An assessment of racial differences in the upper limits of normal ALT levels in children and the effect of obesity on elevated values.

OBJECTIVES: Childhood obesity is a risk factor for non-alcoholic fatty liver disease and poses important public health issues for children. Racial differences in alanine aminotransferase (ALT) levels among children have not been described. This study aimed to identify racial differences in upper limit normal (ULN) ALT levels and evaluate the effect of obesity on elevated levels in children without other metabolic risk factors. METHODS: National Health and Nutrition Examination Surveys and clinical data from the Loyola University Health System were used to determine ULN ALT by race and gender. Quantile regression was used to evaluate the impact of obesity on elevated ALT and to identify potential risk factors for ALT above the ULN. RESULTS: Upper limit normal (ULN) ALT was approximately 28.0 and 21.0-24.0 U/L for boys and girls, respectively. No significant difference in ULN ALT across race was observed. Obesity was significantly associated with elevated ALT; obese children with elevated ALT had values 10 U/L higher than normal-weight children. CONCLUSIONS: Racial differences in ALT levels among adults are not evident in children. Obesity, in the absence of metabolic risk factors and other causes of liver disease, is associated with elevated ALT, providing evidence against the concept of healthy obesity in children.

Protease inhibitors partially overcome the interferon nonresponse phenotype in patients with chronic hepatitis C.

The outcome of triple therapy with protease inhibitors (PI) depends on the intrinsic response to interferon. Interferon-stimulated gene (ISG) expression differs by cell type in the liver and is a strong predictor of interferon responsiveness. Patients who respond well to interferon have low/absent ISG expression in hepatocytes but significant ISG expression in macrophages. Nonresponders (NRs) show the opposite pattern. We aimed to determine the association between cell-type-specific ISG staining and treatment outcome with PI-based triple therapy. Liver biopsy tissue from consecutive patients treated with boceprevir or telaprevir with peginterferon and ribavirin was stained for myxovirus A (MxA). Staining was scored 0-3 in macrophages (M-MxA) and hepatocytes (H-MxA), and IL28B genotyping was performed. Of 56 patients included 41 achieved SVR (73%) (sustained virological response), 2 (4%) relapsed, 10 (18%) were NRs, and 3 (5%) were lost to follow-up. Median M-MxA staining was stronger and H-MxA staining was weaker in patients who achieved SVR. MxA staining correlated with IL28B genotype and with the HCV RNA decline during lead-in phase. However, unlike with dual therapy, the negative predictive value (NPV) of absent or weak M-MxA staining was poor (42%), while the positive predictive value improved (93%). Although by multivariable logistic regression M-MxA staining was significantly associated with SVR (OR 4.35, 1.32-14.28, P = 0.012), the predictive ability was inadequate to withhold therapy. The interaction between macrophages and hepatocytes plays a critical role in interferon responsiveness; however, the addition of a PI at least partially overcomes the interferon nonresponse phenotype making the predictive ability of ISG staining less clinically useful.

Presurgical transarterial chemoembolization does not increase biliary stricture incidence in orthotopic liver transplant patients.

INTRODUCTION: The goal of this study was to compare the incidence of biliary strictures in orthotopic liver transplant (OLT) patients treated with previous transarterial chemoembolization (TACE) versus those with no TACE history. PATIENTS AND METHODS: A single-center retrospective review was performed on 248 patients who underwent OLT from 2006 to 2012. Patient demographic characteristics, history of TACE for treatment of hepatocellular carcinoma, OLT data, and biliary stricture data were obtained. TACE was generally performed in a segmental manner using chemotherapy to ethiodized oil mixture (1:1). Clinically significant biliary strictures resulting in cholestasis or obstructive jaundice were diagnosed by using endoscopic retrograde cholangiopancreatography. Group characteristics were compared by using the Wilcoxon rank sum test, χ(2) analysis, and Kaplan-Meier statistics with log-rank comparison. RESULTS: Forty-six patients (35 men, 11 women; median age, 58 years) with a history of pre-OLT TACE were compared with 185 patients (111 men, 74 women; median age, 54 years) with no history of TACE. TACE and non-TACE patients had 30% and 31% cumulative incidence of biliary stricture, respectively. The median time to stricture was not reached in either group. There was no statistically significant difference in biliary stricture incidence (P = .928) or time to biliary stricture development (P = .803). Biliary strictures were primarily anastomotic in location in both groups: 79% in TACE patients and 84% in non-TACE patients (P = .233). CONCLUSIONS: Selective TACE treatment of hepatocellular carcinoma in pretransplant patients does not increase the rate of posttransplant biliary strictures. These findings corroborate the safety of TACE in the treatment of hepatocellular carcinoma in potential OLT patients as a bridge to transplantation.

Characterizing hepatitis B stigma in Chinese immigrants.

Health-related stigma is a cause of stress, alienation and discrimination that can serve as a barrier to prevention and care for infectious diseases such as HIV. Hepatitis B virus (HBV)-related stigma is common in Asian immigrants, but has not been formally evaluated. The aim of this study was to develop and validate the first HBV stigma instrument and to begin to evaluate HBV stigma in Chinese immigrants. The HBV stigma instrument was developed based on constructs from validated HIV stigma scales and organized into five domains. A written survey was compiled to include demographic data, HBV knowledge questions and stigma items. The survey was pilot tested in English and Chinese and then finalized. Data were obtained from 201 patients seen in an urban Chinatown Internal Medicine practice. The stigma items showed a high degree of reliability when assessed in aggregate (α = 0.85) as well as within individual domains. Stigma was greatest in the Fear of Contagion domain. Knowledge questions showed a corresponding deficit in understanding of modes of HBV transmission. An inverse relationship between stigma scores and familiarity with HBV provided evidence of construct validity. In multivariable analysis, having a family member with HBV and higher HBV knowledge subset scores were associated with lower degrees of stigma. In conclusion, the hepatitis B stigma instrument showed reliability and construct validity. The relationship identified between familiarity and knowledge regarding HBV with lower stigma scores provides the basis for the development of interventions to reduce HBV stigma.

Very early prediction of response to HCV treatment with PEG-IFN-alfa-2a and ribavirin in HIV/HCV-coinfected patients.

The objective of this study was to find very early viral kinetic markers to predict nonresponse to hepatitis C virus (HCV) therapy in a group of human immunodeficiency virus (HIV)/HCV-coinfected patients. Twenty-six patients (15 HCV genotype-1 and 11 genotype-3) were treated with a 48-week regimen of peginterferon-alfa-2a (PEG-IFN) (180 µg/week) and weight-based ribavirin (11 mg/kg/day). Samples were collected at baseline; 4, 8, 12, 18, 24, 30, 36 and 42 h; days 2, 3, 4, 7, 8, 15, 22, 29, 43 and 57 then weekly and monthly. Five patients discontinued treatment. Seven patients (27%) achieved a sustained virological response (SVR). Nadir HCV RNA levels were observed 1.6 ± 0.3 days after initiation of therapy, followed by a 0.3- to 12.9-fold viral rebound until the administration of the second dose of PEG-IFN, which were not associated with SVR or HCV genotype. A viral decline <1.19 log for genotype-1 and <0.97 log for genotype-3, 2 days after starting therapy, had a negative predictive value (NPV) of 100% for SVR. The day 2 virological response had a similar positive predictive value for SVR as a rapid virological response at week 4. In addition, a second-phase viral decline slope (i.e., measured from day 2 to 29) <0.3 log/week had a NPV = 100% for SVR. We conclude that first-phase viral decline at day 2 and second-phase viral decline slope (<0.3 log/week) are excellent predictors of nonresponse. Further studies are needed to validate these viral kinetic parameters as early on-treatment prognosticators of nonresponse in patients with HCV and HIV.

The prevalence and clinical correlates of elevated ALT levels in an urban Chinatown community.

Alanine aminotransferase (ALT) levels are a primary consideration in treatment decisions regarding hepatitis B virus (HBV) infection. Levels can be elevated as a result of HBV-related liver injury or to other causes. The aim of this study was to assess the background prevalence and clinical correlates of elevated ALT levels in Chinese immigrants who were HBsAg negative. Subjects consisted of adults seen in an urban Chinatown Internal Medicine practice between 1, 2006 and 12, 2007. Clinical information was collected retrospectively. An elevated ALT level was defined as >19 U/L for women and >30 U/L for men. The primary analysis focused on 2457 persons who were HBsAg negative. Their mean age was 55 +/- 18 years, 64% were female and 36% were obese. All subjects were ethnically Chinese and 96% were born in Asia. Thirty percent had an elevated ALT level. In univariate analysis, factors associated with elevated ALT included older age (P < 0.001), female gender (P = 0.001), obesity (P < 0.001), diabetes (P < 0.001), hypercholesterolemia (P < 0.001) and hypertension (P < 0.001). In multivariate analysis BMI, diabetes, female gender and hypercholesterolemia were significantly associated with elevated ALT level. An additional analysis focused on a group of patients who were HBsAg positive, HBeAg negative and had HBV-DNA levels <1000 copies/mL. Fifty percent had elevated ALT levels. In conclusion, elevated ALT levels are common among Chinese immigrants without HBV (30%) and are associated with features of the metabolic syndrome. Liver biopsy should be performed in selected patients with HBV to distinguish the cause of ALT elevation before initiating antiviral therapy.

Serological markers of autoimmunity in patients infected with hepatitis C virus: impact of HIV co-infection.

OBJECTIVES: We sought to evaluate the prevalence, predictors and significance of autoantibody expression in patients with chronic hepatitis C (CHC) with or without HIV co-infection. METHODS: Retrospective review of laboratory and histologic data for all patients with CHC who had a liver biopsy available. HIV status was documented in all patients. Results analyzed in SPSS10, Chicago, IL, a p value <0.05 was considered significant. RESULTS: 170 patients with hepatitis C viremia, including 107 (63%) HIV co-infection, who had testing for anti-nuclear antibody (ANA) or anti-smooth muscle antibody (ASMA) and anti-mitochondrial antibody (AMA) were included in the study. Overall, 63% (74/117) of patients were ASMA seropositive and 6% (9/153) were positive for ANA. All 117 patients tested for AMA were negative. HIV co-infected patients were significantly more likely to be ASMA positive 71% (53/75) compared to those with hepatitis C alone (50%) [P=0.026]. There were no significant differences in age, gender, race, risk group, alanine aminotransferase (ALT) levels or grade of inflammation on histology between autoantibody positive and negative patients. ASMA positive patients had significantly higher globulin levels (P=0.036) and a trend towards more bridging fibrosis or cirrhosis. Patients with autoantibody expression rarely had histologic features of AIH. CONCLUSION: We found a high rate of ASMA seropositivity in our cohort of patients with chronic hepatitis C, and HIV co-infection was associated with significantly higher rates of ASMA expression. Autoantibody expression was not associated with demographic or clinical characteristics and does not necessarily preclude antiviral therapy.

A multicentre study of the usefulness of liver biopsy in hepatitis C.

The role of liver biopsy in the assessment of chronic hepatitis C is generally accepted yet there is no prospective data available to quantify its contribution. A previous single centre pilot study suggested that the clinician could predict the amount of fibrosis and to a lesser extent, inflammation with moderate accuracy. The 2002 National Institute of Health Hepatitis C Consensus Conference recommended further study of the role of liver biopsy. Our objective was to compare a prediction of biopsy findings by expert clinicians using usually available clinical and laboratory data to actual biopsy results in order to determine whether biopsy is required routinely. This was a prospective observational study conducted at seven university centres in which the accuracy of clinician's predictions of the degree of inflammation and fibrosis were compared with the actual liver biopsy using an adaptation of a standard histological scoring system. We studied 81 adults with previously untreated chronic hepatitis C, raised serum transaminases and positive HCV-RNA in serum. Clinicians predicted the inflammatory grade in 44 of 80 cases (55%) and the fibrosis stage in 46 of 81 cases (57%). Nine of 17 cirrhotic cases were predicted (sensitivity 53%, specificity 56%). No unexpected additional diagnoses were made on the biopsies. Thus despite knowledge of the clinical and laboratory investigations of patients with hepatitis C, clinicians are unable to accurately predict the hepatic inflammatory grade and fibrotic stage. Liver biopsy is an essential investigation to accurately evaluate the grade and stage of liver disease patients with hepatitis C.

A comparison of hepatitis C treatment and outcomes at academic, private and Veterans' Affairs treatment centres.

BACKGROUND: Currently, there is a lack of published data examining hepatitis C treatment practices in different care settings. AIM: To provide data describing treatment practices for patients with hepatitis C virus infection in actual clinical practice, and to examine clinical outcomes in patients treated with interferon alpha-2b/ribavirin combination therapy in academically affiliated centres, private treatment centres and Veterans' Affairs treatment centres. METHODS: This multi-centre, retrospective, cohort study of 231 patients examined hepatitis C virus treatment practices in patients receiving interferon alpha-2b from January 1997 to May 2001 and explored outcomes in academically affiliated, private and Veterans' Affairs centres. RESULTS: Differences in treatment practice and use of diagnostic procedures were found. Genotype testing was under-utilized in non-academic sites (academic centres, 79.2%; private centres, 33.7%; Veterans' Affairs centres, 35.9%; P<0.001). Liver biopsies were performed less often in private sites (academic centres, 95.8%; private centres, 80.0%; Veterans' Affairs centres, 92.2%; P<0.01). End-of-treatment viral response (academic centres, 40.0%; private centres, 31.3%; Veterans' Affairs centres, 17.2%; P<0.05) was lower than that found in published trial data. Multivariate analysis revealed genotype 1 as the single significant predictor of treatment failure (P<0.01). CONCLUSIONS: Outside of the academic setting, there is significantly less diagnostic work-up performed prior to the initiation of hepatitis C virus therapy. This suggests a need for a standardization of care across treatment settings.

First phase hepatitis c viral kinetics in previous nonresponders patients.

A large proportion of patients fails to respond to treatment for hepatitis C. Initiation of interferon therapy is associated with a rapid first phase decline in viremia, reflecting inhibition of viral production or release from infected cells. We characterized first phase viral kinetics in previous nonresponder patients and compared the antiviral efficacy of interferon in nonresponders to that observed in naive patients. Twenty nonresponders with genotype 1 infection were evaluated. Ten received a single 15 mcg dose of interferon alfacon-1 and ten were given a 30 mcg dose. Viral kinetic data from previously untreated historical control patients with genotype 1 infection who received 9 mcg (n = 12) or 15 mcg (n = 13) of interferon alfacon-1 provided a basis for comparison. Antiviral efficacy was evaluated by calculating the reduction in HCV RNA levels during the first 24 h after interferon administration (log effectiveness). Hepatitis C virus levels decreased exponentially in previous nonresponder patients. Non-responders treated with 30 mcg of interferon alfacon-1 exhibited a greater log drop than non-responders receiving 15 mcg (P = 0.01). The log effectiveness of 15 mcg of interferon alfacon-1 in nonresponders was similar to 9 mcg in naives and was significantly < 15 mcg (P = 0.04) in naïve patients. The 30 mcg dose provided similar log effectiveness in nonresponders compared with 15 mcg in naive patients and exceeded the log effectiveness of 9 mcg in previously untreated patients (P = 0.035). Nonresponders who had greater than a 50% decrease in HCV RNA level from baseline at the end of previous treatment had a larger reduction in viral load at 24 h compared with those who had not achieved that level of response with prior therapy (P = 0.04). In conclusion, the log effectiveness of interferon was lower in nonresponders compared with treatment naive patients. The difference in antiviral effectiveness in previous nonresponders was overcome by higher interferon doses.

Treatment of hepatitis C virus and HIV co-infections.

Hepatitis C coinfection is common in patients with HIV, particularly in injection-drug users. Hepatitis C virus levels tend to be higher in coinfected patients, and histologic progression is more rapid than in patients with HCV alone. The efficacy of interferon monotherapy in HIV patients with an adequate CD4 cell count is comparable to that observed in patients without HIV. The combination of interferon plus ribavirin and pegylated interferon will further improve response rates. Interferon therapy is associated with leukopenia and a decrease in absolute CD4 cell count. Some concern remains that ribavirin might reduce the activity of pyrimidine analogues such as zidovudine and stavudine, and HIV-RNA levels should be followed when these medications are given concurrently. It is hoped that in time, new drug development will make the multiple-drug therapeutic strategy that has been highly successful in the management of HIV feasible for the treatment of HCV.

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.

Physicians' preference values for hepatitis C health states and antiviral therapy: a survey.

BACKGROUND: Physicians' perspectives regarding hepatitis C shape their approach to patient management. We used utility analysis to evaluate physicians' perceptions of hepatitis C-related health states (HS) and their threshold to recommend treatment. METHODS: A written questionnaire was administered to practicing physicians. They were asked to rate hepatitis C health states on a visual analog scale ranging from 0% (death) to 100% (health without hepatitis C). Physicians then judged quality of life associated with the side effects of antiviral therapy for hepatitis C and indicated the sustained virological response rate that they would require to recommend treatment. RESULTS: One hundred and thirteen physicians from five states were included. Median utility ratings for hepatitis C health states declined significantly with increasing severity of symptoms: HS1-No Symptoms, No Cirrhosis (88%; 12% reduction from good health), HS2-Mild Symptoms, No Cirrhosis (66%), HS3-Moderate Symptoms, No Cirrhosis (49%), HS4-Mild Symptoms, Cirrhosis (40%), HS5-Severe Symptoms, Cirrhosis (18%) [p < 0.001]. The median rating for life with side effects of antiviral therapy was 47%, suggesting a 53% reduction from good health. That was similar to the utility value for HS3-Moderate Symptoms, No Cirrhosis. The median threshold value for recommending treatment was a sustained response rate of 60%. CONCLUSIONS: 1) Physicians' utility ratings for hepatitis C health states were inversely related to the severity of disease manifestations described. 2) Physicians viewed side effects of therapy unfavorably and indicated that on average, they would require a 60% sustained response rate before recommending treatment, which far exceeds the efficacy of current antiviral therapy for hepatitis C in the majority of patients.

Resolution of cirrhosis in autoimmune hepatitis with corticosteroid therapy.

Successful therapy for liver diseases, including autoimmune hepatitis, primary biliary cirrhosis, and hepatitis C, has been associated with a reduction in hepatic fibrosis. Recently, a study of needle liver biopsy specimens documented resolution of cirrhosis in a small group of patients with autoimmune hepatitis who responded to corticosteroid therapy. We describe a woman with autoimmune hepatitis who had cirrhosis on a wedge biopsy of the liver in 1985 and who attained a biochemical response with immunosuppressive therapy. A repeat wedge liver biopsy performed 14 years later was normal, providing unequivocal evidence that cirrhosis can reverse completely in autoimmune hepatitis.

Adult living donor liver transplantation: Preferences about donation outside the medical community.

An increasing number of transplant centers are performing adult living donor liver transplantation (LDLT). We evaluated peoples' perspectives on possible outcomes of living donation, thresholds for donating, and views regarding the donation process. One hundred fifty people were surveyed; half were from a medical care group serving an indigent population and half were from a private clinic. Preferences about outcomes of adult living donation were ranked and quantified on a visual analogue scale. Thresholds for donation to a loved one were quantified. Sixty percent of the respondents suggested they would prefer to donate and die and have the transplant recipient live rather than forego donation and have the potential transplant recipient die of liver failure. Participants' stated threshold for living donation was a median survival for themselves of only 79%. They would require that their loved one have a median survival of 55% with transplantation before they would agree to donate. Respondents from the medical care group reported higher survival thresholds for themselves and the transplant recipient, and race was the most statistically significant predictor of those thresholds. Sex was more predictive of threshold probabilities from the private clinic. Eighty-one percent of the respondents believed that the potential donor, not a physician, should have the final say regarding candidacy for living donation. In conclusion, the findings of this survey support the use of adult LDLT. Most respondents were willing to accept mortality rates that far exceed the estimated risk of donation and favored outcomes in which a loved one was saved.

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.

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.

Pretreatment symptoms and dosing regimen predict side-effects of interferon therapy for hepatitis C.

We analysed data from a multicentre interferon (IFN) treatment trial to evaluate symptoms in patients with chronic hepatitis C and to identify factors that might predict development of debilitating IFN side-effects. Two hundred and twenty-two patients (120 US, 102 French) received 3 or 5 million units (MU) of IFN-alpha three times weekly (t.i.w.) for 3 months. Those who had detectable hepatitis C virus (HCV) RNA, as detected by the branched DNA signal amplification (bDNA) assay, at 3 months were intensified to daily therapy, while patients who were bDNA negative continued t.i.w. dosing for the subsequent 3 months of treatment. Symptoms were assessed at baseline, and adverse effects were evaluated at 6 months of therapy. Prior to treatment, the most common symptom that interfered with daily functioning was fatigue, occurring in 25% of patients. The frequency of debilitating fatigue, myalgia, arthralgia, headache, the presence of dry eyes and dry mouth, and use of antidepressant medication increased significantly from baseline to 6 months of IFN therapy (all P < 0.01). In multivariate analysis, the development of a debilitating side-effect at 6 months of treatment was associated with the presence of that symptom prior to therapy in all cases. Symptoms and adverse effects varied by gender and country. Compared with patients maintained on t.i.w. dosing, those who were dose intensified to daily IFN reported more debilitating fatigue, malaise, myalgia, arthralgia, fever, nausea, and headache, and the presence of dry mouth (all P < 0.05). In conclusion, patient characteristics, including pretreatment symptoms, gender and nationality, as well as daily IFN dosing are associated with the development of debilitating adverse effects on IFN therapy.

Hyperbilirubinemia and cholestatic liver injury in hepatitis C-infected liver transplant recipients.

OBJECTIVE: A cholestatic pattern of liver injury has been observed in liver transplant recipients with rapidly progressive hepatitis C. We assessed the frequency and causes of cholestasis in hepatitis C-infected liver transplant patients, and evaluated the clinical and pathological course of those with cholestatic hepatitis C. METHODS: Sixty-nine sequential liver transplant recipients who had detectable hepatitis C viremia were studied retrospectively. Records and diagnostic tests were examined from patients who developed hyperbilirubinemia. RESULTS: Hyperbilirubinemia occurred in 33 of 69 (48%) hepatitis C-infected liver transplant patients. A thorough evaluation including review of clinical and laboratory data, ultrasound with Doppler, cholangiogram, and liver biopsy identified causes of hyperbilirubinemia other than hepatitis C in 26 of 33 patients. Seven patients developed cholestatic hepatitis C characterized by histological features of recurrent hepatitis C and cholestatic liver injury with ballooning of centrilobular hepatocytes, bile ductular proliferation, and canalicular cholestasis, in the absence of other causes of cholestasis. Five progressed rapidly to bridging fibrosis and two died of complications related to liver failure. Four patients with cholestatic hepatitis C showed extended survival after the onset of hyperbilirubinemia. CONCLUSIONS: 1) Hepatitis C is a relatively infrequent cause of cholestasis in liver transplant recipients. 2) The diagnosis of cholestatic hepatitis C requires a multimodality approach to exclude other causes of cholestasis. 3) Cholestatic hepatitis C ranges in severity and is not always associated with rapid development of graft failure, although significant histological abnormalities are frequent.