Hepatitis in marmosets: induction of disease with coded specimens from a human volunteer study.

Marmosets inoculated with plasma from three early acute hepatitis patients developed hepatitis 30 to 40 days later. Other groups of marmosets receiving preinfection plasmas from the same patients showed no evidence of hepatitis in this experiment. It is, therefore, most probable that hepatitis in marmosets represented transmission of human disease rather than activation of latent "marmoset hepatitis."

An analysis of acute changes in interleukin-6 levels after treatment of hepatitis C with consensus interferon.

Cytokine production has been implicated in the antiviral response to interferon-alpha (IFN-alpha) in hepatitis C and in the development of IFN-alpha-related side effects. We characterized acute changes in serum cytokine levels following administration of a single dose of consensus IFN (IFN-con1) and during continuous treatment of chronic hepatitis C patients. Serum samples were collected at baseline, at multiple times early after IFN administration, and weekly thereafter. Viral RNA titers were assessed by RT-PCR, and viral kinetics were followed. ELISA assays were used to measure IFN-gamma, tumor necrosis factor-alpha (TNF-alpha), interleukin-2 (IL-2), IL-4, IL-6, and IL-16. Serum cytokine levels were low at baseline. IL-6 was detected in patients with hepatitis C but not in healthy control subjects by either ELISA or RT-PCR, indicating that low levels of circulating IL-6 were associated with hepatitis C infection. None of the cytokines measured increased significantly after IFN administration except for IL-6. IL-6 levels rose rapidly, peaked at 6-15 h in a dose-dependent manner, and returned to baseline by 48 h in both patients receiving a single dose of IFN and those receiving continuous treatment. This was confirmed by RT-PCR. Pretreatment IL-6 levels were directly correlated with area under the curve (AUC) for IL-6 during the 24 h after IFN dosing (r = 0.611, p = 0.007). Viral titers decreased within 24-48 h after a single dose of IFN-con1. Changes in hepatitis C RNA titers were not significantly associated with pretreatment IL-6 levels or with changes in IL-6 levels. In conclusion, (1) baseline serum cytokine levels, except for IL-6, were low or within the normal range in patients with hepatitis C, (2) IL-6 levels were detected in some patients with hepatitis C before treatment but not in healthy controls, (3) IL-6 levels increased acutely after a single dose of IFN-alpha, and IL-6 induction was related to baseline IL-6 level, and (4) changes in IL-6 levels did not correlate with the early virologic response to IFN.

Daily interferon therapy for hepatitis C virus infection in liver transplant recipients.

BACKGROUND: Hepatitis C virus infection persists after liver transplantation and causes recurrent liver injury in the majority of patients. Standard dose interferon therapy has been largely unsuccessful for hepatitis C in transplant recipients. METHODS: Twelve patients, at least 7 months posttransplant, with detectable hepatitis C virus RNA in serum and features of hepatitis C on liver biopsy were randomized to interferon-alpha2a, 3 mU daily for 12 months (n=8) or no treatment (n=4). The tolerability of daily interferon dosing in liver transplant recipients was evaluated and effects on hepatitis C virus RNA level, quasispecies evolution, and liver histology were studied. RESULTS: Treated patients had an improvement in histological activity index at the end of therapy relative to controls (median reduction of 2 versus median increase of 1.5) (P=0.04). Four treated patients had a virological response (all bDNA negative, one qualitative polymerase chain reaction negative) compared with none of the untreated patients. Only two of six treated patients tested had evidence of quasispecies diversification on therapy. Seven of eight patients in the treatment group required dose reduction for fatigue and/or depression. They tolerated 1.5 mU of interferon-alpha2a daily. Two treated patients developed graft dysfunction, one of who had histological evidence of rejection and subsequent graft loss. CONCLUSIONS: Low daily doses of interferon were tolerated by liver transplant recipients and provided histological benefit without associated quasispecies diversification in most cases. These findings provide a rationale to study low dose daily or pegylated interferon maintenance therapy for the management of hepatitis C posttransplant.

Large focal defect on liver/spleen scan caused by fatty liver and masquerading as neoplasm.

Focal fatty infiltration of the liver may be mistaken for metastatic disease, primary tumor or other space-occupying lesions on CT or ultrasound. Usually, a 99mTc-sulfur colloid scan is sensitive in documenting the presence of Kupffer's cell in such a process. We present a case that was suggestive of focal fatty infiltrate on a CT scan, nondiagnostic on ultrasound, and seen as a large focal defect on the 99mTc-sulfur colloid liver/spleen scan. A 133Xe inhalation study, however, did show uptake in the area of fatty infiltration. A needle biopsy confirmed the diagnosis.

Trichosporon cholangitis associated with hyperbilirubinemia, and findings suggesting primary sclerosing cholangitis on endoscopic retrograde cholangiopancreatography.

Usually, ascending cholangitis is a bacterial process. However, in the debilitated or immunocompromised patient, mycotic cholangitis must be placed in the differential diagnosis. We report a patient with cryptogenic cirrhosis whose presenting problem in his terminal hospitalization was spontaneous bacterial peritonitis, for which he was treated with broad-spectrum antibiotics. Endoscopic retrograde cholangiopancreatogram was performed during the hospital course to explain his profound hyperbilirubinemia. The findings were grossly consistent with primary sclerosing cholangitis or cholangiocarcinoma. The patient subsequently continued to deteriorate, and died with hepatic and renal failure. At autopsy, he was found to have choledocholithiasis, marked biliary duct proliferation, and ascending cholangitis, with Trichosporon demonstrated histologically to be invading the bile ducts. To our knowledge, this is the first reported case of Trichosporon cholangitis.

Transjugular intrahepatic portosystemic shunt in nonliver transplant candidates: is it indicated?

BACKGROUND: Transjugular intrahepatic portosystemic shunt (TIPS) is an effective treatment of severe portal hypertension complications. Liver transplantation (LT) candidacy has not been a prerequisite to TIPS placement in some medical centers. OBJECTIVES: To investigate the outcome and survival of non-LT candidates after TIPS. METHODS: From November 1991 to February 1994, all patients referred for TIPS placement were evaluated for LT candidacy. Exclusions for LT included: age (> 70 yr), other significant medical conditions, or noncompliance. Indications for TIPS included refractory variceal bleeding during an acute bleed, recurrent bleeding after more than or equal to four sessions of sclerotherapy, or refractory ascites. RESULTS: Sixty patients received TIPS. Nineteen were considered non-LT candidates. Over a 2-yr follow-up, 14 of these non-LT candidates did not survive. Their median age was 63.5 compared with 56.5 yr for LT candidate nonsurvivors (p < 0.05). Among the 14 non-LT candidate nonsurvivors, 10 were Childs C class, and eight had emergent TIPS placement. The 2-year mortality rate was 84% for non-LT candidates versus 24% for LT candidates. Median survival time for non-LT candidates was 2.6 months compared with 20 months in the LT candidates (p < 0.001). Only one death was due to a TIPS-related complication. CONCLUSIONS: TIPS is unquestionably an advancement in the management of patients with portal hypertension complications. Non-LT candidates, compared with LT candidates, tended to be older and of a Child-Pugh C class, and they had survival rates often less than 90 days post-TIPS. Given these high mortality rates, we need to address whether TIPS is indicated in these non-LT candidates.

Chronic hepatitis C virus patients with breakthroughs during interferon treatment can successfully be retreated with consensus interferon. The Consensus Interferon Study Group.

Patients with chronic hepatitis C who have not had a sustained hepatitis C virus (HCV)-RNA response or serum alanine transaminase (ALT) response to a 6-month course of interferon (IFN) may respond to higher dose retreatment with consensus interferon (CIFN). Some nonresponders to initial IFN treatment have a transient response defined as undetectable HCV RNA or normalization of ALT during treatment, but subsequently have a "breakthrough" while still on treatment. The aim of this study was to determine if nonresponders who had breakthroughs responded differently to CIFN retreatment than nonresponders without breakthroughs using data from a large, multicenter trial. ALT and HCV RNA were monitored frequently during initial IFN therapy (either 9 mcg CIFN or 3 MU IFN-alpha2b 3 times per week). HCV-RNA breakthroughs were observed in 86 of 467 (18%) of all treated patients, and ALT breakthroughs were observed in 90 of 467 (19%) of all treated patients. There was no association between breakthroughs and the presence of either binding or neutralizing anti-IFN antibodies. When the patients who were nonresponders to initial IFN treatment were retreated with CIFN (15 mcg) for 12 months, 27% of those with viral breakthroughs had a sustained viral response compared with 8% in prior nonresponders without breakthroughs (P =.102). Sustained ALT responses were observed in 39% with breakthroughs compared with 10% in those without breakthroughs (P =.014). The data suggest that prior nonresponders with breakthroughs have a greater chance of responding to retreatment than do nonresponders without breakthroughs. However, most breakthrough patients would be missed unless repeated HCV-RNA testing were conducted during therapy.

Transjugular intrahepatic portosystemic shunt (TIPS) for Budd-Chiari syndrome or portal vein thrombosis: review of indications and problems.

OBJECTIVE: The aim of this study was to evaluate the role of transjugular intrahepatic portosystemic shunt (TIPS) in patients who present with portal vein thrombosis (PVT) or Budd-Chiari Syndrome (BCS). METHODS: Nine patients with recent PVT and four patients with BCS underwent TIPS. The diagnosis was confirmed by color Doppler ultrasound and by angiogram in most patients. Patients were followed clinically and had TIPS checked periodically for patency. The end point was mortality, subsequent surgical shunting or orthotopic liver transplantation (OLT). RESULTS: TIPS was placed in 13 of 15 (87%) patients with BCS or PVT. The mean decrease in pressure gradient was 56%. Median and mean follow-up were 14 months and 16.9 months. Procedure related complications occurred in two of 13 (15%), both in the PVT group. Direct procedural mortality was one of 13 (8%). The majority of patients with PVT (five of eight) underwent OLT. Of the remaining three, one patient subsequently developed a cavernous transformation of portal vein but is stable, one patient is stable, without further variceal bleeding, and one patient died because of multiple organ failure. In patients with BCS, three of four (75%) did well with TIPS, but one patient required immediate surgical shunting after occlusion of the TIPS. Two patients underwent OLT and the fourth patient is stable 2 yr later but has cirrhosis on biopsy. CONCLUSIONS: In patients with BCS, TIPS placement is effective and can be used as a bridge to liver transplantation. TIPS in the noncavernous PVT group should only be recommended when cirrhosis and uncontrollable variceal bleeding are present.

Patients' values for health states associated with hepatitis C and physicians' estimates of those values.

OBJECTIVES: Hepatitis C is the leading cause of chronic hepatitis in the United States. Little information is available regarding how persons with hepatitis C view health with their disease. We studied patients' perceptions about the value of hepatitis C health states and evaluated whether physicians understand their patients' perspectives about this disease. METHODS: A total of 50 consecutive persons with hepatitis C were surveyed when they presented as new patients to a hepatology practice. Subjects provided utility assessments (preference values) for five hepatitis C health states and for treatment side effects. They also stated their threshold for accepting antiviral therapy. Five hepatologists used the same scales to estimate their patients' responses. RESULTS: On average, patients believed that hepatitis C without symptoms was associated with an 11% reduction in preference value from that of life without infection, and the most serious condition (severe symptoms, cirrhosis) was believed to carry a 73% decrement. Patients judged the side effects of antiviral therapy quite unfavorably, and their median stated threshold for accepting treatment was a cure rate of 80%. Physicians' estimates were not significantly associated with patients' preference values for hepatitis C health states, treatment side effects, or with patients' thresholds for accepting treatment. In multivariate analysis, patients' stated thresholds for taking treatment were significantly associated with their decisions regarding therapy (beta = -2.72+/-1.21, p = 0.025). CONCLUSIONS: There was little agreement between patients' preference values about hepatitis C and their physicians' estimates of those values. Utility analysis could facilitate shared decision making about hepatitis C.

Relationship between biochemical and virological responses to interferon therapy in chronic hepatitis C infection. Consensus Interferon Study Group.

We have investigated the relationship between serum alanine aminotransferase (ALT) and hepatitis C virus (HCV) RNA in the assessment of responses to interferon (IFN) therapy in chronic HCV infection. Data from 704 patients with HCV infection who were randomized to receive consensus IFN-alpha (CIFN) 3 micrograms (n = 232 patients) or 9 micrograms (n = 232 patients), or IFN-alpha 2b 3 million units (MU) (n = 240 patients), were used for these analyses. All patients were treated three times weekly. Hepatitis C viral RNA (HCV RNA) was determined by quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) with a lower limit of detection of 100 copies ml-1. Of patients with normal serum ALT concentrations, 53% (120/225) had undetectable HCV RNA at the end-of-treatment period and 47% (51/109) had undetectable HCV RNA at the end of the post-treatment observation period. In contrast, of the patients with undetectable HCV RNA, 75% (120/161) and 84% (51/61) had normal serum ALT activities at the end-of-treatment and post-treatment observations periods, respectively. The majority of patients with undetectable HCV RNA had normal ALT values. In contrast, only half of the patients with normal ALT values were negative for HCV. End-of-treatment HCV RNA response also better predicted sustained virological response than did end-of-treatment ALT response.