Michael D. Voigt

Peginterferon alfa-2a for hepatitis C after liver transplantation: two randomized, controlled trials.

There is currently no effective treatment for recurrent hepatitis C after orthotopic liver transplantation (OLT). We therefore performed two randomized, controlled trials—a prophylaxis trial and a treatment trial—to evaluate the safety and efficacy of peginterferon alfa‐2a in patients who had undergone OLT. The prophylaxis trial enrolled 54 patients within 3 weeks after OLT, and the treatment trial enrolled 67 patients 6 to 60 months after OLT. In each trial, patients were randomized to treatment with once weekly injections of 180 μg peginterferon alfa‐2a or no antiviral treatment for 48 weeks and were followed up for 24 weeks thereafter. Peginterferon alfa‐2a treated patients had significantly lower hepatitis C virus RNA levels and more favorable changes in hepatic histological features compared with untreated controls. However, only 2 treated patients in the prophylaxis trial (8%) and 3 in the treatment trial (12%) achieved a sustained virological response. In the prophylaxis trial, 8 patients (31%) in the peginterferon alfa‐2a group and 9 (32%) in the untreated group were withdrawn prematurely; whereas in the treatment trial, 10 patients (30%) in the peginterferon alfa‐2a group and 6 (19%) in the untreated group were withdrawn prematurely. The incidence of acute rejection was similar in the treated and untreated groups in both the prophylaxis (12% vs. 21%; P = .5) and treatment (12% vs. 0%; P = .1) trials. In conclusion, peginterferon alfa‐2a treatment for 48 weeks is safe and tolerable and offers some efficacy in the post‐OLT setting. Randomized controlled studies are needed to establish the efficacy of pegylated interferon and ribavirin in patients who have undergone OLT. (HEPATOLOGY 2005;41:289–298.)

Liver transplantation for erythropoietic protoporphyria liver disease

In erythropoietic protoporphyria (EPP), there is excessive production of protoporphyrin, primarily in the bone marrow, resulting in increased biliary excretion of this heme precursor. Some patients will develop progressive liver disease that may ultimately require liver transplantation. However, excessive production of protoporphyrin by the bone marrow continues after transplantation, which may cause recurrent disease in the allograft. This study was performed to define post‐transplant survival, the risk of recurrent disease, and specific management issues in patients transplanted for EPP liver disease. The patients studied consisted of twelve males and eight females, with an average age of 31 (range, 13‐56) years at the time of transplantation. The estimated maximum MELD score prior to transplant was 21 (range, 15‐29). Unique complications in the perioperative period were light induced tissue damage in four patients and neuropathy in six, requiring prolonged mechanical ventilation in four. Patient and graft survival rates were 85% at 1 year, 69% at 5 years, and 47% at 10 years. Recurrent EPP liver disease occurred in 11 of 17 patients (65%) who survived more than 2 months. Three patients were retransplanted at 1.8, 12.6, and 14.5 years after the initial transplant for recurrent EPP liver disease. In conclusion, the 5‐year patient survival rate in patients transplanted for EPP liver disease is good, but the recurrence of EPP liver disease appears to diminish long term graft and patient survival. (Liver Transpl 2005;11:1590–1596.)

Older donor livers show early severe histological activity, fibrosis, and graft failure after liver transplantation for hepatitis C.

Background. In hepatitis C virus (HCV)-positive liver transplant recipients, infection of the allograft and recurrent liver disease are important problems. Increased donor age has emerged as an important variable affecting patient and graft survival; however, specific age cutoffs and risk ratios for poor histologic outcomes and graft survival are not clear. Methods. A longitudinal database of all HCV-positive patients transplanted at our center during an 11-year period was used to identify 111 patients who received 124 liver transplants. Graft survival and histological endpoints (severe activity and fibrosis) of HCV infection in the allografts were compared as a function of donor age at transplantation. Results. By Kaplan-Meier analyses, older allografts showed earlier failure and decreased time to severe histological activity and fibrosis as compared with allografts from younger donors. By Cox proportional hazards analysis, older allografts were at greater risk for all severe histologic features and decreased graft survival as compared with younger allografts (P≤0.02 for all outcomes). Analysis of donor age as a dichotomous variable showed that donors greater than 60 yr were at high risk for deleterious histologic outcomes and graft failure. An age cutoff of 60 yr showed a sensitivity of 94% and specificity of 67% for worse graft survival by receiver operating characteristics curve. Conclusions. Advanced donor age is associated with more aggressive recurrent HCV and early allograft failure in HCV-positive liver transplant recipients. Consideration of donor age is important for decisions regarding patient selection, antiviral therapy, and organ allocation.

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)

Prevalence and interaction of hepatitis B and latent tuberculosis in Vietnamese immigrants to the United States

OBJECTIVES:Southeast Asian immigrants, with a high prevalence of both hepatitis B and latent tuberculosis, constitute a large proportion of immigrants to the United States. Isoniazid hepatotoxicity may be associated with hepatitis B. This study was conducted to document the prevalence and interaction of hepatitis B, latent tuberculosis, and isoniazid toxicity.METHODS:Hepatitis B surface antigen (HBsAg) and tuberculin skin testing was done on 743 Vietnamese immigrants to the Midwest between January, 1991 and December, 1999. HBsAg positive cases were tested for hepatitis B e antigen (HBeAg). All tuberculin skin test-positive patients were treated with isoniazid, unless contraindicated. Complications of isoniazid treatment and compliance with hepatitis B virus immunization recommendations were evaluated.RESULTS:One hundred three subjects (13.86%) had HBsAg, and 43 (5.7%) HBeAg. Prevalences of latent tuberculosis were similar in HBsAg positive (53%) and HBsAg negative (45%) subjects. Sixty-two percent of HBeAg positive versus 19% of HBeAg negative subjects had hepatotoxic side effects requiring discontinuation of treatment (relative risk [RR] = 11.38, CI = 5.49 < RR < 23.59, p < 0.001). Three cases of severe isoniazid hepatitis occurred in 21 HBeAg positive subjects, versus no cases in 121 HBeAg negative cases treated with isoniazid (RR = 7.72, CI = 5.02 < RR < 11.88, p < 0.001). Only 58% of subjects at risk of developing hepatitis B virus infection were appropriately immunized.CONCLUSIONS:Vietnamese immigrants have a high prevalence of hepatitis B and latent tuberculosis. HBeAg positive cases have a 7.7-fold increased risk of serious isoniazid toxicity and an 11.3-fold increased risk of isoniazid side effects requiring discontinuation of treatment. HBeAg represents an important risk factor for severe isoniazid hepatitis.

Suprahepatic venacavaplasty (cavaplasty) with retrohepatic cava extension in liver transplantation: experience with first 115 cases.

Background. We first introduced the orthotopic liver transplantation utilizing cavaplasty technique in 1994. This paper describes the surgical technique and assesses the outcome of the cavaplasty OLT. Methods. The cavaplasty procedure was used in 115 consecutive orthotopic liver transplantations, including six left lateral and two right lobe transplantations, between November 1994 and September 2000. Fifty-three (66.3%) transplantations required femoro-axillary veno-venous bypass in the initial 4 years, whereas only eight (22.9%) needed VB in the subsequent 2 years. Conversion to piggyback or standard technique was not necessary in any patient. Results. Median results are as follows: operative time 4.5 hr, warm ischemia time 25 min, and blood transfused (packed red blood cells) 6 units. These findings did not differ between first transplantation and retransplantation. There were no perioperative deaths related to the cavaplasty technique. No hepatic venous outflow obstruction was observed, including living-related OLTs. No patient required postoperative hemodialysis for acute renal failure. The median intensive care and hospital stays were 2 days and 10 days, respectively. Conclusions. The cavaplasty technique requires no retrocaval, hepatic vein, or short hepatic vein dissection, and the inferior vena cava can be preserved, which provides advantages for hepatectomy and easy hemostasis, especially during retransplantation. The wide-open triangular caval anastomosis is easy to perform, allowing short implantation time and size matching and avoiding outflow obstruction. The short implantation time reduces the need for veno-venous bypass. Our experience indicates that the cavaplasty technique can be applied to all patients and is justified by minimal technical complications.

Consecutive occurrence of primary biliary cirrhosis and autoimmune hepatitis: a case report and review of the literature

Autoimmune cholangiopathy is a term that describes a subset of patients with overlapping features of primary biliary cirrhosis (PBC) and autoimmune hepatitis (AH). These patients typically have cholestasis, negative antimitochondrial antibody (AMA), liver histology suggestive of PBC, and may respond clinically to corticosteroid therapy. We describe a patient who presented with typical AMA-positive, biopsy-proven PBC who responded to ursodeoxycholic acid therapy both clinically and biochemically. Approximately 3 yr later, she developed elevated transaminases with biopsy-proven antinuclear antibody (ANA) negative AH. The AMA was negative at this time. After responding to steroid therapy for the AH and after discontinuing the ursodeoxycholic acid, the patient had a clinical recurrence of PBC with renewed AMA positivity.

Locoregional Therapy with Curative Intent versus Primary Liver Transplant for Hepatocellular Carcinoma: Systematic Review and Meta-analysis

Background Locoregional therapy with curative intent (CLRT) followed by salvage liver transplantation (SLT) in case of hepatocellular carcinoma (HCC) recurrence is an alternative to primary liver transplantation (LT) in selected patients with HCC. Methods We performed a systematic review and meta-analysis of studies comparing the survival of patients treated with CLRT versus LT, stratified by the stage of liver disease, extent of cancer, and whether SLT was offered or not. Results We included 48 studies involving 9835 patients (5736 patients with CLRT and 4119 patients with primary LT). Five-year overall survival (OS) and disease-free survival (DFS) was worse for all categories of CLRT combined, than for primary LT (odds ratio [OR] for OS, 0.59; 95% confidence interval [CI], 0.48-0.71; P < 0.01). However, 5-year OS for CLRT and primary LT was not significantly different among patients with (i) Child-A cirrhosis and (ii) single HCC lesion, although DFS was worse. When SLT was offered after CLRT, intention-to-treat analysis showed no significant difference in 5-year OS (OR, 1.0; 95% CI, 0.6-1.7) between CLRT-SLT and primary LT, though noninferiority could not be shown. Only 32.5% patients with HCC recurrence after CLRT actually received SLT, as the rest were not medically eligible. Thus, the DFS was worse with CLRT-SLT (OR, 0.31; 95% CI, 0.2-0.6) compared with LT. Conclusions CLRT-SLT may be offered as first-line therapy to patients with HCC and well-compensated cirrhosis instead of primary LT because it may lead to better utilization of donor liver. However, a large proportion of patients with HCC recurrence after CLRT may not be candidates for SLT.

Positive serum cryoglobulin is associated with worse outcome after liver transplantation for chronic hepatitis C

Background. Recurrent hepatitis C virus (HCV) infection in patients after liver transplantation is an important clinical problem. Because serum cryoglobulins (CG) are known to be associated with an increased incidence of cirrhosis in nontransplant patients, the authors tested the hypothesis that CG would also predict aggressive recurrent HCV in patients after liver transplantation. Methods. Using a longitudinal database, the outcomes of 105 allografts transplanted into 97 HCV-positive patients from 1991 through 2002 were analyzed on the basis of CG status using a retrospective cohort design. Fifty-nine CG-negative and 38 CG-positive patients were identified. Histologic outcomes and graft survival were analyzed using Kaplan-Meier estimates and Cox univariate and multivariate analyses. Both overall survival and HCV-specific survival (non–HVC-related deaths and graft losses censored) were analyzed. Results. By Kaplan-Meier estimates, CG-positive patients showed earlier graft failure with decreased time to severe histologic activity and fibrosis as compared with CG-negative patients (P<0.05 for all outcomes). By univariate analysis, CG-positive patients had significantly higher risk ratios for shortened HCV-specific graft survival, severe activity-free survival, and severe fibrosis-free survival as compared with CG-negative patients (P<0.05 for all outcomes). In the multivariate model, CG was an independent predictor for severe activity-free, severe fibrosis-free, and HCV-specific graft survival (P<0.05 for all outcomes). Conclusions. CG-positivity is associated with severe recurrent HCV disease in liver transplant recipients.

Role of angiotensin in renal sympathetic activation in cirrhotic rats.

Central nervous system (CNS) renin-angiotensin activity influences the basal level of renal sympathetic nerve activity (RSNA) and its reflex regulation. The effect of type 1 angiotensin II (ANG II)-receptor antagonist treatment (losartan) on cardiac baroreflex regulation of RSNA and renal sodium handling was examined in rats with cirrhosis due to common bile duct ligation (CBDL). Basal levels of heart rate, mean arterial pressure (MAP), RSNA, and urinary sodium excretion were not affected by intracerebroventricular administration of either losartan or vehicle to CBDL rats. After acute intravenous isotonic saline loading (10% body wt) in vehicle-treated CBDL rats, MAP was unchanged and the decrease in RSNA seen in normal rats did not occur. However, in losartan-treated CBDL rats, there were significant concurrent but transient decreases in MAP (-20 ± 2 mmHg) and RSNA (-25 ± 3%). The natriuretic response to acute volume loading in losartan-treated CBDL rats was significantly less than that in vehicle-treated CBDL rats only at those time points where there were significant decreases in MAP. Antagonism of CNS ANG II type 1 receptors augments the renal sympathoinhibitory response to acute volume loading in CBDL. However, the natriuretic response to the acute volume loading is not improved, likely due to the strong antinatriuretic influence of the concomitant marked decrease in MAP (renal perfusion pressure) mediated by widespread sympathetic withdrawal from the systemic vasculature.Central nervous system (CNS) renin-angiotensin activity influences the basal level of renal sympathetic nerve activity (RSNA) and its reflex regulation. The effect of type 1 angiotensin II (ANG II)-receptor antagonist treatment (losartan) on cardiac baroreflex regulation of RSNA and renal sodium handling was examined in rats with cirrhosis due to common bile duct ligation (CBDL). Basal levels of heart rate, mean arterial pressure (MAP), RSNA, and urinary sodium excretion were not affected by intracerebroventricular administration of either losartan or vehicle to CBDL rats. After acute intravenous isotonic saline loading (10% body wt) in vehicle-treated CBDL rats, MAP was unchanged and the decrease in RSNA seen in normal rats did not occur. However, in losartan-treated CBDL rats, there were significant concurrent but transient decreases in MAP (-20 +/- 2 mmHg) and RSNA (-25 +/- 3%). The natriuretic response to acute volume loading in losartan-treated CBDL rats was significantly less than that in vehicle-treated CBDL rats only at those time points where there were significant decreases in MAP. Antagonism of CNS ANG II type 1 receptors augments the renal sympathoinhibitory response to acute volume loading in CBDL. However, the natriuretic response to the acute volume loading is not improved, likely due to the strong antinatriuretic influence of the concomitant marked decrease in MAP (renal perfusion pressure) mediated by widespread sympathetic withdrawal from the systemic vasculature.