Liver Disease

Physicians should consider liver cancer screening for all patients with nonalcoholic fatty liver disease (NAFLD) and cirrhosis, according to a new clinical practice update from the American Gastroenterological Association.

Screening “should be offered for patients with cirrhosis of varying etiologies when the risk of hepatocellular carcinoma is approximately at least 1.5% per year, as has been noted with NAFLD cirrhosis,” wrote Rohit Loomba, MD, of the University of California, San Diego, and associates. Although patients with noncirrhotic NAFLD also can develop hepatocellular carcinoma, “[a]t this point, we believe that [the benefit of screening] is restricted to patients with compensated cirrhosis or those with decompensated cirrhosis listed for liver transplantation,” they wrote in Gastroenterology.

Liver cancer in NAFLD often goes undetected until it is advanced enough that patients are not candidates for curative therapy. Current guidelines provide limited recommendations on which patients with NAFLD to monitor for hepatocellular carcinoma, how best to do so, and how often. To fill this gap, Dr. Loomba and associates reviewed and cited 79 published papers and developed eight suggestions for clinical practice.

Patients with NAFLD and stage 0-2 fibrosis are at “extremely low” risk for hepatocellular carcinoma and should not be routinely screened, the practice update stated. Advanced fibrosis is a clear risk factor but can be challenging to detect in NAFLD – imaging is often insensitive, and screening biopsy tends to be infeasible. Hence, the experts suggest considering liver cancer screening if patients with NAFLD show evidence of advanced fibrosis or cirrhosis on at least two noninvasive tests of distinct modalities (that is, the two tests should not both be point-of-care, specialized blood tests or noninvasive imaging). To improve specificity, the recommended cut-point thresholds for cirrhosis are 16.1 kPa for vibration-controlled transient elastography and 5 kPa for magnetic resonance elastography.

Screening ultrasound accurately detects hepatocellular carcinoma in patients with cirrhosis who have a good acoustic window. However, ultrasound quality is operator dependent, and it can be difficult even for experienced users to detect mass lesions in overweight or obese patients. Thus, it is important always to document parenchymal heterogeneity, beam attenuation, and whether the entire liver was visualized. If ultrasound quality is inadequate, patients should be screened every 6 months with CT or MRI, with or without alpha-fetoprotein, according to the practice update.

The authors advised clinicians to counsel all patients with NAFLD and cirrhosis to avoid alcohol and tobacco. “Irrespective of NAFLD, the bulk of epidemiological data support alcohol drinking as a major risk for hepatocellular carcinoma,” they note. Likewise, pooled studies indicate that current smokers are at about 50%-85% greater risk of liver cancer than never smokers. The experts add that “[al]though specific data do not exist, we believe that e-cigarettes may turn out to be equally harmful and patients be counseled to abstain from those as well.”

They also recommended optimally managing dyslipidemia and diabetes among patients with NAFLD who are at risk for hepatocellular carcinoma. Statins are safe for patients with NAFLD and dyslipidemia and may lower hepatocellular carcinoma risk, although more research is needed, according to the experts. For now, they support “the notion that the benefits of statin therapy among patients with dyslipidemia and NAFLD significantly outweigh the risk and should be utilized routinely.” Type 2 diabetes mellitus clearly heightens the risk of hepatocellular carcinoma, which metformin appears to reduce among patients with NAFLD, cirrhosis, and type 2 diabetes. Glucagonlike peptide–1 receptor agonists and some thiazolidinediones also appear to attenuate liver steatosis, inflammation, degeneration, and fibrosis, but it remains unclear if these effects ultimately lower cancer risk.

It is unclear if obesity directly contributes to hepatocellular carcinoma among patients with NAFLD, but obesity is an “important risk factor” for NAFLD itself, and “weight-loss interventions are strongly recommended to improve NAFLD-related outcomes,” the experts wrote. Pending further studies on whether weight loss reduces liver cancer risk in patients with NAFLD, they called for lifestyle modifications, pharmacotherapy, or bariatric surgery or bariatric endoscopy procedures to optimally manage obesity in patients with NAFLD who are at risk for liver cancer.

The authors disclosed funding from the National Institute of Environmental Health Sciences, the National Center for Advancing Translational Sciences, the National Institute of Diabetes and Digestive and Kidney Diseases, the Cancer Prevention & Research Institute of Texas, and the Center for Gastrointestinal Development, Infection and Injury. Dr. Loomba disclosed ties to Intercept Pharmaceuticals, Bird Rock Bio, Celgene, Enanta Pharmaceuticals, and a number of other companies. Two coauthors disclosed ties to Allergan, AbbVie, Conatus Pharmaceuticals, Genfit, Gilead, and Intercept. The remaining coauthor reported having no conflicts of interest.

SOURCE: Loomba R et al. Gastroenterology. 2020 Jan 29. doi: 10.1053/j.gastro.2019.12.053.

Physicians should consider liver cancer screening for all patients with nonalcoholic fatty liver disease (NAFLD) and cirrhosis, according to a new clinical practice update from the American Gastroenterological Association.

Screening “should be offered for patients with cirrhosis of varying etiologies when the risk of hepatocellular carcinoma is approximately at least 1.5% per year, as has been noted with NAFLD cirrhosis,” wrote Rohit Loomba, MD, of the University of California, San Diego, and associates. Although patients with noncirrhotic NAFLD also can develop hepatocellular carcinoma, “[a]t this point, we believe that [the benefit of screening] is restricted to patients with compensated cirrhosis or those with decompensated cirrhosis listed for liver transplantation,” they wrote in Gastroenterology.

Liver cancer in NAFLD often goes undetected until it is advanced enough that patients are not candidates for curative therapy. Current guidelines provide limited recommendations on which patients with NAFLD to monitor for hepatocellular carcinoma, how best to do so, and how often. To fill this gap, Dr. Loomba and associates reviewed and cited 79 published papers and developed eight suggestions for clinical practice.

Patients with NAFLD and stage 0-2 fibrosis are at “extremely low” risk for hepatocellular carcinoma and should not be routinely screened, the practice update stated. Advanced fibrosis is a clear risk factor but can be challenging to detect in NAFLD – imaging is often insensitive, and screening biopsy tends to be infeasible. Hence, the experts suggest considering liver cancer screening if patients with NAFLD show evidence of advanced fibrosis or cirrhosis on at least two noninvasive tests of distinct modalities (that is, the two tests should not both be point-of-care, specialized blood tests or noninvasive imaging). To improve specificity, the recommended cut-point thresholds for cirrhosis are 16.1 kPa for vibration-controlled transient elastography and 5 kPa for magnetic resonance elastography.

Screening ultrasound accurately detects hepatocellular carcinoma in patients with cirrhosis who have a good acoustic window. However, ultrasound quality is operator dependent, and it can be difficult even for experienced users to detect mass lesions in overweight or obese patients. Thus, it is important always to document parenchymal heterogeneity, beam attenuation, and whether the entire liver was visualized. If ultrasound quality is inadequate, patients should be screened every 6 months with CT or MRI, with or without alpha-fetoprotein, according to the practice update.

The authors advised clinicians to counsel all patients with NAFLD and cirrhosis to avoid alcohol and tobacco. “Irrespective of NAFLD, the bulk of epidemiological data support alcohol drinking as a major risk for hepatocellular carcinoma,” they note. Likewise, pooled studies indicate that current smokers are at about 50%-85% greater risk of liver cancer than never smokers. The experts add that “[al]though specific data do not exist, we believe that e-cigarettes may turn out to be equally harmful and patients be counseled to abstain from those as well.”

They also recommended optimally managing dyslipidemia and diabetes among patients with NAFLD who are at risk for hepatocellular carcinoma. Statins are safe for patients with NAFLD and dyslipidemia and may lower hepatocellular carcinoma risk, although more research is needed, according to the experts. For now, they support “the notion that the benefits of statin therapy among patients with dyslipidemia and NAFLD significantly outweigh the risk and should be utilized routinely.” Type 2 diabetes mellitus clearly heightens the risk of hepatocellular carcinoma, which metformin appears to reduce among patients with NAFLD, cirrhosis, and type 2 diabetes. Glucagonlike peptide–1 receptor agonists and some thiazolidinediones also appear to attenuate liver steatosis, inflammation, degeneration, and fibrosis, but it remains unclear if these effects ultimately lower cancer risk.

It is unclear if obesity directly contributes to hepatocellular carcinoma among patients with NAFLD, but obesity is an “important risk factor” for NAFLD itself, and “weight-loss interventions are strongly recommended to improve NAFLD-related outcomes,” the experts wrote. Pending further studies on whether weight loss reduces liver cancer risk in patients with NAFLD, they called for lifestyle modifications, pharmacotherapy, or bariatric surgery or bariatric endoscopy procedures to optimally manage obesity in patients with NAFLD who are at risk for liver cancer.

The authors disclosed funding from the National Institute of Environmental Health Sciences, the National Center for Advancing Translational Sciences, the National Institute of Diabetes and Digestive and Kidney Diseases, the Cancer Prevention & Research Institute of Texas, and the Center for Gastrointestinal Development, Infection and Injury. Dr. Loomba disclosed ties to Intercept Pharmaceuticals, Bird Rock Bio, Celgene, Enanta Pharmaceuticals, and a number of other companies. Two coauthors disclosed ties to Allergan, AbbVie, Conatus Pharmaceuticals, Genfit, Gilead, and Intercept. The remaining coauthor reported having no conflicts of interest.

SOURCE: Loomba R et al. Gastroenterology. 2020 Jan 29. doi: 10.1053/j.gastro.2019.12.053.

Physicians should consider liver cancer screening for all patients with nonalcoholic fatty liver disease (NAFLD) and cirrhosis, according to a new clinical practice update from the American Gastroenterological Association.

Screening “should be offered for patients with cirrhosis of varying etiologies when the risk of hepatocellular carcinoma is approximately at least 1.5% per year, as has been noted with NAFLD cirrhosis,” wrote Rohit Loomba, MD, of the University of California, San Diego, and associates. Although patients with noncirrhotic NAFLD also can develop hepatocellular carcinoma, “[a]t this point, we believe that [the benefit of screening] is restricted to patients with compensated cirrhosis or those with decompensated cirrhosis listed for liver transplantation,” they wrote in Gastroenterology.

Liver cancer in NAFLD often goes undetected until it is advanced enough that patients are not candidates for curative therapy. Current guidelines provide limited recommendations on which patients with NAFLD to monitor for hepatocellular carcinoma, how best to do so, and how often. To fill this gap, Dr. Loomba and associates reviewed and cited 79 published papers and developed eight suggestions for clinical practice.

Patients with NAFLD and stage 0-2 fibrosis are at “extremely low” risk for hepatocellular carcinoma and should not be routinely screened, the practice update stated. Advanced fibrosis is a clear risk factor but can be challenging to detect in NAFLD – imaging is often insensitive, and screening biopsy tends to be infeasible. Hence, the experts suggest considering liver cancer screening if patients with NAFLD show evidence of advanced fibrosis or cirrhosis on at least two noninvasive tests of distinct modalities (that is, the two tests should not both be point-of-care, specialized blood tests or noninvasive imaging). To improve specificity, the recommended cut-point thresholds for cirrhosis are 16.1 kPa for vibration-controlled transient elastography and 5 kPa for magnetic resonance elastography.

Screening ultrasound accurately detects hepatocellular carcinoma in patients with cirrhosis who have a good acoustic window. However, ultrasound quality is operator dependent, and it can be difficult even for experienced users to detect mass lesions in overweight or obese patients. Thus, it is important always to document parenchymal heterogeneity, beam attenuation, and whether the entire liver was visualized. If ultrasound quality is inadequate, patients should be screened every 6 months with CT or MRI, with or without alpha-fetoprotein, according to the practice update.

The authors advised clinicians to counsel all patients with NAFLD and cirrhosis to avoid alcohol and tobacco. “Irrespective of NAFLD, the bulk of epidemiological data support alcohol drinking as a major risk for hepatocellular carcinoma,” they note. Likewise, pooled studies indicate that current smokers are at about 50%-85% greater risk of liver cancer than never smokers. The experts add that “[al]though specific data do not exist, we believe that e-cigarettes may turn out to be equally harmful and patients be counseled to abstain from those as well.”

They also recommended optimally managing dyslipidemia and diabetes among patients with NAFLD who are at risk for hepatocellular carcinoma. Statins are safe for patients with NAFLD and dyslipidemia and may lower hepatocellular carcinoma risk, although more research is needed, according to the experts. For now, they support “the notion that the benefits of statin therapy among patients with dyslipidemia and NAFLD significantly outweigh the risk and should be utilized routinely.” Type 2 diabetes mellitus clearly heightens the risk of hepatocellular carcinoma, which metformin appears to reduce among patients with NAFLD, cirrhosis, and type 2 diabetes. Glucagonlike peptide–1 receptor agonists and some thiazolidinediones also appear to attenuate liver steatosis, inflammation, degeneration, and fibrosis, but it remains unclear if these effects ultimately lower cancer risk.

It is unclear if obesity directly contributes to hepatocellular carcinoma among patients with NAFLD, but obesity is an “important risk factor” for NAFLD itself, and “weight-loss interventions are strongly recommended to improve NAFLD-related outcomes,” the experts wrote. Pending further studies on whether weight loss reduces liver cancer risk in patients with NAFLD, they called for lifestyle modifications, pharmacotherapy, or bariatric surgery or bariatric endoscopy procedures to optimally manage obesity in patients with NAFLD who are at risk for liver cancer.

The authors disclosed funding from the National Institute of Environmental Health Sciences, the National Center for Advancing Translational Sciences, the National Institute of Diabetes and Digestive and Kidney Diseases, the Cancer Prevention & Research Institute of Texas, and the Center for Gastrointestinal Development, Infection and Injury. Dr. Loomba disclosed ties to Intercept Pharmaceuticals, Bird Rock Bio, Celgene, Enanta Pharmaceuticals, and a number of other companies. Two coauthors disclosed ties to Allergan, AbbVie, Conatus Pharmaceuticals, Genfit, Gilead, and Intercept. The remaining coauthor reported having no conflicts of interest.

SOURCE: Loomba R et al. Gastroenterology. 2020 Jan 29. doi: 10.1053/j.gastro.2019.12.053.

In the latest issue of the Morbidity and Mortality Weekly Report, the Centers for Disease Control and Prevention recommended hepatitis C virus screening for all adults and all pregnant women – during each of their pregnancies – in areas where prevalence of the infection is 0.1% or greater.

That’s essentially the entire United States; there’s no state with a statewide adult prevalence below 0.1%, and “few settings are known to exist” otherwise, the CDC noted (MMWR Recomm Rep. 2020 Apr 10;69(2):1-17).

The agency encouraged providers to consult state or local health departments or the CDC directly to determine local HCV prevalence. “As a general guide ... approximately 59% of anti-HCV positive persons are HCV RNA positive,” indicating active infection, the agency noted.

The advice was an expansion from the CDC’s last universal screening recommendation in 2012, which was limited to people born from 1945 to 1965; the incidence of acute infections has climbed since then and is highest now among younger people, so the guideline needed to be revisited, explained authors led by Sarah Schillie, MD, of the CDC’s Division of Viral Hepatitis, Atlanta.

The U.S. Preventive Services Task Force also recently recommended universal adult screening after previously limiting it to baby boomers.

As for pregnancy, the CDC’s past advice was to screen pregnant women with known risk factors, but that needed to be revisited as well. For one thing, the American Association for the Study of Liver Diseases and the Infectious Diseases Society of America have since recommended testing all pregnant women.

But also, the CDC said, it’s an opportune time for screening because “many women only have access to health care during pregnancy and the immediate postpartum period,” when treatment, if needed, can be started. Plus, HCV status is important for management decisions, such as using amniocentesis in positive women instead of chorionic villus sampling.

The rest of CDC’s 2012 recommendations stand, including screening all people with risk factors and repeating screening while they persist. Also, “any person who requests hepatitis C testing should receive it, regardless of disclosure of risk,” because people might be reluctant to report things like IV drug use, the authors said.

Screening in the guidelines means an HCV antibody test, followed by a nucleic acid test to check for active infection. The CDC encouraged automatic reflex testing, meaning immediately checking antibody positive samples for HCV RNA. RNA in the blood indicates active, replicating virus.

The new recommendations penciled out in modeling, with an incremental cost-effectiveness ratio (ICER) for universal adult screening of approximately $36,000 per quality-adjusted life year (QALY) gained, and an ICER of approximately $15,000 per QALY gained for pregnancy screening, where HCV prevalence is 0.1%; the 0.1% cost/benefit cutpoint was one of the reasons it was chosen as the prevalence threshold. An ICER under $50,000 is the conservative benchmark for cost-effectiveness, the authors noted.

There was no external funding, and the authors had no disclosures.

[email protected]

SOURCE: Schillie S et al. MMWR Recomm Rep. 2020 Apr 10;69[2]:1-17).

In the latest issue of the Morbidity and Mortality Weekly Report, the Centers for Disease Control and Prevention recommended hepatitis C virus screening for all adults and all pregnant women – during each of their pregnancies – in areas where prevalence of the infection is 0.1% or greater.

That’s essentially the entire United States; there’s no state with a statewide adult prevalence below 0.1%, and “few settings are known to exist” otherwise, the CDC noted (MMWR Recomm Rep. 2020 Apr 10;69(2):1-17).

The agency encouraged providers to consult state or local health departments or the CDC directly to determine local HCV prevalence. “As a general guide ... approximately 59% of anti-HCV positive persons are HCV RNA positive,” indicating active infection, the agency noted.

The advice was an expansion from the CDC’s last universal screening recommendation in 2012, which was limited to people born from 1945 to 1965; the incidence of acute infections has climbed since then and is highest now among younger people, so the guideline needed to be revisited, explained authors led by Sarah Schillie, MD, of the CDC’s Division of Viral Hepatitis, Atlanta.

The U.S. Preventive Services Task Force also recently recommended universal adult screening after previously limiting it to baby boomers.

As for pregnancy, the CDC’s past advice was to screen pregnant women with known risk factors, but that needed to be revisited as well. For one thing, the American Association for the Study of Liver Diseases and the Infectious Diseases Society of America have since recommended testing all pregnant women.

But also, the CDC said, it’s an opportune time for screening because “many women only have access to health care during pregnancy and the immediate postpartum period,” when treatment, if needed, can be started. Plus, HCV status is important for management decisions, such as using amniocentesis in positive women instead of chorionic villus sampling.

The rest of CDC’s 2012 recommendations stand, including screening all people with risk factors and repeating screening while they persist. Also, “any person who requests hepatitis C testing should receive it, regardless of disclosure of risk,” because people might be reluctant to report things like IV drug use, the authors said.

Screening in the guidelines means an HCV antibody test, followed by a nucleic acid test to check for active infection. The CDC encouraged automatic reflex testing, meaning immediately checking antibody positive samples for HCV RNA. RNA in the blood indicates active, replicating virus.

The new recommendations penciled out in modeling, with an incremental cost-effectiveness ratio (ICER) for universal adult screening of approximately $36,000 per quality-adjusted life year (QALY) gained, and an ICER of approximately $15,000 per QALY gained for pregnancy screening, where HCV prevalence is 0.1%; the 0.1% cost/benefit cutpoint was one of the reasons it was chosen as the prevalence threshold. An ICER under $50,000 is the conservative benchmark for cost-effectiveness, the authors noted.

There was no external funding, and the authors had no disclosures.

[email protected]

SOURCE: Schillie S et al. MMWR Recomm Rep. 2020 Apr 10;69[2]:1-17).

In the latest issue of the Morbidity and Mortality Weekly Report, the Centers for Disease Control and Prevention recommended hepatitis C virus screening for all adults and all pregnant women – during each of their pregnancies – in areas where prevalence of the infection is 0.1% or greater.

That’s essentially the entire United States; there’s no state with a statewide adult prevalence below 0.1%, and “few settings are known to exist” otherwise, the CDC noted (MMWR Recomm Rep. 2020 Apr 10;69(2):1-17).

The agency encouraged providers to consult state or local health departments or the CDC directly to determine local HCV prevalence. “As a general guide ... approximately 59% of anti-HCV positive persons are HCV RNA positive,” indicating active infection, the agency noted.

The advice was an expansion from the CDC’s last universal screening recommendation in 2012, which was limited to people born from 1945 to 1965; the incidence of acute infections has climbed since then and is highest now among younger people, so the guideline needed to be revisited, explained authors led by Sarah Schillie, MD, of the CDC’s Division of Viral Hepatitis, Atlanta.

The U.S. Preventive Services Task Force also recently recommended universal adult screening after previously limiting it to baby boomers.

As for pregnancy, the CDC’s past advice was to screen pregnant women with known risk factors, but that needed to be revisited as well. For one thing, the American Association for the Study of Liver Diseases and the Infectious Diseases Society of America have since recommended testing all pregnant women.

But also, the CDC said, it’s an opportune time for screening because “many women only have access to health care during pregnancy and the immediate postpartum period,” when treatment, if needed, can be started. Plus, HCV status is important for management decisions, such as using amniocentesis in positive women instead of chorionic villus sampling.

The rest of CDC’s 2012 recommendations stand, including screening all people with risk factors and repeating screening while they persist. Also, “any person who requests hepatitis C testing should receive it, regardless of disclosure of risk,” because people might be reluctant to report things like IV drug use, the authors said.

Screening in the guidelines means an HCV antibody test, followed by a nucleic acid test to check for active infection. The CDC encouraged automatic reflex testing, meaning immediately checking antibody positive samples for HCV RNA. RNA in the blood indicates active, replicating virus.

The new recommendations penciled out in modeling, with an incremental cost-effectiveness ratio (ICER) for universal adult screening of approximately $36,000 per quality-adjusted life year (QALY) gained, and an ICER of approximately $15,000 per QALY gained for pregnancy screening, where HCV prevalence is 0.1%; the 0.1% cost/benefit cutpoint was one of the reasons it was chosen as the prevalence threshold. An ICER under $50,000 is the conservative benchmark for cost-effectiveness, the authors noted.

There was no external funding, and the authors had no disclosures.

[email protected]

SOURCE: Schillie S et al. MMWR Recomm Rep. 2020 Apr 10;69[2]:1-17).

Case

A 45-year-old male was admitted to the hospital with severe alcoholic hepatitis. After several days of supportive care and medical therapy, the patient continued to show clinical decline. The patient is now admitted to the intensive-care unit with a Maddrey’s Discriminant Function score of 45 and a Model for End-Stage Liver Disease score of 38. He has no other significant medical comorbidities. On rounds, the patient’s wife, who is at the bedside, asks the team whether her husband would be a candidate for liver transplantation.

Should this patient be offered liver transplantation? What medical and psychosocial factors should we consider? What ethical principles should we consider?

Medical considerations

With the advent of direct-acting antivirals (DAAs), there has been a decline in the number of liver transplants performed for hepatitis C virus–related cirrhosis.¹ Instead, alcohol-related liver disease (ALD) has become the most common indication for liver transplant in the United States.² The 6-month abstinence requirement was a widespread practice within the transplant community that would exclude any patients who were actively drinking from being considered for liver transplant. However, data are inconclusive whether the 6-month rule serves as a predictor of future drinking or poor outcomes after liver transplant.^3,4 Unfortunately, many patients with severe alcoholic hepatitis will not survive long enough to fulfill the 6-month requirement.⁵

In 2011, Mathurin and colleagues led the pivotal European trial demonstrating the effectiveness of liver transplant as a rescue option for highly selected patients with severe alcoholic hepatitis.⁵ The selection criteria included patients with severe alcoholic hepatitis unresponsive to medical therapy, first liver-decompensating event, presence of close supportive family members, absence of severe psychiatric disorders, and agreement by patients to adhere to lifelong total alcohol abstinence. The study showed that the 6-month survival rate of patients who received early liver transplant was 77%, compared with 25% among those who did not. The positive outcomes were subsequently replicated at several centers in the United States, and this led to a wider adoption of early liver transplant for severe alcoholic hepatitis.^6-8

Psychosocial considerations

At present, we do not have well-validated consensus selection criteria to identify patients with alcoholic hepatitis most suitable for liver transplant. Each transplant center employs its own set of selection criteria with slight variations from the original European trial which prompted a national expert consensus meeting in Dallas in 2019.⁹ The consortium published a set of guidelines for centers planning to or already performing alcoholic hepatitis transplants. The proposed criteria to determine liver transplant candidacy are the following: 1) patients presenting for the first time with decompensated liver disease who are nonresponders to medical therapy; 2) assessment by a multidisciplinary psychosocial team including a social worker and an additional specialist; 3) no repeated unsuccessful attempts at addiction rehabilitation; 4) lack of other substance use/dependence; 5) insight with a commitment to sobriety; 6) presence of close supportive family members. The goal was to select candidates with the least likelihood of relapse in the hope of preventing poor outcomes after liver transplant. A study by a Johns Hopkins group comparing patients with severe alcoholic hepatitis who underwent careful psychosocial evaluation versus alcoholic cirrhosis with at least 6 months abstinence found that the survival and alcohol relapse rates were similar between the two groups.⁷

Ethical considerations

Expanding liver transplant indications to include some patients with severe alcoholic hepatitis will uphold the principle of beneficence given clear evidence of a survival benefit. In addition, graft survival rates were comparable with those of patients who underwent liver transplant for other causes.¹⁰ However, in an era of persistent organ shortage, it is important to balance justice or fairness to the patient with utilitarian policies that optimize outcomes for all who are in need of liver transplantation.

Justice

Justice means fair and equal distribution of scarce health resources to patients without bias on account of sex, race, wealth, and the nature of a patient’s disease. Based on the principle of justice, a patient with alcoholic hepatitis should be afforded opportunities for liver transplant equal to patients with other etiologies of liver disease.

Opponents of adoption of liver transplant for alcoholic hepatitis often base their reluctance on the following: patients’ failure to gain control of their alcohol use disorder, fears of alcohol relapse, and ultimately perceptions that these patients may be less deserving, compared with patients with other etiologies of liver disease. But, is this fair to the patient?

Alcohol use disorder, in general, is stigmatized and is considered by some to be a self-inflicted condition. As a medical community, we do not withhold life-saving treatment from patients who had inflicted their own injuries. Nevertheless, the stigma against alcoholism is so entrenched in our society that some fear transplanting a patient who is actively drinking would negatively affect the public’s perception of the transplant community and thus diminish the organ donation rate and harm the common good. Interestingly, a public opinion survey actually showed that the majority of respondents were at least neutral about the idea of transplanting patients with alcoholic hepatitis.¹¹

Utility

Utility means achieving the greatest good for the greatest number of patients. The absolute scarcity of available organs imposes a need for a strict allocation decision. A liver that is used for a patient with severe alcoholic hepatitis is an organ not used for another patient suffering chronic liver disease. It is worth noting that about 20% of patients with severe alcoholic hepatitis might recover without a transplant.⁵ That means about one out of five liver transplants performed for alcoholic hepatitis may have been done in a patient who would have recovered without a transplant. Does this policy optimize the greatest good for everyone who is on the wait list?

Moss and Siegler argued that it was not the alcoholism that made patients with alcoholic liver disease less deserving of liver transplant, but rather their failure to seek treatment for alcoholism that made their claim for liver transplant weaker, compared with those who developed cirrhosis through no fault of their own.¹² This argument is problematic. For example, patients with nonalcoholic steatohepatitis (NASH) are often compared with patients with alcoholic liver disease when it comes to modifiable behaviors that affect their health, whether it is through weight loss or abstinence, respectively. Yet, there is very little argument for lower priority for NASH patients who failed to lose weight. Secondly, alcohol use disorder is a psychosocially complex disease that requires a multidisciplinary treatment approach. Substance abuse rehabilitation is not readily available to most patients and could single out vulnerable patients from lower socioeconomic classes who are at higher risk for developing alcohol use disorder. Imposing a strict abstinence period regardless of a patient’s medical need is punitive and does not treat the underlying disease. Instead of focusing on disease causality, we ought to advocate for medical treatment of the underlying disease.

Conclusions

Liver transplant effectively functions as a zero-sum game. Efforts to save individual patients with severe alcoholic hepatitis can result in trade-offs to other patients on the wait list. Balancing the ethical principles of utility and justice is challenging. A strict 6-month rule, while convenient, does not strike the balance. The decision to transplant a patient with alcoholic hepatitis should be made on a case-by-case basis. As stewards of donor organs, transplant centers have a duty to carefully evaluate a potential candidate based on medical needs and recipient outcome without the influence of bias. We feel that, when considering liver transplant in patients with severe alcoholic hepatitis, the principle of justice or fairness to the patient is the overriding ethical principle. Provided the patient meets medical and psychosocial criteria that available evidence suggests would result in long-term survival post transplantation, we would support listing for liver transplantation.

References

1. Goldberg D et al. Gastroenterology, 2017;152(5):1090-9.e1.

2. Cholankeril G, Ahmed A. Clin Gastroenterol Hepatol. 2018;16(8):1356-8.

3. Neuberger J et al. J Hepatol. 2002;36(1):130-7.

4. DiMartini A, et al. Clin Liver Dis. 2011;15(4):727-51.

5. Mathurin P et al. N Engl J Med, 2011;365(19):1790-800.

6. Im GY et al. Am J Transplant. 2016;16(3):841-9.

7. Lee BP et al. Ann Surg. 2017;265(1):20-9.

8. Lee BP et al. Gastroenterology. 2018. 155(2):422-30.e1.

9. Asrani SK et al. Liver Transpl. 2020;26(1):127-40.

10. Singal AK et al. Transplantation. 2013;95(5):755-60.

11. Stroh G et al. Am J Transplant. 2015;15(6):1598-604.

12. Moss AH, Siegler M. JAMA. 1991;265(10):1295-8.

Dr. Wang is a gastroenterology fellow in the division of gastroenterology, hepatology, and nutrition, department of internal medicine, University of Chicago Medicine; Dr. Aronsohn is associate professor in the division of gastroenterology, hepatology, and nutrition, department of internal medicine, University of Chicago Medicine.

Case

A 45-year-old male was admitted to the hospital with severe alcoholic hepatitis. After several days of supportive care and medical therapy, the patient continued to show clinical decline. The patient is now admitted to the intensive-care unit with a Maddrey’s Discriminant Function score of 45 and a Model for End-Stage Liver Disease score of 38. He has no other significant medical comorbidities. On rounds, the patient’s wife, who is at the bedside, asks the team whether her husband would be a candidate for liver transplantation.

Should this patient be offered liver transplantation? What medical and psychosocial factors should we consider? What ethical principles should we consider?

Medical considerations

With the advent of direct-acting antivirals (DAAs), there has been a decline in the number of liver transplants performed for hepatitis C virus–related cirrhosis.¹ Instead, alcohol-related liver disease (ALD) has become the most common indication for liver transplant in the United States.² The 6-month abstinence requirement was a widespread practice within the transplant community that would exclude any patients who were actively drinking from being considered for liver transplant. However, data are inconclusive whether the 6-month rule serves as a predictor of future drinking or poor outcomes after liver transplant.^3,4 Unfortunately, many patients with severe alcoholic hepatitis will not survive long enough to fulfill the 6-month requirement.⁵

In 2011, Mathurin and colleagues led the pivotal European trial demonstrating the effectiveness of liver transplant as a rescue option for highly selected patients with severe alcoholic hepatitis.⁵ The selection criteria included patients with severe alcoholic hepatitis unresponsive to medical therapy, first liver-decompensating event, presence of close supportive family members, absence of severe psychiatric disorders, and agreement by patients to adhere to lifelong total alcohol abstinence. The study showed that the 6-month survival rate of patients who received early liver transplant was 77%, compared with 25% among those who did not. The positive outcomes were subsequently replicated at several centers in the United States, and this led to a wider adoption of early liver transplant for severe alcoholic hepatitis.^6-8

Psychosocial considerations

At present, we do not have well-validated consensus selection criteria to identify patients with alcoholic hepatitis most suitable for liver transplant. Each transplant center employs its own set of selection criteria with slight variations from the original European trial which prompted a national expert consensus meeting in Dallas in 2019.⁹ The consortium published a set of guidelines for centers planning to or already performing alcoholic hepatitis transplants. The proposed criteria to determine liver transplant candidacy are the following: 1) patients presenting for the first time with decompensated liver disease who are nonresponders to medical therapy; 2) assessment by a multidisciplinary psychosocial team including a social worker and an additional specialist; 3) no repeated unsuccessful attempts at addiction rehabilitation; 4) lack of other substance use/dependence; 5) insight with a commitment to sobriety; 6) presence of close supportive family members. The goal was to select candidates with the least likelihood of relapse in the hope of preventing poor outcomes after liver transplant. A study by a Johns Hopkins group comparing patients with severe alcoholic hepatitis who underwent careful psychosocial evaluation versus alcoholic cirrhosis with at least 6 months abstinence found that the survival and alcohol relapse rates were similar between the two groups.⁷

Ethical considerations

Expanding liver transplant indications to include some patients with severe alcoholic hepatitis will uphold the principle of beneficence given clear evidence of a survival benefit. In addition, graft survival rates were comparable with those of patients who underwent liver transplant for other causes.¹⁰ However, in an era of persistent organ shortage, it is important to balance justice or fairness to the patient with utilitarian policies that optimize outcomes for all who are in need of liver transplantation.

Justice

Justice means fair and equal distribution of scarce health resources to patients without bias on account of sex, race, wealth, and the nature of a patient’s disease. Based on the principle of justice, a patient with alcoholic hepatitis should be afforded opportunities for liver transplant equal to patients with other etiologies of liver disease.

Opponents of adoption of liver transplant for alcoholic hepatitis often base their reluctance on the following: patients’ failure to gain control of their alcohol use disorder, fears of alcohol relapse, and ultimately perceptions that these patients may be less deserving, compared with patients with other etiologies of liver disease. But, is this fair to the patient?

Alcohol use disorder, in general, is stigmatized and is considered by some to be a self-inflicted condition. As a medical community, we do not withhold life-saving treatment from patients who had inflicted their own injuries. Nevertheless, the stigma against alcoholism is so entrenched in our society that some fear transplanting a patient who is actively drinking would negatively affect the public’s perception of the transplant community and thus diminish the organ donation rate and harm the common good. Interestingly, a public opinion survey actually showed that the majority of respondents were at least neutral about the idea of transplanting patients with alcoholic hepatitis.¹¹

Utility

Utility means achieving the greatest good for the greatest number of patients. The absolute scarcity of available organs imposes a need for a strict allocation decision. A liver that is used for a patient with severe alcoholic hepatitis is an organ not used for another patient suffering chronic liver disease. It is worth noting that about 20% of patients with severe alcoholic hepatitis might recover without a transplant.⁵ That means about one out of five liver transplants performed for alcoholic hepatitis may have been done in a patient who would have recovered without a transplant. Does this policy optimize the greatest good for everyone who is on the wait list?

Moss and Siegler argued that it was not the alcoholism that made patients with alcoholic liver disease less deserving of liver transplant, but rather their failure to seek treatment for alcoholism that made their claim for liver transplant weaker, compared with those who developed cirrhosis through no fault of their own.¹² This argument is problematic. For example, patients with nonalcoholic steatohepatitis (NASH) are often compared with patients with alcoholic liver disease when it comes to modifiable behaviors that affect their health, whether it is through weight loss or abstinence, respectively. Yet, there is very little argument for lower priority for NASH patients who failed to lose weight. Secondly, alcohol use disorder is a psychosocially complex disease that requires a multidisciplinary treatment approach. Substance abuse rehabilitation is not readily available to most patients and could single out vulnerable patients from lower socioeconomic classes who are at higher risk for developing alcohol use disorder. Imposing a strict abstinence period regardless of a patient’s medical need is punitive and does not treat the underlying disease. Instead of focusing on disease causality, we ought to advocate for medical treatment of the underlying disease.

Conclusions

Liver transplant effectively functions as a zero-sum game. Efforts to save individual patients with severe alcoholic hepatitis can result in trade-offs to other patients on the wait list. Balancing the ethical principles of utility and justice is challenging. A strict 6-month rule, while convenient, does not strike the balance. The decision to transplant a patient with alcoholic hepatitis should be made on a case-by-case basis. As stewards of donor organs, transplant centers have a duty to carefully evaluate a potential candidate based on medical needs and recipient outcome without the influence of bias. We feel that, when considering liver transplant in patients with severe alcoholic hepatitis, the principle of justice or fairness to the patient is the overriding ethical principle. Provided the patient meets medical and psychosocial criteria that available evidence suggests would result in long-term survival post transplantation, we would support listing for liver transplantation.

References

1. Goldberg D et al. Gastroenterology, 2017;152(5):1090-9.e1.

2. Cholankeril G, Ahmed A. Clin Gastroenterol Hepatol. 2018;16(8):1356-8.

3. Neuberger J et al. J Hepatol. 2002;36(1):130-7.

4. DiMartini A, et al. Clin Liver Dis. 2011;15(4):727-51.

5. Mathurin P et al. N Engl J Med, 2011;365(19):1790-800.

6. Im GY et al. Am J Transplant. 2016;16(3):841-9.

7. Lee BP et al. Ann Surg. 2017;265(1):20-9.

8. Lee BP et al. Gastroenterology. 2018. 155(2):422-30.e1.

9. Asrani SK et al. Liver Transpl. 2020;26(1):127-40.

10. Singal AK et al. Transplantation. 2013;95(5):755-60.

11. Stroh G et al. Am J Transplant. 2015;15(6):1598-604.

12. Moss AH, Siegler M. JAMA. 1991;265(10):1295-8.

Dr. Wang is a gastroenterology fellow in the division of gastroenterology, hepatology, and nutrition, department of internal medicine, University of Chicago Medicine; Dr. Aronsohn is associate professor in the division of gastroenterology, hepatology, and nutrition, department of internal medicine, University of Chicago Medicine.

Case

A 45-year-old male was admitted to the hospital with severe alcoholic hepatitis. After several days of supportive care and medical therapy, the patient continued to show clinical decline. The patient is now admitted to the intensive-care unit with a Maddrey’s Discriminant Function score of 45 and a Model for End-Stage Liver Disease score of 38. He has no other significant medical comorbidities. On rounds, the patient’s wife, who is at the bedside, asks the team whether her husband would be a candidate for liver transplantation.

Should this patient be offered liver transplantation? What medical and psychosocial factors should we consider? What ethical principles should we consider?

Medical considerations

With the advent of direct-acting antivirals (DAAs), there has been a decline in the number of liver transplants performed for hepatitis C virus–related cirrhosis.¹ Instead, alcohol-related liver disease (ALD) has become the most common indication for liver transplant in the United States.² The 6-month abstinence requirement was a widespread practice within the transplant community that would exclude any patients who were actively drinking from being considered for liver transplant. However, data are inconclusive whether the 6-month rule serves as a predictor of future drinking or poor outcomes after liver transplant.^3,4 Unfortunately, many patients with severe alcoholic hepatitis will not survive long enough to fulfill the 6-month requirement.⁵

In 2011, Mathurin and colleagues led the pivotal European trial demonstrating the effectiveness of liver transplant as a rescue option for highly selected patients with severe alcoholic hepatitis.⁵ The selection criteria included patients with severe alcoholic hepatitis unresponsive to medical therapy, first liver-decompensating event, presence of close supportive family members, absence of severe psychiatric disorders, and agreement by patients to adhere to lifelong total alcohol abstinence. The study showed that the 6-month survival rate of patients who received early liver transplant was 77%, compared with 25% among those who did not. The positive outcomes were subsequently replicated at several centers in the United States, and this led to a wider adoption of early liver transplant for severe alcoholic hepatitis.^6-8

Psychosocial considerations

At present, we do not have well-validated consensus selection criteria to identify patients with alcoholic hepatitis most suitable for liver transplant. Each transplant center employs its own set of selection criteria with slight variations from the original European trial which prompted a national expert consensus meeting in Dallas in 2019.⁹ The consortium published a set of guidelines for centers planning to or already performing alcoholic hepatitis transplants. The proposed criteria to determine liver transplant candidacy are the following: 1) patients presenting for the first time with decompensated liver disease who are nonresponders to medical therapy; 2) assessment by a multidisciplinary psychosocial team including a social worker and an additional specialist; 3) no repeated unsuccessful attempts at addiction rehabilitation; 4) lack of other substance use/dependence; 5) insight with a commitment to sobriety; 6) presence of close supportive family members. The goal was to select candidates with the least likelihood of relapse in the hope of preventing poor outcomes after liver transplant. A study by a Johns Hopkins group comparing patients with severe alcoholic hepatitis who underwent careful psychosocial evaluation versus alcoholic cirrhosis with at least 6 months abstinence found that the survival and alcohol relapse rates were similar between the two groups.⁷

Ethical considerations

Expanding liver transplant indications to include some patients with severe alcoholic hepatitis will uphold the principle of beneficence given clear evidence of a survival benefit. In addition, graft survival rates were comparable with those of patients who underwent liver transplant for other causes.¹⁰ However, in an era of persistent organ shortage, it is important to balance justice or fairness to the patient with utilitarian policies that optimize outcomes for all who are in need of liver transplantation.

Justice

Justice means fair and equal distribution of scarce health resources to patients without bias on account of sex, race, wealth, and the nature of a patient’s disease. Based on the principle of justice, a patient with alcoholic hepatitis should be afforded opportunities for liver transplant equal to patients with other etiologies of liver disease.

Opponents of adoption of liver transplant for alcoholic hepatitis often base their reluctance on the following: patients’ failure to gain control of their alcohol use disorder, fears of alcohol relapse, and ultimately perceptions that these patients may be less deserving, compared with patients with other etiologies of liver disease. But, is this fair to the patient?

Alcohol use disorder, in general, is stigmatized and is considered by some to be a self-inflicted condition. As a medical community, we do not withhold life-saving treatment from patients who had inflicted their own injuries. Nevertheless, the stigma against alcoholism is so entrenched in our society that some fear transplanting a patient who is actively drinking would negatively affect the public’s perception of the transplant community and thus diminish the organ donation rate and harm the common good. Interestingly, a public opinion survey actually showed that the majority of respondents were at least neutral about the idea of transplanting patients with alcoholic hepatitis.¹¹

Utility

Utility means achieving the greatest good for the greatest number of patients. The absolute scarcity of available organs imposes a need for a strict allocation decision. A liver that is used for a patient with severe alcoholic hepatitis is an organ not used for another patient suffering chronic liver disease. It is worth noting that about 20% of patients with severe alcoholic hepatitis might recover without a transplant.⁵ That means about one out of five liver transplants performed for alcoholic hepatitis may have been done in a patient who would have recovered without a transplant. Does this policy optimize the greatest good for everyone who is on the wait list?

Moss and Siegler argued that it was not the alcoholism that made patients with alcoholic liver disease less deserving of liver transplant, but rather their failure to seek treatment for alcoholism that made their claim for liver transplant weaker, compared with those who developed cirrhosis through no fault of their own.¹² This argument is problematic. For example, patients with nonalcoholic steatohepatitis (NASH) are often compared with patients with alcoholic liver disease when it comes to modifiable behaviors that affect their health, whether it is through weight loss or abstinence, respectively. Yet, there is very little argument for lower priority for NASH patients who failed to lose weight. Secondly, alcohol use disorder is a psychosocially complex disease that requires a multidisciplinary treatment approach. Substance abuse rehabilitation is not readily available to most patients and could single out vulnerable patients from lower socioeconomic classes who are at higher risk for developing alcohol use disorder. Imposing a strict abstinence period regardless of a patient’s medical need is punitive and does not treat the underlying disease. Instead of focusing on disease causality, we ought to advocate for medical treatment of the underlying disease.

Conclusions

Liver transplant effectively functions as a zero-sum game. Efforts to save individual patients with severe alcoholic hepatitis can result in trade-offs to other patients on the wait list. Balancing the ethical principles of utility and justice is challenging. A strict 6-month rule, while convenient, does not strike the balance. The decision to transplant a patient with alcoholic hepatitis should be made on a case-by-case basis. As stewards of donor organs, transplant centers have a duty to carefully evaluate a potential candidate based on medical needs and recipient outcome without the influence of bias. We feel that, when considering liver transplant in patients with severe alcoholic hepatitis, the principle of justice or fairness to the patient is the overriding ethical principle. Provided the patient meets medical and psychosocial criteria that available evidence suggests would result in long-term survival post transplantation, we would support listing for liver transplantation.

References

1. Goldberg D et al. Gastroenterology, 2017;152(5):1090-9.e1.

2. Cholankeril G, Ahmed A. Clin Gastroenterol Hepatol. 2018;16(8):1356-8.

3. Neuberger J et al. J Hepatol. 2002;36(1):130-7.

4. DiMartini A, et al. Clin Liver Dis. 2011;15(4):727-51.

5. Mathurin P et al. N Engl J Med, 2011;365(19):1790-800.

6. Im GY et al. Am J Transplant. 2016;16(3):841-9.

7. Lee BP et al. Ann Surg. 2017;265(1):20-9.

8. Lee BP et al. Gastroenterology. 2018. 155(2):422-30.e1.

9. Asrani SK et al. Liver Transpl. 2020;26(1):127-40.

10. Singal AK et al. Transplantation. 2013;95(5):755-60.

11. Stroh G et al. Am J Transplant. 2015;15(6):1598-604.

12. Moss AH, Siegler M. JAMA. 1991;265(10):1295-8.

Dr. Wang is a gastroenterology fellow in the division of gastroenterology, hepatology, and nutrition, department of internal medicine, University of Chicago Medicine; Dr. Aronsohn is associate professor in the division of gastroenterology, hepatology, and nutrition, department of internal medicine, University of Chicago Medicine.

A woman presented to the emergency department with high liver enzyme levels and dark urine. She developed fever on day 2 of care, and then tested positive for the new coronavirus, researchers at Northwell Health, in Hempstead, New York, report.

The authors say the case, published online in the American Journal of Gastroenterology, is the first documented instance of a patient with COVID-19 presenting with acute hepatitis as the primary symptom before developing respiratory symptoms.

Prior data show that the most common early indications of COVID-19 are respiratory symptoms with fever, shortness of breath, sore throat, and cough, and with imaging results consistent with pneumonia. However, liver enzyme abnormalities are not uncommon in the disease course.

“In patients who are now presenting with acute hepatitis, people need to think of COVID,” senior author David Bernstein, MD, chief of the Division of Hepatology at Northwell Health, told Medscape Medical News.

In addition to Bernstein, Praneet Wander, MD, also in Northwell’s hepatology division, and Marcia Epstein, MD, with Northwell’s Department of Infectious Disease, authored the case report.

Bernstein said Northwell currently has the largest number of COVID-19 cases in the nation and that many patients are presenting with abnormal liver test results and COVID-19 symptoms.

He said that anecdotally, colleagues elsewhere in the United States are also reporting the connection.

“It seems to be that the liver enzyme elevations are part and parcel of this disease,” he said.

Case Details

According to the case report, the 59-year-old woman, who lives alone, came to the emergency department with a chief complaint of dark urine. She was given a face mask and was isolated, per protocol.

“She denied cough, sore throat, shortness of breath, diarrhea, nausea, vomiting or abdominal pain,” the authors wrote. She denied having been in contact with someone who was sick.

She had well-controlled HIV, and recent outpatient liver test results were normal. Eighteen hours after she came to the ED, she was admitted, owing to concern regarding rising liver enzyme levels in conjunction with her being HIV positive.

On presentation, her temperature was 98.9° F. There were no skin indications, lungs were normal, and “there was no jaundice, right upper quadrant tenderness, hepatomegaly or splenomegaly.”

Liver enzyme levels were as follows: aspartate aminotransferase (AST), 1230 (IU/L); alanine aminotransferase (ALT), 697 IU/L (normal for both is < 50 IU/L); alkaline phosphatase, 141 IU/L (normal, < 125 IU/L).

The patient tested negative for hepatitis A, B, C, E, cytomegalovirus, and Epstein-Barr virus. A respiratory viral panel and autoimmune markers were normal.
 

Fever Appeared on Day 2

She was admitted, and 18 hours after she came to the ED, she developed a fever of 102.2° F. A chest x-ray showed interstitial opacities in both lungs.

Nasopharyngeal samples were taken, and polymerase chain reaction test results were positive for the novel coronavirus. The patient was placed on 3 L of oxygen.

On post admission day 4, a 5-day course of hydroxychloroquine (200 mg twice a day) was initiated.

The patient was discharged to home on hospital day 8. The serum bilirubin level was 0.6 mg/dL; AST, 114 IU/L; ALT, 227 IU/L; and alkaline phosphatase, 259 IU/L.

According to Bernstein, it’s hard to tell in what order COVID-19 symptoms occur because people are staying home with other complaints. They may only present to the emergency department after they develop more typical COVID-19 symptoms, such as shortness of breath.

In this case, the patient noticed a darkening of her urine, “but if she had come the next day, she would have had fever. I think we just happened to catch it early,” Bernstein said.

He added that he saw no connection between the underlying HIV and her liver abnormalities or COVID-19 diagnosis.

Bernstein notes that most COVID-19 patients are not admitted, and he said he worries that a COVID-19 test might not be on the radar of providers in the outpatient setting when a patient presents with elevated liver enzymes levels.

If elevated liver enzyme levels can predict disease course, the information could alter how and where the disease is treated, Bernstein said.

“This is a first report. We’re really right now in the beginning of learning,” he said.

This article first appeared on Medscape.com.

A woman presented to the emergency department with high liver enzyme levels and dark urine. She developed fever on day 2 of care, and then tested positive for the new coronavirus, researchers at Northwell Health, in Hempstead, New York, report.

The authors say the case, published online in the American Journal of Gastroenterology, is the first documented instance of a patient with COVID-19 presenting with acute hepatitis as the primary symptom before developing respiratory symptoms.

Prior data show that the most common early indications of COVID-19 are respiratory symptoms with fever, shortness of breath, sore throat, and cough, and with imaging results consistent with pneumonia. However, liver enzyme abnormalities are not uncommon in the disease course.

“In patients who are now presenting with acute hepatitis, people need to think of COVID,” senior author David Bernstein, MD, chief of the Division of Hepatology at Northwell Health, told Medscape Medical News.

In addition to Bernstein, Praneet Wander, MD, also in Northwell’s hepatology division, and Marcia Epstein, MD, with Northwell’s Department of Infectious Disease, authored the case report.

Bernstein said Northwell currently has the largest number of COVID-19 cases in the nation and that many patients are presenting with abnormal liver test results and COVID-19 symptoms.

He said that anecdotally, colleagues elsewhere in the United States are also reporting the connection.

“It seems to be that the liver enzyme elevations are part and parcel of this disease,” he said.

Case Details

According to the case report, the 59-year-old woman, who lives alone, came to the emergency department with a chief complaint of dark urine. She was given a face mask and was isolated, per protocol.

“She denied cough, sore throat, shortness of breath, diarrhea, nausea, vomiting or abdominal pain,” the authors wrote. She denied having been in contact with someone who was sick.

She had well-controlled HIV, and recent outpatient liver test results were normal. Eighteen hours after she came to the ED, she was admitted, owing to concern regarding rising liver enzyme levels in conjunction with her being HIV positive.

On presentation, her temperature was 98.9° F. There were no skin indications, lungs were normal, and “there was no jaundice, right upper quadrant tenderness, hepatomegaly or splenomegaly.”

Liver enzyme levels were as follows: aspartate aminotransferase (AST), 1230 (IU/L); alanine aminotransferase (ALT), 697 IU/L (normal for both is < 50 IU/L); alkaline phosphatase, 141 IU/L (normal, < 125 IU/L).

The patient tested negative for hepatitis A, B, C, E, cytomegalovirus, and Epstein-Barr virus. A respiratory viral panel and autoimmune markers were normal.
 

Fever Appeared on Day 2

She was admitted, and 18 hours after she came to the ED, she developed a fever of 102.2° F. A chest x-ray showed interstitial opacities in both lungs.

Nasopharyngeal samples were taken, and polymerase chain reaction test results were positive for the novel coronavirus. The patient was placed on 3 L of oxygen.

On post admission day 4, a 5-day course of hydroxychloroquine (200 mg twice a day) was initiated.

The patient was discharged to home on hospital day 8. The serum bilirubin level was 0.6 mg/dL; AST, 114 IU/L; ALT, 227 IU/L; and alkaline phosphatase, 259 IU/L.

According to Bernstein, it’s hard to tell in what order COVID-19 symptoms occur because people are staying home with other complaints. They may only present to the emergency department after they develop more typical COVID-19 symptoms, such as shortness of breath.

In this case, the patient noticed a darkening of her urine, “but if she had come the next day, she would have had fever. I think we just happened to catch it early,” Bernstein said.

He added that he saw no connection between the underlying HIV and her liver abnormalities or COVID-19 diagnosis.

Bernstein notes that most COVID-19 patients are not admitted, and he said he worries that a COVID-19 test might not be on the radar of providers in the outpatient setting when a patient presents with elevated liver enzymes levels.

If elevated liver enzyme levels can predict disease course, the information could alter how and where the disease is treated, Bernstein said.

“This is a first report. We’re really right now in the beginning of learning,” he said.

This article first appeared on Medscape.com.

A woman presented to the emergency department with high liver enzyme levels and dark urine. She developed fever on day 2 of care, and then tested positive for the new coronavirus, researchers at Northwell Health, in Hempstead, New York, report.

The authors say the case, published online in the American Journal of Gastroenterology, is the first documented instance of a patient with COVID-19 presenting with acute hepatitis as the primary symptom before developing respiratory symptoms.

Prior data show that the most common early indications of COVID-19 are respiratory symptoms with fever, shortness of breath, sore throat, and cough, and with imaging results consistent with pneumonia. However, liver enzyme abnormalities are not uncommon in the disease course.

“In patients who are now presenting with acute hepatitis, people need to think of COVID,” senior author David Bernstein, MD, chief of the Division of Hepatology at Northwell Health, told Medscape Medical News.

In addition to Bernstein, Praneet Wander, MD, also in Northwell’s hepatology division, and Marcia Epstein, MD, with Northwell’s Department of Infectious Disease, authored the case report.

Bernstein said Northwell currently has the largest number of COVID-19 cases in the nation and that many patients are presenting with abnormal liver test results and COVID-19 symptoms.

He said that anecdotally, colleagues elsewhere in the United States are also reporting the connection.

“It seems to be that the liver enzyme elevations are part and parcel of this disease,” he said.

Case Details

According to the case report, the 59-year-old woman, who lives alone, came to the emergency department with a chief complaint of dark urine. She was given a face mask and was isolated, per protocol.

“She denied cough, sore throat, shortness of breath, diarrhea, nausea, vomiting or abdominal pain,” the authors wrote. She denied having been in contact with someone who was sick.

She had well-controlled HIV, and recent outpatient liver test results were normal. Eighteen hours after she came to the ED, she was admitted, owing to concern regarding rising liver enzyme levels in conjunction with her being HIV positive.

On presentation, her temperature was 98.9° F. There were no skin indications, lungs were normal, and “there was no jaundice, right upper quadrant tenderness, hepatomegaly or splenomegaly.”

Liver enzyme levels were as follows: aspartate aminotransferase (AST), 1230 (IU/L); alanine aminotransferase (ALT), 697 IU/L (normal for both is < 50 IU/L); alkaline phosphatase, 141 IU/L (normal, < 125 IU/L).

The patient tested negative for hepatitis A, B, C, E, cytomegalovirus, and Epstein-Barr virus. A respiratory viral panel and autoimmune markers were normal.
 

Fever Appeared on Day 2

She was admitted, and 18 hours after she came to the ED, she developed a fever of 102.2° F. A chest x-ray showed interstitial opacities in both lungs.

Nasopharyngeal samples were taken, and polymerase chain reaction test results were positive for the novel coronavirus. The patient was placed on 3 L of oxygen.

On post admission day 4, a 5-day course of hydroxychloroquine (200 mg twice a day) was initiated.

The patient was discharged to home on hospital day 8. The serum bilirubin level was 0.6 mg/dL; AST, 114 IU/L; ALT, 227 IU/L; and alkaline phosphatase, 259 IU/L.

According to Bernstein, it’s hard to tell in what order COVID-19 symptoms occur because people are staying home with other complaints. They may only present to the emergency department after they develop more typical COVID-19 symptoms, such as shortness of breath.

In this case, the patient noticed a darkening of her urine, “but if she had come the next day, she would have had fever. I think we just happened to catch it early,” Bernstein said.

He added that he saw no connection between the underlying HIV and her liver abnormalities or COVID-19 diagnosis.

Bernstein notes that most COVID-19 patients are not admitted, and he said he worries that a COVID-19 test might not be on the radar of providers in the outpatient setting when a patient presents with elevated liver enzymes levels.

If elevated liver enzyme levels can predict disease course, the information could alter how and where the disease is treated, Bernstein said.

“This is a first report. We’re really right now in the beginning of learning,” he said.

This article first appeared on Medscape.com.

Synbiotics can alter gut microbiota in patients with nonalcoholic fatty liver disease (NAFLD), but associated liver benefits remain unseen, according to a recent phase II study.

NAFLD patients who received a year-long regimen of fructo-oligosaccharides and Bifidobacterium animalis had no significant changes in liver fat content or fibrosis, compared with those who received placebo, reported lead author Eleonora Scorletti, MD, of the University of Pennsylvania, Philadelphia, and colleagues.

“There is recent growing interest in the role of gut microbiota in NAFLD pathogenesis, and there are several metaorganismal pathways linking altered gut microbiota ... and NAFLD,” the investigators wrote in Gastroenterology.According to the investigators, previous studies have shown that patients with NAFLD may have some characteristic alterations to their microbiota, such as increased Gram-negative bacteria or more abundant Ruminococcus species, the latter of which were associated with worse fibrosis.

“However, there is currently a lack of consistency in these findings due to the marked variance in the population studied, with differing ages, diets, and geographic locations,” the investigators wrote. “Nonetheless, despite these inconsistencies, there is the possibility that manipulation of the gut microbiota to a more favorable profile could provide a beneficial effect on liver disease in patients with NAFLD.”

To evaluate this possibility, the investigators enrolled 104 patients with NAFLD in the United Kingdom. Patients were randomly divided into a placebo (n = 49) and synbiotic group (n = 55), with the latter receiving 4 grams of fructo-oligosaccharides twice per day plus 10 billion colony-forming units of Bifidobacterium animalis subspecies lactis BB-12 on a daily basis. Treatments were given for 10-14 months.

Diagnostics were conducted across all participants at the beginning and end of the study. These included fecal microbiota analysis by 16s ribosomal DNA sequencing, liver fat measurement by proton magnetic resonance spectroscopy, biomarker-based liver fibrosis scoring, and liver stiffness assessment by vibration-controlled transient elastography.

At the end of the study, patients in the synbiotic group had increased abundance of Bifidobacterium and Faecalibacterium species and reduced proportions of Oscillibacter and Alistipes species, compared with baseline. These changes were not observed in the placebo group.

But changes in microbiota had no apparent impact on liver pathology. Although mean liver fat percentages dropped from 32.3% to 28.5% in the synbiotic group (approximately 4%), they also dropped in the placebo group, from 31.3% to 25.2% (approximately 6%), with differences between groups lacking statistical significance. Using multivariate analysis, the investigators linked these liver fat improvements, which occurred in 65% of participants, with weight loss.

“The fact that most patients had an improvement in ... liver fat, regardless of treatment allocation, is consistent with the so-called clinical trial effect, whereby participants benefit from participating in clinical trials,” the investigators wrote.

Similarly to liver fat content, no significant intergroup differences were found for liver fibrosis or stiffness, whereas, again, weight loss was linked with improvements in both disease parameters.

“Our randomized clinical trial suggests that changing the gut microbiota with this synbiotic may occur without clinically significant effects on the liver in NAFLD,” the investigators concluded.

Still, they noted that the failure of one synbiotic regimen does not discount the possibility of microbiota-based NAFLD interventions as a whole.

“Previous studies that have tested the effects of synbiotic treatment in NAFLD have also used a combination of multiple strains of probiotics as a component of the synbiotic treatment,” the investigators wrote. “Therefore, it might be possible that, because the intestine harbors trillions of bacteria, adding 1 single type of bacterium in a synbiotic may not be as effective as adding 3 or 6 different types of bacteria with the potential to influence many more bacterial species.”

The study was supported by the National Institute of Health Research, the Parnell Diabetes Trust, and Chr. Hansen Holding. One author reported funding from Chr. Hansen unrelated to this trial.

SOURCE: Scorletti E et al. Gastro. 2020 Jan 24. doi: 10.1053/j.gastro.2020.01.031.

Synbiotics can alter gut microbiota in patients with nonalcoholic fatty liver disease (NAFLD), but associated liver benefits remain unseen, according to a recent phase II study.

NAFLD patients who received a year-long regimen of fructo-oligosaccharides and Bifidobacterium animalis had no significant changes in liver fat content or fibrosis, compared with those who received placebo, reported lead author Eleonora Scorletti, MD, of the University of Pennsylvania, Philadelphia, and colleagues.

“There is recent growing interest in the role of gut microbiota in NAFLD pathogenesis, and there are several metaorganismal pathways linking altered gut microbiota ... and NAFLD,” the investigators wrote in Gastroenterology.According to the investigators, previous studies have shown that patients with NAFLD may have some characteristic alterations to their microbiota, such as increased Gram-negative bacteria or more abundant Ruminococcus species, the latter of which were associated with worse fibrosis.

“However, there is currently a lack of consistency in these findings due to the marked variance in the population studied, with differing ages, diets, and geographic locations,” the investigators wrote. “Nonetheless, despite these inconsistencies, there is the possibility that manipulation of the gut microbiota to a more favorable profile could provide a beneficial effect on liver disease in patients with NAFLD.”

To evaluate this possibility, the investigators enrolled 104 patients with NAFLD in the United Kingdom. Patients were randomly divided into a placebo (n = 49) and synbiotic group (n = 55), with the latter receiving 4 grams of fructo-oligosaccharides twice per day plus 10 billion colony-forming units of Bifidobacterium animalis subspecies lactis BB-12 on a daily basis. Treatments were given for 10-14 months.

Diagnostics were conducted across all participants at the beginning and end of the study. These included fecal microbiota analysis by 16s ribosomal DNA sequencing, liver fat measurement by proton magnetic resonance spectroscopy, biomarker-based liver fibrosis scoring, and liver stiffness assessment by vibration-controlled transient elastography.

At the end of the study, patients in the synbiotic group had increased abundance of Bifidobacterium and Faecalibacterium species and reduced proportions of Oscillibacter and Alistipes species, compared with baseline. These changes were not observed in the placebo group.

But changes in microbiota had no apparent impact on liver pathology. Although mean liver fat percentages dropped from 32.3% to 28.5% in the synbiotic group (approximately 4%), they also dropped in the placebo group, from 31.3% to 25.2% (approximately 6%), with differences between groups lacking statistical significance. Using multivariate analysis, the investigators linked these liver fat improvements, which occurred in 65% of participants, with weight loss.

“The fact that most patients had an improvement in ... liver fat, regardless of treatment allocation, is consistent with the so-called clinical trial effect, whereby participants benefit from participating in clinical trials,” the investigators wrote.

Similarly to liver fat content, no significant intergroup differences were found for liver fibrosis or stiffness, whereas, again, weight loss was linked with improvements in both disease parameters.

“Our randomized clinical trial suggests that changing the gut microbiota with this synbiotic may occur without clinically significant effects on the liver in NAFLD,” the investigators concluded.

Still, they noted that the failure of one synbiotic regimen does not discount the possibility of microbiota-based NAFLD interventions as a whole.

“Previous studies that have tested the effects of synbiotic treatment in NAFLD have also used a combination of multiple strains of probiotics as a component of the synbiotic treatment,” the investigators wrote. “Therefore, it might be possible that, because the intestine harbors trillions of bacteria, adding 1 single type of bacterium in a synbiotic may not be as effective as adding 3 or 6 different types of bacteria with the potential to influence many more bacterial species.”

The study was supported by the National Institute of Health Research, the Parnell Diabetes Trust, and Chr. Hansen Holding. One author reported funding from Chr. Hansen unrelated to this trial.

SOURCE: Scorletti E et al. Gastro. 2020 Jan 24. doi: 10.1053/j.gastro.2020.01.031.

Synbiotics can alter gut microbiota in patients with nonalcoholic fatty liver disease (NAFLD), but associated liver benefits remain unseen, according to a recent phase II study.

NAFLD patients who received a year-long regimen of fructo-oligosaccharides and Bifidobacterium animalis had no significant changes in liver fat content or fibrosis, compared with those who received placebo, reported lead author Eleonora Scorletti, MD, of the University of Pennsylvania, Philadelphia, and colleagues.

“There is recent growing interest in the role of gut microbiota in NAFLD pathogenesis, and there are several metaorganismal pathways linking altered gut microbiota ... and NAFLD,” the investigators wrote in Gastroenterology.According to the investigators, previous studies have shown that patients with NAFLD may have some characteristic alterations to their microbiota, such as increased Gram-negative bacteria or more abundant Ruminococcus species, the latter of which were associated with worse fibrosis.

“However, there is currently a lack of consistency in these findings due to the marked variance in the population studied, with differing ages, diets, and geographic locations,” the investigators wrote. “Nonetheless, despite these inconsistencies, there is the possibility that manipulation of the gut microbiota to a more favorable profile could provide a beneficial effect on liver disease in patients with NAFLD.”

To evaluate this possibility, the investigators enrolled 104 patients with NAFLD in the United Kingdom. Patients were randomly divided into a placebo (n = 49) and synbiotic group (n = 55), with the latter receiving 4 grams of fructo-oligosaccharides twice per day plus 10 billion colony-forming units of Bifidobacterium animalis subspecies lactis BB-12 on a daily basis. Treatments were given for 10-14 months.

Diagnostics were conducted across all participants at the beginning and end of the study. These included fecal microbiota analysis by 16s ribosomal DNA sequencing, liver fat measurement by proton magnetic resonance spectroscopy, biomarker-based liver fibrosis scoring, and liver stiffness assessment by vibration-controlled transient elastography.

At the end of the study, patients in the synbiotic group had increased abundance of Bifidobacterium and Faecalibacterium species and reduced proportions of Oscillibacter and Alistipes species, compared with baseline. These changes were not observed in the placebo group.

But changes in microbiota had no apparent impact on liver pathology. Although mean liver fat percentages dropped from 32.3% to 28.5% in the synbiotic group (approximately 4%), they also dropped in the placebo group, from 31.3% to 25.2% (approximately 6%), with differences between groups lacking statistical significance. Using multivariate analysis, the investigators linked these liver fat improvements, which occurred in 65% of participants, with weight loss.

“The fact that most patients had an improvement in ... liver fat, regardless of treatment allocation, is consistent with the so-called clinical trial effect, whereby participants benefit from participating in clinical trials,” the investigators wrote.

Similarly to liver fat content, no significant intergroup differences were found for liver fibrosis or stiffness, whereas, again, weight loss was linked with improvements in both disease parameters.

“Our randomized clinical trial suggests that changing the gut microbiota with this synbiotic may occur without clinically significant effects on the liver in NAFLD,” the investigators concluded.

Still, they noted that the failure of one synbiotic regimen does not discount the possibility of microbiota-based NAFLD interventions as a whole.

“Previous studies that have tested the effects of synbiotic treatment in NAFLD have also used a combination of multiple strains of probiotics as a component of the synbiotic treatment,” the investigators wrote. “Therefore, it might be possible that, because the intestine harbors trillions of bacteria, adding 1 single type of bacterium in a synbiotic may not be as effective as adding 3 or 6 different types of bacteria with the potential to influence many more bacterial species.”

The study was supported by the National Institute of Health Research, the Parnell Diabetes Trust, and Chr. Hansen Holding. One author reported funding from Chr. Hansen unrelated to this trial.

SOURCE: Scorletti E et al. Gastro. 2020 Jan 24. doi: 10.1053/j.gastro.2020.01.031.

Noninvasive fibrosis scores, which are widely used to predict advanced fibrosis in people with nonalcoholic fatty liver disease (NAFLD), do not do a good job of picking up advanced fibrosis in patients with underlying diabetes, according to a new study.

Advanced fibrosis is associated with an increased risk of cirrhosis, end-stage liver disease, and liver failure. Underlying diabetes is a risk factor for both advanced fibrosis and death in patients with NAFLD.

While liver biopsy remains the gold standard for detecting advanced fibrosis, high costs and risks limit its use. Noninvasive scores such as the AST/ALT ratio; AST to platelet ratio index (APRI); fibrosis-4 (FIB-4) index; and NAFLD fibrosis score (NFS) have gained popularity in recent years, as they offer the compelling advantage of using easily and cheaply attained clinical and laboratory measures to assess likelihood of disease.

But their accuracy has come into question, particularly for people with diabetes.

In research published in the Journal of Clinical Gastroenterology, Amandeep Singh, MD, and colleagues at the Cleveland Clinic looked at their center’s records for 1,157 patients with type 2 diabetes (65% women, 88% white, 85% with obesity) who had undergone a liver biopsy for suspected advanced fibrosis between 2000 and 2015. Biopsy results revealed that a third of the cohort (32%) was positive for advanced fibrosis.

The investigators then pulled patients’ laboratory results for AST, ALT, cholesterol, triglycerides, fasting glucose, hemoglobin A_1c, bilirubin, albumin, platelet count, alkaline phosphatase, albumin, and lipid levels, all collected within a year of biopsy. After plugging these into the algorithms of four different scoring systems for advanced fibrosis, they compared results with results from the biopsies.

The scores of AST/ALT greater than 1.4, APRI of at least 1.5, NFS greater than 0.676, and FIB-4 index greater than 2.67 had high specificities of 84%, 97%, 70%, and 93%, respectively, but sensitivities of only 27%, 17%, 64%, and 44%. Even when the cutoff measures were tightened, the scoring systems still missed a lot of disease. This suggests, Dr. Singh and colleagues wrote, that “the presence of diabetes could decrease the predictive value of these scores to detect advanced disease in NAFLD patients.” Reliable noninvasive biomarkers are “urgently needed” for this patient population.

In an interview, Dr. Singh advised that clinicians continue to use current noninvasive scores in patients with diabetes – preferably the NFS – “until we have a better scoring system.” If clinicians suspect advanced fibrosis based on lab tests and clinical data, then “liver biopsy should be considered,” he said.

The investigators described among the limitations of their study its retrospective, single-center design, with patients who were mostly white and from one geographic region.

Dr. Singh and colleagues reported no conflicts of interest or outside funding for their study.

[email protected]

SOURCE: Singh A et al. J Clin Gastroenterol. 2020 Mar 11. doi: 10.1097/MCG.0000000000001339.

Noninvasive fibrosis scores, which are widely used to predict advanced fibrosis in people with nonalcoholic fatty liver disease (NAFLD), do not do a good job of picking up advanced fibrosis in patients with underlying diabetes, according to a new study.

Advanced fibrosis is associated with an increased risk of cirrhosis, end-stage liver disease, and liver failure. Underlying diabetes is a risk factor for both advanced fibrosis and death in patients with NAFLD.

While liver biopsy remains the gold standard for detecting advanced fibrosis, high costs and risks limit its use. Noninvasive scores such as the AST/ALT ratio; AST to platelet ratio index (APRI); fibrosis-4 (FIB-4) index; and NAFLD fibrosis score (NFS) have gained popularity in recent years, as they offer the compelling advantage of using easily and cheaply attained clinical and laboratory measures to assess likelihood of disease.

But their accuracy has come into question, particularly for people with diabetes.

In research published in the Journal of Clinical Gastroenterology, Amandeep Singh, MD, and colleagues at the Cleveland Clinic looked at their center’s records for 1,157 patients with type 2 diabetes (65% women, 88% white, 85% with obesity) who had undergone a liver biopsy for suspected advanced fibrosis between 2000 and 2015. Biopsy results revealed that a third of the cohort (32%) was positive for advanced fibrosis.

The investigators then pulled patients’ laboratory results for AST, ALT, cholesterol, triglycerides, fasting glucose, hemoglobin A_1c, bilirubin, albumin, platelet count, alkaline phosphatase, albumin, and lipid levels, all collected within a year of biopsy. After plugging these into the algorithms of four different scoring systems for advanced fibrosis, they compared results with results from the biopsies.

The scores of AST/ALT greater than 1.4, APRI of at least 1.5, NFS greater than 0.676, and FIB-4 index greater than 2.67 had high specificities of 84%, 97%, 70%, and 93%, respectively, but sensitivities of only 27%, 17%, 64%, and 44%. Even when the cutoff measures were tightened, the scoring systems still missed a lot of disease. This suggests, Dr. Singh and colleagues wrote, that “the presence of diabetes could decrease the predictive value of these scores to detect advanced disease in NAFLD patients.” Reliable noninvasive biomarkers are “urgently needed” for this patient population.

In an interview, Dr. Singh advised that clinicians continue to use current noninvasive scores in patients with diabetes – preferably the NFS – “until we have a better scoring system.” If clinicians suspect advanced fibrosis based on lab tests and clinical data, then “liver biopsy should be considered,” he said.

The investigators described among the limitations of their study its retrospective, single-center design, with patients who were mostly white and from one geographic region.

Dr. Singh and colleagues reported no conflicts of interest or outside funding for their study.

[email protected]

SOURCE: Singh A et al. J Clin Gastroenterol. 2020 Mar 11. doi: 10.1097/MCG.0000000000001339.

Noninvasive fibrosis scores, which are widely used to predict advanced fibrosis in people with nonalcoholic fatty liver disease (NAFLD), do not do a good job of picking up advanced fibrosis in patients with underlying diabetes, according to a new study.

Advanced fibrosis is associated with an increased risk of cirrhosis, end-stage liver disease, and liver failure. Underlying diabetes is a risk factor for both advanced fibrosis and death in patients with NAFLD.

While liver biopsy remains the gold standard for detecting advanced fibrosis, high costs and risks limit its use. Noninvasive scores such as the AST/ALT ratio; AST to platelet ratio index (APRI); fibrosis-4 (FIB-4) index; and NAFLD fibrosis score (NFS) have gained popularity in recent years, as they offer the compelling advantage of using easily and cheaply attained clinical and laboratory measures to assess likelihood of disease.

But their accuracy has come into question, particularly for people with diabetes.

In research published in the Journal of Clinical Gastroenterology, Amandeep Singh, MD, and colleagues at the Cleveland Clinic looked at their center’s records for 1,157 patients with type 2 diabetes (65% women, 88% white, 85% with obesity) who had undergone a liver biopsy for suspected advanced fibrosis between 2000 and 2015. Biopsy results revealed that a third of the cohort (32%) was positive for advanced fibrosis.

The investigators then pulled patients’ laboratory results for AST, ALT, cholesterol, triglycerides, fasting glucose, hemoglobin A_1c, bilirubin, albumin, platelet count, alkaline phosphatase, albumin, and lipid levels, all collected within a year of biopsy. After plugging these into the algorithms of four different scoring systems for advanced fibrosis, they compared results with results from the biopsies.

The scores of AST/ALT greater than 1.4, APRI of at least 1.5, NFS greater than 0.676, and FIB-4 index greater than 2.67 had high specificities of 84%, 97%, 70%, and 93%, respectively, but sensitivities of only 27%, 17%, 64%, and 44%. Even when the cutoff measures were tightened, the scoring systems still missed a lot of disease. This suggests, Dr. Singh and colleagues wrote, that “the presence of diabetes could decrease the predictive value of these scores to detect advanced disease in NAFLD patients.” Reliable noninvasive biomarkers are “urgently needed” for this patient population.

In an interview, Dr. Singh advised that clinicians continue to use current noninvasive scores in patients with diabetes – preferably the NFS – “until we have a better scoring system.” If clinicians suspect advanced fibrosis based on lab tests and clinical data, then “liver biopsy should be considered,” he said.

The investigators described among the limitations of their study its retrospective, single-center design, with patients who were mostly white and from one geographic region.

Dr. Singh and colleagues reported no conflicts of interest or outside funding for their study.

[email protected]

SOURCE: Singh A et al. J Clin Gastroenterol. 2020 Mar 11. doi: 10.1097/MCG.0000000000001339.

In liver transplant recipients or patients with autoimmune hepatitis on immunosuppressive therapy, acute cellular rejection or disease flare should not be presumed in the face of active coronavirus disease 2019 (COVID-19), according to the American Association for the Study of Liver Diseases (AASLD).

Signs that would normally be interpreted as flare or rejection need to be considered more cautiously now because the virus attacks the liver, and elevated aspartate aminotransferase, alanine aminotransferase, and slightly elevated bilirubin are common, ranging from a prevalence of 14% to 53% in COVID-19 patients. Acute liver injury is possible, especially in more severe cases, the group said.

The advice comes from a recently released document from AASLD, called “Clinical Insights for Hepatology and Liver Transplant Providers During the Covid-19 Pandemic,” to help hepatologists and liver transplant providers negotiate the pandemic, according to the latest data. It’s a far-ranging work that contains a lot of now familiar steps for providers to take to protect themselves and patients from the virus, but also much advice specific to liver medicine.

For instance, the group said it’s important to keep in mind that experimental treatments for the infection, including statins, remdesivir, and tocilizumab, can be hepatotoxic. Abnormal liver biochemistries are not a contraindication, but liver biochemistries need to be followed regularly in COVID-19 patients, especially those treated with remdesivir or tocilizumab, regardless of baseline values.

Also, lopinavir/ritonavir is a potent inhibitor of cytochrome P450 enzymes involved with calcineurin inhibitor metabolism, so if it’s used, AASLD said to reduce tacrolimus dosages to 1/20–1/50 of baseline.

The group cautioned against anticipatory adjustments to immunosuppressive drugs or dosages in patients without COVID-19, but if immunosuppressed liver disease patients do get the infection, prednisone doses should be reduced but kept above 10 mg/day to avoid adrenal insufficiency. In the setting of lymphopenia, fever, or worsening COVID-19 pneumonia, it advised reduction of azathioprine and mycophenolate dosages and reduction of, but not stopping, calcineurin inhibitors.

Liver transplants should not be postponed. However, to minimize exposure to the hospital environment, AASLD advised to “consider evaluating only patients with HCC [hepatocellular carcinoma] or those patients with severe disease and high MELD [model for end-stage liver disease] scores who are likely to benefit from immediate liver transplant.”

“An argument that has been put forward to justify deferring some transplants is concern about immunosuppressing patients during the COVID-19 pandemic,” the group said, but “data suggest the innate immune response may be the main driver for pulmonary injury due to COVID-19 and [that] immunosuppression may be protective. ... Posttransplant immunosuppression was not a risk factor for mortality associated with” the severe acute respiratory syndrome pandemic in 2003-2004 or the ongoing Middle East respiratory syndrome pandemic, both also caused by coronaviruses.

AASLD advised against reducing immunosuppression or stopping mycophenolate for asymptomatic patients after transplant, but COVID-19 prevention measures should be emphasized, including frequent hand washing and staying away from large crowds.

People who test positive for COVID-19 are ineligible for organ donation. Bronchoalveolar lavage is the most sensitive test (93%), followed by nasal swabs (63%) and pharyngeal swabs (32%).

In general, the group said elective procedures should be postponed, but urgent ones, such as biliary surgery and transjugular intrahepatic portosystemic shunts for bleeding varices, in addition to liver transplants, should not.

Also, HCC patients “should not wait until the pandemic abates to undergo [surveillance] imaging because the prospective duration of the pandemic is unknown. ... An arbitrary delay of 2 months is reasonable” for imaging based on patient and facility circumstances, but otherwise, “proceed with HCC treatments rather than delaying them due to the pandemic,” the group said.

As for who to bring into the office for an initial consult, “consider seeing in person only new adult and pediatric patients with urgent issues and clinically significant liver disease (e.g., jaundice, elevated ALT or AST above 500 U/L, recent onset of hepatic decompensation),” AASLD said.

[email protected]

In liver transplant recipients or patients with autoimmune hepatitis on immunosuppressive therapy, acute cellular rejection or disease flare should not be presumed in the face of active coronavirus disease 2019 (COVID-19), according to the American Association for the Study of Liver Diseases (AASLD).

Signs that would normally be interpreted as flare or rejection need to be considered more cautiously now because the virus attacks the liver, and elevated aspartate aminotransferase, alanine aminotransferase, and slightly elevated bilirubin are common, ranging from a prevalence of 14% to 53% in COVID-19 patients. Acute liver injury is possible, especially in more severe cases, the group said.

The advice comes from a recently released document from AASLD, called “Clinical Insights for Hepatology and Liver Transplant Providers During the Covid-19 Pandemic,” to help hepatologists and liver transplant providers negotiate the pandemic, according to the latest data. It’s a far-ranging work that contains a lot of now familiar steps for providers to take to protect themselves and patients from the virus, but also much advice specific to liver medicine.

For instance, the group said it’s important to keep in mind that experimental treatments for the infection, including statins, remdesivir, and tocilizumab, can be hepatotoxic. Abnormal liver biochemistries are not a contraindication, but liver biochemistries need to be followed regularly in COVID-19 patients, especially those treated with remdesivir or tocilizumab, regardless of baseline values.

Also, lopinavir/ritonavir is a potent inhibitor of cytochrome P450 enzymes involved with calcineurin inhibitor metabolism, so if it’s used, AASLD said to reduce tacrolimus dosages to 1/20–1/50 of baseline.

The group cautioned against anticipatory adjustments to immunosuppressive drugs or dosages in patients without COVID-19, but if immunosuppressed liver disease patients do get the infection, prednisone doses should be reduced but kept above 10 mg/day to avoid adrenal insufficiency. In the setting of lymphopenia, fever, or worsening COVID-19 pneumonia, it advised reduction of azathioprine and mycophenolate dosages and reduction of, but not stopping, calcineurin inhibitors.

Liver transplants should not be postponed. However, to minimize exposure to the hospital environment, AASLD advised to “consider evaluating only patients with HCC [hepatocellular carcinoma] or those patients with severe disease and high MELD [model for end-stage liver disease] scores who are likely to benefit from immediate liver transplant.”

“An argument that has been put forward to justify deferring some transplants is concern about immunosuppressing patients during the COVID-19 pandemic,” the group said, but “data suggest the innate immune response may be the main driver for pulmonary injury due to COVID-19 and [that] immunosuppression may be protective. ... Posttransplant immunosuppression was not a risk factor for mortality associated with” the severe acute respiratory syndrome pandemic in 2003-2004 or the ongoing Middle East respiratory syndrome pandemic, both also caused by coronaviruses.

AASLD advised against reducing immunosuppression or stopping mycophenolate for asymptomatic patients after transplant, but COVID-19 prevention measures should be emphasized, including frequent hand washing and staying away from large crowds.

People who test positive for COVID-19 are ineligible for organ donation. Bronchoalveolar lavage is the most sensitive test (93%), followed by nasal swabs (63%) and pharyngeal swabs (32%).

In general, the group said elective procedures should be postponed, but urgent ones, such as biliary surgery and transjugular intrahepatic portosystemic shunts for bleeding varices, in addition to liver transplants, should not.

Also, HCC patients “should not wait until the pandemic abates to undergo [surveillance] imaging because the prospective duration of the pandemic is unknown. ... An arbitrary delay of 2 months is reasonable” for imaging based on patient and facility circumstances, but otherwise, “proceed with HCC treatments rather than delaying them due to the pandemic,” the group said.

As for who to bring into the office for an initial consult, “consider seeing in person only new adult and pediatric patients with urgent issues and clinically significant liver disease (e.g., jaundice, elevated ALT or AST above 500 U/L, recent onset of hepatic decompensation),” AASLD said.

[email protected]

In liver transplant recipients or patients with autoimmune hepatitis on immunosuppressive therapy, acute cellular rejection or disease flare should not be presumed in the face of active coronavirus disease 2019 (COVID-19), according to the American Association for the Study of Liver Diseases (AASLD).

Signs that would normally be interpreted as flare or rejection need to be considered more cautiously now because the virus attacks the liver, and elevated aspartate aminotransferase, alanine aminotransferase, and slightly elevated bilirubin are common, ranging from a prevalence of 14% to 53% in COVID-19 patients. Acute liver injury is possible, especially in more severe cases, the group said.

The advice comes from a recently released document from AASLD, called “Clinical Insights for Hepatology and Liver Transplant Providers During the Covid-19 Pandemic,” to help hepatologists and liver transplant providers negotiate the pandemic, according to the latest data. It’s a far-ranging work that contains a lot of now familiar steps for providers to take to protect themselves and patients from the virus, but also much advice specific to liver medicine.

For instance, the group said it’s important to keep in mind that experimental treatments for the infection, including statins, remdesivir, and tocilizumab, can be hepatotoxic. Abnormal liver biochemistries are not a contraindication, but liver biochemistries need to be followed regularly in COVID-19 patients, especially those treated with remdesivir or tocilizumab, regardless of baseline values.

Also, lopinavir/ritonavir is a potent inhibitor of cytochrome P450 enzymes involved with calcineurin inhibitor metabolism, so if it’s used, AASLD said to reduce tacrolimus dosages to 1/20–1/50 of baseline.

The group cautioned against anticipatory adjustments to immunosuppressive drugs or dosages in patients without COVID-19, but if immunosuppressed liver disease patients do get the infection, prednisone doses should be reduced but kept above 10 mg/day to avoid adrenal insufficiency. In the setting of lymphopenia, fever, or worsening COVID-19 pneumonia, it advised reduction of azathioprine and mycophenolate dosages and reduction of, but not stopping, calcineurin inhibitors.

Liver transplants should not be postponed. However, to minimize exposure to the hospital environment, AASLD advised to “consider evaluating only patients with HCC [hepatocellular carcinoma] or those patients with severe disease and high MELD [model for end-stage liver disease] scores who are likely to benefit from immediate liver transplant.”

“An argument that has been put forward to justify deferring some transplants is concern about immunosuppressing patients during the COVID-19 pandemic,” the group said, but “data suggest the innate immune response may be the main driver for pulmonary injury due to COVID-19 and [that] immunosuppression may be protective. ... Posttransplant immunosuppression was not a risk factor for mortality associated with” the severe acute respiratory syndrome pandemic in 2003-2004 or the ongoing Middle East respiratory syndrome pandemic, both also caused by coronaviruses.

AASLD advised against reducing immunosuppression or stopping mycophenolate for asymptomatic patients after transplant, but COVID-19 prevention measures should be emphasized, including frequent hand washing and staying away from large crowds.

People who test positive for COVID-19 are ineligible for organ donation. Bronchoalveolar lavage is the most sensitive test (93%), followed by nasal swabs (63%) and pharyngeal swabs (32%).

In general, the group said elective procedures should be postponed, but urgent ones, such as biliary surgery and transjugular intrahepatic portosystemic shunts for bleeding varices, in addition to liver transplants, should not.

Also, HCC patients “should not wait until the pandemic abates to undergo [surveillance] imaging because the prospective duration of the pandemic is unknown. ... An arbitrary delay of 2 months is reasonable” for imaging based on patient and facility circumstances, but otherwise, “proceed with HCC treatments rather than delaying them due to the pandemic,” the group said.

As for who to bring into the office for an initial consult, “consider seeing in person only new adult and pediatric patients with urgent issues and clinically significant liver disease (e.g., jaundice, elevated ALT or AST above 500 U/L, recent onset of hepatic decompensation),” AASLD said.

[email protected]

Patients with COVID-19 may be at risk for liver injury, but mechanisms of damage remain unclear, according to investigators.

Proposed mechanisms include direct virus-induced effects, immune-induced damage due to excessive inflammatory responses, and drug-induced injury, reported lead author Ling Xu of Huazhong University of Science and Technology, Wuhan, China, and colleagues.

“From a clinical perspective, in addition to actively dealing with the primary disease caused by coronavirus infection, attention should also be paid to monitor the occurrence of liver injury, and to the application of drugs which may induce liver damage,” the investigators wrote in Liver International. “Patients with liver damage are advised to be treated with drugs that could both protect liver functions and inhibit inflammatory responses, such as ammonium glycyrrhizinate, which may, in turn, accelerate the process of disease recovery.”

The review of liver injury associated with major pathogenic coronaviruses included severe acute respiratory syndrome coronavirus (SARS-CoV), the Middle East respiratory syndrome coronavirus (MERS-CoV), and the newly emergent SARS-CoV-2, which causes COVID-19.

In cases of COVID-19, reported incidence of liver injury ranges from 15% to 53%, based on elevations of alanine transaminase (ALT) and aspartate aminotransferase (AST), along with slightly elevated bilirubin levels. In severe cases, albumin decreases have also been documented.

Liver injury appears to be significantly more common among those with severe infection. In one cohort of 82 patients who died from COVID-19, the incidence of liver injury was 78%, while another study of 36 nonsurvivors reported a rate of 58%.

According to the investigators, both bile duct epithelial cells and liver cells express angiotensin converting enzyme II (ACE2), which is an entry receptor for SARS-CoV-2; however, expression of ACE2 in bile duct cells is “much higher” than in liver cells, and comparable with alveolar type 2 cells in the lungs.

“Bile duct epithelial cells are known to play important roles in liver regeneration and immune response,” the investigators noted.

Beyond direct- and immune-induced effects of COVID-19, postmortem findings suggest that drug-induced liver injury may also be a possibility, with a number of theoretical culprits, including antibiotics, steroids, and antivirals. Although the investigators emphasized that data are insufficient to pinpoint an exact agent, they highlighted a recent preprint study, which reported a significantly higher rate of lopinavir/ritonavir administration among patients with abnormal liver function, compared with those who had normal liver function (56.1% vs. 25%; P = .009).

“Drug-induced liver injury during the treatment of coronavirus infection should not be ignored and needs to be carefully investigated,” the investigators concluded.

Fundamental Research Funds for the Central Universities supported the work. The investigators reported no conflicts of interest.

SOURCE: Xu L et al. Liver Int. 2020 Mar 14. doi: 10.1111/liv.14435.

Patients with COVID-19 may be at risk for liver injury, but mechanisms of damage remain unclear, according to investigators.

Proposed mechanisms include direct virus-induced effects, immune-induced damage due to excessive inflammatory responses, and drug-induced injury, reported lead author Ling Xu of Huazhong University of Science and Technology, Wuhan, China, and colleagues.

“From a clinical perspective, in addition to actively dealing with the primary disease caused by coronavirus infection, attention should also be paid to monitor the occurrence of liver injury, and to the application of drugs which may induce liver damage,” the investigators wrote in Liver International. “Patients with liver damage are advised to be treated with drugs that could both protect liver functions and inhibit inflammatory responses, such as ammonium glycyrrhizinate, which may, in turn, accelerate the process of disease recovery.”

The review of liver injury associated with major pathogenic coronaviruses included severe acute respiratory syndrome coronavirus (SARS-CoV), the Middle East respiratory syndrome coronavirus (MERS-CoV), and the newly emergent SARS-CoV-2, which causes COVID-19.

In cases of COVID-19, reported incidence of liver injury ranges from 15% to 53%, based on elevations of alanine transaminase (ALT) and aspartate aminotransferase (AST), along with slightly elevated bilirubin levels. In severe cases, albumin decreases have also been documented.

Liver injury appears to be significantly more common among those with severe infection. In one cohort of 82 patients who died from COVID-19, the incidence of liver injury was 78%, while another study of 36 nonsurvivors reported a rate of 58%.

According to the investigators, both bile duct epithelial cells and liver cells express angiotensin converting enzyme II (ACE2), which is an entry receptor for SARS-CoV-2; however, expression of ACE2 in bile duct cells is “much higher” than in liver cells, and comparable with alveolar type 2 cells in the lungs.

“Bile duct epithelial cells are known to play important roles in liver regeneration and immune response,” the investigators noted.

Beyond direct- and immune-induced effects of COVID-19, postmortem findings suggest that drug-induced liver injury may also be a possibility, with a number of theoretical culprits, including antibiotics, steroids, and antivirals. Although the investigators emphasized that data are insufficient to pinpoint an exact agent, they highlighted a recent preprint study, which reported a significantly higher rate of lopinavir/ritonavir administration among patients with abnormal liver function, compared with those who had normal liver function (56.1% vs. 25%; P = .009).

“Drug-induced liver injury during the treatment of coronavirus infection should not be ignored and needs to be carefully investigated,” the investigators concluded.

Fundamental Research Funds for the Central Universities supported the work. The investigators reported no conflicts of interest.

SOURCE: Xu L et al. Liver Int. 2020 Mar 14. doi: 10.1111/liv.14435.

Patients with COVID-19 may be at risk for liver injury, but mechanisms of damage remain unclear, according to investigators.

Proposed mechanisms include direct virus-induced effects, immune-induced damage due to excessive inflammatory responses, and drug-induced injury, reported lead author Ling Xu of Huazhong University of Science and Technology, Wuhan, China, and colleagues.

“From a clinical perspective, in addition to actively dealing with the primary disease caused by coronavirus infection, attention should also be paid to monitor the occurrence of liver injury, and to the application of drugs which may induce liver damage,” the investigators wrote in Liver International. “Patients with liver damage are advised to be treated with drugs that could both protect liver functions and inhibit inflammatory responses, such as ammonium glycyrrhizinate, which may, in turn, accelerate the process of disease recovery.”

The review of liver injury associated with major pathogenic coronaviruses included severe acute respiratory syndrome coronavirus (SARS-CoV), the Middle East respiratory syndrome coronavirus (MERS-CoV), and the newly emergent SARS-CoV-2, which causes COVID-19.

In cases of COVID-19, reported incidence of liver injury ranges from 15% to 53%, based on elevations of alanine transaminase (ALT) and aspartate aminotransferase (AST), along with slightly elevated bilirubin levels. In severe cases, albumin decreases have also been documented.

Liver injury appears to be significantly more common among those with severe infection. In one cohort of 82 patients who died from COVID-19, the incidence of liver injury was 78%, while another study of 36 nonsurvivors reported a rate of 58%.

According to the investigators, both bile duct epithelial cells and liver cells express angiotensin converting enzyme II (ACE2), which is an entry receptor for SARS-CoV-2; however, expression of ACE2 in bile duct cells is “much higher” than in liver cells, and comparable with alveolar type 2 cells in the lungs.

“Bile duct epithelial cells are known to play important roles in liver regeneration and immune response,” the investigators noted.

Beyond direct- and immune-induced effects of COVID-19, postmortem findings suggest that drug-induced liver injury may also be a possibility, with a number of theoretical culprits, including antibiotics, steroids, and antivirals. Although the investigators emphasized that data are insufficient to pinpoint an exact agent, they highlighted a recent preprint study, which reported a significantly higher rate of lopinavir/ritonavir administration among patients with abnormal liver function, compared with those who had normal liver function (56.1% vs. 25%; P = .009).

“Drug-induced liver injury during the treatment of coronavirus infection should not be ignored and needs to be carefully investigated,” the investigators concluded.

Fundamental Research Funds for the Central Universities supported the work. The investigators reported no conflicts of interest.

SOURCE: Xu L et al. Liver Int. 2020 Mar 14. doi: 10.1111/liv.14435.

The first randomized trial to see if a short course of a direct-acting antiviral works as well for acute hepatitis C virus (HCV) infection as the standard 12-week course was stopped early after it became clear that it did not, according to a report at the Conference on Retroviruses & Opportunistic Infections.

In the end, 6 weeks of sofosbuvir-velpatasvir (Epclusa) “was inferior” to 12 weeks, said investigators led by Gail Matthews, MD, PhD, an associate professor in the Viral Hepatitis Clinical Research Program at the Kirby Institute, in Sydney, New South Wales, Australia.

Guidelines recommend 12 weeks of direct-acting antiviral treatment, but a few observational studies have suggested that 6 weeks might be enough. Since that would make it easier for physicians and patients, and would save money, Dr. Matthews and her team set out to resolve the uncertainty with a randomized trial.

Enrollment was halted short of the 250 target because of an “unacceptably high” relapse rate of 9.7% among 93 people randomized to 6 weeks of sofosbuvir-velpatasvir versus 2% among 99 subjects randomized to the standard 12-week regimen. All the relapse patients except for one in the 12-week arm were more than 95% adherent to treatment, she at the meeting, which was scheduled to be in Boston, but was held online this year because of concerns about spreading the COVID-19 virus.

There were 17 treatment failures (18.3%) in the short arm: two deaths, three reinfections, three lost to follow-up, and the nine relapses 12 weeks out from the end of treatment. There were eight failures (8%) in the long arm, including two reinfections, two lost to follow-up, and the two relapses, but no deaths. Excluding patients with no virologic reason for failure, Dr. Matthews said, “we see the difference in the two arms even more clearly,” with viral RNA undetectable in 98% of the 12-week patients – which is in keeping with label data – versus 89% in the short arm.

The groups were well balanced. Almost all the subjects were men and the majority were white; the median age was 43 years. Almost two-thirds had a primary infection at baseline and HCV genotype 1 a/b was the most common in both groups. Patients had been infected for a year or less, with a median of 25 weeks.

The majority of subjects picked up the virus through homosexual sex, but about 20% by injection drug use. Over two-thirds had well-controlled HIV. There were no treatment related discontinuations, and all the relapsed patients were successfully treated with subsequent therapy, Dr. Matthews said.

The study was conducted in the United States, Europe, Canada, New Zealand, and Australia, and funded by the National Institutes of Health. Dr. Matthews reported research grants to her institution form Abbvie and Gilead, maker of Epclusa.

[email protected]

SOURCE: Matthews G. CROI 2020 abstract 121.

The first randomized trial to see if a short course of a direct-acting antiviral works as well for acute hepatitis C virus (HCV) infection as the standard 12-week course was stopped early after it became clear that it did not, according to a report at the Conference on Retroviruses & Opportunistic Infections.

In the end, 6 weeks of sofosbuvir-velpatasvir (Epclusa) “was inferior” to 12 weeks, said investigators led by Gail Matthews, MD, PhD, an associate professor in the Viral Hepatitis Clinical Research Program at the Kirby Institute, in Sydney, New South Wales, Australia.

Guidelines recommend 12 weeks of direct-acting antiviral treatment, but a few observational studies have suggested that 6 weeks might be enough. Since that would make it easier for physicians and patients, and would save money, Dr. Matthews and her team set out to resolve the uncertainty with a randomized trial.

Enrollment was halted short of the 250 target because of an “unacceptably high” relapse rate of 9.7% among 93 people randomized to 6 weeks of sofosbuvir-velpatasvir versus 2% among 99 subjects randomized to the standard 12-week regimen. All the relapse patients except for one in the 12-week arm were more than 95% adherent to treatment, she at the meeting, which was scheduled to be in Boston, but was held online this year because of concerns about spreading the COVID-19 virus.

There were 17 treatment failures (18.3%) in the short arm: two deaths, three reinfections, three lost to follow-up, and the nine relapses 12 weeks out from the end of treatment. There were eight failures (8%) in the long arm, including two reinfections, two lost to follow-up, and the two relapses, but no deaths. Excluding patients with no virologic reason for failure, Dr. Matthews said, “we see the difference in the two arms even more clearly,” with viral RNA undetectable in 98% of the 12-week patients – which is in keeping with label data – versus 89% in the short arm.

The groups were well balanced. Almost all the subjects were men and the majority were white; the median age was 43 years. Almost two-thirds had a primary infection at baseline and HCV genotype 1 a/b was the most common in both groups. Patients had been infected for a year or less, with a median of 25 weeks.

The majority of subjects picked up the virus through homosexual sex, but about 20% by injection drug use. Over two-thirds had well-controlled HIV. There were no treatment related discontinuations, and all the relapsed patients were successfully treated with subsequent therapy, Dr. Matthews said.

The study was conducted in the United States, Europe, Canada, New Zealand, and Australia, and funded by the National Institutes of Health. Dr. Matthews reported research grants to her institution form Abbvie and Gilead, maker of Epclusa.

[email protected]

SOURCE: Matthews G. CROI 2020 abstract 121.

The first randomized trial to see if a short course of a direct-acting antiviral works as well for acute hepatitis C virus (HCV) infection as the standard 12-week course was stopped early after it became clear that it did not, according to a report at the Conference on Retroviruses & Opportunistic Infections.

In the end, 6 weeks of sofosbuvir-velpatasvir (Epclusa) “was inferior” to 12 weeks, said investigators led by Gail Matthews, MD, PhD, an associate professor in the Viral Hepatitis Clinical Research Program at the Kirby Institute, in Sydney, New South Wales, Australia.

Guidelines recommend 12 weeks of direct-acting antiviral treatment, but a few observational studies have suggested that 6 weeks might be enough. Since that would make it easier for physicians and patients, and would save money, Dr. Matthews and her team set out to resolve the uncertainty with a randomized trial.

Enrollment was halted short of the 250 target because of an “unacceptably high” relapse rate of 9.7% among 93 people randomized to 6 weeks of sofosbuvir-velpatasvir versus 2% among 99 subjects randomized to the standard 12-week regimen. All the relapse patients except for one in the 12-week arm were more than 95% adherent to treatment, she at the meeting, which was scheduled to be in Boston, but was held online this year because of concerns about spreading the COVID-19 virus.

There were 17 treatment failures (18.3%) in the short arm: two deaths, three reinfections, three lost to follow-up, and the nine relapses 12 weeks out from the end of treatment. There were eight failures (8%) in the long arm, including two reinfections, two lost to follow-up, and the two relapses, but no deaths. Excluding patients with no virologic reason for failure, Dr. Matthews said, “we see the difference in the two arms even more clearly,” with viral RNA undetectable in 98% of the 12-week patients – which is in keeping with label data – versus 89% in the short arm.

The groups were well balanced. Almost all the subjects were men and the majority were white; the median age was 43 years. Almost two-thirds had a primary infection at baseline and HCV genotype 1 a/b was the most common in both groups. Patients had been infected for a year or less, with a median of 25 weeks.

The majority of subjects picked up the virus through homosexual sex, but about 20% by injection drug use. Over two-thirds had well-controlled HIV. There were no treatment related discontinuations, and all the relapsed patients were successfully treated with subsequent therapy, Dr. Matthews said.

The study was conducted in the United States, Europe, Canada, New Zealand, and Australia, and funded by the National Institutes of Health. Dr. Matthews reported research grants to her institution form Abbvie and Gilead, maker of Epclusa.

[email protected]

SOURCE: Matthews G. CROI 2020 abstract 121.

The risk of liver cancer and liver-related death in patients with chronic viral hepatitis was substantially reduced with the use of low-dose aspirin, results from a nationwide study from Sweden suggest.

The risk of hepatocellular carcinoma (HCC) was reduced by 31% compared with no aspirin use, and liver-related mortality dropped by 27%, as long as aspirin use continued.

“We were excited to find for the first time in a nationwide Western population that low-dose aspirin use was associated with substantial reduction in risk of developing incident HCC,” lead author Tracey G. Simon, MD, MPH, of Massachusetts General Hospital and Harvard Medical School in Boston, told Medscape Medical News.

The study was published in the March 12 issue of the New England Journal of Medicine.

HCC is the fourth-leading cause of cancer mortality worldwide, and is driven mostly by viral hepatitis B (HBV) and viral hepatitis C (HCV) infection, noted Jennifer A. Flemming, MD, of Queen’s University, Kingston, Canada, an expert not involved with the study. HCC is also one of the only cancers to show a rising incidence over the past several decades, she added .

However, the results of this do not change clinical practice. “It is premature to prescribe low dose ASA [acetylsalicylic acid] in patients with viral hepatitis for the sole indication of HCC prevention in routine clinical practice without support from prospective randomized data,” she said.

“The results of this study make it clear that a prospective randomized study comparing ASA to placebo in patients with viral hepatitis without an indication for low-dose ASA is justified to evaluate the risk of incident HCC,” she told Medscape Medical News.

The study authors agree, and they also emphasize that the findings from this observational study “should not yet change clinical practice.”

More research is needed in populations with compensated and decompensated cirrhosis to determine the optimal timing of aspirin initiation — or cessation of therapy — that will maximize benefit and prevent adverse events, said Simon.

Study Details

Although several earlier studies have suggested a duration-dependent benefit of aspirin use in preventing HCC in smaller populations, this study is the first to confirm a duration-response relationship with low-dose aspirin use in an unselected European population with confirmed viral hepatitis, Simon pointed out.

For their study, Simon and colleagues used the Swedish Register for Surveillance of Communicable Diseases database to identify 50,275 adults diagnosed between 2005 and 2015 with acute and chronic HBV and HCV infection. Some 13,276 adults had HBV and 36,999 had HCV, and this included 14,205 low-dose (75 mg or 160 mg) aspirin users and 36,070 nonusers.

The analysis showed that in aspirin users, the 10-year cumulative incidence of HCC was 4% compared with 8.3% in nonusers. After multivariable adjustment, aspirin users had a risk of HCC that was 31% lower compared with nonusers (adjusted subhazard ratio, 0.69; 95% confidence interval [CI], 0.62 - 0.76).

Patients taking low-dose aspirin had a 10-year liver-related mortality of 11% compared with 17.9% among nonusers. The adjusted risk of liver-related mortality was 27% lower in aspirin users than in nonusers.

There was no significant difference in the 10-year risk of gastrointestinal bleeding between users and nonusers of aspirin (7.8% and 6.9%, respectively). In addition, the analysis showed that the risks of any gastrointestinal bleeding were similar among aspirin-users with compensated cirrhosis and those without cirrhosis (8.3% and 7.5%, respectively).

Notably, the risk of HCC was significantly lower after 3 to 5 years of aspirin use and after 5 or more years of use (adjusted hazard ratio [HR], 0.66, 0.57, respectively) compared with short-term use (3 months to <1 year; adjusted HR, 0.90) or with intermittent, discontinued, or no aspirin use. But when those with chronic viral hepatitis stopped taking aspirin, their risk of HCC rose to become 22% higher compared with peers who continued to use aspirin.

The risk of liver-related death also rose by 31% in aspirin users who stopped taking aspirin compared with those who did not stop (subhazard ratio, 1.31). Again, this relationship appeared to be duration-dependent, with the risk of incident HCC rising sharply among those who discontinued aspirin and increasing in magnitude over time.

The consistency of aspirin use also influenced risk. In individuals who had an on-again, off-again pattern of aspirin use, the incidence of HCC was 5.9% compared with 1.1% in those who used it consistently.

“Our results were consistent regardless of sex, cause of hepatitis, or underlying compensated cirrhosis,” the authors write. “The consistent duration-response associations lend further credence to a potential causal relationship.”

Limitations of the Study

The current study findings are not new, but this is the best-designed study to date, commented Flemming. Still, there were a number of limitations, she noted. Although cirrhosis is the strongest risk factor for HCC in patients with viral hepatitis, for instance, it was assessed only at cohort entry, and not during the median 8 years of follow-up. There was also a lack of information about sustained virologic response (SVR) rates.

Since less than 25% of patients with HCV received HCV therapy, this indicates they were likely treated with interferon-based therapy, Flemming suggested. Interferon-based therapy is associated with much lower SVR rates than direct acting antiviral (DAA) therapy, which can produce SVR in approximately 95% of patients, she pointed out.

“Therefore, a large proportion of the study patients were likely viremic and at a higher baseline risk of HCC than contemporary HCV populations.”

Evidence from a number of studies indicates that achieving SVR with DAA therapy is associated with a 70% risk reduction for incident HCC and liver-related events, Flemming said. “Whether the use of ASA in patients who have achieved SVR provides the same HCC risk reduction and decrease in hepatic outcomes is unknown.”

Also, the study did not provide information on the specific type of HBV therapy used in patients with HBV, Flemming noted. When considering the prevention of HCC in patients with chronic HBV infection, recent data support a differential protective effect of tenofovir disoproxil fumarate (multiple brands) compared with entecavir (Baraclude, Bristol-Myers Squibb), she pointed out. As previously reported by Medscape Medical News, these data also indicate that tenofovir may be more effective than entecavir in reducing the risk of liver failure and all-cause mortality.

This study was funded by the US National Institutes of Health, Nyckelfonden, Region Stockholm County, the American Association for the Study of Liver Diseases, Boston Nutrition Obesity Research Council, Region Örebro County, and Karolinska Institutet. Simon has disclosed no relevant financial relationships. A number of study coauthors disclosed having relationships with industry; the full list can be found with the original article. Flemming reported relationships with Gilead Sciences Canada, AbbVie, and Lupin Pharmaceuticals.

This article first appeared on Medscape.com.

N Engl J Med. 2020 Mar 12. doi: 10.1056/NEJMoa1912035.

The risk of liver cancer and liver-related death in patients with chronic viral hepatitis was substantially reduced with the use of low-dose aspirin, results from a nationwide study from Sweden suggest.

The risk of hepatocellular carcinoma (HCC) was reduced by 31% compared with no aspirin use, and liver-related mortality dropped by 27%, as long as aspirin use continued.

“We were excited to find for the first time in a nationwide Western population that low-dose aspirin use was associated with substantial reduction in risk of developing incident HCC,” lead author Tracey G. Simon, MD, MPH, of Massachusetts General Hospital and Harvard Medical School in Boston, told Medscape Medical News.

The study was published in the March 12 issue of the New England Journal of Medicine.

HCC is the fourth-leading cause of cancer mortality worldwide, and is driven mostly by viral hepatitis B (HBV) and viral hepatitis C (HCV) infection, noted Jennifer A. Flemming, MD, of Queen’s University, Kingston, Canada, an expert not involved with the study. HCC is also one of the only cancers to show a rising incidence over the past several decades, she added .

However, the results of this do not change clinical practice. “It is premature to prescribe low dose ASA [acetylsalicylic acid] in patients with viral hepatitis for the sole indication of HCC prevention in routine clinical practice without support from prospective randomized data,” she said.

“The results of this study make it clear that a prospective randomized study comparing ASA to placebo in patients with viral hepatitis without an indication for low-dose ASA is justified to evaluate the risk of incident HCC,” she told Medscape Medical News.

The study authors agree, and they also emphasize that the findings from this observational study “should not yet change clinical practice.”

More research is needed in populations with compensated and decompensated cirrhosis to determine the optimal timing of aspirin initiation — or cessation of therapy — that will maximize benefit and prevent adverse events, said Simon.

Study Details

Although several earlier studies have suggested a duration-dependent benefit of aspirin use in preventing HCC in smaller populations, this study is the first to confirm a duration-response relationship with low-dose aspirin use in an unselected European population with confirmed viral hepatitis, Simon pointed out.

For their study, Simon and colleagues used the Swedish Register for Surveillance of Communicable Diseases database to identify 50,275 adults diagnosed between 2005 and 2015 with acute and chronic HBV and HCV infection. Some 13,276 adults had HBV and 36,999 had HCV, and this included 14,205 low-dose (75 mg or 160 mg) aspirin users and 36,070 nonusers.

The analysis showed that in aspirin users, the 10-year cumulative incidence of HCC was 4% compared with 8.3% in nonusers. After multivariable adjustment, aspirin users had a risk of HCC that was 31% lower compared with nonusers (adjusted subhazard ratio, 0.69; 95% confidence interval [CI], 0.62 - 0.76).

Patients taking low-dose aspirin had a 10-year liver-related mortality of 11% compared with 17.9% among nonusers. The adjusted risk of liver-related mortality was 27% lower in aspirin users than in nonusers.

There was no significant difference in the 10-year risk of gastrointestinal bleeding between users and nonusers of aspirin (7.8% and 6.9%, respectively). In addition, the analysis showed that the risks of any gastrointestinal bleeding were similar among aspirin-users with compensated cirrhosis and those without cirrhosis (8.3% and 7.5%, respectively).

Notably, the risk of HCC was significantly lower after 3 to 5 years of aspirin use and after 5 or more years of use (adjusted hazard ratio [HR], 0.66, 0.57, respectively) compared with short-term use (3 months to <1 year; adjusted HR, 0.90) or with intermittent, discontinued, or no aspirin use. But when those with chronic viral hepatitis stopped taking aspirin, their risk of HCC rose to become 22% higher compared with peers who continued to use aspirin.

The risk of liver-related death also rose by 31% in aspirin users who stopped taking aspirin compared with those who did not stop (subhazard ratio, 1.31). Again, this relationship appeared to be duration-dependent, with the risk of incident HCC rising sharply among those who discontinued aspirin and increasing in magnitude over time.

The consistency of aspirin use also influenced risk. In individuals who had an on-again, off-again pattern of aspirin use, the incidence of HCC was 5.9% compared with 1.1% in those who used it consistently.

“Our results were consistent regardless of sex, cause of hepatitis, or underlying compensated cirrhosis,” the authors write. “The consistent duration-response associations lend further credence to a potential causal relationship.”

Limitations of the Study

The current study findings are not new, but this is the best-designed study to date, commented Flemming. Still, there were a number of limitations, she noted. Although cirrhosis is the strongest risk factor for HCC in patients with viral hepatitis, for instance, it was assessed only at cohort entry, and not during the median 8 years of follow-up. There was also a lack of information about sustained virologic response (SVR) rates.

Since less than 25% of patients with HCV received HCV therapy, this indicates they were likely treated with interferon-based therapy, Flemming suggested. Interferon-based therapy is associated with much lower SVR rates than direct acting antiviral (DAA) therapy, which can produce SVR in approximately 95% of patients, she pointed out.

“Therefore, a large proportion of the study patients were likely viremic and at a higher baseline risk of HCC than contemporary HCV populations.”

Evidence from a number of studies indicates that achieving SVR with DAA therapy is associated with a 70% risk reduction for incident HCC and liver-related events, Flemming said. “Whether the use of ASA in patients who have achieved SVR provides the same HCC risk reduction and decrease in hepatic outcomes is unknown.”

Also, the study did not provide information on the specific type of HBV therapy used in patients with HBV, Flemming noted. When considering the prevention of HCC in patients with chronic HBV infection, recent data support a differential protective effect of tenofovir disoproxil fumarate (multiple brands) compared with entecavir (Baraclude, Bristol-Myers Squibb), she pointed out. As previously reported by Medscape Medical News, these data also indicate that tenofovir may be more effective than entecavir in reducing the risk of liver failure and all-cause mortality.

This study was funded by the US National Institutes of Health, Nyckelfonden, Region Stockholm County, the American Association for the Study of Liver Diseases, Boston Nutrition Obesity Research Council, Region Örebro County, and Karolinska Institutet. Simon has disclosed no relevant financial relationships. A number of study coauthors disclosed having relationships with industry; the full list can be found with the original article. Flemming reported relationships with Gilead Sciences Canada, AbbVie, and Lupin Pharmaceuticals.

This article first appeared on Medscape.com.

N Engl J Med. 2020 Mar 12. doi: 10.1056/NEJMoa1912035.

The risk of liver cancer and liver-related death in patients with chronic viral hepatitis was substantially reduced with the use of low-dose aspirin, results from a nationwide study from Sweden suggest.

The risk of hepatocellular carcinoma (HCC) was reduced by 31% compared with no aspirin use, and liver-related mortality dropped by 27%, as long as aspirin use continued.

“We were excited to find for the first time in a nationwide Western population that low-dose aspirin use was associated with substantial reduction in risk of developing incident HCC,” lead author Tracey G. Simon, MD, MPH, of Massachusetts General Hospital and Harvard Medical School in Boston, told Medscape Medical News.

The study was published in the March 12 issue of the New England Journal of Medicine.

HCC is the fourth-leading cause of cancer mortality worldwide, and is driven mostly by viral hepatitis B (HBV) and viral hepatitis C (HCV) infection, noted Jennifer A. Flemming, MD, of Queen’s University, Kingston, Canada, an expert not involved with the study. HCC is also one of the only cancers to show a rising incidence over the past several decades, she added .

However, the results of this do not change clinical practice. “It is premature to prescribe low dose ASA [acetylsalicylic acid] in patients with viral hepatitis for the sole indication of HCC prevention in routine clinical practice without support from prospective randomized data,” she said.

“The results of this study make it clear that a prospective randomized study comparing ASA to placebo in patients with viral hepatitis without an indication for low-dose ASA is justified to evaluate the risk of incident HCC,” she told Medscape Medical News.

The study authors agree, and they also emphasize that the findings from this observational study “should not yet change clinical practice.”

More research is needed in populations with compensated and decompensated cirrhosis to determine the optimal timing of aspirin initiation — or cessation of therapy — that will maximize benefit and prevent adverse events, said Simon.

Study Details

Although several earlier studies have suggested a duration-dependent benefit of aspirin use in preventing HCC in smaller populations, this study is the first to confirm a duration-response relationship with low-dose aspirin use in an unselected European population with confirmed viral hepatitis, Simon pointed out.

For their study, Simon and colleagues used the Swedish Register for Surveillance of Communicable Diseases database to identify 50,275 adults diagnosed between 2005 and 2015 with acute and chronic HBV and HCV infection. Some 13,276 adults had HBV and 36,999 had HCV, and this included 14,205 low-dose (75 mg or 160 mg) aspirin users and 36,070 nonusers.

The analysis showed that in aspirin users, the 10-year cumulative incidence of HCC was 4% compared with 8.3% in nonusers. After multivariable adjustment, aspirin users had a risk of HCC that was 31% lower compared with nonusers (adjusted subhazard ratio, 0.69; 95% confidence interval [CI], 0.62 - 0.76).

Patients taking low-dose aspirin had a 10-year liver-related mortality of 11% compared with 17.9% among nonusers. The adjusted risk of liver-related mortality was 27% lower in aspirin users than in nonusers.

There was no significant difference in the 10-year risk of gastrointestinal bleeding between users and nonusers of aspirin (7.8% and 6.9%, respectively). In addition, the analysis showed that the risks of any gastrointestinal bleeding were similar among aspirin-users with compensated cirrhosis and those without cirrhosis (8.3% and 7.5%, respectively).

Notably, the risk of HCC was significantly lower after 3 to 5 years of aspirin use and after 5 or more years of use (adjusted hazard ratio [HR], 0.66, 0.57, respectively) compared with short-term use (3 months to <1 year; adjusted HR, 0.90) or with intermittent, discontinued, or no aspirin use. But when those with chronic viral hepatitis stopped taking aspirin, their risk of HCC rose to become 22% higher compared with peers who continued to use aspirin.

The risk of liver-related death also rose by 31% in aspirin users who stopped taking aspirin compared with those who did not stop (subhazard ratio, 1.31). Again, this relationship appeared to be duration-dependent, with the risk of incident HCC rising sharply among those who discontinued aspirin and increasing in magnitude over time.

The consistency of aspirin use also influenced risk. In individuals who had an on-again, off-again pattern of aspirin use, the incidence of HCC was 5.9% compared with 1.1% in those who used it consistently.

“Our results were consistent regardless of sex, cause of hepatitis, or underlying compensated cirrhosis,” the authors write. “The consistent duration-response associations lend further credence to a potential causal relationship.”

Limitations of the Study

The current study findings are not new, but this is the best-designed study to date, commented Flemming. Still, there were a number of limitations, she noted. Although cirrhosis is the strongest risk factor for HCC in patients with viral hepatitis, for instance, it was assessed only at cohort entry, and not during the median 8 years of follow-up. There was also a lack of information about sustained virologic response (SVR) rates.

Since less than 25% of patients with HCV received HCV therapy, this indicates they were likely treated with interferon-based therapy, Flemming suggested. Interferon-based therapy is associated with much lower SVR rates than direct acting antiviral (DAA) therapy, which can produce SVR in approximately 95% of patients, she pointed out.

“Therefore, a large proportion of the study patients were likely viremic and at a higher baseline risk of HCC than contemporary HCV populations.”

Evidence from a number of studies indicates that achieving SVR with DAA therapy is associated with a 70% risk reduction for incident HCC and liver-related events, Flemming said. “Whether the use of ASA in patients who have achieved SVR provides the same HCC risk reduction and decrease in hepatic outcomes is unknown.”

Also, the study did not provide information on the specific type of HBV therapy used in patients with HBV, Flemming noted. When considering the prevention of HCC in patients with chronic HBV infection, recent data support a differential protective effect of tenofovir disoproxil fumarate (multiple brands) compared with entecavir (Baraclude, Bristol-Myers Squibb), she pointed out. As previously reported by Medscape Medical News, these data also indicate that tenofovir may be more effective than entecavir in reducing the risk of liver failure and all-cause mortality.

This study was funded by the US National Institutes of Health, Nyckelfonden, Region Stockholm County, the American Association for the Study of Liver Diseases, Boston Nutrition Obesity Research Council, Region Örebro County, and Karolinska Institutet. Simon has disclosed no relevant financial relationships. A number of study coauthors disclosed having relationships with industry; the full list can be found with the original article. Flemming reported relationships with Gilead Sciences Canada, AbbVie, and Lupin Pharmaceuticals.

This article first appeared on Medscape.com.

N Engl J Med. 2020 Mar 12. doi: 10.1056/NEJMoa1912035.