Faculty Bibliography

The use of sirolimus as an alternative to calcineurin inhibitors for posttransplant immunosuppression is associated with a variety of inflammatory conditions. In this report, we describe the case of a 34-year-old man who developed abnormal liver tests 6 years after live-donor kidney transplantation and 5 years after initiation of sirolimus-based immunosuppression. Elevated aminotransferase levels persisted after withdrawal of potentially hepatotoxic medications, and serologic evaluation for viral hepatitis, autoimmune disease, and genetic disorders was unrevealing. Liver biopsy revealed prominent hepatocellular injury associated with a mixed inflammatory infiltrate and liver tests normalized within 2 weeks of discontinuation of sirolimus. In this report, we review previous reports of sirolimus hepatotoxicity and propose a unifying hypothesis for the various inflammatory conditions that have been attributed to sirolimus

Background: Hyponatremia is a prevalent condition in patients hospitalized across a broad range of conditions, including heart failure, cirrhosis, and the syndrome of inappropriate antidiuretic hormone (SIADH) secretion. Whether present on admission or developing during hospitalization, hyponatremia has been associated with increased mortality, longer hospital stays, and higher costs. Little is known, however, about its management and outcomes outside of clinical trial settings. Methods: The Hyponatremia Registry (HN Registry) is a prospective, observational, multicenter, multinational study of patients hospitalized with either hypervolemic hyponatremia (cirrhosis and heart failure) in the United States or euvolemic hyponatremia (SIADH) in both the United States and Europe. Study enrollment began in September 2010 at community, tertiary, and academic medical centers. Overall, the HN Registry is expected to enroll >5,000 patients with hyponatremia, at >280 sites. Data will be used to characterize demographic and clinical characteristics of patients hospitalized with hyponatremia, evaluate the comparative effectiveness of available treatment modalities, and document and compare length of hospital stay as a reflection of resource use associated with hospital management. Discussion: Despite better understanding of the clinical consequences, economic impact, and prognostic significance of euvolemic and hypervolemic hyponatremia, there remains a need to evaluate current "real-world" management. The HN Registry is designed to provide contemporary data on in-hospital evaluation, management, and length of stay in a large cohort of adult patients with hyponatremia. The HN Registry generated several design and analytical challenges that required unique approaches to facilitate collection of the most clinically relevant data.

The development of hepatorenal syndrome type 1 (HRS1) is associated with a poor prognosis. Liver transplantation improves this prognosis, but the degree of the improvement is unclear. Most patients receive vasoconstrictors such as terlipressin before transplantation, and this may affect the posttransplant outcomes. We examined a cohort of patients with access to liver transplantation from our previously published study of terlipressin plus albumin versus albumin alone in the treatment of HRS1. The purpose of this analysis was the quantification of the survival benefits of liver transplantation for patients with HRS1. Ninety-nine patients were randomized to terlipressin or placebo. Thirty-five patients (35%) received a liver transplant. Among those receiving terlipressin plus albumin, the 180-day survival rates were 100% for transplant patients and 34% for nontransplant patients; among those receiving only albumin, the rates were 94% for transplant patients and 17% for nontransplant patients. The survival rate was significantly better for those achieving a reversal of hepatorenal syndrome (HRS) versus those not achieving a reversal (47% versus 4%, P < 0.001), but it was significantly lower for the responders versus those undergoing liver transplantation (97%). We conclude that the use of terlipressin plus albumin has no significant impact on posttransplant survival. Liver transplantation offers a clear survival benefit to HRS1 patients regardless of the therapy that they receive or the success or failure of HRS reversal. The most likely benefit of terlipressin in patients undergoing liver transplantation for HRS1 is improved pretransplant renal function, and this should make the posttransplant management of this difficult group of patients easier. For patients not undergoing transplantation, HRS reversal with terlipressin and/or albumin improves survival.

The development of hyponatremia represents an ominous event in the progression of cirrhosis to end-stage liver disease. It usually develops in those with refractory ascites and is a manifestation of the non-osmotic release of arginine vasopressin (AVP). In the hospitalized cirrhotic patient, hyponatremia is associated with increased disease severity and mortality. In this article, we review the pathophysiology of hyponatremia, its clinical implications, evaluation, and treatment.

BACKGROUND: Hepatic encephalopathy is a chronically debilitating complication of hepatic cirrhosis. The efficacy of rifaximin, a minimally absorbed antibiotic, is well documented in the treatment of acute hepatic encephalopathy, but its efficacy for prevention of the disease has not been established. METHODS: In this randomized, double-blind, placebo-controlled trial, we randomly assigned 299 patients who were in remission from recurrent hepatic encephalopathy resulting from chronic liver disease to receive either rifaximin, at a dose of 550 mg twice daily (140 patients), or placebo (159 patients) for 6 months. The primary efficacy end point was the time to the first breakthrough episode of hepatic encephalopathy. The key secondary end point was the time to the first hospitalization involving hepatic encephalopathy. RESULTS: Rifaximin significantly reduced the risk of an episode of hepatic encephalopathy, as compared with placebo, over a 6-month period (hazard ratio with rifaximin, 0.42; 95% confidence interval [CI], 0.28 to 0.64; P<0.001). A breakthrough episode of hepatic encephalopathy occurred in 22.1% of patients in the rifaximin group, as compared with 45.9% of patients in the placebo group. A total of 13.6% of the patients in the rifaximin group had a hospitalization involving hepatic encephalopathy, as compared with 22.6% of patients in the placebo group, for a hazard ratio of 0.50 (95% CI, 0.29 to 0.87; P=0.01). More than 90% of patients received concomitant lactulose therapy. The incidence of adverse events reported during the study was similar in the two groups, as was the incidence of serious adverse events. CONCLUSIONS: Over a 6-month period, treatment with rifaximin maintained remission from hepatic encephalopathy more effectively than did placebo. Rifaximin treatment also significantly reduced the risk of hospitalization involving hepatic encephalopathy. (ClinicalTrials.gov number, NCT00298038.)

BACKGROUND: Portal hypertension is a potentially life-threatening complication of cirrhosis, resulting from increased intrahepatic resistance and portal inflow. OBJECTIVE: Given the complex nature of this disorder, a more complete understanding of the pathophysiology of portal hypertension is necessary to develop new therapies that target specific pathways that regulate portal pressure. METHODS: This review is based on a literature search of published articles and abstracts on the pathophysiology of portal hypertension, its complications and its treatment. RESULTS/CONCLUSION: A number of therapies have been developed or are under investigation for the treatment of portal hypertension and its complications. These agents may reduce mortality and improve quality of life for patients with advanced liver disease