An Official ATS Statement: Hepatotoxicity of Antituberculosis Therapy (2006)
Total Page：16
File Type：pdf, Size：1020Kb
American Thoracic Society Documents An Official ATS Statement: Hepatotoxicity of Antituberculosis Therapy Jussi J. Saukkonen, David L. Cohn, Robert M. Jasmer, Steven Schenker, John A. Jereb, Charles M. Nolan, Charles A. Peloquin, Fred M. Gordin, David Nunes, Dorothy B. Strader, John Bernardo, Raman Venkataramanan, and Timothy R. Sterling, on behalf of the ATS Hepatotoxicity of Antituberculosis Therapy Subcommittee This official statement was approved by the ATS Board of Directors, March 2006 Methods of tuberculosis (TB) infection. The liver has a central role in drug The Liver: Structure and Function metabolism and detoxification, and is consequently vulnerable to Hepatic Drug Metabolism: Transporters, Enzymes, and injury. The pathogenesis and types of DILI are presented, ranging Excretion from hepatic adaptation to hepatocellular injury. Knowledge of the Drug-induced Liver Injury: General Concepts metabolism of anti-TB medications and of the mechanisms of TB Definition DILI is incomplete. Understanding of TB DILI has been hampered Dimensions of the Problem by differences in study populations, definitions of hepatotoxicity, Pathogenesis of DILI and monitoring and reporting practices. Available data regarding the incidence and severity of TB DILI overall, in selected demo- Hepatic Enzyme Measurement graphic groups, and in those coinfected with HIV or hepatitis B or Types of DILI C virus are presented. Systematic steps for prevention and manage- DILI during Treatment of Latent TB Infection ment of TB DILI are recommended. These include patient and regi- Isoniazid men selection to optimize benefits over risks, effective staff and Rifampin patient education, ready access to care for patients, good communi- Isoniazid and Rifampin cation among providers, and judicious use of clinical and biochemi- Pyrazinamide cal monitoring. During treatment of latent TB infection (LTBI) ala- Rifampin and Pyrazinamide nine aminotransferase (ALT) monitoring is recommended for those Rifabutin who chronically consume alcohol, take concomitant hepatotoxic Ethambutol drugs, have viral hepatitis or other preexisting liver disease or ab- Fluoroquinolones normal baseline ALT, have experienced prior isoniazid hepatitis, Hepatotoxicity during Treatment of TB Disease are pregnant or are within 3 months postpartum. During treatment Age over 35 of TB disease, in addition to these individuals, patients with HIV Children infection should have ALT monitoring. Some experts recommend Sex biochemical monitoring for those older than 35 years. Treatment Cofactors should be interrupted and, generally, a modified or alternative regimen used for those with ALT elevation more than three times Abnormal Baseline Transaminases the upper limit of normal (ULN) in the presence of hepatitis symp- Acetylator Status toms and/or jaundice, or five times the ULN in the absence of Other Factors symptoms. Priorities for future studies to develop safer treatments Regimen for LTBI and for TB disease are presented. HIV-infected Individuals Hepatitis B Keywords: hepatitis; treatment; latent tuberculosis Hepatitis C DILI with Second-line Anti-TB Agents METHODS Recommendations regarding TB DILI Material presented here was generated by a multidisciplinary Program Infrastructure symposium held on November 13–14, 2002, which included Provider Education and Resources presentations and discussion by specialists in tuberculosis (TB), Pretreatment Clinical Evaluation pharmacology, and hepatology. This information was supple- Patient Education mented by material obtained through literature searches per- Medication Administration and Pharmacy formed before and after the symposium during the course of Treatment of LTBI this project. PubMed searches used various combinations of the Treatment of TB Disease terms “tuberculosis,” “treatment,” “hepatitis,” “liver injury,” Priorities for Research of Hepatotoxicity in Treatment of LTBI “hepatotoxicity,” “adverse events,” “latent,” “infection,” and/or and of TB Disease individual names of the anti-TB medications mentioned here. Conclusions The bibliographies of publications were also reviewed for addi- tional references. Publications were evaluated for numbers of Drug-induced liver injury (DILI) is a problem of increasing signifi- patients treated, regimens used, incidence and severity of hepa- cance, but has been a long-standing concern in the treatment totoxicity, confounding features, and type of publication. THE LIVER: STRUCTURE AND FUNCTION Am J Respir Crit Care Med Vol 174. pp 935–952, 2006 DOI: 10.1164/rccm.200510-1666ST The liver is situated between the alimentary tract and the sys- Internet address: www.atsjournals.org temic circulation to maximize processing of absorbed nutrients 936 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 174 2006 and to minimize exposure of the body to toxins and foreign rapidly. Injurious free radicals cause hepatocyte necrosis in zones chemicals. Consequently, the liver may be exposed to large con- farthest from the hepatic arterioles, where metabolism is greatest centrations of exogenous substances and their metabolites. and antioxidant detoxifying capacity is the least (10, 11). Unpredictable or idiosyncratic reactions comprise most types Hepatic Drug Metabolism: Transporters, Enzymes, and of DILI. These hypersensitivity or metabolic reactions occur Excretion largely independent of dose and relatively rarely for each drug, The splanchnic circulation carries ingested drugs directly into and may result in hepatocellular injury and/or cholestasis. Hepa- the liver, a phenomenon known as the “first pass” through tocyte necrosis is often distributed throughout hepatic lobules the liver. Metabolic enzymes convert these chemicals through rather than being zonal, as is often seen with predictable DILI. In phase 1 pathways of oxidation, reduction, or hydrolysis, which hypersensitivity reactions, immunogenic drug or its metabolites are carried out principally by the cytochrome P450 class of en- may be free or covalently bound to hepatic proteins, form- zymes. Phase 2 pathways include glucuronidation, sulfation, ace- ing haptens or “neoantigens.” Antibody-dependent cytotoxic, tylation, and glutathione conjugation to form compounds that T-cell, and occasionally eosinophilic hypersensitivity responses ␣ are readily excreted from the body. Other subsequent steps may be evoked. Released tumor necrosis factor- , interleukin ␥ include deacetylation and deaminidation. Many drugs may be (IL)-12, and IFN- promote hepatocellular programmed cell metabolized through alternative pathways, and their relative death (apoptosis), an effect opposed by IL-4, IL-10, IL-13, and contributions may explain some differences in toxicity between monocyte chemotactic protein-1 (12). individuals. In phase 3 pathways, cellular transporter proteins Metabolic idiosyncratic reactions may result from genetic facilitate excretion of these compounds into bile or the systemic or acquired variations in drug biotransformation pathways, with circulation. Transporters and enzyme activities are influenced synthesis or abnormally slow detoxification of a hepatotoxic by endogenous factors such as circadian rhythms, hormones, metabolite. Metabolic idiosyncratic reactions may have a widely cytokines, disease states, genetic factors, sex, ethnicity, age, and variable latent period, but recur within days to weeks after nutritional status, as well as by exogenous drugs or chemicals re-exposure (4). (1). Bile is the major excretory route for hepatic metabolites. Hepatic Enzyme Measurement Compounds excreted in bile may undergo enterohepatic circula- tion, being reabsorbed in the small intestine and re-entering the An increase in serum ALT, formerly known as serum glutamate portal circulation (2). pyruvate transaminase (SGPT), is more specific for hepatocellu- lar injury than an increase in aspartate aminotransferase (AST or serum glutamic oxaloacetic transaminase [SGOT]), which can DRUG-INDUCED LIVER INJURY: GENERAL CONCEPTS also signify abnormalities in muscle, heart, or kidney (13, 14). Definition Serum enzyme concentrations are measured by functional Drug-induced liver injury (DILI) is ultimately a clinical diagnosis catalytic assays with normal values established from “healthy” of exclusion. Histologic specimens of the liver are often not populations. The normal range lies within 2 standard deviations obtained. Other causes of liver injury, such as acute viral hepatitis, of the mean of the distribution, with 2.5% of persons who are should be methodically sought, and their absence makes the diag- otherwise healthy having concentrations above and below the nosis plausible. Usually, the time of onset to acute injury is within limits of normal on a single measurement (15). Populations used months of initiating a drug. Rechallenge with the suspected of- to set standard values in the past probably included individuals fending agent with more than twofold serum alanine aminotrans- with occult liver disease, whose exclusion has led to decreases ferase (ALT) elevation, and discontinuation leading to a fall in in the upper limit of normal (ULN) (16). Interlaboratory varia- tion in assay results can be substantial. Consequently, compari- ALT, is the strongest confirmation of the diagnosis (3). Rechal- son of multiples of the ULN has become standard (13, 14). lenge may, in some instances, endanger the patient and is usually In an individual, transaminases may vary as much as 45% on confined to essential drugs or used when multiple potentially hepa- a single day, with the highest