A. Scott Mills

A randomized, double-blind, placebo-controlled trial of ursodeoxycholic acid in primary biliary cirrhosis

One hundred fifty-one patients with primary biliary cirrhosis (PBC) grouped into four strata based on entry serum bilirubin ( or +2 (strata 3 and 4). Histology was favorably affected by ursodiol in patients in strata 1 and 2 but not in strata 3 and 4. Ursodiol enrichment in fasting bile obtained at the conclusion of the trail was approximately 40% and comparable in all strata. Thus, differences in ursodiol enrichment of the bile acid pool do not explain better responses of laboratory tests and histology found in patients with less advanced PBC. Patients treated will ursodiol tended to develop a treatment failure less frequently that those who received placebo, particularly in strata 1 and 2 (ursodiol 42%, placebo 60%, P = .078). Development of severe symptoms (fatigue/pruritus) and doubling of serum bilirubin were reduced significantly in ursodiol-treated patients.(ABSTRACT TRUNCATED AT 250 WORDS)

A Randomized, Controlled Trial of Maintenance Interferon Therapy for Patients With Chronic Hepatitis C Virus and Persistent Viremia

BACKGROUND & AIMS : At least half of patients with chronic hepatitis C virus (HCV) fail to respond to interferon or interferon/ribavirin therapy. Histological improvement is observed in some nonresponders. We conducted a randomized, controlled trial to determine if maintenance interferon therapy could prevent histological progression in this subset of nonresponders. METHODS Fifty-three patients with chronic HCV were enrolled. All were HCV-RNA positive after 6 months of treatment with interferon alfa-2b but had a histological response. Twenty-seven of the patients were randomly assigned to continue interferon (3 MU 3 times weekly) for 24 months; 26 patients discontinued treatment and were observed prospectively. Alanine aminotransferase (ALT) level and HCV-RNA titer were monitored, and liver biopsy was repeated every 12 months. RESULTS Before interferon therapy, the 2 groups were well matched for all demographic factors, serum ALT (94.0 +/- 15.6), log HCV-RNA titer (5. 85 +/- 0.15 copies/mL), histology score (9.5 +/- 0.2), and percentage with cirrhosis (25%). After 6 months of treatment, significant reductions (P < 0.05) in serum ALT level (62.6 +/- 9.6), log HCV-RNA titer (4.79 +/- 0.13 copies/mL), and hepatic inflammation (4.0 +/- 0.2) were observed. These improvements were maintained in the patients randomized to continue interferon. Stopping treatment was associated with an increase in serum ALT, log HCV-RNA, and hepatic inflammation back to baseline. After 30 months of treatment, mean fibrosis score declined from 2.5 to 1.7 and 80% of patients had histological improvement (P < 0.03). Discontinuation of interferon was associated with an increase in mean fibrosis score from 2.2 to 2.4 and worsening of hepatic histology in 30% of patients (P < 0.01). CONCLUSIONS These data support the hypothesis that maintenance interferon may prevent histological progression of chronic HCV in patients who remain viremic.

Nonalcoholic fatty liver disease in patients with hepatitis C is associated with features of the metabolic syndrome.

OBJECTIVES:The objectives of this study were to determine the following: 1) whether chronic hepatitis C virus (HCV) infection was specifically associated with nonalcoholic fatty liver disease (NAFLD); 2) the factors associated with NAFLD in patients with HCV; and 3) the clinical and histological spectrum of NAFLD occurring together with HCV.METHODS:A retrospective analysis of 3826 biopsies was performed to compare the prevalence of NAFLD in those with HCV versus that in other liver diseases, e.g., hepatitis B, primary biliary cirrhosis, and α1-antitrypsin deficiency. Patients with HCV and NAFLD were also compared with an age- and gender-matched control group with HCV and <5% hepatic steatosis.RESULTS:The prevalence of NAFLD in patients with HCV was similar to that in hepatitis B, primary biliary cirrhosis, or α1-antitrypsin deficiency. The risk of having NAFLD in patients with HCV correlated with body weight (r= 0.7, p < 0.02). Compared with a control group with HCV alone (n = 75), patients with HCV and NAFLD (n = 69) were likely to be heavier (mean BMI 27 vs 30, p < 0.003), diabetic (eight vs 21, p < 0.005), hypertensive (14 vs 25, p < 0.05), and hypertriglyceridemic (15 vs 33, p < 0.05). The HCV viral load, genotype distribution, liver enzymes, liver functions, and ferritin levels were comparable across the study groups. Those with HCV and NAFLD were more likely to have advanced fibrosis (bridging fibrosis or cirrhosis) (26% vs 53%, p < 0.03). Weight, diabetes, and cytological ballooning were independent predictors of advanced fibrosis in those with HCV and NAFLD.CONCLUSION:The presence of NAFLD in patients with HCV is strongly associated with features of the metabolic syndrome and is a risk factor for advanced fibrosis. Advanced fibrosis in such patients is related to weight, presence of diabetes, and presence and degree of cytological ballooning.

Effects of interferon treatment on liver histology and allograft rejection in patients with recurrent hepatitis C following liver transplantation

Recurrent hepatitis C after liver transplantation remains a significant cause of graft loss and retransplantation. Although treatment of recurrent hepatitis C with interferon‐based regimens has become widely accepted as safe and can lead to sustained virologic clearance of hepatitis C virus (HCV) RNA, long‐term histologic improvement and the risk of precipitating graft rejection remain controversial. The present study is a retrospective evaluation of the clinical and histological consequences of treating recurrent hepatitis C with interferon‐based therapy in a selected group of liver transplant recipients. Twenty‐three liver transplant recipients with recurrent hepatitis C and histologic evidence of progressive fibrosis completed at least 6 months of interferon, 83% of whom received pegylated‐interferon α‐2b; only 4 tolerated ribavirin. Overall, 11 patients (48%) had undetectable HCV RNA at the end of 6 months of treatment. Of these patients, 3 remained HCV RNA–negative on maintenance interferon monotherapy for 33 months, and the other 8 (35%) completed treatment and remained HCV RNA–undetectable 24 weeks after discontinuation of interferon. Overall necroinflammatory activity in liver biopsies obtained 2 years after HCV RNA became undetectable decreased significantly (7.73 ± 2.37 vs. 5.64 ± 2.94 units before and after treatment, respectively; P = .016). However, 5 of these 11 patients had no histologic improvement in follow‐up liver histology. Liver biopsies in the 12 nonresponders demonstrated disease progression. Of the 23 patients treated with interferon, 8 (35%) had evidence of acute or chronic rejection on posttreatment liver biopsy, most of whom had no previous history of rejection (P < .01 for comparison of pretreatment and posttreatment prevalence of histologic rejection), and 2 experienced graft loss from chronic rejection, requiring retransplantation. In conclusion, interferon treatment of recurrent hepatitis C does not consistently improve histologic disease after virologic response, and it may increase the risk of allograft rejection. (Liver Transpl 2004;10:850–858.)

Histologic recurrence of chronic hepatitis C virus in patients after living donor and deceased donor liver transplantation

Hepatitis C virus (HCV) recurs in nearly all patients after liver transplantation. This recurrence is associated with progressive fibrosis and graft loss. It remains unclear whether the natural course of HCV recurrence is altered in patients who undergo living donor liver transplantation (LDLT). We conducted a prospective, controlled trial using protocol liver biopsies to evaluate the histologic outcome of recurrent HCV in 23 patients who underwent LDLT and 53 patients who underwent transplantation with a deceased donor liver (DDLT) during the same period of time. Patients who did not survive at least 6 months after transplantation or who had hepatocellular carcinoma or any other coexistent liver disease were excluded from analysis. All patients underwent protocol liver biopsy at 6 months and at 12 months and at yearly intervals thereafter. The mean age, sex, racial distribution, and serum HCV RNA and the percentage of patients with genotype 1 were similar in the 2 groups of patients. The model for end‐stage liver disease score at the time of transplantation was slightly lower in patients who underwent LDLT, but this difference was not significant. The distribution of immunosuppression agents used, the mean doses of calcineurin agents, the use of mycophenolate mofetil, and the dose and tapering schedule for prednisone were similar in both groups of patients. The mean duration of follow‐up was 40 months. No significant difference in either graft or patient survival or the percentage of patients who developed acute rejection was noted in the 2 groups of patients. At 48 months, graft and patient survival were 82% and 82% and 75% and 79% for patients who underwent DDLT and LDLT, respectively. The degree of hepatic inflammation increased stepwise over 3 years but was not significantly different in the 2 patient groups. In contrast, the mean fibrosis score and the percentage of patients with fibrosis increased stepwise after DDLT but appeared to plateau 12 months after LDLT. At 36 months, fibrosis was present in 78% of DDLT patients, and mean fibrosis score was 1.9, compared with 59% with fibrosis and a mean score of .9 after LDLT. In conclusion, these data strongly suggest that fibrosis progression from recurrent HCV is not more severe in patients after LDLT. (Liver Transpl 2004;10:1248–1255.)

A prospective evaluation of fibrosis progression in patients with recurrent hepatitis C virus following liver transplantation

Recurrence of hepatitis C virus (HCV) following liver transplantation (LT) is universal. A subset of these patients develop advanced fibrosis and cirrhosis and it is believed that this leads to increased posttransplantation mortality. The specific aims of this study were to determine the incidence of advanced fibrosis and those factors associated with this process, and to evaluate causes for mortality in patients with recurrent HCV. A total of 227 patients who underwent LT with chronic HCV were monitored prospectively. The mean age of this group at LT was 49.5 yr; 76% were male and 85% were Caucasian. Fibrosis progression was monitored by protocol liver biopsy, initially performed 6 months after LT and then at 6‐ to 24‐month intervals. Advanced fibrosis, defined as the bridging fibrosis or cirrhosis, developed in 1%, 11%, 25%, and 41% of patients after 1, 3, 5, and 6‐10 yr, respectively. Acute cellular rejection hepatic steatosis, a persistent elevation in serum alanine aminotransferase and donor‐race were associated with the development of advanced fibrosis. In contrast, the development of advanced fibrosis was not affected by the use of interferon prior to undergoing LT, cytomegalovirus disease, or donor age. A total of 60 patients (26%) died over 15 yr of follow‐up. Although graft failure accounted for 45% of deaths in patients with advanced fibrosis, this represented only 8% of all deaths in patients with recurrent HCV. Sepsis was the most common cause of death and this was observed with similar frequency in patients who developed advanced fibrosis (45%) and in those with less advanced fibrosis (47%). In conclusion, approximately 41% of patients with recurrent HCV developed advanced fibrosis 6‐10 yr after LT. However, complications associated with sepsis, not recurrent cirrhosis, was the most common cause of death in patients with recurrent HCV and this was similar in patients with or without advanced fibrosis. Liver Transpl 13:975–983, 2007.

Chronic hepatitis C infection in patients with end stage renal disease: characterization of liver histology and viral load in patients awaiting renal transplantation

Chronic hepatitis C infection in patients with end stage renal disease: characterization of liver histology and viral load in patients awaiting renal transplantation

Methotrexate (MTX) plus ursodeoxycholic acid (UDCA) in the treatment of primary biliary cirrhosis.

This placebo‐controlled, randomized, multicenter trial compared the effects of MTX plus UDCA to UDCA alone on the course of primary biliary cirrhosis (PBC). Two hundred and sixty five AMA positive patients without ascites, variceal bleeding, or encephalopathy; a serum bilirubin less than 3 mg/dL; serum albumin 3 g/dL or greater, who had taken UDCA 15 mg/kg daily for at least 6 months, were stratified by Ludwigs histological staging and then randomized to MTX 15 mg/m2 body surface area (maximum dose 20 mg) once a week while continuing on UDCA. The median time from randomization to closure of the study was 7.6 years (range: 4.6‐8.8 years). Treatment failure was defined as death without liver transplantation; transplantation; variceal bleeding; development of ascites, encephalopathy, or varices; a doubling of serum bilirubin to 2.5 mg/dL or greater; a fall in serum albumin to 2.5 g/dL or less; histological progression by at least two stages or to cirrhosis. Patients were continued on treatment despite failure of treatment, unless transplantation ensued, drug toxicity necessitated withdrawal, or the patient developed a cancer. There were no significant differences in these parameters nor to the time of development of treatment failures observed for patients taking UDCA plus MTX, or UDCA plus placebo. The trial was conducted with a stopping rule, and was stopped early by the National Institutes of Health at the advice of our Data Safety Monitoring Board for reasons of futility. In conclusion, methotrexate when added to UDCA for a median period of 7.6 years had no effect on the course of PBC treated with UDCA alone. Supplementary material for this article can be found on the HEPATOLOGY website (http://www.interscience.wiley.com/jpages/0270‐9139/suppmat/index.html). (HEPATOLOGY 2005;42:1184–1193.)

Prognostic value of Ishak fibrosis stage: findings from the hepatitis C antiviral long-term treatment against cirrhosis trial.

Studies of the prognostic value of Ishak fibrosis stage are lacking. We used multi‐year follow‐up of the Hepatitis C Antiviral Long‐Term Treatment Against Cirrhosis (HALT‐C) Trial to determine whether individual Ishak fibrosis stages predicted clinical outcomes in patients with chronic hepatitis C. Baseline liver biopsy specimens from 1050 patients with compensated chronic hepatitis C who had failed combination peginterferon and ribavirin were reviewed by a panel of expert hepatopathologists. Fibrosis was staged with the Ishak scale (ranging from 0 = no fibrosis to 6 = cirrhosis). Biopsy fragmentation and length as well as number of portal tracts were recorded. We compared rates of prespecified clinical outcomes of hepatic decompensation and hepatocellular carcinoma across individual Ishak fibrosis stages. Of 1050 biopsy specimens, 25% were fragmented, 63% longer than 1.5 cm, 69% larger than 10 mm2, and 75% had 10 or more portal tracts. Baseline laboratory markers of liver disease severity were worse and the frequency of esophageal varices higher with increasing Ishak stage (P < 0.0001). The 6‐year cumulative incidence of first clinical outcome was 5.6% for stage 2, 16.1% for stage 3, 19.3% for stage 4, 37.8% for stage 5, and 49.3% for stage 6. Among nonfragmented biopsy specimens, the predictive ability of Ishak staging was enhanced; however, no association was observed between Ishak stage and outcomes for fragmented biopsy specimens because of high rates of outcomes for patients with noncirrhotic stages. Similar results were observed with liver transplantation or liver‐related death as the outcome. Conclusion: Ishak fibrosis stage predicts clinical outcomes, need for liver transplantation, and liver‐related death in patients with chronic hepatitis C. Patients with fragmented biopsy specimens with low Ishak stage may be understaged histologically. (HEPATOLOGY 2010;51:585–594.)

A comparison of the spectrum of chronic hepatitis C virus between Caucasians and African Americans

BACKGROUND & AIMS Differences in hepatitis C virus (HCV)-related liver disease between Caucasians and African Americans remain controversial. METHODS We performed a retrospective analysis of 302 consecutive inmates in the Virginia Department of Corrections evaluated for HCV between October 1998 and July 2002. All subjects were anti-HCV positive, HCV treatment naive, human immunodeficiency virus and HBV negative, and had compensated liver disease. RESULTS The mean age of the cohort was 41 years; they were 91% male and 51% Caucasian. The mean ALT level was 94 U/L, 49% had a normal ALT level, and 80% were genotype 1. The mean Knodell histologic activity index (HAI) was 7.03, with bridging fibrosis in 18% and cirrhosis in 6%. When analyzed by race, the mean ALT level (106 vs. 79 U/L; P = 0.01), proportion with normal ALT level (46% vs. 57%; P = 0.06), and proportion with genotype 1 (67% vs. 94%; P < 0.001) were different between Caucasians and African Americans, respectively. Although the HAI and proportion with bridging fibrosis/cirrhosis were similar between groups, African Americans had lower piecemeal necrosis (1.41 vs. 1.72; P = 0.034) and fibrosis (1.12 vs. 1.40; P = 0.047) scores compared to Caucasians. Multivariate analysis demonstrated that age, ALT, and race were significant independent variables associated with total HAI, piecemeal necrosis, and fibrosis scores. CONCLUSIONS Although the overall spectrum of liver disease is similar, African Americans have less piecemeal necrosis and lower fibrosis scores independent of age and ALT compared with Caucasians.