“I took so much medicine, that I was ill for a long time, after I got well” - Carl Sandbera.

Tuberculosis continues to remain a significant infectious disease across much of the developing world. It exacts a significant socioeconomic burden on the individual and society. India is home to a fifth (21%) of the world’s TB population and is the country with the highest TB burden.[1] The incidence of TB in India is 1.96 million cases annually, contributing to>300,000 deaths annually, including 1000 deaths every day.1 Although the western world has seen a declining trend in the incidence and prevalence of tuberculosis, the emergence of HIV/AIDS has complicated the efforts of controlling the disease, particularly in developing countries. Co-infection with HIV increases the risk of tuberculosis 6-50 fold.[2] Indeed both TB and HIV coexist in the same population making it a “cursed duet”.[3] Although newer and safer drugs are continuously being sought after and used in the treatment of HIV, the mainstay of drugs used in the treatment of tuberculosis still includes the first line drugs identified more than 5-6 decades ago. These include isoniazid (INH), rifampicin (RIF), pyrazinamide (PZY) and ethambutol (EMB). Although a vast majority of patients tolerate the drugs, some develop adverse effects of which hepatotoxicity is the most significant.[4] Twenty percent of patients develop asymptomatic elevation of liver enzymes which is self limiting (as a result of adaptation or discontinuance) in a majority of patients[4,5,6,7] but the outlook may be less favorable in those with develop jaundice, ascites, encephalopathy or acute liver failure.[8,9] Furthermore, the ripple effects of hepatotoxicity include disruption of treatment with potential for prolongation of treatment, genesis of drug resistance and suboptimal cure. Hepatotoxicity or DILI due to antituberculosis drug-induced liver injury (DILI) encompasses a wide spectrum of liver injury ranging from asymptomatic minimal elevation of liver enzymes to acute liver failure, often leading to death or liver transplantation. Indeed, it is a leading cause of drug-induced liver injury in India and of drug-induced acute liver failure leading to death (DIALF).[8,9,10] In contrast, non-TB antibiotics and paracetamol are the commonest causes of DILI and drug-induced ALF in western countries.[11,12,13] In a single center registry of 303 patients from Bangalore, antituberculosis drugs contributed to 58% cases of DILI.[10] In another large series investigating acute liver failure in New Delhi, anti-TB drugs contributed to 5.7% patients with ALF(70/ 1223), with 67% mortality.[8] This review examines the current perspectives of TB DILI. For a complete and exhaustive overview of TB DILI, excellent reviews have been published.[5,6,7]

Definition

Earlier definitions were plagued by inconsistencies in elevation of numerical levels of transaminases needed for a diagnosis of DILI. Presently, there is a fair amount of consistency in the criteria used for diagnosing DILI including TB DILI. In the absence of symptoms, elevation of transaminases up to 5 times the upper limit of normal (ULN) and in the presence of symptoms up to three times the ULN or twice the ULN of bilirubin constitutes DILI,[6,14,15] provided competing causes such as acute viral hepatitis, autoimmune hepatitis and others liver diseases are ruled out. Although physicians often use elevation of transaminases or bilirubin as default criteria for diagnosing TB DILI, recent studies underscore the importance of concomitant viral hepatitis A-E as a reason for elevation in liver biochemical tests. A recent study by Sarda and colleagues[16] identified acute viral hepatitis as a competing cause in 14.7% of patients. Routine use of causality assessment scores such as Roussel Uclaf Causality Assessment Method (RUCAM) or Drug Induced Liver Injury Network (DILIN) criteria will bring some objectivity to the likelihood/probability scores of DILI and minimize errors.[14,15] Besides the above definition in patients with HIV, the AIDS Clinical Trials Group criteria is used, which is as follows: Grade 1: transaminases 1.25 - 2.5 × upper limit of normal (ULN); Grade 2: 2.6 - 5 × ULN; Grade 3: 5.1 - 10 × ULN; and Grade 4: >10 × ULN.[17]

Incidence, interactive toxicity and mechanism of toxicity

The overall incidence of TB DILI in the population is unknown and is probably unrecognized. Toxicity occurs both during primary prophylaxis (preventive therapy) and treatment of tuberculosis; and is dependent on the dynamics of drugs, drugdisease and drug-host interactions.

Among the first-line drugs (isoniazid, rifampicin, pyrazinamide and ethambutol), the first three have the potential for hepatotoxicity with pyrazinamide being the most hepatotoxic followed by isoniazid and rifampicin.[18,19] Rifampicin combined with PZA is more hepatotoxic than with INH.[20,21] Pyrazinamide contributes significantly to ALF.[22] There is some evidence to suggest the protective effect of isoniazid on hepatotoxicity of RIF and PZA in combination regimens.[23,24] However, when DILI occurs following the use of 4-drug combination regimen, it is impossible to quantify the contribution of each drug in the development of DILI.

Pathogenesis and mechanisms

Most cases of DILI are idiosyncratic in nature, meaning it is the characteristics of the host and not the characteristic of the drug which are responsible for the liver injury. Idiosyncratic reactions may be hypersensitive or metabolic.[25] Hypersensitive idiosyncrasy is often associated with skin rashes, fever, eosinophilia and/or lymphadenopathy. This is uncommon in anti-TB drugs, being more common with antiepileptics and sulfonomides.[26] More commonly, TB DILI is due to metabolic idiosyncrasy due to the metabolites released or accumulated during the metabolic process. Recent evidence indicates that drugs taken in quantities of >50 grams/day[27]are more likely to produce hepatotoxicity, which results from the formation or reduced clearance of toxic metabolites.[28] This may be facilitated by genetic factors or polymorphism of drug metabolizing enzymes (see section on genetic polymorphism).

Presentation, adaptation and clinical evaluation of DILI

Antituberculosis DILI has a wide spectrum of presentations, ranging from asymptomatic mild rise in liver biochemical tests to acute hepatitis and acute liver failure. The mild increase in aminotransferases experienced by ~20% of patients is usually asymptomatic.[5] Clinical hepatitis is seen in 1-6% of patients taking isoniazid prophylaxis or combination drugs.[29] A feature peculiar to anti-TB drugs is the development of adaptation or tolerance to the drugs. Indeed, adaptation during INH or anti- TB use is an illustrative example for adaptation. This is defined as elevation of transaminases and or bilirubin, without any symptoms, which resolves with continuation of the drugs. Rarely, despite marked rise in transaminases and bilirubin, patients may still be asymptomatic.[30] Awareness of the phenomenon of adaptation is critical in tuberculosis to prevent inadvertent discontinuation of antitubercular drugs which are critical for successful treatment of TB patients. Since liver biochemical tests are not routinely monitored in TB patients on the 4 antitubercular drugs, the actual incidence of this condition remains unknown but is believed to be in the order of ~20%.5 When elevated liver enzymes are noted in a TB patient on ATT, the major challenge for the treating physician is to determine whether the elevation is a sign of adaptation or a sign of incipient liver injury. The current recommended diagnostic criteria laid down by the DILIN and other groups may assist in resolving this issue. TB drugs can be continued till AST/ALT is 5 × ULN, in the absence of hyperbilirubinemia or symptoms; or up to 3 × ULN in the presence of symptoms or hyperbilirubinemia (bilirubin 2 × ULN). Competing etiologies particularly acute viral hepatitis may need to be excluded.

Risk factors for TB DILI

Interactions between genetic, host and environmental factors contribute towards the development of TB DILI. The following is a summary of the most important factors.

Age: Recent studies have noted patients older than 35 years are at 4 times increased risk to develop TB DILI.[31] Other studies on latent disease indicate that 1.7% of those >35 years developed TB DILI compared to 0.2% in those younger than 35. However in their meta-analysis, Steele et al[29] observed hepatitis in 1 - 6.9% of children compared to 1.6 - 2.5% of adults taking INH and RIF combination; implying that all age groups are at risk for DILI. Roy et al[32] observed an incidence of 8% in children while Devrim noted an incidence of 1.7% in Turkey.[33] Indeed, the fatal effects of the 4 drug ATT combination is marked with 50% mortality in those with TB DILI, including >80% mortality in those with TB DILI ALF,26 which is higher than the mortality of 67% reported in adults.[8,9]

Gender: Although women have traditionally been considered more susceptible to develop TB DILI, recent reports suggests that men outnumber women in the incidence of TB DILI.[9,10] This likely reflects the demographic disparity where more men than women are under treatment for tuberculosis. However, female gender is a positive predictor of more severe liver disease including death.[10]

Organ involvement / extent of TB disease: The extent of tuberculosis including cavitory disease, multibacillary TB and extrapulmonary organ involvement have been incriminated as positive predictors for TB DILI by some authors,[34,35] while others have failed to note any significant association[36] In a study from south India, TB DILI was detected in 16-39% of children with tuberculous meningitis, compared to 10% in spinal tuberculosis and 2-8% in pulmonary tuberculosis.[34] The strikingly high 39% DILI in the above study was also attributed to the high dose of pyrazinamide (20 mg/kg body weight) compared to 16% in those who received a 12 mg/kg dose. Interestingly, a recent meta-analysis of 29 studies did not find any significant hepatotoxicity between high-dose pyrazinamide (60 mg/kg) compared to medium (40 mg/kg) and low dose (30 mg/kg) regimens.[37]

Malnutrition: Recent reports continue to confirm the relevance of hypoalbuminemia as a surrogate marker of malnutrition and a risk factor for TB DILI. Singla et al and Sharma et al demonstrated that patients with low albumin (<3.5 mg/dl) had three fold higher risk of developing TB DILI.[31,35] A recent report incriminated weight loss as an important risk factor for DILI.[38]

Alcohol: The influence of alcohol as a risk factor is equivocal. Patients who drink frequently often underestimate the quantity consumed and continue to drink despite recommendations to the contrary. Alcohol as a risk factor has been ascribed to under-nutrition and depleted glutathione stores.[7]

Hepatitis B: The risk of DILI is increased 4 fold in HBsAg carriers compared to non-carriers (34.9% vs. 9.4%, p<0.001). Replicating status (HBeAg) may play a pathophysiological role although even inactive carriers are at risk to develop DILI.[39] A recent study found high baseline HBV DNA in patient samples to be a risk factor for DILI.[36] The probability of an acute flare should be considered during the time of raised transaminases.[36]

Hepatitis C: Combination chemotherapy and isoniazid monotherapy is associated with a 5 fold increased risk of DILI. Similar to hepatitis B, the HCV viral count may play a critical role during transaminase elevation.[40]

Dosing schedules: The role of daily vs. intermittent high dose schedules including DOTS (directly observed therapy, short-course) continues to be debated. Chang and associated did not find a link between dosing schedule and hepatotoxicity.[41] Many of the patients in a recent series from India developed TB DILI while receiving DOTS therapy.[9,42] The role of an overstretched health care system and workers who disregard or ignore minimal signs and symptoms of DILI may be a contributing factor.

Genetic polymorphism: The role of three enzymes important for metabolism of INH has been extensively investigated. They include, N-acetyltransferase 2 (NAT2), CYP 2E1 and glutathione S-transferase.[43,44]

Increasing number of studies are reporting the plausible impact of N-acetyltransferase 2 (NAT2) gene/enzyme polymorphisms on the metabolism of isoniazid and susceptibility to DILI. While early reports linked fast acetylators (normal level of NAT2 enzyme) with susceptibility to TB DILI, later studies have uniformly incriminated slow acetylators lacking NAT2 activity with TB DILI.[45] Bose and colleagues demonstrated NAT2 slow-acetylator genotype in 71% patients with TB DILI compared to 45% patients without DILI (p<0.05).[46] This is consistent with similar results reported by Huang YS et a[47] who found a higher risk of hepatotoxicity in slow acetylators than rapid acetylators (26.4% vs. 11.1%; p=0.013), and also demonstrated that slow acetylators were at higher risk for developing severe liver injury.[47] In contrast, Roy et al[48] did not find any association between NAT2 slow acetylators and DILI, or CYP 2E1 *1A/*1A and DILI. However a subgroup analysis found an association of CYP 2E1 DraI in children with DILI.[49] This was confirmed by a recent study by Bose et al[46] which found an association of DraI polymorphism of CYP 2E1 gene with DILI (85% DILI vs. 64% non-DILI, p<0.05). Vuilleumier et al[50] also concluded that CYP 2E *1A/*1A was a risk factor for INH induced hepatitis in patients with latent tuberculosis.

In another study Roy and associates[48] observed an increased risk of TB DILI in individuals with glutathione Stransferase M1"null” mutation, a result similar to that reported by Huang et al in an Asian population.[51] Leiro and colleagues concluded similar results among Caucasians with regard to GSTT1 homozygous null mutation and anti-TB DILI.[52] Paradoxically, a recent study by Chatterjee et al did not show any association with either GSTT1 or GSTM1 gene deletion in TB DILI.[53] The reasons for such discordant findings are unclear, but could be due to the variability in small patient cohorts and the limited impact of these polymorphisms on DILI.

Role of HLA on DILI

Antituberculous class of drugs are among the growing list of drugs linked to human leukocyte antigen (HLA) class II. Sharma et al reported the presence of HLA-DQB1*0201 and the absence of HLA-DQA1*0102 with AT DILI with odds ratio of 1.9 and 4.0 respectively.[42] The low odds ratio is in marked contrast to the odds ratio of 80.6 with flucloxacillin in patients with HLA B*5701.[54] HLA B*5701 is also linked strongly with abacavir induced hypersensitivity reactions. Given the modest increase in the risk of developing TB DILI, the role of pharmacogenetics particularly for drugs such as antituberculous agents will be limited given the global burden of disease, the absence of potent second line drugs and the costs associated with pharmacogenomic testing. The importance of host and environmental factors such as weight based dosage, appropriate indications, concomitant drug history and stopping drugs at the first sign of hepatic injury will likely make greater contribution towards minimizing the incidence and progression of DILI.

HIV infection

Tuberculosis and HIV often coexist and are emerging as a global problem of alarming proportions. The ~ 40 million people living with HIV infection are 6-50 times more likely to develop active TB than those without HIV infection.2 Both diseases need multidrug therapy, resulting in up to 18% incidence of hepatotoxicity.[55] The likely causes include drug-drug and potential drug-disease interactions. In addition, the presence of hepatitis B and hepatitis C complicate and markedly increase 170 the risk of hepatotoxicity.[7] For example, HIV alone and coinfection with hepatitis C increases the risk of TB DILI 4 and 14 fold respectively, in patients on antituberculous drug therapy.[40]

TB DILI in children

Although DILI occurs less frequently in children than adults, it is by no means uncommon. DILI contributes to 4-8% and 8.7% pediatric cases in the west and India, respectively.[26] The commonest cause among Indian children and adolescents is antituberculous agents used for treatment of tuberculosis usually with a 4-drug combination regimen. In children too, the mortality is substantial, occurring in 50 % of patients with TB DILI, largely due to metabolic idiosyncrasy. In a retrospective study of 99 children from Japan, 8 children developed TB DILI.[56] Younger age and the use of pyrazinamide were factors associated with risk of hepatotoxicity.[56] DILI due to antituberculous agents is seen more commonly due in extensive disease particularly tuberculous meningitis,[57] whereas TB DILI during chemoprophylaxis is distinctly uncommon.[57] However, studies from Bangalore,[26] Japan,[56] and elsewhere[57] remind us that children receiving antituberculosis combination drugs are
at risk of TB DILI and should be monitored for hepatotoxicity.

While all the above factors are important and may well contribute towards development of DILI, studies from India suggest that 42-63% of individuals who developed DILI and TB DILAF never required anti-TB drugs in the first place and were being treated empirically for suspected tuberculosis.[8,9]

Management of hepatotoxicity

Prevention of DILI: Various predictive factors have been implicated in DILI and caution should be exercised in such patients. Not all studies have identified the same risk factors. Education of the patient and their family members about the risk of TB drugs and the critical need to stop the drug immediately on development of symptoms should be emphasized. In a study of 11,144 patients on INH chemoprophylaxis, only 0.6% subjects developed clinically relevant DILI without the use of liver biochemical tests.[58] The above study highlights the role played by primary care providers and patient education, and emphasizes the importance of immediate discontinuance of the drug in order to prevent progressive liver disease. Since old age is a risk factor, a recent study concluded that co-prescription with Nacetylcysteine (NAC) in patients above 60 years prevented DILI, when compared to those who did not receive NAC.[59] Further studies are needed to confirm this finding.

Management after diagnosis of DILI: Elevated liver biochemical tests alone are often used as to diagnose DILI and should be discouraged. While it is prudent to discontinue the hepatotoxic drugs, a search for an alternative cause such as acute viral hepatitis A-E should be undertaken before a diagnosis of DILI can be made. Various guidelines for the management of DILI have been propounded by the American Thoracic Society (ATS),[6] British Thoracic Society (BTS),[60] the World Health Organization (WHO) and the International Union Against Tuberculosis and Lung Disease. There are minor variations among these guidelines including the necessity or not of liver biochemical tests. There are no studies validating the utility of liver biochemical tests in prevention of DILI or assessing its severity. Such monitoring is often seen as inconvenient, expensive and inefficient by both patients and doctors, and thus the monitoring recommendations are poorly followed.[61] However, monitoring with liver tests is recommended in the following groups: patients who consume alcohol, individuals with chronic hepatitis B or C, and those on concomitant hepatotoxic drugs, have elevated baseline transaminase levels, suffer from underlying liver disease and those with HIV.[6] Symptoms of DILI are often the first clue to an early diagnosis of the disorder and should not be disregarded. After the diagnosis of DILI, the 3 hepatotoxic drugs, namely INH, RIF and PYZ are to be withheld immediately. Depending upon the urgency of the underlying tuberculous condition second line drugs such as streptomycin or amikacin, ciprofloxacin or ofloxacillin, may be initiated till such time the liver tests return to normal, or jaundice abates or the transaminases drop to <2 × ULN.[6] Alternatively newer drugs such as moxifloxacillin may be used in lieu of the first line drugs. Although most cases may resolve with omission of the offending drugs (dechallenge), unfortunately a few cases will continue to progress despite drug withdrawal. Reintroduction of the primary agents after DILI has resolved is subject of much debate. The common regimen consisting of sequential treatment, first with rifampicin followed by isoniazid 3-7 days later may be undertaken. If tolerated, pyrazinamide may be started with monitoring of liver tests. Alternatively pyrazinamide may be omitted and both isoniazid and rifampicin may be continued for a longer duration of 9-12 months depending on the underlying disease.

A recent study evaluated the safety of reintroduction of 3 antituberculosis regimens either as sequential treatment or concomitant treatment in 175 patients with TB DILI.[42] In this study the three treatment arms were as follows: arm I (n=58), patients received maximum doses of INH, RIF, PZA simultaneously, arm II (n=59), patients received treatment as per ATS guidelines, i.e. RIF followed by INH after 7 days, followed by PZA after 7 days, all with maximum doses. In arm III (n=58), patients received sequential treatment with graded doses according to British Society Study (BTS) guidelines. The doses of INH, RIF and PZA were gradually escalated sequentially after the maximum dose of the preceding drugs was achieved. The authors concluded that the recurrence of DILI was similar between the three treatment arms, namely 8, 6, and 5 patients respectively (p=0.69).[42] In contrast, the only other randomized study by Tahaoglu and associates[62] on 45 patients concluded that reintroduction regimens containing maximum dose of antituberculosis drugs including pyrazinamide (group 1, n=25) caused more hepatotoxicity than gradual reintroduction without pyrazinamide, (group 2, n=25).[62] The authors noted hepatotoxicity in 6 (24%) patients in group I, compared to none in group 2 (p=0.021). The differences between the above two studies could be due to a smaller number of patients in the second study and the lower treatment limiting cut-offs in the former study, a number of whom may have had adaptation.[63] The advantage of sequential treatment is its ability to delineate the hepatotoxic drug and the choice of not using pyrazinamide which appears to be the most hepatotoxic drug among the 3. The jury is still out regarding the optimal regimen and dose for reintroduction of anti-TB drugs after hepatotoxicity. However, caution should be exercised while treating patients with chronic liver disease or cirrhosis. Pyrazinamide may be withheld particularly in individuals with cirrhosis and a dual combination consisting of INH and RIF may likely be safer.[64,65]

N-acetylcysteine has been shown to be useful in drug induced liver injury. In the randomized controlled trial assessing the utility of NAC in all forms of acute liver failure, NAC was found useful in coma progression in DILI (p=<0.05).[66] Although further studies are needed to validate this result in AT DILI, indirect evidence of the usefulness of NAC comes from another study by Baniasadi et al[59] demonstrating the usefulness of limiting liver enzyme elevation in patients over 60 years when NAC was used prophylactically along with antituberculosis drugs.

Management in specific setting such as liver or organ transplantation: Patients who undergo liver transplantation for acute liver failure due to TB DILI may need to be on antituberculosis medications. Rifampin’s potent induction of CYP 450 system may cause decrease in the concentration of immunosuppressive drugs leading to acute rejection of transplant organs. Therefore caution should be exercised when rifampin is prescribed. Alternatively, drugs such as rifabutin or other second line drugs may be instituted in order to minimize the risk of rejection and maximize the efficacy of treating tuberculosis simultaneously.[67]

Conclusions

Comprehensive case series on DILI in India, including TB DILI and TB DIALF continue to improve our awareness and understanding of the clinical spectrum, natural history, outcome and genetic predictors of TB DILI. The high mortality associated with TB DILI should serve as a caution to minimize diagnostic and prescription errors. While reintroduction regimen after antituberculosis drug hepatotoxicity remain debatable, sequential treatment appears safer. The recent warning from WHO against the use of inaccurate and inconsistent blood tests for tuberculosis may mitigate the occurrence of TB DILI.[68]

References