Neeral L. Shah

Effects of n-3 fish oil on metabolic and histological parameters in NASH: A double-blind, randomized, placebo-controlled trial

BACKGROUND & AIMS This studys aim was to assess the histological and metabolic effects of n-3 polyunsaturated fatty acids (PUFAs) vs. placebo while adjusting for the impact of age and weight change in NASH patients. (ClinicalTrials.gov: NCT00681408). METHODS Forty-one subjects with non-cirrhotic NASH were enrolled, and 34 completed the study. 17 received n-3 fish oil 3000 mg/day and 17 received placebo daily for 1 year with typical counselling on caloric intake and physical activity for all subjects. RESULTS N-3- and placebo-treated groups showed no significant difference for the primary end point of NASH activity score (NAS) reduction ⩾ 2 points without fibrosis progression after adjustment for known covariates (n-3, 4/17 (23.5%); placebo, 3/17, (17.6%), p = 0.99). Among subjects with increased or stable weight, n-3 subjects showed a larger decrease in liver fat content by MRI than placebo-treated subjects (p = 0.014 for 2nd quartile, p = 0.003 for 3rd quartile of weight change). N-3 treatment showed significant fat reduction on the paired analysis of image-assisted fat morphometry regardless of weight loss or gain. Exercise capacity remained markedly reduced in all subjects. No independent effects on markers of hepatocyte injury or insulin sensitivity indices were observed. CONCLUSION N-3 PUFAs at 3000 mg/day for one year did not lead to an improvement in the primary outcome of histological activity in NASH patients (⩾ 2 point NAS reduction). N-3 led to reduced liver fat by multiple measures. Other metabolic effects were not seen, although no detrimental effects were apparent. Whether longer duration, higher dose, or different composition of n-3 therapy would lead to additional benefits is uncertain.

Excess mortality on the liver transplant waiting list: Unintended policy consequences and model for End‐Stage Liver Disease (MELD) inflation

The Model for End‐Stage Liver Disease (MELD) allocation system for liver transplantation provides “exceptions” for diseases such as hepatocellular carcinoma (HCC). It was the aim of this study to assess equipoise between exception candidates and nonexception candidates on the waiting list and to assess if the exception system contributes to steadily increasing regional MELD at transplant. In all, 78,595 adult liver transplant candidates between January 2005 and December 2012 were analyzed. Yearly trends in waiting list characteristics and transplantation rates were analyzed for statistical association with MELD exceptions. Regional variations in these associations and the effect of exceptions on regional MELD scores at transplant were also analyzed. 27.29% of the waiting list was occupied by candidates with exceptions. Candidates with exceptions fared much better on the waiting list compared to those without exceptions in mean days waiting (HCC 237 versus non‐HCC 426), transplantation rates (HCC 79.05% versus non‐HCC 40.60%), and waiting list death rates (HCC 4.49% versus non‐HCC 24.63%). Strong regional variation in exception use occurred but exceptions were highly correlated with waiting list death rates, transplantation rates, and MELD score at removal in all regions. In a multivariate model predicting MELD score at transplant within regions, the percentage of HCC MELD exceptions was the strongest independent predictor of regional MELD score at transplant. Conclusion: Liver transplant candidates with MELD exceptions have superior outcomes compared to nonexception candidates and the current MELD exception system is largely responsible for steadily increasing MELD scores at transplant independent of geography. (Hepatology 2015;61:285–291)

Randomized, double-blind, controlled study of glycerol phenylbutyrate in hepatic encephalopathy

Glycerol phenylbutyrate (GPB) lowers ammonia by providing an alternate pathway to urea for waste nitrogen excretion in the form of phenylacetyl glutamine, which is excreted in urine. This randomized, double‐blind, placebo‐controlled phase II trial enrolled 178 patients with cirrhosis, including 59 already taking rifaximin, who had experienced two or more hepatic encephalopathy (HE) events in the previous 6 months. The primary endpoint was the proportion of patients with HE events. Other endpoints included the time to first event, total number of events, HE hospitalizations, symptomatic days, and safety. GPB, at 6 mL orally twice‐daily, significantly reduced the proportion of patients who experienced an HE event (21% versus 36%; P = 0.02), time to first event (hazard ratio [HR] = 0.56; P < 0.05), as well as total events (35 versus 57; P = 0.04), and was associated with fewer HE hospitalizations (13 versus 25; P = 0.06). Among patients not on rifaximin at enrollment, GPB reduced the proportion of patients with an HE event (10% versus 32%; P < 0.01), time to first event (HR = 0.29; P < 0.01), and total events (7 versus 31; P < 0.01). Plasma ammonia was significantly lower in patients on GPB and correlated with HE events when measured either at baseline or during the study. A similar proportion of patients in the GPB (79%) and placebo groups (76%) experienced adverse events. Conclusion: GPB reduced HE events as well as ammonia in patients with cirrhosis and HE and its safety profile was similar to placebo. The findings implicate ammonia in the pathogenesis of HE and suggest that GPB has therapeutic potential in this population. (Clinicaltrials.gov, NCT00999167). (Hepatology 2014;59:1073‐1083)

Reactivation of hepatitis B with reappearance of hepatitis B surface antigen after chemotherapy and immunosuppression.

BACKGROUND & AIMS HBV infection may reactivate in the setting of immunosuppression, although the frequency and consequences of HBV reactivation are not well known. We report 6 patients who experienced loss of serologic markers of hepatitis B immunity and reappearance of HBsAg in the serum as a result of a variety of acquired immune deficiencies. METHODS Between 2000 and 2005, six patients with reactivation of hepatitis B were seen in consultation by the Liver Diseases Branch at the Clinical Center, National Institutes of Health. The course and outcome of these 6 patients were reviewed. RESULTS All 6 patients developed reappearance of HBsAg and evidence of active liver disease after stem cell transplantation (n = 4), immunosuppressive therapy (n = 1), or change in human immunodeficiency virus antiretroviral regimen (n = 1), despite having antibody to HBsAg (anti-HBs) or antibody to hepatitis B core antigen (anti-HBc) without HBsAg before. All 6 patients developed chronic hepatitis B, 2 patients transmitted hepatitis B to their spouses, and 1 patient developed cirrhosis. The diagnosis of hepatitis B reactivation was frequently missed or delayed and often required interruption of the therapy for the underlying condition. None of the patients received antiviral prophylaxis against HBV reactivation. CONCLUSIONS Serologic evidence of recovery from hepatitis B infection does not preclude its reactivation after immunosuppression. Screening for serologic evidence of hepatitis B and prophylaxis of those with positive results by using nucleoside analogue antiviral therapy should be provided to individuals in whom immunosuppressive therapy is planned.

Combined liver-kidney and liver transplantation in patients with renal failure outcomes in the MELD era.

With the implementation of the Model for End‐Stage Liver Disease (MELD) scoring system, the number of combined liver–kidney transplants (CLKT) has increased dramatically. The United Network for Organ Sharing (UNOS) dataset was analysed for adult recipients with renal failure for the period between February 2002 and April 2006. This group was subdivided into patients on hemodialysis (HD) and to those not on HD prior to transplantation. All recipients in renal failure (serum creatinine ≥2.5 mg/dl) at the time of transplantation were included. A total of 1397 subjects were in renal failure but not on HD (18% received a CLKT, 82% underwent LT alone). Another 1740 subjects were on HD prior to transplantation (41% received a CLKT while 59% received a LT). In dialysis‐dependent recipients, Cox regression analysis demonstrated CLKT had an independent protective effect. In subjects on HD, CLKT had improved survival at 1 year (79.4 vs. 73.7%, P = 0.004). In patients in renal failure without HD, CLKT was not protective. CLKT subjects had a nonsignificant difference in survival as compared with patients who had undergone liver transplantation alone, at 1 year (81.0% vs. 78.8%, P > 0.10). In subjects undergoing CLKT, there was improved survival at 1 year as compared with LT‐alone patients on hemodialysis; however, in patients with renal failure, but not on hemodialysis, there was no difference in survival when comparing CLKT to LT‐alone.

Prophylactic anticoagulation for venous thromboembolism in hospitalized cirrhosis patients is not associated with high rates of gastrointestinal bleeding

Hospitalized patients with cirrhosis are at risk to develop venous thromboembolism. Although current guidelines support the routine administration of thromboprophylaxis to hospitalized patients, there is limited data regarding the safety or efficacy of this practice in hospitalized cirrhosis patients.

Hepatic Decompensation Likely Attributable to Simeprevir in Patients with Advanced Cirrhosis

BackgroundHyperbilirubinemia is a common side effect of protease inhibitors used to treat chronic hepatitis C (HCV), and most patients do not experience without clinically overt hepatotoxicity. The safety of second-wave protease inhibitors, including simeprevir, has not been well studied in patients with advanced cirrhosis.Materials & MethodsWe report two cases of suspected drug-induced liver injury leading to hepatic decompensation in patients with advanced HCV cirrhosis treated with the combination of simeprevir and sofosbuvir on a compassionate basis. Both patients developed marked hyperbilirubinemia out of proportion to their aminotransferases, despite clearance of hepatitis C RNA. RUCAM scoring was probable and possible, respectively. While other factors may have contributed to the liver injury, including infection and concurrent administration of other medications, we believe that the potentially deleterious hepatic effects of simeprevir on transporters or other key functional components were the main reason for their decompensation.ConclusionsProtease inhibitors should be used with caution, if at all, in patients with cirrhosis, especially in those with the most advanced disease. We await newer, safer, direct-acting antiviral therapies for such patients, especially those on our transplant list.

Persistence of mixed cryoglobulinemia despite cure of hepatitis C with new oral antiviral therapy including direct-acting antiviral sofosbuvir: A case series

Abstract Objective. Obtaining a sustained virologic response (SVR) in patients with chronic hepatitis C virus (HCV) can decrease hepatic complications and be curative, however, extrahepatic manifestations including mixed cryoglobulinemia (MCN) may persist with interferon-based therapy. Our objective was to review our experience in treating patients with new oral antiviral agents and to assess common factors associated with MCN persistence despite SVR. Methods. We analyzed a case series of five patients with genotype one chronic HCV complicated by MCN who had persistence of cryoglobulins despite completion of triple therapy with oral antiviral agents (boceprivir, telaprivir or sofosbuvir). Results. Patients with cirrhosis appear to have a decreased ability to clear immune complexes. We observed that early viral response by week 8 of therapy and longer periods of undetectable virus on treatment correlated with eventual clearance of serum cryoglobulins in patients without cirrhosis. Two patients were treated with anti-B-cell agent rituximab prior to starting therapy for HCV; this did not lead to a more effective clearance of cryoglobulins. Conclusions. We suggest that a longer treatment course than the standard 24 weeks with triple therapy could aid in the clearance of these immune complexes and cryoglobulins in cirrhotics. More studies to determine the ideal duration of treatment for chronic HCV and coincident MCN are needed, especially in light of the new all oral direct-acting antiviral regimens that are now recommended for HCV treatment.

Increased risk of portal vein thrombosis in patients with cirrhosis due to nonalcoholic steatohepatitis

Portal vein thrombosis (PVT) is a common complication of cirrhosis sometimes implicated in hepatic decompensation. There are no consistent epidemiologic data to suggest an increased risk of thrombotic complications in nonalcoholic steatohepatitis (NASH); however, research suggests an increased risk of thrombosis. Our aim was to examine the independent association between NASH cirrhosis and PVT in patients who underwent liver transplantation (LT) in a cross‐sectional study. Data on all LTs occurring in the United States between January 1, 2003 and December 31, 2012 were obtained from the United Network for Organ Sharing. Multivariable models were constructed to assess the statistical associations and risk factors for the development of PVT. A total of 33,368 patients underwent transplantation. Of these, 2096 (6.3%) had PVT. Of the patients with PVT, 12.0% had NASH. When we compared these patients to a composite of all other causes of cirrhosis, an increased prevalence of PVT was again found, with 10.1% having PVT at the time of transplantation versus 6.0% without NASH (P < 0.001). The strongest risk factor independently associated with a diagnosis of PVT in a multivariable analysis was NASH cirrhosis (odds ratio, 1.55; 95% confidence interval, 1.33‐1.81; P < 0.001). NASH cirrhosis appears to predispose a patient to PVT independently of other risk factors. These epidemiological findings provide support for the idea that NASH is a prothrombotic state, and they should lead to more research in treatment and prevention in this population. Liver Transpl 21:1016‐1021, 2015.

Sorafenib therapy for hepatocellular carcinoma prior to liver transplant is associated with increased complications after transplant

This study compared post‐transplant outcomes of patients with hepatocellular carcinoma (HCC) who took sorafenib prior to orthotopic liver transplantation (OLT) with those patients who were not treated with sorafenib. Thirty‐three patients with HCC who were listed for liver transplantation were studied: 10 patients were treated with sorafenib prior to transplantation in an attempt to prevent progression of HCC while awaiting transplant. The remaining 23 patients were considered controls. The mean duration of sorafenib use was 19.2 (SD 25.2) weeks. Overall death rates were similar between the sorafenib group and control group (20% vs. 8.7%, respectively, P = 0.56). However, the patients in the sorafenib group had a higher incidence of acute cellular rejection following transplantation (67% vs. 22%, OR = 7.2, 95% CI 1.3–39.6, P = 0.04). The sorafenib group also had a higher rate of early biliary complications (67% vs. 17%, OR = 9.5, 1.6–55.0, P = 0.01). The use of sorafenib was found to be an independent predictor of post‐transplant biliary complications (OR 12.6, 1.4–116.2, P = 0.03). Sorafenib administration prior to OLT appears to be associated with an increase in biliary complications and possibly in acute rejection following liver transplantation. Caution should be taken in this setting until larger studies are completed.