randomized controlled trials focused on solid food diets for IBD that was published with the Cochrane Collaboration. At that time, the data were considered sparse, and the certainty of evidence was very low or low. Since then, several high-quality trials have been published.
For this study, Dr. Limketkai and colleagues conducted an updated review of 36 studies and a meta-analysis of 27 studies that compared a solid food diet with a control diet in patients with Crohn’s disease or ulcerative colitis. The intervention arm had to involve a well-defined diet, not merely a “usual” diet.
Among the studies, 12 evaluated dietary interventions for inducing clinical remission in patients with active Crohn’s disease, and 639 patients were involved. Overall, a low–refined carbohydrate diet was superior to a high-carbohydrate diet or a low-fiber diet. In addition, a symptoms-guided diet, which sequentially eliminated foods that aggravated a patient’s symptoms, was superior to conventional nutrition advice. However, the studies had serious imprecisions and very low certainty of evidence.
Compared with respective controls, a highly restrictive organic diet, a low-microparticle diet, and a low-calcium diet were ineffective at inducing remission of Crohn’s disease. Studies focused on immunoglobulin G-based measures were also inconsistent.
When comparing diets touted to benefit patients with Crohn’s disease, the Specific Carbohydrate Diet was similar to the Mediterranean diet and the whole-food diet, though the certainty of evidence was low. Partial enteral nutrition was similar to exclusive enteral nutrition, though there was substantial statistical heterogeneity between studies and very low certainty of evidence.
For maintenance of Crohn’s disease remission, researchers evaluated 14 studies that included 1,211 patients with inactive disease. Partial enteral nutrition appeared to reduce the risk of relapse, although evidence certainty was very low. In contrast, reducing red meat or refined carbohydrates did not lower the risk of relapse.
“These findings seemingly contradict our belief that red meat and refined carbohydrates have proinflammatory effects, although there are other studies that appear to show inconsistent, weak, or no association between consumption of unprocessed red meat and disease,” Dr. Limketkai said. “The caveat is that our findings are based on weak evidence, which may change as more studies are performed over time.”
For induction of remission in ulcerative colitis, researchers evaluated three studies that included 124 participants with active disease. When compared with participants’ usual diet, there was no benefit from a diet that excluded symptom-provoking foods, fried foods, refined carbohydrates, additives, preservatives, most condiments, spices, and beverages other than boiled water. Other studies found no benefit from eliminating cow milk protein or gluten.
For maintenance of ulcerative colitis remission, they looked at four studies that included 101 patients with inactive disease. Overall, there was no benefit from a carrageenan-free diet, anti-inflammatory diet, or cow milk protein elimination diet.
Helping patients
Although the certainty of evidence remains very low or low for most dietary trials in IBD, the emerging data suggest that nutrition plays an important role in IBD management and should be considered in the overall treatment plan for patients, the study authors wrote.
“Patients continue to look for ways to control their IBD, particularly with diet. Providers continue to struggle with making evidence-based recommendations about dietary interventions for IBD. This systematic review is a useful tool for providers to advise their patients,” James D. Lewis, MD, associate director of the inflammatory bowel diseases program at the University of Pennsylvania, Philadelphia, said in an interview.
Dr. Lewis, who wasn’t involved with this study, has researched dietary interventions for IBD. He and his colleagues have found that reducing red meat does not lower the rate of Crohn’s disease flares and that the Mediterranean diet and Specific Carbohydrate Diet appear to be similar for inducing clinical remission.
Based on this review, partial enteral nutrition could be an option for patients with Crohn’s disease, Dr. Lewis said.
“Partial enteral nutrition is much easier than exclusive enteral nutrition for patients,” he said. “However, there remains uncertainty as to whether the solid food component of a partial enteral nutrition approach impacts outcomes.”
As more dietary studies become available, the certainty of evidence could improve and lead to better recommendations for patients, Dr. Limketkai and colleagues wrote. They are conducting several studies focused on the concept of precision nutrition.
“While certain diets may be helpful and effective for IBD, different diets work differently in different people. This concept is no different than the fact that different IBD medications work differently in different individuals,” Dr. Limketkai said. “However, given the current state of evidence for dietary interventions in IBD, we still have a long path of research ahead of us.”
The study received no funding. The study authors reported no conflicts of interest. Dr. Lewis reported no relevant disclosures.
A version of this article first appeared on Medscape.com.
FROM CLINICAL GASTROENTEROLOGY AND HEPATOLOGY
Liver cancer exacts high financial toll on older adults
In the first year after a diagnosis of HCC, median Medicare payments exceed $65,000 and out-of-pocket costs top $10,000.
Even after adjustment for the presence of cirrhosis and its related costs, patients with HCC still have Medicare payments exceeding $50,000 and out-of-pocket costs topping $7000.
Amit Singal, MD, of UT Southwestern Medical Center in Dallas, and colleagues reported their findings in Clinical Gastroenterology and Hepatology.
Common and costly
HCC, the most common type of primary liver cancer, is a leading cause of death in patients with cirrhosis and is projected to become the third leading cause of cancer-related death in the United States by 2040, the researchers wrote.
The treatment landscape for HCC has changed over the past decade, with expanded surgical options, introduction of radiation-based therapies, and approval of immunotherapies – all of which are costly.
Yet the magnitude of financial burden of HCC therapy has been understudied, the researchers noted.
To investigate, Dr. Singal and colleagues evaluated Surveillance, Epidemiology, and End Results (SEER)–Medicare data for 4,525 adults with traditional Medicare coverage who were diagnosed with HCC between 2011 and 2015 and a propensity-matched cohort of 4,525 adults with cirrhosis but no HCC as a comparator group to tease out HCC-specific costs beyond those related to cirrhosis. Patients in Medicare managed care were excluded because their cost information is not available in the database.
In the first year after a diagnosis of HCC, the median total Medicare payments were $66,338 (interquartile range [IQR], $30,931-$158,740) and patient liabilities (a proxy for out-of-pocket costs) were $10,008 (IQR, $5,427-$19,669).
First-year costs were higher for patients with HCC than matched patients without HCC; the former group incurred median incremental Medicare payments of $50,110 (IQR, $14,242-$136,239) and patient liabilities of $7,166 (IQR, $2,401-$16,099), the investigators found.
Patients with early-stage HCC had lower incremental patient liabilities (median, $4,195 vs. $8,238) and Medicare payments (median, $28,207 vs. $59,509) than did their peers with larger tumor burden.
NAFLD notably tied to higher costs
Factors associated with higher HCC-related costs were nonalcoholic fatty liver disease (NAFLD) etiology, higher comorbidities, presence of ascites and hepatic encephalopathy, and larger tumor burden.
The researchers said that the link between NAFLD and higher costs is notable, given that NAFLD is an increasingly common underlying cause of HCC.
The link between larger tumor burden and higher costs underscores “another benefit of HCC surveillance and early detection,” they added.
“By separating the financial liabilities borne by patients and Medicare, we provide a clearer outlook of how cancer-related costs are distributed between patients and public payers,” Dr. Singal and colleagues said.
“Our findings will inform policy interventions and will help formulate better financial supports targeting the most vulnerable HCC patients,” they concluded.
The study had no commercial funding. Dr. Singal has been on advisory boards and served as a consultant for Wako Diagnostics, Glycotest, Exact Sciences, Roche, Genentech, Bayer, Eisai, BMS, Exelixis, AstraZeneca, and TARGET RWE.
A version of this article first appeared on Medscape.com.
In the first year after a diagnosis of HCC, median Medicare payments exceed $65,000 and out-of-pocket costs top $10,000.
Even after adjustment for the presence of cirrhosis and its related costs, patients with HCC still have Medicare payments exceeding $50,000 and out-of-pocket costs topping $7000.
Amit Singal, MD, of UT Southwestern Medical Center in Dallas, and colleagues reported their findings in Clinical Gastroenterology and Hepatology.
Common and costly
HCC, the most common type of primary liver cancer, is a leading cause of death in patients with cirrhosis and is projected to become the third leading cause of cancer-related death in the United States by 2040, the researchers wrote.
The treatment landscape for HCC has changed over the past decade, with expanded surgical options, introduction of radiation-based therapies, and approval of immunotherapies – all of which are costly.
Yet the magnitude of financial burden of HCC therapy has been understudied, the researchers noted.
To investigate, Dr. Singal and colleagues evaluated Surveillance, Epidemiology, and End Results (SEER)–Medicare data for 4,525 adults with traditional Medicare coverage who were diagnosed with HCC between 2011 and 2015 and a propensity-matched cohort of 4,525 adults with cirrhosis but no HCC as a comparator group to tease out HCC-specific costs beyond those related to cirrhosis. Patients in Medicare managed care were excluded because their cost information is not available in the database.
In the first year after a diagnosis of HCC, the median total Medicare payments were $66,338 (interquartile range [IQR], $30,931-$158,740) and patient liabilities (a proxy for out-of-pocket costs) were $10,008 (IQR, $5,427-$19,669).
First-year costs were higher for patients with HCC than matched patients without HCC; the former group incurred median incremental Medicare payments of $50,110 (IQR, $14,242-$136,239) and patient liabilities of $7,166 (IQR, $2,401-$16,099), the investigators found.
Patients with early-stage HCC had lower incremental patient liabilities (median, $4,195 vs. $8,238) and Medicare payments (median, $28,207 vs. $59,509) than did their peers with larger tumor burden.
NAFLD notably tied to higher costs
Factors associated with higher HCC-related costs were nonalcoholic fatty liver disease (NAFLD) etiology, higher comorbidities, presence of ascites and hepatic encephalopathy, and larger tumor burden.
The researchers said that the link between NAFLD and higher costs is notable, given that NAFLD is an increasingly common underlying cause of HCC.
The link between larger tumor burden and higher costs underscores “another benefit of HCC surveillance and early detection,” they added.
“By separating the financial liabilities borne by patients and Medicare, we provide a clearer outlook of how cancer-related costs are distributed between patients and public payers,” Dr. Singal and colleagues said.
“Our findings will inform policy interventions and will help formulate better financial supports targeting the most vulnerable HCC patients,” they concluded.
The study had no commercial funding. Dr. Singal has been on advisory boards and served as a consultant for Wako Diagnostics, Glycotest, Exact Sciences, Roche, Genentech, Bayer, Eisai, BMS, Exelixis, AstraZeneca, and TARGET RWE.
A version of this article first appeared on Medscape.com.
In the first year after a diagnosis of HCC, median Medicare payments exceed $65,000 and out-of-pocket costs top $10,000.
Even after adjustment for the presence of cirrhosis and its related costs, patients with HCC still have Medicare payments exceeding $50,000 and out-of-pocket costs topping $7000.
Amit Singal, MD, of UT Southwestern Medical Center in Dallas, and colleagues reported their findings in Clinical Gastroenterology and Hepatology.
Common and costly
HCC, the most common type of primary liver cancer, is a leading cause of death in patients with cirrhosis and is projected to become the third leading cause of cancer-related death in the United States by 2040, the researchers wrote.
The treatment landscape for HCC has changed over the past decade, with expanded surgical options, introduction of radiation-based therapies, and approval of immunotherapies – all of which are costly.
Yet the magnitude of financial burden of HCC therapy has been understudied, the researchers noted.
To investigate, Dr. Singal and colleagues evaluated Surveillance, Epidemiology, and End Results (SEER)–Medicare data for 4,525 adults with traditional Medicare coverage who were diagnosed with HCC between 2011 and 2015 and a propensity-matched cohort of 4,525 adults with cirrhosis but no HCC as a comparator group to tease out HCC-specific costs beyond those related to cirrhosis. Patients in Medicare managed care were excluded because their cost information is not available in the database.
In the first year after a diagnosis of HCC, the median total Medicare payments were $66,338 (interquartile range [IQR], $30,931-$158,740) and patient liabilities (a proxy for out-of-pocket costs) were $10,008 (IQR, $5,427-$19,669).
First-year costs were higher for patients with HCC than matched patients without HCC; the former group incurred median incremental Medicare payments of $50,110 (IQR, $14,242-$136,239) and patient liabilities of $7,166 (IQR, $2,401-$16,099), the investigators found.
Patients with early-stage HCC had lower incremental patient liabilities (median, $4,195 vs. $8,238) and Medicare payments (median, $28,207 vs. $59,509) than did their peers with larger tumor burden.
NAFLD notably tied to higher costs
Factors associated with higher HCC-related costs were nonalcoholic fatty liver disease (NAFLD) etiology, higher comorbidities, presence of ascites and hepatic encephalopathy, and larger tumor burden.
The researchers said that the link between NAFLD and higher costs is notable, given that NAFLD is an increasingly common underlying cause of HCC.
The link between larger tumor burden and higher costs underscores “another benefit of HCC surveillance and early detection,” they added.
“By separating the financial liabilities borne by patients and Medicare, we provide a clearer outlook of how cancer-related costs are distributed between patients and public payers,” Dr. Singal and colleagues said.
“Our findings will inform policy interventions and will help formulate better financial supports targeting the most vulnerable HCC patients,” they concluded.
The study had no commercial funding. Dr. Singal has been on advisory boards and served as a consultant for Wako Diagnostics, Glycotest, Exact Sciences, Roche, Genentech, Bayer, Eisai, BMS, Exelixis, AstraZeneca, and TARGET RWE.
A version of this article first appeared on Medscape.com.
FROM CLINICAL GASTROENTEROLOGY AND HEPATOLOGY
Upadacitinib curbed UC symptoms from Day 1 in study
Patients with ulcerative colitis who were treated with upadacitinib showed significant improvement in symptoms compared to placebo within days of starting treatment, according to results of a new study.
Immunosuppressants and biologics used to treat moderate to severe disease can vary in their response times from weeks to months, and some ambulatory patients fail to respond to these treatments, wrote Edward V. Loftus Jr., MD, of the Mayo Clinic, Rochester, Minn., and colleagues.
“The lack of effective, quick-acting therapies may lead patients to experience prolonged relapses, reduced quality of life, and a significant burden of illness,” the researchers said.
Upadacitinib, an oral, once-daily reversible JAK inhibitor, is approved by the Food and Drug Administration for patients with moderate to severe ulcerative colitis (UC) who have not responded to at least one tumor necrosis factor (TNF) blocker, but the time frame for response to upadacitinib has not been well studied, they said.
In a study published online in Clinical Gastroenterology and Hepatology, the researchers reviewed data from two phase 3 randomized, placebo-controlled induction trials, U-ACHIEVE Induction (NCT02819635) and U-ACCOMPLISH (NCT03653026), that assessed the safety and efficacy of a 45-mg daily dose of upadacitinib for managing symptoms of moderate to severe UC over an 8-week period.
The intent-to-treat analysis included 660 patients who had been randomized to received upadacitinib and 328 in the placebo group. Demographics were similar between the groups. Symptom improvement was based on changes in inflammatory markers high-sensitivity C-reactive protein (hs-CRP) and fecal calprotectin (FCP) measured at week 2. Quality of life was assessed at 2 and 8 weeks.
Between 1 and 3 days after starting treatment, significantly greater percentages of patients in the treatment arm achieved a reduction of at least 50% from baseline in hs-CRP (75.7% vs. 21.9%) and FCP (48.2% vs. 20.2%).
The significant differences in symptom improvement persisted for 14 days from the first dose.
Patients in the upadacitinib group also showed increased rates of clinical remission/response (26.9%/59.4%) based on Partial Mayo scores at week 2 compared with placebo patients (4.3%/22.3%). Treated patients showed significant improvements in quality of life at weeks 2 and 8.
In addition, patient-reported UC symptoms of stool frequency, rectal bleeding, abdominal pain, and bowel urgency improved significantly compared with placebo by day 3, the researchers noted. “In this study, upadacitinib led to absence of rectal bleeding by day 1 and absence of abdominal pain and bowel urgency by day 3 in a significant proportion of patients vs. placebo (all P < .05),” they said.
The findings were limited by the post hoc design, but reflect results of other studies, including those of the JAK inhibitor tofacitinib, the researchers noted. The results of the current study demonstrate the ability of upadacitinib to alleviate key UC symptoms as early as 1 day after the first dose, they concluded.
Need for rapid onset treatment
A majority of biologics used to treat IBD take weeks to months to exert an effect, “so it is crucial that a drug with more rapid onset of action become available,” Atsushi Sakuraba, MD, director of clinical trial/IBD research at the University of Chicago, said in an interview.
Dr. Sakuraba, who was not involved in the study, said he was surprised by the findings.
“It is amazing that upadacitinib started to show response in 1-3 days and showed superior rates of remission/response versus placebo by week 2,” he said.
“Clinicians treating IBD patients should take the time to response into consideration, because it leads to rapid improvement in quality of life and reduced need for steroids,” Dr. Sakuraba said. The current study findings need to be confirmed in real life studies, he cautioned.
Expanding clinical options
Jeffrey Berinstein, MD, of the University of Michigan, Ann Arbor, who was not involved with the study, said in an interview that he was not surprised by upadacitinib’s quick action, which supports what he has seen in clinical practice. “We now have post hoc data from the phase 3, multicenter induction trials ... to provide us with hard evidence to support our observations,” he noted.
The current study is important because many patients with UC can be very symptomatic, with rectal bleeding, diarrhea, urgency, and abdominal pain, he said in an interview.
“It is often critical to have a fast-acting medication to avoid worsening symptoms, hospitalization, and severe complications. This study shows that upadacitinib, a new oral small molecule that selectively inhibits JAK-1, works within 1 day to improve symptoms and within 2 weeks to improve CRP and fecal calprotectin,” he said.
The takeaway message to clinicians is that upadacitinib is effective, relatively safe, and fast-acting option for patients with UC who have previously failed an anti-TNF agent, he said.
Challenges remain, however.
“Despite this exciting new therapeutic, there is still significant research needed to break our current therapeutic efficacy ceiling and get more IBD patients into a stable and durable remission,” Dr. Berinstein said. “Additional research is needed to develop personalized treatment strategies to address the unique needs of individual patients and to guide optimal medical management.”
Dr. Berinstein and his team are exploring the use of upadacitinib on the sickest IBD patients, “those admitted to the hospital with acute severe ulcerative colitis,” he said. Emerging data from multiple academic centers suggest that “upadacitinib induction may be a viable treatment strategy for these very high-risk patients. Of course, large prospective trials will be needed to confirm this,” he added.
The study was funded by AbbVie, which markets upadacitinib (Rinvoq). Lead author Dr. Loftus and several study authors disclosed financial relationships with AbbVie and other companies. Dr. Sakuraba and Dr. Berinstein reported having no relevant financial conflicts.
Patients with ulcerative colitis who were treated with upadacitinib showed significant improvement in symptoms compared to placebo within days of starting treatment, according to results of a new study.
Immunosuppressants and biologics used to treat moderate to severe disease can vary in their response times from weeks to months, and some ambulatory patients fail to respond to these treatments, wrote Edward V. Loftus Jr., MD, of the Mayo Clinic, Rochester, Minn., and colleagues.
“The lack of effective, quick-acting therapies may lead patients to experience prolonged relapses, reduced quality of life, and a significant burden of illness,” the researchers said.
Upadacitinib, an oral, once-daily reversible JAK inhibitor, is approved by the Food and Drug Administration for patients with moderate to severe ulcerative colitis (UC) who have not responded to at least one tumor necrosis factor (TNF) blocker, but the time frame for response to upadacitinib has not been well studied, they said.
In a study published online in Clinical Gastroenterology and Hepatology, the researchers reviewed data from two phase 3 randomized, placebo-controlled induction trials, U-ACHIEVE Induction (NCT02819635) and U-ACCOMPLISH (NCT03653026), that assessed the safety and efficacy of a 45-mg daily dose of upadacitinib for managing symptoms of moderate to severe UC over an 8-week period.
The intent-to-treat analysis included 660 patients who had been randomized to received upadacitinib and 328 in the placebo group. Demographics were similar between the groups. Symptom improvement was based on changes in inflammatory markers high-sensitivity C-reactive protein (hs-CRP) and fecal calprotectin (FCP) measured at week 2. Quality of life was assessed at 2 and 8 weeks.
Between 1 and 3 days after starting treatment, significantly greater percentages of patients in the treatment arm achieved a reduction of at least 50% from baseline in hs-CRP (75.7% vs. 21.9%) and FCP (48.2% vs. 20.2%).
The significant differences in symptom improvement persisted for 14 days from the first dose.
Patients in the upadacitinib group also showed increased rates of clinical remission/response (26.9%/59.4%) based on Partial Mayo scores at week 2 compared with placebo patients (4.3%/22.3%). Treated patients showed significant improvements in quality of life at weeks 2 and 8.
In addition, patient-reported UC symptoms of stool frequency, rectal bleeding, abdominal pain, and bowel urgency improved significantly compared with placebo by day 3, the researchers noted. “In this study, upadacitinib led to absence of rectal bleeding by day 1 and absence of abdominal pain and bowel urgency by day 3 in a significant proportion of patients vs. placebo (all P < .05),” they said.
The findings were limited by the post hoc design, but reflect results of other studies, including those of the JAK inhibitor tofacitinib, the researchers noted. The results of the current study demonstrate the ability of upadacitinib to alleviate key UC symptoms as early as 1 day after the first dose, they concluded.
Need for rapid onset treatment
A majority of biologics used to treat IBD take weeks to months to exert an effect, “so it is crucial that a drug with more rapid onset of action become available,” Atsushi Sakuraba, MD, director of clinical trial/IBD research at the University of Chicago, said in an interview.
Dr. Sakuraba, who was not involved in the study, said he was surprised by the findings.
“It is amazing that upadacitinib started to show response in 1-3 days and showed superior rates of remission/response versus placebo by week 2,” he said.
“Clinicians treating IBD patients should take the time to response into consideration, because it leads to rapid improvement in quality of life and reduced need for steroids,” Dr. Sakuraba said. The current study findings need to be confirmed in real life studies, he cautioned.
Expanding clinical options
Jeffrey Berinstein, MD, of the University of Michigan, Ann Arbor, who was not involved with the study, said in an interview that he was not surprised by upadacitinib’s quick action, which supports what he has seen in clinical practice. “We now have post hoc data from the phase 3, multicenter induction trials ... to provide us with hard evidence to support our observations,” he noted.
The current study is important because many patients with UC can be very symptomatic, with rectal bleeding, diarrhea, urgency, and abdominal pain, he said in an interview.
“It is often critical to have a fast-acting medication to avoid worsening symptoms, hospitalization, and severe complications. This study shows that upadacitinib, a new oral small molecule that selectively inhibits JAK-1, works within 1 day to improve symptoms and within 2 weeks to improve CRP and fecal calprotectin,” he said.
The takeaway message to clinicians is that upadacitinib is effective, relatively safe, and fast-acting option for patients with UC who have previously failed an anti-TNF agent, he said.
Challenges remain, however.
“Despite this exciting new therapeutic, there is still significant research needed to break our current therapeutic efficacy ceiling and get more IBD patients into a stable and durable remission,” Dr. Berinstein said. “Additional research is needed to develop personalized treatment strategies to address the unique needs of individual patients and to guide optimal medical management.”
Dr. Berinstein and his team are exploring the use of upadacitinib on the sickest IBD patients, “those admitted to the hospital with acute severe ulcerative colitis,” he said. Emerging data from multiple academic centers suggest that “upadacitinib induction may be a viable treatment strategy for these very high-risk patients. Of course, large prospective trials will be needed to confirm this,” he added.
The study was funded by AbbVie, which markets upadacitinib (Rinvoq). Lead author Dr. Loftus and several study authors disclosed financial relationships with AbbVie and other companies. Dr. Sakuraba and Dr. Berinstein reported having no relevant financial conflicts.
Patients with ulcerative colitis who were treated with upadacitinib showed significant improvement in symptoms compared to placebo within days of starting treatment, according to results of a new study.
Immunosuppressants and biologics used to treat moderate to severe disease can vary in their response times from weeks to months, and some ambulatory patients fail to respond to these treatments, wrote Edward V. Loftus Jr., MD, of the Mayo Clinic, Rochester, Minn., and colleagues.
“The lack of effective, quick-acting therapies may lead patients to experience prolonged relapses, reduced quality of life, and a significant burden of illness,” the researchers said.
Upadacitinib, an oral, once-daily reversible JAK inhibitor, is approved by the Food and Drug Administration for patients with moderate to severe ulcerative colitis (UC) who have not responded to at least one tumor necrosis factor (TNF) blocker, but the time frame for response to upadacitinib has not been well studied, they said.
In a study published online in Clinical Gastroenterology and Hepatology, the researchers reviewed data from two phase 3 randomized, placebo-controlled induction trials, U-ACHIEVE Induction (NCT02819635) and U-ACCOMPLISH (NCT03653026), that assessed the safety and efficacy of a 45-mg daily dose of upadacitinib for managing symptoms of moderate to severe UC over an 8-week period.
The intent-to-treat analysis included 660 patients who had been randomized to received upadacitinib and 328 in the placebo group. Demographics were similar between the groups. Symptom improvement was based on changes in inflammatory markers high-sensitivity C-reactive protein (hs-CRP) and fecal calprotectin (FCP) measured at week 2. Quality of life was assessed at 2 and 8 weeks.
Between 1 and 3 days after starting treatment, significantly greater percentages of patients in the treatment arm achieved a reduction of at least 50% from baseline in hs-CRP (75.7% vs. 21.9%) and FCP (48.2% vs. 20.2%).
The significant differences in symptom improvement persisted for 14 days from the first dose.
Patients in the upadacitinib group also showed increased rates of clinical remission/response (26.9%/59.4%) based on Partial Mayo scores at week 2 compared with placebo patients (4.3%/22.3%). Treated patients showed significant improvements in quality of life at weeks 2 and 8.
In addition, patient-reported UC symptoms of stool frequency, rectal bleeding, abdominal pain, and bowel urgency improved significantly compared with placebo by day 3, the researchers noted. “In this study, upadacitinib led to absence of rectal bleeding by day 1 and absence of abdominal pain and bowel urgency by day 3 in a significant proportion of patients vs. placebo (all P < .05),” they said.
The findings were limited by the post hoc design, but reflect results of other studies, including those of the JAK inhibitor tofacitinib, the researchers noted. The results of the current study demonstrate the ability of upadacitinib to alleviate key UC symptoms as early as 1 day after the first dose, they concluded.
Need for rapid onset treatment
A majority of biologics used to treat IBD take weeks to months to exert an effect, “so it is crucial that a drug with more rapid onset of action become available,” Atsushi Sakuraba, MD, director of clinical trial/IBD research at the University of Chicago, said in an interview.
Dr. Sakuraba, who was not involved in the study, said he was surprised by the findings.
“It is amazing that upadacitinib started to show response in 1-3 days and showed superior rates of remission/response versus placebo by week 2,” he said.
“Clinicians treating IBD patients should take the time to response into consideration, because it leads to rapid improvement in quality of life and reduced need for steroids,” Dr. Sakuraba said. The current study findings need to be confirmed in real life studies, he cautioned.
Expanding clinical options
Jeffrey Berinstein, MD, of the University of Michigan, Ann Arbor, who was not involved with the study, said in an interview that he was not surprised by upadacitinib’s quick action, which supports what he has seen in clinical practice. “We now have post hoc data from the phase 3, multicenter induction trials ... to provide us with hard evidence to support our observations,” he noted.
The current study is important because many patients with UC can be very symptomatic, with rectal bleeding, diarrhea, urgency, and abdominal pain, he said in an interview.
“It is often critical to have a fast-acting medication to avoid worsening symptoms, hospitalization, and severe complications. This study shows that upadacitinib, a new oral small molecule that selectively inhibits JAK-1, works within 1 day to improve symptoms and within 2 weeks to improve CRP and fecal calprotectin,” he said.
The takeaway message to clinicians is that upadacitinib is effective, relatively safe, and fast-acting option for patients with UC who have previously failed an anti-TNF agent, he said.
Challenges remain, however.
“Despite this exciting new therapeutic, there is still significant research needed to break our current therapeutic efficacy ceiling and get more IBD patients into a stable and durable remission,” Dr. Berinstein said. “Additional research is needed to develop personalized treatment strategies to address the unique needs of individual patients and to guide optimal medical management.”
Dr. Berinstein and his team are exploring the use of upadacitinib on the sickest IBD patients, “those admitted to the hospital with acute severe ulcerative colitis,” he said. Emerging data from multiple academic centers suggest that “upadacitinib induction may be a viable treatment strategy for these very high-risk patients. Of course, large prospective trials will be needed to confirm this,” he added.
The study was funded by AbbVie, which markets upadacitinib (Rinvoq). Lead author Dr. Loftus and several study authors disclosed financial relationships with AbbVie and other companies. Dr. Sakuraba and Dr. Berinstein reported having no relevant financial conflicts.
FROM CLINICAL GASTROENTEROLOGY AND HEPATOLOGY
Higher BMI may dampen steroid response in eosinophilic esophagitis
The higher the patient’s BMI level, the lower the individual’s response to tCS therapy from a symptomatic, endoscopic, and histologic perspective, researchers observed in a retrospective study.
Because there are few clinical predictors of response to topical steroids, clinicians may want to consider BMI in their treatment algorithm and when discussing therapeutic treatment options with patients with EoE, the investigators write in an article published online in Clinical Gastroenterology and Hepatology.
For EoE, current guidelines recommend the use of proton-pump inhibitor (PPI) therapy, topical steroids, and dietary elimination. In addition, the biologic dupilumab (Dupixent) was recently approved in the United States for EoE.
Determining what therapy patients with EoE will respond best to remains a challenge, and obesity’s role in treatment response has been unclear.
To investigate the effect patients’ weight might have on tCS therapy, Evan Dellon, MD, MPH, and colleagues at the University of North Carolina School of Medicine, Chapel Hill, reviewed cases involving 296 adults and adolescents aged 14 years and older who had received topical steroids for EoE.
Baseline characteristics were similar, although heartburn was more common among the 68 patients with obesity than among the non-obese patients (59% vs. 37%; P = .001), and the rate of hiatal hernias detected endoscopically was higher among the patients with obesity (22% vs. 11%; P = .02).
Following tCS treatment, peak eosinophil counts were higher for patients with obesity, compared with non-obese patients (36.1 vs. 21.5; P = .003).
Histologic response was significantly higher in non-obese patients, compared with patients with obesity, at less than 15 eosinophils per high-power field (eos/hpf: 61% vs. 47%; P = .049) and less than or equal to 6 eos/hpf (54% vs. 38%; P = .02).
Among the non-obese patients with EoE, global endoscopic response to tCS was significantly greater than among the patients with obesity (76% vs. 59%; P = .006).
In additon, among non-obese patients, the post-treatment EoE-Endoscopic Reference Score (2.4 vs. 3.2; P = .01) and the endoscopic severity score were significantly lower (2.0 vs. 2.4; P = .05).
Global symptomatic response to tCS was seen in 84% of non-obese patients, versus only 67% of those with obesity (P = .03).
On multivariate analysis, increasing BMI was independently associated with decreased histologic response after accounting for age, heartburn, dilation, and hiatal hernia.
This relationship persisted whether BMI was assessed as a continuous variable (adjusted odds ratio, 0.93 for each unit increase in BMI), as non-obese versus obese (aOR 0.38), as overweight versus normal weight (aOR 0.46), or obese versus normal weight (aOR 0.26).
Different treatment algorithm?
The results remained generally similar when patients were stratified by PPI response status and by continued use of PPIs.
The investigators note that in their cohort, only five patients responded to PPI therapy; all were non-obese. It’s possible, they note, that patients with a higher BMI may benefit from dual PPI/tCS treatment initially, but this strategy would require prospective assessment.
As for the mechanism behind obesity’s apparent negative impact on tCS therapy, the researchers say the low-grade systemic inflammatory state of obesity may make tCS therapy less effective, but they add that studies are needed to pinpoint the exact mechanism.
The study suggests that “a clinician can now add another epidemiologic risk factor for potential poor response to treatment for EoE, specifically steroids,” Philip Katz, MD, professor of medicine, division of gastroenterology and hepatology, Weill Cornell Medicine, New York, said in an interview when reached for comment.
However, it is “difficult, if not impossible, to discern from a retrospective study like this why higher BMI would be a risk factor for poor response,” said Dr. Katz, who was not affiliated with the study.
“The main potential clinical message here is that people who are overweight with EoE perhaps need to be looked at differently and might require a different treatment algorithm or treatment approach than a person who is ideal body weight,” Dr. Katz added.
Also commenting for this article, Shreya Chablaney, MD, a gastroenterologist at NYU Langone Health’s Center for Esophageal Health and clinical instructor at NYU Grossman School of Medicine, noted that predictors of patient response to various treatment options for EoE are not well understood and that more robust data are needed to guide appropriate patient selection when considering them.
“Though this is a relatively small, single-center, retrospective study, it shows an interesting finding, that high BMI is independently associated with a decrease in histologic, symptomatic, and endoscopic response to topical steroids, even when controlling for heartburn and the presence of a hiatal hernia,” she said.
“While these findings may not yet affect current management, it highlights the need for more prospective research to see if dosing adjustment, type of topical steroid, or alternative therapy altogether should be considered in patients who are obese,” Dr. Chablaney said.
Support for the study was provided by the National Institutes of Health. Dr. Dellon is a consultant for Abbott, AbbVie, Adare/ Ellodi, Aimmune, Akesobio, ALK, Allakos, Amgen, Arena, Aslan, AstraZeneca, Avir, Biorasi, Calypso, Celgene/Receptos/BMS, Celldex, Eli Lilly, EsoCap, Eurpaxia, Ferring, GSK, Gossamer Bio, Invea, Landos, LucidDx, Morphic, Nutricia, Parexel/Calyx, Phathom, Regeneron, Revolo, Robarts/Alimentiv, Salix, Sanofi, Shire/Takeda, and Target RWE. Dr. Katz is a consultant for Phathom Pharmaceuticals and Sebella Pharmaceuticals and serves on an advisory board for AstraZeneca. Dr. Chablaney reports no relevant financial relationships.
A version of this article first appeared on Medscape.com.
The higher the patient’s BMI level, the lower the individual’s response to tCS therapy from a symptomatic, endoscopic, and histologic perspective, researchers observed in a retrospective study.
Because there are few clinical predictors of response to topical steroids, clinicians may want to consider BMI in their treatment algorithm and when discussing therapeutic treatment options with patients with EoE, the investigators write in an article published online in Clinical Gastroenterology and Hepatology.
For EoE, current guidelines recommend the use of proton-pump inhibitor (PPI) therapy, topical steroids, and dietary elimination. In addition, the biologic dupilumab (Dupixent) was recently approved in the United States for EoE.
Determining what therapy patients with EoE will respond best to remains a challenge, and obesity’s role in treatment response has been unclear.
To investigate the effect patients’ weight might have on tCS therapy, Evan Dellon, MD, MPH, and colleagues at the University of North Carolina School of Medicine, Chapel Hill, reviewed cases involving 296 adults and adolescents aged 14 years and older who had received topical steroids for EoE.
Baseline characteristics were similar, although heartburn was more common among the 68 patients with obesity than among the non-obese patients (59% vs. 37%; P = .001), and the rate of hiatal hernias detected endoscopically was higher among the patients with obesity (22% vs. 11%; P = .02).
Following tCS treatment, peak eosinophil counts were higher for patients with obesity, compared with non-obese patients (36.1 vs. 21.5; P = .003).
Histologic response was significantly higher in non-obese patients, compared with patients with obesity, at less than 15 eosinophils per high-power field (eos/hpf: 61% vs. 47%; P = .049) and less than or equal to 6 eos/hpf (54% vs. 38%; P = .02).
Among the non-obese patients with EoE, global endoscopic response to tCS was significantly greater than among the patients with obesity (76% vs. 59%; P = .006).
In additon, among non-obese patients, the post-treatment EoE-Endoscopic Reference Score (2.4 vs. 3.2; P = .01) and the endoscopic severity score were significantly lower (2.0 vs. 2.4; P = .05).
Global symptomatic response to tCS was seen in 84% of non-obese patients, versus only 67% of those with obesity (P = .03).
On multivariate analysis, increasing BMI was independently associated with decreased histologic response after accounting for age, heartburn, dilation, and hiatal hernia.
This relationship persisted whether BMI was assessed as a continuous variable (adjusted odds ratio, 0.93 for each unit increase in BMI), as non-obese versus obese (aOR 0.38), as overweight versus normal weight (aOR 0.46), or obese versus normal weight (aOR 0.26).
Different treatment algorithm?
The results remained generally similar when patients were stratified by PPI response status and by continued use of PPIs.
The investigators note that in their cohort, only five patients responded to PPI therapy; all were non-obese. It’s possible, they note, that patients with a higher BMI may benefit from dual PPI/tCS treatment initially, but this strategy would require prospective assessment.
As for the mechanism behind obesity’s apparent negative impact on tCS therapy, the researchers say the low-grade systemic inflammatory state of obesity may make tCS therapy less effective, but they add that studies are needed to pinpoint the exact mechanism.
The study suggests that “a clinician can now add another epidemiologic risk factor for potential poor response to treatment for EoE, specifically steroids,” Philip Katz, MD, professor of medicine, division of gastroenterology and hepatology, Weill Cornell Medicine, New York, said in an interview when reached for comment.
However, it is “difficult, if not impossible, to discern from a retrospective study like this why higher BMI would be a risk factor for poor response,” said Dr. Katz, who was not affiliated with the study.
“The main potential clinical message here is that people who are overweight with EoE perhaps need to be looked at differently and might require a different treatment algorithm or treatment approach than a person who is ideal body weight,” Dr. Katz added.
Also commenting for this article, Shreya Chablaney, MD, a gastroenterologist at NYU Langone Health’s Center for Esophageal Health and clinical instructor at NYU Grossman School of Medicine, noted that predictors of patient response to various treatment options for EoE are not well understood and that more robust data are needed to guide appropriate patient selection when considering them.
“Though this is a relatively small, single-center, retrospective study, it shows an interesting finding, that high BMI is independently associated with a decrease in histologic, symptomatic, and endoscopic response to topical steroids, even when controlling for heartburn and the presence of a hiatal hernia,” she said.
“While these findings may not yet affect current management, it highlights the need for more prospective research to see if dosing adjustment, type of topical steroid, or alternative therapy altogether should be considered in patients who are obese,” Dr. Chablaney said.
Support for the study was provided by the National Institutes of Health. Dr. Dellon is a consultant for Abbott, AbbVie, Adare/ Ellodi, Aimmune, Akesobio, ALK, Allakos, Amgen, Arena, Aslan, AstraZeneca, Avir, Biorasi, Calypso, Celgene/Receptos/BMS, Celldex, Eli Lilly, EsoCap, Eurpaxia, Ferring, GSK, Gossamer Bio, Invea, Landos, LucidDx, Morphic, Nutricia, Parexel/Calyx, Phathom, Regeneron, Revolo, Robarts/Alimentiv, Salix, Sanofi, Shire/Takeda, and Target RWE. Dr. Katz is a consultant for Phathom Pharmaceuticals and Sebella Pharmaceuticals and serves on an advisory board for AstraZeneca. Dr. Chablaney reports no relevant financial relationships.
A version of this article first appeared on Medscape.com.
The higher the patient’s BMI level, the lower the individual’s response to tCS therapy from a symptomatic, endoscopic, and histologic perspective, researchers observed in a retrospective study.
Because there are few clinical predictors of response to topical steroids, clinicians may want to consider BMI in their treatment algorithm and when discussing therapeutic treatment options with patients with EoE, the investigators write in an article published online in Clinical Gastroenterology and Hepatology.
For EoE, current guidelines recommend the use of proton-pump inhibitor (PPI) therapy, topical steroids, and dietary elimination. In addition, the biologic dupilumab (Dupixent) was recently approved in the United States for EoE.
Determining what therapy patients with EoE will respond best to remains a challenge, and obesity’s role in treatment response has been unclear.
To investigate the effect patients’ weight might have on tCS therapy, Evan Dellon, MD, MPH, and colleagues at the University of North Carolina School of Medicine, Chapel Hill, reviewed cases involving 296 adults and adolescents aged 14 years and older who had received topical steroids for EoE.
Baseline characteristics were similar, although heartburn was more common among the 68 patients with obesity than among the non-obese patients (59% vs. 37%; P = .001), and the rate of hiatal hernias detected endoscopically was higher among the patients with obesity (22% vs. 11%; P = .02).
Following tCS treatment, peak eosinophil counts were higher for patients with obesity, compared with non-obese patients (36.1 vs. 21.5; P = .003).
Histologic response was significantly higher in non-obese patients, compared with patients with obesity, at less than 15 eosinophils per high-power field (eos/hpf: 61% vs. 47%; P = .049) and less than or equal to 6 eos/hpf (54% vs. 38%; P = .02).
Among the non-obese patients with EoE, global endoscopic response to tCS was significantly greater than among the patients with obesity (76% vs. 59%; P = .006).
In additon, among non-obese patients, the post-treatment EoE-Endoscopic Reference Score (2.4 vs. 3.2; P = .01) and the endoscopic severity score were significantly lower (2.0 vs. 2.4; P = .05).
Global symptomatic response to tCS was seen in 84% of non-obese patients, versus only 67% of those with obesity (P = .03).
On multivariate analysis, increasing BMI was independently associated with decreased histologic response after accounting for age, heartburn, dilation, and hiatal hernia.
This relationship persisted whether BMI was assessed as a continuous variable (adjusted odds ratio, 0.93 for each unit increase in BMI), as non-obese versus obese (aOR 0.38), as overweight versus normal weight (aOR 0.46), or obese versus normal weight (aOR 0.26).
Different treatment algorithm?
The results remained generally similar when patients were stratified by PPI response status and by continued use of PPIs.
The investigators note that in their cohort, only five patients responded to PPI therapy; all were non-obese. It’s possible, they note, that patients with a higher BMI may benefit from dual PPI/tCS treatment initially, but this strategy would require prospective assessment.
As for the mechanism behind obesity’s apparent negative impact on tCS therapy, the researchers say the low-grade systemic inflammatory state of obesity may make tCS therapy less effective, but they add that studies are needed to pinpoint the exact mechanism.
The study suggests that “a clinician can now add another epidemiologic risk factor for potential poor response to treatment for EoE, specifically steroids,” Philip Katz, MD, professor of medicine, division of gastroenterology and hepatology, Weill Cornell Medicine, New York, said in an interview when reached for comment.
However, it is “difficult, if not impossible, to discern from a retrospective study like this why higher BMI would be a risk factor for poor response,” said Dr. Katz, who was not affiliated with the study.
“The main potential clinical message here is that people who are overweight with EoE perhaps need to be looked at differently and might require a different treatment algorithm or treatment approach than a person who is ideal body weight,” Dr. Katz added.
Also commenting for this article, Shreya Chablaney, MD, a gastroenterologist at NYU Langone Health’s Center for Esophageal Health and clinical instructor at NYU Grossman School of Medicine, noted that predictors of patient response to various treatment options for EoE are not well understood and that more robust data are needed to guide appropriate patient selection when considering them.
“Though this is a relatively small, single-center, retrospective study, it shows an interesting finding, that high BMI is independently associated with a decrease in histologic, symptomatic, and endoscopic response to topical steroids, even when controlling for heartburn and the presence of a hiatal hernia,” she said.
“While these findings may not yet affect current management, it highlights the need for more prospective research to see if dosing adjustment, type of topical steroid, or alternative therapy altogether should be considered in patients who are obese,” Dr. Chablaney said.
Support for the study was provided by the National Institutes of Health. Dr. Dellon is a consultant for Abbott, AbbVie, Adare/ Ellodi, Aimmune, Akesobio, ALK, Allakos, Amgen, Arena, Aslan, AstraZeneca, Avir, Biorasi, Calypso, Celgene/Receptos/BMS, Celldex, Eli Lilly, EsoCap, Eurpaxia, Ferring, GSK, Gossamer Bio, Invea, Landos, LucidDx, Morphic, Nutricia, Parexel/Calyx, Phathom, Regeneron, Revolo, Robarts/Alimentiv, Salix, Sanofi, Shire/Takeda, and Target RWE. Dr. Katz is a consultant for Phathom Pharmaceuticals and Sebella Pharmaceuticals and serves on an advisory board for AstraZeneca. Dr. Chablaney reports no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM CLINICAL GASTROENTEROLOGY AND HEPATOLOGY
Bloating common but often ignored: Survey
, some of whom said they weren’t comfortable discussing it with their doctor, according to a large national survey.
The findings suggest doctors should “proactively” ask about bloating, especially in adults at increased risk, including women and those with irritable bowel syndrome (IBS) or inflammatory bowel disease (IBD), the researchers say.
“Bloating is common because it usually has multifactorial causes and can also be a secondary symptom to another gastrointestinal (GI) symptom or condition. Its mechanisms are complex and individualized, making it difficult for providers to identify and treat each patient,” Janice E. Oh, MD, department of medicine, Cedars-Sinai Medical Center, Los Angeles, said in an interview.
“Thus, many adults may be persistently suffering without proper diagnosis or management,” Dr. Oh added.
Results of the survey are published online in Clinical Gastroenterology and Hepatology.
Common problem, incompletely understood
To get a better handle on the nationwide prevalence and health-related impact of bloating in the United States, Dr. Oh and her colleagues conducted an online survey of a nationally representative group of 88,795 adults aged 18 years or older.
Altogether, 12,324 (14%) respondents reported bloating in the past week.
The likelihood of bloating was significantly higher in women (odds ratio, 2.56) and in those with certain comorbid conditions, especially IBS, chronic constipation, and ulcerative colitis, the authors write.
The odds of bloating were also higher in adults with other concomitant GI symptoms, especially abdominal pain and excess gas.
Factors associated with more severe bloating included the presence of IBS, IBD, celiac disease, bowel incontinence, abdominal pain, constipation (functional and opioid-induced), and excess gas.
Bloating severity increased with age up to 59 years and then decreased in people aged 60 years or older.
Suffering in silence?
Notably, more than half (59%) of people who reported recent bloating never sought care for the problem. About one-third of them reported that bloating resolved on its own, and 30% said the symptoms were not bothersome.
About 1 in 5 adults who did not seek care said that they were managing symptoms on their own with over-the-counter medications or lifestyle modifications. And 9% of those who did not seek care said that they were uncomfortable discussing the problem with their doctor.
“The hesitancy in seeking health care or discussing bloating in patients may be attributed to lack of routine screening for bloating, lack of focus on bloating complaints by providers, or patients’ dissatisfaction with management of bloating symptoms,” the researchers say.
Adults most apt to seek care for bloating were those older than 29 years; non-Hispanic Black persons; those with comorbid conditions, such as celiac disease, IBD, and IBS; and those with more severe bloating symptoms.
A limitation is that individuals with GI symptoms or conditions may be more likely to participate in a GI-focused survey, leading to a possible overestimation of the prevalence of bloating.
Also, the survey was conducted during the COVID-19 pandemic, which has the potential to overestimate the prevalence or severity of bloating because COVID-19 is known to affect the GI system.
Despite these limitations, the researchers encourage health care professionals to routinely ask their patients about bloating as a first step in appropriate management.
“Bloating can be associated with nutrition/diet, the gut microbiome, anatomical issues, or underlying conditions that range from neurologic to gynecologic disorders. And, the majority of the time, it is usually more than one distinct issue that is attributing to the bloating,” Dr. Oh said.
“Understanding the patterns of bloating occurrence, psychosocial factors, past medical history, and nutrition can help providers determine the causes. We hope to identify a more standardized method to identify causes of bloating,” Dr. Oh added.
Support for the survey was provided by Ironwood Pharmaceuticals in the form of an institutional research grant to Cedars-Sinai. The authors have no relevant disclosures.
A version of this article first appeared on Medscape.com.
, some of whom said they weren’t comfortable discussing it with their doctor, according to a large national survey.
The findings suggest doctors should “proactively” ask about bloating, especially in adults at increased risk, including women and those with irritable bowel syndrome (IBS) or inflammatory bowel disease (IBD), the researchers say.
“Bloating is common because it usually has multifactorial causes and can also be a secondary symptom to another gastrointestinal (GI) symptom or condition. Its mechanisms are complex and individualized, making it difficult for providers to identify and treat each patient,” Janice E. Oh, MD, department of medicine, Cedars-Sinai Medical Center, Los Angeles, said in an interview.
“Thus, many adults may be persistently suffering without proper diagnosis or management,” Dr. Oh added.
Results of the survey are published online in Clinical Gastroenterology and Hepatology.
Common problem, incompletely understood
To get a better handle on the nationwide prevalence and health-related impact of bloating in the United States, Dr. Oh and her colleagues conducted an online survey of a nationally representative group of 88,795 adults aged 18 years or older.
Altogether, 12,324 (14%) respondents reported bloating in the past week.
The likelihood of bloating was significantly higher in women (odds ratio, 2.56) and in those with certain comorbid conditions, especially IBS, chronic constipation, and ulcerative colitis, the authors write.
The odds of bloating were also higher in adults with other concomitant GI symptoms, especially abdominal pain and excess gas.
Factors associated with more severe bloating included the presence of IBS, IBD, celiac disease, bowel incontinence, abdominal pain, constipation (functional and opioid-induced), and excess gas.
Bloating severity increased with age up to 59 years and then decreased in people aged 60 years or older.
Suffering in silence?
Notably, more than half (59%) of people who reported recent bloating never sought care for the problem. About one-third of them reported that bloating resolved on its own, and 30% said the symptoms were not bothersome.
About 1 in 5 adults who did not seek care said that they were managing symptoms on their own with over-the-counter medications or lifestyle modifications. And 9% of those who did not seek care said that they were uncomfortable discussing the problem with their doctor.
“The hesitancy in seeking health care or discussing bloating in patients may be attributed to lack of routine screening for bloating, lack of focus on bloating complaints by providers, or patients’ dissatisfaction with management of bloating symptoms,” the researchers say.
Adults most apt to seek care for bloating were those older than 29 years; non-Hispanic Black persons; those with comorbid conditions, such as celiac disease, IBD, and IBS; and those with more severe bloating symptoms.
A limitation is that individuals with GI symptoms or conditions may be more likely to participate in a GI-focused survey, leading to a possible overestimation of the prevalence of bloating.
Also, the survey was conducted during the COVID-19 pandemic, which has the potential to overestimate the prevalence or severity of bloating because COVID-19 is known to affect the GI system.
Despite these limitations, the researchers encourage health care professionals to routinely ask their patients about bloating as a first step in appropriate management.
“Bloating can be associated with nutrition/diet, the gut microbiome, anatomical issues, or underlying conditions that range from neurologic to gynecologic disorders. And, the majority of the time, it is usually more than one distinct issue that is attributing to the bloating,” Dr. Oh said.
“Understanding the patterns of bloating occurrence, psychosocial factors, past medical history, and nutrition can help providers determine the causes. We hope to identify a more standardized method to identify causes of bloating,” Dr. Oh added.
Support for the survey was provided by Ironwood Pharmaceuticals in the form of an institutional research grant to Cedars-Sinai. The authors have no relevant disclosures.
A version of this article first appeared on Medscape.com.
, some of whom said they weren’t comfortable discussing it with their doctor, according to a large national survey.
The findings suggest doctors should “proactively” ask about bloating, especially in adults at increased risk, including women and those with irritable bowel syndrome (IBS) or inflammatory bowel disease (IBD), the researchers say.
“Bloating is common because it usually has multifactorial causes and can also be a secondary symptom to another gastrointestinal (GI) symptom or condition. Its mechanisms are complex and individualized, making it difficult for providers to identify and treat each patient,” Janice E. Oh, MD, department of medicine, Cedars-Sinai Medical Center, Los Angeles, said in an interview.
“Thus, many adults may be persistently suffering without proper diagnosis or management,” Dr. Oh added.
Results of the survey are published online in Clinical Gastroenterology and Hepatology.
Common problem, incompletely understood
To get a better handle on the nationwide prevalence and health-related impact of bloating in the United States, Dr. Oh and her colleagues conducted an online survey of a nationally representative group of 88,795 adults aged 18 years or older.
Altogether, 12,324 (14%) respondents reported bloating in the past week.
The likelihood of bloating was significantly higher in women (odds ratio, 2.56) and in those with certain comorbid conditions, especially IBS, chronic constipation, and ulcerative colitis, the authors write.
The odds of bloating were also higher in adults with other concomitant GI symptoms, especially abdominal pain and excess gas.
Factors associated with more severe bloating included the presence of IBS, IBD, celiac disease, bowel incontinence, abdominal pain, constipation (functional and opioid-induced), and excess gas.
Bloating severity increased with age up to 59 years and then decreased in people aged 60 years or older.
Suffering in silence?
Notably, more than half (59%) of people who reported recent bloating never sought care for the problem. About one-third of them reported that bloating resolved on its own, and 30% said the symptoms were not bothersome.
About 1 in 5 adults who did not seek care said that they were managing symptoms on their own with over-the-counter medications or lifestyle modifications. And 9% of those who did not seek care said that they were uncomfortable discussing the problem with their doctor.
“The hesitancy in seeking health care or discussing bloating in patients may be attributed to lack of routine screening for bloating, lack of focus on bloating complaints by providers, or patients’ dissatisfaction with management of bloating symptoms,” the researchers say.
Adults most apt to seek care for bloating were those older than 29 years; non-Hispanic Black persons; those with comorbid conditions, such as celiac disease, IBD, and IBS; and those with more severe bloating symptoms.
A limitation is that individuals with GI symptoms or conditions may be more likely to participate in a GI-focused survey, leading to a possible overestimation of the prevalence of bloating.
Also, the survey was conducted during the COVID-19 pandemic, which has the potential to overestimate the prevalence or severity of bloating because COVID-19 is known to affect the GI system.
Despite these limitations, the researchers encourage health care professionals to routinely ask their patients about bloating as a first step in appropriate management.
“Bloating can be associated with nutrition/diet, the gut microbiome, anatomical issues, or underlying conditions that range from neurologic to gynecologic disorders. And, the majority of the time, it is usually more than one distinct issue that is attributing to the bloating,” Dr. Oh said.
“Understanding the patterns of bloating occurrence, psychosocial factors, past medical history, and nutrition can help providers determine the causes. We hope to identify a more standardized method to identify causes of bloating,” Dr. Oh added.
Support for the survey was provided by Ironwood Pharmaceuticals in the form of an institutional research grant to Cedars-Sinai. The authors have no relevant disclosures.
A version of this article first appeared on Medscape.com.
FROM CLINICAL GASTROENTEROLOGY AND HEPATOLOGY
Exosomes may drive HBV spread
Hepatitis B virus (HBV), which can lead to acute and chronic hepatitis, infects more than 2 billion people worldwide, according to serological evidence. Although vaccines and treatments are available, there are approximately 1.5 million new HBV infections each year globally.
A new study has revealed a key step in the HBV life cycle: Researchers found that HBV virions can be released within exosomes, which are capable of infecting neighboring cells. The authors, led by Qingyan Wu of the department of virology, Paul-Ehrlich-Institute, Langen, Germany, suggest this strategy may help the virus escape immune surveillance and target a new hepatocyte.
The study was published online in Cellular and Molecular Gastroenterology and Hepatology.
The researchers isolated exosomes from the supernatants of HBV-producing cells using exosomal and HBV markers. Electron microscopy using ultrathin sectioning along with immunogold labeling confirmed the presence of intact HBV virions in exosomes. The ultracentrifugation enabled the separation of the free virion fraction from the virions enclosed in exosomes. These findings fit in with previous discoveries of quasi-enveloped hepatitis A virus and hepatitis E virus.
The exosomes released free HBV virion and naked capsid after exposure to detergent. Cellular exposure to exosome morphogenesis inhibitors interfered with the release of exosome-packaged HBV. The researchers also observed large HBV surface antigens (LHB) on the external surface of the exosomes and found that the antigens allowed the exosome to infect susceptible cells through interaction with the sodium-taurocholate co-transporting polypeptide. LHB may also play an additional role in infectivity by countering the ability of antibodies to neutralize HBV.
However, the researchers also found that an LHB-specific neutralizing antibody inhibited infection of differentiated HepaRG cells with exosome-containing HBV. One explanation is that the antibody blocks the interaction between LHB and the target cell. Another is that the exosome disassembles near the target cell membrane and releases the virus, which is then blocked by the antibody since it can block entry of released virus.
To investigate the release pathway, the researchers used three different exosome release inhibitors and found that all three interfered with HBV exosomal release. They also found that cells deficient in the exosome proteins Alix and syntenin did not release exosomal HBV.
Alix appears to be involved in HBV exosomal release, as evidenced by the fact that release of exosomal HBV is boosted in Alix-deficient cells following rescue through overexpression of mCherry-Alix fusion construct. Overexpression of mCherry-Alix had no effect on release of free HBV virions.
The researchers also found evidence that two other exosomal proteins, CD63 and TSG101, play a role in incorporation of LHBs in the HBV envelope, as well as release of HBV through interactions with the protein alpha-taxilin. CD63 and TSG101 are also critical to the formation of exosomes, and the authors suggest further research into their functioning could be fruitful.
Whether exosome-released HBV results from crosstalk between the virus and host cells still needs to be determined. If host factors play a role in connecting HBV to exosomes, it will be interesting to work out which conditions trigger this process, as well as determine which events trigger the release of free virus through multivesicular bodies.
The researchers posit that LHBs could perform a similar function as classical hepatitis B surface antigens and filaments in foiling the immune response. Such a function would require that the virus escape from antibodies before opsonin proteins tag the antigens. It’s also possible that LHBs enable infection of nonhepatic tissues, though this would likely be inefficient.
Many other host proteins have been observed in exosomes released by HBV-infected hepatocytes, suggesting that host proteins may play other roles. A proteomics analysis found proteasome subunit proteins in HepAD38-derived exosomes. The authors suggest that those proteins may allow the exosomes to mediate transcellular immune regulation.
Subviral particles may enhance viral infection, and exosomes from HBV-positive cells may contribute, possibly through exosome surface LHBs, according to the authors. They found that an LHB-specific neutralizing antibody inhibited infection of differentiated HepaRG cells. One explanation is that the antibody blocks the interaction between LHB and the target cell. Another is that the exosome disassembles near the target cell membrane and releases the virus, which is then blocked by the antibody since it can block entry of released virus.
“This previously undiscovered strategy of sequestering HBV particles in exosomes could be a strategy to escape from the immune response and to target them, protected by the exosomal membrane, to the hepatocyte. Exosomes that carry HBV particles seem also to have the potential to deliver HBV to nonpermissive cells with low efficiency. This suggests that exosomes could be an additional factor that contributes to the spread of HBV,” the authors wrote.
The authors had no financial conflicts. This research was funded by the LOEWE Center ACLF, DRUID, the Germany Research Foundation, and the China Scholarship Council.
Viral cell entry and viral neutralization by antibodies are largely defined by the virion structure. Not surprisingly, viruses have evolved strategies to hijack cellular pathways for their morphogenesis to promote their dissemination and escape host immune responses. Hepatitis B viruses (HBV) are released as infectious enveloped virions from infected cells through the multivesicular body pathway. Moreover, excess HBV envelope proteins are exported as noninfectious subviral particles that can act as decoys to trap neutralizing antibodies.
Using cell culture models, investigators from the Hildt lab show in this study that a minority of enveloped virions are released within exosomes, the biogenesis of which is closely linked to HBV morphogenesis. The authors report that exosome-associated HBV can infect HBV-susceptible hepatoma cells and thus contribute to viral dissemination. The molecular mechanisms underlying infection of target cells by exosome-associated HBV and virions are largely comparable.
There is no major alternative entry pathway for HBV transported by exosomes, thus they can be inhibited by antibodies directed against the large HBV surface antigen (LHB) and the entry inhibitor Myrcludex. In addition to its role in exosome-cell interaction, the LHB on the exosome surface represents a target for neutralizing antibodies and, by providing an alternative target for humoral responses, could contribute to the evasion of infectious virions. The relative contribution of exosomes to HBV dissemination vs. escape remains to be determined.
Studies using HBV derived from the blood of HBV-infected patients are required to assess the relevance of these processes in vivo and if/how these are affected by antiviral therapies.
Mirjam B. Zeisel, PharmD, PhD, is with the Cancer Research Center of Lyon, Université de Lyon, France, and reports no conflicts of interest.
Viral cell entry and viral neutralization by antibodies are largely defined by the virion structure. Not surprisingly, viruses have evolved strategies to hijack cellular pathways for their morphogenesis to promote their dissemination and escape host immune responses. Hepatitis B viruses (HBV) are released as infectious enveloped virions from infected cells through the multivesicular body pathway. Moreover, excess HBV envelope proteins are exported as noninfectious subviral particles that can act as decoys to trap neutralizing antibodies.
Using cell culture models, investigators from the Hildt lab show in this study that a minority of enveloped virions are released within exosomes, the biogenesis of which is closely linked to HBV morphogenesis. The authors report that exosome-associated HBV can infect HBV-susceptible hepatoma cells and thus contribute to viral dissemination. The molecular mechanisms underlying infection of target cells by exosome-associated HBV and virions are largely comparable.
There is no major alternative entry pathway for HBV transported by exosomes, thus they can be inhibited by antibodies directed against the large HBV surface antigen (LHB) and the entry inhibitor Myrcludex. In addition to its role in exosome-cell interaction, the LHB on the exosome surface represents a target for neutralizing antibodies and, by providing an alternative target for humoral responses, could contribute to the evasion of infectious virions. The relative contribution of exosomes to HBV dissemination vs. escape remains to be determined.
Studies using HBV derived from the blood of HBV-infected patients are required to assess the relevance of these processes in vivo and if/how these are affected by antiviral therapies.
Mirjam B. Zeisel, PharmD, PhD, is with the Cancer Research Center of Lyon, Université de Lyon, France, and reports no conflicts of interest.
Viral cell entry and viral neutralization by antibodies are largely defined by the virion structure. Not surprisingly, viruses have evolved strategies to hijack cellular pathways for their morphogenesis to promote their dissemination and escape host immune responses. Hepatitis B viruses (HBV) are released as infectious enveloped virions from infected cells through the multivesicular body pathway. Moreover, excess HBV envelope proteins are exported as noninfectious subviral particles that can act as decoys to trap neutralizing antibodies.
Using cell culture models, investigators from the Hildt lab show in this study that a minority of enveloped virions are released within exosomes, the biogenesis of which is closely linked to HBV morphogenesis. The authors report that exosome-associated HBV can infect HBV-susceptible hepatoma cells and thus contribute to viral dissemination. The molecular mechanisms underlying infection of target cells by exosome-associated HBV and virions are largely comparable.
There is no major alternative entry pathway for HBV transported by exosomes, thus they can be inhibited by antibodies directed against the large HBV surface antigen (LHB) and the entry inhibitor Myrcludex. In addition to its role in exosome-cell interaction, the LHB on the exosome surface represents a target for neutralizing antibodies and, by providing an alternative target for humoral responses, could contribute to the evasion of infectious virions. The relative contribution of exosomes to HBV dissemination vs. escape remains to be determined.
Studies using HBV derived from the blood of HBV-infected patients are required to assess the relevance of these processes in vivo and if/how these are affected by antiviral therapies.
Mirjam B. Zeisel, PharmD, PhD, is with the Cancer Research Center of Lyon, Université de Lyon, France, and reports no conflicts of interest.
Hepatitis B virus (HBV), which can lead to acute and chronic hepatitis, infects more than 2 billion people worldwide, according to serological evidence. Although vaccines and treatments are available, there are approximately 1.5 million new HBV infections each year globally.
A new study has revealed a key step in the HBV life cycle: Researchers found that HBV virions can be released within exosomes, which are capable of infecting neighboring cells. The authors, led by Qingyan Wu of the department of virology, Paul-Ehrlich-Institute, Langen, Germany, suggest this strategy may help the virus escape immune surveillance and target a new hepatocyte.
The study was published online in Cellular and Molecular Gastroenterology and Hepatology.
The researchers isolated exosomes from the supernatants of HBV-producing cells using exosomal and HBV markers. Electron microscopy using ultrathin sectioning along with immunogold labeling confirmed the presence of intact HBV virions in exosomes. The ultracentrifugation enabled the separation of the free virion fraction from the virions enclosed in exosomes. These findings fit in with previous discoveries of quasi-enveloped hepatitis A virus and hepatitis E virus.
The exosomes released free HBV virion and naked capsid after exposure to detergent. Cellular exposure to exosome morphogenesis inhibitors interfered with the release of exosome-packaged HBV. The researchers also observed large HBV surface antigens (LHB) on the external surface of the exosomes and found that the antigens allowed the exosome to infect susceptible cells through interaction with the sodium-taurocholate co-transporting polypeptide. LHB may also play an additional role in infectivity by countering the ability of antibodies to neutralize HBV.
However, the researchers also found that an LHB-specific neutralizing antibody inhibited infection of differentiated HepaRG cells with exosome-containing HBV. One explanation is that the antibody blocks the interaction between LHB and the target cell. Another is that the exosome disassembles near the target cell membrane and releases the virus, which is then blocked by the antibody since it can block entry of released virus.
To investigate the release pathway, the researchers used three different exosome release inhibitors and found that all three interfered with HBV exosomal release. They also found that cells deficient in the exosome proteins Alix and syntenin did not release exosomal HBV.
Alix appears to be involved in HBV exosomal release, as evidenced by the fact that release of exosomal HBV is boosted in Alix-deficient cells following rescue through overexpression of mCherry-Alix fusion construct. Overexpression of mCherry-Alix had no effect on release of free HBV virions.
The researchers also found evidence that two other exosomal proteins, CD63 and TSG101, play a role in incorporation of LHBs in the HBV envelope, as well as release of HBV through interactions with the protein alpha-taxilin. CD63 and TSG101 are also critical to the formation of exosomes, and the authors suggest further research into their functioning could be fruitful.
Whether exosome-released HBV results from crosstalk between the virus and host cells still needs to be determined. If host factors play a role in connecting HBV to exosomes, it will be interesting to work out which conditions trigger this process, as well as determine which events trigger the release of free virus through multivesicular bodies.
The researchers posit that LHBs could perform a similar function as classical hepatitis B surface antigens and filaments in foiling the immune response. Such a function would require that the virus escape from antibodies before opsonin proteins tag the antigens. It’s also possible that LHBs enable infection of nonhepatic tissues, though this would likely be inefficient.
Many other host proteins have been observed in exosomes released by HBV-infected hepatocytes, suggesting that host proteins may play other roles. A proteomics analysis found proteasome subunit proteins in HepAD38-derived exosomes. The authors suggest that those proteins may allow the exosomes to mediate transcellular immune regulation.
Subviral particles may enhance viral infection, and exosomes from HBV-positive cells may contribute, possibly through exosome surface LHBs, according to the authors. They found that an LHB-specific neutralizing antibody inhibited infection of differentiated HepaRG cells. One explanation is that the antibody blocks the interaction between LHB and the target cell. Another is that the exosome disassembles near the target cell membrane and releases the virus, which is then blocked by the antibody since it can block entry of released virus.
“This previously undiscovered strategy of sequestering HBV particles in exosomes could be a strategy to escape from the immune response and to target them, protected by the exosomal membrane, to the hepatocyte. Exosomes that carry HBV particles seem also to have the potential to deliver HBV to nonpermissive cells with low efficiency. This suggests that exosomes could be an additional factor that contributes to the spread of HBV,” the authors wrote.
The authors had no financial conflicts. This research was funded by the LOEWE Center ACLF, DRUID, the Germany Research Foundation, and the China Scholarship Council.
Hepatitis B virus (HBV), which can lead to acute and chronic hepatitis, infects more than 2 billion people worldwide, according to serological evidence. Although vaccines and treatments are available, there are approximately 1.5 million new HBV infections each year globally.
A new study has revealed a key step in the HBV life cycle: Researchers found that HBV virions can be released within exosomes, which are capable of infecting neighboring cells. The authors, led by Qingyan Wu of the department of virology, Paul-Ehrlich-Institute, Langen, Germany, suggest this strategy may help the virus escape immune surveillance and target a new hepatocyte.
The study was published online in Cellular and Molecular Gastroenterology and Hepatology.
The researchers isolated exosomes from the supernatants of HBV-producing cells using exosomal and HBV markers. Electron microscopy using ultrathin sectioning along with immunogold labeling confirmed the presence of intact HBV virions in exosomes. The ultracentrifugation enabled the separation of the free virion fraction from the virions enclosed in exosomes. These findings fit in with previous discoveries of quasi-enveloped hepatitis A virus and hepatitis E virus.
The exosomes released free HBV virion and naked capsid after exposure to detergent. Cellular exposure to exosome morphogenesis inhibitors interfered with the release of exosome-packaged HBV. The researchers also observed large HBV surface antigens (LHB) on the external surface of the exosomes and found that the antigens allowed the exosome to infect susceptible cells through interaction with the sodium-taurocholate co-transporting polypeptide. LHB may also play an additional role in infectivity by countering the ability of antibodies to neutralize HBV.
However, the researchers also found that an LHB-specific neutralizing antibody inhibited infection of differentiated HepaRG cells with exosome-containing HBV. One explanation is that the antibody blocks the interaction between LHB and the target cell. Another is that the exosome disassembles near the target cell membrane and releases the virus, which is then blocked by the antibody since it can block entry of released virus.
To investigate the release pathway, the researchers used three different exosome release inhibitors and found that all three interfered with HBV exosomal release. They also found that cells deficient in the exosome proteins Alix and syntenin did not release exosomal HBV.
Alix appears to be involved in HBV exosomal release, as evidenced by the fact that release of exosomal HBV is boosted in Alix-deficient cells following rescue through overexpression of mCherry-Alix fusion construct. Overexpression of mCherry-Alix had no effect on release of free HBV virions.
The researchers also found evidence that two other exosomal proteins, CD63 and TSG101, play a role in incorporation of LHBs in the HBV envelope, as well as release of HBV through interactions with the protein alpha-taxilin. CD63 and TSG101 are also critical to the formation of exosomes, and the authors suggest further research into their functioning could be fruitful.
Whether exosome-released HBV results from crosstalk between the virus and host cells still needs to be determined. If host factors play a role in connecting HBV to exosomes, it will be interesting to work out which conditions trigger this process, as well as determine which events trigger the release of free virus through multivesicular bodies.
The researchers posit that LHBs could perform a similar function as classical hepatitis B surface antigens and filaments in foiling the immune response. Such a function would require that the virus escape from antibodies before opsonin proteins tag the antigens. It’s also possible that LHBs enable infection of nonhepatic tissues, though this would likely be inefficient.
Many other host proteins have been observed in exosomes released by HBV-infected hepatocytes, suggesting that host proteins may play other roles. A proteomics analysis found proteasome subunit proteins in HepAD38-derived exosomes. The authors suggest that those proteins may allow the exosomes to mediate transcellular immune regulation.
Subviral particles may enhance viral infection, and exosomes from HBV-positive cells may contribute, possibly through exosome surface LHBs, according to the authors. They found that an LHB-specific neutralizing antibody inhibited infection of differentiated HepaRG cells. One explanation is that the antibody blocks the interaction between LHB and the target cell. Another is that the exosome disassembles near the target cell membrane and releases the virus, which is then blocked by the antibody since it can block entry of released virus.
“This previously undiscovered strategy of sequestering HBV particles in exosomes could be a strategy to escape from the immune response and to target them, protected by the exosomal membrane, to the hepatocyte. Exosomes that carry HBV particles seem also to have the potential to deliver HBV to nonpermissive cells with low efficiency. This suggests that exosomes could be an additional factor that contributes to the spread of HBV,” the authors wrote.
The authors had no financial conflicts. This research was funded by the LOEWE Center ACLF, DRUID, the Germany Research Foundation, and the China Scholarship Council.
FROM CELLULAR AND MOLECULAR GASTROENTEROLOGY AND HEPATOLOGY