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Cirrhosis model predicts decompensation across diverse populations
A prognostic model that uses serum albumin-bilirubin (ALBI) and Fibrosis-4 (FIB-4) scores can identify patients with cirrhosis who are at high risk of liver decompensation, according to investigators.
During validation testing, the scoring system performed well among European and Middle Eastern patients, which supports prognostic value across diverse populations, reported lead author Neil Guha, MRCP, PhD, of the University of Nottingham (U.K.) and his colleagues, who suggested that the scoring system could fix an important practice gap.
“Identification of patients [with chronic liver disease] that need intensive monitoring and timely intervention is challenging,” the investigators wrote in Clinical Gastroenterology and Hepatology. “Robust prognostic tools using simple laboratory variables, with potential for implementation in nonspecialist settings and across different health care systems, have significant appeal.”
Although existing scoring systems have been used for decades, they have clear limitations, the investigators noted, referring to predictive ability that may be too little, too late.
“[T]hese scoring systems provide value after synthetic liver function has become significantly deranged and provide only short-term prognostic value,” the investigators wrote. “Presently, there are no scores, performed in routine clinical practice, that provide robust prognostic stratification within early, compensated cirrhosis over the medium/long term.”
To fulfill this need, the investigators developed and validated a prognostic model that incorporates data from the ALBI and FIB-4 scoring systems because these tests measure both fibrosis and function. The development phase involved 145 patients with compensated cirrhosis from Nottingham. Almost half of the cohort had liver disease because of alcohol (44.8%), while about one out of three patients had nonalcoholic fatty liver disease (29.7%). After investigators collected baseline clinical features and scores, patients were followed for a median of 4.59 years, during which time decompensation events were recorded (ascites, variceal bleeding, and encephalopathy). Decompensation occurred in about one out of five patients (19.3%) in the U.K. group, with ascites being the most common (71.4%). Using these findings, the investigators created the prognostic model, which classified patients as having either low or high risk of decompensation. In the development cohort, patients with high risk scores had a hazard ratio for decompensation of 7.10.
In the second part of the study, the investigators validated their model with two clinically distinct groups in Dublin, Ireland (prospective; n = 141), and Menoufia, Egypt (retrospective; n = 93).
In the Dublin cohort, the most common etiologies were alcohol (39.7%) and hepatitis C (29.8%). Over a maximum observational period of 6.4 years, the decompensation rate was lower than the development group, at 12.1%. Types of decompensation also differed, with variceal bleeding being the most common (47.1%). Patients with high risk scores had a higher HR for decompensation than the U.K. cohort, at 12.54.
In the Egypt group, the most common causes of liver disease were nonalcoholic fatty liver disease (47.3%) and hepatitis C (34.4%). The maximum follow-up period was 10.6 years, during which time 38.7% of patients experienced decompensation, with ascites being the most common form (57.1%). The HR of 5.10 was the lowest of all cohorts.
The investigators noted that the cohorts represented unique patient populations with different etiological patterns. “This provides reassurance that the model has generalizability for stratifying liver disease at an international level,” the investigators wrote, suggesting that ALBI and FIB-4 can be used in low-resource and community settings.
“A frequently leveled criticism of algorithms such as ALBI-FIB-4 is that they are too complicated to be applied routinely in the clinical setting,” the investigators wrote. “To overcome this problem we developed a simple online calculator which can be accessed using the following link: https://jscalc.io/calc/gdEJj89Wz5PirkSL.”
“We have shown that routinely available laboratory variables, combined in a novel algorithm, ALBI-FIB-4, can stratify patients with cirrhosis for future risk of liver decompensation,” the investigators concluded. “The ability to do this in the context of early, compensated cirrhosis with preserved liver synthetic function whilst also predicting long-term clinical outcomes has clinical utility for international health care systems.”
The study was funded by National Institute for Health Research (NIHR) Nottingham Digestive Diseases Biomedical Research Centre based at Nottingham University Hospitals NHS Trust and the University of Nottingham. The investigators declared no conflicts of interest.
SOURCE: Guha N et al. CGH. 2019 Feb 1. doi: 10.1016/j.cgh.2019.01.042.
A prognostic model that uses serum albumin-bilirubin (ALBI) and Fibrosis-4 (FIB-4) scores can identify patients with cirrhosis who are at high risk of liver decompensation, according to investigators.
During validation testing, the scoring system performed well among European and Middle Eastern patients, which supports prognostic value across diverse populations, reported lead author Neil Guha, MRCP, PhD, of the University of Nottingham (U.K.) and his colleagues, who suggested that the scoring system could fix an important practice gap.
“Identification of patients [with chronic liver disease] that need intensive monitoring and timely intervention is challenging,” the investigators wrote in Clinical Gastroenterology and Hepatology. “Robust prognostic tools using simple laboratory variables, with potential for implementation in nonspecialist settings and across different health care systems, have significant appeal.”
Although existing scoring systems have been used for decades, they have clear limitations, the investigators noted, referring to predictive ability that may be too little, too late.
“[T]hese scoring systems provide value after synthetic liver function has become significantly deranged and provide only short-term prognostic value,” the investigators wrote. “Presently, there are no scores, performed in routine clinical practice, that provide robust prognostic stratification within early, compensated cirrhosis over the medium/long term.”
To fulfill this need, the investigators developed and validated a prognostic model that incorporates data from the ALBI and FIB-4 scoring systems because these tests measure both fibrosis and function. The development phase involved 145 patients with compensated cirrhosis from Nottingham. Almost half of the cohort had liver disease because of alcohol (44.8%), while about one out of three patients had nonalcoholic fatty liver disease (29.7%). After investigators collected baseline clinical features and scores, patients were followed for a median of 4.59 years, during which time decompensation events were recorded (ascites, variceal bleeding, and encephalopathy). Decompensation occurred in about one out of five patients (19.3%) in the U.K. group, with ascites being the most common (71.4%). Using these findings, the investigators created the prognostic model, which classified patients as having either low or high risk of decompensation. In the development cohort, patients with high risk scores had a hazard ratio for decompensation of 7.10.
In the second part of the study, the investigators validated their model with two clinically distinct groups in Dublin, Ireland (prospective; n = 141), and Menoufia, Egypt (retrospective; n = 93).
In the Dublin cohort, the most common etiologies were alcohol (39.7%) and hepatitis C (29.8%). Over a maximum observational period of 6.4 years, the decompensation rate was lower than the development group, at 12.1%. Types of decompensation also differed, with variceal bleeding being the most common (47.1%). Patients with high risk scores had a higher HR for decompensation than the U.K. cohort, at 12.54.
In the Egypt group, the most common causes of liver disease were nonalcoholic fatty liver disease (47.3%) and hepatitis C (34.4%). The maximum follow-up period was 10.6 years, during which time 38.7% of patients experienced decompensation, with ascites being the most common form (57.1%). The HR of 5.10 was the lowest of all cohorts.
The investigators noted that the cohorts represented unique patient populations with different etiological patterns. “This provides reassurance that the model has generalizability for stratifying liver disease at an international level,” the investigators wrote, suggesting that ALBI and FIB-4 can be used in low-resource and community settings.
“A frequently leveled criticism of algorithms such as ALBI-FIB-4 is that they are too complicated to be applied routinely in the clinical setting,” the investigators wrote. “To overcome this problem we developed a simple online calculator which can be accessed using the following link: https://jscalc.io/calc/gdEJj89Wz5PirkSL.”
“We have shown that routinely available laboratory variables, combined in a novel algorithm, ALBI-FIB-4, can stratify patients with cirrhosis for future risk of liver decompensation,” the investigators concluded. “The ability to do this in the context of early, compensated cirrhosis with preserved liver synthetic function whilst also predicting long-term clinical outcomes has clinical utility for international health care systems.”
The study was funded by National Institute for Health Research (NIHR) Nottingham Digestive Diseases Biomedical Research Centre based at Nottingham University Hospitals NHS Trust and the University of Nottingham. The investigators declared no conflicts of interest.
SOURCE: Guha N et al. CGH. 2019 Feb 1. doi: 10.1016/j.cgh.2019.01.042.
A prognostic model that uses serum albumin-bilirubin (ALBI) and Fibrosis-4 (FIB-4) scores can identify patients with cirrhosis who are at high risk of liver decompensation, according to investigators.
During validation testing, the scoring system performed well among European and Middle Eastern patients, which supports prognostic value across diverse populations, reported lead author Neil Guha, MRCP, PhD, of the University of Nottingham (U.K.) and his colleagues, who suggested that the scoring system could fix an important practice gap.
“Identification of patients [with chronic liver disease] that need intensive monitoring and timely intervention is challenging,” the investigators wrote in Clinical Gastroenterology and Hepatology. “Robust prognostic tools using simple laboratory variables, with potential for implementation in nonspecialist settings and across different health care systems, have significant appeal.”
Although existing scoring systems have been used for decades, they have clear limitations, the investigators noted, referring to predictive ability that may be too little, too late.
“[T]hese scoring systems provide value after synthetic liver function has become significantly deranged and provide only short-term prognostic value,” the investigators wrote. “Presently, there are no scores, performed in routine clinical practice, that provide robust prognostic stratification within early, compensated cirrhosis over the medium/long term.”
To fulfill this need, the investigators developed and validated a prognostic model that incorporates data from the ALBI and FIB-4 scoring systems because these tests measure both fibrosis and function. The development phase involved 145 patients with compensated cirrhosis from Nottingham. Almost half of the cohort had liver disease because of alcohol (44.8%), while about one out of three patients had nonalcoholic fatty liver disease (29.7%). After investigators collected baseline clinical features and scores, patients were followed for a median of 4.59 years, during which time decompensation events were recorded (ascites, variceal bleeding, and encephalopathy). Decompensation occurred in about one out of five patients (19.3%) in the U.K. group, with ascites being the most common (71.4%). Using these findings, the investigators created the prognostic model, which classified patients as having either low or high risk of decompensation. In the development cohort, patients with high risk scores had a hazard ratio for decompensation of 7.10.
In the second part of the study, the investigators validated their model with two clinically distinct groups in Dublin, Ireland (prospective; n = 141), and Menoufia, Egypt (retrospective; n = 93).
In the Dublin cohort, the most common etiologies were alcohol (39.7%) and hepatitis C (29.8%). Over a maximum observational period of 6.4 years, the decompensation rate was lower than the development group, at 12.1%. Types of decompensation also differed, with variceal bleeding being the most common (47.1%). Patients with high risk scores had a higher HR for decompensation than the U.K. cohort, at 12.54.
In the Egypt group, the most common causes of liver disease were nonalcoholic fatty liver disease (47.3%) and hepatitis C (34.4%). The maximum follow-up period was 10.6 years, during which time 38.7% of patients experienced decompensation, with ascites being the most common form (57.1%). The HR of 5.10 was the lowest of all cohorts.
The investigators noted that the cohorts represented unique patient populations with different etiological patterns. “This provides reassurance that the model has generalizability for stratifying liver disease at an international level,” the investigators wrote, suggesting that ALBI and FIB-4 can be used in low-resource and community settings.
“A frequently leveled criticism of algorithms such as ALBI-FIB-4 is that they are too complicated to be applied routinely in the clinical setting,” the investigators wrote. “To overcome this problem we developed a simple online calculator which can be accessed using the following link: https://jscalc.io/calc/gdEJj89Wz5PirkSL.”
“We have shown that routinely available laboratory variables, combined in a novel algorithm, ALBI-FIB-4, can stratify patients with cirrhosis for future risk of liver decompensation,” the investigators concluded. “The ability to do this in the context of early, compensated cirrhosis with preserved liver synthetic function whilst also predicting long-term clinical outcomes has clinical utility for international health care systems.”
The study was funded by National Institute for Health Research (NIHR) Nottingham Digestive Diseases Biomedical Research Centre based at Nottingham University Hospitals NHS Trust and the University of Nottingham. The investigators declared no conflicts of interest.
SOURCE: Guha N et al. CGH. 2019 Feb 1. doi: 10.1016/j.cgh.2019.01.042.
FROM CLINICAL GASTROENTEROLOGY AND HEPATOLOGY
Will inpatient albumin help in decompensated cirrhosis?
PHILADELPHIA – , according to Vijay Shah, MD, chair of the division of gastroenterology and hepatology at Mayo Clinic, Rochester, Minn.
“These are interesting studies, but I don’t think we’re ready yet to use this broadly,” Dr. Shah said at the meeting jointly provided by Rutgers and Global Academy for Medical Education.
Current guidelines do describe the use of albumin for large-volume paracentesis and other specific inpatient situations; however, extrapolating its long-term use has been explored in two major studies that recently came out with contradictory findings.
In the ANSWER trial, as reported in the Lancet, investigators at 33 centers randomized patients with cirrhosis and uncomplicated ascites to either standard medical treatment with or without human albumin, at 40 g twice weekly for 2 weeks, followed by 40 g weekly for up to 18 months.
Those investigators found that long-term albumin prolonged overall survival, with a 38% reduction in the mortality hazard ratio, with similar rates of serious, nonliver adverse events, leading them to conclude that this intervention may act as a disease-modifying treatment in decompensated cirrhosis patients.
By contrast, however, a recent randomized, placebo-controlled trial reported in the Journal of Hepatology showed that albumin plus midodrine, an alpha-adrenergic vasoconstrictor, did not improve survival among patients with decompensated cirrhosis on the liver transplant waiting list, at least at the doses administered (midodrine 15-30 mg/day and albumin 40 g every 15 days for a year).
While this particular combination of albumin plus midodrine did decrease renin and aldosterone levels, the intervention did not prevent complications or improve survival, investigators said at the time. Complication rates were 37% and 43% for treatment and placebo, respectively (P = .402), with low rates of death in both groups and no significant difference in mortality at 1 year (P = .527).
Dr. Shah said the discrepant results may be attributable to specific differences in study design or enrollment.
“It’s just hand waving, but it may be related to the dose of albumin, or may be related to the types of patients – the second study was in patients who are waiting for liver transplantation,” he told attendees. “But I don’t think that there’s currently enough evidence to use albumin in your patients in the outpatient setting.”
There is a third study, recently published in the American Journal of Gastroenterology, looking at data for a large end-stage liver disease cohort with hyponatremia. Investigators observed a higher rate of hyponatremia resolution and improved 30-day survival in those who had received albumin (total mean amount, 225 g) versus those who had not.
Considering all of this evidence taken together, Dr. Shah said he would not favor using outpatient albumin at this point – though he advised attendees to watch for a currently recruiting phase 3 randomized study, known as PRECIOSA, which is evaluating long-term administration of human albumin 20% injectable solution, dosed by body weight, in patients with decompensated cirrhosis and ascites.
Dr. Shah indicated that he is a consultant for Afimmune, Durect Corporation, Enterome, GRI Bio, Merck Research Laboratories, Novartis Pharma, and Vital Therapeutics. Global Academy and this news organization are owned by the same company.
PHILADELPHIA – , according to Vijay Shah, MD, chair of the division of gastroenterology and hepatology at Mayo Clinic, Rochester, Minn.
“These are interesting studies, but I don’t think we’re ready yet to use this broadly,” Dr. Shah said at the meeting jointly provided by Rutgers and Global Academy for Medical Education.
Current guidelines do describe the use of albumin for large-volume paracentesis and other specific inpatient situations; however, extrapolating its long-term use has been explored in two major studies that recently came out with contradictory findings.
In the ANSWER trial, as reported in the Lancet, investigators at 33 centers randomized patients with cirrhosis and uncomplicated ascites to either standard medical treatment with or without human albumin, at 40 g twice weekly for 2 weeks, followed by 40 g weekly for up to 18 months.
Those investigators found that long-term albumin prolonged overall survival, with a 38% reduction in the mortality hazard ratio, with similar rates of serious, nonliver adverse events, leading them to conclude that this intervention may act as a disease-modifying treatment in decompensated cirrhosis patients.
By contrast, however, a recent randomized, placebo-controlled trial reported in the Journal of Hepatology showed that albumin plus midodrine, an alpha-adrenergic vasoconstrictor, did not improve survival among patients with decompensated cirrhosis on the liver transplant waiting list, at least at the doses administered (midodrine 15-30 mg/day and albumin 40 g every 15 days for a year).
While this particular combination of albumin plus midodrine did decrease renin and aldosterone levels, the intervention did not prevent complications or improve survival, investigators said at the time. Complication rates were 37% and 43% for treatment and placebo, respectively (P = .402), with low rates of death in both groups and no significant difference in mortality at 1 year (P = .527).
Dr. Shah said the discrepant results may be attributable to specific differences in study design or enrollment.
“It’s just hand waving, but it may be related to the dose of albumin, or may be related to the types of patients – the second study was in patients who are waiting for liver transplantation,” he told attendees. “But I don’t think that there’s currently enough evidence to use albumin in your patients in the outpatient setting.”
There is a third study, recently published in the American Journal of Gastroenterology, looking at data for a large end-stage liver disease cohort with hyponatremia. Investigators observed a higher rate of hyponatremia resolution and improved 30-day survival in those who had received albumin (total mean amount, 225 g) versus those who had not.
Considering all of this evidence taken together, Dr. Shah said he would not favor using outpatient albumin at this point – though he advised attendees to watch for a currently recruiting phase 3 randomized study, known as PRECIOSA, which is evaluating long-term administration of human albumin 20% injectable solution, dosed by body weight, in patients with decompensated cirrhosis and ascites.
Dr. Shah indicated that he is a consultant for Afimmune, Durect Corporation, Enterome, GRI Bio, Merck Research Laboratories, Novartis Pharma, and Vital Therapeutics. Global Academy and this news organization are owned by the same company.
PHILADELPHIA – , according to Vijay Shah, MD, chair of the division of gastroenterology and hepatology at Mayo Clinic, Rochester, Minn.
“These are interesting studies, but I don’t think we’re ready yet to use this broadly,” Dr. Shah said at the meeting jointly provided by Rutgers and Global Academy for Medical Education.
Current guidelines do describe the use of albumin for large-volume paracentesis and other specific inpatient situations; however, extrapolating its long-term use has been explored in two major studies that recently came out with contradictory findings.
In the ANSWER trial, as reported in the Lancet, investigators at 33 centers randomized patients with cirrhosis and uncomplicated ascites to either standard medical treatment with or without human albumin, at 40 g twice weekly for 2 weeks, followed by 40 g weekly for up to 18 months.
Those investigators found that long-term albumin prolonged overall survival, with a 38% reduction in the mortality hazard ratio, with similar rates of serious, nonliver adverse events, leading them to conclude that this intervention may act as a disease-modifying treatment in decompensated cirrhosis patients.
By contrast, however, a recent randomized, placebo-controlled trial reported in the Journal of Hepatology showed that albumin plus midodrine, an alpha-adrenergic vasoconstrictor, did not improve survival among patients with decompensated cirrhosis on the liver transplant waiting list, at least at the doses administered (midodrine 15-30 mg/day and albumin 40 g every 15 days for a year).
While this particular combination of albumin plus midodrine did decrease renin and aldosterone levels, the intervention did not prevent complications or improve survival, investigators said at the time. Complication rates were 37% and 43% for treatment and placebo, respectively (P = .402), with low rates of death in both groups and no significant difference in mortality at 1 year (P = .527).
Dr. Shah said the discrepant results may be attributable to specific differences in study design or enrollment.
“It’s just hand waving, but it may be related to the dose of albumin, or may be related to the types of patients – the second study was in patients who are waiting for liver transplantation,” he told attendees. “But I don’t think that there’s currently enough evidence to use albumin in your patients in the outpatient setting.”
There is a third study, recently published in the American Journal of Gastroenterology, looking at data for a large end-stage liver disease cohort with hyponatremia. Investigators observed a higher rate of hyponatremia resolution and improved 30-day survival in those who had received albumin (total mean amount, 225 g) versus those who had not.
Considering all of this evidence taken together, Dr. Shah said he would not favor using outpatient albumin at this point – though he advised attendees to watch for a currently recruiting phase 3 randomized study, known as PRECIOSA, which is evaluating long-term administration of human albumin 20% injectable solution, dosed by body weight, in patients with decompensated cirrhosis and ascites.
Dr. Shah indicated that he is a consultant for Afimmune, Durect Corporation, Enterome, GRI Bio, Merck Research Laboratories, Novartis Pharma, and Vital Therapeutics. Global Academy and this news organization are owned by the same company.
REPORTING FROM DIGESTIVE DISEASES: NEW ADVANCES
Dr. Julie Thompson Discusses Primary Biliary Cholangitis
At Digestive Diseases: New Advances (DDNA 2019), Dr. Julie A. Thompson of the University of Minnesota reviews key issues surrounding primary biliary cholangitis, including difficult symptoms to treat, an update on clinical trials, and patients that take medication and see no improvements.
At Digestive Diseases: New Advances (DDNA 2019), Dr. Julie A. Thompson of the University of Minnesota reviews key issues surrounding primary biliary cholangitis, including difficult symptoms to treat, an update on clinical trials, and patients that take medication and see no improvements.
At Digestive Diseases: New Advances (DDNA 2019), Dr. Julie A. Thompson of the University of Minnesota reviews key issues surrounding primary biliary cholangitis, including difficult symptoms to treat, an update on clinical trials, and patients that take medication and see no improvements.
AT DIGESTIVE DISEASES: NEW ADVANCES
HCC with no cirrhosis is more common in HIV patients
SEATTLE – Hepatocellular carcinoma (HCC) is on the rise in HIV-positive individuals, its incidence having quadrupled since 1996, and HIV-positive individuals have about a 300% increase risk of HCC, compared with the general population. However, more than 40% of patients with HIV who develop HCC have a Fibrosis-4 score (FIB-4) suggesting a lack of cirrhosis, according to a new retrospective analysis. By contrast, only about 13% of typical HCC patients have no cirrhosis.
The study also revealed some of the risk factors associated with HCC in this population, including longer duration of HIV viremia and lower CD4 cell counts, as well as markers of metabolic syndrome. “There was some signal that perhaps other markers of metabolic syndrome, obesity and diabetes, were more prevalent in those [who developed HCC] without advanced fibrosis or cirrhosis, suggesting that there may be other underlying etiologies of liver disease that we should be wary of when evaluating somebody for their risk of HCC,” Jessie Torgersen, MD, said in an interview.
Dr. Torgersen is an instructor of medicine at the University of Pennsylvania, Philadelphia. She presented the study at the Conference on Retroviruses & Opportunistic Infections.
The results of the study are tantalizing, but not yet practice changing. “I don’t think we have enough information from this study to recommend a dramatic overhaul of the current HCC screening guidelines, but with the anticipated elimination of hepatitis C, I think the emergence of [metabolic factors and their] contributions to our HIV-positive population’s risk of HCC needs to be better understood. Hopefully this will serve as a first step in further understanding those risks,” Dr. Torgersen said.
She also hopes to get a better handle on the biological mechanisms that might drive HCC in the absence of cirrhosis. “While the mechanisms are unclear as to why HCC would develop in HIV-positive patients without cirrhosis, there are a lot of biologically plausible mechanisms that seem to make [sense],” said Dr. Torgersen. The team hopes to get a better understanding of those mechanisms in order to information evaluation and screening for HCC.
The researchers analyzed data from the Veterans Affairs Cancer Registry as well as EMRs for HIV-positive veterans across the United States. The study included 2,497 participants with a FIB-4 score greater than 3.25, and 29,836 with an FIB-4 score less than or equal to 3.25. At baseline, subjects with FIB-4 greater than 3.25 were more likely to have an alcohol-related diagnosis (47% vs. 29%), be positive for hepatitis C virus RNA (59% vs. 30%), be positive for the hepatitis B surface antigen (10% versus 5%), have HIV RNA greater than or equal to 500 copies/mL (63% vs. 56%), and to have a CD4+ cell count less than 200 cells/m3 (39% vs. 26%).
A total of 278 subjects were diagnosed with HCC; 43% had an FIB-4 less than or equal to 3.25. Among those 43%, more patients had a body mass index of 30 or higher (16% vs. 12%), had diabetes (31% vs. 25%), and tested positive for the hepatitis B surface antigen (26% vs. 17%).
Among subjects with FIB-4 less than or equal to 3.25, factors associated with greater HCC risk included higher HIV RNA level (hazard ratio, 1.24 per 1.0 log10 copies/mL), CD4+ cell count less than 200 cells/m3 (HR, 1.78), hepatitis C virus infection (HR, 6.32), and positive hepatitis B surface antigen (HR, 4.93).
Among subjects with FIB-4 greater than 3.25, increased HCC risk was associated with HCV infection (HR, 6.18) and positive hepatitis B surface antigen (HR, 2.12).
The study was funded by the National Institutes of Health. Dr. Torgersen reported no financial disclosures.
SOURCE: Torgersen J et al. CROI 2019, Abstract 90.
SEATTLE – Hepatocellular carcinoma (HCC) is on the rise in HIV-positive individuals, its incidence having quadrupled since 1996, and HIV-positive individuals have about a 300% increase risk of HCC, compared with the general population. However, more than 40% of patients with HIV who develop HCC have a Fibrosis-4 score (FIB-4) suggesting a lack of cirrhosis, according to a new retrospective analysis. By contrast, only about 13% of typical HCC patients have no cirrhosis.
The study also revealed some of the risk factors associated with HCC in this population, including longer duration of HIV viremia and lower CD4 cell counts, as well as markers of metabolic syndrome. “There was some signal that perhaps other markers of metabolic syndrome, obesity and diabetes, were more prevalent in those [who developed HCC] without advanced fibrosis or cirrhosis, suggesting that there may be other underlying etiologies of liver disease that we should be wary of when evaluating somebody for their risk of HCC,” Jessie Torgersen, MD, said in an interview.
Dr. Torgersen is an instructor of medicine at the University of Pennsylvania, Philadelphia. She presented the study at the Conference on Retroviruses & Opportunistic Infections.
The results of the study are tantalizing, but not yet practice changing. “I don’t think we have enough information from this study to recommend a dramatic overhaul of the current HCC screening guidelines, but with the anticipated elimination of hepatitis C, I think the emergence of [metabolic factors and their] contributions to our HIV-positive population’s risk of HCC needs to be better understood. Hopefully this will serve as a first step in further understanding those risks,” Dr. Torgersen said.
She also hopes to get a better handle on the biological mechanisms that might drive HCC in the absence of cirrhosis. “While the mechanisms are unclear as to why HCC would develop in HIV-positive patients without cirrhosis, there are a lot of biologically plausible mechanisms that seem to make [sense],” said Dr. Torgersen. The team hopes to get a better understanding of those mechanisms in order to information evaluation and screening for HCC.
The researchers analyzed data from the Veterans Affairs Cancer Registry as well as EMRs for HIV-positive veterans across the United States. The study included 2,497 participants with a FIB-4 score greater than 3.25, and 29,836 with an FIB-4 score less than or equal to 3.25. At baseline, subjects with FIB-4 greater than 3.25 were more likely to have an alcohol-related diagnosis (47% vs. 29%), be positive for hepatitis C virus RNA (59% vs. 30%), be positive for the hepatitis B surface antigen (10% versus 5%), have HIV RNA greater than or equal to 500 copies/mL (63% vs. 56%), and to have a CD4+ cell count less than 200 cells/m3 (39% vs. 26%).
A total of 278 subjects were diagnosed with HCC; 43% had an FIB-4 less than or equal to 3.25. Among those 43%, more patients had a body mass index of 30 or higher (16% vs. 12%), had diabetes (31% vs. 25%), and tested positive for the hepatitis B surface antigen (26% vs. 17%).
Among subjects with FIB-4 less than or equal to 3.25, factors associated with greater HCC risk included higher HIV RNA level (hazard ratio, 1.24 per 1.0 log10 copies/mL), CD4+ cell count less than 200 cells/m3 (HR, 1.78), hepatitis C virus infection (HR, 6.32), and positive hepatitis B surface antigen (HR, 4.93).
Among subjects with FIB-4 greater than 3.25, increased HCC risk was associated with HCV infection (HR, 6.18) and positive hepatitis B surface antigen (HR, 2.12).
The study was funded by the National Institutes of Health. Dr. Torgersen reported no financial disclosures.
SOURCE: Torgersen J et al. CROI 2019, Abstract 90.
SEATTLE – Hepatocellular carcinoma (HCC) is on the rise in HIV-positive individuals, its incidence having quadrupled since 1996, and HIV-positive individuals have about a 300% increase risk of HCC, compared with the general population. However, more than 40% of patients with HIV who develop HCC have a Fibrosis-4 score (FIB-4) suggesting a lack of cirrhosis, according to a new retrospective analysis. By contrast, only about 13% of typical HCC patients have no cirrhosis.
The study also revealed some of the risk factors associated with HCC in this population, including longer duration of HIV viremia and lower CD4 cell counts, as well as markers of metabolic syndrome. “There was some signal that perhaps other markers of metabolic syndrome, obesity and diabetes, were more prevalent in those [who developed HCC] without advanced fibrosis or cirrhosis, suggesting that there may be other underlying etiologies of liver disease that we should be wary of when evaluating somebody for their risk of HCC,” Jessie Torgersen, MD, said in an interview.
Dr. Torgersen is an instructor of medicine at the University of Pennsylvania, Philadelphia. She presented the study at the Conference on Retroviruses & Opportunistic Infections.
The results of the study are tantalizing, but not yet practice changing. “I don’t think we have enough information from this study to recommend a dramatic overhaul of the current HCC screening guidelines, but with the anticipated elimination of hepatitis C, I think the emergence of [metabolic factors and their] contributions to our HIV-positive population’s risk of HCC needs to be better understood. Hopefully this will serve as a first step in further understanding those risks,” Dr. Torgersen said.
She also hopes to get a better handle on the biological mechanisms that might drive HCC in the absence of cirrhosis. “While the mechanisms are unclear as to why HCC would develop in HIV-positive patients without cirrhosis, there are a lot of biologically plausible mechanisms that seem to make [sense],” said Dr. Torgersen. The team hopes to get a better understanding of those mechanisms in order to information evaluation and screening for HCC.
The researchers analyzed data from the Veterans Affairs Cancer Registry as well as EMRs for HIV-positive veterans across the United States. The study included 2,497 participants with a FIB-4 score greater than 3.25, and 29,836 with an FIB-4 score less than or equal to 3.25. At baseline, subjects with FIB-4 greater than 3.25 were more likely to have an alcohol-related diagnosis (47% vs. 29%), be positive for hepatitis C virus RNA (59% vs. 30%), be positive for the hepatitis B surface antigen (10% versus 5%), have HIV RNA greater than or equal to 500 copies/mL (63% vs. 56%), and to have a CD4+ cell count less than 200 cells/m3 (39% vs. 26%).
A total of 278 subjects were diagnosed with HCC; 43% had an FIB-4 less than or equal to 3.25. Among those 43%, more patients had a body mass index of 30 or higher (16% vs. 12%), had diabetes (31% vs. 25%), and tested positive for the hepatitis B surface antigen (26% vs. 17%).
Among subjects with FIB-4 less than or equal to 3.25, factors associated with greater HCC risk included higher HIV RNA level (hazard ratio, 1.24 per 1.0 log10 copies/mL), CD4+ cell count less than 200 cells/m3 (HR, 1.78), hepatitis C virus infection (HR, 6.32), and positive hepatitis B surface antigen (HR, 4.93).
Among subjects with FIB-4 greater than 3.25, increased HCC risk was associated with HCV infection (HR, 6.18) and positive hepatitis B surface antigen (HR, 2.12).
The study was funded by the National Institutes of Health. Dr. Torgersen reported no financial disclosures.
SOURCE: Torgersen J et al. CROI 2019, Abstract 90.
REPORTING FROM CROI 2019
High-calorie diet may worsen Wilson disease
A high-calorie diet may cause earlier onset of more severe Wilson disease, according to a rodent study.
If translatable to humans, the results could explain “striking phenotype-genotype discrepancies” between patients with Wilson disease, and may give reason to monitor nutrition more closely, particularly dietary levels of fat and sugar, reported lead author Claudia Einer, a PhD candidate at the German Research Center for Environmental Health in Neuherberg, Germany, and her colleagues. Their findings clarify an association between impaired copper metabolism, which defines Wilson disease, and liver steatosis, a common finding in affected patients.
“Indeed, Wilson disease often may be misdiagnosed as nonalcoholic fatty liver disease (NAFLD),” the investigators wrote in Cellular and Molecular Gastroenterology and Hepatology. They noted that previous reports showed similar mitochondrial alterations in the livers of patients with NAFLD and those with Wilson disease. Furthermore, in a case report of two twins with Wilson disease, the twin with bulimia nervosa developed severe liver disease, whereas the other twin, who was undernourished, had mild liver disease. Considering these observations and other supportive evidence, the investigators tested this apparent relationship between a high-fat diet and liver damage in Wilson disease.
“The rationale of this study was that both enriched copper and fatty acids cause bioenergetic defects and therefore synergistically and detrimentally may coincide on hepatic mitochondria, which was found to be dramatically the case,” the investigators wrote.
The study involved homozygous Atp7b–/– rats, which mirror Wilson disease, and heterozygous Atp7b+/– rats, which served as control subjects because they lack copper accumulation. The high-calorie diet contained high fat and sugar levels to mirror “the eating habits in Western society, causing the ‘American-lifestyle-induced-obesity syndrome.’ ”
Within several weeks of starting the high-calorie diet, both control and Wilson disease rats showed higher liver triglyceride levels and visceral fat mass compared with rats on the normal diet, with liver histology also showing macrosteatosis and increased NAFLD Activity Score (NAS). Control rats maintained similar body and liver weights regardless of diet; in contrast, Wilson disease rats on the high-calorie diet showed increased liver weight, compared with Wilson disease rats on the normal diet. In addition, Wilson disease rats fed the high-calorie diet had clinical liver injury, supported by elevated aspartate aminotransferase (AST) levels and gross hepatic damage. Under the microscope, histology revealed widespread necrosis, apoptosis, inflammation, and fibrosis; findings were sufficient to constitute nonalcoholic steatohepatitis in all Wilson disease rats fed the high-calorie diet, compared with just one-third of the control rats receiving high calories. Additional testing showed that Wilson disease rats fed the high-calorie diet had disease onset 20 days sooner than did Wilson disease rats fed the normal diet.
“This is a remarkable disease acceleration,” the investigators noted, highlighting the median survival of 106 days in Wilson disease rats fed a normal diet.
Copper testing showed that Wilson disease rats fed the high-calorie diet had high serum levels of non–ceruloplasmin-bound copper, which is a sign of overt liver damage; based on histologic findings, the copper likely came from destroyed hepatocytes. Regardless of diet type, Wilson disease rats developed high levels of copper within the liver, suggesting comparable copper consumption via water sources. Regardless of genotype, the high-calorie diet led to higher mitochondrial copper levels than those of the normal diet, but Wilson disease rats showed the highest levels of copper sequestration in mitochondria, to an extreme degree.
“Importantly,” the investigators wrote, “such increased mitochondrial copper significantly correlated with a higher NAS and a progressive Histologic Activity Index score.”
Closer inspection showed that the mitochondria of Wilson disease rats were abnormal regardless of diet, but those fed the high-calorie diet had “a most severe mitochondrial phenotype,” including detached membranes and ballooned cristae.
“These structural impairments were paralleled by remarkable mitochondrial functional deficits,” the investigators reported, referring to a significant decrease in adenosine triphosphate production and an increase in mitochondrial H2O2. In response to these mitochondrial abnormalities, cholesterol-related enzymes quadrupled, most prominently for biliary excretion. The investigators summed up these hepatic events as a “toxic triad of adenosine triphosphate depletion, increased reactive oxygen species, and increased bile salts [that led] to an earlier onset of the disease and to enhanced disease progression.”
To complete the set of experiments, rats were given the copper chelator methanobactin. This treatment effectively mitigated structural and functional abnormalities in mitochondria, which drove serum levels of AST, copper, and bile salts toward normalcy. Although treatment halted overt liver damage, histology revealed that resolution was incomplete.
“We conclude that lipid accumulation in copper-burdened hepatocytes may represent a ‘second-hit’ in Wilson disease, inducing liver damage, and suggest that further research should establish whether dietary counseling of Wilson disease patients may be of therapeutic benefit,” the investigators concluded.
The study was funded by Deutsche Forschungsgemeinschaft and the WiFoMed Society. The investigators reported no conflicts of interest.
SOURCE: Einer et al. Cell Mol Gastroenterol Hepatol. 2019 Jan 11. doi: 10.1016/j.jcmgh.2018.12.005.
A high-calorie diet may cause earlier onset of more severe Wilson disease, according to a rodent study.
If translatable to humans, the results could explain “striking phenotype-genotype discrepancies” between patients with Wilson disease, and may give reason to monitor nutrition more closely, particularly dietary levels of fat and sugar, reported lead author Claudia Einer, a PhD candidate at the German Research Center for Environmental Health in Neuherberg, Germany, and her colleagues. Their findings clarify an association between impaired copper metabolism, which defines Wilson disease, and liver steatosis, a common finding in affected patients.
“Indeed, Wilson disease often may be misdiagnosed as nonalcoholic fatty liver disease (NAFLD),” the investigators wrote in Cellular and Molecular Gastroenterology and Hepatology. They noted that previous reports showed similar mitochondrial alterations in the livers of patients with NAFLD and those with Wilson disease. Furthermore, in a case report of two twins with Wilson disease, the twin with bulimia nervosa developed severe liver disease, whereas the other twin, who was undernourished, had mild liver disease. Considering these observations and other supportive evidence, the investigators tested this apparent relationship between a high-fat diet and liver damage in Wilson disease.
“The rationale of this study was that both enriched copper and fatty acids cause bioenergetic defects and therefore synergistically and detrimentally may coincide on hepatic mitochondria, which was found to be dramatically the case,” the investigators wrote.
The study involved homozygous Atp7b–/– rats, which mirror Wilson disease, and heterozygous Atp7b+/– rats, which served as control subjects because they lack copper accumulation. The high-calorie diet contained high fat and sugar levels to mirror “the eating habits in Western society, causing the ‘American-lifestyle-induced-obesity syndrome.’ ”
Within several weeks of starting the high-calorie diet, both control and Wilson disease rats showed higher liver triglyceride levels and visceral fat mass compared with rats on the normal diet, with liver histology also showing macrosteatosis and increased NAFLD Activity Score (NAS). Control rats maintained similar body and liver weights regardless of diet; in contrast, Wilson disease rats on the high-calorie diet showed increased liver weight, compared with Wilson disease rats on the normal diet. In addition, Wilson disease rats fed the high-calorie diet had clinical liver injury, supported by elevated aspartate aminotransferase (AST) levels and gross hepatic damage. Under the microscope, histology revealed widespread necrosis, apoptosis, inflammation, and fibrosis; findings were sufficient to constitute nonalcoholic steatohepatitis in all Wilson disease rats fed the high-calorie diet, compared with just one-third of the control rats receiving high calories. Additional testing showed that Wilson disease rats fed the high-calorie diet had disease onset 20 days sooner than did Wilson disease rats fed the normal diet.
“This is a remarkable disease acceleration,” the investigators noted, highlighting the median survival of 106 days in Wilson disease rats fed a normal diet.
Copper testing showed that Wilson disease rats fed the high-calorie diet had high serum levels of non–ceruloplasmin-bound copper, which is a sign of overt liver damage; based on histologic findings, the copper likely came from destroyed hepatocytes. Regardless of diet type, Wilson disease rats developed high levels of copper within the liver, suggesting comparable copper consumption via water sources. Regardless of genotype, the high-calorie diet led to higher mitochondrial copper levels than those of the normal diet, but Wilson disease rats showed the highest levels of copper sequestration in mitochondria, to an extreme degree.
“Importantly,” the investigators wrote, “such increased mitochondrial copper significantly correlated with a higher NAS and a progressive Histologic Activity Index score.”
Closer inspection showed that the mitochondria of Wilson disease rats were abnormal regardless of diet, but those fed the high-calorie diet had “a most severe mitochondrial phenotype,” including detached membranes and ballooned cristae.
“These structural impairments were paralleled by remarkable mitochondrial functional deficits,” the investigators reported, referring to a significant decrease in adenosine triphosphate production and an increase in mitochondrial H2O2. In response to these mitochondrial abnormalities, cholesterol-related enzymes quadrupled, most prominently for biliary excretion. The investigators summed up these hepatic events as a “toxic triad of adenosine triphosphate depletion, increased reactive oxygen species, and increased bile salts [that led] to an earlier onset of the disease and to enhanced disease progression.”
To complete the set of experiments, rats were given the copper chelator methanobactin. This treatment effectively mitigated structural and functional abnormalities in mitochondria, which drove serum levels of AST, copper, and bile salts toward normalcy. Although treatment halted overt liver damage, histology revealed that resolution was incomplete.
“We conclude that lipid accumulation in copper-burdened hepatocytes may represent a ‘second-hit’ in Wilson disease, inducing liver damage, and suggest that further research should establish whether dietary counseling of Wilson disease patients may be of therapeutic benefit,” the investigators concluded.
The study was funded by Deutsche Forschungsgemeinschaft and the WiFoMed Society. The investigators reported no conflicts of interest.
SOURCE: Einer et al. Cell Mol Gastroenterol Hepatol. 2019 Jan 11. doi: 10.1016/j.jcmgh.2018.12.005.
A high-calorie diet may cause earlier onset of more severe Wilson disease, according to a rodent study.
If translatable to humans, the results could explain “striking phenotype-genotype discrepancies” between patients with Wilson disease, and may give reason to monitor nutrition more closely, particularly dietary levels of fat and sugar, reported lead author Claudia Einer, a PhD candidate at the German Research Center for Environmental Health in Neuherberg, Germany, and her colleagues. Their findings clarify an association between impaired copper metabolism, which defines Wilson disease, and liver steatosis, a common finding in affected patients.
“Indeed, Wilson disease often may be misdiagnosed as nonalcoholic fatty liver disease (NAFLD),” the investigators wrote in Cellular and Molecular Gastroenterology and Hepatology. They noted that previous reports showed similar mitochondrial alterations in the livers of patients with NAFLD and those with Wilson disease. Furthermore, in a case report of two twins with Wilson disease, the twin with bulimia nervosa developed severe liver disease, whereas the other twin, who was undernourished, had mild liver disease. Considering these observations and other supportive evidence, the investigators tested this apparent relationship between a high-fat diet and liver damage in Wilson disease.
“The rationale of this study was that both enriched copper and fatty acids cause bioenergetic defects and therefore synergistically and detrimentally may coincide on hepatic mitochondria, which was found to be dramatically the case,” the investigators wrote.
The study involved homozygous Atp7b–/– rats, which mirror Wilson disease, and heterozygous Atp7b+/– rats, which served as control subjects because they lack copper accumulation. The high-calorie diet contained high fat and sugar levels to mirror “the eating habits in Western society, causing the ‘American-lifestyle-induced-obesity syndrome.’ ”
Within several weeks of starting the high-calorie diet, both control and Wilson disease rats showed higher liver triglyceride levels and visceral fat mass compared with rats on the normal diet, with liver histology also showing macrosteatosis and increased NAFLD Activity Score (NAS). Control rats maintained similar body and liver weights regardless of diet; in contrast, Wilson disease rats on the high-calorie diet showed increased liver weight, compared with Wilson disease rats on the normal diet. In addition, Wilson disease rats fed the high-calorie diet had clinical liver injury, supported by elevated aspartate aminotransferase (AST) levels and gross hepatic damage. Under the microscope, histology revealed widespread necrosis, apoptosis, inflammation, and fibrosis; findings were sufficient to constitute nonalcoholic steatohepatitis in all Wilson disease rats fed the high-calorie diet, compared with just one-third of the control rats receiving high calories. Additional testing showed that Wilson disease rats fed the high-calorie diet had disease onset 20 days sooner than did Wilson disease rats fed the normal diet.
“This is a remarkable disease acceleration,” the investigators noted, highlighting the median survival of 106 days in Wilson disease rats fed a normal diet.
Copper testing showed that Wilson disease rats fed the high-calorie diet had high serum levels of non–ceruloplasmin-bound copper, which is a sign of overt liver damage; based on histologic findings, the copper likely came from destroyed hepatocytes. Regardless of diet type, Wilson disease rats developed high levels of copper within the liver, suggesting comparable copper consumption via water sources. Regardless of genotype, the high-calorie diet led to higher mitochondrial copper levels than those of the normal diet, but Wilson disease rats showed the highest levels of copper sequestration in mitochondria, to an extreme degree.
“Importantly,” the investigators wrote, “such increased mitochondrial copper significantly correlated with a higher NAS and a progressive Histologic Activity Index score.”
Closer inspection showed that the mitochondria of Wilson disease rats were abnormal regardless of diet, but those fed the high-calorie diet had “a most severe mitochondrial phenotype,” including detached membranes and ballooned cristae.
“These structural impairments were paralleled by remarkable mitochondrial functional deficits,” the investigators reported, referring to a significant decrease in adenosine triphosphate production and an increase in mitochondrial H2O2. In response to these mitochondrial abnormalities, cholesterol-related enzymes quadrupled, most prominently for biliary excretion. The investigators summed up these hepatic events as a “toxic triad of adenosine triphosphate depletion, increased reactive oxygen species, and increased bile salts [that led] to an earlier onset of the disease and to enhanced disease progression.”
To complete the set of experiments, rats were given the copper chelator methanobactin. This treatment effectively mitigated structural and functional abnormalities in mitochondria, which drove serum levels of AST, copper, and bile salts toward normalcy. Although treatment halted overt liver damage, histology revealed that resolution was incomplete.
“We conclude that lipid accumulation in copper-burdened hepatocytes may represent a ‘second-hit’ in Wilson disease, inducing liver damage, and suggest that further research should establish whether dietary counseling of Wilson disease patients may be of therapeutic benefit,” the investigators concluded.
The study was funded by Deutsche Forschungsgemeinschaft and the WiFoMed Society. The investigators reported no conflicts of interest.
SOURCE: Einer et al. Cell Mol Gastroenterol Hepatol. 2019 Jan 11. doi: 10.1016/j.jcmgh.2018.12.005.
FROM CELLULAR AND MOLECULAR GASTROENTEROLOGY AND HEPATOLOGY
Women survive more often than men do when hospitalized with cirrhosis
Women hospitalized with cirrhosis are less likely to die in the hospital than are men, according to a retrospective analysis of more than half a million patients.
Although women more often had infections and comorbidities, men more often had liver decompensation, which contributed most significantly to their higher mortality rate, reported lead author Jessica Rubin, MD, of the University of California, San Francisco, and her colleagues.
Their findings add to an existing body of knowledge about sex-related differences in chronic liver disease. Women are less likely to develop chronic liver disease; however, when women do develop disease, it often follows a unique clinical course, with milder early disease followed by more severe end-stage disease, meaning many women are too sick for a transplant, or die on the waiting list.
“The reasons behind this ‘reversal’ in [sex] disparities is unknown,” the investigators wrote in Journal of Clinical Gastroenterology.
Considering recent findings that showed a correlation between hospitalization and mortality rates in chronic liver disease, the investigators believed that a comparison of hospital-related outcomes in men and women could explain why women apparently fare worse when dealing with end-stage disease.
The retrospective, cross-sectional study involved 553,017 patients (median age, 57 years) who were hospitalized for cirrhosis between 2009 and 2013. Data were drawn from the National Inpatient Sample (NIS). Inpatient mortality was the primary outcome.
In agreement with previous findings, the minority of patients were women (39%). Against expectations, however, women had a significantly lower mortality rate than that of men (5.7% vs. 6.4%; multivariable analysis odds ratio, 0.86). Better survival was associated with lower rates of decompensation (Baveno IV criteria; 34% vs. 38.8%) and other cirrhosis complications, such as hepatorenal syndrome, variceal bleeding, ascites, and spontaneous bacterial peritonitis. The only cirrhosis complication more common in women than men was hepatic encephalopathy (17.8% vs. 16.8%). Owing to fewer complications, fewer women required liver-related interventions, including transjugular intrahepatic portosystemic shunt (0.8% vs. 1.0%), upper endoscopy (12.8% vs. 13.0%), or paracentesis (17.6% vs. 20.6%).
While less frequent complications and a lower mortality rate might suggest that women were admitted with better overall clinical pictures, not all data supported this conclusion. For instance, women were more likely to have noncirrhosis comorbidities, including diabetes, hypertension, heart failure, stroke, and cancer. Furthermore, women had a higher rate of acute bacterial infection than that of men (34.9% vs. 28.2%), although this disparity should be considered in light of urinary tract infections (UTIs), which were significantly more common among women (18.8% vs. 8.0%).
“Interestingly, infections were a stronger predictor of inpatient mortality in women than men,” the investigators wrote. “Despite this, women in our cohort were less likely to die in the hospital than men.”
Additional analysis revealed etiological differences that may have contributed to differences in mortality rates. For instance, women less often had liver disease due to viral hepatitis (27.6% vs. 35.2%) or alcohol (24.1% vs. 38.7%). In contrast, women more often had autoimmune hepatitis (2.5% vs. 0.4%) or cirrhosis due to unspecified or miscellaneous reasons (45.7% vs. 25.7%).
“Our data suggest that differential rates of ongoing liver injury – including by cofactors such as active alcohol use – explain some but not all of the [sex] difference we observed in hepatic decompensation,” the investigators wrote, before redirecting focus to a clearer clinical finding. “The poor prognosis of decompensated cirrhosis ... provides a reasonable explanation for the higher rates of in-hospital mortality seen among men versus women,” they concluded.
Considering the surprising findings and previously known sex disparities, Dr. Rubin and her colleagues suggested that more research in this area is needed, along with efforts to deliver sex-appropriate care.
“The development of [sex]-specific cirrhosis management programs – focused on interventions to manage the interaction between cirrhosis and other common comorbidities, improving physical function both before and during hospitalization, and postacute discharge programs to facilitate resumption of independent living – would target differential needs of women and men living with cirrhosis, with the ultimate goal of improving long-term outcomes in these patients,” the investigators wrote.
The study was funded by a National Institute on Aging Paul B. Beeson Career Development Award in Aging and a National Institute of Diabetes and Digestive and Kidney Diseases National Research Service Award hepatology training grant. The investigators declared no conflicts of interest.
SOURCE: Rubin et al. J Clin Gastroenterol. 2019 Feb 22. doi: 10.1097/MCG.0000000000001192.
Women hospitalized with cirrhosis are less likely to die in the hospital than are men, according to a retrospective analysis of more than half a million patients.
Although women more often had infections and comorbidities, men more often had liver decompensation, which contributed most significantly to their higher mortality rate, reported lead author Jessica Rubin, MD, of the University of California, San Francisco, and her colleagues.
Their findings add to an existing body of knowledge about sex-related differences in chronic liver disease. Women are less likely to develop chronic liver disease; however, when women do develop disease, it often follows a unique clinical course, with milder early disease followed by more severe end-stage disease, meaning many women are too sick for a transplant, or die on the waiting list.
“The reasons behind this ‘reversal’ in [sex] disparities is unknown,” the investigators wrote in Journal of Clinical Gastroenterology.
Considering recent findings that showed a correlation between hospitalization and mortality rates in chronic liver disease, the investigators believed that a comparison of hospital-related outcomes in men and women could explain why women apparently fare worse when dealing with end-stage disease.
The retrospective, cross-sectional study involved 553,017 patients (median age, 57 years) who were hospitalized for cirrhosis between 2009 and 2013. Data were drawn from the National Inpatient Sample (NIS). Inpatient mortality was the primary outcome.
In agreement with previous findings, the minority of patients were women (39%). Against expectations, however, women had a significantly lower mortality rate than that of men (5.7% vs. 6.4%; multivariable analysis odds ratio, 0.86). Better survival was associated with lower rates of decompensation (Baveno IV criteria; 34% vs. 38.8%) and other cirrhosis complications, such as hepatorenal syndrome, variceal bleeding, ascites, and spontaneous bacterial peritonitis. The only cirrhosis complication more common in women than men was hepatic encephalopathy (17.8% vs. 16.8%). Owing to fewer complications, fewer women required liver-related interventions, including transjugular intrahepatic portosystemic shunt (0.8% vs. 1.0%), upper endoscopy (12.8% vs. 13.0%), or paracentesis (17.6% vs. 20.6%).
While less frequent complications and a lower mortality rate might suggest that women were admitted with better overall clinical pictures, not all data supported this conclusion. For instance, women were more likely to have noncirrhosis comorbidities, including diabetes, hypertension, heart failure, stroke, and cancer. Furthermore, women had a higher rate of acute bacterial infection than that of men (34.9% vs. 28.2%), although this disparity should be considered in light of urinary tract infections (UTIs), which were significantly more common among women (18.8% vs. 8.0%).
“Interestingly, infections were a stronger predictor of inpatient mortality in women than men,” the investigators wrote. “Despite this, women in our cohort were less likely to die in the hospital than men.”
Additional analysis revealed etiological differences that may have contributed to differences in mortality rates. For instance, women less often had liver disease due to viral hepatitis (27.6% vs. 35.2%) or alcohol (24.1% vs. 38.7%). In contrast, women more often had autoimmune hepatitis (2.5% vs. 0.4%) or cirrhosis due to unspecified or miscellaneous reasons (45.7% vs. 25.7%).
“Our data suggest that differential rates of ongoing liver injury – including by cofactors such as active alcohol use – explain some but not all of the [sex] difference we observed in hepatic decompensation,” the investigators wrote, before redirecting focus to a clearer clinical finding. “The poor prognosis of decompensated cirrhosis ... provides a reasonable explanation for the higher rates of in-hospital mortality seen among men versus women,” they concluded.
Considering the surprising findings and previously known sex disparities, Dr. Rubin and her colleagues suggested that more research in this area is needed, along with efforts to deliver sex-appropriate care.
“The development of [sex]-specific cirrhosis management programs – focused on interventions to manage the interaction between cirrhosis and other common comorbidities, improving physical function both before and during hospitalization, and postacute discharge programs to facilitate resumption of independent living – would target differential needs of women and men living with cirrhosis, with the ultimate goal of improving long-term outcomes in these patients,” the investigators wrote.
The study was funded by a National Institute on Aging Paul B. Beeson Career Development Award in Aging and a National Institute of Diabetes and Digestive and Kidney Diseases National Research Service Award hepatology training grant. The investigators declared no conflicts of interest.
SOURCE: Rubin et al. J Clin Gastroenterol. 2019 Feb 22. doi: 10.1097/MCG.0000000000001192.
Women hospitalized with cirrhosis are less likely to die in the hospital than are men, according to a retrospective analysis of more than half a million patients.
Although women more often had infections and comorbidities, men more often had liver decompensation, which contributed most significantly to their higher mortality rate, reported lead author Jessica Rubin, MD, of the University of California, San Francisco, and her colleagues.
Their findings add to an existing body of knowledge about sex-related differences in chronic liver disease. Women are less likely to develop chronic liver disease; however, when women do develop disease, it often follows a unique clinical course, with milder early disease followed by more severe end-stage disease, meaning many women are too sick for a transplant, or die on the waiting list.
“The reasons behind this ‘reversal’ in [sex] disparities is unknown,” the investigators wrote in Journal of Clinical Gastroenterology.
Considering recent findings that showed a correlation between hospitalization and mortality rates in chronic liver disease, the investigators believed that a comparison of hospital-related outcomes in men and women could explain why women apparently fare worse when dealing with end-stage disease.
The retrospective, cross-sectional study involved 553,017 patients (median age, 57 years) who were hospitalized for cirrhosis between 2009 and 2013. Data were drawn from the National Inpatient Sample (NIS). Inpatient mortality was the primary outcome.
In agreement with previous findings, the minority of patients were women (39%). Against expectations, however, women had a significantly lower mortality rate than that of men (5.7% vs. 6.4%; multivariable analysis odds ratio, 0.86). Better survival was associated with lower rates of decompensation (Baveno IV criteria; 34% vs. 38.8%) and other cirrhosis complications, such as hepatorenal syndrome, variceal bleeding, ascites, and spontaneous bacterial peritonitis. The only cirrhosis complication more common in women than men was hepatic encephalopathy (17.8% vs. 16.8%). Owing to fewer complications, fewer women required liver-related interventions, including transjugular intrahepatic portosystemic shunt (0.8% vs. 1.0%), upper endoscopy (12.8% vs. 13.0%), or paracentesis (17.6% vs. 20.6%).
While less frequent complications and a lower mortality rate might suggest that women were admitted with better overall clinical pictures, not all data supported this conclusion. For instance, women were more likely to have noncirrhosis comorbidities, including diabetes, hypertension, heart failure, stroke, and cancer. Furthermore, women had a higher rate of acute bacterial infection than that of men (34.9% vs. 28.2%), although this disparity should be considered in light of urinary tract infections (UTIs), which were significantly more common among women (18.8% vs. 8.0%).
“Interestingly, infections were a stronger predictor of inpatient mortality in women than men,” the investigators wrote. “Despite this, women in our cohort were less likely to die in the hospital than men.”
Additional analysis revealed etiological differences that may have contributed to differences in mortality rates. For instance, women less often had liver disease due to viral hepatitis (27.6% vs. 35.2%) or alcohol (24.1% vs. 38.7%). In contrast, women more often had autoimmune hepatitis (2.5% vs. 0.4%) or cirrhosis due to unspecified or miscellaneous reasons (45.7% vs. 25.7%).
“Our data suggest that differential rates of ongoing liver injury – including by cofactors such as active alcohol use – explain some but not all of the [sex] difference we observed in hepatic decompensation,” the investigators wrote, before redirecting focus to a clearer clinical finding. “The poor prognosis of decompensated cirrhosis ... provides a reasonable explanation for the higher rates of in-hospital mortality seen among men versus women,” they concluded.
Considering the surprising findings and previously known sex disparities, Dr. Rubin and her colleagues suggested that more research in this area is needed, along with efforts to deliver sex-appropriate care.
“The development of [sex]-specific cirrhosis management programs – focused on interventions to manage the interaction between cirrhosis and other common comorbidities, improving physical function both before and during hospitalization, and postacute discharge programs to facilitate resumption of independent living – would target differential needs of women and men living with cirrhosis, with the ultimate goal of improving long-term outcomes in these patients,” the investigators wrote.
The study was funded by a National Institute on Aging Paul B. Beeson Career Development Award in Aging and a National Institute of Diabetes and Digestive and Kidney Diseases National Research Service Award hepatology training grant. The investigators declared no conflicts of interest.
SOURCE: Rubin et al. J Clin Gastroenterol. 2019 Feb 22. doi: 10.1097/MCG.0000000000001192.
FROM JOURNAL OF CLINICAL GASTROENTEROLOGY
Possible biomarkers found for progression to liver cancer in chronic HCV infection
according to the results of a biochemical analysis of human blood samples performed by PhD student Paywast J. Jalal of the University of Sulaimani (Iraq) and colleagues.
Archived HCV-positive serum samples, including those from 31 patients who had developed HCC, were retrieved from the Trent HCV clinical cohort. They were compared with each other over time and against samples from HCV-infected individuals in the cohort who did not develop HCC. In addition, HCV-negative serum samples were obtained commercially and assessed identically. Circulating liver-expressed lectins, ficolin-2, ficolin-3, and MBL were all examined as potential biomarkers for the development of HCC, the authors wrote in Virology.
Binding of ficolin-3 to reference ligands was greater in chronic HCV infection, while ficolin-2 and MBL were significantly elevated in individuals who develop HCC, compared with HCV-infected individuals without HCC. Ficolin-2 and MBL were found to be elevated at 1 and 3 years prior to HCC diagnosis, respectively, suggesting they could be used as prognostic serum markers for the development of HCC.
“The strong evidence for an association between elevated MBL binding activity and the development of HCC is supportive for a larger prospective study of these biomarkers in HCV-induced liver cancer,” the researchers concluded.
This study was funded by a split-site PhD scholarship between the University of Sulaimani and the University of Nottingham (England). The authors reported they had no conflicts.
SOURCE: Jalal PJ et al. Virology. 2019;530:99-106.
according to the results of a biochemical analysis of human blood samples performed by PhD student Paywast J. Jalal of the University of Sulaimani (Iraq) and colleagues.
Archived HCV-positive serum samples, including those from 31 patients who had developed HCC, were retrieved from the Trent HCV clinical cohort. They were compared with each other over time and against samples from HCV-infected individuals in the cohort who did not develop HCC. In addition, HCV-negative serum samples were obtained commercially and assessed identically. Circulating liver-expressed lectins, ficolin-2, ficolin-3, and MBL were all examined as potential biomarkers for the development of HCC, the authors wrote in Virology.
Binding of ficolin-3 to reference ligands was greater in chronic HCV infection, while ficolin-2 and MBL were significantly elevated in individuals who develop HCC, compared with HCV-infected individuals without HCC. Ficolin-2 and MBL were found to be elevated at 1 and 3 years prior to HCC diagnosis, respectively, suggesting they could be used as prognostic serum markers for the development of HCC.
“The strong evidence for an association between elevated MBL binding activity and the development of HCC is supportive for a larger prospective study of these biomarkers in HCV-induced liver cancer,” the researchers concluded.
This study was funded by a split-site PhD scholarship between the University of Sulaimani and the University of Nottingham (England). The authors reported they had no conflicts.
SOURCE: Jalal PJ et al. Virology. 2019;530:99-106.
according to the results of a biochemical analysis of human blood samples performed by PhD student Paywast J. Jalal of the University of Sulaimani (Iraq) and colleagues.
Archived HCV-positive serum samples, including those from 31 patients who had developed HCC, were retrieved from the Trent HCV clinical cohort. They were compared with each other over time and against samples from HCV-infected individuals in the cohort who did not develop HCC. In addition, HCV-negative serum samples were obtained commercially and assessed identically. Circulating liver-expressed lectins, ficolin-2, ficolin-3, and MBL were all examined as potential biomarkers for the development of HCC, the authors wrote in Virology.
Binding of ficolin-3 to reference ligands was greater in chronic HCV infection, while ficolin-2 and MBL were significantly elevated in individuals who develop HCC, compared with HCV-infected individuals without HCC. Ficolin-2 and MBL were found to be elevated at 1 and 3 years prior to HCC diagnosis, respectively, suggesting they could be used as prognostic serum markers for the development of HCC.
“The strong evidence for an association between elevated MBL binding activity and the development of HCC is supportive for a larger prospective study of these biomarkers in HCV-induced liver cancer,” the researchers concluded.
This study was funded by a split-site PhD scholarship between the University of Sulaimani and the University of Nottingham (England). The authors reported they had no conflicts.
SOURCE: Jalal PJ et al. Virology. 2019;530:99-106.
FROM VIROLOGY
Novel capsid assembly modulator shows promise in HBV
For adults with chronic hepatitis B virus infection, treatment with a novel investigational capsid assembly modulator was well tolerated and showed antiviral activity against HBV, according to the results of a phase 1 study of 73 patients.
“Substantial and correlated reductions in serum HBV DNA and HBV RNA levels were observed consistently with the higher-dose cohorts and were notably greatest for combination treatment with NVR 3-778 and pegIFN [pegylated interferon],” Man Fung Yuen, MD, of the University of Hong Kong, and his associates wrote in a report published in Gastroenterology. Hence, this first-in-class capsid assembly modulator might help prolong treatment responses, “most likely as a component of new combination treatment regimens for HBV-infected patients.” However, one patient developed severe rash immediately after completing treatment that took 6 months of intensive outpatient treatment to resolve, they noted.
Chronic viral hepatitis due to HBV is a major cause of early death worldwide, and new therapies are needed to help prevent severe liver disease and liver death from this infection. Current treatments for HBV infection consist of nucleoside or nucleotide analogs or pegylated interferon. These suppress HBV replication in many patients, but most patients do not achieve durable responses. Consequently, most patients require long-term treatment with HBV nucleosides and nucleotide analogs, which they may find difficult to tolerate or adhere to and to which their infections can become resistant, the researchers said.
The HBV virion contains a viral core protein (HBc) that is required to encapsidate viral polymerase and pregenomic HBV RNA into a nucleocapsid. To target this process, researchers developed NVR 3-778, a first-in-class, orally bioavailable small molecule that binds HBc so that HBc forms a defective capsid that lacks nuclear material. Hence, NVR 3-778 is intended to stop the production of HBV nucleocapsids and keep infected cells from releasing the enveloped infectious viral particles that perpetuate HBV infection.
To assess the safety, pharmacokinetics, and antiviral activity of NVR 3-778, the researchers conducted a phase 1 study of 73 patients with chronic HBV infection who tested positive for hepatitis B e-antigen (HBeAg) and had no detectable cirrhosis. Patients were randomly assigned to receive oral NVR 3-778 (100 mg, 200 mg, or 400 mg daily or 600 mg or 1,000 mg twice daily ) or placebo for 28 days. Some patients received combination therapy with pegylated interferon plus either NVR 3-778 (600 mg twice daily) or placebo. Treatment was generally well tolerated, and adverse events were usually mild and deemed unrelated to therapy. No patient stopped treatment for adverse effects.
The only serious adverse event in the study consisted of grade 3 rash that developed in a 42-year-old male after 22 days of treatment at the lowest dose of NVR 3-778 (100 mg per day). This patient completed treatment and ultimately developed a severe papulovesicular rash with a predominantly acral distribution over the hands, arm, side of neck, and one leg (palmar plantar erythrodysesthesia), the researchers said. “There were no perioral or mucosal lesions, no ecchymotic skin involvement, no bullae, and no systemic manifestations or hematological abnormalities,” they wrote. “The rash was subsequently managed with a psoriasis-like treatment regimen of psoralen, ultraviolet light, and topical steroid ointment during outpatient follow-up and resolved after approximately 6 months.”
Another three cases of “minor” skin rash were considered probably related to treatment in the cohort that received 600 mg NVR 3-778 b.i.d. plus pegylated interferon, the investigators said. Two additional cases of mild rash were deemed unrelated to treatment.
“The observed reductions in HBV RNA confirmed the novel mechanism of NVR 3-778,” the researchers concluded. “This class of compounds can also inhibit replenishment of intranuclear covalently closed circular DNA over time and may have immunomodulatory properties.” Longer treatment periods would be needed to study these mechanisms and to quantify reductions in serum HBsAg and HBeAG, they noted.
Novira Therapeutics developed NVR 3-778 and is a Janssen Pharmaceutical Company. Janssen provided funding for editorial support. Dr. Yuen disclosed relationships with AbbVie, Biocartis, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Ionis, Roche, Vir Biotechnology, and several other pharmaceutical companies. Other coinvestigators disclosed ties to pharmaceutical companies; eight reported employment by Novira or a Janssen company.
SOURCE: Yuen MF et al. Gastroenterology. 2019 Jan 5. doi: 10.1053/j.gastro.2018.12.023.
For adults with chronic hepatitis B virus infection, treatment with a novel investigational capsid assembly modulator was well tolerated and showed antiviral activity against HBV, according to the results of a phase 1 study of 73 patients.
“Substantial and correlated reductions in serum HBV DNA and HBV RNA levels were observed consistently with the higher-dose cohorts and were notably greatest for combination treatment with NVR 3-778 and pegIFN [pegylated interferon],” Man Fung Yuen, MD, of the University of Hong Kong, and his associates wrote in a report published in Gastroenterology. Hence, this first-in-class capsid assembly modulator might help prolong treatment responses, “most likely as a component of new combination treatment regimens for HBV-infected patients.” However, one patient developed severe rash immediately after completing treatment that took 6 months of intensive outpatient treatment to resolve, they noted.
Chronic viral hepatitis due to HBV is a major cause of early death worldwide, and new therapies are needed to help prevent severe liver disease and liver death from this infection. Current treatments for HBV infection consist of nucleoside or nucleotide analogs or pegylated interferon. These suppress HBV replication in many patients, but most patients do not achieve durable responses. Consequently, most patients require long-term treatment with HBV nucleosides and nucleotide analogs, which they may find difficult to tolerate or adhere to and to which their infections can become resistant, the researchers said.
The HBV virion contains a viral core protein (HBc) that is required to encapsidate viral polymerase and pregenomic HBV RNA into a nucleocapsid. To target this process, researchers developed NVR 3-778, a first-in-class, orally bioavailable small molecule that binds HBc so that HBc forms a defective capsid that lacks nuclear material. Hence, NVR 3-778 is intended to stop the production of HBV nucleocapsids and keep infected cells from releasing the enveloped infectious viral particles that perpetuate HBV infection.
To assess the safety, pharmacokinetics, and antiviral activity of NVR 3-778, the researchers conducted a phase 1 study of 73 patients with chronic HBV infection who tested positive for hepatitis B e-antigen (HBeAg) and had no detectable cirrhosis. Patients were randomly assigned to receive oral NVR 3-778 (100 mg, 200 mg, or 400 mg daily or 600 mg or 1,000 mg twice daily ) or placebo for 28 days. Some patients received combination therapy with pegylated interferon plus either NVR 3-778 (600 mg twice daily) or placebo. Treatment was generally well tolerated, and adverse events were usually mild and deemed unrelated to therapy. No patient stopped treatment for adverse effects.
The only serious adverse event in the study consisted of grade 3 rash that developed in a 42-year-old male after 22 days of treatment at the lowest dose of NVR 3-778 (100 mg per day). This patient completed treatment and ultimately developed a severe papulovesicular rash with a predominantly acral distribution over the hands, arm, side of neck, and one leg (palmar plantar erythrodysesthesia), the researchers said. “There were no perioral or mucosal lesions, no ecchymotic skin involvement, no bullae, and no systemic manifestations or hematological abnormalities,” they wrote. “The rash was subsequently managed with a psoriasis-like treatment regimen of psoralen, ultraviolet light, and topical steroid ointment during outpatient follow-up and resolved after approximately 6 months.”
Another three cases of “minor” skin rash were considered probably related to treatment in the cohort that received 600 mg NVR 3-778 b.i.d. plus pegylated interferon, the investigators said. Two additional cases of mild rash were deemed unrelated to treatment.
“The observed reductions in HBV RNA confirmed the novel mechanism of NVR 3-778,” the researchers concluded. “This class of compounds can also inhibit replenishment of intranuclear covalently closed circular DNA over time and may have immunomodulatory properties.” Longer treatment periods would be needed to study these mechanisms and to quantify reductions in serum HBsAg and HBeAG, they noted.
Novira Therapeutics developed NVR 3-778 and is a Janssen Pharmaceutical Company. Janssen provided funding for editorial support. Dr. Yuen disclosed relationships with AbbVie, Biocartis, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Ionis, Roche, Vir Biotechnology, and several other pharmaceutical companies. Other coinvestigators disclosed ties to pharmaceutical companies; eight reported employment by Novira or a Janssen company.
SOURCE: Yuen MF et al. Gastroenterology. 2019 Jan 5. doi: 10.1053/j.gastro.2018.12.023.
For adults with chronic hepatitis B virus infection, treatment with a novel investigational capsid assembly modulator was well tolerated and showed antiviral activity against HBV, according to the results of a phase 1 study of 73 patients.
“Substantial and correlated reductions in serum HBV DNA and HBV RNA levels were observed consistently with the higher-dose cohorts and were notably greatest for combination treatment with NVR 3-778 and pegIFN [pegylated interferon],” Man Fung Yuen, MD, of the University of Hong Kong, and his associates wrote in a report published in Gastroenterology. Hence, this first-in-class capsid assembly modulator might help prolong treatment responses, “most likely as a component of new combination treatment regimens for HBV-infected patients.” However, one patient developed severe rash immediately after completing treatment that took 6 months of intensive outpatient treatment to resolve, they noted.
Chronic viral hepatitis due to HBV is a major cause of early death worldwide, and new therapies are needed to help prevent severe liver disease and liver death from this infection. Current treatments for HBV infection consist of nucleoside or nucleotide analogs or pegylated interferon. These suppress HBV replication in many patients, but most patients do not achieve durable responses. Consequently, most patients require long-term treatment with HBV nucleosides and nucleotide analogs, which they may find difficult to tolerate or adhere to and to which their infections can become resistant, the researchers said.
The HBV virion contains a viral core protein (HBc) that is required to encapsidate viral polymerase and pregenomic HBV RNA into a nucleocapsid. To target this process, researchers developed NVR 3-778, a first-in-class, orally bioavailable small molecule that binds HBc so that HBc forms a defective capsid that lacks nuclear material. Hence, NVR 3-778 is intended to stop the production of HBV nucleocapsids and keep infected cells from releasing the enveloped infectious viral particles that perpetuate HBV infection.
To assess the safety, pharmacokinetics, and antiviral activity of NVR 3-778, the researchers conducted a phase 1 study of 73 patients with chronic HBV infection who tested positive for hepatitis B e-antigen (HBeAg) and had no detectable cirrhosis. Patients were randomly assigned to receive oral NVR 3-778 (100 mg, 200 mg, or 400 mg daily or 600 mg or 1,000 mg twice daily ) or placebo for 28 days. Some patients received combination therapy with pegylated interferon plus either NVR 3-778 (600 mg twice daily) or placebo. Treatment was generally well tolerated, and adverse events were usually mild and deemed unrelated to therapy. No patient stopped treatment for adverse effects.
The only serious adverse event in the study consisted of grade 3 rash that developed in a 42-year-old male after 22 days of treatment at the lowest dose of NVR 3-778 (100 mg per day). This patient completed treatment and ultimately developed a severe papulovesicular rash with a predominantly acral distribution over the hands, arm, side of neck, and one leg (palmar plantar erythrodysesthesia), the researchers said. “There were no perioral or mucosal lesions, no ecchymotic skin involvement, no bullae, and no systemic manifestations or hematological abnormalities,” they wrote. “The rash was subsequently managed with a psoriasis-like treatment regimen of psoralen, ultraviolet light, and topical steroid ointment during outpatient follow-up and resolved after approximately 6 months.”
Another three cases of “minor” skin rash were considered probably related to treatment in the cohort that received 600 mg NVR 3-778 b.i.d. plus pegylated interferon, the investigators said. Two additional cases of mild rash were deemed unrelated to treatment.
“The observed reductions in HBV RNA confirmed the novel mechanism of NVR 3-778,” the researchers concluded. “This class of compounds can also inhibit replenishment of intranuclear covalently closed circular DNA over time and may have immunomodulatory properties.” Longer treatment periods would be needed to study these mechanisms and to quantify reductions in serum HBsAg and HBeAG, they noted.
Novira Therapeutics developed NVR 3-778 and is a Janssen Pharmaceutical Company. Janssen provided funding for editorial support. Dr. Yuen disclosed relationships with AbbVie, Biocartis, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Ionis, Roche, Vir Biotechnology, and several other pharmaceutical companies. Other coinvestigators disclosed ties to pharmaceutical companies; eight reported employment by Novira or a Janssen company.
SOURCE: Yuen MF et al. Gastroenterology. 2019 Jan 5. doi: 10.1053/j.gastro.2018.12.023.
FROM GASTROENTEROLOGY
AGA Clinical Practice Update: Surgical risk assessment and perioperative management in cirrhosis
Patients with cirrhosis should be risk stratified and counseled accordingly before all but the most urgent surgeries, cautions a clinical practice update from the American Gastroenterological Association.
These risks, which include mortality and reflect “the profound effects of hepatic synthetic dysfunction and portal hypertension,” require presurgical evaluation based on CTP score (Child-Pugh class), Model for End-Stage Liver Disease (MELD) score, Mayo Postoperative Mortality Risk Score, or another proven risk-stratification system, writes Patrick G. Northup, MD, of the University of Virginia, Charlottesville, together with his associates. “There is no single definitive risk-stratification system to determine operative risk in all patients with cirrhosis, and we recommend using multiple methods,” they elaborated in Clinical Gastroenterology and Hepatology.
The prevalence of cirrhosis is rising, affected patients are living longer, and liver disease is more advanced and may involve comorbidities that merit consideration of surgery, noted Dr. Northup and his associates. However, cirrhosis increases the risk for serious postoperative complications, including hepatic decompensation, worsening of liver synthetic function, exacerbated portal hypertension, wound dehiscence, pleural effusions, pneumonia, bacterial peritonitis, bleeding, and multiple organ failure. Because clinical trials of surgery in cirrhotic patients are lacking, the experts stress the need for case-by-case management.
There is no definite threshold that precludes all surgeries in cases of cirrhosis, but a Child-Pugh class C (CTP score over 10) or MELD score over 20 greatly increases the risk of postoperative decompensation and death. For these patients, “all but the most urgent and life-saving procedures” should be canceled or postponed until after liver transplantation, the experts wrote. For less severe cirrhosis, it is key to consider the type and anatomic site of the proposed surgery. Hepatobiliary surgeries, other intra-abdominal surgeries, cardiovascular surgeries, and thoracic procedures are most likely to lead to serious complications.
Preoperative care should emphasize control of ascites, variceal bleeding risk, and hepatic encephalopathy. Bleeding and clotting safety thresholds in cirrhosis are unknown, and individualized management, ideally with viscoelastic testing–directed therapy, is warranted instead of protocol transfusions to a target international normalized ratio (INR). Bleeding events are more common in critically ill patients with plasma fibrinogen ratios under 100 mg/dL.
Segmental hepatic resection (usually for malignancy), the most studied procedure in cirrhosis, is generally safe in the absence of clinically significant portal hypertension. For patients who do have portal hypertension, transjugular intrahepatic portosystemic shunt (TIPS) has not clearly been shown to outperform conservative management, although small case series have found that TIPS during deep pelvic or colonic resection decompresses abdominal collaterals.
Because of the risk of poor outcomes, patients with cirrhosis and incompletely controlled ascites should not undergo abdominal hernia repair unless they have an incarceration that is not manually reducible or suspected strangulation. Bariatric surgery is contraindicated in cases of clinically significant portal hypertension but otherwise can be performed at a center with cirrhosis expertise. Sleeve gastrectomy at the same time as liver transplantation is also an option for select patients with obesity.
Elective cholecystectomy should be avoided, and required cases should be performed in experienced centers. “The gallbladder wall may appear thickened on imaging, which may lead to the erroneous diagnosis of acute cholecystitis,” the experts noted. Hence, the diagnosis “should be made only in the appropriate clinical setting, usually in the presence of biliary pain.”
Hepatic decompensation after surgery can be severe enough to merit liver transplantation. There is no agreed-on MELD score that mandates liver transplant evaluation before elective surgery, but the experts recommend doing so if the MELD score is 15 or greater or if risk of mortality within 3 months after surgery exceeds 15%.
Postoperative management of patients with cirrhosis should include aggressive measures to prevent portal hypertension. Monitor renal function closely and avoid volume depletion or overload, the experts advised. Patients should receive only short-acting benzodiazepines and lower opiate doses, administered less often, than in the general population. Avoiding constipation is vital to minimize hepatic encephalopathy, which makes oral rifaximin a better choice than lactulose. Patients should not receive NSAIDs, which can impair renal blood flow. To prevent liver toxicity, they should not be discharged on opiate/acetaminophen combinations, which they might unknowingly take along with another drug that contains acetaminophen.
The experts disclosed no external funding sources and reported having no conflicts of interest.
SOURCE: Northup PG et al. Clin Gastroenterol Hepatol. 2018 Sep 28. doi: 10.1016/j.cgh.2018.09.043.
Patients with cirrhosis should be risk stratified and counseled accordingly before all but the most urgent surgeries, cautions a clinical practice update from the American Gastroenterological Association.
These risks, which include mortality and reflect “the profound effects of hepatic synthetic dysfunction and portal hypertension,” require presurgical evaluation based on CTP score (Child-Pugh class), Model for End-Stage Liver Disease (MELD) score, Mayo Postoperative Mortality Risk Score, or another proven risk-stratification system, writes Patrick G. Northup, MD, of the University of Virginia, Charlottesville, together with his associates. “There is no single definitive risk-stratification system to determine operative risk in all patients with cirrhosis, and we recommend using multiple methods,” they elaborated in Clinical Gastroenterology and Hepatology.
The prevalence of cirrhosis is rising, affected patients are living longer, and liver disease is more advanced and may involve comorbidities that merit consideration of surgery, noted Dr. Northup and his associates. However, cirrhosis increases the risk for serious postoperative complications, including hepatic decompensation, worsening of liver synthetic function, exacerbated portal hypertension, wound dehiscence, pleural effusions, pneumonia, bacterial peritonitis, bleeding, and multiple organ failure. Because clinical trials of surgery in cirrhotic patients are lacking, the experts stress the need for case-by-case management.
There is no definite threshold that precludes all surgeries in cases of cirrhosis, but a Child-Pugh class C (CTP score over 10) or MELD score over 20 greatly increases the risk of postoperative decompensation and death. For these patients, “all but the most urgent and life-saving procedures” should be canceled or postponed until after liver transplantation, the experts wrote. For less severe cirrhosis, it is key to consider the type and anatomic site of the proposed surgery. Hepatobiliary surgeries, other intra-abdominal surgeries, cardiovascular surgeries, and thoracic procedures are most likely to lead to serious complications.
Preoperative care should emphasize control of ascites, variceal bleeding risk, and hepatic encephalopathy. Bleeding and clotting safety thresholds in cirrhosis are unknown, and individualized management, ideally with viscoelastic testing–directed therapy, is warranted instead of protocol transfusions to a target international normalized ratio (INR). Bleeding events are more common in critically ill patients with plasma fibrinogen ratios under 100 mg/dL.
Segmental hepatic resection (usually for malignancy), the most studied procedure in cirrhosis, is generally safe in the absence of clinically significant portal hypertension. For patients who do have portal hypertension, transjugular intrahepatic portosystemic shunt (TIPS) has not clearly been shown to outperform conservative management, although small case series have found that TIPS during deep pelvic or colonic resection decompresses abdominal collaterals.
Because of the risk of poor outcomes, patients with cirrhosis and incompletely controlled ascites should not undergo abdominal hernia repair unless they have an incarceration that is not manually reducible or suspected strangulation. Bariatric surgery is contraindicated in cases of clinically significant portal hypertension but otherwise can be performed at a center with cirrhosis expertise. Sleeve gastrectomy at the same time as liver transplantation is also an option for select patients with obesity.
Elective cholecystectomy should be avoided, and required cases should be performed in experienced centers. “The gallbladder wall may appear thickened on imaging, which may lead to the erroneous diagnosis of acute cholecystitis,” the experts noted. Hence, the diagnosis “should be made only in the appropriate clinical setting, usually in the presence of biliary pain.”
Hepatic decompensation after surgery can be severe enough to merit liver transplantation. There is no agreed-on MELD score that mandates liver transplant evaluation before elective surgery, but the experts recommend doing so if the MELD score is 15 or greater or if risk of mortality within 3 months after surgery exceeds 15%.
Postoperative management of patients with cirrhosis should include aggressive measures to prevent portal hypertension. Monitor renal function closely and avoid volume depletion or overload, the experts advised. Patients should receive only short-acting benzodiazepines and lower opiate doses, administered less often, than in the general population. Avoiding constipation is vital to minimize hepatic encephalopathy, which makes oral rifaximin a better choice than lactulose. Patients should not receive NSAIDs, which can impair renal blood flow. To prevent liver toxicity, they should not be discharged on opiate/acetaminophen combinations, which they might unknowingly take along with another drug that contains acetaminophen.
The experts disclosed no external funding sources and reported having no conflicts of interest.
SOURCE: Northup PG et al. Clin Gastroenterol Hepatol. 2018 Sep 28. doi: 10.1016/j.cgh.2018.09.043.
Patients with cirrhosis should be risk stratified and counseled accordingly before all but the most urgent surgeries, cautions a clinical practice update from the American Gastroenterological Association.
These risks, which include mortality and reflect “the profound effects of hepatic synthetic dysfunction and portal hypertension,” require presurgical evaluation based on CTP score (Child-Pugh class), Model for End-Stage Liver Disease (MELD) score, Mayo Postoperative Mortality Risk Score, or another proven risk-stratification system, writes Patrick G. Northup, MD, of the University of Virginia, Charlottesville, together with his associates. “There is no single definitive risk-stratification system to determine operative risk in all patients with cirrhosis, and we recommend using multiple methods,” they elaborated in Clinical Gastroenterology and Hepatology.
The prevalence of cirrhosis is rising, affected patients are living longer, and liver disease is more advanced and may involve comorbidities that merit consideration of surgery, noted Dr. Northup and his associates. However, cirrhosis increases the risk for serious postoperative complications, including hepatic decompensation, worsening of liver synthetic function, exacerbated portal hypertension, wound dehiscence, pleural effusions, pneumonia, bacterial peritonitis, bleeding, and multiple organ failure. Because clinical trials of surgery in cirrhotic patients are lacking, the experts stress the need for case-by-case management.
There is no definite threshold that precludes all surgeries in cases of cirrhosis, but a Child-Pugh class C (CTP score over 10) or MELD score over 20 greatly increases the risk of postoperative decompensation and death. For these patients, “all but the most urgent and life-saving procedures” should be canceled or postponed until after liver transplantation, the experts wrote. For less severe cirrhosis, it is key to consider the type and anatomic site of the proposed surgery. Hepatobiliary surgeries, other intra-abdominal surgeries, cardiovascular surgeries, and thoracic procedures are most likely to lead to serious complications.
Preoperative care should emphasize control of ascites, variceal bleeding risk, and hepatic encephalopathy. Bleeding and clotting safety thresholds in cirrhosis are unknown, and individualized management, ideally with viscoelastic testing–directed therapy, is warranted instead of protocol transfusions to a target international normalized ratio (INR). Bleeding events are more common in critically ill patients with plasma fibrinogen ratios under 100 mg/dL.
Segmental hepatic resection (usually for malignancy), the most studied procedure in cirrhosis, is generally safe in the absence of clinically significant portal hypertension. For patients who do have portal hypertension, transjugular intrahepatic portosystemic shunt (TIPS) has not clearly been shown to outperform conservative management, although small case series have found that TIPS during deep pelvic or colonic resection decompresses abdominal collaterals.
Because of the risk of poor outcomes, patients with cirrhosis and incompletely controlled ascites should not undergo abdominal hernia repair unless they have an incarceration that is not manually reducible or suspected strangulation. Bariatric surgery is contraindicated in cases of clinically significant portal hypertension but otherwise can be performed at a center with cirrhosis expertise. Sleeve gastrectomy at the same time as liver transplantation is also an option for select patients with obesity.
Elective cholecystectomy should be avoided, and required cases should be performed in experienced centers. “The gallbladder wall may appear thickened on imaging, which may lead to the erroneous diagnosis of acute cholecystitis,” the experts noted. Hence, the diagnosis “should be made only in the appropriate clinical setting, usually in the presence of biliary pain.”
Hepatic decompensation after surgery can be severe enough to merit liver transplantation. There is no agreed-on MELD score that mandates liver transplant evaluation before elective surgery, but the experts recommend doing so if the MELD score is 15 or greater or if risk of mortality within 3 months after surgery exceeds 15%.
Postoperative management of patients with cirrhosis should include aggressive measures to prevent portal hypertension. Monitor renal function closely and avoid volume depletion or overload, the experts advised. Patients should receive only short-acting benzodiazepines and lower opiate doses, administered less often, than in the general population. Avoiding constipation is vital to minimize hepatic encephalopathy, which makes oral rifaximin a better choice than lactulose. Patients should not receive NSAIDs, which can impair renal blood flow. To prevent liver toxicity, they should not be discharged on opiate/acetaminophen combinations, which they might unknowingly take along with another drug that contains acetaminophen.
The experts disclosed no external funding sources and reported having no conflicts of interest.
SOURCE: Northup PG et al. Clin Gastroenterol Hepatol. 2018 Sep 28. doi: 10.1016/j.cgh.2018.09.043.
FROM CLINICAL GASTROENTEROLOGY AND HEPATOLOGY
Ultrasound method predicts liver complications in pediatric transplant
HOUSTON – An ultrasound method for assessing liver stiffness might be useful for predicting which pediatric patients will develop a life-threatening complication of hematopoietic stem cell transplantation.
Shear wave elastography values predicted severe hepatic sinusoidal obstruction syndrome/veno-occlusive disease (SOS/VOD) at least 4 days before standard diagnostic criteria in most patients treated in a small, prospective, two-center study, Sherwin S. Chan, MD, PhD, said at the Transplantation & Cellular Therapy Meetings.
Early identification of SOS/VOD using elastography could be beneficial in light of data showing that timing is critical in the administration of defibrotide, a treatment recommended for severe and very severe patients, according to Dr. Chan, vice chair of radiology for the University of Missouri at Kansas City.
“If you’re able to initiate it early, you can really increase day 100 survival,” Dr. Chan said in an oral presentation.
The data presented included 54 pediatric patients undergoing transplantation at one of two institutions.
At one site, the patients underwent shear wave elastography evaluation 10 days before the conditioning regimen began, and again at 5 and 14 days after the transplant. At the other site, patients with suspected SOS/VOD were enrolled and underwent elastography every other day for up to 10 exams.
Those are very different imaging protocols, Dr. Chan acknowledged in his presentation, noting that the studies started independently and data were pooled as investigators at the two institutions became aware of one another’s work.
A total of 16 patients, or 30%, developed SOS/VOD, Dr. Chan reported. Of those 16 cases, 12 (75%) were severe or very severe by the recent European Society for Blood and Marrow Transplantation (EBMT) criteria.
Increased shear wave elastography velocity was the best predictor of severe SOS/VOD, according to Dr. Chan, with a cutoff value of 1.65 m/s being 92% sensitive and 67% specific for severe SOS/VOD.
That threshold was passed at least 4 days before severe grading or death in 9 out of the 12 severe cases, he added.
Accordingly, a prospective, multicenter trial has been initiated at a number of U.S. centers to investigate whether the findings of this study are generalizable to other patient populations, Dr. Chan said at the meeting held by the American Society of Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research. At this meeting, the American Society for Blood and Marrow Transplantation announced a new name for the society: American Society for Transplantation and Cellular Therapy.
That prospective, multicenter trial is supported by Jazz Pharmaceuticals, according to Dr. Chan, who reported consulting with Jazz Pharmaceuticals in his disclosure statement.
SOURCE: Chan SS et al. TCT 2019, Abstract 55.
HOUSTON – An ultrasound method for assessing liver stiffness might be useful for predicting which pediatric patients will develop a life-threatening complication of hematopoietic stem cell transplantation.
Shear wave elastography values predicted severe hepatic sinusoidal obstruction syndrome/veno-occlusive disease (SOS/VOD) at least 4 days before standard diagnostic criteria in most patients treated in a small, prospective, two-center study, Sherwin S. Chan, MD, PhD, said at the Transplantation & Cellular Therapy Meetings.
Early identification of SOS/VOD using elastography could be beneficial in light of data showing that timing is critical in the administration of defibrotide, a treatment recommended for severe and very severe patients, according to Dr. Chan, vice chair of radiology for the University of Missouri at Kansas City.
“If you’re able to initiate it early, you can really increase day 100 survival,” Dr. Chan said in an oral presentation.
The data presented included 54 pediatric patients undergoing transplantation at one of two institutions.
At one site, the patients underwent shear wave elastography evaluation 10 days before the conditioning regimen began, and again at 5 and 14 days after the transplant. At the other site, patients with suspected SOS/VOD were enrolled and underwent elastography every other day for up to 10 exams.
Those are very different imaging protocols, Dr. Chan acknowledged in his presentation, noting that the studies started independently and data were pooled as investigators at the two institutions became aware of one another’s work.
A total of 16 patients, or 30%, developed SOS/VOD, Dr. Chan reported. Of those 16 cases, 12 (75%) were severe or very severe by the recent European Society for Blood and Marrow Transplantation (EBMT) criteria.
Increased shear wave elastography velocity was the best predictor of severe SOS/VOD, according to Dr. Chan, with a cutoff value of 1.65 m/s being 92% sensitive and 67% specific for severe SOS/VOD.
That threshold was passed at least 4 days before severe grading or death in 9 out of the 12 severe cases, he added.
Accordingly, a prospective, multicenter trial has been initiated at a number of U.S. centers to investigate whether the findings of this study are generalizable to other patient populations, Dr. Chan said at the meeting held by the American Society of Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research. At this meeting, the American Society for Blood and Marrow Transplantation announced a new name for the society: American Society for Transplantation and Cellular Therapy.
That prospective, multicenter trial is supported by Jazz Pharmaceuticals, according to Dr. Chan, who reported consulting with Jazz Pharmaceuticals in his disclosure statement.
SOURCE: Chan SS et al. TCT 2019, Abstract 55.
HOUSTON – An ultrasound method for assessing liver stiffness might be useful for predicting which pediatric patients will develop a life-threatening complication of hematopoietic stem cell transplantation.
Shear wave elastography values predicted severe hepatic sinusoidal obstruction syndrome/veno-occlusive disease (SOS/VOD) at least 4 days before standard diagnostic criteria in most patients treated in a small, prospective, two-center study, Sherwin S. Chan, MD, PhD, said at the Transplantation & Cellular Therapy Meetings.
Early identification of SOS/VOD using elastography could be beneficial in light of data showing that timing is critical in the administration of defibrotide, a treatment recommended for severe and very severe patients, according to Dr. Chan, vice chair of radiology for the University of Missouri at Kansas City.
“If you’re able to initiate it early, you can really increase day 100 survival,” Dr. Chan said in an oral presentation.
The data presented included 54 pediatric patients undergoing transplantation at one of two institutions.
At one site, the patients underwent shear wave elastography evaluation 10 days before the conditioning regimen began, and again at 5 and 14 days after the transplant. At the other site, patients with suspected SOS/VOD were enrolled and underwent elastography every other day for up to 10 exams.
Those are very different imaging protocols, Dr. Chan acknowledged in his presentation, noting that the studies started independently and data were pooled as investigators at the two institutions became aware of one another’s work.
A total of 16 patients, or 30%, developed SOS/VOD, Dr. Chan reported. Of those 16 cases, 12 (75%) were severe or very severe by the recent European Society for Blood and Marrow Transplantation (EBMT) criteria.
Increased shear wave elastography velocity was the best predictor of severe SOS/VOD, according to Dr. Chan, with a cutoff value of 1.65 m/s being 92% sensitive and 67% specific for severe SOS/VOD.
That threshold was passed at least 4 days before severe grading or death in 9 out of the 12 severe cases, he added.
Accordingly, a prospective, multicenter trial has been initiated at a number of U.S. centers to investigate whether the findings of this study are generalizable to other patient populations, Dr. Chan said at the meeting held by the American Society of Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research. At this meeting, the American Society for Blood and Marrow Transplantation announced a new name for the society: American Society for Transplantation and Cellular Therapy.
That prospective, multicenter trial is supported by Jazz Pharmaceuticals, according to Dr. Chan, who reported consulting with Jazz Pharmaceuticals in his disclosure statement.
SOURCE: Chan SS et al. TCT 2019, Abstract 55.
REPORTING FROM TCT 2019