Antituberculosis drug-induced liver injury in chronic hepatitis and cirrhosis

doi:10.1016/j.jinf.2010.07.009

Journal of Infection

Volume 61, Issue 4, October 2010, Pages 323-329

https://doi.org/10.1016/j.jinf.2010.07.009 Get rights and content

Summary

Objectives

To evaluate the incidence, risk factors and outcomes for anti-tuberculosis (TB) drug-induced liver injury (DILI) in patients with chronic liver disease including cirrhosis.

Methods

A total of 107 patients with chronic liver disease were assessed for anti-TB DILI. Anti-TB DILI was defined as elevation of alkaline phosphatase (ALP), aspartate transaminase, or alanine transaminase, or an increase in Child-Turcotte-Pugh score within 2 months of initiating anti-TB medication. The risk factors for anti-TB DILI were evaluated by multivariate logistic regression analysis.

Results

Fifty-eight (54%) patients had cirrhosis. Of 93 patients receiving one or more hepatotoxic anti-TB drugs, 18 (17%) experienced DILI: 11 (24%) among 46 patients with chronic hepatitis and 7 (15%) among 46 patients with compensated liver cirrhosis (P = 0.271). Independent risk factors for DILI were female sex, number of hepatotoxic anti-TB drugs administered and baseline ALP levels but not cirrhosis itself. Of the 18 patients with DILI, 13 (72%) successfully completed anti-TB treatment after switching to less hepatotoxic drug regimens.

Conclusions

Hepatotoxic anti-TB drugs may be safely used in the patients with chronic liver disease including compensated cirrhosis if number of hepatotoxic drugs used is adjusted appropriately.

Introduction

Hepatotoxicity is a major adverse effect of certain anti-tuberculosis (TB) drugs including isoniazid (INH), rifampin (RIF), and pyrazinamide (PZA). Anti-TB drug-induced liver injury (DILI) is a challenge for patients with chronic liver disease, especially cirrhosis, because many physicians believe that it occurs more commonly in this special population and leads to more severe outcomes in patients with cirrhosis than those without cirrhosis. However, there are insufficient data on the incidence and outcome of anti-TB DILI in patients with advanced liver disease.¹

In some studies2, 3 but not others,⁴ anti-TB DILI was found to be more frequent and severe in hepatitis B virus (HBV) carriers than in non-carriers. Another study has reported that anti-TB DILI was more common in hepatitis C virus (HCV)-infected patients.⁵

However, to our knowledge there has been no study of whether anti-TB DILI is more common or more severe in patients with liver cirrhosis than in those with chronic hepatitis without clinical or radiologic evidence of cirrhosis. In addition, there are no concrete data on the incidence of anti-TB DILI as a function of the number of hepatotoxic anti-TB drugs used in patients with chronic liver disease. Such data are important in order to determine the appropriate chemoregimen in TB-infected patients with chronic hepatitis or liver cirrhosis.⁶ Current guidelines for the anti-TB regimen in patients with liver cirrhosis are based on expert opinion.⁷

We previously reported the clinical characteristics of TB in patients with liver cirrhosis.⁸ In the present work we more specifically investigated anti-TB DILI in patients with cirrhosis compared with chronic hepatitis, and the study population was expanded by extending the study period and participant centers. The aim of the study was to evaluate the incidence, risk factors and outcomes, for anti-TB DILI in patients with chronic liver disease with or without cirrhosis.

Section snippets

Study population

The study population included all patients with chronic hepatitis or liver cirrhosis who were confirmed or suspected to have active TB and who received anti-TB medication in standard doses for at least five days at Seoul National University Hospital (SNUH, Seoul, South Korea) or Seoul National University Boramae Medical Center (SNUBMC, Seoul, South Korea) between January 2000 and July 2008. Seven patients who underwent liver transplantation prior to diagnosis of TB were excluded from the study.

Baseline characteristics of the patients with chronic liver disease

A total of 107 patients were included in this study. Mean age (±SD) was 51 ± 14 years (range, 19–77), and 81 (75.7%) were males (Table 1). Eighty-six (80.4%) patients were followed at SNUH and 21 (19.6%) at SNUBMC. Twenty-seven (25.2%) had a history of active TB prior to study entry.

The most common etiology of chronic liver disease was HBV (n = 64, 59.8%) followed by alcohol (n = 21, 19.6%) and HCV (n = 17, 15.9%) (Table 1). Fifty-eight (54.2%) patients had radiologic or clinical evidence of

Discussion

This study describes the incidence of anti-TB DILI in patients with chronic liver disease in relation to the number of hepatotoxic anti-TB drugs administered and the presence of cirrhosis. We demonstrated that number of hepatotoxic anti-TB drugs and baseline ALP levels were significant risk factors for anti-TB DILI in those with chronic liver disease. We also found that mild to moderate cirrhosis itself did not seem to increase the risk of anti-TB DILI compared with chronic hepatitis, although

Conflict of interest

None.

Funding

None.

References (23)

B.H. Lee et al.
Inactive hepatitis B surface antigen carrier state and hepatotoxicity during antituberculosis chemotherapy
Chest
(2005)
R.A. Nathwani et al.
Drug hepatotoxicity
Clin Liver Dis
(2006)
Y.S. Huang et al.
Polymorphism of the N-acetyltransferase 2 gene as a susceptibility risk factor for antituberculosis drug-induced hepatitis
Hepatology
(2002)
M. Dossing et al.
Liver injury during antituberculosis treatment: an 11-year study
Tuber Lung Dis
(1996)
Y.S. Huang et al.
Genetic polymorphisms of manganese superoxide dismutase, NAD(P)H:quinone oxidoreductase, glutathione S-transferase M1 and T1, and the susceptibility to drug-induced liver injury
J Hepatol
(2007)
N.K. Gupta et al.
The use of potentially hepatotoxic drugs in patients with liver disease
Aliment Pharmacol Ther
(2008)
W.M. Wong et al.
Antituberculosis drug-related liver dysfunction in chronic hepatitis B infection
Hepatology
(2000)
S.J. Hwang et al.
A prospective clinical study of isoniazid–rifampicin–pyrazinamide-induced liver injury in an area endemic for hepatitis B
J Gastroenterol Hepatol
(1997)
J.R. Ungo et al.
Antituberculosis drug-induced hepatotoxicity. The role of hepatitis C virus and the human immunodeficiency virus
Am J Respir Crit Care Med
(1998)
H.M. Blumberg et al.
American thoracic Society/Centers for disease Control and Prevention/Infectious diseases Society of America: treatment of tuberculosis
Am J Respir Crit Care Med
(2003)

J.J. Saukkonen et al.

An official ATS statement: hepatotoxicity of antituberculosis therapy

Am J Respir Crit Care Med

(2006)

Cited by (32)

Anti-tuberculosis drug-induced liver injury in patient with hepatitis B and cirrhosis: A case report
2022, Annals of Medicine and Surgery
Citation Excerpt :
Anti-tuberculosis DILI was reported at 2–28% globally [5]. In addition, hepatitis and cirrhosis are risk factors for the severity of anti-tuberculosis DILI [6,7]. We reported a case of an Indonesian female with anti-tuberculosis DILI, hepatitis B and cirrhosis.
Pulmonary tuberculosis patients infected with hepatitis B are at high risk for drug-induced liver injury.
A 42-year-old Indonesian female complained of sclera icterus, tea-colored urine, vomiting, dyspnea, and swollen stomach and legs. The patient experienced this condition after taking anti-tuberculosis drugs for five days. Her medical history showed hepatitis B and cirrhosis. Follow-up examination included chest X-ray and GeneXpert supported a diagnosis of pulmonary tuberculosis. However, abdominal ultrasonography indicated ascites and cirrhosis. We diagnosed the patient with anti-tuberculosis DILI, cirrhosis Child-Pugh C (score 12) related to hepatitis B, and pulmonary tuberculosis. We decided to stop the anti-tuberculosis drug. We treated the patient using tenofovir, hepatoprotective drug, diuretics, and albumin infusion. On the third day, the patient received new anti-tuberculosis drugs, including levofloxacin 750 mg, ethambutol 1000 mg, and streptomycin 1000 mg (LES). The patient's condition then gradually improved.
The dilemma of treating tuberculosis in liver disease is treating tuberculosis without ignoring hepatitis B and cirrhosis.
Administration of anti-tuberculosis drugs based on liver tolerance of hepatotoxic drug in patients with hepatitis B and cirrhosis.
Tuberculosis in Cirrhosis – A Diagnostic and Management Conundrum
2022, Journal of Clinical and Experimental Hepatology
Citation Excerpt :
Subjective and/or objective improvement in presenting symptoms such reduction in ascites/regaining of diuretic responsiveness (reduced dose of diuretics) and/or resolution of pleural effusion and/or cold abscess and/or regression of lymphadenopathy depending on site of tubercular involvement. ATT-induced hepatitis in patients with cirrhosis was defined as a rise in transaminases by >2 times the baseline value or bilirubin >2 mg/dl, after exclusion of other possible causes.7,14,15 SBP was diagnosed if the ascitic fluid absolute polymorphonuclear leukocyte (PMN) count was ≥250 cells/ml with or without culture positivity in the absence of any intra-abdominal or surgically treatable source of infection.16
Diagnosis and management of tuberculosis (TB) in patients with cirrhosis remains challenging. We studied the clinical spectrum, diagnosis, and management of TB along with the assessment of the diagnostic utility of various laboratory investigations in this cohort.
A retrospective review of records of patients with cirrhosis (July 2017 and December 2019) was done. Out of 30 patients with cirrhosis and TB, 20 patients with pleural/peritoneal TB (cases) were compared with 20 consecutively selected spontaneous bacterial peritonitis (SBP) controls. Composite of clinical, laboratory, radiologic features and response to antituberculosis therapy (ATT) was taken as the gold standard to diagnose TB.
Extrapulmonary TB (EPTB) (n = 23, 76.7%) was more common. Overall, 9 (30%) patients presented with ATT-induced hepatitis. Patients with pleural/peritoneal TB had less severe hepatic dysfunction as compared to SBP group with significantly lower CTP [8 ± 1.5 vs. 9 ± 1.7 (P = 0.01)], MELD [16.3 ± 5.8 vs. 20.2 ± 6.6 (P = 0.02)] and MELD-Na [18.8 ± 5.9 vs. 22.5 ± 7.1 (P = 0.03)] scores. Median ascitic/pleural fluid total protein [2.7 (2.4–3.1) vs. 1.1 (0.9–1.2); P < 0.0001] and adenosine deaminase (ADA) levels [34.5 (30.3–42.7) vs. 15 (13–16); P < 0.0001] were significantly higher in the TB group. Total protein levels had a sensitivity and specificity 81% and 93.3%, respectively, at cut off value of >2 g/dl with an AUROC of 0.89 [(0.79–0.96); P < 0.001] whereas ADA levels at cutoff >26 IU/L showed 80% sensitivity and 90% specificity to diagnose pleural/peritoneal TB with an AUROC of 0.93 [(0.82–0.97); P < 0.001]. Only 11 (36.7%), and 8 (26.6%) patients showed positivity on GeneXpert and mTB-PCR, respectively. Patients with Child-Turcotte-Pugh scores of ≤7 and 8–10 tolerated well two and one hepatotoxic drugs, respectively.
EPTB is more frequent in patients with cirrhosis. Relatively lower cutoffs of ascitic/pleural fluid total protein and ADA may be useful to diagnose EPTB in patients with high pretest probability. Individualized ATT with close monitoring and dynamic modifications is effective and well-tolerated.
EASL Clinical Practice Guidelines: Drug-induced liver injury
2019, Journal of Hepatology
Idiosyncratic (unpredictable) drug-induced liver injury is one of the most challenging liver disorders faced by hepatologists, because of the myriad of drugs used in clinical practice, available herbs and dietary supplements with hepatotoxic potential, the ability of the condition to present with a variety of clinical and pathological phenotypes and the current absence of specific biomarkers. This makes the diagnosis of drug-induced liver injury an uncertain process, requiring a high degree of awareness of the condition and the careful exclusion of alternative aetiologies of liver disease. Idiosyncratic hepatotoxicity can be severe, leading to a particularly serious variety of acute liver failure for which no effective therapy has yet been developed. These Clinical Practice Guidelines summarize the available evidence on risk factors, diagnosis, management and risk minimization strategies for drug-induced liver jury.
Clinical and biochemical profile of tuberculosis in patients with liver cirrhosis
2015, Journal of Clinical and Experimental Hepatology
Citation Excerpt :
All these patients were seen by the authors of these studies and patients who were diagnosed to have cirrhosis and tuberculosis were regularly followed up and their data was collected. Drug induced liver injury (DILI) was defined as follows (1) an aspartate aminotransferase (AST)/alanine aminotransferase (ALT) value exceeding 3 times the normal upper limit if the baseline level was normal (<40 IU/L), or an AST/ALT exceeding 2 times the baseline level if the baseline level was abnormal or absolute increase in serum bilirubin >2 mg/dl in absence of no other alternative identifiable reason for the above changes.14 Statistical comparisons were performed using spss (SPSS for Windows, version 12.0; SPSS; Chicago, IL, USA).
There is paucity of data on tuberculosis and antituberculous therapy (ATT) induced hepatotoxicity in patients with chronic liver disease.
To study demographic, clinical characteristics of tuberculosis, pattern of drug induced liver injury and treatment responses to ATT in patients with liver cirrhosis.
All cases of liver cirrhosis diagnosed with tuberculosis (TB) between January 2010 and June 2013 were enrolled. Drug induced liver injury (DILI) was defined as follows (1) an aspartate aminotransferase (AST)/alanine aminotransferase (ALT) value exceeding 3 times the normal upper limit if the baseline level was normal (<40 IU/L), or an AST/ALT exceeding 2 times the baseline level if the baseline level was abnormal and an absolute increase in serum bilirubin >2 mg/dl from baseline.
Sixty seven patients had confirmed TB with underlying cirrhosis and formed the study group. The mean age was 52 ± 12 years and M:F ratio was 57:10. Mean Child Turcotte Pugh (CTP) score 8.5 ± 1.5 (CTP A:B:C:7:44:16). The sites of TB included: pulmonary (25, 37%); pleural effusion (10, 16%) peritoneal (19, 29%); chest lymph nodes (3, 4%); liver (1, 1.5%); intestines (3, 4%), vertebra (3, 4%), brain (1, 1.5%) and disseminated (2, 3%). Thus, extrapulmonary TB was more common in the cirrhotic patients as compared to pulmonary TB. Patients with Child's status A (n = 7) received 4 drugs (R: rifampicin, H: Isoniazid, E: ethambutol, Z: pyrizinamide) and could tolerate well even during follow up without any drug induced toxicity. In rest of patients commonest regimen followed was combination of drugs (RHEO, n = 32) followed by RHE (n = 11). DILI occurred in 35% started with either RHEO, HEO and REO. Median time of onset of DILI was 12 days (4–34) days. There was no DILI related death during hospital stay or follow up.
Extrapulmonary TB is common in patients with cirrhosis and DILI is common in Child B and C with combination of rifampicin and isoniazid regimen.
Hepatotoxicity of antibiotics. A review and update for the clinician.
2013, Clinics in Liver Disease
Citation Excerpt :
Ethambutol, a fluoroquinolone and a second-line agent, may be used in Child-Pugh Class C disease.258 In contrast to these studies, Park and colleagues265 did not find that cirrhosis was an independent risk factor for hepatotoxicity, and that ATDs can be used safely in patients with CLD. Stucchi and colleagues207 confirmed the safe use of INH in a series of 27 pretransplant cirrhotic patients with a positive PPD and a mean MELD score of 20.
Discovery of novel inhibitors of LEDGF/p75-IN protein-protein interactions
2013, Bioorganic and Medicinal Chemistry
Citation Excerpt :
Several lead molecules containing N-acylhydrazones were then subjected to substructure and similarity studies which led to the discovery of new acylhydrazone and hydrazine-based LEDGF/p75-IN inhibitors. N-Acylhydrazones are known to treat tuberculosis via a mechanism of action targeting the biosynthesis of mycolic acids of the bacteria cell wall.25,26 Antibacterial salinizide, aconiazide, and other acylhydrazone prodrugs are hydrolyzed to the active hydrazide component isoniazid (Fig. 2).27,28
Human lens epithelium-derived growth factor (LEDGF)/p75 plays an important role in the HIV life cycle by stimulating integrase (IN)-led viral DNA integration into cellular chromosomes. Mechanistic studies show the majority of IN inhibitors chelate magnesium ions in the catalytic active site, a region topologically distant from the LEDGF/p75 binding site. Compounds disrupting the formation of LEDGF/p75 and IN complexes serve as a novel mechanistic approach different from current antiretroviral therapies. We previously built pharmacophore models mimicking LEDGF/p75 residues and identified four classes of LEDGF/p75-IN inhibitors. Substructure and similarity searches yielded additional LEDGF/p75-IN inhibitors containing an acylhydrazone moiety. The most potent of the acylhydrazones inhibited LEDGF/p75-IN interaction with an IC₅₀ value of 400 nM. We explored structure–activity relationships (SAR) and identified new acylhydrazones, hydrazines, and diazenes as lead molecules for further optimization. Two lead LEDGF/p75-IN inhibitors showed antiviral activity.

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Antituberculosis drug-induced liver injury in chronic hepatitis and cirrhosis

Summary

Objectives

Methods

Results

Conclusions

Introduction

Section snippets

Study population

Baseline characteristics of the patients with chronic liver disease

Discussion

Conflict of interest

Funding

Chest

Clin Liver Dis

Hepatology

Tuber Lung Dis

J Hepatol

The use of potentially hepatotoxic drugs in patients with liver disease

Aliment Pharmacol Ther

Antituberculosis drug-related liver dysfunction in chronic hepatitis B infection

Hepatology

A prospective clinical study of isoniazid–rifampicin–pyrazinamide-induced liver injury in an area endemic for hepatitis B

J Gastroenterol Hepatol

Antituberculosis drug-induced hepatotoxicity. The role of hepatitis C virus and the human immunodeficiency virus

Am J Respir Crit Care Med

American thoracic Society/Centers for disease Control and Prevention/Infectious diseases Society of America: treatment of tuberculosis

Am J Respir Crit Care Med

An official ATS statement: hepatotoxicity of antituberculosis therapy

Am J Respir Crit Care Med