AT THE LIVER MEETING 2017
WASHINGTON (FRONTLINE MEDICAL NEWS) – Research into alcoholic liver disease, drug-induced liver injury, the complications of chronic liver disease, and cholestatic liver diseases were among the clinical hepatology highlights presented at the annual meeting of the American Association for the Study of Liver Diseases.
This year’s debrief was given by Kris V. Kowdley, MD , of Swedish Medical Center in Seattle.
Dr. Kowdley first focused on alcoholic liver disease, highlighting the ACCELERATE-AH (abstract 12) trial of outcomes in early liver transplant for alcoholic hepatitis.
Over a median of 1.6 years of follow-up, 27% of patients resumed alcohol consumption post transplant with a median time to alcohol of 160 days, according to Brian Lee, MD, of the University of California, San Francisco. Younger age and lack of complete acceptance of their alcoholic hepatitis diagnosis were significant predictors of alcohol use post transplant while factors such as length of abstinence, race/ethnicity, insurance status, history of illicit drug use, and history of failed rehab attempts were not. Further, heavy drinking at presentation (more than 10 drinks per day), any alcohol use post transplant, and sustained alcohol use post transplant were significant predictors of posttransplant death.
Alcoholic hepatitis now “appears to be affecting more and more younger women, who present with a higher level of acuity,” Dr. Kowdley noted. He added that, while recent advances have decreased the absolute number of hepatitis C patients with decompensated liver disease who are listed for liver transplant, “the number is increasing rapidly in alcoholic liver disease, approaching the rate of patients being listed for hepatitis C.”
Unknown ingredients in herbal and dietary supplements continue to be of concern, Dr. Kowdley noted, as highlighted by Victor J. Navarro, MD, of Einstein Healthcare Network, Philadelphia, and his colleagues at the Drug-Induced Liver Injury Network (DILIN).
Investigators collected herbal and dietary supplements from patients enrolled in the DILIN prospective study and had chemical analysis performed by an outside laboratory. Labeled contents could not be verified in over half of the supplements collected and several unlabeled hepatotoxic ingredients were identified, Dr. Navarro and colleagues found (abstract 264).
“Even though we collect the supplements and review them with the patients, it’s not clear that we even know what it is that they are taking,” Dr. Kowdley commented.
Another DILIN study, this one presented by Jawad Ahmad, MD, of the Icahn School of Medicine at Mount Sinai, New York, “provided an opportunity for pause,” Dr. Kowdley said.
Dr. Ahmad and colleagues looked at hepatitis C virus (HCV) testing in DILIN patients and were able to correlate anti-HCV test results with HCV RNA tests results in more than 95% of 1,500 patients (abstract 16). About 7% of patients were HCV positive, and 23 cases of acute hepatitis were identified (16 with anti-HCV antibodies and HCV RNA, 7 with HCV RNA alone, and none with anti-HCV antibodies alone).
“So the take-home message here for me is, even if we think the patient has drug-induced liver injury, if they have not been tested for hepatitis C, especially if in the hospitalized setting … it is important to check not only the antibody test but also the RNA test,” Dr. Kowdley said.
Finally, in children, minocycline and valproate were the most commonly indicated agents in pediatric drug-induced liver injury, according to Frank DiPaola, MD, of the University of Michigan, and colleagues, on behalf of DILIN (abstract 13).
Dr. Kowdley also highlighted a couple of studies that addressed the complications of chronic liver disease.
The ADAPT-1 and ADAPT-2 trials (abstract 217) studied the use of avatrombopag, a thrombopoietin (TPO)–receptor agonist, to reduce severe thrombocytopenia in patients with chronic liver disease. Platelet transfusion is the current standard of care to reduce the risk of bleeding during invasive procedures in these patients; currently there are no drugs approved for this indication, Dr. Kowdley said.
Avatrombopag is an oral, small molecule TPO-receptor agonist, he said. “Because it binds to a different site on the TPO receptor than endogenous TPO, the effects are additive.”
In the phase 3 ADAPT-1 and ADAPT-2, the proportion of patients who did not require platelet transfusion or any rescue procedure for bleeding was significantly less in avatrombopag-treated patients than those receiving placebo. The effect was the same for patients with a low baseline platelet count (less than 40,000 platelets per mcL) as well as those with a high baseline platelet count (between 40,000/mcL and 50,000/mcL). Further, the proportion of patients who by procedure day achieved platelet count of at least 50,000/mcL was significantly higher in patients on the study drug.
Data on lusutrombopag, another TPO-receptor agonist, was presented as a late-breaker at the meeting, with very similar results in avoiding platelet transfusion, Dr. Kowdley noted.Two abstracts (502 and 219) focused on reducing ammonia levels in hospitalized cirrhosis patients with hepatic encephalitis.
Patients in the STOP-HE trial were randomized to either physician’s choice for standard of care or standard of care plus continuous infusion of ornithine phenylacetate for up to 5 days. Patients were assigned to one of three dosing groups (20 g, 15 g, or 10 g), based on severity of underlying liver disease; those with the most severe disease received the lowest dose.
Reduction in plasma ammonia levels correlated significantly with clinical improvement. At 48 hours, meaningful clinical improvement occurred in 84% of patients on ornithine phenylacetate, compared with 58% of placebo patients, according to Robert S. Rahimi, MD, of Baylor University, Dallas, and his colleagues.
“So, this may be an option for our hepatic encephalopathy patients who are admitted to the hospital and need acute treatment,” Dr. Kowdley said.
Dr. Kowdley finished up with two studies on primary biliary cholangitis (PBC).
Carla Murillo Perez, MD, of Toronto General Hospital and her colleagues in the Global PBC Study Group investigated the role of serum bilirubin in predicting transplant-free survival in patients with PBC (abstract 70).
When serum bilirubin levels from a previous study were input into a Cox regression analysis as a cubic spline function, then adjusted for factors such as age, sex, treatment with ursodeoxycholic acid, and year of diagnosis, the investigators found that patients with serum bilirubin levels of 0.7 times the upper limit of normal had a significantly increased risk of liver transplantation or death.
“We may want to be more sensitive in looking at bilirubin levels,” Dr. Kowdley said.
Another small but notable study presented by Gideon M. Hirschfield, MD, of the University of Birmingham (England), looked into whether a lower dose of seladelpar would safely and effectively lower alkaline phosphatase (AP) levels in PBC patients. A previous study of seladelpar at 50 mg and 200 mg doses indicated the drug’s effectiveness; however, the study was stopped because of the development of grade 3 alanine aminotransferase increases in a number of patients (Lancet Gastroenterol Hepatol. 2017;2;716-26).
Dr. Hirschfield and colleagues enrolled 24 patients and randomized 12 to seladelpar 5 mg and another 12 to 10 mg. The study cohort was mostly female, with an average age of 58 years. Most were either intolerant of or inadequately treated by ursodeoxycholic acid. AP levels were reduced significantly over time in both groups; however, differences between the groups were not significant, the investigators noted.
The Liver Meeting will be held in San Francisco in 2018, taking place Nov. 9-13. Many investigators in these trials reported relevant conflicts of interest; information is available (open access) in a supplement to Hepatology.
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