Anti-tuberculosis Drug-induced Hepatitis Research Articles

Case report on anti-tuberculosis drug-induced hepatitis and pancreatitis

Tuberculosis (TB) is a widespread infectious disease primarily impacting the lungs but with potential effects on various organs, such as bones, kidneys, and intestines. This case underscores a rare yet serious complication associated with anti-TB drug (ATD) treatment-the development of drug-induced acute pancreatitis. In this instance, a 65-year-old male undergoing ATD therapy exhibited symptoms including fever, vomiting, and fatigue. Despite receiving medical intervention, including intravenous antibiotics and hepatoprotective drugs, the patient's condition progressively worsened, ultimately resulting in a fatal outcome. This case emphasizes the crucial significance of early identification and effective management of such complications, highlighting the necessity for vigilant monitoring and regular assessment of liver function tests throughout ATD treatment.

Anti-tuberculosis Drug-induced Hepatitis

Among the first line anti-TB drugs, INH, Rifampicin and Pyrazinamide are considered to be the most hepatotoxic drugs and cause drug induced hepatitis. Pyrazinamide causes both dose-dependent and idiosyncratic hepatitis whereas Isoniazid and Rifampicin induced hepatotoxicity are considered to be idiosyncratic. There are several risk factors for hepatotoxicity such as old age, malnutrition, genetic predisposition, HIV infection as well as chronic Hepatitis B and C infections. Anti-TB drug induced hepatitis usually occurs within 2 months after starting treatment. Patient may present with mild symptoms to severe acute hepatitis or even acute liver failure. Various guidelines have been published regarding the management of ATT and restarting anti TB drugs. This article reviews the incidence, risk factors, mechanism, diagnosis and management strategies of anti-TB drug induced hepatitis.
 BANGLADESH J CHILD HEALTH 2022; VOL 46 (1) : 23-27

The relationship between relative telomere length and anti-tuberculosis drug-induced hepatitis : A case-control study

Anti-tuberculosis drug-induced hepatitis (AT-DIH) is a common and serious adverse drug reaction of tuberculosis treatment. Evidence demonstrated that many factors could affect the occurrence of AT-DIH, such as ageing, smoking, alcohol, oxidative stress, etc., while these factors could also promote telomere shortening. Therefore, relative telomere length (RTL) is indirectly related to the occurrence of AT-DIH. The present study aimed to explore and validate this relationship in Chinese tuberculosis patients. A 1:4 matched case-control study was undertaken using 202 AT-DIH cases and 808 controls. Logistic regression models were used to estimate the association between RTL and AT-DIH with odds ratios (ORs) and 95% confidence intervals (CIs). The area under receiver operating characteristic curve (AUC) was calculated to estimate the discriminative performance for distinguishing AT-DIH cases from controls. The average RTL in AT-DIH cases was significantly shorter than that in controls (1.24 vs. 1.46, P=0.002). Patients with longer RTL were at a reduced risk of AT-DIH (OR=0.79, 95% CI: 0.66-0.94, P=0.009), and a dose-response relationship also existed between RTL and lower AT-DIH risk (P for trend=0.012). Under the optimal RTL cut-off value of 1.22, the corresponding AUCs were 0.57 (95% CI: 0.53-0.62, P=0.001) in the univariate model and 0.62 (95% CI: 0.57-0.66, P<0.001) in the multivariate model. This study showed that the shorter the RTL, the higher the risk of AT-DIH during an anti-tuberculosis treatment. The short RTL could potentially serve as a risk factor or a predictive test of the hepatotoxic risk associated with anti-tuberculosis treatments.

Magnitude, outcome, and associated factors of anti-tuberculosis drug-induced hepatitis among tuberculosis patients in a tertiary hospital in North Ethiopia: A cross-sectional study.

Short-course chemotherapy comprising isoniazid, rifampicin, ethambutol, and pyrazinamide has proved to be highly effective in the treatment of tuberculosis (TB). However, the most common adverse effect of this regimen leading to interruption of therapy is hepatotoxicity. There is a paucity of evidence in Tigray region on anti-tuberculosis drug-induced hepatitis. Therefore, this study aims to determine the magnitude, outcomes, and associated factors of drug-induced hepatitis in Ayder specialized comprehensive hospital tuberculosis clinic. An institution-based cross-sectional study was done on 188 cases of patients who took anti-tuberculosis drugs from August 4, 2015 to June 30, 2018 in tuberculosis clinic, Ayder Comprehensive Specialized Hospital, Northern Ethiopia. Data on socio-demography, clinical characteristics and magnitude of the incidence and outcome of anti-tuberculosis drugs-induced hepatitis were collected using structured checklist from patients' records using census method. Then, we entered and analyzed the data using statistical packages for social sciences (SPSS) statistical software version 21. Descriptive statistics were done in tables, counts, proportions, median and range. Bivariate and multivariable regression analyses were done to identify factors that are associated with drug-induced hepatitis. Confidence interval was taken at 95% and p-value of less than 0.05 was used to denote significance. We approached a total of 226 patients' records, and we collected data from188 records (83.2%response rate). Anti-tuberculosis drug-induced hepatitis was found in 26 (13.8%) of the patients, of which 3 (11.54%) have died. Using multivariable logistic regression analyses, preexisting liver disease (AOR: 42.01, 95% CI: 4.22-417.49), taking other hepatotoxic drugs (AOR: 23.66, 95% CI: 1.77-314.79), and having lower serum albumin (AOR: 10.55, 95% CI: 2.57-43.32) were found to be significantly associated with the development of anti-tuberculosis drug-induced hepatitis. The incidence of anti-tuberculosis drug-induced hepatitis was high. Patients with low baseline serum albumin, taking other hepatotoxic drugs and having preexisting liver disease should be followed with serial liver enzymes after initiation of anti-tuberculosis medications. These patients should be followed with frequent measurement of liver enzymes to assess for the development of drug-induced hepatitis.

Evaluation of Risk Factors and Changes in Liver Enzymes among the Patients with Antituberculosis Drug-Induced Hepatitis: A Teaching Hospital Based Study

Evaluation of Risk Factors and Changes in Liver Enzymes among the Patients with Antituberculosis Drug-Induced Hepatitis: A Teaching Hospital Based Study

Risk Factors and Pattern of Changes in Liver Enzymes Among the Patients With Anti-Tuberculosis Drug-Induced Hepatitis

Background: Hepatotoxicity is one of the most frequent adverse events that occurs during tuberculosis treatment and is associated with mortality of 6% - 12% if drugs are continued after the appearance of symptoms. In most of the cases, hepatitis is evident within three months after induction of anti-tuberculosis treatment. Objectives: The current study aimed to define the pattern of changes in liver transaminases and the associated risk factors among the patients with anti-tuberculosis drug-induced hepatitis who admitted to Boo-Ali Hospital in Zahedan, Southeastern Iran. Patients and Methods: The current descriptive cross-sectional study reviewed all files of the patients with anti-tuberculosis Drug-Induced Hepatitis (DIH) who referred to Boo-Ali Hospital in Zahedan, Southeastern Iran, in five years. All patients were above 14 years, and were treated with the standard regimen (a combination of isoniazid, rifampin, pyrazinamide, and ethambutol ± streptomycin). Hepatotoxicity was defined when the liver transaminases were more than five, the Upper Limit of Normal (ULN), or had clinical symptoms with an increase of liver transaminases ≥ 3 ULN. Results: Among the 946 patients with tuberculosis disease (44% men; 56% women), 52 (5.5%) cases had drug-induced hepatotoxicity. Only 25% of the patients with anti-tuberculosis drug-induced hepatitis were below 52; 50% of the cases occurred within the first two weeks after the treatment onset. Conclusions: Anti-tuberculosis drugs-induced hepatotoxicity caused treatment interruption in 5.5% of the patients with tuberculosis. The majority of the patients with DIH were above fifty, and 50% the cases occurred during the first two weeks after treatment onset. Physicians must carefully and closely monitor such patients.

Analysis of IL-6, STAT3 and HSPA1L gene polymorphisms in anti-tuberculosis drug-induced hepatitis in a nested case-control study.

ObjectivesTo investigate the association of IL-6, STAT3 and HSPA1L polymorphisms with the risk of anti-tuberculosis drug-induced hepatitis (ATDH) in Chinese Han population.MethodsThe study was designed as a nested case-control study within a prospective cohort. Each case was matched with four controls by sex, age at baseline (±5 years), treatment history, disease severity, drug dosage and place of sample collection. Genetic polymorphisms of IL-6, STAT3 and HSPA1L were determined blindly by TaqMan single-nucleotide polymorphism (SNP) genotyping assay. Odds ratio (OR) with 95% confidence intervals (CIs) was estimated by conditional logistic regression model to measure the association between selected SNPs and the risk of ATDH.ResultsA total of 89 incident ATDH cases and 356 ATDH-free controls were genotyped for IL-6 (rs2066992, rs2069837, rs1524107), STAT3 (rs1053004, rs1053023, rs1053005) and HSPA1L (rs2227956). In genotype analysis, no significant difference was observed in genotypes frequencies of the seven selected SNPs between case and control group after Bonferroni correction. In haplotype analysis, carriers with STAT3 GAT and AGC (rs1053023-rs1053005-rs1053004) haplotypes had a significantly higher risk of ATDH compared with wild-type haplotype (P<0.0001).ConclusionThis study suggested that genetic variants of STAT3 might contribute to ATDH susceptibility in Chinese Han population. Studies in larger, varied populations are required to confirm these findings.

Superoxide Dismutase Gene (SOD1, SOD2, and SOD3) Polymorphisms and Antituberculosis Drug-induced Hepatitis.

PurposeDrug-induced liver injury (DILI) is a serious issue often leading to discontinuation of the proper regimen of antituberculosis drugs (ATD). Previous studies have suggested that antioxidant enzymes play an important role in DILI.MethodsWe explored whether polymorphisms in superoxide dismutase genes, including Cu/Zn superoxide dismutase (SOD1), manganese superoxide dismutase (SOD2) and extracellular superoxide dismutase (SOD3) are associated with ATD-induced hepatitis. Genotype distributions of four single nucleotide polymorphisms (SNPs) in three genes (rs2070424, SOD1; rs4880, SOD2; rs2536512, and rs1799895, SOD3) were compared between 84 patients with ATD-induced hepatitis and 237 patients tolerant to ATD.ResultsIntron SNP rs2070424 of SOD1 showed a significant association with ATD-induced hepatitis. The frequency of genotypes carrying minor alleles (GA or GG) was significantly higher in the case group than that of controls (P=0.019, OR=2.26, 95% CI 1.14-4.49). For the other SNPs of SOD2 and SOD3, there were no differences in genotype frequencies between ATD-induced hepatitis and ATD-tolerant controls.ConclusionsThese findings suggest that rs2070424 of SOD1 is significantly associated with ATD-induced hepatitis. This genetic variant may be a risk factor for ATD-induced hepatitis in individuals from Korea.

Polymorphisms in CYP2E1, GSTM1 and GSTT1 and anti-tuberculosis drug-induced hepatotoxicity

Anti-tuberculosis drug-induced hepatitis (ATD- induced hepatitis) has been linked to polymorphisms in genes encoding drug metabolizing enzymes. N-acetyltransferase 2 (NAT2), cytochrome P450 2E1 (CYP2E1) and glutathione S-transferase (loci GSTM1 and GSTT1) are involved in the metabolism of isoniazid, the most toxic drug for the treatment of tuberculosis (TB). This study was designed to determine the frequency and to evaluate whether polymorphisms at CYP2E1, GSTM1 and GSTT1 genes are associated with drug response, as well as to identify clinical risk factors for ATD-induced hepatitis. A total of 245 Brazilian patients undergoing treatment for TB were genotyped using polymerase chain reaction and restriction fragment length polymorphism and sequencing methods. The frequencies of the CYP2E1 polymorphic alleles RsaI, PstI and DraI are 8%, 8.5% and 12%, respectively. GSTM1 and GSTT1 genes are deleted in 42.9% and 12.4% of the population, respectively. Fifteen patients (6.1%) developed hepatotoxicity. Clinical (HIV, female sex and extrapulmonary TB) and genetic characteristics (CYP2E1 without any mutations, having NAT2 slow acetylator profile) are at higher risk of developing ATD-induced hepatitis in this population. Genotyping for GSTM1 and GSTT1 showed no influence on drug response.

Cytochrome P450 2E1 Gene Polymorphisms/Haplotypes and Anti-Tuberculosis Drug-Induced Hepatitis in a Chinese Cohort

ObjectiveThe pathogenic mechanism of anti-tuberculosis (anti-TB) drug-induced hepatitis is associated with drug metabolizing enzymes. No tagging single-nucleotide polymorphisms (tSNPs) of cytochrome P450 2E1(CYP2E1) in the risk of anti-TB drug-induced hepatitis have been reported. The present study was aimed at exploring the role of tSNPs in CYP2E1 gene in a population-based anti-TB treatment cohort.Methods and DesignA nested case-control study was designed. Each hepatitis case was 14 matched with controls by age, gender, treatment history, disease severity and drug dosage. The tSNPs were selected by using Haploview 4.2 based on the HapMap database of Han Chinese in Beijing, and detected by using TaqMan allelic discrimination technology.ResultsEighty-nine anti-TB drug-induced hepatitis cases and 356 controls were included in this study. 6 tSNPs (rs2031920, rs2070672, rs915908, rs8192775, rs2515641, rs2515644) were genotyped and minor allele frequencies of these tSNPs were 21.9%, 23.0%, 19.1%, 23.6%, 20.8% and 44.4% in the cases and 20.9%, 22.7%, 18.9%, 23.2%, 18.2% and 43.2% in the controls, respectively. No significant difference was observed in genotypes or allele frequencies of the 6 tSNPs between case group and control group, and neither of haplotypes in block 1 nor in block 2 was significantly associated with the development of hepatitis.ConclusionBased on the Chinese anti-TB treatment cohort, we did not find a statistically significant association between genetic polymorphisms of CYP2E1 and the risk of anti-TB drug-induced hepatitis. None of the haplotypes showed a significant association with the development of hepatitis in Chinese TB population.

Anti-tuberculosis drug-induced hepatitis in renal transplant patient with pulmonary and extra pulmonary tuberculosis

Hepatotoxicity is a major side-effect of the medicines used in tuberculosis therapy. Although the guidelines for the management of antituberculosis drug induced hepatitis have been published from varieties of health institutes and organizations, they are to a great extent highly similar, there are nevertheless some important differences.We report a case of hepatitis in a renal transplant recipient admitted with pulmonary and extra pulmonary (abdominal) tuberculosis and review the literature on this topic.The introduction of antimicrobial teams, including specialist pharmacists, microbiologists and infectious disease physicians, is a major factor to improve the quality of care and faces the overcoming of antimicrobial resistance. Reintroducing one antituberculosis drug at a time with close monitoring of liver enzymes seems to be the optimal approach in the management of antituberculosis drug induced hepatitis.With multi-disciplinary clinical approach the patient has been successfully cured and has returned to normal active life.

Genetic polymorphisms of NAT2, CYP2E1 and GST enzymes and the occurrence of antituberculosis drug-induced hepatitis in Brazilian TB patients

Isoniazid (INH), one of the most important drugs used in antituberculosis (anti-TB) treatment, is also the major drug involved in hepatotoxicity. Differences in INH-induced toxicity have been attributed to genetic variability at several loci, such as NAT2, CYP2E1, GSTM1 and GSTT1, that code for drug-metabolising enzymes. Our goal was to examine the polymorphisms in these enzymes as susceptibility factors to anti-TB drug-induced hepatitis in Brazilian individuals. In a case-control design, 167 unrelated active tuberculosis patients from the University Hospital of the Federal University of Rio de Janeiro, Brazil, were enrolled in this study. Patients with a history of anti-TB drug-induced acute hepatitis (cases with an increase to 3 times the upper limit of normal serum transaminases and symptoms of hepatitis) and patients with no evidence of anti-TB hepatic side effects (controls) were genotyped for NAT2, CYP2E1, GSTM1 and GSTT1 polymorphisms. Slow acetylators had a higher incidence of hepatitis than intermediate/rapid acetylators [22% (18/82) vs. 9.8% (6/61), odds ratio (OR), 2.86, 95% confidence interval (CI), 1.06-7.68, p = 0.04). Logistic regression showed that slow acetylation status was the only independent risk factor (OR 3.59, 95% CI, 2.53-4.64, p = 0.02) for the occurrence of anti-TB drug-induced hepatitis during anti-TB treatment with INH-containing schemes in Brazilian individuals.

Anti-tuberculosis drug-induced hepatitis

In 1996 a six-month short-course chemotherapy was adopted as a standard chemotherapy for pulmonary tuberculosis in Japan. The frequency of implementation of short course chemotherapy for smear positive new case was only sixty percent in 2003, although a short course chemotherapy was recommended all over the world for avoidance of acquiring a new resistance among new drug resistant tuberculosis. The reasons for the low adaptation of short course chemotherapy were speculated that high rate of elderly patients, and high frequency of drug-induced hepatitis. From our 14-year experience, the frequency of drug-induced hepatitis was 7.8% for all patients with standard 6-month or 9-month regimen, 7.2% in the patients with normal liver function tests at the start of chemotherapy, and 11.8% in the patients with any kinds of abnormality. The death rate was 0.04% among treated patients, and fatality was 0.49% among the patients with drug-induced hepatitis. Positive HCV antibody and less than 1,000 cells/microL of peripheral lymphocyte count at the beginning of treatment were independent risk factors for drug-induced hepatitis. The management of hepatitis during antituberculosis treatment was also referred.

Antituberculosis drug-induced hepatotoxicity: a comparison between patients with and without human immunodeficiency virus seropositivity

The prevalence and risk factors for rifampin, isoniazid and pyrazinamide hepatotoxicity were evaluated in HIV-infected subjects and controls. Patients with tuberculosis (30 HIV positive and 132 HIV negative), aged between 18 and 80 years-old, admitted to hospital in Brazil, from 2005 to 2007, were selected for this investigation. Three definitions of hepatotoxicity were used: I) a 3-fold increase in the lower limit of normal for alanine-aminotransferase (ALT); II) a 3-fold increase in the upper limit of normal (ULN) for ALT, and III) a 3-fold increase in the ULN for ALT plus a 2-fold increase in the ULN of total bilirubin. In groups with and without HIV infection the frequency of hepatotoxicity I was 77% and 46%, respectively (p < 0.01). Using hepatotoxicity II and III definitions no difference was observed in the occurrence of antituberculosis drug-induced hepatitis. Of the 17 patients with hepatotoxicity by definition III, 3 presented no side effects and treatment was well tolerated. In 8 (36.4%) out of 22, symptoms emerged and treatment was suspended. Alcohol abuse was related to hepatotoxicity only for definition I. Depending on the definition of drug-induced hepatitis, HIV infection may or may not be associated with hepatotoxicity. The impact that minor alterations in the definition had on the results was impressive. No death was related to drug-induced hepatotoxicity. The emergence of new symptoms after initiating antituberculosis therapy could not be attributed to hepatotoxicity in over one third of the cases.

The association between NAT2 polymorphism and anti-tuberculosis drug-induced hepatitis

The association between NAT2 polymorphism and anti-tuberculosis drug-induced hepatitis

Antituberculosis drug-induced clinical diagnosis and treatment of drug-induced liver injury

Objective To evaluate the anti-tuberculosis drug-induced drug-induced hepatitis clinical characteristics, anti-tuberculosis drug-induced liver injury and its prevention and reasonable diagnosis and treatment. Methods According to clinical drug history, clinical symptoms, liver function tests, imaging examinations and drug-induced liver disease diagnosis and drug-induced liver disease diagnostic criteria of the site from 2004 to 2006 the governance of anti-TB treatment of TB patients after liver injury 61 patients were retrospectively analyzed. Results 348 cases of TB patients receiving anti-TB drugs after treatment, 61 patients the emergence of drug-induced liver disease, drug-induced liver disease incidence of 17.53%, 348 patients in the HBSAG positive for 32 cases, of which 13 cases of the emergence of drug-induced liver injury, accounting for 40.63%. Conclusions The anti-tuberculosis drug-induced liver injury more common in patients with risk factors, and multi-drug use occurred in the first 1 week to the first 8 weeks. Anti-TB treatment during routine examination before liver function, HBSAG, treatment should be regularly checked liver function. Anti-tuberculosis drug-induced liver damage on the early diagnosis and timely and reasonable treatment, can return to normal liver function in patients and help patients with the successful completion of anti-TB treatment regimens. Key words: Tuberculosis; Liver damage; Anti-TB drugs; Prevention and treatment

Genetic polymorphisms of NAT2 and CYP2E1 associated with antituberculosis drug-induced hepatotoxicity in Korean patients with pulmonary tuberculosis

Antituberculosis drug-induced hepatitis attributed to isoniazid (INH) is one of the most prevalent drug-induced liver injuries. INH is metabolized by hepatic N-acetyltransferase (NAT) and cytochrome P450 2E1 (CYP2E1) to form hepatotoxins. The aim of this study was to evaluate whether polymorphisms of the NAT2 and/or CYP2E1 genes were associated with antituberculosis drug-induced hepatotoxicity in Korean patients. A total of 132 patients with tuberculosis who received antituberculosis treatment were followed prospectively. Their NAT2 and CYP2E1 genotypes were determined using polymerase chain reaction (PCR) with or without sequencing. Eighteen (13.6%) patients developed antituberculosis drug-induced hepatotoxicity. Regarding NAT2, slow acetylators had a higher incidence of hepatotoxicity than rapid acetylators (36.8% vs. 9.7%, P=0.005) and there was a 3.8-fold risk of hepatotoxicity for the slow acetylators compared to the rapid acetylators. For the CYP2E1 gene, the RsaI polymorphism in the 5' untranslated region, and a polymorphic repetitive sequence at the CYP2E1 5'-flaking region were analyzed; there was no significant association between any CYP2E1 genotype and antituberculosis drug-induced hepatotoxicity. In conclusion, slow acetylator status of NAT2 was a significant susceptibility risk factor for antituberculosis drug-induced hepatotoxicity; NAT2 genotyping may be a useful tool for predicting antituberculosis drug-induced hepatotoxicity.

Cytochrome P450 2E1 genotype and the susceptibility to antituberculosis drug-induced hepatitis

Most cases with antituberculosis drug-induced hepatitis have been attributed to isoniazid. Isoniazid is metabolized by hepatic N-acetyltransferase (NAT) and cytochrome P450 2E1 (CYP2E1) to form hepatotoxins. However, the role of CYP2E1 in this hepatotoxicity has not yet been reported. The aim of this study was to evaluate whether the polymorphism of the CYP2E1 gene is associated with antituberculosis drug-induced hepatitis. A total of 318 tuberculosis patients who received antituberculosis treatment were followed prospectively. Their CYP2E1 and NAT2 genotypes were determined using a polymerase chain reaction with restriction fragment length polymorphism method. Twenty-one healthy volunteers were recruited for CYP2E1 phenotype study using a chlorzoxazone test. Forty-nine (15.4%) patients were diagnosed to have drug-induced hepatotoxicity. Patients with homozygous wild genotype CYP2E1 c1/c1 had a higher risk of hepatotoxicity (20.0%; odds ratio [OR], 2.52) than those with mutant allele c2 ( CYP2E1 c1/c2 or c2/c2, 9.0%, P = .009). If CYP2E1 c1/c2 or c2/c2 genotype combined with rapid acetylator status was regarded as the reference group, the risk of hepatotoxicity increased from 3.94 for CYP2E1 c1/c1 with rapid acetylator status to 7.43 for CYP2E1 c1/c1 with slow acetylator status. After adjustment for acetylator status and age, the CYP2E1 c1/c1 genotype remained an independent risk factor for hepatotoxicity (OR, 2.38; P = .017). Furthermore, under the administration of isoniazid, the volunteers with CYP2E1 c1/c1 genotype had higher CYP2E1 activity than those with other genotypes had and, hence, might produce more hepatotoxins. In conclusion, CYP 2E1 genetic polymorphism may be associated with susceptibility to antituberculosis drug-induced hepatitis. (H epatology 2003;37:924-930.)

Cytochrome P450 2E1 genetic polymorphism and susceptibility to anti-tuberculosis drug-induced hepatitis

Cytochrome P450 2E1 genetic polymorphism and susceptibility to anti-tuberculosis drug-induced hepatitis