User login
Risk of cancer in NAFLD is 91% higher than in control subjects
SAN FRANCISCO –
Those are key findings from a community cohort study with up to 21 years of follow-up, which one of the authors, Alina M. Allen, MD, discussed during a press briefing at the annual meeting of the American Association for the Study of Liver Diseases.
“NAFLD is the most common chronic liver disease in the Western world,” said Dr. Allen, a gastroenterologist at the Mayo Clinic, Rochester, Minn. “It affects one in four adults in the U.S. It is related to fat accumulation in the liver in people who are overweight or obese and can lead to cirrhosis and liver-related mortality. However, the most common cause of death in this population is not liver disease but malignancy and cardiovascular disease. There is a paucity of epidemiologic studies of extrahepatic cancer in NAFLD. It is not clear what types of cancers and how much higher their cancer risk is in reference to the general population.”
In an effort to determine the incidence of cancer diagnoses in NALFD, compared with controls, in a U.S. community, Dr. Allen and her colleagues drew from the Rochester Epidemiology Project to evaluate 4,791 adults diagnosed with NAFLD and 14,432 age- and sex-matched control subjects in Olmstead County, Minn., during 1997-2017. The researchers obtained corresponding Surveillance, Epidemiology, and End Results Program (SEER) rates as a quality check and used a regression model to assess the malignancy risk in NAFLD overall and by cancer type, age, sex, and body mass index. They recorded all new diagnoses of cancers that developed in both groups until 2018, for a total possible follow-up of 21 years, and they reported results in incidence rate ratios, a risk estimate similar to hazard ratios.
The mean age of the study population was 53 years, 53% were female, and the mean follow-up was 8 years with a range from 1 to 21 years. New cancers were identified in 16% of subjects with NALFD and in 12% of control subjects. The overall risk of malignancy was 91% higher in NAFLD subjects, compared with control subjects; there were higher rates in the NAFLD subjects for most types of cancers, but the largest increases were in GI cancers. The greatest malignancy risk was for cancer of the liver (RR, 3.24), followed by cancer of the uterus (RR, 2.39), stomach (RR, 2.34), pancreas (RR, 2.09), and colon (RR, 1.75). “Interestingly, the risk of colon cancer increased only in men but not in women,” Dr. Allen said. “These data provide an important hierarchical overview of the top most important malignancy risks associated with NAFLD that the medical community should be aware of.”
When the researchers looked for differences in age at cancer diagnosis between NAFLD and controls, they found that pancreas cancer occurred at a younger age among subjects with NAFLD. They also observed that colon cancer occurred at a younger age in men with NAFLD, but not in women with the disease. “What was most interesting to us was the assessment of cancer risk in NAFLD versus obesity alone,” Dr. Allen said. “Previous studies from the general population have linked obesity to a higher risk of cancer. Whether the presence of fatty liver disease would impact that risk has not been assessed. We showed that obesity is associated with a higher risk of cancer only in those with NAFLD, not in those without. If validated in independent cohorts, these findings could change our understanding of the relationship between obesity and cancer and the importance of screening for NAFLD – not only to risk-stratify liver disease but also for the risk of extrahepatic malignancy.”
Dr. Allen concluded her presentation by noting that findings from large population-based studies such as the Rochester Epidemiology Project “can offer important epidemiologic data regarding the biggest threats to the health of a community,” she said. “Such data increase awareness, enable appropriate counseling, and could inform screening policies. There is a signal in the fact that the GI cancers are increased [in NAFLD]. It’s an interesting signal that needs to be studied further.”
Dr. Allen reported having no financial conflicts.
Source: Allen AM. Hepatol. 2018;68[S1]: Abstract 31.
SAN FRANCISCO –
Those are key findings from a community cohort study with up to 21 years of follow-up, which one of the authors, Alina M. Allen, MD, discussed during a press briefing at the annual meeting of the American Association for the Study of Liver Diseases.
“NAFLD is the most common chronic liver disease in the Western world,” said Dr. Allen, a gastroenterologist at the Mayo Clinic, Rochester, Minn. “It affects one in four adults in the U.S. It is related to fat accumulation in the liver in people who are overweight or obese and can lead to cirrhosis and liver-related mortality. However, the most common cause of death in this population is not liver disease but malignancy and cardiovascular disease. There is a paucity of epidemiologic studies of extrahepatic cancer in NAFLD. It is not clear what types of cancers and how much higher their cancer risk is in reference to the general population.”
In an effort to determine the incidence of cancer diagnoses in NALFD, compared with controls, in a U.S. community, Dr. Allen and her colleagues drew from the Rochester Epidemiology Project to evaluate 4,791 adults diagnosed with NAFLD and 14,432 age- and sex-matched control subjects in Olmstead County, Minn., during 1997-2017. The researchers obtained corresponding Surveillance, Epidemiology, and End Results Program (SEER) rates as a quality check and used a regression model to assess the malignancy risk in NAFLD overall and by cancer type, age, sex, and body mass index. They recorded all new diagnoses of cancers that developed in both groups until 2018, for a total possible follow-up of 21 years, and they reported results in incidence rate ratios, a risk estimate similar to hazard ratios.
The mean age of the study population was 53 years, 53% were female, and the mean follow-up was 8 years with a range from 1 to 21 years. New cancers were identified in 16% of subjects with NALFD and in 12% of control subjects. The overall risk of malignancy was 91% higher in NAFLD subjects, compared with control subjects; there were higher rates in the NAFLD subjects for most types of cancers, but the largest increases were in GI cancers. The greatest malignancy risk was for cancer of the liver (RR, 3.24), followed by cancer of the uterus (RR, 2.39), stomach (RR, 2.34), pancreas (RR, 2.09), and colon (RR, 1.75). “Interestingly, the risk of colon cancer increased only in men but not in women,” Dr. Allen said. “These data provide an important hierarchical overview of the top most important malignancy risks associated with NAFLD that the medical community should be aware of.”
When the researchers looked for differences in age at cancer diagnosis between NAFLD and controls, they found that pancreas cancer occurred at a younger age among subjects with NAFLD. They also observed that colon cancer occurred at a younger age in men with NAFLD, but not in women with the disease. “What was most interesting to us was the assessment of cancer risk in NAFLD versus obesity alone,” Dr. Allen said. “Previous studies from the general population have linked obesity to a higher risk of cancer. Whether the presence of fatty liver disease would impact that risk has not been assessed. We showed that obesity is associated with a higher risk of cancer only in those with NAFLD, not in those without. If validated in independent cohorts, these findings could change our understanding of the relationship between obesity and cancer and the importance of screening for NAFLD – not only to risk-stratify liver disease but also for the risk of extrahepatic malignancy.”
Dr. Allen concluded her presentation by noting that findings from large population-based studies such as the Rochester Epidemiology Project “can offer important epidemiologic data regarding the biggest threats to the health of a community,” she said. “Such data increase awareness, enable appropriate counseling, and could inform screening policies. There is a signal in the fact that the GI cancers are increased [in NAFLD]. It’s an interesting signal that needs to be studied further.”
Dr. Allen reported having no financial conflicts.
Source: Allen AM. Hepatol. 2018;68[S1]: Abstract 31.
SAN FRANCISCO –
Those are key findings from a community cohort study with up to 21 years of follow-up, which one of the authors, Alina M. Allen, MD, discussed during a press briefing at the annual meeting of the American Association for the Study of Liver Diseases.
“NAFLD is the most common chronic liver disease in the Western world,” said Dr. Allen, a gastroenterologist at the Mayo Clinic, Rochester, Minn. “It affects one in four adults in the U.S. It is related to fat accumulation in the liver in people who are overweight or obese and can lead to cirrhosis and liver-related mortality. However, the most common cause of death in this population is not liver disease but malignancy and cardiovascular disease. There is a paucity of epidemiologic studies of extrahepatic cancer in NAFLD. It is not clear what types of cancers and how much higher their cancer risk is in reference to the general population.”
In an effort to determine the incidence of cancer diagnoses in NALFD, compared with controls, in a U.S. community, Dr. Allen and her colleagues drew from the Rochester Epidemiology Project to evaluate 4,791 adults diagnosed with NAFLD and 14,432 age- and sex-matched control subjects in Olmstead County, Minn., during 1997-2017. The researchers obtained corresponding Surveillance, Epidemiology, and End Results Program (SEER) rates as a quality check and used a regression model to assess the malignancy risk in NAFLD overall and by cancer type, age, sex, and body mass index. They recorded all new diagnoses of cancers that developed in both groups until 2018, for a total possible follow-up of 21 years, and they reported results in incidence rate ratios, a risk estimate similar to hazard ratios.
The mean age of the study population was 53 years, 53% were female, and the mean follow-up was 8 years with a range from 1 to 21 years. New cancers were identified in 16% of subjects with NALFD and in 12% of control subjects. The overall risk of malignancy was 91% higher in NAFLD subjects, compared with control subjects; there were higher rates in the NAFLD subjects for most types of cancers, but the largest increases were in GI cancers. The greatest malignancy risk was for cancer of the liver (RR, 3.24), followed by cancer of the uterus (RR, 2.39), stomach (RR, 2.34), pancreas (RR, 2.09), and colon (RR, 1.75). “Interestingly, the risk of colon cancer increased only in men but not in women,” Dr. Allen said. “These data provide an important hierarchical overview of the top most important malignancy risks associated with NAFLD that the medical community should be aware of.”
When the researchers looked for differences in age at cancer diagnosis between NAFLD and controls, they found that pancreas cancer occurred at a younger age among subjects with NAFLD. They also observed that colon cancer occurred at a younger age in men with NAFLD, but not in women with the disease. “What was most interesting to us was the assessment of cancer risk in NAFLD versus obesity alone,” Dr. Allen said. “Previous studies from the general population have linked obesity to a higher risk of cancer. Whether the presence of fatty liver disease would impact that risk has not been assessed. We showed that obesity is associated with a higher risk of cancer only in those with NAFLD, not in those without. If validated in independent cohorts, these findings could change our understanding of the relationship between obesity and cancer and the importance of screening for NAFLD – not only to risk-stratify liver disease but also for the risk of extrahepatic malignancy.”
Dr. Allen concluded her presentation by noting that findings from large population-based studies such as the Rochester Epidemiology Project “can offer important epidemiologic data regarding the biggest threats to the health of a community,” she said. “Such data increase awareness, enable appropriate counseling, and could inform screening policies. There is a signal in the fact that the GI cancers are increased [in NAFLD]. It’s an interesting signal that needs to be studied further.”
Dr. Allen reported having no financial conflicts.
Source: Allen AM. Hepatol. 2018;68[S1]: Abstract 31.
REPORTING FROM THE LIVER MEETING 2018
Key clinical point: The risk of cancer in patients with nonalcoholic fatty liver disease is 91% higher than in control subjects.
Major finding: Among subjects with NAFLD, the greatest malignancy risk was for cancer of the liver (risk ratio, 3.24).
Study details: A cohort study of 4,791 adults diagnosed with NAFLD and 14,432 age- and sex-matched control subjects from the Rochester Epidemiology Project.
Disclosures: Dr. Allen reported having no financial conflicts.
Source: Allen AM. Hepatol. 2018;68[S1]:Abstract 31
NASH drug passes phase 2 trial
SAN FRANCISCO – In a phase 2 clinical trial of nonalcoholic steatohepatitis (NASH), the thyroid hormone receptor (THR)–beta agonist MCL-3196 improved various measures of liver function and led to significant levels of NASH resolution.
“I think this is an ideal candidate to take into a registration trial for patients with NASH that have stage 2-3 fibrosis,” Stephen Harrison, MD, a visiting professor of hepatology at the University of Oxford (England), said in an interview. He presented the results at the annual meeting of the American Association for the Study of Liver Diseases.
THR-beta acts primarily through nuclear receptors, where it alters gene expression in target cells. THR-beta agonism can lead to a wide range of physiological effects, including reduction of LDL cholesterol, triglycerides, and liver fat. The latter activity has the potential to reduce lipotoxicity and improve NASH. According to a press release from drug sponsor Madrigal Pharmaceuticals, MCL-3196 is more selective for THR-beta than previous drug candidates and is also targeted to the liver, a combination the company hopes will avoid toxicities and nontarget effects that hampered previous THR-beta agonist development.
The study did not include patients with cirrhosis, and the researchers aren’t yet ready to test that population. “Everyone wants to jump into cirrhosis, but cirrhotic patients are a tougher nut to crack,” Dr. Harrison said. “There are a lot nuances – there is well-compensated cirrhosis, and cirrhosis with portal hypertension, and then there’s decompensation. We need to carefully, methodically, study the milder cirrhotics, and then those with portal hypertension that is clinically significant, and then decompensation as a last resort. But if you don’t show that in early phase development, then in my opinion we shouldn’t go to phase 3 in a cirrhotic population.”
The phase 2 study included 18 sites in the United States. The researchers randomly assigned 84 patients to MGL-3196 and 41 to placebo. The treatment group received 80 mg oral MGL-3196 once per day, with an option to adjust the dose 20 mg higher or lower at week 4. All patients underwent liver biopsy at baseline and again at 36 weeks.
At 12 weeks, there was a 36% relative reduction in fat across all patients taking MGL-3196, compared with a 10% reduction in the placebo group (P less than .0001). The difference at 36 weeks was 37% versus 8% (P less than .0001). In a predefined group who received high exposure to MCL-3196, the fat reduction was 42% at 12 weeks and 49% at 36 weeks.
At 36 weeks, 68% of all comers on the drug had lost at least 30% of liver fat, compared with 18% in the placebo group (P less than .0001). A total of 77% in the high-exposure group had a similar outcome (P less than .0001), as did 68% of patients with fibrosis stage 2 or 3 (P = .009).
The researchers also found a reduction at 36 weeks in liver enzyme levels among patients in the treatment group who had elevated levels at baseline, including a 40% reduction in ALT, compared with placebo (P = .01). There were smaller, but still significant, reductions in AST and gamma-glutamyltransferase at week 36 in the treatment group, compared with placebo (P = .002 for both).
A 2-point reduction in Nonalcoholic Fatty Liver Disease Activity Score occurred at week 36 in 32% of placebo subjects, compared with 51% (P = .09) of all patients in the treatment group and 61% of the high-exposure group (P = .02). Among patients judged to have been responders based on MRI, 65% had a 2-point reduction (P = .006). NASH resolution occurred in 6% of the placebo group, 27% of the treatment group (P = .02), and 39% of MRI responders (P = .003).
Adverse events were mild and similar between the treatment group and placebo, with the exception of loose stools, which were single events restricted to the initiation of therapy.
The study was funded by Madrigal Pharmaceuticals. Dr. Harrison is a consultant for Madrigal.
SAN FRANCISCO – In a phase 2 clinical trial of nonalcoholic steatohepatitis (NASH), the thyroid hormone receptor (THR)–beta agonist MCL-3196 improved various measures of liver function and led to significant levels of NASH resolution.
“I think this is an ideal candidate to take into a registration trial for patients with NASH that have stage 2-3 fibrosis,” Stephen Harrison, MD, a visiting professor of hepatology at the University of Oxford (England), said in an interview. He presented the results at the annual meeting of the American Association for the Study of Liver Diseases.
THR-beta acts primarily through nuclear receptors, where it alters gene expression in target cells. THR-beta agonism can lead to a wide range of physiological effects, including reduction of LDL cholesterol, triglycerides, and liver fat. The latter activity has the potential to reduce lipotoxicity and improve NASH. According to a press release from drug sponsor Madrigal Pharmaceuticals, MCL-3196 is more selective for THR-beta than previous drug candidates and is also targeted to the liver, a combination the company hopes will avoid toxicities and nontarget effects that hampered previous THR-beta agonist development.
The study did not include patients with cirrhosis, and the researchers aren’t yet ready to test that population. “Everyone wants to jump into cirrhosis, but cirrhotic patients are a tougher nut to crack,” Dr. Harrison said. “There are a lot nuances – there is well-compensated cirrhosis, and cirrhosis with portal hypertension, and then there’s decompensation. We need to carefully, methodically, study the milder cirrhotics, and then those with portal hypertension that is clinically significant, and then decompensation as a last resort. But if you don’t show that in early phase development, then in my opinion we shouldn’t go to phase 3 in a cirrhotic population.”
The phase 2 study included 18 sites in the United States. The researchers randomly assigned 84 patients to MGL-3196 and 41 to placebo. The treatment group received 80 mg oral MGL-3196 once per day, with an option to adjust the dose 20 mg higher or lower at week 4. All patients underwent liver biopsy at baseline and again at 36 weeks.
At 12 weeks, there was a 36% relative reduction in fat across all patients taking MGL-3196, compared with a 10% reduction in the placebo group (P less than .0001). The difference at 36 weeks was 37% versus 8% (P less than .0001). In a predefined group who received high exposure to MCL-3196, the fat reduction was 42% at 12 weeks and 49% at 36 weeks.
At 36 weeks, 68% of all comers on the drug had lost at least 30% of liver fat, compared with 18% in the placebo group (P less than .0001). A total of 77% in the high-exposure group had a similar outcome (P less than .0001), as did 68% of patients with fibrosis stage 2 or 3 (P = .009).
The researchers also found a reduction at 36 weeks in liver enzyme levels among patients in the treatment group who had elevated levels at baseline, including a 40% reduction in ALT, compared with placebo (P = .01). There were smaller, but still significant, reductions in AST and gamma-glutamyltransferase at week 36 in the treatment group, compared with placebo (P = .002 for both).
A 2-point reduction in Nonalcoholic Fatty Liver Disease Activity Score occurred at week 36 in 32% of placebo subjects, compared with 51% (P = .09) of all patients in the treatment group and 61% of the high-exposure group (P = .02). Among patients judged to have been responders based on MRI, 65% had a 2-point reduction (P = .006). NASH resolution occurred in 6% of the placebo group, 27% of the treatment group (P = .02), and 39% of MRI responders (P = .003).
Adverse events were mild and similar between the treatment group and placebo, with the exception of loose stools, which were single events restricted to the initiation of therapy.
The study was funded by Madrigal Pharmaceuticals. Dr. Harrison is a consultant for Madrigal.
SAN FRANCISCO – In a phase 2 clinical trial of nonalcoholic steatohepatitis (NASH), the thyroid hormone receptor (THR)–beta agonist MCL-3196 improved various measures of liver function and led to significant levels of NASH resolution.
“I think this is an ideal candidate to take into a registration trial for patients with NASH that have stage 2-3 fibrosis,” Stephen Harrison, MD, a visiting professor of hepatology at the University of Oxford (England), said in an interview. He presented the results at the annual meeting of the American Association for the Study of Liver Diseases.
THR-beta acts primarily through nuclear receptors, where it alters gene expression in target cells. THR-beta agonism can lead to a wide range of physiological effects, including reduction of LDL cholesterol, triglycerides, and liver fat. The latter activity has the potential to reduce lipotoxicity and improve NASH. According to a press release from drug sponsor Madrigal Pharmaceuticals, MCL-3196 is more selective for THR-beta than previous drug candidates and is also targeted to the liver, a combination the company hopes will avoid toxicities and nontarget effects that hampered previous THR-beta agonist development.
The study did not include patients with cirrhosis, and the researchers aren’t yet ready to test that population. “Everyone wants to jump into cirrhosis, but cirrhotic patients are a tougher nut to crack,” Dr. Harrison said. “There are a lot nuances – there is well-compensated cirrhosis, and cirrhosis with portal hypertension, and then there’s decompensation. We need to carefully, methodically, study the milder cirrhotics, and then those with portal hypertension that is clinically significant, and then decompensation as a last resort. But if you don’t show that in early phase development, then in my opinion we shouldn’t go to phase 3 in a cirrhotic population.”
The phase 2 study included 18 sites in the United States. The researchers randomly assigned 84 patients to MGL-3196 and 41 to placebo. The treatment group received 80 mg oral MGL-3196 once per day, with an option to adjust the dose 20 mg higher or lower at week 4. All patients underwent liver biopsy at baseline and again at 36 weeks.
At 12 weeks, there was a 36% relative reduction in fat across all patients taking MGL-3196, compared with a 10% reduction in the placebo group (P less than .0001). The difference at 36 weeks was 37% versus 8% (P less than .0001). In a predefined group who received high exposure to MCL-3196, the fat reduction was 42% at 12 weeks and 49% at 36 weeks.
At 36 weeks, 68% of all comers on the drug had lost at least 30% of liver fat, compared with 18% in the placebo group (P less than .0001). A total of 77% in the high-exposure group had a similar outcome (P less than .0001), as did 68% of patients with fibrosis stage 2 or 3 (P = .009).
The researchers also found a reduction at 36 weeks in liver enzyme levels among patients in the treatment group who had elevated levels at baseline, including a 40% reduction in ALT, compared with placebo (P = .01). There were smaller, but still significant, reductions in AST and gamma-glutamyltransferase at week 36 in the treatment group, compared with placebo (P = .002 for both).
A 2-point reduction in Nonalcoholic Fatty Liver Disease Activity Score occurred at week 36 in 32% of placebo subjects, compared with 51% (P = .09) of all patients in the treatment group and 61% of the high-exposure group (P = .02). Among patients judged to have been responders based on MRI, 65% had a 2-point reduction (P = .006). NASH resolution occurred in 6% of the placebo group, 27% of the treatment group (P = .02), and 39% of MRI responders (P = .003).
Adverse events were mild and similar between the treatment group and placebo, with the exception of loose stools, which were single events restricted to the initiation of therapy.
The study was funded by Madrigal Pharmaceuticals. Dr. Harrison is a consultant for Madrigal.
REPORTING FROM THE LIVER MEETING 2018
Key clinical point: If approved, MCL-3196 would be the first drug for the treatment of nonalcoholic steatohepatitis.
Major finding: At 36 weeks, the drug was associated with a 37% reduction in liver fat, compared with 8% in the placebo group.
Study details: A randomized, controlled trial with 125 patients with nonalcoholic steatohepatitis.
Disclosures: The study was funded by Madrigal Pharmaceuticals. Dr. Harrison is a consultant for Madrigal.
Chronic liver disease independently linked to increased risk of falls
SAN FRANCISCO – .
“We have previously known that having cirrhosis, for example, is associated with the risk of falling, but we didn’t have any data from a nationally representative sample,” lead study author Maria Camila Pérez-Matos, MD, said in an interview at the annual meeting of the American Association for the Study of Liver Diseases. “What surprised us is that just by having chronic liver disease – any subtype – you’re more likely to fall, and also to have a fracture after you have fallen.”
In an effort to define the association between CLD and fall history and its related injuries, Dr. Pérez-Matos of the division of gastroenterology and hepatology at Beth Israel Deaconess Medical Center, Boston, and her associates examined data from 5,363 subjects aged 60 years and older in the Third National Health and Nutrition Examination Survey, which represents the noninstitutionalized civilian population in the United States. Their outcomes of interest were one or more falls occurring in the previous 12 months and fall-related injuries. The main exposure was definitive CLD, defined by chronic viral hepatitis (hepatitis C RNA or hepatitis B surface antigen), nonalcoholic steatohepatitis (NASH; hepatosteatosis by ultrasound with abnormal transaminases), and alcohol-related liver disease (females consuming more than 7 drinks/week and males consuming 14 drinks/week among, plus having abnormal transaminases). Suspected CLD was defined as having abnormal alanine aminotransferase levels (males greater than 30 IU/L, females greater than 19 IU/L), aspartate aminotransferase levels above 33 IU/L, or alkaline phosphatase levels above 100 IU/L. The researchers used univariate and multivariate logistic regression to examine associations.
The average age of subjects was 70 years, and 59% were female. Of the 5,363 subjects, 340 had definitive CLD. Of these, 234 (69%) had NASH, 85 (25%) had viral hepatitis, and 21 (6%) had alcoholic liver disease. Subjects with definitive CLD were more likely to be female and have diabetes mellitus, a higher body mass index, and physical/functional impairment. Dr. Pérez-Matos and her colleagues found that definitive CLD was associated with a 52% increase in the odds of having a history of falls (odds ratio, 1.52; P = .01). The association remained significant after controlling for age, sex, smoking, race, physical or functional impairment, impaired vision, polypharmacy, and body mass index. The degree of excess falling risk posed by CLD was similar to that of having impaired vision (OR, 1.48; P less than .001).
Of the CLD subtypes, subjects with viral hepatitis had the strongest association with a history of falls (OR, 2.2; P = .001). In addition, definitive CLD was found to have significant association with any physical impairment, even after adjusting for relevant covariates (OR, 1.63; P = .001).
Finally, multivariate logistic regression revealed that both suspected and definitive CLD were associated with injurious falls (OR, 1.40 and OR of 1.67, respectively). “Everyone is interested in preventing falls because of its public health impact, and predictors of falls are relatively limited,” said Elliott B. Tapper, MD, the study’s principal investigator, who is with the division of gastroenterology and hepatology at the University of Michigan, Ann Arbor. “Because chronic liver disease is increasingly common, our data is speaking to a hitherto unknown risk factor: one which if you apply it to other data sets might help figure out why more people are falling. The lesson is, there’s something about chronic liver disease; it’s a sign. If it’s fatty liver disease, it’s a sign that diabetes has taken its toll on the body – its nerves and muscles. There’s something about what’s going on in that person that’s worse than it is for other people. We don’t know cause or effect, but the association is strong and deserves further study, particularly when it comes to determining [which patients] in our clinics are at higher risk and making sure they’re doing physical therapy to prevent falls in the future.”
Dr. Tapper disclosed that she has a career development award from the National Institutes of Health. Dr. Pérez-Matos reported having no monetary conflicts.
Source: Hepatol. 2018;68[S1], Abstract 756.
SAN FRANCISCO – .
“We have previously known that having cirrhosis, for example, is associated with the risk of falling, but we didn’t have any data from a nationally representative sample,” lead study author Maria Camila Pérez-Matos, MD, said in an interview at the annual meeting of the American Association for the Study of Liver Diseases. “What surprised us is that just by having chronic liver disease – any subtype – you’re more likely to fall, and also to have a fracture after you have fallen.”
In an effort to define the association between CLD and fall history and its related injuries, Dr. Pérez-Matos of the division of gastroenterology and hepatology at Beth Israel Deaconess Medical Center, Boston, and her associates examined data from 5,363 subjects aged 60 years and older in the Third National Health and Nutrition Examination Survey, which represents the noninstitutionalized civilian population in the United States. Their outcomes of interest were one or more falls occurring in the previous 12 months and fall-related injuries. The main exposure was definitive CLD, defined by chronic viral hepatitis (hepatitis C RNA or hepatitis B surface antigen), nonalcoholic steatohepatitis (NASH; hepatosteatosis by ultrasound with abnormal transaminases), and alcohol-related liver disease (females consuming more than 7 drinks/week and males consuming 14 drinks/week among, plus having abnormal transaminases). Suspected CLD was defined as having abnormal alanine aminotransferase levels (males greater than 30 IU/L, females greater than 19 IU/L), aspartate aminotransferase levels above 33 IU/L, or alkaline phosphatase levels above 100 IU/L. The researchers used univariate and multivariate logistic regression to examine associations.
The average age of subjects was 70 years, and 59% were female. Of the 5,363 subjects, 340 had definitive CLD. Of these, 234 (69%) had NASH, 85 (25%) had viral hepatitis, and 21 (6%) had alcoholic liver disease. Subjects with definitive CLD were more likely to be female and have diabetes mellitus, a higher body mass index, and physical/functional impairment. Dr. Pérez-Matos and her colleagues found that definitive CLD was associated with a 52% increase in the odds of having a history of falls (odds ratio, 1.52; P = .01). The association remained significant after controlling for age, sex, smoking, race, physical or functional impairment, impaired vision, polypharmacy, and body mass index. The degree of excess falling risk posed by CLD was similar to that of having impaired vision (OR, 1.48; P less than .001).
Of the CLD subtypes, subjects with viral hepatitis had the strongest association with a history of falls (OR, 2.2; P = .001). In addition, definitive CLD was found to have significant association with any physical impairment, even after adjusting for relevant covariates (OR, 1.63; P = .001).
Finally, multivariate logistic regression revealed that both suspected and definitive CLD were associated with injurious falls (OR, 1.40 and OR of 1.67, respectively). “Everyone is interested in preventing falls because of its public health impact, and predictors of falls are relatively limited,” said Elliott B. Tapper, MD, the study’s principal investigator, who is with the division of gastroenterology and hepatology at the University of Michigan, Ann Arbor. “Because chronic liver disease is increasingly common, our data is speaking to a hitherto unknown risk factor: one which if you apply it to other data sets might help figure out why more people are falling. The lesson is, there’s something about chronic liver disease; it’s a sign. If it’s fatty liver disease, it’s a sign that diabetes has taken its toll on the body – its nerves and muscles. There’s something about what’s going on in that person that’s worse than it is for other people. We don’t know cause or effect, but the association is strong and deserves further study, particularly when it comes to determining [which patients] in our clinics are at higher risk and making sure they’re doing physical therapy to prevent falls in the future.”
Dr. Tapper disclosed that she has a career development award from the National Institutes of Health. Dr. Pérez-Matos reported having no monetary conflicts.
Source: Hepatol. 2018;68[S1], Abstract 756.
SAN FRANCISCO – .
“We have previously known that having cirrhosis, for example, is associated with the risk of falling, but we didn’t have any data from a nationally representative sample,” lead study author Maria Camila Pérez-Matos, MD, said in an interview at the annual meeting of the American Association for the Study of Liver Diseases. “What surprised us is that just by having chronic liver disease – any subtype – you’re more likely to fall, and also to have a fracture after you have fallen.”
In an effort to define the association between CLD and fall history and its related injuries, Dr. Pérez-Matos of the division of gastroenterology and hepatology at Beth Israel Deaconess Medical Center, Boston, and her associates examined data from 5,363 subjects aged 60 years and older in the Third National Health and Nutrition Examination Survey, which represents the noninstitutionalized civilian population in the United States. Their outcomes of interest were one or more falls occurring in the previous 12 months and fall-related injuries. The main exposure was definitive CLD, defined by chronic viral hepatitis (hepatitis C RNA or hepatitis B surface antigen), nonalcoholic steatohepatitis (NASH; hepatosteatosis by ultrasound with abnormal transaminases), and alcohol-related liver disease (females consuming more than 7 drinks/week and males consuming 14 drinks/week among, plus having abnormal transaminases). Suspected CLD was defined as having abnormal alanine aminotransferase levels (males greater than 30 IU/L, females greater than 19 IU/L), aspartate aminotransferase levels above 33 IU/L, or alkaline phosphatase levels above 100 IU/L. The researchers used univariate and multivariate logistic regression to examine associations.
The average age of subjects was 70 years, and 59% were female. Of the 5,363 subjects, 340 had definitive CLD. Of these, 234 (69%) had NASH, 85 (25%) had viral hepatitis, and 21 (6%) had alcoholic liver disease. Subjects with definitive CLD were more likely to be female and have diabetes mellitus, a higher body mass index, and physical/functional impairment. Dr. Pérez-Matos and her colleagues found that definitive CLD was associated with a 52% increase in the odds of having a history of falls (odds ratio, 1.52; P = .01). The association remained significant after controlling for age, sex, smoking, race, physical or functional impairment, impaired vision, polypharmacy, and body mass index. The degree of excess falling risk posed by CLD was similar to that of having impaired vision (OR, 1.48; P less than .001).
Of the CLD subtypes, subjects with viral hepatitis had the strongest association with a history of falls (OR, 2.2; P = .001). In addition, definitive CLD was found to have significant association with any physical impairment, even after adjusting for relevant covariates (OR, 1.63; P = .001).
Finally, multivariate logistic regression revealed that both suspected and definitive CLD were associated with injurious falls (OR, 1.40 and OR of 1.67, respectively). “Everyone is interested in preventing falls because of its public health impact, and predictors of falls are relatively limited,” said Elliott B. Tapper, MD, the study’s principal investigator, who is with the division of gastroenterology and hepatology at the University of Michigan, Ann Arbor. “Because chronic liver disease is increasingly common, our data is speaking to a hitherto unknown risk factor: one which if you apply it to other data sets might help figure out why more people are falling. The lesson is, there’s something about chronic liver disease; it’s a sign. If it’s fatty liver disease, it’s a sign that diabetes has taken its toll on the body – its nerves and muscles. There’s something about what’s going on in that person that’s worse than it is for other people. We don’t know cause or effect, but the association is strong and deserves further study, particularly when it comes to determining [which patients] in our clinics are at higher risk and making sure they’re doing physical therapy to prevent falls in the future.”
Dr. Tapper disclosed that she has a career development award from the National Institutes of Health. Dr. Pérez-Matos reported having no monetary conflicts.
Source: Hepatol. 2018;68[S1], Abstract 756.
REPORTING FROM THE LIVER MEETING 2018
Key clinical point: Attention to falls is warranted in chronic liver disease (CLD) patients at all stages of disease.
Major finding: Having definitive CLD was associated with a 52% increase in the odds of having a history of falls (OR 1.52; P = .01).
Study details: A cross-sectional analysis of 5,363 subjects in the Third National Health and Nutrition Examination Survey.
Disclosures: Dr. Tapper disclosed that he has a career development award from the National Institutes of Health. Dr. Perez-Matos reported having no monetary conflicts.
Source: Hepatol. 2018;68[S1]:Abstract 756.
About 13% of liver transplant recipients affected by PTSD
SAN FRANCISCO –
“Serving the emotional and mental health of these patients is just as important as [improving] liver function and their immunosuppression,” study author Meg O’Meara, NP, said in an interview at the annual meeting of the American Association for the Study of Liver Diseases.
Recent data suggests that patients who undergo significant medical events like solid organ transplantation face a risk of developing PTSD, but limited information exists regarding the psychological effects following adult liver transplantation, said Ms. O’Meara, a nurse practitioner in the division of gastroenterology and hepatology at the University of Colorado at Denver, Aurora. In an effort to determine the prevalence of and risk factors for PTSD in adult liver transplant recipients, she and her associates used the PCL-5 to screen 71 patients seen at the university’s posttransplant clinic from Dec. 1, 2017, to May 31, 2018. The PCL-5 is a validated 20-item questionnaire that corresponds to the DSM-5 symptom criteria for PTSD.
The researchers also collected clinical and demographic information including pretransplant disease severity, history of psychiatric disease, duration of transplant hospitalization, and need for rehospitalization. They used a multivariable regression model to evaluate associations between clinical and demographic variables and a positive screen for PTSD.
The median age of the 71 patients was 58 years; 61% were male. A preexisting diagnosis of depression was present in 25 patients (35%), their mean Model for End-Stage Liver Disease (MELD) score at time of transplant was 31, and their median time from transplant was 1,163 days. In all, nine patients (12.7%) tested positive for PTSD on the PCL-5, and all met criteria for a provisional diagnosis of PTSD based on the DSM-5 criteria. This prevalence is about two times higher than the prevalence of PTSD in the general population (6.7%), comparable with that reported for heart transplant recipients (10.8%) and coronary artery disease (9%), but lower than that reported for ICU patients (38%), HIV patients (35.3%), and in those with Crohn’s disease (19.1%).
On multivariable logistic regression, only three factors were found to be significantly associated with the development of PTSD: younger age at transplant (P = .019), history of depression (P = .008), and a history of PTSD (P less than .001). “What I found surprising was that the MELD score at the time of transplant and the number of readmissions or complications around the time of transplant were not predictive of PTSD,” Ms. O’Meara said.
One possible explanation for the finding of younger age being a predictor of PTSD, she continued, is that younger liver transplant patients may lack certain coping skills, compared with their older counterparts. “Maybe patients who have had more years to deal with their disease are more accepting of it and they learn how to use productive tools to manage it.”
In their abstract, the researchers acknowledged certain limitations of the study, including its cross-sectional design, small sample size, and lack of corresponding pretransplant data.
The researchers reported having no financial disclosures.
SAN FRANCISCO –
“Serving the emotional and mental health of these patients is just as important as [improving] liver function and their immunosuppression,” study author Meg O’Meara, NP, said in an interview at the annual meeting of the American Association for the Study of Liver Diseases.
Recent data suggests that patients who undergo significant medical events like solid organ transplantation face a risk of developing PTSD, but limited information exists regarding the psychological effects following adult liver transplantation, said Ms. O’Meara, a nurse practitioner in the division of gastroenterology and hepatology at the University of Colorado at Denver, Aurora. In an effort to determine the prevalence of and risk factors for PTSD in adult liver transplant recipients, she and her associates used the PCL-5 to screen 71 patients seen at the university’s posttransplant clinic from Dec. 1, 2017, to May 31, 2018. The PCL-5 is a validated 20-item questionnaire that corresponds to the DSM-5 symptom criteria for PTSD.
The researchers also collected clinical and demographic information including pretransplant disease severity, history of psychiatric disease, duration of transplant hospitalization, and need for rehospitalization. They used a multivariable regression model to evaluate associations between clinical and demographic variables and a positive screen for PTSD.
The median age of the 71 patients was 58 years; 61% were male. A preexisting diagnosis of depression was present in 25 patients (35%), their mean Model for End-Stage Liver Disease (MELD) score at time of transplant was 31, and their median time from transplant was 1,163 days. In all, nine patients (12.7%) tested positive for PTSD on the PCL-5, and all met criteria for a provisional diagnosis of PTSD based on the DSM-5 criteria. This prevalence is about two times higher than the prevalence of PTSD in the general population (6.7%), comparable with that reported for heart transplant recipients (10.8%) and coronary artery disease (9%), but lower than that reported for ICU patients (38%), HIV patients (35.3%), and in those with Crohn’s disease (19.1%).
On multivariable logistic regression, only three factors were found to be significantly associated with the development of PTSD: younger age at transplant (P = .019), history of depression (P = .008), and a history of PTSD (P less than .001). “What I found surprising was that the MELD score at the time of transplant and the number of readmissions or complications around the time of transplant were not predictive of PTSD,” Ms. O’Meara said.
One possible explanation for the finding of younger age being a predictor of PTSD, she continued, is that younger liver transplant patients may lack certain coping skills, compared with their older counterparts. “Maybe patients who have had more years to deal with their disease are more accepting of it and they learn how to use productive tools to manage it.”
In their abstract, the researchers acknowledged certain limitations of the study, including its cross-sectional design, small sample size, and lack of corresponding pretransplant data.
The researchers reported having no financial disclosures.
SAN FRANCISCO –
“Serving the emotional and mental health of these patients is just as important as [improving] liver function and their immunosuppression,” study author Meg O’Meara, NP, said in an interview at the annual meeting of the American Association for the Study of Liver Diseases.
Recent data suggests that patients who undergo significant medical events like solid organ transplantation face a risk of developing PTSD, but limited information exists regarding the psychological effects following adult liver transplantation, said Ms. O’Meara, a nurse practitioner in the division of gastroenterology and hepatology at the University of Colorado at Denver, Aurora. In an effort to determine the prevalence of and risk factors for PTSD in adult liver transplant recipients, she and her associates used the PCL-5 to screen 71 patients seen at the university’s posttransplant clinic from Dec. 1, 2017, to May 31, 2018. The PCL-5 is a validated 20-item questionnaire that corresponds to the DSM-5 symptom criteria for PTSD.
The researchers also collected clinical and demographic information including pretransplant disease severity, history of psychiatric disease, duration of transplant hospitalization, and need for rehospitalization. They used a multivariable regression model to evaluate associations between clinical and demographic variables and a positive screen for PTSD.
The median age of the 71 patients was 58 years; 61% were male. A preexisting diagnosis of depression was present in 25 patients (35%), their mean Model for End-Stage Liver Disease (MELD) score at time of transplant was 31, and their median time from transplant was 1,163 days. In all, nine patients (12.7%) tested positive for PTSD on the PCL-5, and all met criteria for a provisional diagnosis of PTSD based on the DSM-5 criteria. This prevalence is about two times higher than the prevalence of PTSD in the general population (6.7%), comparable with that reported for heart transplant recipients (10.8%) and coronary artery disease (9%), but lower than that reported for ICU patients (38%), HIV patients (35.3%), and in those with Crohn’s disease (19.1%).
On multivariable logistic regression, only three factors were found to be significantly associated with the development of PTSD: younger age at transplant (P = .019), history of depression (P = .008), and a history of PTSD (P less than .001). “What I found surprising was that the MELD score at the time of transplant and the number of readmissions or complications around the time of transplant were not predictive of PTSD,” Ms. O’Meara said.
One possible explanation for the finding of younger age being a predictor of PTSD, she continued, is that younger liver transplant patients may lack certain coping skills, compared with their older counterparts. “Maybe patients who have had more years to deal with their disease are more accepting of it and they learn how to use productive tools to manage it.”
In their abstract, the researchers acknowledged certain limitations of the study, including its cross-sectional design, small sample size, and lack of corresponding pretransplant data.
The researchers reported having no financial disclosures.
REPORTING FROM THE LIVER MEETING 2018
Key clinical point: Liver transplant recipients have a higher rate of PTSD than the general population and younger patients may be at a higher risk.
Major finding: In all, nine liver transplant patients (12.7%) tested positive for PTSD, which is about two times higher than the prevalence of PTSD in the general population (6.7%).
Study details: A cross-sectional analysis of 71 liver transplant recipients.
Disclosures: The researchers reported having no financial disclosures.
Novel acetaminophen hepatotoxicity strategy curbs inflammation
SAN FRANCISCO – A novel therapeutic strategy shows initial promise in dampening hepatic cell injury in mice caused by overexposure to acetaminophen. The approach relies on a synthetic version of heparan sulfate, which is believed to interfere with recruitment of neutrophils to the site of hepatic injury. That reduces harm caused by inflammation and may offer a longer therapeutic window than N-acetyl cysteine, which is the current standard therapy but is only effective if given within 8 hours of the injury.
The endogenous syndecan-1, which is a heparan sulfate, is also known to act as a native defense mechanism against inflammatory injury to hepatocytes. “It looks like heparan sulfate attenuates inflammatory responses,” said Jian Liu, PhD, during a presentation of his research at the annual meeting of the American Association for the Study of Liver Diseases. Dr. Liu is a professor of chemical biology and medicinal chemistry at the University of North Carolina at Chapel Hill.
The heparan sulfate analogue heparin has long been used as an anticoagulant, of course, which suggests that a novel heparan sulfate has a good chance of also being safe.
Dr. Liu’s team had to identify a heparan sulfate that had a hepatoprotective effect, but a heparan sulfate’s unique biological activity depends on the specific pattern of sulfation on the heparan molecule. Heparans isolated from natural sources are generally a complex mixture, which makes them difficult to study and produce in large enough quantities to be therapeutically useful.
Dr. Liu’s team used a combinatory approach, harnessing various enzymes to produce hundreds of different heparan sulfate variants, and then screened them for hepatoprotective activity. That process identified an 18-chain heparan sulfate with hepatoprotective activity. With an active formula in hand, they could employ the enzymes to create enough of the pure compound to further the research. “It’s probably two to three hundred times more efficient than the traditional chemical synthesis,” said Dr. Liu.
In mice, researchers injected the 18-mer 30 minutes after a hepatotoxic dose of acetaminophen and again after 12 hours. Tissue staining showed less migration of neutrophils, as well as lower concentrations of tumor necrosis factor–alpha. The animals also had lower alanine transferase levels than did the untreated animals, as well as greater survival after 4 days.
The pathological process surrounding acetaminophen overdose involves release of the high mobility group box 1 (HMGB1) protein from necrotic hepatocytes, which in turn binds to the receptor for advanced glycation end-products (RAGE). The HMGB1/RAGE complex then binds to neutrophils, recruiting them to the site of the injury and initiating inflammation.
To better understand the molecule’s role in the pathological process, the researchers studied RAGE knockout mice, and found that the 18-mer had no protective effect in these animals, suggesting that it relies on RAGE for its biological activity.
Heparan sulfates are widely present in the body, which prompted the researchers to investigate their endogenous effect. In the liver, the primary heparan sulfate is syndecan-1. The researchers demonstrated that the molecule is shed from cell surfaces in response to acetaminophen toxicity and that the levels correlate with HMGB1 release.
Dr. Liu believes that syndecan-1 acts as a natural buffer to inflammation, helping to neutralize HMGB1 and limit damage. “The problem is that when the damage is massive, the shed of syndecan-1 is not enough,” said Dr. Liu. He hopes that something like his team’s heparan sulfate 18-mer can be used therapeutically to bolster these endogenous controls and prevent further damage.
The research was funded by Glycan Therapeutics. Dr. Liu founded Glycan, which offers custom-synthesized heparan sulfates and chondroitin sulfates for research purposes.
SOURCE: Liu J. AASLD 2018, Abstract 0040.
SAN FRANCISCO – A novel therapeutic strategy shows initial promise in dampening hepatic cell injury in mice caused by overexposure to acetaminophen. The approach relies on a synthetic version of heparan sulfate, which is believed to interfere with recruitment of neutrophils to the site of hepatic injury. That reduces harm caused by inflammation and may offer a longer therapeutic window than N-acetyl cysteine, which is the current standard therapy but is only effective if given within 8 hours of the injury.
The endogenous syndecan-1, which is a heparan sulfate, is also known to act as a native defense mechanism against inflammatory injury to hepatocytes. “It looks like heparan sulfate attenuates inflammatory responses,” said Jian Liu, PhD, during a presentation of his research at the annual meeting of the American Association for the Study of Liver Diseases. Dr. Liu is a professor of chemical biology and medicinal chemistry at the University of North Carolina at Chapel Hill.
The heparan sulfate analogue heparin has long been used as an anticoagulant, of course, which suggests that a novel heparan sulfate has a good chance of also being safe.
Dr. Liu’s team had to identify a heparan sulfate that had a hepatoprotective effect, but a heparan sulfate’s unique biological activity depends on the specific pattern of sulfation on the heparan molecule. Heparans isolated from natural sources are generally a complex mixture, which makes them difficult to study and produce in large enough quantities to be therapeutically useful.
Dr. Liu’s team used a combinatory approach, harnessing various enzymes to produce hundreds of different heparan sulfate variants, and then screened them for hepatoprotective activity. That process identified an 18-chain heparan sulfate with hepatoprotective activity. With an active formula in hand, they could employ the enzymes to create enough of the pure compound to further the research. “It’s probably two to three hundred times more efficient than the traditional chemical synthesis,” said Dr. Liu.
In mice, researchers injected the 18-mer 30 minutes after a hepatotoxic dose of acetaminophen and again after 12 hours. Tissue staining showed less migration of neutrophils, as well as lower concentrations of tumor necrosis factor–alpha. The animals also had lower alanine transferase levels than did the untreated animals, as well as greater survival after 4 days.
The pathological process surrounding acetaminophen overdose involves release of the high mobility group box 1 (HMGB1) protein from necrotic hepatocytes, which in turn binds to the receptor for advanced glycation end-products (RAGE). The HMGB1/RAGE complex then binds to neutrophils, recruiting them to the site of the injury and initiating inflammation.
To better understand the molecule’s role in the pathological process, the researchers studied RAGE knockout mice, and found that the 18-mer had no protective effect in these animals, suggesting that it relies on RAGE for its biological activity.
Heparan sulfates are widely present in the body, which prompted the researchers to investigate their endogenous effect. In the liver, the primary heparan sulfate is syndecan-1. The researchers demonstrated that the molecule is shed from cell surfaces in response to acetaminophen toxicity and that the levels correlate with HMGB1 release.
Dr. Liu believes that syndecan-1 acts as a natural buffer to inflammation, helping to neutralize HMGB1 and limit damage. “The problem is that when the damage is massive, the shed of syndecan-1 is not enough,” said Dr. Liu. He hopes that something like his team’s heparan sulfate 18-mer can be used therapeutically to bolster these endogenous controls and prevent further damage.
The research was funded by Glycan Therapeutics. Dr. Liu founded Glycan, which offers custom-synthesized heparan sulfates and chondroitin sulfates for research purposes.
SOURCE: Liu J. AASLD 2018, Abstract 0040.
SAN FRANCISCO – A novel therapeutic strategy shows initial promise in dampening hepatic cell injury in mice caused by overexposure to acetaminophen. The approach relies on a synthetic version of heparan sulfate, which is believed to interfere with recruitment of neutrophils to the site of hepatic injury. That reduces harm caused by inflammation and may offer a longer therapeutic window than N-acetyl cysteine, which is the current standard therapy but is only effective if given within 8 hours of the injury.
The endogenous syndecan-1, which is a heparan sulfate, is also known to act as a native defense mechanism against inflammatory injury to hepatocytes. “It looks like heparan sulfate attenuates inflammatory responses,” said Jian Liu, PhD, during a presentation of his research at the annual meeting of the American Association for the Study of Liver Diseases. Dr. Liu is a professor of chemical biology and medicinal chemistry at the University of North Carolina at Chapel Hill.
The heparan sulfate analogue heparin has long been used as an anticoagulant, of course, which suggests that a novel heparan sulfate has a good chance of also being safe.
Dr. Liu’s team had to identify a heparan sulfate that had a hepatoprotective effect, but a heparan sulfate’s unique biological activity depends on the specific pattern of sulfation on the heparan molecule. Heparans isolated from natural sources are generally a complex mixture, which makes them difficult to study and produce in large enough quantities to be therapeutically useful.
Dr. Liu’s team used a combinatory approach, harnessing various enzymes to produce hundreds of different heparan sulfate variants, and then screened them for hepatoprotective activity. That process identified an 18-chain heparan sulfate with hepatoprotective activity. With an active formula in hand, they could employ the enzymes to create enough of the pure compound to further the research. “It’s probably two to three hundred times more efficient than the traditional chemical synthesis,” said Dr. Liu.
In mice, researchers injected the 18-mer 30 minutes after a hepatotoxic dose of acetaminophen and again after 12 hours. Tissue staining showed less migration of neutrophils, as well as lower concentrations of tumor necrosis factor–alpha. The animals also had lower alanine transferase levels than did the untreated animals, as well as greater survival after 4 days.
The pathological process surrounding acetaminophen overdose involves release of the high mobility group box 1 (HMGB1) protein from necrotic hepatocytes, which in turn binds to the receptor for advanced glycation end-products (RAGE). The HMGB1/RAGE complex then binds to neutrophils, recruiting them to the site of the injury and initiating inflammation.
To better understand the molecule’s role in the pathological process, the researchers studied RAGE knockout mice, and found that the 18-mer had no protective effect in these animals, suggesting that it relies on RAGE for its biological activity.
Heparan sulfates are widely present in the body, which prompted the researchers to investigate their endogenous effect. In the liver, the primary heparan sulfate is syndecan-1. The researchers demonstrated that the molecule is shed from cell surfaces in response to acetaminophen toxicity and that the levels correlate with HMGB1 release.
Dr. Liu believes that syndecan-1 acts as a natural buffer to inflammation, helping to neutralize HMGB1 and limit damage. “The problem is that when the damage is massive, the shed of syndecan-1 is not enough,” said Dr. Liu. He hopes that something like his team’s heparan sulfate 18-mer can be used therapeutically to bolster these endogenous controls and prevent further damage.
The research was funded by Glycan Therapeutics. Dr. Liu founded Glycan, which offers custom-synthesized heparan sulfates and chondroitin sulfates for research purposes.
SOURCE: Liu J. AASLD 2018, Abstract 0040.
REPORTING FROM AASLD 2018
High rates of prescription opioid, benzodiazepine use observed in chronic liver disease
SAN FRANCISCO – .
“Middle-aged individuals and those with a background of substance abuse and mental health conditions appear to have highest rates of use and represent populations for which targeted interventions to curb use could be highest yield,” lead study author Monica Konerman, MD, said in an interview in advance of the annual meeting of the American Association for the Study of Liver Diseases.
In an effort to better understand the rates of prescription opioid and benzodiazepine use in chronic liver disease, Dr. Konerman, director of the Michigan Medicine NAFLD Clinic at the University of Michigan, Ann Arbor, and her colleagues drew from the Truven Health Analytics Marketscan databases from 2009 to 2015. They limited the analysis to individuals with drug coverage who had chronic hepatitis C (HCV) without cirrhosis, cirrhosis, congestive heart failure (CHF), or chronic obstructive pulmonary disease (COPD), and examined pharmacy files for outpatient prescriptions.
Dr. Konerman reported data from 210,191 patients with HCV, 79,332 with cirrhosis, 766,840 with CHF, and 1,438,798 with COPD. Their median age was 59 years, and 51% were female. In per person-years, the prevalence of prescription opioid use was 25% among patients with chronic HCV, 53% among patients with cirrhosis, 26% among those with CHF, and 24% among those with COPD. At the same time, in per person-years, the prevalence of benzodiazepine use was 12% among patients with chronic HCV, 21% among patients with cirrhosis, 12% among those with CHF, and 13% among those with COPD. Use of opioids was greatest in adults 40-59 years of age (P less than .001). High-dose opioid use, defined as 100 opioid morphine equivalents per day or greater, occurred in 23% of those with cirrhosis and in 22% of those with HCV.
“The significant increase in rates of use in chronic liver disease, compared to other chronic conditions was remarkable, particularly given that patients with liver disease are at higher risk for adverse consequences of use due to hepatic metabolism of these medications,” Dr. Konerman said.
She went on to acknowledge “inherent limitations to studies that are secondary database analyses that rely on diagnosis codes for categorization of disease with potential for both over and under classification. We also did not capture inpatient prescriptions,” she said.
Dr. Konerman reported having no financial disclosures.
SAN FRANCISCO – .
“Middle-aged individuals and those with a background of substance abuse and mental health conditions appear to have highest rates of use and represent populations for which targeted interventions to curb use could be highest yield,” lead study author Monica Konerman, MD, said in an interview in advance of the annual meeting of the American Association for the Study of Liver Diseases.
In an effort to better understand the rates of prescription opioid and benzodiazepine use in chronic liver disease, Dr. Konerman, director of the Michigan Medicine NAFLD Clinic at the University of Michigan, Ann Arbor, and her colleagues drew from the Truven Health Analytics Marketscan databases from 2009 to 2015. They limited the analysis to individuals with drug coverage who had chronic hepatitis C (HCV) without cirrhosis, cirrhosis, congestive heart failure (CHF), or chronic obstructive pulmonary disease (COPD), and examined pharmacy files for outpatient prescriptions.
Dr. Konerman reported data from 210,191 patients with HCV, 79,332 with cirrhosis, 766,840 with CHF, and 1,438,798 with COPD. Their median age was 59 years, and 51% were female. In per person-years, the prevalence of prescription opioid use was 25% among patients with chronic HCV, 53% among patients with cirrhosis, 26% among those with CHF, and 24% among those with COPD. At the same time, in per person-years, the prevalence of benzodiazepine use was 12% among patients with chronic HCV, 21% among patients with cirrhosis, 12% among those with CHF, and 13% among those with COPD. Use of opioids was greatest in adults 40-59 years of age (P less than .001). High-dose opioid use, defined as 100 opioid morphine equivalents per day or greater, occurred in 23% of those with cirrhosis and in 22% of those with HCV.
“The significant increase in rates of use in chronic liver disease, compared to other chronic conditions was remarkable, particularly given that patients with liver disease are at higher risk for adverse consequences of use due to hepatic metabolism of these medications,” Dr. Konerman said.
She went on to acknowledge “inherent limitations to studies that are secondary database analyses that rely on diagnosis codes for categorization of disease with potential for both over and under classification. We also did not capture inpatient prescriptions,” she said.
Dr. Konerman reported having no financial disclosures.
SAN FRANCISCO – .
“Middle-aged individuals and those with a background of substance abuse and mental health conditions appear to have highest rates of use and represent populations for which targeted interventions to curb use could be highest yield,” lead study author Monica Konerman, MD, said in an interview in advance of the annual meeting of the American Association for the Study of Liver Diseases.
In an effort to better understand the rates of prescription opioid and benzodiazepine use in chronic liver disease, Dr. Konerman, director of the Michigan Medicine NAFLD Clinic at the University of Michigan, Ann Arbor, and her colleagues drew from the Truven Health Analytics Marketscan databases from 2009 to 2015. They limited the analysis to individuals with drug coverage who had chronic hepatitis C (HCV) without cirrhosis, cirrhosis, congestive heart failure (CHF), or chronic obstructive pulmonary disease (COPD), and examined pharmacy files for outpatient prescriptions.
Dr. Konerman reported data from 210,191 patients with HCV, 79,332 with cirrhosis, 766,840 with CHF, and 1,438,798 with COPD. Their median age was 59 years, and 51% were female. In per person-years, the prevalence of prescription opioid use was 25% among patients with chronic HCV, 53% among patients with cirrhosis, 26% among those with CHF, and 24% among those with COPD. At the same time, in per person-years, the prevalence of benzodiazepine use was 12% among patients with chronic HCV, 21% among patients with cirrhosis, 12% among those with CHF, and 13% among those with COPD. Use of opioids was greatest in adults 40-59 years of age (P less than .001). High-dose opioid use, defined as 100 opioid morphine equivalents per day or greater, occurred in 23% of those with cirrhosis and in 22% of those with HCV.
“The significant increase in rates of use in chronic liver disease, compared to other chronic conditions was remarkable, particularly given that patients with liver disease are at higher risk for adverse consequences of use due to hepatic metabolism of these medications,” Dr. Konerman said.
She went on to acknowledge “inherent limitations to studies that are secondary database analyses that rely on diagnosis codes for categorization of disease with potential for both over and under classification. We also did not capture inpatient prescriptions,” she said.
Dr. Konerman reported having no financial disclosures.
REPORTING FROM THE LIVER MEETING 2018
Key clinical point: About one-fourth of patients with chronic hepatitis C use prescription opioids.
Major finding: In per person-years, the prevalence of prescription opioid use was 25% among patients with chronic HCV, 53% among patients with cirrhosis, 26% among those with congestive heart failure, and 24% among those with chronic obstructive pulmonary disease.
Study details: An analysis of 210,191 patients who had chronic hepatitis C.
Disclosures: Dr. Konerman reported having no financial disclosures.
U.S. death rates from chronic liver disease continue to rise
SAN FRANCISCO –
“I believe it’s all related to a big increase in obesity and type 2 diabetes in this country,” lead study author Zobair M. Younossi, MD, MPH, said in an interview in advance of the annual meeting of the American Association for the Study of Liver Diseases. “Those two risk factors drive NAFLD and its progressive type, nonalcoholic steatohepatitis (NASH). That accounts for at least part of the increase in mortality related to liver disease.”
In an effort to evaluate recent mortality trends in chronic liver disease in the United States, Dr. Younossi and his colleagues drew from National Vital Statistics Data during 2007-2016. They used ICD-10 codes to select mortality data for alcoholic liver disease, chronic hepatitis B and C, iron overload, NAFLD, cirrhosis, and hepatocellular carcinoma. NAFLD cases were defined as those having an ICD-10 code for NAFLD/NASH or an ICD-10 code for “cirrhosis of unknown etiology.” Next, the researchers adjusted age-standardized death rates to the 2000 U.S. Census population and used logistic regression and propensity scores to estimate predictors of chronic liver disease-related deaths.
Dr. Younossi, who chairs the department of medicine at Inova Fairfax Medical Campus, in Falls Church, Va., and his colleagues reported findings from 838,809 chronic liver disease–related deaths during the study period. They found that the age-standardized death rate for chronic liver disease increased from 21.9/100,000 population in 2007 to 24.9/100,000 population in 2016, which translated into an annual percentage change of 1.3% for males and 2.5% for females. Chronic liver disease–related deaths increased with age and were highest among those aged 55-64 years, followed by those aged 65-74 years – an average annual percentage change of 3.4% and 3.1% in each group.
Among chronic liver disease–related deaths, the most common diagnostic etiology was NAFLD (34.7%), followed by alcoholic liver disease (28.8%) and chronic hepatitis C (21.1%). Between 2007 and 2016, death rates increased from 7.6 to 9.0 per 100,000 population for NAFLD (an average annual percentage change of 2.1%) and from 6.1 to 7.9 per 100,000 population for alcoholic liver disease (an average annual percentage change of 3.1%). “What surprised me was that, despite highly effective treatment for HCV, we still have a burden of hepatitis C in this country,” Dr. Younossi said. “It’s still the most common cause of liver disease in the U.S. But it seems like hepatitis C–related liver disease is being replaced quickly by liver disease from nonalcoholic steatohepatitis. This transition between hepatitis C as the most important cause of liver disease and liver mortality to NASH or obesity-related NASH is becoming more rapid than I expected.”
On multivariate analysis, three factors were independently associated with an increased risk of death in NAFLD: the presence of type 2 diabetes (odds ratio, 1.78), cardiovascular disease (OR, 1.07), and renal failure (OR, 1.08).
“One important message from this study is that NASH is very common in the U.S. population,” said Dr. Younossi, who is also a professor of medicine at Virginia Commonwealth University, Richmond. “These patients are underrecognized and underdiagnosed because they are asymptomatic. The second message is that there is a subtype of patients with fatty liver disease – even a subtype of NASH – that can progress to cirrhosis and its complications. We have to pay attention to this silent disease to identify patients who are at risk for progressive liver disease and try to address some of the risk issues, such as tight control of diabetes, obesity, and control of hypertension and hyperlipidemia. Short of that, right now we have very few medical treatments such as vitamin E and pioglitazone recommended for a very selected group. In contrast, there are plenty of new medications that are being developed. The first step in tackling this disease is to identify who the patients are with fatty liver disease who are at risk for bad outcomes and make sure they’re linked to care by a knowledgeable caregiver [who] understands the importance of NASH.”
Dr. Younossi acknowledged certain limitations of the study, including the fact that liver disease diagnoses were based on ICD-10 coding. He disclosed that he is a consultant for Gilead, Intercept, Novo Nordisk, BMS, AbbVie, Viking, Term Quest Diagnostics, Echosens,and Shionogi. He has also received grant/research support from Gilead, Intercept, and BMS.
Source: Hepatol. 2018;68[S1], Abstract 763.
SAN FRANCISCO –
“I believe it’s all related to a big increase in obesity and type 2 diabetes in this country,” lead study author Zobair M. Younossi, MD, MPH, said in an interview in advance of the annual meeting of the American Association for the Study of Liver Diseases. “Those two risk factors drive NAFLD and its progressive type, nonalcoholic steatohepatitis (NASH). That accounts for at least part of the increase in mortality related to liver disease.”
In an effort to evaluate recent mortality trends in chronic liver disease in the United States, Dr. Younossi and his colleagues drew from National Vital Statistics Data during 2007-2016. They used ICD-10 codes to select mortality data for alcoholic liver disease, chronic hepatitis B and C, iron overload, NAFLD, cirrhosis, and hepatocellular carcinoma. NAFLD cases were defined as those having an ICD-10 code for NAFLD/NASH or an ICD-10 code for “cirrhosis of unknown etiology.” Next, the researchers adjusted age-standardized death rates to the 2000 U.S. Census population and used logistic regression and propensity scores to estimate predictors of chronic liver disease-related deaths.
Dr. Younossi, who chairs the department of medicine at Inova Fairfax Medical Campus, in Falls Church, Va., and his colleagues reported findings from 838,809 chronic liver disease–related deaths during the study period. They found that the age-standardized death rate for chronic liver disease increased from 21.9/100,000 population in 2007 to 24.9/100,000 population in 2016, which translated into an annual percentage change of 1.3% for males and 2.5% for females. Chronic liver disease–related deaths increased with age and were highest among those aged 55-64 years, followed by those aged 65-74 years – an average annual percentage change of 3.4% and 3.1% in each group.
Among chronic liver disease–related deaths, the most common diagnostic etiology was NAFLD (34.7%), followed by alcoholic liver disease (28.8%) and chronic hepatitis C (21.1%). Between 2007 and 2016, death rates increased from 7.6 to 9.0 per 100,000 population for NAFLD (an average annual percentage change of 2.1%) and from 6.1 to 7.9 per 100,000 population for alcoholic liver disease (an average annual percentage change of 3.1%). “What surprised me was that, despite highly effective treatment for HCV, we still have a burden of hepatitis C in this country,” Dr. Younossi said. “It’s still the most common cause of liver disease in the U.S. But it seems like hepatitis C–related liver disease is being replaced quickly by liver disease from nonalcoholic steatohepatitis. This transition between hepatitis C as the most important cause of liver disease and liver mortality to NASH or obesity-related NASH is becoming more rapid than I expected.”
On multivariate analysis, three factors were independently associated with an increased risk of death in NAFLD: the presence of type 2 diabetes (odds ratio, 1.78), cardiovascular disease (OR, 1.07), and renal failure (OR, 1.08).
“One important message from this study is that NASH is very common in the U.S. population,” said Dr. Younossi, who is also a professor of medicine at Virginia Commonwealth University, Richmond. “These patients are underrecognized and underdiagnosed because they are asymptomatic. The second message is that there is a subtype of patients with fatty liver disease – even a subtype of NASH – that can progress to cirrhosis and its complications. We have to pay attention to this silent disease to identify patients who are at risk for progressive liver disease and try to address some of the risk issues, such as tight control of diabetes, obesity, and control of hypertension and hyperlipidemia. Short of that, right now we have very few medical treatments such as vitamin E and pioglitazone recommended for a very selected group. In contrast, there are plenty of new medications that are being developed. The first step in tackling this disease is to identify who the patients are with fatty liver disease who are at risk for bad outcomes and make sure they’re linked to care by a knowledgeable caregiver [who] understands the importance of NASH.”
Dr. Younossi acknowledged certain limitations of the study, including the fact that liver disease diagnoses were based on ICD-10 coding. He disclosed that he is a consultant for Gilead, Intercept, Novo Nordisk, BMS, AbbVie, Viking, Term Quest Diagnostics, Echosens,and Shionogi. He has also received grant/research support from Gilead, Intercept, and BMS.
Source: Hepatol. 2018;68[S1], Abstract 763.
SAN FRANCISCO –
“I believe it’s all related to a big increase in obesity and type 2 diabetes in this country,” lead study author Zobair M. Younossi, MD, MPH, said in an interview in advance of the annual meeting of the American Association for the Study of Liver Diseases. “Those two risk factors drive NAFLD and its progressive type, nonalcoholic steatohepatitis (NASH). That accounts for at least part of the increase in mortality related to liver disease.”
In an effort to evaluate recent mortality trends in chronic liver disease in the United States, Dr. Younossi and his colleagues drew from National Vital Statistics Data during 2007-2016. They used ICD-10 codes to select mortality data for alcoholic liver disease, chronic hepatitis B and C, iron overload, NAFLD, cirrhosis, and hepatocellular carcinoma. NAFLD cases were defined as those having an ICD-10 code for NAFLD/NASH or an ICD-10 code for “cirrhosis of unknown etiology.” Next, the researchers adjusted age-standardized death rates to the 2000 U.S. Census population and used logistic regression and propensity scores to estimate predictors of chronic liver disease-related deaths.
Dr. Younossi, who chairs the department of medicine at Inova Fairfax Medical Campus, in Falls Church, Va., and his colleagues reported findings from 838,809 chronic liver disease–related deaths during the study period. They found that the age-standardized death rate for chronic liver disease increased from 21.9/100,000 population in 2007 to 24.9/100,000 population in 2016, which translated into an annual percentage change of 1.3% for males and 2.5% for females. Chronic liver disease–related deaths increased with age and were highest among those aged 55-64 years, followed by those aged 65-74 years – an average annual percentage change of 3.4% and 3.1% in each group.
Among chronic liver disease–related deaths, the most common diagnostic etiology was NAFLD (34.7%), followed by alcoholic liver disease (28.8%) and chronic hepatitis C (21.1%). Between 2007 and 2016, death rates increased from 7.6 to 9.0 per 100,000 population for NAFLD (an average annual percentage change of 2.1%) and from 6.1 to 7.9 per 100,000 population for alcoholic liver disease (an average annual percentage change of 3.1%). “What surprised me was that, despite highly effective treatment for HCV, we still have a burden of hepatitis C in this country,” Dr. Younossi said. “It’s still the most common cause of liver disease in the U.S. But it seems like hepatitis C–related liver disease is being replaced quickly by liver disease from nonalcoholic steatohepatitis. This transition between hepatitis C as the most important cause of liver disease and liver mortality to NASH or obesity-related NASH is becoming more rapid than I expected.”
On multivariate analysis, three factors were independently associated with an increased risk of death in NAFLD: the presence of type 2 diabetes (odds ratio, 1.78), cardiovascular disease (OR, 1.07), and renal failure (OR, 1.08).
“One important message from this study is that NASH is very common in the U.S. population,” said Dr. Younossi, who is also a professor of medicine at Virginia Commonwealth University, Richmond. “These patients are underrecognized and underdiagnosed because they are asymptomatic. The second message is that there is a subtype of patients with fatty liver disease – even a subtype of NASH – that can progress to cirrhosis and its complications. We have to pay attention to this silent disease to identify patients who are at risk for progressive liver disease and try to address some of the risk issues, such as tight control of diabetes, obesity, and control of hypertension and hyperlipidemia. Short of that, right now we have very few medical treatments such as vitamin E and pioglitazone recommended for a very selected group. In contrast, there are plenty of new medications that are being developed. The first step in tackling this disease is to identify who the patients are with fatty liver disease who are at risk for bad outcomes and make sure they’re linked to care by a knowledgeable caregiver [who] understands the importance of NASH.”
Dr. Younossi acknowledged certain limitations of the study, including the fact that liver disease diagnoses were based on ICD-10 coding. He disclosed that he is a consultant for Gilead, Intercept, Novo Nordisk, BMS, AbbVie, Viking, Term Quest Diagnostics, Echosens,and Shionogi. He has also received grant/research support from Gilead, Intercept, and BMS.
Source: Hepatol. 2018;68[S1], Abstract 763.
AT THE LIVER MEETING 2018
Key clinical point: Nonalcoholic steatohepatitis is very common in the U.S. population.
Major finding: Between 2007 and 2016, the age-standardized death rate for chronic liver disease increased from 21.9/100,000 population to 24.9/100,000 population.
Study details: An analysis of 838,809 chronic liver disease–related deaths from 2007 to 2016.
Disclosures: Dr. Younossi disclosed that he is a consultant for Gilead, Intercept, Novo Nordisk, Bristol-Myers Squibb, AbbVie, Viking, Term Quest Diagnostics, Echosens, and Shionogi. He has also received grant/research support from Gilead, Intercept, and Bristol-Myers Squibb.
Source: Hepatol. 2018;68[S1], Abstract 763.