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Unlabelled: Liver biopsy is important for diagnosing primary biliary cirrhosis (PBC). Prior investigations suggest that immunostaining for biliary keratin 19 (K19) may show the earliest changes suspicious for PBC, namely, loss of the canals of Hering (CoH). We aimed to study the clinical outcomes of patients whose biopsy specimens appeared histologically near normal or with minimal inflammatory changes, but in which K19 staining revealed widespread periportal CoH loss, a finding we termed "minimal change PBC." Ten patients were identified prospectively as having nearly normal or mildly inflamed biopsy specimens without diagnostic or suggestive histologic features of PBC, but with near complete CoH loss; six had available follow-up clinical data, one had follow-up biopsy. Controls for clinical and/or K19 analysis included six normal livers and biopsy specimens from 10 patients with confirmed early PBC, 10 with early stage chronic hepatitis C (CHC), and nine with resolving, self-limited hepatitis (RSLH). Staining for K19 in normal controls, livers with "minimal change" PBC, CHC, and RSLH showed 9.2 ± 6.0, 0.44 ± 0.37 (P < 0.0001), 5.7 ± 4.6 (n.s.), 4.1 ± 2.1 (P < 0.02) CoH per portal tract, respectively. Patients with available clinical follow up, compared to patients with diagnostic early-stage PBC biopsies, showed identical treatment responses to ursodeoxycholic acid, similar rates and types of nonhepatic autoimmune diseases, and/or subsequent development of autoimmune hepatitis overlap syndrome., Conclusion: We suggest that CoH loss demonstrated by K19 immunostaining is an early feature in PBC. Clinical findings in the years following biopsy, including response to ursodeoxycholic acid, show identical changes to patients with biopsy confirmed PBC. We suggest that this "minimal change" feature may support a clinical diagnosis of PBC even in the absence of characteristic, granulomatous, duct destructive lesions., (Copyright © 2012 American Association for the Study of Liver Diseases.)

The low-density lipoprotein receptor (LDLR) has been proposed as a candidate receptor for the hepatitis C virus (HCV). Competitive inhibition of HCV binding to the LDLR by low-density lipoprotein (LDL) has been shown in vitro. If similar inhibition occurs in vivo, an elevated serum concentration of beta-lipoproteins may reduce the efficiency of infecting hepatocytes with HCV by competitively inhibiting HCV viral receptor binding. We investigated the role of baseline lipid values in influencing the outcome of HCV treatment. We conducted a retrospective chart review of patients treated with an interferon-based regimen at our liver and gastroenterology clinics between 1998 and 2004. Of 99 patients enrolled in the study, 49 (49.5%) had HCV genotype 1 (LDL 100.2 +/- 30.2 mg/dL [mean +/- SD]), and 50 patients (50.5%) had genotype 2 or 3 (LDL 110.1 +/- 40 mg/dL) infection. Early viral response (EVR), end-of-treatment response (ETR), and sustained viral response (SVR) were documented in 99, 88, and 77 patients, respectively. LDL and cholesterol levels prior to treatment were found to be higher in patients with positive EVR, ETR, and SVR. This difference remained significant independent of age. Multivariate analysis controlling for genotype and age showed that the higher the cholesterol and LDL levels prior to treatment, the greater the odds of responding to treatment. In conclusion, having higher serum LDL and cholesterol levels before treatment may be significant prognostic indicators for treatment outcome of those with chronic hepatitis C infection, particularly in genotypes 1 and 2.

In chronic liver disease associated with histological necroinflammation, clinical severity is frequently greater in those with higher grades of activity. Conventional wisdom assumes that necroinflammation is mild or absent in patients with end-stage hepatitis B virus (HBV) cirrhosis due to the frequent presence of mildly elevated aminotransferase levels, the absence of hepatitis B e antigen (HBeAg), and low or undetectable HBV deoxyribonucleic acid (DNA) levels. However, a histopathologic analysis of such patients has not been undertaken. The aims of this study were 1) to assess severity and histological features of inflammation, 2) to correlate the severity of inflammation with biochemical and virologic parameters, and 3) to define the relationship between inflammation and clinical severity in explanted livers from patients undergoing liver transplantation for HBV cirrhosis. Characteristics of 34 consecutive patients undergoing liver transplantation for HBV cirrhosis were correlated with inflammation and immunohistological findings in the explanted livers. High-grade inflammation (grades 3 and 4) was found in many cases (47.1% interface hepatitis; 14.8% lobular inflammation; and 20.6% portal inflammation). The presence of positive cytoplasmic staining for hepatitis B core antigen (HBcAg) was associated with grade 3 or 4 interface hepatitis (P = .046) and lobular hepatitis (P = .005). There was no correlation between inflammatory activity and age, Asian ethnicity, aminotransferase levels, total bilirubin levels, HBeAg seropositivity, and detectable HBV DNA level. Patients with high-grade inflammation had greater degrees of hepatic decompensation. In conclusion, high-grade inflammation is common in end-stage HBV cirrhosis, but it is not readily detected by biochemical and virologic parameters. High-grade inflammation is associated with a greater degree of hepatic decompensation.

Clinical recurrence of hepatitis C after liver transplantation can lead to cirrhosis, liver failure, and death. In patients undergoing liver transplantation for hepatitis C, we assessed the efficacy of interferon alfa-2b (IFN) in preventing recurrent hepatitis. We randomized 86 patients to either an IFN group (3 MU three times a week starting within 2 weeks after transplantation and continued for 1 year) or a control (no IFN) group. Recurrence, the primary end point, was diagnosed on biopsy performed at 1 year or for abnormal biochemistries. HCV RNA levels were measured by branched-chain DNA (bcDNA) assay and arbitrarily defined as low, moderate, or high (< 10 x 10(5), 10-100 x 10(5), or > 100 x 10(5) Eq/mL, respectively). Data on 30 IFN patients and 41 no-IFN patients who survived > or = 3 months were reviewed. Mean follow-up was 669 +/- 228 days for IFN patients and 594 +/- 254 days for no-IFN patients. IFN patients were less likely to develop recurrent hepatitis (8 IFN vs. 22 no-IFN patients, P = .017, log rank analysis). IFN and 1-month HCV RNA level were independent predictors of recurrence. IFN reduced the risk of recurrence by a factor of 0.4 (P = .04, Cox proportional hazards model); HCV RNA level > 100 x 10(5) Eq/mL at 1 month after transplantation increased the risk by a factor of 3.1 (P = .01). Low, moderate, and high viral levels at 1 and 3 months were associated with significantly different rates of recurrence in IFN patients (P = .05 at 1 month and P = .003 at 3 months) but not in untreated patients (P = .28 at 1 month and P = .25 at 3 months). In patients with two or more rejections, the risk of recurrence was increased by a factor of 2.17 (P = .05). On 47 1-year biopsies (24 IFN; 23 no IFN), piecemeal necrosis was more common in untreated patients (P < .02). One- and 2-year patient survival, respectively, was 96% and 96% with IFN and 91.2% and 87.2% without (P = NS). Prophylactic IFN reduced the incidence of recurrent hepatitis after transplant. Although IFN was most effective in patients with low HCV RNA levels, we also noted an effect in patients with moderate levels. IFN did not prevent viremia, suggesting that it may work through alternative mechanisms.

Hepatitis C is a common cause of chronic liver disease that may progress to cirrhosis. We conducted a multicenter double-blind placebo-controlled trial of ribavirin 600 mg given orally twice daily for 36 weeks with follow-up off therapy for an additional 16 weeks. Fifty-nine patients with compensated chronic hepatitis C were entered. Efficacy was measured at the end of therapy and after follow-up by normalization of alanine aminotransferase (ALT), improvement in liver histology, reduction in hepatitis C virus (HCV) RNA level and improvement of symptoms. Among the ribavirin recipients, 12 of 29 (41.4%) had normal ALT values at 36 weeks compared with only 1 of 30 (3.3%) placebo recipients (P < .001). No patient maintained a normal ALT when therapy was stopped. No significant decrease in level of HCV RNA was observed during the study. Histological improvement among subjects who normalized ALT (-1.67 Knodell index) was significantly greater than that in other treated patients (+0.33 Knodell index; P < .05). Fatigue improved in 19.2% of ribavirin-treated subjects and in 8.3% of placebo recipients whereas no worsening of fatigue was reported by ribavirin recipients compared with 16.7% of controls. This difference in fatigue was significant at weeks 36 and 52 (P < .05; .02, respectively). Adverse events were generally comparable between treatment groups except for a reversible hemolytic anemia experienced by ribavirin recipients. Chest pain was noted in four patients on ribavirin. Ribavirin was well tolerated and improved aminotransferase values and reduced fatigue in patients with hepatitis C viral infection while treatment was being administered. Because this action was produced without change in viral level, the mechanism of action of this agent requires further investigation.

To evaluate response rates to 3, 5, or 10 million units (MU) of interferon alfa-2b, given thrice weekly, and to determine whether higher doses of interferon increase the likelihood or durability of the response, a multicenter, randomized trial was performed at nine academic medical centers in the United States. Two hundred forty eight patients with chronic hepatitis C were randomized to receive 3, 5, or 10 MU of interferon alfa-2b thrice weekly for 12 weeks. Based on the alanine aminotransferase (ALT) response at treatment-week 12, the patients were rerandomized to additional therapy at the same or at increased doses for an additional 12 to 36 weeks; in the case of no response to the highest dose, the patients were discontinued from the study. Serum ALT concentrations and liver histology were measured. The overall complete response rates to 3, 5, or 10 MU were not different at treatment-week 12 (31% vs. 42% vs. 40%, not significant). The majority of week-12 responders continued to respond during additional treatment. When the treatment was discontinued, 15.4% to 19.0% of patients maintained their response. Of the nonresponders to 3 MU at week 12, who were continued on 3 MU for an additional 12 weeks, none responded. However, response to additional therapy occurred in 12% of week-12 nonresponders, whose dose was escalated from 3 or 5 MU to 10 MU. The only baseline features associated with the treatment response were the absence of fibrosis or cirrhosis on the pretreatment liver biopsy and viral genotype. We conclude that the initial response to interferon in patients with chronic hepatitis C is not increased by treatment with higher doses of the drug. Patients who do not respond to 3 MU by treatment-week 12 will not respond with continued therapy at that dose; however, a proportion of patients who do not respond to 12 weeks of treatment with 3 or 5 MU may respond to higher doses. Although the long-term sustained response rates are marginally increased with interferon doses above 3 MU three times per week, the side effects are difficult to tolerate. The analysis of baseline factors in relation to response identified no single baseline factor associated with a low-enough response rate to warrant withholding interferon therapy from patients with chronic hepatitis C.

Recurrent infection with hepatitis C virus (HCV) is almost universal following orthotopic liver transplantation although clinical severity varies. Data on 135 patients who underwent transplantation for hepatitis C cirrhosis were reviewed. We describe a progressive, severe cholestatic form of hepatitis occurring in a subgroup of patients with recurrent hepatitis C. Ten patients with severe recurrent hepatitis C were identified; 1 has died, 1 awaits retransplantation, and 8 have undergone retransplantation. All 10 developed severe progressive cholestatic hepatitis, with a mean rise in bilirubin to 24.7 mg/dL at the time of retransplantation. Histology at initial recurrence was of mild hepatitis without evidence of rejection. The failed grafts showed either cirrhosis or confluent hepatic necrosis. The onset of cholestasis preceded retransplantation by less than 5 months. Our study suggests that a minority of patients with recurrent hepatitis C after undergoing liver transplantation develop a severe progressive cholestatic hepatitis and liver failure.

We conducted a prospective clinical trial to assess the relative efficacy and safety of high- vs. low-dose D-penicillamine in patients with primary biliary cirrhosis. Following clinical tests and liver biopsy diagnostic of primary biliary cirrhosis, 56 patients were randomized to receive either 250 or 750 mg D-penicillamine daily. Patients were monitored with clinical tests and annual liver biopsy. Randomization produced two groups without differences in demographic, clinical or histologic characteristics. During the trial, no differences were seen between the mean change in liver test results in patients in either treatment group. The 11% per year rise of bilirubin in the 750 mg dose group during the first 3 years was not significantly different from the 18% per year rise in the 250 mg dose group. No patient showed improvement on liver biopsy although patients on 750 mg D-penicillamine deteriorated more slowly. Side effects, particularly rash and dysgeusia, were more common in the 750 mg dose group. The frequency and severity of side effects were responsible for the early conclusion of our trial. Twenty-six patients experienced side effects necessitating discontinuation of D-penicillamine. No evidence of increased efficacy was demonstrated by high-dose D-penicillamine therapy, and side effects were observed in patients on 250 mg D-penicillamine daily. With the severity of adverse effects and continued progression of disease, D-penicillamine is not a clinically useful therapy in primary biliary cirrhosis.

Several drugs which react with DNA decrease hepatitis B viral (HBV) DNA polymerase activity in vitro. Because such an alteration of viral replication, if produced in patients with hepatitis B surface antigen (HBsAg)-positive chronic hepatitis, may lead to elimination of viral infection, we conducted a controlled trial of the use of the intercalating agent, quinacrine hydrochloride, in treatment of HBsAg-positive chronic hepatitis. No patient converted from HBsAg positive to negative during the trial and no consistent effect on HBV DNA polymerase activity was noted. Following treatment, elevated transaminase values and alterations of HBV markers were observed in several patients. Fluctuations of transaminase values and HBV markers may reflect alterations in host immunity and viral replication. Quinacrine alone is ineffective in therapy of chronic HBV infection. Additional study with intercalating agents, perhaps in conjunction with other drugs, is suggested.

We have characterized the cell and tissue binding specificity of a newly generated monoclonal antibody, Mab Ku-1, which shows selective reactivity with rat macrophages and Kupffer cells. The hybridoma secreting Mab Ku-1 was constructed by fusion of 8653 myeloma cells with spleen cells isolated from a mouse immunized with nonparenchymal liver cells coated with antihepatocyte antibodies. When binding was assessed by indirect immunofluorescence on frozen sections from normal liver tissue, Mab Ku-1 showed strong reactivity with Kupffer cells but was unreactive with hepatocytes, endothelial cells, bile ducts or lymphocytes. Both resident and activated macrophages bound Mab Ku-1. Reactivity in other tissues was compatible with specificity for macrophages. In the gut, scattered cells in the lamina propria were positive, whereas epithelial cells were negative. Individual cells in the lung were reactive. In the spleen, cells in the red pulp peripheral to germinal centers bound antibody. Reactivity of Mab Ku-1 to isolated Kupffer cells correlated with endogenous peroxidase activity. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis analysis of components immunoprecipitated by Mab Ku-1 from detergent lysates of Kupffer cells biosynthetically labeled with 35S-cysteine and 35S-methionine demonstrated that the reactive antigen was a peptide with an apparent molecular weight of 107 kD. This rat macrophage-reactive monoclonal antibody is a useful marker for identification of macrophage populations in tissue as well as in isolated cell populations.

We report a patient in whom hemochromatosis with high transferrin saturation developed during long-term cimetidine administration. Prior reports have noted impaired iron absorption to be associated with short-term cimetidine use. The effect of chronic cimetidine administration on iron absorption and metabolism has not been studied. We believe this to be the first, and so far the only report of increased iron absorption with long-term cimetidine use.

Primary sclerosing cholangitis (PSC) is a syndrome of unknown etiology characterized by an association with inflammatory bowel disease in 50% or more cases. Since altered immunity, including circulating immune complexes, has been implicated in the pathogenesis of inflammatory bowel disease, we postulated that humoral immune mechanisms might also be important in the development of PSC. Therefore, as an initial step in testing this hypothesis, we examined sera of patients with PSC for the presence of circulating immune complexes by two independent methods: C1q binding and Raji cell assays. Twenty-four patients with PSC, 16 of whom had coexisting chronic ulcerative colitis, were prospectively selected by predefined biochemical, histologic, and radiographic criteria. Sixteen patients with inflammatory bowel disease and normal liver tests as well as six patients with extrahepatic biliary obstruction served as disease controls. Sera were positive for circulating immune complexes by at least one method in 80% (16/20) of patients with PSC; 70% (14/20 were positive by the Raji cell assay, 58% (14/24) by the C1q binding assay, and 45% (9/20) by both methods. Levels of circulating immune complexes by each assay were higher in sera from patients with PSC than in sera from healthy controls or patients with inflammatory bowel disease alone (p less than 0.01). There were no differences in the levels of circulating immune complexes or in the frequency of positive tests in PSC patients with or without associated inflammatory bowel disease. In addition, there was no difference between the Raji cell binding of sera from six patients with extrahepatic biliary obstruction and six healthy controls tested concurrently. These data are consistent with the hypothesis that immunologic mechanisms may be important in the pathogenesis of PSC.