Systematic Reviews Open Access
Copyright ©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastrointest Pharmacol Ther. May 5, 2021; 12(3): 40-55
Published online May 5, 2021. doi: 10.4292/wjgpt.v12.i3.40
Overview of drug induced liver injury in Brazil: What is the role of public health policy on the evidence?
Matheus William Becker, Karin Hepp Schwambach, Michele Lunardelli, Carine Raquel Blatt
Matheus William Becker, Karin Hepp Schwambach, Michele Lunardelli, Carine Raquel Blatt, Graduate Program in Medicine-Hepatology, Federal University of Health Sciences of Porto Alegre, Porto Alegre 90050-170, RS, Brazil
Carine Raquel Blatt, Pharmacoscience Department, Federal University of Health Sciences of Porto Alegre, Porto Alegre 90050-170, RS, Brazil
ORCID number: Matheus William Becker (0000-0002-0190-3688); Karin Hepp Schwambach (0000-0003-3271-2566); Michele Lunardelli (0000-0003-3093-7374); Carine Raquel Blatt (0000-0001-5935-1196).
Author contributions: Becker MW, Lunardelli M, and Blatt CR collected the data and wrote the paper; Becker MW, Schwambach KH, Blatt CR wrote and revised the paper.
Conflict-of-interest statement: Authors declare no conflict of interests for this article.
PRISMA 2009 Checklist statement: The guidelines of the PRISMA 2009 statement have been adopted.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
Corresponding author: Matheus William Becker, MSc, Pharmacist, Graduate Program in Medicine-Hepatology, Federal University of Health Sciences of Porto Alegre, Sarmento Leite, 245 Street, Porto Alegre 90050-170, RS, Brazil.
Received: November 25, 2020
Peer-review started: November 25, 2020
First decision: January 7, 2021
Revised: January 20, 2021
Accepted: April 25, 2021
Article in press: April 25, 2021
Published online: May 5, 2021


Adverse drug reactions are responsible for increased costs and morbidity in the health system. Hepatotoxicity can be induced both by non-prescription drugs and by those used for chronic diseases. It is the main cause of safety-related drug marketing withdrawals and could be responsible for irreversible and fatal injuries.


To identify and to summarize Brazilian studies reporting the drug-induced liver injury.


A systematic review of Brazilian studies was carried out until June 2020. It was found 32 studies, being 10 retrospective cohorts, 12 prospective cohorts, 5 cross-sectional, 3 case-control, one case series and one randomized clinical trial. In most studies were investigated tuberculosis patients followed by other infectious conditions like human immunodeficiency virus (HIV) and hepatitis C virus. The hepatotoxicity ranged from one to 57%, led by isoniazid, rifampicin, and pyrazinamide. Few studies reported algorithm to assess causality. In most studies, there were moderate outcomes and it was necessary drug interruption. However, few severe outcomes, such as chronic liver damage and liver transplantation were reported.


Twenty-two different criteria for hepatotoxicity were found. The great heterogeneity did not allow a meta-analysis. Standardization of parameter of drug-induced liver injury and greater effort in pharmacovigilance could contribute to learn more about drug-induced liver injury (DILI)’s epidemiology in Brazil.


The development of strategic public health policies seems to have an influence on the DILI scientific evidence in Brazil due to main studies are in HIV and tuberculosis line care, two strategic health policies in Brazil.

Key Words: Chemical and drug-induced liver injury, Pharmacovigilance, Pharmacoepidemiology, Adverse effects, Infectious disease medicine, Hepatotoxicity

Core Tip: Hepatotoxicity is the main cause of safety-related drug marketing withdrawals and could be responsible for irreversible and fatal injuries. A systematic review of Brazilian studies was found 32 studies and the hepatotoxicity ranged from one to 57%, led by isoniazid, rifampicin, and pyrazinamide. Few studies reported algorithm to assess causality and twenty-two different criteria for hepatotoxicity were found. Standardization of parameter of drug-induced liver injury and greater effort in pharmacovigilance could contribute to learn more about drug-induced liver injury’s epidemiology in Brazil.


Drug-induced liver injury, also known as drug-induced liver injury (DILI), is the main cause of discontinuation of new drug research and for their withdrawal from the market during the marketing period[1]. Some mechanisms have been described according to the drug, but these are not fully known yet[2]. Identification is a challenge due to the diversity of drugs with hepatotoxic potential, the lack of symptoms specificity, and the absence of specific biomarkers for DILI in the clinical practice[3]. In France and Iceland, incidences of 13.9/100000 and 19.1/100000 inhabitants/year were identified, respectively, in the general population[4,5]. DILI manifests itself through elevation of hepatic transaminases, in addition to alteration of hepatic function markers, and may vary from asymptomatic presentation to hepatic encephalopathy[6]. Detection is done by exclusion of other causes along with the use of a drug with hepatotoxic potential. The Russel Uclaf Causality Assessment Method (RUCAM) algorithm is the most accepted tool to aid in DILI detection[7]. Some risk factors have been described, such as gender, age, lifestyle, but the huge diversity of drugs hinders generalization; it is believed that individual characteristics, drug properties, and genetic, metabolic and immunological factors have an important impact on the development of idiosyncratic DILI[6].

Idiosyncratic reactions may occur at therapeutic doses with a latency of 5 to 90 d after the use of the drug. The drugs most commonly associated with this type of reaction are antimicrobials, with many cases for amoxicillin associated with clavulanate[5,8-10]. In prospective studies published in 2005 and 2013, the drugs most frequently related to DILI were erythromycin, sulfamethoxazole/trimethoprim, diclofenac, isoniazid, and ibuprofen[5,8,11]. When DILI is not detected early, it may progress to acute liver failure, rapidly leading to death. However, when well managed it evolves favorably with the suspension of medication and support measures for the symptoms[12]. Different treatment strategies are adopted, but with little evidence of efficacy. The use of corticosteroids has been the most frequent practice. In addition, N-acetylcysteine is used in cases of acute hepatic impairment induced by medication, but, except for paracetamol, it has limited efficacy[13]. In the presence of cholestasis, ursodeoxycholic acid and cholestyramine are reported in the management[14]. In Japan, a compound consisting of L-cysteine, glycine and Glycyrrhiza glabra is routinely used in DILI intoxications[15]. Silymarin, used preventively along with tuberculostatics, has presented good results, but these are still preliminary[16,17]. In the most acute cases, plasma exchange, among other extracorporeal therapies, are alternatives to avoid transplantation[13,18].

The notification and diagnosis of the cases as well as the knowledge and involvement of health professionals regarding the hepatotoxicity of the drugs are of great importance for the early detection and reduction of damages to the patients affected by DILI[19-21]. In this context, this paper aims to identify Brazilian studies with data on drug-induced hepatotoxicity in order to know the profile of DILI in Brazil.


A systematic review of published Brazilian studies of drug-induced liver injury was performed. The databases searched were PubMed, Scielo, Science Direct and the Brazilian thesis bank. The search strategy combined the descriptors for DILI with Brazil in Portuguese and English as follows: (Hepatotoxicity or drug-induced liver injury or liver injury or hepatotoxic adverse drug) and (Brasil or Brazil or Brazilian). There was no limitation by language, year of publication or study design. Other sources of access to the studies were used, such as contact with authors and references. The last search was performed in June 2020.

The eligibility of the studies was defined by the identification or suspicion of DILI due to drug or plant use and by being Brazilian studies. In order organize the results, case reports were excluded from this publication.

The selection of the studies was performed by two independent reviewers and in three sequential stages by reading the title, the abstract and the full text. A third reviewer resolved the disagreements. Data extraction are doing independently, the following variables were analyzed: Age; gender, comorbidities; local; and design; sample size; suspected drugs; HIV, tuberculosis (TB) or HCV infection; use of algorithm to support diagnosis; classification criteria for hepatotoxicity; outcomes related to DILI; frequency of DILI.

All Brazilian DILI cases reports are included. Risk of bias in individual studies aren’t available and we didn’t perform a summary of measures or a sensitivity or subgroup analyses.


Initially, 441 studies were found. After excluding case reports and duplicates and including gray literature, 32 studies were included as can be seen in Figure 1. The selected studies comprised 29 articles, 2 dissertations, and one monograph.

Figure 1
Figure 1 Flowchart of studies selection about drug-induced liver injury published in Brazil.

Table 1 presents some data from the studies included in this review. The publication date of the studies ranged from 1989 to 2015. Among the Brazilian states, Rio Grande do Sul, Rio de Janeiro and São Paulo accounted for 62% of the studies. Regarding the studied population, the average age was 37.9 years. In studies that DILI was analyzed by gender (n = 8), on average 55% of all patients who developed DILI were men.

Table 1 Summary of published Brazilian studies on drug-induced hepatotoxicity data.
Ref.YearPlaceStateDesignnClass or medicationUse of algorithmFrequency of DILI
Silva et al[22]2019HoBACross-cut306MTXNo2.0%
Alves et al[59]2011HoSCCross-cut71MTX/LEFNo11.0%
Carvalho et al[74]2014ARJCross-cut219AzathioprineNo2.7%
de-Medeiros et al[75]1998HoPRRCT37TretinoinNo16.0%
Werner et al[61]1989HoSPPC389PropylthiouracilNo1.3%
Santos et al[63]2013HoRSRC1855-FluorouracilNo57.8%
Uehara et al[76]2005HoSPRC12Amphotericin BNo30.0%
Magalhães[26]2015HoBACase series31MultipleRUCAMNA
Prado et al[27]2019ABAPC149Nimesulide, budesonide and valacyclovirRUCAM2.0%
Antonello et al[55]2014HoRSPC65ARVNo45.0%
Tovo et al[47]2006HoRSPCCI 385 MI 198ARVNoCI 57.8% MI 13.0%
Kondo et al[49]2008APRRC157NevirapineNo4.0%
Gil et al[48]2007ASPCross-cut152Tuberculostatic ARV and sulfonamidesNo19.7%
Tomich et al[77]2015HoSPRC149Tuberculostatic, ARV among others1No22.1%
Santos et al[23]2019HoRJPC45TuberculostaticNo13.0%
Monteiro et al[25]2012ARJPC177TuberculostaticRUCAM33.3%
Gusmão Filho et al[43]2001HoPERC52RHZ/ RHE/No35.6%
Lima Mde et al[65]2012HoPEControl case156RHZ and RHZENo26.9%
Zaverucha-do-Valle et al[41]2014ARJRC131RHZNo26.7%
Coca et al[73]2010HoMGControl case162RHZNoH3 56.2% and H4 10.4%
de Castro et al[44]2010ARJPC154RHZNo19.5%
Nader et al[45]2010HoRSRC534RHZNo8.8%
Vieira et al[78]2008ASPRC297RHZNo8.1%
de Souza et al[79]1996HoMGPC1096RHZNI6.0%
Fernandes et al[68]2015HoPAPC220RHZ/RHNo14.1%
Brito et al[64]2014ARSPC245RHZ/RHNo6.1%
Schultz et al[46]2014HoRSRC69RifampicinNo33.3%
Santos et al[53]2013APAPC270IsoniazidNo6.5%
Teixeira et al[52]2011ARJControl case167IsoniazidNo16.0%
Szklo et al[67]2007ARJRC40SEO32/EO92No12.5%
Picon et al[66]2002ARSPC78SHE32/HE32/H32No1.3%

Concerning the study design, we identified cohort studies (n = 22), 10 retrospective and 12 prospective, cross-sectional (n = 5), case-control (n = 3), case series (n = 1) studies and randomized clinical trial (n = 1). The studies were performed in outpatient (45%) and hospital settings (55%).

Analyzing the populations, 24 studies investigated patients under treatment for tuberculosis, 7 of them had patients co-infected with HIV, of which 5 had HIV and HCV. We identified studies with patients under treatment for acute myeloid leukemia (n = 2), metabolic syndrome (n = 1), colorectal cancer (n = 1), rheumatoid arthritis (n = 1), ulcerative colitis (= 1) and other unspecific severe disease (n = 1).

The main drugs associated with DILI were: Rifampicin, Isoniazid, and Pyrazinamide (RHZ), Nevirapine; Azathioprine; Fluorouracil; Methotrexate; Leflunomide; Tretinoin; Amphotericin B deoxycholate; and Propylthiouracil.

In four studies, causality algorithms were used to identify the drug responsible for hepatotoxicity. The Naranjo algorithm used generically for adverse drug reactions was used in one study[22-24]; RUCAM, used specifically in liver injury by drugs, was used in tree studies[25-27]. In addition, 22 different criteria for DILI determination were identified, categorized and summarized in Table 2.

Table 2 Criteria used for the definition of liver injury.
Criteria applied for liver injury definitionRef.Condition
Elevated ALT Tovo et al[47], 2006HIV/HCV
ALT > 2 × ULNMonteiro et al[25], 2012TB
ALT > 2.5 × ULNZaverucha-do-Valle et al[41], 2014; Kondo et al[49], 2008TB/smoker; HIV
ALT > 3 × ULNFernandes et al[68], 2015; Santos et al[53] 2013;TB; TB
ALT or AST > 2 × ULNAlves et al[59], 2011; de Castro et al[44], 2010AR; TB/HBV
ALT or AST > 3 × ULNHeinrich[24], 2014; Vieira et al[78], 2008; Uehara et al[76] 2005TB/ indigenous; TB; IMQ
ALT or AST > 3 × or BT > 1.5 ×Schultz et al[46], 2014TB/TX
ALT > 3 × ULN; BT > 2 ×Brito et al[64], 2014; Nader et al[45], 2010TB/HCV
ALT or AST > 3 × ULN; BT > 2 ×Lima Mde et al[65], 2012; Picon et al[66], 2002TB/HIV; TB
ALT ≥ 5 × LSN ou FA ≥ 2 × LSN ou ALT ≥ 3 × ULN e BT ≥ 2 × LSNPrado et al[27], 2019Gastro-hepatology conditions
(1) ALT > 3 × lower limit of normality; (2) ALT > 3 × ULN; (3) ALT > 3 × ULN and BT > 2 × ULNCoca et al[73], 2010TB/HIV
ALT or AST: (1) 1.25 a 2.5 × ULN; (2) 2.6 a 5 × ULN; (3) 5.1 a 10 × ULN; (4) > 10 × ULNAntonello et al[55], 2014HIV
ALT or AST: (1) 1.25 a 2.5 × ULN; (2) 2.6 a 5 × ULN; (3) 5.1 a 10 × ULN; (4) > 10 × ULN or BT – (1) 1.1 a 1.5 × ULN; (2) 1.6 a 2.5 × ULN; (3) 2.6 a 5.0 × ULN; (4) > 5.0 × ULNTomich et al[77], 2015TB/HIV
Altered ALT or AST (hepatotoxicity) and ALT or AST > 5 × (hepatitis)Gusmão Filho et al[43], 2001TB/children
ALT or AST > 3 × ULN and hepatitis syndromesTeixeira et al[52], 2011TB
AST > 3 × ULN and hepatitis syndromesSzklo et al[67], 2007TB/previous liver injury
Altered ALT, AST, AP or BTde Souza et al[79], 1996TB
Increase in liver function testsde-Medeiros et al[75], 1998LMA
Histological assessmentsSantos[63], 2013QT/HPTC
AST or ALT: (1) 1.1-4.9 × ULN; (2) 5.0-9.9 × ULN; (3) 10.0-15.0 × ULN; (4) > 15.0 × ULNGil et al[48], 2007HIV/child/adolescent
ALT > 2 times ULN or the ALT/AP ratio ≥ 5 or AP > 2 times ULN ALT/AP ratio ≤ 2 or ALT > 2 times ULN and ALT/AP ratio between 2 and 5Magalhães[26], 2015Several
ALT ou AST > 2 × LSN e BT > 1.3 mg/dLSantos et al[23], 2019TB
NISilva et al[22], 2019; Carvalho et al[74], 2014; Werner et al[61], 1989IBD; Ulcerative colitis; Grave’s disease

Concerning studies evaluating DILI-related outcomes (n = 16), only one did not require drug suspension or dose adjustment; one case progressed to chronic hepatitis and one reported the need for liver transplantation according to data presented in Table 3. A summary of the Brazilian studies and their findings is shown in Table 4.

Table 3 Main outcomes related to drug-induced liver injury in Brazilian studies.
Ref.DILI outcomesMedications
Santos et al[23], 20196 Cases were resolved after the suspension of medicationsTuberculostatic
Magalhães[26], 201521 Cases were resolved after the suspension of the substance, but without the use of medications; 9 cases were resolved with the suspension of the substance associated with medications; 1 case with acute hepatic failure, requiring liver transplantationIsoniazid, valproic acid, amitriptyline, cyclosporine, clozapine, dasatinib, imatinib, ACO, simvastatin, melphalan, and others
Antonello et al[55], 2014There was no need to suspend or change the treatmentARV
Kondo et al[49], 20087/157 Patients (4.4%) were hospitalized and, after discontinuation of Nevirapine, all presented clinical and laboratory improvementNevirapine
Brito et al[64], 2014Changed therapeutic regimen in all who developed DILI 15/245 (6.1%)RHZ
Lima Mde et al[65], 2012Drug maintenance 26/156 (16.6%), temporary interruption 12/156 (7.7%), treatment change 11/156 (7%), suspension of medications TB 7/156 (4.5%)RHZ, RHZE
Coca et al[73], 2010Medication suspended in 7/30 (23.3%) HIV and 15/132 (11.4%) non-HIVRHZ
Vieira et al[79], 2008There was a need to modify the treatment regimen in 11/24 (45%) of the patientsRHZ
Picon et al[66], 2002RHZ: 45 cases changed treatment; SHM: 1 case changed treatmentRHZ, SHM
Gusmão Filho et al[43], 20013/52 (5.76%) Required replacement of the medication. In 16/52 (30.7%) there was no need for intervention and in other 13/52 (25%) only the doses of Isoniazid and Rifampicin were changedRHZ, RHE
de-Medeiros et al[75], 1998Medication was suspended and 1/37 (2%) patient was excluded from the RCTTretinoin
Alves et al[59], 2011Medication doses were temporarily reducedMTX
Prado et al[27], 2019The culprit drug was discontinued, and drug therapy was not necessary to resolve the problem in 3 patientsNimesulide, budesonide, valacyclovir
Werner et al[61], 1989There was clinical and laboratory Improvement with the suspension of the medication in 4/389 (1%) and 1/389 (0.25%) evolved to chronic hepatitisMethimazole, Propylthiouracil
Table 4 Summarization of the Brazilian studies according to the drugs evaluated.
Summary of Brazilian researches
Santos et al[23], 2019TuberculostaticsPatients with the CYP2E1 variant genotype or Null GSTT1 showed higher risk of presenting DILI. Individuals with both genotypes had no increased risk compared to individuals with one genotype
Prado et al[27], 2019Nimesulide, budesonide, valacyclovirThe present prospective study allowed reporting new cases of DILI in 2% outpatients. It also allowed estimating the incidence of hepatotoxicity induced by allopathic medicines, which are standardized by public healthcare authorities
Silva et al[22], 2019MTXThe frequency of drug hepatotoxicity was about 2% of hepatobiliary disorders in inflammatory bowel disease patients
Fernandes et al[68], 2015RHZAn association founded between the 516 TT polymorphism and drug-induced hepatotoxicity
Tomich et al[77], 2015Tuberculostatics ARV, sulfonamide drugs, statins, imidazoles anticonvulsants, non-steroidal anti-inflammatoryIn HIV patients admitted to a tertiary hospital, it was found a high incidence (22.1%) of severe DILI. The use of anti-tuberculosis drugs and baseline liver injury were independent factors associated with severe DILI during a hospital stay
Magalhães[26], 2015VariousHepatotoxicity caused by a wide variety of medicines, plant supplies, and dietary supplements. Anti-infectives and chemotherapeutics were responsible for most reactions, in 41% and 19% of cases, respectively. There is a shortage of records in information records to evaluate the causality of reactions
Antonello et al[55], 2014ARVThe coinfected patients are at an increased risk for developing hepatotoxicity, but the clinical and immunological benefits of highly active antiretroviral therapy are higher than the risk of hepatotoxicity and rarely justify discontinuation of therapy
Heinrich[24], 2014TuberculostaticsAge over 60 year old, the time after the start of treatment (15 d) and being indigenous (Brazilian native American) are risk factors for the development hepatotoxicity during treatment of TB
Zaverucha-do-Valle et al[41], 2014RHZThe anti-TB drugs interactions with smoking on hepatotoxicity, as well as the NAT2 phenotype, may require adjusting therapeutic regimen dosages or alarm in case of adverse event developments
Schultz et al[46], 2014RifampinThe use of rifampin at daily doses of 600 mg or higher and lung transplantation founded to be an independent risk factor for liver toxicity in solid organ transplants recipients. Kidney transplantation appeared as a protective factor. Mortality was higher in the patients who had hepatotoxicity (43.5%), compared with those who did not
Brito et al[64], 2014RHZClinical (HIV, female and extrapulmonary TB) and genetic characteristics (CYP2E1 without any mutations, having NAT2 slow acetylator profile) are at higher risk of developing DILI in this population. Genotyping for glutathione S-transferase GSTM1 and GSTT1 showed no influence on drug response
Santos et al[53], 20135-fluorouracilPatients exposed to chemotherapy have a 2.2-fold increase in the risk of developing hepatic steatosis
Santos et al[63], 2013IsoniazidLarge-scale screening for NAT2 and CYP2E1 genotypes can prove useful in predicting the risk of adverse effects
Monteiro et al[25], 2012TuberculostaticsGSTM1 and GSTT1 null genotypes do not seem to play important roles in DILI in Brazilians. However, there was evidence that GSTM1 polymorphisms were possibly related to the intensity of toxicity. Active HBV and initial high ALT could predict DILI
Lima Mde et al[65], 2012RHZ, RHZEThe absence of hepatotoxicity was a protective factor against death. Coinfection with the B and C hepatitis virus and a T CD4+ cell count below 200 cells/mm3 were independent risk factors for hepatotoxicity in these patients
Teixeira et al[52], 2011IsoniazidSlow acetylators had a higher incidence of hepatitis than intermediate/rapid acetylators. Slow acetylation status was the only independent risk factor for the occurrence of anti-TB drug-induced hepatitis during anti-TB treatment with INH-containing schemes in Brazilian individuals
Alves et al[59], 2011MTX, LeflunomideThere was no difference between the elevation of aminotransferases in patients treated with MTX alone or with combined therapy
Coca et al[73], 2010RHZDepending on the definition of drug-induced hepatitis, HIV infection may or may not be associated with hepatotoxicity. The impact that minor alterations in the definition had on the results was impressive. The emergence of new symptoms after initiating antituberculosis therapy could not be attributed to hepatotoxicity in over one-third of the cases
Nader et al[45], 2010RHZThe anti-HIV drugs and high doses of isoniazid were considered independent risk factors for hepatotoxicity due to RHZ regimen in this study. Though univariate analysis showed that anti-HCV drugs was associated with the outcome, it was not identified as an independent risk factor for hepatotoxicity related to the use of RHZ when the analysis controlled to HIV
de Castro et al[44], 2010RHZActive HBV, indicated by the detection of surface antigen HBV, could predict hepatotoxicity, although with low precision
Vieira et al[78], 2008RHZThe frequency of adverse effects related to the treatment of tuberculosis with RHZ was 49.1% in this group of patients. However, in most cases, there was no need to modify the treatment regimen due to adverse effects
Kondo et al[49], 2008NevirapineThere was no correlation between high CD4 counts and adverse events when skin and hepatic reactions were analyzed together. However, hepatotoxicity occurred only in pregnant women with a CD4 count of ≥ 250 cells/μL
Szklo et al[67], 2007SEO3/EO9In this series of TB patients with serious liver injury, 3SEO/9EO was well tolerated, and it was effective in 85% of patients when used under routine clinical care conditions
Gil et al[48], 2007tuberculostatics, ARV, sulfonamide drugsOne-fifth of patients experienced mild hepatotoxicity, attributed to antituberculosis agents and sulfonamides. Our results suggest that the ARV was well tolerated
Tovo et al[47], 2006ARVThere was no difference between the groups concerning the type of ARV used, as well as cases of hepatotoxicity attributed to PI. There was no difference concerning tolerability to PI between the two groups
Picon et al[66], 2002SHE3/HE3/H3Streptomycin, isoniazid, and ethambutol regimen may be recommended as an alternative for the treatment of tuberculosis whenever the RHZ regimen cannot be indicated
de Souza et al[79], 1996RHZLiver changes characterized as of small and medium intensity translated as pure cholestasis or hepatocanalicular hepatic reactions. Possibly Rifampicin was important in this evolution, acting as a potentiator of the actions triggered by isoniazid and pyrazinamide
Werner et al[61], 1989PropylthiouracilThe adverse effects of thionamide drugs were similar in both high- and low-dose regimens. These undesirable effects demand a strict follow-up, as well as the high dose regimen for Graves' disease treatment particularly advised for patients with severe symptoms

Some systematic reviews about DILI[28-31] can be found in the literature, but none in the Brazilian studies. The hepatotoxicity frequency ranged from one to 57%; however, as these studies investigate specific populations, these data do not allow to infer the frequency of DILI or to generalize the findings. The drugs with the highest number of reports were those with known hepatotoxic potential, such as isoniazid, pyrazinamide, and rifampicin, nevirapine[9].

The low incidence of DILI makes it difficult to develop prospective cohort studies, which would be more robust in verifying the causality between the drug and liver damage. In this review, one-third of the studies were prospective. The low frequency of clinical trials with hepatotoxicity data, attributed to the low number of clinical trials exclusively in the Brazilian population, is noteworthy. Clinical trials are not the best study design to assess drug safety, in addition to involving the potential of conflict of interests. Therefore, the cohort study is the ideal design for detecting ADRs, since it frequently reveals toxicities undetected in clinical trials.

Pharmacovigilance studies may be alternatives for better knowledge about DILI, but when coming from spontaneous reports they have the underreporting bias[32]. A Brazilian study found only ten cases of hepatotoxicity by herbal medicines from notification data of the regulatory agency, in a 10-year interval. Two cases developed acute liver failure and died, both of which reported the use of kava[33]. Liver transplantation was recently performed by kava in Brazil[34]. Through RUCAM it was considered probable, therefore it was possible to exclude extrinsic toxicity and contaminants after performing chemical analyses of the drug used. In this way, the pharmacovigilance studies associated with the appropriate technical support should be stimulated to facilitate the detection and elucidation of the cases.

The DILI studies were concentrated in the southern and southeastern regions of Brazil. In addition, most of the studies were conducted by research groups linked to academic centers. In Brazil, the continental dimension, the large population, and the great cultural diversity make it difficult to carry out a single representative study in the country. For this reason, it is important to encourage further regional studies.

Most Brazilian studies on drug-induced liver injury investigate population groups using drugs for the treatment of infection and chronic diseases–whose ambulatory therapy is provided by the Unified Health System–such as Tuberculosis, HIV, Rheumatoid Arthritis, Ulcerative Rectocolitis, and Acute Myeloid Leukemia. Public health policies like specialized care offered by these lines of care, and the clinical protocols and therapeutic guidelines are technologies that seem to be effective in the prevention and the management of these ADRs. Whereas the hepatotoxic potential is foreseen in the guidelines, a structured information technology and resources for monitoring pharmacotherapy are required for the operations of these services. The well-structured care line makes it possible to gather a large volume of data at the national level. Professional performance in the care lines also plays a role in training and research, enabling the formation of research groups. This impulse in scientific production seems to be able to influence the existing evidence at the national level.

Some risk factors were associated to DILI such as previous liver disease, immune dysfunction, diabetes, hypertension, alcohol consumption, gestation, female age, advanced age, polymedicine, dose and lipophilicity of the drug, among others[1,35,36]. The female gender was associated with the occurrence of hepatotoxicity with tuberculostatic drugs[10,37-39], but Brazilian studies, as well as in a Peruvian study[40], have shown a lower frequency of DILI in women. In the population with TB, unexpectedly, a higher prevalence of DILI was found in nonsmoking patients when compared to smokers; however, it was argued that the genetic profile of the sample could have influenced the result[41]. No further development of DILI in advanced age was found, unlike in international studies[5,10,42], but it is suggested that the specificity of the populations studied cannot be comparable. A differential factor in Brazilian studies is the frequent profile of infectious diseases. American and European studies generally present populations with chronic diseases. Therefore, the frequency of DILI related to certain drugs may change regionally according to the characteristics of the populations studied and the profile of drug use. Some authors have studied specific populations taking tuberculostatic drugs, such as Brazilian native Americans[24], children[43], hepatitis B[44], hepatitis C[45], solid organ transplanted patients[46], smokers[41], HCV/HIV coinfected[47], and antiretroviral (ARV) in children and adolescents[48] and nevirapine in pregnant women[49].

This review found that when patients using RHZ were analyzed the frequency ranged from 6% to 14%; however, some characteristics such as HIV infection, alcohol use, and polypharmacy were present and may have contributed to the frequency found. Some studies were developed from the analysis of drugs prescription. The DILI frequency by the drug was estimated. The number of prescriptions by a number of exposed users further the DILI frequency. In a study of hospitalized patients, the risk of developing DILI for erythromycin was 14 per 100000 prescriptions, penicillin had a risk of 10.9 per 10000 users of the drug[50]. Another study found DILI risk around 1 per 1000 users for chlorpromazine, azathioprine, and sulfasalazine[51]. Two Brazilian studies attributed RHZ hepatotoxicity more specifically to isoniazid[52,53]. In a United Kingdom study, Isoniazid, together with chlorpromazine, was associated with a DILI risk of 100/100000 users[54].

Considering the ARVs, nevirapine, abacavir, and ritonavir are the main hepatotoxic agents[47,55]. The information regarding the hepatotoxicity of ARVs is known and presented in the Brazilian clinical protocol for the management of HIV in adults. In addition, in the mentioned protocol there is a classification of the severity of hepatotoxicity according to the levels of transaminases[56,57]. In relation to TB treatment, the most reported was the basic regimen with RHZ for 2 mo, followed by Rifampicin and Isoniazid for 4 mo. Since 2009, ethambutol has been added to this treatment regimen. Known as a quadruple regimen, one tablet has all four drugs to facilitate adherence to treatment, but in the case of hepatotoxicity, there is no way to identify which drug is responsible[58]. In general, co-infection with HIV and TB seems to be one of the situations that draw the most attention to the monitoring of hepatotoxicity, since both treatments are complex and contain drugs with potential for hepatotoxicity. Both protocols emphasize the need for caution in the administration of the two concomitant therapies. Few serious outcomes were found in this review, perhaps because in most cases the suspension or change of the drug was clinically sufficient for regression of the injury. The structuring of specialized centers, the development of clinical protocols and efficient pharmaceutical assistance seems to have been essential for the monitoring, knowledge, and management of adverse drug reactions in these patient groups.

Some studies compared different treatment regimens or combinations compared to monotherapy with drugs of known hepatotoxic potential, in order to establish a safety relation in its use. In one of the Brazilian studies of patients with rheumatoid arthritis, the use of methotrexate (MTX) or MTX associated with leflunomide had no significant difference in DILI[59]. An Argentine study in rheumatoid and psoriatic arthritis found a higher incidence of DILI in NSAIDs, whereas MTX was responsible for steatosis, but without the need to interrupt treatment[60]. Although MTX is a drug known to be hepatotoxic, it has been shown to be safe in association with leflunomide. However, monitoring of hepatic enzymes and liver function seems to be important in patients treated with other hepatotoxic drugs. In patients with Graves’ disease treated in groups with propylthiouracil or methimazole at high or low doses, there was no difference in hepatotoxicity between the groups[61]. However, several cases have been reported, with the most serious cases being children and adolescents who show a frequency of acute liver failure of 1:2000 children[62]. In both studies, the safety profile for hepatotoxicity was evaluated, however, in the treatment of chronic diseases, safety should also be evaluated in the long term, in this case only cohorts with long follow-up, and pharmacovigilance studies can establish a long-term safety profile.

Amoxicillin with clavulanate leads the cases of DILI in the United States, Spain, France, and Iceland[4,5,8,42]. Drugs such as antimicrobials, non-steroidal anti-inflammatory, and other chronic medications have demonstrated a high DILI index in the world, but its prevalence of toxicity in the Brazilian population is not known[9]. However, in a case series study, anti-infective were the main hepatotoxic drugs, followed by chemotherapies[26]. Santos[63] described that patients with metastases in colorectal cancer, who underwent hepatectomy and underwent chemotherapy, had a 2.2-fold increased risk of hepatic steatosis. The most commonly reported antineoplastic drugs are immunobiological drugs, such as imatinib, and hormone antagonists, such as cyproterone and tamoxifen, but irinotecan also appears in the list of most commonly reported. However, it is hard to define the causality of antineoplastic agents when there is hepatic metastases[9].

In HIV-positive patients, HCV coinfection increased the risk of liver damage but did not justify the suspension of ARVs, as well as the use or not of protease inhibitors, which had no significant difference between monoinfected and coinfected[47,48,55,63]. In a study that evaluated the population using TBS, independent risk factors for the development of DILI were considered: age above 60 years, the first 15 d of treatment, extra pulmonary TB, HCV/HBV coinfection, CD4 count < 200 μL cells, being indigenous[28,64,65]. In a study with transplant patients, doses of rifampicin above 600 mg and lung transplantation were found to be risk factors for DILI, just as kidney transplantation seemed to act as a protective factor[46]. Two studies have demonstrated the safety of alternative TB regimens after the previous hepatotoxicity; the association of streptomycin, ofloxacin, and ethambutol for three months followed by another nine months with ofloxacin and ethambutol, and the association of streptomycin, ethambutol, and isoniazid for three months followed by ethambutol and isoniazid three months and isoniazid three months[66,67].

Some lines of Brazilian research have evaluated the genetic profile associated with the development of DILI with tuberculostatics. The CYP2B6 gene had the 516 TT polymorphism associated with DILI[68]. Genotypes of CYP2E1 and CYP3A4 were not associated with hepatotoxicity; when different acetylators of NAT2 were analyzed, slow acetylators had an increased risk of DILI[41,52,64]. Another study defined the genetic profile of NAT2 and CYP2E1 as predictors of the development of adverse reactions with isoniazid[53,65]. In two studies, glutathione S transferase genotypes were not associated with the development of DILI[25,64]. Thus, it can be seen that the development of DILI has been investigated at the molecular genetics level, and Brazil has conducted important studies on the knowledge of the variants in its population.

The causality algorithms for the identification of adverse reactions are tools that help in the detection and classification of the suspicious factor probability. Only four studies reported using an algorithm. The Naranjo algorithm was one of the precursors, but its general character does not allow contemplating the specificity of DILI[69]. The RUCAM was the first and most widely used algorithm specific for DILI. Subsequently, others emerged, such as Maria and Vitorino, Drug-induced Liver Injury Network and Digestive Disease Week Japan Scale[8,51,70,71]. Algorithms are great tools for prospective data analysis. However, its validity for retrospective studies is questionable because registry biases may compromise the validity of the result[7]. The fact that there is low frequency use of these tools makes it possible to launch some hypotheses. Are researcher’s unfamiliarity regarding algorithms? Or do they think that it is hard applying them? This gap found in Brazilian studies cannot be easily answered. The use of algorithms in clinical practice is often unfeasible since they require considerable time for their application in addition to an excess of information or exams sometimes unavailable or considered unnecessary. However, in the field of research it would be very important that the algorithms were widely used tools to determine the causality of the liver injury. In addition to greater reliability of the results, would improve data quality, which would make possible to classify the liver injury and improve the knowledge of the outcomes.

Twenty-two different strategies in the definition of liver injury were found, and also made it difficult to compare the findings. HIV Research Groups consider the guideline of the AIDS Clinical Trials Group to grade the hepatic lesion according to the transaminase value range[56]. Studies with TB often follow the standards of the II Brazilian Consensus on Tuberculosis[72]. The RUCAM algorithm performs the best definition, which is the most internationally accepted standard in the determination of liver damage by drugs or plants[7].

However, in Brazil the divergences of the guidelines promoted by the public policies hinder the formation of a national database on hepatotoxicity. The concept of hepatic injury adopted is decisive in the study findings, as indicated in a study comparing three different DILI criteria in HIV patients; in these patients, DILI may be undetectable or may affect up to 77% depending on the criteria adopted[73]. This study reinforces the need for standardization of the definition of drug-induced liver injury in Brazil, also in national guideline with tools like RUCAM. The follow-up of patients undergoing treatment for chronic diseases should include the identification of adverse drug reactions and the reporting of adverse drug reactions when suspected. Monitoring of ADRs is essential to establish the safety profile of medicines during their marketing. Encouraging the use of this resource will be important to improve not only the criteria but also the definition of causality in cases of DILI[74-79].

This review had as a limitation the impossibility of inferring a frequency of DILI in Brazilian studies through meta-analysis since few of the studies found were performed aiming to determine liver injury as well as the high heterogeneity found. In this sense, all studies with hepatotoxicity data were included. The studies included with few or incomplete data could result in low quality of evidence, but due to the scarcity of Brazilian studies, we decided to maintain them. The quality of the studies included in the review was not evaluated. Due to the impossibility of performing a meta-analysis, this study aimed to have an exploratory and baseline character for future studies in the area. Retrospective studies are biased by the lack of available information, and some studies have not used criteria for the identification of drug-induced liver injury. Despite these limitations, the studies included in this review have contributed to learn more about achievements and challenges in Brazilian DILI’s researches. The DILI’s evidence in Brazil has been strongly influenced by public health policy. However, this relationship between health policies and evidence must be reversed with the evidence guiding public health policies.


The drugs associated with liver injury reported in the Brazilian studies were Isoniazid, Rifampicin and Pyrazinamide, Nevirapine, in addition to methotrexate, propylthiouracil, azathioprine; the Brazilian studies published on DILI investigate specific populations with chronic use of drugs, mainly tuberculostatic and antiretrovirals. These patients are included in priority health policies of care, which favors the detection of DILI and the proper management of the patient, reducing the frequency of more severe outcomes. The diversity of methods and criteria for the definition of hepatotoxicity did not allow obtaining frequency estimates. The standardization of criteria for identification of drug-induced liver injury and greater effort in pharmacovigilance could contribute to the knowledge on the injury as well as on the safety profile of drugs marketed in Brazil. This research is expected to broaden the debate to establish a solid pharmacovigilance policy and the creation of a wide national DILI monitoring network and his integration with other DILI networks. Finally, bringing together experiences and cases bringing doctors, pharmacists, industry and patients closer together.

Research background

Drug-induced liver injury (DILI) is the main cause of safety-related drug marketing withdrawals and could increase costs and morbidity in the health system. DILI identification is a challenge due to the diversity of drugs with hepatotoxic potential, the lack of symptoms specificity, and the absence of specific biomarkers in the clinical practice.

Research motivation

Identify and summarize Brazilian studies reporting the drug-induced liver injury.

Research objectives

The aim of this study was to know the profile of DILI in Brazil. A systematic review of Brazilian DILI studies was carried out until June 2020. It was found 32 studies, being 10 retrospective cohorts, 12 prospective cohorts, 5 cross-sectional, 3 case-control, one case series and one randomized clinical trial. Tuberculosis, human immunodeficiency virus and hepatitis C virus patients were the mainly group investigated the hepatotoxicity rate ranged from one to 57%, led by isoniazid, rifampicin, and pyrazinamide. Few studies reported algorithm to assess causality Drug interruption and moderate outcomes are report in the most of studies. Severe outcomes, such as chronic liver damage and liver transplantation were reported in some studies.

Research methods

It was found 32 studies, being 10 retrospective cohorts, 12 prospective cohorts, 5 cross-sectional, 3 case-control, one case series and one randomized clinical trial. In most studies were investigated tuberculosis patients followed by other infectious conditions like human immunodeficiency virus (HIV) and hepatitis C virus. The hepatotoxicity ranged from one to 57%, led by isoniazid, rifampicin, and pyrazinamide. Few studies reported algorithm to assess causality. In most studies, there were moderate outcomes and it was necessary drug interruption. However, few severe outcomes, such as chronic liver damage and liver transplantation were reported.

Research results

DILI could be caused both by non-prescription drugs and by those used for chronic diseases. The diagnosis and notification of the DILI cases are of great importance for the early detection and reduction of damages to the patients.

Research conclusions

Twenty-two different criteria for hepatotoxicity were found. Standardization of parameter of drug-induced liver injury and greater effort in pharmacovigilance could contribute to learn more about DILI's epidemiology in Brazil.

Research perspectives

This research is expected to broaden the debate to establish a solid pharmacovigilance policy and the creation of a wide national DILI monitoring network and his integration with other DILI networks. Finally, bringing together experiences and cases bringing doctors, pharmacists, industry and patients closer together.


Manuscript source: Invited manuscript

Specialty type: Gastroenterology and hepatology

Country/Territory of origin: Brazil

Peer-review report’s scientific quality classification

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P-Reviewer: Di Pasqua LG, Pavlovic M, Volynets GV S-Editor: Zhang L L-Editor: A P-Editor: Liu JH

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