Increased risk of antituberculosis drug-induced hepatotoxicity in individuals with glutathione S-transferase M1 'null' mutation

BACKGROUND: Pathogenesis and genetic factors influencing predisposition to antituberculosis drug (ATD)-induced hepatotoxicity are not clear. Polymorphism at the genetic locus of a drug and xenobiotic compound metabolizing enzyme, N-acetyltransferase type 2 (NAT2), is reported to be associated with the excess generation of toxic reactive metabolites. Polymorphisms at the glutathione S-transferase (GST) loci (GSTM1 and GSTT1) are involved in the detoxification of these toxic metabolites in the human body to a lesser extent. We have examined whether polymorphisms at these loci are associated with the risk of ATD-induced hepatotoxicity. METHODS: In this case-control study, 33 pulmonary tuberculosis patients with ATD-induced hepatotoxicity and 33 pulmonary tuberculosis patients receiving ATD drugs without any evidence of hepatotoxicity were considered as cases and controls, respectively. Point mutations at NAT2 and homozygous 'null' mutations at GSTM1 and GSTT1 genes were looked into genomic DNA, isolated from peripheral blood mononuclear cells by using polymerase chain reaction (PCR). RESULTS: The frequency of homozygous 'null' mutation at the GSTM1 gene was significantly higher among cases (n = 17, 52%) than controls (n = 8, 24%) (P < 0.05, relative risk 2.13, 95% CI: 1.25-3.10). Frequencies of mutations at GSTT1 and NAT2 genes did not differ significantly between cases and controls. CONCLUSION: Homozygous 'null' mutation at the GSTM1 gene might predispose an individual to ATD-induced hepatotoxicity.     

Drug-induced liver injury in hospitalized HIV patients: high incidence and association with drugs for tuberculosis

Background. The evaluation of liver disease in HIV patients is cumbersome because may result from a number of different causes. The aim of this retrospective study was to estimate the incidence of severe drug induced liver injury (DILI) in a group of HIV inpatients and investigate potential risk factors.Material and methods. We performed a retrospective analysis of data from HIV-infected patients hospitalized between August 2010 and August 2011 in a tertiary hospital in São Paulo, Brazil. Severe hepatotoxicity was defined as grade 3 (5.1 to 10 × ULN) or 4 (> 10 × ULN) of ALT and AST levels. Factors analyzed included demographics, infection with hepatitis viruses, alcohol history and use of hepatotoxic drugs prior to or during hospital admission.Results. A total of 149 patients with HIV were hospitalized during the study period. The majority were male over 42 years of age and 82 (55%) were taking HAART initiated prior to admission. Mean CD4 counts were 164 cells/mm³. Thirty three patients (22.1%) developed severe DILI during hospital stay, which had a mean duration of 26 days. Factors associated with severe DILI in the multivariate analysis were abnormal baseline ALT levels [OR 2.02 (95%CI 1.13-3.59); p = 0.017] and tuberculosis therapy [OR 2.31 (95% CI 1.27-4.19); p = 0.006]. In conclusion, in this group of HIV patients admitted to a tertiary hospital in Brazil, we found a high incidence (22.1%) of severe DILI. The use of anti-tuberculosis drugs and baseline liver injury were independent factors associated with severe DILI during hospital stay.     

Polymorphism of the N-acetyltransferase 2 gene as a susceptibility risk factor for antituberculosis drug-induced hepatitis

Antituberculosis drug-induced hepatitis is one of the most prevalent drug-induced liver injuries. Isoniazid is the major drug incriminated in this hepatotoxicity. Isoniazid is mainly metabolized to hepatotoxic intermediates by N-acetyltransferase (NAT). However, the association of polymorphic NAT acetylator status and antituberculosis drug-induced hepatitis is debatable. To determine whether acetylator status is a risk factor for antituberculosis drug-induced hepatitis, we genotyped NAT2 in 224 incident tuberculosis patients who received antituberculosis treatment. Antituberculosis drug-induced hepatitis was diagnosed based on a positive isoniazid rechallenge test and exclusion of viral hepatitis. Acetylator status was determined by genotyping NAT2 in patients using a polymerase chain reaction with restriction fragment length polymorphism. Univariate analysis and logistic regression analysis were used to evaluate the risk factors of isoniazid-induced hepatitis. Thirty-three patients (14.7%) were diagnosed with antituberculosis drug-induced hepatitis. Slow acetylators had a higher risk of hepatotoxicity than rapid acetylators (26.4% vs. 11.1%, P =.013). Among patients with hepatotoxicity, slow acetylators had significantly higher serum aminotransferase levels than rapid acetylators. Logistic regression showed that slow-acetylator status (odds ratio [OR], 3.66; 95% CI, 1.58-8.49; P =.003) and age (OR, 1.09; 95% CI, 1.04-1.14; P <.001) were the only 2 independent risk factors for antituberculosis drug-induced hepatitis. In conclusion, slow-acetylator status of NAT2 is a significant susceptibility risk factor for antituberculosis drug-induced hepatitis. Additionally, slow acetylators are prone to develop more severe hepatotoxicity than rapid acetylators. Regular monitoring of serum aminotransferase levels is mandatory in patients receiving antituberculosis treatment, especially in slow acetylators.     

Isoniazid preventive therapy, hepatitis C virus infection, and hepatotoxicity among injection drug users infected with Mycobacterium tuberculosis.

Treatment of latent Mycobacterium tuberculosis infection with isoniazid can cause hepatotoxicity, but the risk of isoniazid-associated hepatotoxicity among persons coinfected with hepatitis C virus (HCV) is unknown. We conducted a prospective study among 146 injection drug users with M. tuberculosis infection and normal baseline hepatic transaminase values who were treated with isoniazid. Of 146 participants, 138 (95%) were HCV-seropositive. Thirty-seven participants (25%) were human immunodeficiency virus (HIV)-seropositive. Thirty-two (22%; 95% confidence interval [CI], 16%-30%) of 146 participants developed transaminase value elevations to >3 times the upper limit of normal. Transaminase value elevation was associated with concurrent alcohol use but not with race, age, presence of hepatitis B surface antigen, HIV-1 infection, or current injection drug use. Isoniazid was withdrawn from 11 participants (8%; 95% CI, 4%-13%). Of 8 deaths during follow-up, none were attributed to isoniazid-associated hepatotoxicity. The risk of transaminase value elevation and drug discontinuation for HCV-infected persons receiving isoniazid was within the range reported for populations with lower HCV prevalence.     

Liver enzymes elevation after HAART in HIV-HCV co-infection

Hepatitis C virus (HCV) co-infection is common among human immunodeficiency virus (HIV) patients. The incidence and risk factors associated with hepatotoxicity in this population after high active antiretroviral therapy (HAART) is initiated are still not well-understood. We argued to evaluate the incidence and risk factors associated with liver enzyme elevation (LEE) and their clinical significance. A retrospective chart review of patients who started HAART and had follow up at our centre for at least 1 year was undertaken. The frequency and severity of alanine aminotransferase (ALT)/aspartate aminotransferase (AST) elevation after treatment initiation were investigated and searched for clinical manifestations. Between January 1996 and March 2002, 85 HIV-HCV co-infected patients began HAART and continued follow up for at least 1 year. The incidence of severe toxicity [grades 3 + 4 LEE: >5 and >10 times the upper limit of normal (ULN) of ALT or AST] was calculated at 4% per person-years. There were no clinical manifestations of liver toxicity, and patients continued their treatment with a trend towards a decrease of their enzymes. No statistical differences in opportunistic infections or mortality were evident. The variables associated with severe hepatotoxicity were a higher baseline AST, higher international normalized ratio (INR) and lower albumin. A baseline AST < 2.1 ULN had a negative predictive value of 92% of leading to severe hepatotoxicity. In HIV-HCV co-infected patients therefore, the group at a higher risk of developing higher transaminase elevations is the one with a higher baseline AST, higher INR and lower albumin.     

Rifampin Hepatotoxicity Associated With Treatment of Latent Tuberculosis Infection

BackgroundTo determine the occurrence of hepatotoxicity associated with rifampin treatment of latent tuberculosis infection in patients from a public health tuberculosis clinic.MethodsEvaluation of rifampin hepatotoxicity in adults aged ≥18 years from a database maintained from June 2001 to May 2007 in a public health department clinic. Rifampin 600 mg daily for 4 months was prescribed. Hepatotoxicity was defined as aspartate aminotransferase (AST) or alanine aminotransferase (ALT) levels more than 3 times the upper limit of normal (ULN) with symptoms or more than 5 times the ULN without symptoms.ResultsRifampin therapy was initiated in 348 patients. Among 205 patients with evaluable data, 4 (1.95%, 95% confidence interval: 0%–4.33%) had AST or ALT levels >5 times the ULN (2 patients at 1 month and 2 patients at 3 months). Three of these patients had elevated AST/ALT at baseline; 1 had hepatitis C and 1 had an unconfirmed history of hepatitis. Adherence to clinic visits and prescribed treatment was poor.ConclusionsRifampin hepatotoxicity associated with treatment of latent tuberculosis infection is rare. Our report suggests that hepatotoxicity is more likely in patients with baseline hepatic dysfunction and the need for increased vigilance in monitoring transaminases in these patients.     

Initial experience on rifampin and pyrazinamide vs isoniazid in the treatment of latent tuberculosis infection among patients with silicosis in Hong Kong

OBJECTIVE: To compare the adverse effects and treatment adherence between 2 months of rifampin plus pyrazinamide (2RZ) and 6 months of isoniazid (6H). BACKGROUND: Patients with silicosis in Hong Kong are at high risk of acquiring tuberculosis. A previous study showed that treatment with 6H reduced the risk of silico-tuberculosis by one half. METHOD: Patients with silicosis and a Mantoux skin test reaction > or =10 mm were randomized to receive either 2RZ or 6H daily. Liver function testing was done monthly during the initial 2 months. The adverse effects and treatment adherence were compared between the two regimens. RESULTS: Forty patients (mean age, 61.6 +/- 9.1 years) and 36 patients (mean age, 57.6 +/- 9.7 years) were randomized to the 2RZ and 6H arms, respectively (p > 0.05) [+/- SD]. Baseline characteristics were comparable. Nineteen patients in the 2RZ arm had peak alanine transaminase (ALT) levels > 1.5 times the upper limit of normal (ULN) in comparison with only five study subjects of the 6H arm (47.5% vs 13.9%, p < 0.01). Fourteen patients (35%) in the 2RZ arm and 1 patient (2.8%) in the 6H arm had peak ALT levels more than five times the ULN (p < 0.001). Only seven patients had symptoms suggestive of hepatitis; none of the patients had jaundice. All recovered after withholding treatment. In the 2RZ study arm, none of the baseline characteristics predicted hepatotoxicity. Other adverse effects were generally mild and comparable between both study arms. Treatment was stopped prematurely in 45% and 36.1% of patients in the 2RZ and 6H arms, respectively (p = 0.43). The main reasons were hepatotoxicity for the 2RZ arm and voluntary withdrawal after experiencing other minor adverse effects for the 6H arm. CONCLUSION: A higher incidence of hepatotoxicity was associated with rifampin plus pyrazinamide than isoniazid in the treatment of latent tuberculosis infection among patients with silicosis in Hong Kong.     

Pyrazinamide and rifampin vs isoniazid for the treatment of latent tuberculosis: improved completion rates but more hepatotoxicity

CONTEXT: American Thoracic Society guidelines recommend a 9-month course of therapy with isoniazid for treatment of persons with latent tuberculosis infection who are at high risk for reactivation of disease. Major liver injury has been reported with the alternative regimen, a 2-month course of pyrazinamide and rifampin. OBJECTIVE: To evaluate the rate of completion and incidence of hepatotoxicity of a short regimen of pyrazinamide and rifampin for latent tuberculosis as compared with standard isoniazid therapy before and after instituting an intensive monitoring program. Design, setting, and participants: Prospective cohort study of 224 patients in a community setting between 1999 and 2001. INTERVENTIONS: Daily pyrazinamide and rifampin for 2 months or daily isoniazid for 6 months. MAIN OUTCOME MEASURES: Treatment completion, hepatotoxicity (fourfold increase of alanine transaminase [ALT]), severe hepatotoxicity (40-fold increase in ALT). RESULTS: Treatment was completed by 71% (78 of 110 patients) in the pyrazinamide/rifampin group and by 59% (67 of 114 patients) in the isoniazid group (p = 0.07). Hepatotoxicity (ALT > 160 U/L) was documented in 13% (14 of 110 patients) in the pyrazinamide/rifampin group and in 4% (5 of 114 patients) in the isoniazid group (p = 0.03). Severe hepatotoxicity (ALT > 1,600 U/L) occurred in 2 of 43 patients (5%) receiving pyrazinamide/rifampin prior to instituting intensive monitoring. Once more intensive monitoring of liver enzymes was implemented, severe hepatotoxicity occurred in none of 67 patients. CONCLUSION: The risk of hepatitis in patients receiving pyrazinamide/rifampin for prevention of latent tuberculosis is increased threefold as compared to patients receiving isoniazid. When patients were monitored more intensively, severe hepatotoxicity did not develop, but the difference did not reach statistical significance (p = 0.15).     

Association of promoter polymorphism of the CD14 C （-159） T endotoxin receptor gene with chronic hepatitis B

INTRODUCTION An estimated 350 million persons worldwide are infected with hepatitis B virus (HBV). Hepatitis B carriers are at risk for development of cirrhosis and hepatocellular carcinoma. Persons with chronic hepatitis B infection need life-long monito…     

Evaluation of clinical and immunogenetic risk factors for the development of hepatotoxicity during antituberculosis treatment

Though several risk factors for the development of hepatotoxicity due to antituberculosis drugs have been suggested, involvement of genetic factors is not fully established. We have studied the major histocompatibility complex (MHC) class II alleles and clinical risk factors for the development of hepatotoxicity in 346 North Indian patients with tuberculosis undergoing antituberculosis treatment. Of these, 56 patients developed drug-induced hepatotoxicity (DIH group), whereas the remaining 290 patients did not (non-DIH group). The DIH group was comparatively older, had lower pretreatment serum albumin, and a higher frequency of moderately/far advanced disease radiographically than the latter. Further, patients with high alcohol intake had threefold higher odds of developing hepatotoxicity. In multivariate logistic regression analysis, older age (odds ratio [OR] 1.2), moderately/far advanced disease (OR 2.0), serum albumin < 3.5 g/dl (OR 2.3), absence of HLA-DQA1*0102 (OR 4.0), and presence of HLA-DQB1*0201 (OR 1.9) were independent risk factors for DIH. Our results suggest that the risk of hepatotoxicity from antituberculosis drugs is influenced by clinical and genetic factors.     

Ethnicity, socioeconomic status, transfusions and risk of hepatitis B and hepatitis C infection

This study identifies the risk factors for hepatitis B virus (HBV) and hepatitis C virus (HCV) and measures the prevalence of hepatitis B surface antigen (HBsAg) and antibody to hepatitis C (anti-HCV) in the general population of Jakarta. A population-based sample of 985 people aged 15 and above was surveyed. Risk factors were identified through questionnaires and home visits. Serum was analysed for HBsAg, antibody to hepatitis B surface antigen (anti-HBs), anti-HCV, aspartate aminotransferase (AST) and alanine aminotransferase (ALT). The seroprevalence was: 4.0% (39/985) for HBsAg, 17.2% (170/985) for anti-HBs, and 3.9% (38/985) for anti-HCV. The risk factors for hepatitis B and hepatitis C infection had little in common. Low socioeconomic status was a strong risk factor for HBsAg (adjusted odds ratio (OR) 18.09; 95% confidence interval (CI) 2.35–139.50). In addition, the Chinese group has 2.97 higher risk of having HBV infection compared with the Malayan ethnic group (adjusted OR 2.97; 95% CI 1.22–7.83). There was moderate positive trend between family size and risk of HBsAg positivity (P= 0.130). Age over 50 (adjusted OR 14.72; 95% CI 4.35–49.89) and history of transfusion were significant risk factors for hepatitis C (adjusted OR 3.03; 95% CI 1.25–7.33). Hepatitis B and hepatitis C infections have different risk factors in Jakarta, a high risk in population for both diseases. Hepatitis B transmission is associated with low socioeconomic status, Chinese ethnic group and large family size, while hepatitis C is associated with an older age and a history of transfusions.     

Influence of glutathione S‐transferase M1 and T1 homozygous null mutations on the risk of antituberculosis drug‐induced hepatotoxicity in a Caucasian population

Objectives: Genetic variations in enzymes of isoniazid metabolism confer an increased risk for antituberculosis drug‐induced hepatotoxicity in Asian populations. The present study was aimed at investigating the possible association of antituberculosis drug‐induced hepatotoxicity with polymorphisms at the glutathione S‐transferase (GST) gene in a Caucasian population. Methods: A prospective case–control study was nested in a cohort of patients with active tuberculosis who were treated with a combination of isoniazid, rifampicin and pyrazinamide. Cases constituted patients with antituberculosis drug‐induced hepatotoxicity (n=35), and controls constituted patients without any evidence of this complication (n=60). Homozygous null polymorphisms at GST loci M1 and T1 were analysed from genomic DNA from all participants. Results: The GSTT1 homozygous null polymorphism was significantly associated with antituberculosis drug‐induced hepatotoxicity [odds ratio (OR) 2.60, 95% confidence interval (CI) 1.08–6.24, P=0.03]. No significant association was observed between the GSTM1 homozygous null polymorphism and antituberculosis drug‐induced hepatotoxicity (OR 0.73, 95% CI 0.31–1.73, P=0.48). Conclusion: The GSTT1 homozygous null polymorphism may be a risk factor of antituberculosis drug‐induced hepatotoxicity in Caucasians.     

Histological findings and clinical characteristics associated with hepatic steatosis in patients coinfected with HIV and hepatitis C virus

BACKGROUND: Hepatic steatosis, a common histological finding in hepatitis C virus (HCV)-infected patients, is associated with severity of fibrosis. The prevalence and significance of steatosis in patients coinfected with human immunodeficiency virus (HIV) and HCV are not well characterized. METHODS: To determine the prevalence and severity of steatosis, a single pathologist evaluated liver-biopsy samples from 106 patients coinfected with HIV and HCV but without hepatitis B infection (negative results for hepatitis B surface antigen) for findings associated with steatosis or steatohepatitis and viral hepatitis. Medical records were reviewed retrospectively to elucidate risk factors for steatosis. RESULTS: Steatosis was present in 56% of biopsy samples, with moderate to severe grades in 9%. Severity of steatosis was associated with fibrosis (odds ratio [OR], 1.84 [95% confidence interval (CI), 1.06-3.20]; P=.03) but not with necroinflammation. In multivariate analysis, the severity of steatosis was associated with lower levels of high-density lipoprotein cholesterol (OR, 0.71 per 10-mg/dL increase [95% CI, 0.52-0.95]; P=.02), higher body-mass index (OR, 1.30 per kg/m2 increase [95% CI, 1.13-1.49]; P<.001), and the presence of lipodystrophy (OR, 3.82 [95% CI, 1.13-12.88]; P=.03). There was a trend toward an association between the severity of steatosis and fibrosis in multivariate analysis (OR, 1.69 [95% CI, 0.91-3.16]; P=.10). CONCLUSIONS: In patients coinfected with HIV and HCV, hepatic steatosis is common and associated with more-advanced fibrosis. Lower levels of high-density lipoprotein cholesterol, higher body-mass index, and lipodystrophy are potentially modifiable risk factors associated with the severity of steatosis.     

Isoniazid hepatotoxicity associated with treatment of latent tuberculosis infection: a 7-year evaluation from a public health tuberculosis clinic

OBJECTIVES: To determine the overall incidence of isoniazid (INH) hepatotoxicity in a public health tuberculosis clinic over a 7-year period, and to determine if systematic, limited aspartate aminotransferase (AST) monitoring would be of benefit in detecting INH hepatotoxicity. METHODS: Evaluation of INH hepatotoxicity in adults aged > or = 25 years from a database maintained from fall 1996 to 2003 in a public health department clinic. Hepatotoxicity was defined as AST levels more than five times the upper limit of normal (ULN). RESULTS: Among 3,377 patients started on INH therapy, 19 patients had AST levels more than five times the ULN, or a rate of 5.6 per 1,000 patients. Only 1 of 19 patients had prodromal symptoms associated with hepatotoxicity. After 1 month, 3 months, and 6 months of therapy, the numbers of hepatotoxic events per 1,000 patients were 2.75, 7.20, and 4.10. The age-specific numbers of hepatotoxic events per 1,000 patients were 4.40 for those from 25 to 34 years of age, inclusive; 8.54 for those between 35 to 49 years of age, inclusive; and 20.83 for those > or = 50 years old. Age > 49 years (p < 0.02) and baseline AST greater than ULN (p < 0.0003) were risk factors for hepatotoxicity. CONCLUSIONS: Consistent with earlier trials, INH hepatoxicity is age related. Our results suggest hepatotoxicity is also related to baseline AST greater than ULN. Moderate-to-severe hepatotoxicity frequently occurs without symptoms, suggesting the value of more widespread AST monitoring.     

Habitual betel quid chewing and risk for hepatocellular carcinoma complicating cirrhosis

This case-control study aimed to assess the independent and interactive role of habitual betel quid chewing and known risk factors for hepatocellular carcinoma (HCC). Subjects enrolled included 210 pairs of sex- and age-matched cirrhotic patients with HCC, patients with cirrhosis alone, and healthy controls. Information on risk factors was obtained through serologic examination of hepatitis B surface antigen (HBsAg) and antibodies to hepatitis C virus (anti-HCV), and a standardized personal interview with a structured questionnaire. Multivariate analysis indicated that betel quid chewing (odds ratio [OR], 5.81; 95% confidence interval [CI], 2.26-14.94); HBsAg (OR, 37.98; 95% CI, 19.65-73.42); and anti-HCV (OR, 47.23; 95% CI, 18.86-118.25) were independent risk factors for HCC when HCC patients were compared with healthy controls. Using patients with cirrhosis alone as a reference group, multivariate analysis indicated that only betel quid chewing (OR, 1.69; 95% CI, 1.04-2.76) and HBsAg (OR, 1.54; 95% CI, l.01-2.37) were independent risk factors for HCC. There was an additive interaction between betel quid chewing and the presence of either HBsAg (synergy index, 5.22) or anti-HCV (synergy index, 1.35). Moreover, a higher risk of HCC was associated with a longer duration of betel quid chewing and a larger amount of betel quid consumed (each p(for trend) < 0.0001). In conclusion, betel quid chewing is an independent risk factor for cirrhotic HCC. There is an additive interaction between betel quid chewing and chronic hepatitis B and/or hepatitis C virus infection.     

Antituberculosis drug‐induced hepatotoxicity is uncommon in Tanzanian hospitalized pulmonary TB patients

Data on antituberculosis drug‐induced hepatotoxicity in sub Saharan Africa are limited, probably because liver function tests are not carried out routinely during tuberculosis treatment in most African countries. We monitored the liver function of 112 Tanzanian hospitalized pulmonary tuberculosis patients during the first 2 months (i.e. the intensive phase) of tuberculosis treatment. The rate of hepatotoxicity in our study was 0.9% (95% CI 0.04–4.3%). It is encouraging to find a lower rate of antituberculosis drug‐induced hepatotoxicity than one would expect based on the high prevalence of risk factors such as HIV and hepatitis B.     

Factors predicting relapse and poor outcome in type I autoimmune hepatitis: role of cirrhosis development, patterns of transaminases during remission and plasma cell activity in the liver biopsy

AIM: To determine factors predicting relapse and poor outcome in patients with type I autoimmune hepatitis (AIH). METHODS: Patients with AIH were retrospectively recruited. Definitions-remission: AST/ALT < 2 ULN; relapse: AST/ALT > or = 2 ULN; poor outcome: cirrhosis complications, transplantation (OLTx), and death; abnormal transaminases: AST/ALT > ULN but within the remission range; abnormal transaminases index (ATI): number of occasions AST/ALT abnormal/years of remission. Liver biopsies were assessed by Ishak system, and additional score given for portal and parenchymal plasma cells. Data are presented as median (range). RESULTS: Seventy-one patients were identified. Twenty (28%) had cirrhosis at presentation, 14 (20%) developed it during follow-up of 52 months (18-336). Of the 14, four had histological confirmation, and the remainder had clinical/radiological evidence of cirrhosis. Factors independently associated with cirrhosis development were inability to have consistently normal transaminases during remission, OR 19.3 (95% CI 2.2-40), p = 0.002. Treatment was discontinued in 40/69 patients of whom 30 (75%) relapsed within 2 months (1-23), culminating in one death. Factors independently associated with relapse were: time to initial remission, OR 5.5, 95% CI 1.3-22, p = 0.01; failure to have consistently normal transaminases during remission OR 11.8, 95% CI 1.3-100, p = 0.02; and portal plasma cell score (PPCS) OR 10.6 (95% CI 1.0-107), p = 0.04. Time to remission > or = 5 months, PPCS > or = 3 and ATI > or = 2 was associated with > 90% probability of relapse (PPV 100%). Fifteen percent had a poor outcome. Independent predictors of poor outcome were: globulins at onset OR 3.4 (95% CI 1.1-10.1), p = 0.02 and cirrhosis development, OR 23 (95% CI 1.7-307), p = 0. CONCLUSIONS: Seventy percent of patients with AIH relapse upon drug cessation. Time to remission > or = 5 months, ATI > or = 2 and PPCS > or = 3 were associated with > 90% probability of relapse. Factors predicting poor outcome were globulins at onset and cirrhosis development.     

Updated thresholds for alanine aminotransferase do not exclude significant histological disease in chronic hepatitis C

Background and aim: Histological changes in hepatitis C virus (HCV)‐infected patients with persistently normal alanine aminotransferase (PNALT) have not been evaluated for updated upper limits of normal (ULN; ≤19/30U/L for females/males). We assessed significant fibrosis (≥F2, METAVIR) in patients with PNALT and persistently elevated alanine aminotransferase (PEALT). Patients and methods: Nine hundred and twenty consecutive, unselected HCV patients were stratified into four groups: Group I: (n=124) PNALT within the updated ULN [0.5 × ULN (corresponding to ≤19 U/L) for females; 0.75 × ULN (corresponding to ≤30 U/L) for males]; Group II (n=173): PNALT≤1 × ULN but greater than Group I; Group III (n=313): PEALT 1–2 × ULN; and Group IV (n=310): PEALT>2 × ULN. PNALT was defined as ≥3 determinations within the normal range over ≥6 months. Results: Advanced ≥F3 and ≥F2 fibrosis increased incrementally across Groups I; II; III; and IV: 24.2 and 45.2%; 25.4 and 56.1%; 36.1 and 64.2%; and 50 and 77.1% respectively (P<0.0001 for both). Multivariable logistic regression analysis identified age [odds ratio (OR), 1.05; 95% confidence intervals (CI): 1.02–1.08; P<0.0001], alanine aminotransferase (ALT) groups (OR 1.38; 95% CI: 1.03–1.83; P=0.030), presence of moderate–severe steatosis (OR 2.70; 95% CI: 1.19–6.15; P=0.018) and ≥A2 necroinflammation (OR 17.9; 95% CI: 8.88–36.20; P<0.0001) as independent predictors of ≥F2 fibrosis. Updated ULN for ALT were better at excluding ≥F2 fibrosis compared with traditional ULN (90.6 vs. 74.2%, P=0.0041) but less specific (20.8 vs. 44%, P=0.0007) with similar positive/negative predictive values. Conclusions: HCV patients with ‘updated’ normal ALT have the lowest prevalence of significant fibrosis, although utilizing these levels without resorting to biopsy would miss significant fibrosis in almost one‐half of such patients.