Antitubercular therapy in patients with cirrhosis: Challenges and options

Kumar, Naveen; Kedarisetty, Chandan Kumar; Kumar, Sachin; Khillan, Vikas; Sarin, Shiv Kumar

doi:10.3748/wjg.v20.i19.5760

Cited by 34 publications

(34 citation statements)

References 87 publications

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“…Hepatotoxicity is the major adverse effect of PZA and usually occurs in the first 2 months of treatment (2). Previously reported studies showed a high incidence of hepatotoxicity with a high dosage of 40 to 70 mg/kg of body weight and a low rate of liver injury with a daily dose of Ͻ35 mg/kg (3).…”

mentioning

confidence: 99%

Liver Fatty Acid Binding Protein Deficiency Provokes Oxidative Stress, Inflammation, and Apoptosis-Mediated Hepatotoxicity Induced by Pyrazinamide in Zebrafish Larvae

Zhang

Liu

Hassan

et al. 2016

Antimicrob Agents Chemother

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g Pyrazinamide (PZA) is an essential antitubercular drug, but little is still known about its hepatotoxicity potential. This study examined the effects of PZA exposure on zebrafish (Danio rerio) larvae and the mechanisms underlying its hepatotoxicity. A transgenic line of zebrafish larvae that expressed enhanced green fluorescent protein (EGFP) in the liver was incubated with 1, 2.5, and 5 mM PZA from 72 h postfertilization (hpf). Different endpoints such as mortality, morphology changes in the size and shape of the liver, histological changes, transaminase analysis and apoptosis, markers of oxidative and genetic damage, as well as the expression of certain genes were selected to evaluate PZA-induced hepatotoxicity. Our results confirm the manner of PZA dose-dependent hepatotoxicity. PZA was found to induce marked injury in zebrafish larvae, such as liver atrophy, elevations of transaminase levels, oxidative stress, and hepatocyte apoptosis. To further understand the mechanism behind PZA-induced hepatotoxicity, changes in gene expression levels in zebrafish larvae exposed to PZA for 72 h postexposure (hpe) were determined. The results of this study demonstrated that PZA decreased the expression levels of liver fatty acid binding protein (L-FABP) and its target gene, peroxisome proliferator-activated receptor ␣ (PPAR-␣), and provoked more severe oxidative stress and hepatitis via the upregulation of inflammatory cytokines such as tumor necrosis factor alpha (TNF-␣) and transforming growth factor ␤ (TGF-␤). These findings suggest that L-FABP-mediated PPAR-␣ downregulation appears to be a hepatotoxic response resulting from zebrafish larva liver cell apoptosis, and L-FABP can be used as a biomarker for the early detection of PZA-induced liver damage in zebrafish larvae. P yrazinamide (PZA) is an important first-line drug in tuberculosis (TB) combination chemotherapy and is used during the initial 2 months of treatment for its remarkable sterilizing activity (1). Hepatotoxicity is the major adverse effect of PZA and usually occurs in the first 2 months of treatment (2). Previously reported studies showed a high incidence of hepatotoxicity with a high dosage of 40 to 70 mg/kg of body weight and a low rate of liver injury with a daily dose of Ͻ35 mg/kg (3). Although a reduction of the clinical dose considerably decreased the rate of PZA-induced hepatotoxic side effects, PZA is still considered to induce higher hepatotoxicity than other first-line antituberculosis drugs (4, 5). PZA hepatotoxicity cannot be ignored; however, little is known about the exact mechanism of PZA-induced hepatotoxicity.Previous research, by using microarray analyses and proteomics studies, found that metabolism, inflammation, and oxidative stress pathways were probably involved in PZA-induced hepatotoxicity (6, 7). A recent investigation showed that the metabolite 5-hydroxypyrazinoic acid (5-OH-PA) is responsible for PZAinduced hepatotoxicity (8). Despite an increasing number of researchers who are trying to reevaluate the hepatotoxic potentia...

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confidence: 99%

Liver Fatty Acid Binding Protein Deficiency Provokes Oxidative Stress, Inflammation, and Apoptosis-Mediated Hepatotoxicity Induced by Pyrazinamide in Zebrafish Larvae

Zhang

Liu

Hassan

et al. 2016

Antimicrob Agents Chemother

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“…Third, the short-term administration of hepatoprotectants might be considered another limitation. Although the normal duration of anti-TB treatment is 6 months [23], the longest duration of hepatoprotectant use in the included studies was 8 weeks.…”

Section: Discussionmentioning

confidence: 99%

Is the Prophylactic Use of Hepatoprotectants Necessary in Anti-Tuberculosis Treatment?

Zhang²,

Chen³

et al. 2017

Chemotherapy

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Background: Liver injury is one of the serious side effects of anti-tuberculosis (TB) drugs. It is controversial whether hepatoprotectant prophylaxis is efficient and safe in anti-TB treatment, so we aimed to assess the efficacy and safety of hepatoprotectant prophylaxis in patients who had received anti-TB treatment. Methods: PubMed, the Cochrane library, Embase, Ovid, Springer link, Wiley, Elsevier, Web of Science, and the Karger Online Journal were systematically searched prior to April 2016 for articles related to hepatoprotectant prophylaxis in the treatment of TB. A meta-analysis was conducted to estimate the effect of hepatoprotective agents on liver function and adverse events (AEs) in patients who had received anti-TB drugs. The primary outcomes were changes in alanine transaminase (ALT) and aspartate transaminase (AST) levels. The other outcomes were drug-induced liver injury (DILI) and AEs. Results: In our review, 6 trials that involved 1,227 patients were included. Our analysis indicated that hepatoprotective agents exerted protective effects on liver function in patients who had received anti-TB drugs (weighted mean difference, WMD = -7.81, 95% CI [-12.26, -3.37], p = 0.0006 [ALT]; WMD = -7.07, 95% CI [-11.43, -2.72], p = 0.001 [AST]) in any age group. However, in the subgroup analysis of treatment duration, the use of hepatoprotective agents was not associated with significant changes in ALT and AST levels after 2 weeks of treatment and exhibited a positive effect on liver function after 4 weeks of treatment. Moreover, the use of hepatoprotectants significantly decreased the number of DILI cases (risk ratio, RR 0.50, 95% CI [0.34-0.73], p = 0.0004). However, the use of hepatoprotectants led to similar AEs in the control groups (RR 1.07, 95% CI [0.82-1.39], p = 0.62). Conclusions: The use of hepatoprotective drugs may prevent liver injury in patients who are receiving anti-TB drugs without any significant AEs 4 weeks after the initiation of hepatoprotective medication.

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“…The major challenge in successful TB treatment is the management of cirrhosis and its associated immune problems [3]. Lymphocyte and macrophage dysfunction, and decreased production of interferon gamma and tumor necrosis factor alpha, have been associated with cirrhosis progression and increased risk of TB infection [3].…”

Section: Introductionmentioning

confidence: 99%

“…Although TB mortality rates decreased by approximately 35 % between 1990 and 2009, because of advances in medical treatment, TB remains the major serious infectious disease in Taiwan [1]. Isoniazid (INH) and rifampicin (RIF), or their combination (INH + RIF), are the most commonly used anti-TB chemotherapeutic drugs [2,3]. However, the use of these compounds is associated with severe liver disease in developing countries [4].…”

Section: Introductionmentioning

confidence: 99%

Anti-tuberculosis treatments and risk of hepatocellular carcinoma in tuberculosis patients with liver cirrhosis: a population-based case–control study

Lim

Lin

Hung

et al. 2014

Eur J Clin Microbiol Infect Dis

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The objective of this study was to evaluate the association between the use of anti-tuberculosis (anti-TB) agents, isoniazid (INH), rifampicin (RIF), and their combination (INH + RIF), and the risk of hepatocellular carcinoma (HCC) in cirrhotic patients. This population-based case-control study was conducted using a research database of Taiwan's National Health Insurance program. Cirrhotic patients first diagnosed with HCC between 1996 and 2011 (n = 50,351), among whom 4,738 were anti-TB medication users, were evaluated. Cirrhotic patients who did not develop HCC within the same period, frequency-matched according to age, sex, and index year, were evaluated as the control group (n = 47,488). The adjusted odds ratio (OR) of HCC was 1.34 [95 % confidence interval (CI), 1.20-1.50] in INH + RIF users compared with non-INH + RIF users. Long-term (>12 months) use of INH, RIF, and INH + RIF was significantly associated with increased risk of HCC, with an adjusted OR of 3.51 (95 % CI, 2.11-5.84), 4.17 (95 % CI, 2.76-4.31), and 7.17 (95 % CI, 4.08-12.6), respectively, after adjusting for age, sex, and comorbidities. An average dose of INH + RIF >16,050 mg/year was associated with increased risk of HCC in cirrhotic patients, with an adjusted OR of 1.48 (95 % CI, 1.27-1.73). Our results indicate that cirrhotic patients with long-term or high-dose INH and RIF treatment, particularly their combination, are associated with increased risk of HCC development.

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Antitubercular therapy in patients with cirrhosis: Challenges and options

Cited by 34 publications

References 87 publications

Liver Fatty Acid Binding Protein Deficiency Provokes Oxidative Stress, Inflammation, and Apoptosis-Mediated Hepatotoxicity Induced by Pyrazinamide in Zebrafish Larvae

Liver Fatty Acid Binding Protein Deficiency Provokes Oxidative Stress, Inflammation, and Apoptosis-Mediated Hepatotoxicity Induced by Pyrazinamide in Zebrafish Larvae

Is the Prophylactic Use of Hepatoprotectants Necessary in Anti-Tuberculosis Treatment?

Anti-tuberculosis treatments and risk of hepatocellular carcinoma in tuberculosis patients with liver cirrhosis: a population-based case–control study

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