Isoniazid (INH) remains a mainstay for the treatment of tuberculosis despite the fact that it can cause liver failure. Previous mechanistic hypotheses have classified this type of drug‐induced liver injury (DILI) as ‘metabolic idiosyncrasy’ which was thought not to involve an immune response and was mainly due to the bioactivation of the acetylhydrazine metabolite. However, more recent studies support an alternative hypothesis, specifically, that INH itself is directly bioactivated to a reactive metabolite, which in some patients leads to an immune response and liver injury. Furthermore, there appear to be two phenotypes of INH‐induced liver injury. Most cases involve mild liver injury, which resolves with immune tolerance, while other cases appear to have a more severe phenotype that is associated with the production of anti‐drug/anti‐CYP P450 antibodies and can progress to liver failure.
Keywords: biomarker, hepatotoxicity, immune mediated, reactive metabolite, tolerance
Clinical characteristics of isoniazid‐induced liver injury
Due to its high efficacy, isoniazid (INH) remains the drug of choice for treatment of latent tuberculosis (TB) despite the fact that it can cause liver failure 1. Although drug‐induced liver injury (DILI) caused by different drugs is somewhat different, the clinical characteristics of INH‐induced liver injury are fairly typical for idiosyncratic DILI and include malaise, fatigue, nausea and vomiting 2, 3. The duration of therapy before manifestation of jaundice can vary between 1–25 weeks with an average of 12 weeks 2, 3. Fever affects on average 20% of the patients and eosinophilia is present in up to 15% of the affected individuals 2, 4. In most cases, liver injury is asymptomatic and is only detected by measuring markers of hepatocyte injury such as alanine aminotransferase (ALT) and aspartate aminotransferase (AST). This is especially true for mild cases of liver injury, which occur in up to 20% of patients treated with the drug 5. However, in most patients, liver function returns to normal despite continued treatment with the drug, a phenomenon referred to as ‘adaptation’ by hepatologists 6. Severe liver injury is seen in up to 1% of the patients 2, 4. Elevations in ALT and AST can start as early as 1 week and sometimes as late as 9 months after starting treatment with INH. However, in more than half of the patients an ALT increase occurs between 1–6 months 2, 3, 5. The abrupt increase in ALT that leads to liver failure is idiosyncratic in nature and is not clearly related to the duration of treatment, the dose of the drug, fever or eosinophil count 2. When liver injury is identified, the first line of treatment is to stop the drug and monitor the patient for recovery. In most cases patients recover. However, rechallenge of patients with more severe liver injury can result in a rapid onset of symptoms (within hours) and is contraindicated 2, 3. Histological characteristics of severe INH‐induced liver injury include hepatocellular injury with multilobular necrosis and a mononuclear cell infiltrate, which is generally indistinguishable from viral hepatitis 2. Steatosis is unusual in INH‐induced liver injury. However, during active TB treatment, when INH is given in combination with other agents such as ethambutol, pyrazinamide and rifampicin (RMP), there have been reported cases of steatosis and cholestatic liver injury 7, 8, 9. Prolonged treatment with INH can also lead to a lupus‐like autoimmune reaction with the presence of antinuclear antibodies 2, 10, which occurs in up to 20% of the patients 4.
Reactive metabolites proposed to be responsible for INH‐induced liver injury
INH is a hydrazide that is readily oxidized 11. Three metabolites have been proposed to be responsible for INH‐induced liver injury, acetyl hydrazine (AcHz), hydrazine (Hz) and more recently a metabolite resulting from the bioactivation of INH itself 12.
Experiments implicating AcHz and Hz as hepatotoxic species were performed several decades ago, mostly in rats where the acute liver injury correlated with covalent binding of AcHz and with blood levels of Hz 12. At the time, the parent drug (INH) was not thought to contribute to liver injury because its administration did not produce severe liver injury. However, these experiments utilized ring‐labelled acetylisoniazid (AcINH) 5. This conclusion was not warranted because the drug that was administered was not INH. It was AcINH in which the hydrazine is blocked. If hydrolysis led to AcHz and isonicotinic acid, no covalent binding of the pyridine ring would occur. In addition, the characteristics of the liver toxicity in these studies were different from that in humans. In particular, it was an acute rather than a delayed onset idiosyncratic liver injury. Furthermore, the metabolism in humans may be different from that in rats. However, the conclusion that direct bioactivation of INH does not occur has persisted.
Recently, a reactive metabolite resulting from bioactivation of INH itself has been shown to form covalent adducts to liver macromolecules 13, 14, 15, 16, 17. Covalent binding of this metabolite is more likely to lead to an immune response than the reactive metabolite of AcHz which would only acetylate proteins (Figure 1). Using western blots and mass spectrometry, it has been shown that the reactive metabolite of INH can react with multiple lysine residues on hepatic proteins 13, 17. Further characterization using mass spectrometry revealed drug adducts on D‐dopachrome decarboxylase, prohibitin 2 and macrophage migration inhibitory factor 18. Autooxidation of INH involving free radicals has also been reported 17. It is unclear whether this is significant in vivo where there are many antioxidant systems.
Figure 1.
Proposed pathway for an immune mediated reaction to INH in the liver
Relationship between covalent binding and liver injury
Covalent binding of drugs to hepatocytes appears to be an important predictor of hepatic toxicity 19. This concept goes back to early in vivo studies where treatment of mice with hepatotoxic drugs showed a correlation between covalent binding of reactive metabolites and liver injury 20. However, such studies utilized acute treatment of animals with high doses. The mechanism of liver injury with a delayed onset may be very different from acute toxicity and the metabolites responsible for such injury may be different. With chronic treatment, the amount of INH covalent binding reaches a maximum after 1 week 14. We have argued that the mechanism of idiosyncratic drug‐induced liver injury (IDILI) is best explained by the combination of covalent binding and an immune response to drug‐modified liver proteins 12, 21, 22. A pathogenic autoimmune response could also explain cases of DILI that continue to progress even after the drug administration has stopped.
Risk factors associated with INH‐induced liver injury
The incidence of INH‐induced liver injury appears to be higher in patients with the slow acetylator phenotype 23, 24. This was explained on the basis that slow acetylators have higher concentrations of the AcHz metabolite compared with rapid acetylators 25. However, this observation is also consistent with the fact that slow acetylators have higher blood concentrations of INH itself. In fact, data from Lauterburg et al.’s study indicate that the difference in INH blood concentrations between slow and fast acetylators is greater than that for the AcHz metabolite (Figure 2) 26. This suggests that the higher incidence of liver injury in slow acetylators, and in particular those cases of liver injury that appear to have a immune‐mediated phenotype, may be due to higher blood concentrations of INH rather than AcHz. Other known risk factors for INH‐induced liver injury include increased age 4, 23 and induction of CYP metabolism by RMP 27. More recently, additional risk factors for INH‐induced liver injury have been identified, and they include polymorphisms in glutathione S‐transferase 28, 29, CYP2E1 30, manganese superoxide dismutase 31, UDP glucuronosyltransferase, HLA‐DQB1*02:01 32, TNF‐α, and other polymorphisms in anti‐oxidative pathways as reviewed elsewhere 33.
Figure 2.
Area under the curve (AUC) of INH and AcHz in slow vs. fast acetylators. Data are adapted from Table 1 of Lauterburg et al. 26. A conventional cut‐off of 120 nmol ml–1 h was used to separate slow vs. fast acetylators for INH and a cut‐off of 200 nmol ml–1 h was used to separate slow vs. fast acetylators for AcHz
Involvement of the immune system in INH‐induced liver injury
Most cases of INH‐induced liver injury do not have the classical characteristics of fever, rash, eosinophilia and quick onset of INH‐DILI upon rechallenge. The absence of such features was used as evidence against an immune mediated mechanism. However, most cases of more severe INH‐induced liver injury are associated with a rapid onset on rechallenge 2. The failure to find anti‐INH antibodies also argued against an immune reaction 3, 34, 35. However, the studies that failed to find anti‐INH antibodies only involved patients with mild INH‐induced liver injury. In addition, the absence of anti‐drug antibodies is not conclusive evidence against an immune mechanism 36. A recent study did identify anti‐INH antibodies and anti‐P450 autoantibodies in patients diagnosed with INH‐induced liver failure 22. This is consistent with covalent binding of the parent drug to liver macromolecules that presumably leads to an immune‐mediated response. This is further supported by Warrington et al.’s data, which demonstrated a positive lymphocyte transformation test for mild cases of INH‐induced DILI when patients lymphocytes were exposed to INH‐modified proteins, and in the more severe cases of liver injury, this response spread to the recognition of the parent drug 35, 37.
There appear to be two phenotypes of INH‐induced liver injury, mild cases of liver injury that resolve despite continued treatment with the drug and more severe cases that progress to fulminant liver failure. We have argued that most cases of mild INH‐induced DILI with resolution represent immune tolerance that prevents further liver injury 12. Recently, it was reported that patients who have a mild increase in ALT also have an increase in T‐cells producing IL‐10 and IL‐17. Th‐17 cells have been shown to produce cytokines such as IL‐17, IL‐6, TNF‐α and IL‐22, which are implicated in pathogen elimination 38, autoimmune disease 38, and other types of liver disease 39. IL‐10 can inhibit innate and adaptive immune responses through production of the repressor cytokine SOCS3 40. Specifically, IL‐10 can inhibit Th1 and Th2 immune responses, and this is consistent with the lack of an increase in IL‐4 and IFN‐ɣ in those patients with mild liver injury 41, although IL‐10 does not inhibit Th17 cells 40. Therefore it is likely that INH‐induced liver injury may involve an immune mediated mechanism involving Th17 cells and the induction of IL‐10 is consistent with immunosuppression 41 that could be, at least in part, responsible for immune tolerance and explain why patients with mild liver injury do not progress to liver failure. On the other hand, the more severe cases of liver injury are associated with anti‐INH antibodies of the IgG3 phenotype, which are involved in complement activation and can cause hepatocyte damage 42. These cases are consistent with a reaction that has spread from the drug to native proteins and to the development of autoimmunity. This is supported, in part, by the fact that patients with INH‐induced liver failure, in addition to having anti‐INH antibodies, also had antibodies against INH‐modified cytochromes P450 and native P450s, specifically CYP2E1, CYP3A4 and CYP2C9 22. This immunologic response can progress even after drug administration is discontinued. Similarly, INH can induce a lupus‐like syndrome 10 if continued for several months.
Human leukocyte antigen and INH‐induced liver injury
Over the last decade there have been a number of new discoveries associating major histocompatibility complex (MHC) class I and II alleles and severe T cell‐mediated drug reactions 43. For some drugs, this led to the further discovery of novel mechanisms uncovering the structural, biochemical and functional basis of MHC restricted drug reactions 44. DILI has also been associated with various class I and class II MHC alleles. The strongest associations are between HLA‐B*57:01 and flucloxacillin DILI and the class I/II haplotype HLA‐A*02:01/DRB1*15:01/DQB1*06:02 and amoxicillin‐clavulanate DILI 43. Lumiracoxib, a drug that was taken off the market because of a relatively high incidence of DILI, was also associated with the class II haplotype, HLA‐DRB1*15:01/DQB1*06:02 45. The DILI caused by ximelagatran, a thrombin inhibitor that was also taken off the market, was associated with HLA‐DRB1*07:01 46. Lapatinib‐induced DILI is associated with the HLA class II haplotype HLA‐DRB1*07:01‐DQA1*02:01‐DQB1*02:02, and a recent GWAS study suggested the dominant effect was associated with HLA‐DRB1*07:01 47. Although these HLA associations have contributed to our understanding of the immunopathogenesis of DILI, the very poor positive predictive value of the HLA allele for development of DILI means that other factors must be involved, and the associations will not translate into a viable screening strategy to prevent the development of disease.
Currently there are few data to support a direct association between HLA alleles and INH‐induced liver injury. However, this is hampered by the types of analyses that have been done and the small sample size amongst phenotypes that may be heterogeneous. The presence of anti‐INH antibodies and autoantibodies is consistent with covalent binding of the parent drug to liver macromolecules, and it may represent an additional way of phenotyping patients who have an immune component contributing to INH‐mediated liver injury. An association with a specific MHC gene may be present within this more severe group of patients with INH antibodies and autoantibodies. Associations with INH hepatitis and polymorphisms in the minor variant allele A (AG or AA genotypes) of the TNF‐α gene (TNF‐α‐308 G>A) in Korean patients and the presence of class II MHC allele HLA‐DQB1*02:01 as a risk factor and absence of HLA‐DQA1*01:02 as protective in Indian patients have been described, although the effect and samples sizes are small 32, 48. In larger GWAS studies of DILI, a portion of which included patients with liver injury associated with INH, there was no signal in chromosome 6 to support an association within the MHC. However, the sample size of < 50, given the heterogeneity of the INH hepatitis phenotype, may have been too small to show such an effect 4. Although INH‐induced liver injury does not appear to have a strong association with a specific HLA genotype, it does not appear that the studies employing the correct extreme phenotype of INH‐induced liver injury mediated through the adaptive immune system with a sufficiently large sample size has been done. Specific HLA class I and II alleles share peptide binding specificities and this may be relevant. Furthermore, the reactive metabolite of INH binds non‐specifically to all proteins containing lysine groups. It is likely that most patients would have some HLA/T‐cell receptor (TCR) complex that would recognize one of the many drug‐modified peptides that are presented.
Animal models of liver injury
DILI is as idiosyncratic in animals as it is in humans and a valid animal model of INH‐induced liver injury has been very difficult to develop 14, 15, 49. It appears that in animals, the dominant response, especially in the liver, is immune tolerance, which prevents significant liver injury 14, 15. In fact, in mice it appears that INH can have immunosuppressive effects 14, 15. Most histopathological characteristics from murine studies suggest an early onset of steatosis 15, 50, 51. An extensive study in a panel of genetically diverse mice demonstrated a pattern of metabolic changes and steatosis at a dose that did not cause overt liver toxicity. This is consistent with mitochondrial injury 50. Even though steatosis is not typically observed in the histology of patients with INH‐induced liver injury, INH could cause mild mitochondrial injury in humans with the release of damage‐associated molecular pattern molecules, and this could be important for the induction of the immune response that results in liver injury 52. An animal model where pregnane X receptor (PXR)‐humanized mice were co‐treated with INH + RMP for 4 weeks showed elevations in ALT, alkaline phosphatase (ALP) and bile plug formation 53. This model is consistent with the fact that RMP is a human PXR‐specific activator and has only a weak effect on mouse Pxr 54. The severity of liver injury in this model is also consistent the fact that liver injury has a higher incidence in patients who are co‐treated with INH and RMP 27. Studies in this model also found that liver injury was more prominent when RMP was co‐administered with INH than rather its metabolites AcHz and Hz, which suggests that an immune response arising from a reactive metabolite involving the parent drug itself is more likely to explain severe cases of INH‐induced liver injury. The evidence of bile plug formation in this model is seen in some cases of INH‐induced liver injury involving co‐treatment with RMP 55 However, the clinical characteristics in this model are not those of hepatocellular necrosis, which appears to be what most often leads to liver failure. The fact that bile plugs and cholestasis are usually only seen when RMP is added to INH therapy suggests that RMP is the cause and not INH.
Recently, a model of IDILI which involves a delayed onset has been reported for the antimalarial drug amodiaquine (AQ) 56. The characteristics of this model are consistent with those in humans and the injury appears to be dependent on covalent binding of the drug to liver macromolecules followed by an immune response. The mild phenotype of liver injury induced by AQ in this animal model can be converted into a more severe phenotype by blocking PD‐1 and CTLA4 (two important co‐stimulatory molecules that lead to immune tolerance) 21. It has recently been reported that this approach (double blockade of PD‐1/CTLA4) has been successful in producing mild liver injury with INH or nevirapine 57, emphasizing the importance of immune tolerance in the response to drugs that cause such idiosyncratic reactions. Although liver injury induced by INH in this model was mild, it suggests that impairing immune tolerance may be a general strategy of developing animal models that can serve as tools to test mechanistic hypothesis.
Another added difficulty in developing such models is the increasing relevance of a specific human leukocyte antigen (HLA) in such reactions. To date there has only been one animal model of hypersensitivity that has been successfully developed, and it included the HLA for beryllium disease 58. This suggests that for those drugs that display a strong HLA association in humans, having the correct HLA in mice would be crucial. Whether this approach can be applied to other drugs that display strong HLA associations such as abacavir and carbamazepine hypersensitivity syndrome remains to be investigated 43. Furthermore, a particular TCR may be needed 59. This, together with differences in drug metabolism has made it very difficult to replicate idiosyncratic adverse reactions in animals.
Conclusions and perspective
INH‐induced liver injury remains a significant clinical problem. Previous studies suggested that bioactivation of AcHz was involved in the injury, but more recent studies point to direct oxidation of INH as the pathway leading to liver injury. Previous studies had also suggested that the injury, especially mild injury, was not immune mediated. However, recent evidence suggests that INH‐induced liver injury is indeed immune mediated, but most cases are mild and resolve with immune tolerance. Severe injury may include an autoimmune component, which makes it difficult for patients to recover even if the drug is stopped, often resulting in liver transplantation or death. Understanding the mechanism of INH‐induced liver injury may make it possible to prevent progression of the injury after the drug has been stopped. If the injury is immune mediated, in particular mediated by lymphocytes as the histology suggests, treatment with agents such as anti‐thymocyte globulin may be effective.
Competing Interests
All authors have completed the Unified Competing Interest form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare no support from any organization for the submitted work, no financial relationships with any organizations that might have an interest in the submitted work in the previous 3 years and no other relationships or activities that could appear to have influenced the submitted work.
Acknowledgements
We would like to thank Dr Robert Fitzgerald at the University of California San Diego for editing the manuscript. Imir G. Metushi's fellowship in clinical chemistry is supported by Roche diagnostics. J. Uetrecht holds the Canada Research Chair in Adverse Drug Reactions.
Metushi, I. , Uetrecht, J. , and Phillips, E. (2016) Mechanism of isoniazid‐induced hepatotoxicity: then and now. Br J Clin Pharmacol, 81: 1030–1036. doi: 10.1111/bcp.12885.
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