Liver Research xxx (xxxx) xxx

Contents lists available at ScienceDirect

Liver Research
journal homepage: http://www.keaipublishing.com/en/journals/liver-research

Review Article

Clinical perspectives of isoniazid-induced liver injury*

Saifei Lei, Ruizhi Gu, Xiaochao Ma*
Center for Pharmacogenetics, Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, USA

a r t i c l e i n f o a b s t r a c t

Article history: Isoniazid (INH) is a synthetic anti-mycobacterial agent used to treat active or latent tuberculosis (TB). INH
Received 2 December 2020 has been in clinical use for nearly 70 years and remains broadly utilized at the front line of anti-TB
Received in revised form treatment. However, the potential for liver damage and even fulminant liver failure during INH-based
10 January 2021
TB treatment presents a major challenge for TB control programs worldwide. In this review, we
Accepted 5 February 2021
discuss the hepatotoxic effects of INH and provide an overview of the mechanisms and their applications
in prediction and prevention of INH hepatotoxicity in clinical practice.
Keywords:
© 2021 The Third Affiliated Hospital of Sun Yat-sen University. Publishing Services by Elsevier B. V. on
Hepatotoxicity
Liver injury
behalf of KeAi Communications Co., Ltd. This is an open access article under the CC BY license (http://
Isoniazid (INH) creativecommons.org/licenses/by/4.0/).
Tuberculosis (TB)

1. Introduction with the keywords “INH”, “hepatotoxicity”, “liver injury”, and

“clinic”. Literatures were sorted by “best match” and selected by
Tuberculosis (TB) remains the world’s 10th leading cause of clinical relevance and reliability.
death and the single greatest cause of death from an infectious
agent.1 An estimated one-fourth of the world’s population is 2. Symptoms of INH-induced liver injury
infected with Mycobacterium tuberculosis, with an estimated 10
million new cases and 1.5 million deaths reported in 2018.1 Isoni- Various agents can result in hepatocyte or bile duct injury, or
azid (INH) is arguably among the most clinically successful and both, with a pattern that is hepatocellular, cholestatic, or mixed.9
extensively studied TB drugs ever to have been developed. It is a INH-induced hepatotoxicity manifests mainly as hepatocellular
bactericide that inhibits the synthesis of mycolic acids in the bac- necrosis.5 Medications can cause liver injury in a predictable time-
terial cell wall, and it is effective against intracellular and extra- and dose-dependent manner (e.g., high doses of acetaminophen),
cellular organisms.2 INH has been approved for inclusion in whereas others such as INH do so more unpredictably or in an
combination therapies for active infection and has also been “idiosyncratic” manner. INH-induced liver injury typically occurs
approved as a prophylactic monotherapy to prevent disease in in- within weeks to months rather than days to weeks of onset.5 About
dividuals with an asymptomatic or latent tuberculosis infection 60% of the incidence of INH hepatotoxicity in the U.S. Public Health
(LTBI).3 Service (USPHS) study occurred in the first 3 months of treatment,
Despite INH’s proven and robust efficacy, it has long been and 80% of the incidence occurred in the first 6 months.7,8,10 A
recognized as hepatotoxic and can cause liver failure.4e8 In spite of retrospective case fatality review reported a median interval of 16
this long-standing awareness and extensive studies, the underlying weeks from treatment initiation to symptom onset.11
mechanisms of INH hepatotoxicity remain poorly understood. In While some individuals may be asymptomatic, others may
addition, the predictive measures for those most at risk of INH experience symptomatic hepatotoxicity.5,12,13 The asymptomatic
hepatotoxicity are sorely lacking. The present review summarizes patients exhibit up to a three-fold increase over upper limit of
clinical insights and perspectives into INH hepatotoxicity, including normal range (ULN) of serum alanine transaminase (ALT) and
symptoms, incidence, risk factors, mechanisms, and management. aspartate transaminase (AST). Most cases of INH hepatotoxicity are
Literatures were searched through PubMed and Google Scholar mild and typically resolve despite continued therapy with INH.

*
Edited by Peiling Zhu and Genshu Wang.
* Corresponding author.
E-mail address: [email protected] (X. Ma).

https://doi.org/10.1016/j.livres.2021.02.001
2542-5684/© 2021 The Third Affiliated Hospital of Sun Yat-sen University. Publishing Services by Elsevier B. V. on behalf of KeAi Communications Co., Ltd. This is an open
access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

Please cite this article as: S. Lei, R. Gu and X. Ma, Clinical perspectives of isoniazid-induced liver injury, Liver Research, https://doi.org/10.1016/
j.livres.2021.02.001
S. Lei, R. Gu and X. Ma Liver Research xxx (xxxx) xxx

However, a small number of patients taking INH develop severe increase with age, with higher mortality in those over 50 years of
hepatitis that may progress to liver failure. INH-treated patients age.5,11,20
who are severely affected may manifest few symptoms until
insidious and potentially lethal liver damage has occurred. 4.2. Gender
Abdominal pain, nausea, and vomiting are observed in 50e75% of
patients with severe hepatotoxicity, fever is noted in 10% and rash Although it has been suggested that INH hepatotoxicity might
in 5% of patients, and dark urine, overt jaundice, and clay-colored be more common in females than in males, especially the more
stools are late signs of clinical worsening.5,11,12,14 Clinical symp- severe forms of hepatitis leading to liver failure and death,26 not all
toms of liver dysfunction, such as encephalopathy or jaundice, as studies have reported this finding and no clear evidence indicates
well as the presence of severe hepatitis with aminotransferase an overall sex-related difference in the incidence of INH hepato-
levels >10-fold ULN are associated with a poor prognosis.14 toxicity. The SeattleeKing County study reported a nonsignificant
trend toward higher INH-related hepatotoxicity in women
compared with men, although the incidence of severe hepatotox-
3. Incidence of INH-induced liver injury
icity was relatively low in both men and women.23 The USPHS
study showed no overall difference between women and men in
INH hepatotoxicity is a common complication of anti-TB ther-
rates of probable INH hepatotoxicity.7 The San Diego and Memphis
apy, ranging in severity from a transient, low-grade asymptomatic
studies also reported no significant associations between INH
elevation of serum transaminases to fulminant hepatic failure
hepatotoxicity and sex.8,24
necessitating liver transplantation.5,15,16 Numerous surveillance
studies have assessed the overall rates of INH-induced hepatotox-
4.3. Racial differences
icity, however, the drug-induced liver injury (DILI) Network has
recently indicated that the true incidence of INH-induced liver
In the aforementioned USPHS study, African-American males
injury is largely under-reported in the United States, and it is the
exhibited a diminished risk of INH related hepatitis compared to
second-ranking drug that causes liver injury in spite of under-
white males, but no difference was noted for women of any race.7
reporting.17
The SeattleeKing County study reported a nonsignificant trend
A surveillance study by the USPHS of 14,000 INH-treated in-
toward higher hepatotoxicity in white individuals.23 The Memphis
dividuals determined a 1% overall rate (which comprises approxi-
study failed to find associations with INH hepatotoxicity among
mately 10% of patients with mild transaminase elevations) of
racial groups or demographic subgroups.8 Thus, the data regarding
significant, probable INH-related hepatitis.7 A subsequent report by
racially based risks for high-grade INH-related hepatotoxicity are
the International Union Against Tuberculosis (IUAT) utilized passive
inconsistent, and at present, insufficient evidence exists to consider
detection and determined a 0.5% overall rate of hepatitis in patients
any ethnic group as a high-risk population that warrants specific
receiving up to 12 months of INH, versus 0.1% receiving placebo.10
follow-up or treatment modification.25
In a Meta-analysis of patients receiving combination therapies
that include INH but not rifampicin (RIF), the incidence of hepa-
4.4. Co-treated drugs
totoxic effects was around 1.6%; the corresponding value for regi-
mens containing both INH and RIF was 2.5%.18 Death resulting from
When INH is administered for active TB in combination with
INH when used for treatment of LTBI is rare (an incidence of around
other drugs, the incidence of hepatotoxicity is greater. RIF, a first
0.057%) and occurs even less frequently if proper monitoring of
line anti-TB drug, is a human specific activator of pregnane X re-
liver function guidelines is followed.19 A review based on data from
ceptor (PXR), a xenobiotic nuclear receptor that regulates the
the U.S. Food and Drug Administration (FDA) estimated 23.2 INH-
expression of drug-metabolizing enzymes including cytochromes
associated hepatitis deaths per 100,000 patients receiving INH
P450 (CYP).27e29 In patients receiving INH, RIF appears to promote
based prophylactic therapy.20
the formation of toxic INH metabolites and potentiate INH hepa-
totoxicity.18,30 Similar to RIF, CYP inducers carbamazepine and
4. Risk factors associated with INH hepatotoxicity phenobarbital also increase the risk of INH-induced liver injury.31,32
In addition, subjects who abuse alcohol and/or drugs have a higher
4.1. Age risk for hepatotoxicity while taking INH.33,34 Ethionamide and
para-aminosalicylic acid may exacerbate the toxicity of INH by
Most cases of INH hepatotoxicity are associated with age, pre- interfering with its acetylation.35e37 Furthermore, when other
sumably reflecting aging-related changes in liver metabolism, and hepatotoxic medications (e.g., azole antifungals, methotrexate, an-
susceptibility to INH-induced hepatitis and subsequent death ap- ticonvulsants, halothane or acetaminophen) are used alongside
pears to increase dramatically with advancing age.7,8,21,22 The anti-TB therapy, rates of hepatotoxic effects can increase.38,39
Seattle-King County-based study of INH hepatotoxicity reported
that the incidence of symptomatic transaminase elevation ranged 4.5. Pre-existing liver diseases
from 0 in those less than 14 years of age to 0.28% in those older than
65 years,23 while the San Diego County study reported a similar Not surprisingly, the hepatotoxic effect of INH becomes more
trend toward age-related hepatotoxicity.24 The Memphis observa- evident in individuals with pre-existing liver diseases.39,40 Elevated
tional study of hepatotoxicity from INH monotherapy during LTBI baseline transaminases are an independent risk factor for INH
treatment reported that AST elevation >5-fold ULN ranged from hepatotoxicity.8,41 The Memphis retrospective study of INH-treated
0.44% in those below 35 years of age to 2.08% for those older than TB patients found that a baseline AST greater than the ULN was a
49 years, a statistically significant difference.8 Differences in the risk factor for developing transaminase elevation greater than five
findings among these studies may be attributed to differences in times the ULN upon INH treatment.8 Similarly, the severity of DILI
sample size for the relevant age groups, differing definitions of may be greater in INH-treated patients with pre-existing liver
hepatotoxicity, patient selection, and inability to exclude con- diseases,41 but the underlying mechanism remains unclear. In-
founding causes of hepatotoxicity.25 The severity of INH hepato- flammatory status in pre-existing liver diseases was believed to
toxicity and consequent mortality has also been reported to contribute to the elevated risk of INH hepatotoxicity. Hepatocytes
2
S. Lei, R. Gu and X. Ma Liver Research xxx (xxxx) xxx

are more sensitive to INH toxicity when exposed to a non-toxic was also found to be associated with the susceptibility of INH
level of H2O2.42 In addition, a low dose of endotoxin lipopolysac- hepatotoxicity.68,69 However, more studies are needed to confirm
charide (LPS), a cellular mediator of inflammation, potentiates INH these findings.70
hepatotoxicity.43 Furthermore, the immune tolerance impaired
mouse models are more sensitive to INH hepatotoxicity.44 5. Mechanisms of INH-induced liver injury

4.6. Genetic predisposition The mechanisms of INH-induced liver injury have been exten-
sively investigated in clinical and preclinical studies with per-
Genetic predisposition to INH-related hepatotoxicity is an spectives from INH metabolites, INH-endobiotics interactions,
important risk factor, but currently no clinical test for such pre- oxidative stress, mitochondrial injury, and immune response.
disposition is available.7,45,46 The acetylation rate is a genetic
phenotype that varies from patient to patient, and acetylation is a
crucial step in INH metabolism. Although early studies reported a 5.1. Association of INH metabolites with liver injury
bimodal pattern of drug acetylation in a given population,47,48 more
recent studies have genotyped variants of N-acetyl transferase 2 Orally administered INH is absorbed rapidly through the
(NAT2), the dominant enzyme that catalyzes the acetylation of INH, gastrointestinal tract and is distributed to many organs, including
to define acetylator phenotype, and the single nucleotide poly- the liver, kidney, and brain.71 INH is predominantly metabolized in
morphisms that have been investigated vary between studies. the liver, and three metabolites of INH have been posited to be
NAT2 genotypes can be grouped into three different phenotypes: responsible for INH-induced liver injury (Fig. 1): hydrazine (Hz),
slow acetylator, intermediate acetylator, and rapid acetylator.49 acetylhydrazine (AcHz), and a radical metabolite resulting from the
While these phenotypes exhibit equivalent INH antimicrobial ac- bioactivation of INH itself.72e77 The isonicotinic acyl radical can
tivity, it is presently controversial and unclear whether patients of form covalent adducts to liver macromolecules and potentially
the slow acetylator phenotype are more likely than rapid acetyla- trigger immune responses.74,78 Indeed, mass spectrometric char-
tors to manifest INH hepatotoxicity. Nevertheless, most recent acterization has revealed INH adducts on several murine liver
studies suggest that the risk of INH hepatotoxicity increases in slow proteins.79 However, the mechanisms for the formation of INH
acetylators.50,51 It has been shown that individuals carrying NAT2 radical and its interaction with liver proteins remain unclear. It is
variant alleles at position 481C > T, 590G > A, 857G > A had a higher also unknown whether CYPs are necessary in INH bioactivation;
risk of INH hepatotoxicity.52 In addition, polymorphisms of NAT2 and if CYPs are needed, it is unknown which CYP isoform(s) is
appear to influence its reactivity with INH and eventually INH essential. CYPs have also been proposed in AcHz bioactivation,77
safety.53 which can produce reactive metabolites and covalently bind to
The risk factors for INH-induced liver injury have been identi- liver macromolecules, leading to liver damage. However, it is also
fied among polymorphisms of drug-metabolizing enzymes other unclear whether and which CYP(s) is involved in AcHz
than NAT. CYP2E1 is well-known for its involvement in the for- bioactivation.
mation of reactive oxidative species and bioactivation of hep- In addition to isonicotinic acyl radical and AcHz, Hz has also
atotoxins such as carbon tetrachloride and acetaminophen.54 been proposed as a cause of INH-induced liver injury.75,76 Hz is
Subjects homozygous for the CYP2E1 c1 (wild type) allele exhibi- produced through the hydrolysis of INH or AcHz (Fig. 1). INH
ted higher transaminase activity and a 2.5-fold increased risk of metabolism through these hydrolysis pathways is significantly
INH-related hepatotoxicity compared to those with one or more increased in slow acetylators,80 especially in association with RIF
CYP2E1 c2 allele. The risk of INH hepatotoxicity increased 7-fold co-treatment.30 CYP2E1 has been thought to be critical in Hz bio-
when CYP2E1 c1/c1 was combined with slow-acetylator sta- activation to produce reactive derivatives/metabolites with greater
tus.55e57 However, other reports have come to different conclu- toxicity, and subjects with CYP2E1 c1/c1 alleles and higher enzy-
sions, showing no significant association of CYP2E1 genotype with matic activity have been shown to be more prone to INH hepato-
anti-TB DILI,58,59 thus the role of CYP2E1 polymorphism in INH toxicity.55,56 However, no direct evidence is available to prove the
hepatotoxicity remains controvertible and merits further role of CYP2E1 in Hz metabolism and bioactivation.81 In addition,
investigation. treatment with a high dose of Hz in mice failed to cause significant
In addition, deficiency of glutathione S-transferases (GSTs) ac- liver damage, especially for hepatocellular necrosis.82
tivity due to a homozygous null genotype of either or both of the
GSTM1 and GSTT1 genes can influence susceptibility to INH hep- 5.2. INH-endobiotics interactions and their contributions to INH-
atotoxicity and appears to be associated with a high incidence of induced liver injury
hepatotoxic effects of anti-TB therapy.60e62 Deficiency of superox-
ide dismutase (SOD) may also increase the risk of INH hepatox- Chronic treatment with INH causes protoporphyrin IX (PPIX)
icity.63 Furthermore, polymorphisms in the carboxylesterase 1 accumulation in mouse liver.83 PPIX, an intermediate in the heme
(CES1) gene have a possible association with INH hepatotoxicity, biosynthesis pathway, is known to be a hepatotoxin, and has been
but the authors acknowledged the necessity for replication of the implicated in cholestasis in both mice and humans.84e86 INH causes
results in a larger cohort for confirmation of these possible corre- PPIX accumulation in the liver through the induction of delta-
lations.64 Associations with INH hepatitis and polymorphisms in aminolevulinate synthase 1 (ALAS1) and downregulation of ferro-
the tumor necrosis factor-alpha (TNF-a) gene and the class II major chelatase (FECH), both of which are pivotal enzymes in regulating
histocompatibility complex (MHC) allele HLA-DQB1*02:01 have heme biosynthesis.83 Rather than being caused by INH itself, PPIX
also been described, although the effect and sample sizes in these accumulation is due to Hz and INH-vitamin B6 conjugate, which
studies were small.65,66 upregulates ALAS1 and decreases FECH, respectively.87 When INH
Moreover, polymorphisms of nitric oxide synthase (NOS), BTB is co-treated with RIF, more PPIX is accumulated in mouse liver
and CNC homology (BACH), and the small Maf basic leucine zipper because RIF-mediated PXR activation strongly upregulates ALAS1
protein MafK, which are involved in the antioxidative response, expression.88 However, PPIX mainly contributes to cholestatic
appear to be genetic determinants in anti-TB drug induced hepa- injury,84e86 but not hepatocellular injury, the major form of liver
totoxicity.67 Uridine 50 -diphospho glucuronosyltransferase (UGT) damage caused by INH.5,6
3
S. Lei, R. Gu and X. Ma Liver Research xxx (xxxx) xxx

Fig. 1. The major metabolic pathways of INH and its association with hepatotoxicity. Acetylation via NAT2 is a predominant pathway in INH metabolism in the liver. INH
metabolites including Hz, AcHz, and isonicotinic acyl radical have been considered as a cause of INH hepatotoxicity. Abbreviations: AcHz, acetylhydrazine; CYP, cytochrome P450;
Hz, hydrazine; INH, isoniazid; NAT2, N-acetyl transferase 2.

In addition to PPIX, INH can directly react with and conjugate that co-exposure of hepatocytes to INH and nontoxic concentra-
with a number of endogenous metabolites including ketone acids, tions of the complex I inhibitors result in massive ATP depletion
leading to the formation of hydrazones. The condensations with and cell death.102 The same study also found that Hz directly in-
INH include pyruvic acid (PA) and vitamin B6, which respectively hibits the activity of complex II, suggesting that underlying inhi-
form INH-pyruvic acid (INH-PA) adduct and INH-pyridoxal (INH- bition of complex I can potentiate INH-induced hepatocellular
PL) adduct.89e91 The latter conjugation of INH with vitamin B6 injury.102 In addition, polymorphic alleles of SOD, a mitochondrial
leads to the depletion of pyridoxal-5-phosphate in both humans matrix-resident protein that plays a crucial role in the detoxifica-
and rodents.92,93 Five novel INH-hydrazones were identified in tion of superoxide anion radicals that arise constantly during
human urine via an LC-MS-based metabolomics approach as the electron transport have been associated with susceptibility to INH-
condensation of INH with keto acids that are intermediates in the related hepatotoxicity.63,103 Furthermore, a recent study demon-
metabolism of leucine and/or isoleucine, lysine, tyrosine, trypto- strated that INH induces oxidative stress and mitochondrial
phan, and phenylalanine.89 INH can also react with b-nicotinamide dysfunction in isolated liver mitochondria, and posited that INH
adenine dinucleotide (NADþ) to form INH-NAD adduct as catalyzed hepatoxicity may be mediated through an interaction with the
by the cluster of differentiation 38, a multifunctional enzyme with electron transport chain, lipid peroxidation, mitochondrial mem-
NADþ nucleosidase activity.90,94,95 However, whether these INH- brane potential change, and cytochrome c extrusion, ultimately
endobiotics interactions play a role in INH hepatotoxicity remains resulting in detrimental cell signaling.104 Moreover, a pattern of
to be determined. metabolic changes and steatosis consistent with mitochondrial
injury was observed in comprehensive studies of INH in a panel of
genetically diverse mice.105 However, convincing data from pre-
5.3. Oxidative stress and mitochondrial damage in INH-induced
clinical studies, such as development of animal models with
liver injury
obvious INH-induced liver injury, are lacking to prove the roles of
oxidative stress and mitochondrial damage in INH hepatotoxicity.
The association between INH hepatotoxicity and oxidative
stress/reactive oxygen species (ROS) has been proposed.96,97 As
discussed in the risk factors section above, deficiency in GST activity
due to homozygous null mutations at GSTM1 and GSTT1 loci can 5.4. Immune response in INH-induced liver injury
influence susceptibility to INH hepatotoxicity. Earlier animal ex-
periments have shown reduced levels of GSTs and other anti- Involvement of immune responses in INH hepatotoxicity has
oxidative enzymes after the administration of Hz.98 In addition, a been proposed for a long time. A positive lymphocyte trans-
murine study has established the role of microRNA-122 in oxidative formation test was found in mild cases of INH-induced liver injury
stress-related liver injury by INH.99 Further evidence indicates that when patients’ lymphocytes were exposed to INH-modified pro-
dysregulation of transcription factors that regulate glutathione teins; in the more severe cases of liver injury, this response spread
synthesis and detoxification enzymes, including the transcription to the recognition of the parent drug.106,107 A further study in 2014
factor nuclear factor erythroid 2-related factor 2 (Nrf2), small Maf identified anti-INH antibodies and anti-CYP antibodies in the sera
basic leucine zipper proteins, and the transcription factor Bach 1, of patients with INH-induced liver injury,78 indicating that CYP-
may contribute to the propagation of anti-TB DILI.67 Moreover, re- mediated INH metabolism produces reactive metabolite(s), which
ports have suggested a stronger correlation of higher severity of covalently binds to CYPs and other proteins in the liver and triggers
INH hepatotoxicity with reactive nitrite species (RNS) than with immune responses. The same study identified antibodies to CYP2E1
ROS; thus it is possible that peroxynitrite (ONOO) generation and modified by INH, CYP2E1, CYP3A4, and CYP2C9, none of which
mitochondrial dysfunction contribute significantly to such were detected in sera from INH-treated control subjects without
toxicity.100,101 significant liver injury.78 These are the most promising data
Mitochondria are an important target in DILI, as inhibition of the showing that INH-induced liver injury is dependent on CYP-
mitochondrial respiratory chain results in adenosine triphosphate mediated INH bioactivation and immune responses. Follow-up
(ATP) depletion and accumulation of ROS. An in vitro study found studies are highly suggested to explore the application of anti-
4
S. Lei, R. Gu and X. Ma Liver Research xxx (xxxx) xxx

INH and anti-CYP antibodies in the clinic to predict and prevent predict and prevent such toxicity.5,13,20,97 From clinical practice,
INH-induced liver injury. multiple risk factors of INH hepatotoxicity have been identified
including aging, co-treatment with drugs as CYP inducers, and in-
dividuals with pre-existing liver diseases (Fig. 2).7,8,18,21,22,30e32,39,40
6. Management of INH-induced liver injury
However, the detailed mechanisms by which these factors poten-
tiate INH-induced liver injury remain unclear. In addition, many
While most cases of INH hepatotoxicity are mild and resolve
genetic polymorphisms have been found to be associated with INH-
despite continued therapy with INH, a small number of patients
induced liver injury (Fig. 2), but currently no clinical test for such
taking INH develop severe hepatitis that may progress to fulminant
genetic predisposition is used in clinical practice to improve the
liver failure and death if INH is not stopped promptly. Biochemical
safety profile of INH.7,45,46
tests (ALT and AST) together with the appearance of clinical
Although extensively studied, the underlying mechanisms for
symptoms (fatigue, nausea, poor appetite or jaundice) have been
INH-induced hepatotoxicity remain enigmatic. This is partly due to
used to guide decisions on discontinuation of INH therapy to pre-
the complexity of these mechanisms, but also because of the dif-
vent serious liver injury.12 However, INH hepatotoxicity remains a
ficulty of distinguishing between patient-related and drug-specific
serious safety concern in the clinic because of its idiosyncratic na-
factors that may determine susceptibility to INH hepatotoxicity.96
ture. In addition, no specific therapies are currently available for the
Multiple mechanisms of INH hepatotoxicity have been proposed,
treatment of INH-induced liver injury. Corticosteroids, a class of
including INH metabolite-mediated toxicity, disruption of endobi-
steroid hormones that have anti-inflammatory and immunosup-
otic homeostasis, oxidative stress, mitochondrial damage, and
pressive effects, are often used, but the outcomes are not
immune-mediated toxicity.72,73,78,88,96,97,102 However, most of these
convincing.12 Therefore, mechanism-based strategies are urgently
mechanisms are drawn based upon preclinical studies and are
needed for the management of INH-induced liver injury.
inconclusive. The identification of anti-INH antibodies and anti-CYP
antibodies in the sera of human subjects with INH-induced liver
7. Summary injury strongly supports the role of immune responses in INH
hepatotoxicity,78 which also sheds light on the prediction and
After nearly 70 years of clinical use, INH remains a steadfast and prevention of INH hepatotoxicity, but so far no follow up report is
broadly used frontline drug for TB chemotherapy and prophylaxis available to show its application in the clinic.
due to its powerful efficacy, cost-effectiveness, and usually favor- In summary, INH hepatotoxicity remains a safety concern in
able safety profile. However, INH-induced liver injury continues as clinical practice and no mechanism-based approaches are available
a major concern in clinical practice and it remains unknown how to to predict, prevent, and cure such toxicity. Further clinical and pre-
clinical studies coupled with cutting-edge technologies are neces-
sary to better elucidate and address the unanswered questions and
underlying mechanisms of INH hepatotoxicity.

Authors’ contributions

S. Lei, R. Gu, and X. Ma conducted literature search and drafted

the manuscript. S. Lei and X. Ma revised the manuscript.

Declaration of competing interest

The authors declare that they have no conflict of interest.

Acknowledgements

This work was supported in part by the National Institute of

Allergy and Infectious Diseases (R01AI131983) and the National
Center for Complementary and Integrative Health (R21AT011088).

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