Systematic Reviews
Copyright ©The Author(s) 2021.
World J Gastrointest Pharmacol Ther. May 5, 2021; 12(3): 40-55
Published online May 5, 2021. doi: 10.4292/wjgpt.v12.i3.40
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%
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
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