Isoniazid Hepatotoxicity Research Articles

Synergistic toxicity with copper contributes to NAT2-associated isoniazid toxicity

Anti-tuberculosis (AT) medications, including isoniazid (INH), can cause drug-induced liver injury (DILI), but the underlying mechanism remains unclear. In this study, we aimed to identify genetic factors that may increase the susceptibility of individuals to AT-DILI and to examine genetic interactions that may lead to isoniazid (INH)-induced hepatotoxicity. We performed a targeted sequencing analysis of 380 pharmacogenes in a discovery cohort of 112 patients (35 AT-DILI patients and 77 controls) receiving AT treatment for active tuberculosis. Pharmacogenome-wide association analysis was also conducted using 1048 population controls (Korea1K). NAT2 and ATP7B genotypes were analyzed in a replication cohort of 165 patients (37 AT-DILI patients and 128 controls) to validate the effects of both risk genotypes. NAT2 ultraslow acetylators (UAs) were found to have a greater risk of AT-DILI than other genotypes (odds ratio [OR] 5.6 [95% confidence interval; 2.5–13.2], P = 7.2 × 10−6). The presence of ATP7B gene 832R/R homozygosity (rs1061472) was found to co-occur with NAT2 UA in AT-DILI patients (P = 0.017) and to amplify the risk in NAT2 UA (OR 32.5 [4.5–1423], P = 7.5 × 10−6). In vitro experiments using human liver-derived cell lines (HepG2 and SNU387 cells) revealed toxic synergism between INH and Cu, which were strongly augmented in cells with defective NAT2 and ATP7B activity, leading to increased mitochondrial reactive oxygen species generation, mitochondrial dysfunction, DNA damage, and apoptosis. These findings link the co-occurrence of ATP7B and NAT2 genotypes to the risk of INH-induced hepatotoxicity, providing novel mechanistic insight into individual AT-DILI susceptibility.Yoon et al. showed that individuals who carry NAT2 UAs and ATP7B 832R/R genotypes are at increased risk of developing isoniazid hepatotoxicity, primarily due to the increased synergistic toxicity between isoniazid and copper, which exacerbates mitochondrial dysfunction-related apoptosis.

ISONIAZID-INDUCED LIVER INJURY: PHARMACOGENETIC ASPECTS

Inter-individual differences in anti-tuberculosis chemotherapy outcomes have been demonstrated in clinical practice, such as, achievement of intended therapeutic effect in some patients, and insufficiency or absence of response to treatment in others, with development of adverse drug reactions, especially, isoniazid-induced liver injury. Isoniazid-induced liver injuries are the main reason for isoniazid discontinuation, which further leads to considerably reduced effectiveness of anti-tuberculosis chemotherapy, increased relapse risk, and secondary drug-resistance of M. tuberculosis. Hepatotoxic reactions to chemotherapy are predicated by mutations in genes encoding enzymes participating in isoniazid biotransformation: N-acetyltransferase 2 (NAT2), cytochrome P450 2Е1, and glutathione-S-transferase. NAT2 gene polymorphism has been identified as risk factor for isoniazid hepatotoxicity. Nucleotide substitutions in NAT2 gene cause modification of enzyme protein structure, reduction of enzyme synthesis and alteration of its activity. Based on genetically-determined isoniazid acetylation rate, patients are referred to three acetylator types: rapid, intermediate, and slow. Correlations have been established in meta-reviews and systematic reviews between slow acetylator type and frequency of hepatotoxic reactions to isoniazid. Based on study findings, interrelation was shown between cytochrome P450 CYP2E1 gene polymorphism and increased risk of liver injury during chemotherapy with isoniazid. Contribution of GSTM1 and GSTT1 genotypes to isoniazid toxicity requires further exploration, as the obtained results were ambiguous and controversial.

Influence of the Acetylation Type on the Incidence of Isoniazid-Induced Hepatotoxicity in Patients with Newly Diagnosed Pulmonary Tuberculosis

Introduction. Liver damage can be a dangerous side effect of using isoniazid. Individual susceptibility to isoniazid in humans is dependent on the presence of N-acetyltransferase 2 allelic variants in genome. It was imperative to assess the effect of genetically determined isoniazid acetylation rate in terms of risk of developing isoniazid-induced hepatotoxicity, as well as prevention of potential hepatopathy, and improvement of tuberculosis chemotherapy safety. Aim. To study the effect of acetylation type on the incidence of isoniazid hepatotoxicity in residents of the Sakha Republic (Yakutia) with newly diagnosed pulmonary tuberculosis. Methods. The study included 112 patients with newly diagnosed pulmonary tuberculosis. Genotyping was performed using real-time polymerase chain reaction. The following single nucleotide polymorphisms were studied: rs1801280, rs1799930, rs1799931, rs1799929, rs1208, rs1041983. Hepatotoxicity was determined based on the results of clinical laboratory monitoring and using the criteria developed by the European Association for the Study of the Liver (2019). Results. Hepatotoxic reactions developed more often in slow acetylators (43.2%), compared to fast acetylators (20.7%) and intermediate acetylators (10.9%); p=0.002. Serum alanine aminotransferase activity was 5 or more times above the upper limit of normal activity in 37.8% of slow acetylators, and in 8.7% of intermediate acetylators; p=0.001. Clinical manifestations of isoniazid hepatotoxicity were observed more often in slow acetylators (29.7%), than in fast acetylators (3.4%); p=0.000. Conclusion. Slow acetylation type ought to be considered an important risk factor for developing isoniazid hepatotoxicity in patients with pulmonary tuberculosis.

Cocrystallization with syringic acid presents a new opportunity for effectively reducing the hepatotoxicity of isoniazid

Objective: With the aim of surmounting the severe hepatotoxicity induced by antituberculosis drug isoniazid (INH), a novel cocrystal of INH with hepatoprotective nutraceutical syringic acid (SYA), namely INH–SYA, was designed and prepared through cocrystallization strategy, which is an intriguing attempt to reduce the toxic side effects of INH.Significance: The study not only provides new thinking for inhibiting toxic side effects of drugs through cocrystallization strategy, but also opens a new pathway for the application of nutraceuticals in the pharmacy.Methods: INH and SYA were successfully crystallized into the same crystal lattice through combining volatilization with solvent assisted methods. The resulting cocrystal was structurally characterized by single crystal X-ray diffraction (SCXRD), powder X-ray diffraction (PXRD), and differential scanning calorimetry (DSC).Results: The SCXRD analysis for the present cocrystal revealed that it has a 1:1 ratio of INH to SYA with two molecules INH homodimers and two SYA molecules, in which they are arranged alternately linked by hydrogen bonds to form a six molecules ring structure (R66(40)) in crystal. The systematic evaluation of the in vitro/in vivo suggested that, owing to the formation of cocrystal, the dissolution efficiency of SYA was increased 5.85-fold compared with that of coarse SYA, and the oral bioavailability of the cocrystal in rats was enhanced by 3.66 times. As a result, the present INH–SYA cocrystal almost removed INH induced serious hepatotoxicity, which was further demonstrated by the hepatotoxicity studies in rats.Conclusion: INH–SYA cocrystal could effectively reduce the hepatotoxicity of INH.

A new cocrystal of isoniazid-quercetin with hepatoprotective effect: The design, structure, and in vitro/in vivo performance evaluation

With the purpose of overcoming the serious hepatotoxicity of antituberculosis drug isoniazid (INH), a cocrystallization strategy based on complementary advantages was implemented by choosing the hepatoprotective nutraceutical quercetin (QCT) as the cocrystal former. The strategy plays the solubility advantage of INH to improve the bioavailability of the insoluble QCT, thereby significantly enhancing the QCT's hepatoprotective effects. The optimized protective effects of QCT, in turn, feed back to INH to reduce its hepatotoxicity. Along this line, a novel INH-QCT cocrystal was successfully prepared and structurally characterized. The systematic evaluation results of the in vitro/in vivo revealed that, due to the advantage of INH's solubility, the dissolution efficiency of QCT from the cocrystal was increased 51.67-fold compared with that of coarse quercetin, and the oral bioavailability of the cocrystal in rats was enhanced by 28.91 times. As a result, the INH-QCT cocrystal almost removed INH induced serious hepatotoxicity, which has been demonstrated by the hepatotoxicity studies in rats. These findings present new opportunities for the advantageous solid forms of low-toxic antituberculosis drugs, and open new avenues against toxic side effects of drugs through the cocrystallization mean.

A comparison of hepatoprotective activity of Bacoside to Silymarin treatment against a combined Isoniazid and Rifampin-induced hepatotoxicity in female Wistar rats

ABSTRACTThe liver is an important organ that plays a vital role in homeostasis maintenance and regulation. Any liver damage or injury caused by drugs or chemicals is called hepatotoxicity. Isoniazid and rifampin are drugs used separately to treat tuberculosis but have unique side effects and potential hepatotoxicity. The metabolism of isoniazid (INH) and rifampin (RIF) takes place in liver hence hepatotoxicity is the main cause of their continuous use. Bacoside was obtained from the plant Bacopa monnieri, a dammarene type triterpenoid saponin, found distributed throughout India. Bacoside has been used as a nerve tonic, a free radical scavenger, and antioxidant. It is known that the combined INH-RIF induced hepatotoxicity can be antagonized by maintaining hepatocyte membrane integrity in rats. Silymarin, an herbal drug, and its component silybin were reported to work as lipid peroxidation inhibitors and antioxidants which scavenge free radicals. Due to minimal toxicity and no adverse drug interactions, Silymarin is used to treat various medically confirmed hepatic disorders. The aim of this study was to evaluate the beneficial effect of Bacoside against INH- and RIF-induced toxicity in livers of Wistar albino rats. Four experimental groups of rats were used to study four parameters; bodyweight, liver enzyme markers, liver antioxidant, and liver histopathology. INH- and RIF-treated rats showed abnormalities in liver markers which were normalized by Bacoside and that seems similar to the normal control and Silymarin-treated groups. Thus, the current study demonstrated the hepatoprotective effect of Bacoside against INH- and RIF-induced toxicity in Wistar albino rats.

Protective effects of salep against isoniazid liver toxicity in wistar rats

IntroductionIsoniazid is a drug for treatment of tuberculosis. One of the main side effects of this drug is hepatotoxicity, which is a major cause of treatment interruption in tuberculosis. This study is about the preventive effect of Salep on this side effect of isoniazid. Materials and methodsThis study is an experimental study in which the preventive effect of salep on isoniazid hepatotoxicity is evaluated. In this study 56 rats were randomly placed in 7 eight members groups including: control group, sham, isoniazid and four isoniazid/salep groups. At the end of the study the laboratory criteria and histological features of liver toxicity were compared in different mentioned groups. ResultsSignificant lower serum levels of liver enzymes, billirubin, MDA and TOC; and significant higher levels of TAC and total proteins, were revealed in isoniazid/salep group in compare to isoniazid alone group.In addition, histological studies had not showed liver injury in isoniazid/salep group, while there was significant liver injury in isoniazid alone group. ConclusionsOrchid extract (salep), probably because of its antioxidant properties, prevent the destructive effects of isoniazid on the liver.

Arylamine N-acetyltransferase 2 gene polymorphism in an Algerian population

Background: The arylamine N-acetyltransferase 2 (NAT2) is a key enzyme in the biotransformation of xenobiotics. NAT2 gene polymorphisms have been associated with the risk of isoniazid hepatotoxicity and these polymorphisms change among different populations.Aim: The objective of this study is to investigate NAT2 polymorphisms in order to predict the prevalence of NAT2 phenotype in an Algerian population.Subjects and methods: Genotyping of NAT2 was done using a PCR-RFLP method. Haplotype was analysed using the software package PHASE, version 2.0.Results: The major haplotypes were NAT2*5B (23.72%), NAT2*6 A (18.61%), NAT2*4 (14.60%) and NAT2*5 F (10%). The average of the expected slow acetylator phenotype was 53%.Conclusion: Our results suggest that the high frequency of slow acetylator phenotype requires investigation into its possible association with ATDH.

Comparative Hepatoprotective Activity of Fumaria farviflora Lam. Leaf Extract and Silymarin on Isoniazid and Rifampicin-induced Hepatotoxic Rats

Isoniazid and rifampicin are first line drugs used for the treatment of tuberculosis but their use is associated with potentially serious toxic manifestation in the liver leading to necrosis, cirrhosis and hepatitis causing poor patient compliance. The present study was conducted to evaluate hepatoprotective activity of Fumaria parviflora leaf extract in isoniazid and rifampicin-induced hepatotoxic rats. Acute toxicity was conducted with single oral doses of F. parviflora leaf extracts at 300, 2000 and 5000 mg/kg and rats were observed for changes in body weight, hematological parameters, behavioral changes and signs of toxicity. Hepatoprotective activity of F. parviflora leaf extract (100, 200 and 300 mg/kg, p.o.) was evaluated on isoniazid and rifampicin (50 mg/kg, i.p.) induced hepatotoxic rats using silymarin as a reference drug (100 mg/kg, p.o.). F. parviflora leaf extract was found to be safe up to 5 g/kg. From biochemical and histopathological parameters it was found that pretreatment of rats with F. parviflora leaf extract an hour prior to start isoniazid and rifampicin resulted in a significant decline in the serum levels of aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase and total bilirubin as well as normal histology of liver biopsy specimens. It was concluded that F. parviflora leaf extract has significant hepatoprotective activity at the dose of 200 mg/kg comparable with that of silymarin. The plant extract appeared to have the potential to be used as a dietary supplement to antiTB therapy to protect against the hepatotoxicity of isoniazid and rifampicin.

Evaluation of Quantitative Phytochemicals, Liver Enzymes and Histological Changes in Isoniazid Induced Hepatotoxicity in Adult Male Wistar Rats Treated with Aqueous Extracts of <i>Brysocarpus coccineus</i>

Isoniazid induced hepatotoxicity is a major concern in patients taking anti tuberculosis treatment and prophylaxis. It can result in elevated serum liver enzymes and hepatic failure. The aim of the study was to evaluate the phytochemicals and ameliorative effects of aqueous extracts of Brysocarpus coccineus on serum liver enzymes in isoniazid (INH) induced hepatotoxicity in adult male Wistar rats. Thirty six (36) adult male Wistar rats were divided into six groups of six rats each and were treated orally for 30 days as follows: Group I: 1 ml/kg of distilled water; group II: Isoniazid (27 mg/kg); group III: Isoniazid (27 mg/kg) + Livolin forte (20 mg/kg); group IV: Isoniazid (27 mg/kg) + B. coccineus (200 mg/kg); group V: Isoniazid (27 mg/kg) + B. coccineus (400 mg/kg); group VI: Isoniazid (27 mg/kg) + B. coccineus (800 mg/kg). At the end of the experiments, the Wistar rats were sacrificed and sera obtained for liver enzymes assay, whereas the liver tissue was also harvested and used for histological studies. Tanins, saponins, alkaloids and flavonoids were quantitatively present at 2.29%, 18.05%, 23.24% and 18.99%, respectively. There was an increase in the serum AST and ALT in the isoniazid treated group, which was reversed by livolin forte and the aqueous extracts at a dose of 200 mg/kg, however the extracts increased the serum levels of AST and ALT at higher doses, which was however not significant (p > 0.05) when compared to the controls. There was evidence of a reduction in hepatocytes damage in the extract treated groups when compared to the Isoniazid untreated group. In conclusion, aqueous extracts of B. coccineus shows hepatoprotective effects at 200 mg/kg in isoniazid hepatotoxicity in adult male Wistar rats.

Baseline abnormal liver function tests are more important than age in the development of isoniazid-induced hepatoxicity for patients receiving preventive therapy for latent tuberculosis infection.

One of the cornerstones of Australia's public health programmes to eliminate tuberculosis (TB) is the identification and treatment of latent tuberculosis infection (LTBI). The main aim of this study is to determine the demographics, compliance, completion rates and adverse events of patients on preventive therapy (PT) for LTBI at our institution. The secondary aim is to determine the rates of isoniazid (INH) hepatotoxicity and identify any contributory factors. The method used was an audit using medical records of 100 consecutive patients (2010-2014) treated with PT for LTBI. Seventy-two patients with confirmed LTBI started 9 months of INH and 22 started 4 months of rifampicin (RIF). The median age was 30 years. Half the patients were born in high TB-prevalence countries. Fifty-six per cent were contacts of index cases with confirmed TB, and 26% were pre-immunosuppression. Seventy-seven per cent completed PT with adequate compliance. Thirty-three per cent on INH and 23% on RIF experienced some liver function test (LFT) abnormality while on treatment. INH was ceased in 3% due to asymptomatic hepatic dysfunction (transaminases >5x upper limit of normal). No patients had permanent liver damage. Significant risk factors for liver dysfunction during PT were risk factors for liver disease (χ(3)(2) = 8.7; P = 0.03) or abnormal pre-therapy LFT (χ(3)(2)= 22.4; P < 0.001). No patients developed active TB. The completion rate of 77% and rate of INH-induced hepatic dysfunction of 3% is comparable with the literature. We found no age association with the risk of INH-induced hepatic dysfunction; however, there was a significant and linear association with the degree of liver function abnormality during INH therapy and the presence of abnormal baseline LFT. Routine LFT monitoring allowed early cessation of INH in those with significant but asymptomatic hepatitis who did not meet criteria for ATS/CDC LFT monitoring.

Isoniazid-induced hepatotoxicity in children with latent tuberculosis infection.

We aimed to determine overall incidence of severe and mild isoniazid (INH) hepatotoxicity and outcome of hepatotoxicity in children who were receiving INH for latent tuberculosis. Patients who had received isoniazid for treatment of latent tuberculosis were included in the study. Hepatotoxicity was classified according to the World Health Organization Toxicity Classification Standards. Among 1038 patients, overall hepatotoxicity was observed in 22 patients (2.2%), while 5 patients (0.48%) had moderate-severe hepatotoxicity; while other 17 patients had grade I-II hepatotoxicity (1.63%). Age and gender did not appear to be risk factors for hepatotoxicity. The median time for therapy rechallenge in patients with grade III-IV hepatotoxicity was 21 days (ranging from 14 to 25 days). Isoniazid hepatotoxicity is lower and generally reversible after cessation of INH in children. The grade of hepatotoxicity affects the duration for recovery of hepatotoxicity and restarting of INH therapy.

Under-reporting and Poor Adherence to Monitoring Guidelines for Severe Cases of Isoniazid Hepatotoxicity

Isoniazid is a leading cause of liver injury but it is not clear how many cases are reported or how many clinicians and patients adhere to American Thoracic Society (ATS) guidelines. We collected data on cases of isoniazid hepatotoxicity and assessed adherence to ATS guidelines and reports to the Centers for Disease Control's (CDC) isoniazid severe adverse events program. We analyzed Drug-Induced Liver Injury Network (DILIN) cases considered definite, highly likely, or probable for isoniazid injury from 2004 through 2013. We assessed the delays in isoniazid discontinuance according to ATS criteria and hepatotoxicity severity by Severity Index Score. We checked reporting to the CDC by matching cases based on age, latency, indication, reporting period, and comorbidities. Isoniazid was the second most commonly reported agent in the DILIN, with 69 cases; 60 of these met inclusion criteria. The median age of cases was 49 years (range, 4-68 y), 70% were female, 97% had latent tuberculosis, and 62% were hospitalized. Patients took a median of 9 days to stop taking isoniazid (range, 0-99 days). Thirty-three cases (55%) continued taking isoniazid for more than 7 days after the ATS criteria for stopping were met. Twenty-four cases (40%) continued isoniazid for more than 14 days after meeting criteria for stopping. A delay in stopping was associated with more severe injury (P < .05). Of 13 patients who died or underwent liver transplantation, 9 (70%) continued taking isoniazid for more than 7 days after meeting criteria for stopping. Only 1 of 25 cases of isoniazid hepatotoxicity eligible for reporting to the CDC was reported. Poor adherence to ATS guidelines is common in cases of hepatotoxicity and is associated with more severe outcomes including hospitalization, death, and liver transplantation. Isoniazid continues to be a leading cause of DILI in the United States, and its hepatotoxicity is under-reported significantly.

38. Histological and biochemical changes following isoniazid induced hepatotoxicity in young and old fischer 344 rats

Background A spectrum of histopathological changes have been described in isoniazid hepatotoxicity. The cause of increased isoniazid hepatotoxicity in old age is uncertain. Aims To investigate the influence of age on histological and biochemical outcomes following a toxic regimen of isoniazid in male Fischer 344 rats. Methods Young (6 months) and old (24 months) rats were fasted for 16 hours followed by a toxic regimen of isoniazid or saline vehicle (4 doses/day: 100, 75, 75, 75 mg/kg i.p. every 3 hours over 2 days). Fifteen hours after the last dose livers were prepared for histology and sera were collected for biochemical analysis. Results Without reaching significance, the prevalence of necrosis was higher in young than old isoniazid treated animals (young 5/7, old 1/5; p p p > 0.05) Again relative to saline, serum hepatotoxicity markers ALT and AST in isoniazid treated animals were unchanged or higher in young but unchanged or lower in old animals ( p p Conclusion Different patterns of injury to toxic doses of isoniazid were observed with age, with young rats showing a necroinflammatory pattern of injury, and old rats showing steatosis and higher levels of toxic intermediates.

Under-reporting and Poor Adherence to Monitoring Guidelines for Severe Cases of Isoniazid Hepatotoxicity

Under-reporting and Poor Adherence to Monitoring Guidelines for Severe Cases of Isoniazid Hepatotoxicity

1694Risk factors and outcomes of isoniazid hepatotoxicity in children with latent tuberculosis

1694Risk factors and outcomes of isoniazid hepatotoxicity in children with latent tuberculosis

Isoniazid hepatotoxicity: Progress in understanding the immunologic component

Isoniazid hepatotoxicity: Progress in understanding the immunologic component

Hepatotoxicity in Children Receiving Isoniazid Therapy for Latent Tuberculosis Infection.

The frequency of isoniazid hepatotoxicity is low in children receiving isoniazid therapy for latent tuberculosis infection. However, isoniazid hepatotoxicity may cause liver failure and death. We evaluated children who developed isoniazid hepatotoxicity to determine demographic and clinical characteristics. A retrospective review was performed of medical records of 1582 patients aged <18 years who were evaluated for isoniazid therapy at a public health department and clinic in California. There were 13 patients who had latent tuberculosis infection and who developed isoniazid hepatotoxicity (0.8% of all 1582 patients who started isoniazid; 1.1% of 1235 patients who completed the 9-month isoniazid therapy). There were 8 girls (62%) and 9 Hispanic children (69%) who had hepatotoxicity. Sex, age, and race were not independently associated with the development of isoniazid hepatotoxicity. Symptoms and signs of hepatotoxicity were present in 11 of the 13 patients, and 2 other patients had alanine aminotransferase >5 times the upper limit of normal and no signs of hepatotoxicity. The most common symptoms included abdominal pain, anorexia, vomiting, and nausea. Most patients developed hepatotoxicity within 6 months of starting isoniazid, but 3 patients developed hepatotoxicity ≥6 months after starting isoniazid. After stopping isoniazid, the alanine aminotransferase levels decreased to normal in all patients. In children who have latent tuberculosis infection, isoniazid hepatotoxicity has low frequency and typically is reversible when isoniazid is stopped. Evidence of late drug-induced liver injury indicates the importance of monitoring symptoms and serum transaminases throughout isoniazid therapy.

Two “Lost Boys of Sudan” Undergo Liver Transplantation

Two “Lost Boys of Sudan” Undergo Liver Transplantation

Use of rifabutin for the treatment of a latent tuberculosis infection in a patient after solid organ transplantation

Latent tuberculosis infection is an important problem for solid organ transplant recipients because of the frequency of its occurrence and its potential for reactivation. Because of the high mortality rate associated with active tuberculosis infections in transplant recipients, guidelines from the American Thoracic Society recommend treatment for latent tuberculosis in this population. However, the choice of treatments is often difficult because liver transplant recipients may be more sensitive to isoniazid hepatotoxicity, and rifampin has significant drug interactions with the calcineurin inhibitors used for immunosuppression. Two prior case reports described success with the use of rifabutin, a rifampin alternative, as part of a multidrug treatment regimen for active tuberculosis in posttransplant patients; however, there is no prior literature describing any experience with rifabutin for the treatment of latent tuberculosis in the posttransplant setting. We present a summary of tacrolimus drug levels and corresponding dose requirements for a single posttransplant patient during the administration of 3 different latent tuberculosis drug regimens: rifampin alone, rifampin plus ketoconazole, and rifabutin. In this patient's case, rifabutin allowed the maintenance of adequate tacrolimus levels, although an approximate 2.5-fold increase in the dose was required. Rifampin alone was associated with inadequate immunosuppressant levels, and rifampin plus ketoconazole was associated with a problematically prolonged QT interval and concerns about inadequate tuberculosis treatment.