Table S1 Characteristics of Studies on Non-Genetic Risk Factors of ATDH
Table S1 Characteristics of studies on non-genetic risk factors of ATDH
Study(Reference) / Ethnicity / Design / Patients / Sample size(Total(case)) / Incidence rate (%) / Drugs / Diagnosis
(Babalik et al. 2012) / Turkish / Cohort / TB / 1443(106) / 7.3 / INH+RMP+PZA+EMB+/SM / AST/ALT>3×ULN, TBIL>1.5mg/dL, any increase in AST and/or ALT compared to pre-treatment levels accompanied with anorexia, nausea, vomiting, and jaundice; absence of serologic evidence of infection with hepatitis virus
(Baghaei et al. 2010) / Mixed / Case-control / TB / 99/662 / - / INH+RMP+PZA+EMB / NR
(Chang et al. 2008) / Chinese / Cohort /nested case-control / TB / 3007(150) / 5 / INH+RMP+PZA / ALT>3×ULN in the absence of alternative clinical diagnoses
(Chien et al. 2010) / Chinese / Cohort / TB / 295(25) / 8.5 / INH+RMP+PZA+EMB / ALT and/or AST⩾5×ULN without symptoms
(de Castro et al. 2010) / Brazilian / Cohort / TB / 154(30) / 19.5 / INH+RMP+PZA / ALT>2×ULN (ALT⩾45IU/L)or at least a two-fold increase in ALT initial levels for those patients with a baseline ALT>90 IU/L.
(Dossing et al. 1996) / Caucasian / Cohort / TB / 752(61) / 8.1 / INH+RMP+PZA+EMB / AST>2×ULN
(Feng et al. 2014) / Chinese / Case-control / TB / 173/173 / - / INH+RMP+PZA / Serum transaminase>3×ULN and symptoms compatible with hepatitis
(Fernandes et al. 2014) / Brazilian / Cohort / TB / 220(31) / 14.1 / INH+RMP+PZA / ALT>3×ULN
(Fernandez-Villar et al. 2004) / Caucasian / Cohort / TB / 471(35) / 7.4 / INH+RMP+PZA+EMB+/SM / AST and/or ALT>3×ULN or with hepatitis symptoms such as anorexia, nausea or vomiting, or abdominal pain
(Fountain et al. 2005) / Mixed / Cohort / TB / 3377(19) / 0.6 / INH at least / AST>5×ULN
(Gordin et al. 2004) / Mixed / RCT / TB+HIV / 1583（18/27） / - / INH (791)or RMP+PZA(792) / Increase in bilirubin level by ⩾0.5 mg/dL or Increase in AST level by⩾40 U/L
(Ho et al. 2009) / Chinese / Cohort / TB / 1191(134) / 11.3 / INH+RMP+PZA+EMB+/SM / Transaminase levels >3×ULN in the presence of symptoms such as anorexia, nausea, vomiting, or abdominal pain or transaminase levels >5×ULN without symptoms
(Horita et al. 2013) / Japanese / Cohort / TB inpatients / 346(37) / 10.7 / INH+RMP+PZA+EMB or INH+RMP +EMB / Transaminase levels >3×ULN with jaundice and/or hepatitis symptoms, or transaminase levels >5×ULN
(Hwang et al. 1997) / Chinese / Cohort / TB / 240(63) / 26.3 / INH+RMP+PZA+EMB / (1) serum anti-HAV IgM, anti-HBcIgM and anti-HCV were negative during serum ALT elevation; (2) causality assessment from the time of drug administration to the apparent onset of serum ALT elevation fulfilled the criteria of suggestive or compatible adverse drug reactions; and (3) other possible causes of liver injury were excluded
(Kato et al. 2013) / Japanese / Cohort / TB+elevated bilirubin / 356(16) / 4.5 / INH+RMP+PZA+EMB / Transaminase levels >3×ULN with jaundice and/or hepatitis symptoms, or transaminase levels >5×ULN; or TBIL level⩾2.0 mg/dL, regardless of the level of transaminase.
(Lee et al. 2002) / Mixed / Cohort / LTBI / 148(14) / 9.5 / RMP+PZA / AST/ALT>5×ULN
(Lee et al. 2005) / Korean / Case-control / TB+/HBV / 110/97(13DIH) / - / INH+RMP +EMB+/PZA / transaminase level > 120 IU/L
(Lima Mde and Melo 2012) / Brazilian / Case-control / TB+HIV / 156(57) / - / INH at least / (1) jaundice,whether associated or not with symptoms suggestive of hepatitis, including nausea, vomiting, anorexia, asthenia or pain in the upper right abdominal quadrant; (2) ALT/AST >3×ULN; (3) TBIL>2×ULN.
(Lobato et al. 2005) / Mixed / Cohort / LTBI / 715(78) / 10.9 / RMP+PZA / AST>2.5×ULN
(Lomtadze et al. 2013) / Caucasian / Cohort / TB+/HCV / 288(54) / 18.8 / INH+RMP+PZA+EMB / An increase in 1 or more grades from baseline ALT level (during any of the 6 monthly follow up visits).
(Mankhatitham et al. 2011) / Thai / RCT / TB+HIV / 134(46) / - / INH+RMP+PZA+EMB+ ART / An elevation in serum AST or ALT level from the normal range
(Mansukhani and Shah 2012) / Indian / Cohort / TB children / 46(7) / 15.2 / INH+RMP+PZA+EMB / SGPT>3 normal value of baseline
(Marra et al. 2007) / Mixed / Cohort / TB / 1061(148) / 13.9 / INH+RMP+PZA+EMB / AST>3×ULN in the presence of gastrointestinal symptoms or AST>5×ULN in the absence of symptoms
(Marzuki et al. 2008) / Mixed / Case-control / TB / 46/138 / - / INH+RMP+PZA+EMB/SM / AST and/or ALT≥ 120 IU/L and/or an increase in total bilirubin to > 1.5 mg/dL (25 μmol/L) at least five days after starting anti-TB drugs with no other apparent causes of abnormal liver function tests.
(Monteiro et al. 2012) / Mixed / Case-control / TB / 177(59) / - / INH+RMP+PZA+EMB / ALT>2 ×ULN
(Nader et al. 2010) / Brazilian / Cohort / TB / 534(47) / 8.8 / INH+RMP+PZA / ALT>3×ULN and/or TBIL>2×ULN
(Nolan et al. 1999) / Mixed / Cohort / LTBI / 11141(11) / 0.1 / INH / Symptoms of hepatitis; AST>5×ULN with or without elevation of serum bilirubin level
(Ohkawa et al. 2002) / Japanese / Cohort / TB children / 117(8) / 6.8 / INH+RMP+PZA+EMB+SM / AST/ALT>5×ULN
(Pande et al. 1996) / Inidan / Case-control / TB / 86/406 / - / INH+RMP+PZA+EMB+SM / (1) clinical features of icteric hepatitis (anorexia, nausea, and jaundice; (2) SGOT and SGPT>150U/L on three consecutive occasions or >250 U/L on one occasion; (3) serum total bilirubin of >34.2umol/L; and (4) absence of serological evidence of infection with hepatitis virus A, B, or C.
(Park et al. 2010) / Korean / Cohort / TB+chronic liver disease / 107(18) / 16.8 / INH+RMP+PZA / (1) ALP/AST/ALT>3×ULN if the baseline level was normal, or ALP/AST/ALT>1.5×ULN if the baseline level was abnormal, or a Child-Turcotte-Pugh (CTP) score above the baseline score within 2 months of initiation of anti-TB medication; and (2) no other identifiable reason for the above change(s) such as increased HBV or HCV load
(Pukenyte et al. 2007) / Mixed / Cohort / TB+HIV / 144(15) / 10.4 / INH+RMP+PZA+EMB / ALT>5×ULN or >25IU/L, TBIL >32.5mmol/l or >2.5×ULN
(Sadaphal et al. 2001) / Mixed / Cohort / TB+Injection Drug Users / 146(32) / 21.9 / INH+ Vitamin B6 / AST/ALT>3×ULN
(Satyaraddi et al. 2014) / Indian / Cohort / TB / 110(15) / 13.6 / INH+RMP+PZA+EMB / (1) serum aminotransferase levels >5×ULN (50 IU/l) on one occasion or >3×ULN on three consecutive occasions, with clinical symptoms as described; (2) TBIL >2 mg/dl with serum aminotransferases >3×ULN; (3) increase in serum aminotransferase level above pre-treatment values with the presence of all the following symptoms: anorexia, nausea, vomiting, abdominal pain and jaundice
(Senaratne et al. 2006) / Sri Lankan / Cohort / TB / 783(74) / 9.5 / INH+RMP+PZA+EMB / TBLI >1.1 mg/dL or when ALT117 IU/L or both with decreased appetite and nausea or vomiting
(Shakya et al. 2004) / Nepal / Cohort / TB / 50(4) / 8 / INH+RMP+PZA+EMB / (1)ALT and/or AST⩾5×ULN, (2) TBIL >1.5 mg/dL, and (3)any increase in AST and/or ALT levels above pretreatment values together with anorexia, nausea, vomiting, and jaundice.
(Sharifzadeh et al. 2005) / Mixed / Cohort / TB / 112(31) / 27.7 / INH+RMP+PZA+EMB / AST and ALT>3×ULN (40U/L) with any other clinical signs and symptoms
(Sharma et al. 2002) / Indian / Cohort / TB / 346(56) / 16.2 / INH+RMP+PZA+EMB/SM / (1) AST and/or ALT>5×ULN; (2) TBIL>1.5 mg/dl; (3) any increase in AST and/or ALT above pretreatment levels together with anorexia, nausea, vomiting, and jaundice; (4) absence of serologic evidence of infection with hepatitis virus A, B, C, or E
(Shin et al. 2014) / Korean / Case-control / TB+ liver cirrhosis / 50/147(8) / - / INH+RMP+PZA/EMB / ALT > 120 IU/L with hepatitis symptoms or ALT > 200 IU/L
(Shu et al. 2013) / Chinese / Cohort / TB / 926(111) / 12 / INH+RMP+PZA / AST/ALT ⩾ 3×ULN plus clinical symptoms of hepatitis or AST/ALT⩾5 ×ULN with or without symptoms of hepatitis
(Singh et al. 1995) / Indian / Case-control / TB / 60/60 / - / INH+RMP+PZA+EMB+SM+ Cycloserine / Clinical manifestations of hepatitis along with serum aminotransferase levels>2×ULN
(Singla et al. 2010) / Indian / Case-control / TB / 175/428 / - / INH+RMP+PZA / (1) AST and/or ALT>5×ULN on one occasion or AST and/or ALT>3×ULN on three consecutive occasions; (2)TBIL> 1.5 mg/dL; (3) any increase in serum AST and or ALT above pre-treatment values together with anorexia, nausea, vomiting and jaundice; (4) absence of serological evidence of infection with hepatitis viruses A, B, C, or E; and (5) improvement in liver functions (TBIL < 1 mg/dl , AST and ALT <100 ) after withdrawal of anti-TB drugs
(Teleman et al. 2002) / Mixed / Cohort / TB / 1036(55) / 5.3 / INH+RMP+PZA+/EMB+/SM / (1) ALT and/or AST>3 ×ULN, or (2) elevation of serum bilirubin>×ULN and ALT and/ or AST >2 ×ULN
(Ungo et al. 1998) / Caucasians / Cohort / TB / 134(22) / 16.4 / INH+RMP+PZA+EMB / ALT and/or AST > 120 IU/L and/or TBIL> 1.5 mg/dl
(van Hest et al. 2004) / Mixed / Cohort / LTBI / 1104(46) / 4.2 / RMP+PZA or INH or INH+RMP+PZA / Primary: ALT/AST>5×ULN; Secondary: an increase of AST or ALT serum levels from normal to between normal and 5 times the upper reference values
(Wong et al. 2000) / Chinese / Cohort / TB+HBV / 324(48) / 14.8 / INH+RMP+PZA+EMB / ALT>1.5×ULN on at least 2 consecutive occasions within 4 weeks
(Xiang et al. 2014) / Uyghur / Cohort / TB / 2244(89) / 4 / INH+RMP+PZA+EMB+/SM / ALT/AST/bilirubin>2×ULN
(Yee et al. 2003) / Mixed / Cohort / TB / 429(12) / 2.8 / INH+RMP+PZA / Liver transaminases>3×ULN in the presence of symptoms such as anorexia, nausea, vomiting, or abdominal pain, or transaminases>5×ULN without symptoms
(Yimer et al. 2008) / Ethiopian / Case-control / TB+-HIV / 103/94 / - / INH+RMP+PZA+EMB / Biochemical DIH: ALT>3×ULN (31 U/L) and no sign and symptom of DIH; Clinical DIH: biochemical hepatotoxicity plus symptoms of DIH including: nausea, vomiting, weakness and jaundice
(Yimer et al. 2011) / Ethiopian / Cohort / TB+HIV / 353(65) / 18.4 / INH+RMP+PZA+EMB +ART / For patients whose baseline ALT or ALP were below the ×ULN: ALT ⩾×ULN, ALP ⩾2×ULN or ALT⩾3×ULN and total bilirubin ⩾2×ULN;For patients whose baseline ALT or ALP above the ULN: ⩾5 ALT from baseline value⩾2ALP from baseline value or ⩾3ALT from baseline value and ⩾2×ULN total bilirubin
(Yimer et al. 2014) / Ethiopian / Cohort / TB / 1066(159) / 14.9 / RMP and anti-HIV drugs / ALT⩾5×ULN or equal to threefold elevation and TBIL⩾2×ULN
(Zaverucha-do-Valle et al. 2014) / Brazilian / Case-control / TB / 48/79 / - / INH+RMP+PZA / ALT>2×ULN
NR: Not report
Abbreviations：
ALT / Alanine aminotransferase
ART / Antiretroviral therapy
AST / Aspartate transaminase
DIH / Drug-induced hepatotoxicity
EMB / Ethambutol
HBV / Hepatitis B virus
HCV / Hepatitis C virus
HIV / Human immunodeficiency virus
INH / Isoniazid
LTBI / Latent Tuberculosis Infection
PZA / Pyrazinamide
RMP / Rifampicin
SGOT / serum aspartate aminotransferase
SGPT / Serum glutamic pyruvic transaminase
SM / Streptomycin
TB / Tuberculosis
Table S2 Results of studies on non-genetic risk factors of ATDH
Study / RF1 / RF2 / RF3 / RF4 / RF5 / RF6 / RF7 / RF8 / RF9 / RF10 / RF11 / RF12 / RF13 / RF14 / RF15 / RF16 / RF17 / RF18 / RF19 / RF20 / RF21 / RF22 / RF23 / RF24(Babalik et al. 2012) / + / NS / NR / NR / NR / NR / NR / NR / NR / NR / NR / NR / NR / NR / NR / NR / NR / NR / NS / NR / NS / NR / NR / NR
(Baghaei et al. 2010) / + / NS / NS / NR / NR / NR / NR / NR / NR / NR / NR / NR / NR / NR / NS / NR / NR / NR / NS / NR / NR / NR / NR / NR
(Chang et al. 2008) / NS / NS / NS / NR / NR / NR / NR / NR / NR / + / NS / NR / NS / NR / NS / NR / + / NS / NS / NR / NR / NR / + / NR
(Chien et al. 2010) / NS / NS / NR / NR / NS / NS / NR / NS / NR / NS / + / NR / NR / NR / NR / NR / NR / NR / NR / NR / NR / NR / NS / NR
(de Castro et al. 2010) / NS / NS / + / NR / NS / + / NR / NS / NR / + / NS / NS / + / NR / NR / NR / NR / NS / NS / NR / NR / NR / NR / NR
(Dossing et al. 1996) / + / + / NR / NR / NR / NR / NR / NR / NR / NR / NR / NR / NR / + / NR / NR / NR / - / NR / NR / NR / NR / NR / NR
(Feng et al. 2014) / NR / NR / NR / + / NR / NR / NR / NR / NR / NR / NR / NR / NR / NR / NR / NR / NR / + / NR / NR / NR / NR / NR / NR
(Fernandes et al. 2014) / NS / NS / NS / NR / NR / NS / NR / NR / NR / NR / NR / + / NR / NR / NR / NR / NR / + / + / NR / NR / NR / NR / +
(Fernandez-Villar et al. 2004) / NS / NR / NR / NS / + / + / NR / NR / NR / NS / NS / NR / NR / NR / NR / NR / NS / NS / NR / NR / NR / NR / NR / NS
(Fountain et al. 2005) / + / NS / NS / NR / + / NR / NR / NR / NR / NR / NR / NR / NR / NR / NR / NR / NS / NS / NR / NR / NR / NR / NR / NR
(Gordin et al. 2004) / + / - / NS / NR / NR / NR / NR / NR / NR / NR / NR / NR / NR / NR / NR / NR / NR / NR / NR / NR / NR / NR / NR / NR
(Ho et al. 2009) / NS / NS / NR / NS / + / + / NR / NR / NS / NS / NS / NS / NS / NR / NS / NR / NR / NS / NR / NR / NR / NR / + / NR
(Horita et al. 2013) / NS / NS / NR / NR / NS / + / NR / NR / NS / NS / NS / NS / NR / NR / NS / NS / NS / NS / NR / + / NR / NR / NS / NR
(Hwang et al. 1997) / + / NS / NR / NR / NR / NR / NR / NR / NR / NS / NS / NR / NR / NS / NR / NR / NR / NR / NR / NR / NR / NR / NR / NR
(Kato et al. 2013) / NS / NS / NR / NR / NS / NS / NR / NR / NS / NS / NS / NS / NR / NR / NS / + / NS / NS / NR / + / NR / NR / NS / NR
(Lee et al. 2002) / NS / + / NS / NR / NR / NR / NR / NR / NR / NR / NR / NR / NR / NR / NR / NR / NR / NS / NR / NR / NR / NR / NR / NR
(Lee et al. 2005) / NS / NS / NR / NS / NS / NS / NR / NR / NS / NR / NR / NR / NR / NR / NR / NR / NR / NR / NR / NR / NR / NR / NS / NR
(Lima Mde and Melo 2012) / NS / NS / NS / NR / NR / NR / NR / NR / NR / + / + / NS / NS / NR / NR / NR / + / NS / NS / NR / NR / NR / NS / NR
(Lobato et al. 2005) / + / NS / NS / NR / + / NR / NR / NR / NR / NR / NR / NR / NR / NR / NR / NR / NR / NS / NR / NR / NR / NR / NR / NR
(Lomtadze et al. 2013) / NS / NS / NR / NR / NR / NR / NR / NR / NR / NS / + / NS / NR / NR / NR / NR / NR / NS / NS / NR / NR / NR / NR / NR
(Mankhatitham et al. 2011) / NS / NS / NR / NR / NR / NS / NR / NR / NS / NS / + / NS / NS / NR / NR / NR / NR / NR / NR / NR / NR / NR / NR / NR
(Mansukhani and Shah 2012) / + / NS / NR / NS / NR / NR / NR / NR / NR / NR / NR / NR / NS / NS / NR / NR / NR / NR / NR / NR / NR / NR / NR / NR
(Marra et al. 2007) / + / + / NS / NR / + / NR / NR / NR / NR / NS / NS / NS / NS / NR / NR / NR / NR / NR / NR / NR / NR / NR / + / NR
(Marzuki et al. 2008) / NS / NS / NR / NS / NS / NS / NR / NS / + / NS / NR / + / + / NR / NR / NR / NR / NR / NR / NR / + / NR / + / NR
(Monteiro et al. 2012) / NS / NS / NS / NR / NR / + / NR / NR / NR / + / NS / NS / NS / NR / NR / NR / NR / NS / NS / NR / NR / NR / NR / NR
(Nader et al. 2010) / NS / NS / NR / NR / NR / NR / NR / NR / NR / NR / NS / + / NR / NR / NR / NR / NR / NS / NR / NR / NR / + / NR / NR
(Nolan et al. 1999) / + / NS / NS / NR / NR / NR / NR / NR / NR / NR / NR / NR / NR / NR / NR / NR / NR / NR / NR / NR / NR / NR / NR / NR
(Ohkawa et al. 2002) / - / NS / NR / NS / NR / NR / NR / NR / NR / NS / NS / NS / NS / NR / NR / NR / NS / NR / NR / NR / NR / NR / + / NR
(Pande et al. 1996) / NS / NS / NR / NS / NR / NR / NR / NR / NR / NR / NR / NR / NR / + / NR / NR / NR / + / NR / NR / NR / NR / + / NR
(Park et al. 2010) / NS / NS / NR / NR / NS / NS / + / NR / NR / NS / NS / NR / NR / NR / NR / NR / NS / NR / NR / NR / NR / NR / NR / NR
(Pukenyte et al. 2007) / NS / NS / NS / NR / NR / NS / NR / + / NR / NS / NS / NR / NR / NR / NR / NR / NR / NR / NR / NR / NR / NR / NS / NR
(Sadaphal et al. 2001) / NS / NS / NS / NR / NR / NR / NR / NR / NR / NS / NR / NS / NR / NR / NR / NR / NR / + / NR / NR / NR / NR / NR / NR
(Satyaraddi et al. 2014) / NS / + / NR / + / NS / NS / NS / NS / + / NR / NR / NR / NS / NR / NR / NR / NR / NR / NR / NR / NR / NR / NR / NR
(Senaratne et al. 2006) / + / NS / NR / + / NR / NS / NR / NS / NR / NR / NR / NR / + / NR / NR / NR / NS / NS / NR / NR / NR / NR / NR / NR
(Shakya et al. 2004) / NS / NS / NR / NS / NR / NR / NR / NR / NS / NR / NR / NR / NR / NR / NR / NR / NR / NR / NR / NR / NR / NR / NR / NR
(Sharifzadeh et al. 2005) / NS / NS / NS / NS / NR / NR / NR / NR / NR / NR / NR / NR / NR / NR / NR / NR / NR / NR / NR / NR / NR / NR / NR / NR
(Sharma et al. 2002) / + / NS / NR / NS / NR / NR / NR / NR / + / NR / NR / NR / NR / + / NR / NR / NR / NS / NR / NR / NR / NR / NR / NR
(Shin et al. 2014) / NS / NS / NR / NR / NS / NS / NR / NR / NR / NR / NR / NR / NR / NR / NR / NR / NR / NR / NR / NR / NR / NR / NS / NR
(Shu et al. 2013) / + / + / NR / NR / NS / NS / NR / NR / NR / NS / NS / + / NR / NR / NR / NR / NR / NR / NR / NR / NR / NR / NR / NR
(Singh et al. 1995) / NS / NS / NR / + / NR / NR / NR / NR / NR / NS / NR / NR / NR / NR / NR / NR / NS / NS / NR / NR / NR / NR / + / NR
(Singla et al. 2010) / + / NS / NR / + / NS / NS / NS / NS / + / NR / NR / NR / NS / NR / NR / NR / NR / NR / NR / NR / NR / NR / NR / NR
(Teleman et al. 2002) / + / + / NS / NR / NR / + / + / + / NR / NR / NR / NR / NR / NR / NS / NR / NR / NS / NR / NR / NR / NR / NR / NR
(Ungo et al. 1998) / NS / NS / NR / NR / NR / NR / NR / NR / NR / NR / NR / NR / NR / NR / NR / NR / NR / NS / NR / NR / NR / NR / NR / NR
(van Hest et al. 2004) / + / NS / NR / NR / NR / NR / NR / NR / NR / + / NR / NR / NR / NR / NR / NR / NR / NR / NR / NR / NR / NS / NR / NR
(Wong et al. 2000) / + / NR / NR / NR / NR / NR / NR / NR / NR / NR / + / + / NR / NR / NR / NR / NR / NR / NR / NR / NR / NR / NR / NR
(Xiang et al. 2014) / - / - / NR / NR / NR / NR / NR / NR / NR / NR / NR / NR / NR / NR / NR / NR / NR / NR / NR / NR / NR / NR / NR / NR
(Yee et al. 2003) / + / NS / NS / NR / NR / NR / NR / NR / NR / NR / NR / NS / NR / NR / NR / NR / NR / NR / NR / NR / NS / NR / NR / NR
(Yimer et al. 2008) / NS / NS / NR / NS / NR / NR / NR / NR / NR / NS / NS / + / NR / NR / NR / NR / NR / NR / NR / NR / NR / NR / NR / NR
(Yimer et al. 2011) / NR / + / NR / NS / + / NS / NS / NS / NS / NS / NS / NR / NR / NR / NR / NR / NR / NR / NR / NR / NR / NR / NR / NR
(Yimer et al. 2014) / NS / NS / NR / NS / + / NS / NS / + / NS / NS / NS / NR / NR / NR / NR / NR / NR / NR / NR / NR / NR / NR / NR / +
(Zaverucha-do-Valle et al. 2014) / NS / NS / NR / NR / NR / NR / NR / NR / NR / NS / NS / NS / NR / NR / NR / NR / NR / NS / - / NR / NR / NR / NR / NR
+: Positive significant association
-: Negative significant association
NS: Not significant
NR: Not report
Abbreviations for risk factors:
RF1 / Older age / RF13 / Site of TB(Extra-pulmonary)
RF2 / Female sex / RF14 / Extensive TB
RF3 / Race (Wight) / RF15 / Diabetes mellitus
RF4 / Malnutrition / RF16 / Chronic cardiac disease
RF5 / Baseline AST elevation / RF17 / Previous hepatotoxicity or liver disease
RF6 / Baseline ALT elevation / RF18 / Alcohol intake
RF7 / Baseline ALP elevation / RF19 / Cigarette smoking
RF8 / Baseline bilirubin elevation / RF20 / Decreased activity of daily living
RF9 / Baseline albumin decrease / RF21 / High doses of isoniazid
RF10 / HBV infection / RF22 / Pyrazinamide use
RF11 / HCV infection / RF23 / Other drugs intake
RF12 / HIV infection / RF24 / Drug resistance
Table S3Candidate gene studies on associations between polymorphisms of genes and the risk of ATDH
Study(Reference) / Ethnicity / Genes / Cases / Controls / Drugs / Main diagnosis / Genetic risk factor of ATDH
(An et al. 2012a; An et al. 2012b) / Chinese / CYP2E1, NAT2, MonSOD / 101 / 107 / INH+RMP+PZA+EMB / ALT/CBIL>2×ULN or a concurrent increase in AST / Increased risk of ATDH in NAT2 slow acetylators (NAT2*6A/7B and NAT2*6A/6A) and MnSOD 47 C/C genotype
(Ben Mahmoud et al. 2012) / Tunisian / NAT2 / 14 / 52 / INH / ALT>2 ×ULN / Increased risk of ATDH in NAT2 slow acetylators (NAT2*5B/5B, NAT2*6A/6A)
(Bose et al. 2011) / Indian / CYP2E1, NAT2 / 41 / 177 / INH+RMP+PZA+EMB / Liver biochemical parameters>2×ULN / Increased risk of ATDH in NAT2 slow acetylators and the CYP2E1 C/D or C/C genotype together
(Bozok Cetintas et al. 2008) / Turkish / NAT2 / 30 / 70 / INH+RMP+PZA+EMB / ALT/AST>3× or 5×ULN or any bilirubin elevation / Increased incidence of ATDH in NAT2 slow acetylator
(Chang et al. 2012) / Chinese / UGT1A1 / 17 / 81 / At least INH+RMP / ALT>2×ULN or a combined increase in AST/TBIL>2×ULN / Increased risk of ATDH in compound heterozygous UGT1A1*27 and UGT1A1*28 genotypes
(Chatterjee et al. 2010) / Indian / GSTM1, GSTT1 / 51 / 100 / INH+RMP+PZA / ALT⩾3×ULN or TBIL>1.0 mg/dL or ALT<3×ULN but associated with severe anorexia, nausea, vomiting / No risk factors of ATDH
(Chen et al. 2010) / Chinese / CYP2E1 / 103 / 236 / INH+RMP+PZA+EMB / ALT/AST>2×ULN / Increased risk of ATDH in CYP 2E1 7632T/A, 1259G/C and 1019C/T genotypes
(Chen et al. 2014) / Chinese / HLA-DQB1 / 89 / 89 / INH+RMP+PZA+EMB+/SM / ALT>2 ×ULN or a combined increase in AST/TBIL> 2×ULN / No risk factors of ATDH
(Cho et al. 2007) / Korean / CYP2E1, NAT2 / 18 / 114 / INH+RMP+PZA+EMB / ALT >2 ×ULN / Increased risk of ATDH in NAT2 slow acetylator
(Feng et al. 2014) / Chinese / NAT2, CYP2E1, GSTM1, GSTT1 / 173 / 173 / INH+RMP+PZA / Serum transaminase3×ULN and symptoms compatible with hepatitis / Increased risk of ATDH in NAT2 slow acetylator, CYP2E1-1259G>C, -1019C>T wild-type and the GSTM1 null genotype
(Fernandes et al. 2014) / Brazilian / CYP2B6, CYP3A5 / 31 / 189 / INH+RMP+PZA / ALT>3×ULN / Increased risk of ATDH in CYP2B6 rs3745274 T/T genotype
(Guo et al. 2010; Guo et al. 2009) / Chinese / GSTM1, GSTT1, NAT2 / 106 / 106 / INH+RMP+PZA+EMB+/SM / ALT or ALT or IBIL>2×ULN or elevation of ASP, AP and TBIL with one of them>2×ULN / Increased risk of ATDH in GSTM1 null genotype and NAT2 slow acetylator
(Gupta et al. 2013a) / Indian / CYP2E1, NAT2 / 50 / 165 / INH+RMP+PZA+EMB / ALT>2×ULN or a combined increase in AST/TBIL>2×ULN / Increased risk of ATDH in NAT2 slow acetylators
(Gupta et al. 2013b) / Indian / GSTM1, GSTT1 / 50 / 246 / INH+RMP+PZA+EMB / ALT>2×ULN or a combined increase in AST/TBIL>2×ULN or any increase in ALT and/or AST above the baseline leves / Increased risk of ATDH in GSTM1 null genotype alone or in both GSTM1 and GSTT1 null genotypes
(Hao et al. 2011) / Chinese / UGT1A6 / 202 / 239 / NR / ALT>2×ULN or a combined increase in AST/TBIL>2×ULN / Increased risk of ATDH in UGTlA6 -19T/G, -308C/A and -541A/G genotypes
(Higuchi et al. 2007) / Japanese / NAT2 / 18 / 82 / INH+RMP / ALT>2×ULN or a combined increase in AST/TBIL>2×ULN / Increased risk of ATDH in NAT2 slow acetylator (NAT2*6A)
(Ho et al. 2013) / Chinese / NAT2 / 20 / 328 / INH+RMP+PZA+EMB / ALT>5×ULN or ALT>3×ULN with symptoms / Increased risk of ATDH in NAT2 rs1495741 AA genotypes
(Huang et al. 2002) / Chinese / NAT2 / 33 / 191 / INH+RMP+PZA+EMB / ALT >2 ×ULN / Increased risk of ATDH in NAT2 slow acetylator
(Huang et al. 2003) / Chinese / NAT2, CYP2E1 / 49 / 269 / INH+RMP+PZA+EMB / ALT >2 ×ULN / Increased risk of ATDH in CYP2E1 c1/c2 or c2/c2 genotype
(Huang et al. 2007) / Chinese / GSTM1, GSTT1, MnSOD, NQO1 / 115 / 115 / NR / ALT/AST>5×ULN or ALP>2×ULN / Increased risk of ATDH in MnSOD T/C or C/C genotype
(Huang et al. 2011) / Chinese / NAT2 / 119 / 198 / INH at least / ALT >2×ULN / Increased risk of ATDH in NAT2 slow acetylators
(Khalili et al. 2011) / Iranian / NAT2 / 50 / 50 / INH+RMP+PZA+EMB / ALT/AST>2×ULN / No risk factors of ATDH
(Kim et al. 2009; Kim et al. 2012a) / Korean / CYP2E1, NAT2, CYP2C9, CYP2C19, CYP2D6, UGT1A1, UGT1A3, ABCB1, SLCO1B1, ABCC2 / 67 / 159 / INH+RMP+PZA+EMB / ALT >2 ×ULN / Increased risk of ATDH in NAT2 slow acetylators (NAT2*6)
(Kim et al. 2010) / Korean / GSTM1, GSTT1 / 57 / 190 / INH+RMP+PZA+EMB / ALT/AST>3×ULN / No risk factors of ATDH
(Kim et al. 2012b) / Korean / TNF- / 77 / 229 / INH+RMP+EMB+PZA / ALT or AST >3×ULN / Increased risk of ATDH in TNF-
-308G/A genotype
(Lee et al. 2010) / Chinese / CYP2E1, NAT2 / 45 / 95 / INH+RMP+PZA+EMB / ALT >2 ×ULN / Increased risk of ATDH in NAT2 slow acetylators
(Leiro et al. 2008) / Spanish / GSTM1, GSTT1 / 35 / 60 / INH+RMP+PZA / ALT/AST >3×ULN / Increased incidence of ATDH in GSTM1 null genotype
(Leiro-Fernandez et al. 2011) / Spanish / NAT2 / 41 / 58 / At least INH+RMP+PZA / ALT/AST>3×ULN / No risk factors of ATDH
(Li et al. 2012) / Chinese / SLCO1B1 / 155 / 118 / RMP / ALT⩾3×ULN and/or TBIL⩾2×ULN / Increased risk of ATDH in SLCO1B1*15 haplotype
(Liu et al. 2014) / Chinese / GSTM, GSTT1 / 20 / 143 / INH+RMP+PZA+EMB+SM / ALT>2×ULN or DBIL>2×ULN
or increases of AST, ALP and TBIL with one of them>2×ULN; or any index mentioned above>1×ULN and associated with liver damage symptoms, such as skin or sclera yellow dye, severe anorexia, nausea, vomiting, fever, rash, itching. / No risk factors of ATDH
(Lu et al. 2013) / Chinese / GSTM1, GSTT1 / 99 / 25 / NR / ALT >2×ULN or elevation of ASP and ALP with one of them>2×ULN / Increased risk of ATDH in GSTM1 null and GSTT1 null genotypes
(Chen et al. 2015; Lv et al. 2012; Tang et al. 2013a; Tang et al. 2013b; Tang et al. 2012; Wang et al. 2014) / Chinese / CYP2E1, GSTM1, GSTT1, NAT2, CYP3A4, CYP2C9, CYP2C19, IL4, IL-10,SLCO1B1,SLC10A1 / 89 / 356 / INH+RMP+PZA+EMB+/SM / ALT>2×ULN or a combined increase in AST/TBIL>2×ULN / Decreased risk of ATDH in SLCO1B1 SNP rs4149014 G/G genotype; increased risk of ATDH in SLCO1B1 *15 haplotype
(Mishra et al. 2013) / Indian / CYP2E1, NAT2 / 33 / 173 / NR / ALT/AST>3×ULN / Increased risk of ATDH in NAT2 rs1799930 A/A and A/G genotypes
(Monteiro et al. 2012) / Mixed* / GSTM1, GSTT1 / 59 / 118 / INH+RMP+PZA+EMB / ALT>2 ×ULN / No risk factors of ATDH
(Nanashima et al. 2012) / Japanese / NOS2A, NQO1, HMOX1, NFE2L2, BACH1, MAFF, KEAP1, XPO1 / 18 / 82 / INH+RMP / ALT⩾2×ULN or combined increase in AST/TBIL>2×ULN / Increased risk of ATDH in NOS2A rs11080344 C/C genotype, BACH1 rs2070401 C/C genotype, and MAFK rs4720833 G/A or A/A genotype
(Ng et al. 2014) / Mixed / NAT2 / 26 / 191 / INH+RMP+PZA+EMB / ALT ⩾5×ULN, ALP ⩾2×ULN, or ALT ⩾3×ULN and TBIL ⩾2×ULN / No risk factors of ATDH
(Ohno et al. 2000) / Japanese / NAT2 / 14 / 63 / INH+RMP / ALT and/or AST>1.5 ×ULN / Increased risk of ATDH in NAT2 slow acetylators (NAT2*4)
(Possuelo et al. 2008) / Brazilian / NAT2 / 14 / 240 / INH+RMP+PZA / ALT/AST>3×ULN / Increased risk of ATDH in NAT2 slow acetylator
(Rana et al. 2011; Rana et al. 2014) / Indian / NAT2, CYP2E1, GSTM1, GSTT1 / 55 / 245 / INH+RMP+PZA+EMB / AST/ALT⩾5×ULN or AST/ALT⩾2×ULN with hyperbilirubinaemia / Increased risk of ATDH in NAT2 slow acetylators (NAT*5/7 and NAT2*6/7) and GSTM1null genotype
(Roy et al. 2001) / Indian / NAT2, GSTM1, GSTT1 / 33 / 33 / INH+RMP+PZA+EMB / ALT>2×ULN and serum bilirubin >3.0mg/dL / Increased risk of ATDH in GSTM1 null genotype
(Roy et al. 2006) / Indian / CYP2E1 / 8 / 101 / INH+RMP+PZA+EMB / NR / Increased risk of ATDH in CYP2E1 genotype C/C and I/I and haplotype (c1-I-C)
(Santos et al. 2013) / Brazilian / CYP2E1, NAT2 / 18 / 252 / INH+RMP+PZA / ALT>3×ULN / Increased risk of ATDH in NAT2 slow acetylators
(Sarma et al. 1986) / Indian / CYP2E1, GSTM1 / 113 / 201 / INH+RMP+PZA / AST>5×ULN and/or ALT>5 ×ULN; or TBIL>1.5mg/dl; or any increase in AST and/or ALT above pretreatment levels together with anorexia, nausea, vomiting, and jaundice / No risk factors of ATDH
(Sharma et al. 2002) / Indian / HLA-DQB1 / 56 / 290 / INH / AST> 5×ULN and/or ALT>5 ×ULN; or TBIL >1.5 mg/dl; or any increase in AST and/or ALT above pretreatment levels together with anorexia, nausea, vomiting, and jaundice / Increased risk of ATDH in HLA-DQB1*0201 genotype
(Shimizu et al. 2006) / Japanese / NAT2 / 10 / 32 / INH / ALT and/or AST>2×ULN / Increased risk of ATDH in NAT2 slow acetylator
(Singh et al. 2014) / Indian / CYP2E1, NAT2, NR113, MDR1, SLCO1B1, SLC22A1, SLC22A3 / 50 / 135 / INH+RMP+PZA+EMB / ALT>2×ULN or a combined increase in AST/TBIL>2×ULN / Increased risk of ATDH in CYP2E1*5 C/C, NAT2*5 T/T and NAT2*6 G/A genotypes
(Singla et al. 2014) / Inidan / CYP2E1, NAT2, GSTM1, GSTT1 / 17 / 391 / At least INH / ALT and AST>2×ULN / Increased risk of ATDH in NAT2 slow acetylators, CYP2E1*5B c1/c2 and GSTM1 and GSTT1 double null genotypes
(Sistanizad et al. 2011) / Iranian / NAT2 / 14 / 36 / INH+RMP+PZA+EMB / ALT/AST>2×ULN or clinically symptoms / Increased risk of ATDH in slow acetylators
(Sotsuka et al. 2011) / Japanese / CYP2E1, NAT2, GSTM1, GSTT1 / 52 / 92 / INH+RMP+PZA+EMB+/SM / ALT/AST>3×ULN / No risk factors of ATDH
(Teixeira et al. 2011) / Brazilian / CYP2E1, NAT2, GSTM1, GSTT1 / 26 / 141 / INH at least / Transaminase values>3×ULN and symptoms compatible with hepatitis / Increased risk of ATDH in NAT2 slow acetylators
(Vuilleumier et al. 2006) / Mixed / CYP2E1, NAT2 / 8 / 63 / INH+vitamin B6 / AST and/or ALT levels >4 ×ULN / No risk factors of ATDH
(Wang et al. 2004) / Chinese / NAT2 / 32 / 35 / INH+RMP+PZA+EMB+/SM / ALT ⩾1 ×ULN / Increased risk of ATDH in NAT2 *7B
(Wang et al. 2009a) / Chinese / NAT2 / 36 / 36 / INH+RMP+PZA+EMB+/SM / ALT/AST>3 or 5×ULN or any bilirubin elevation / Increased risk of ATDH in NAT2 slow acetylators
(Wang et al. 2009b) / Chinese / CYP2E1 / 85 / 100 / INH+RMP+PZA+EMB / ALT or IBIL>2×ULN or elevation of ASP, AP and TBIL with one of them>2×ULN / Increased incidence of ATDH in CYP2E1 c1/c1 genotype
(Wang et al. 2010) / Chinese / CYP2E1, GSTM1 / 104 / 111 / INH+RMP+PZA+EMB / ALT >2 ×ULN / Increased risk of ATDH in CYP2E1 RsaI c1/c1 and GSTM1 RsaI null genotypes
(Wu et al. 2010) / Chinese / NAT2 / 155 / 162 / At least INH / ALT/AST/TBIL⩾2×ULN / Increased risk of ATDH in NAT2*6
(Wu et al. 2012) / Chinese / CES1 / 200 / 273 / INH+RMP+PZA / ALT>2×ULN or elevation of AST or ALT with hyperbilirubinemia / Increased risk of ATDH in CES1 rs8192950 A/C genotype and rs1968743 G/G genotpye
(Xiang et al. 2014) / Uyghur / CYP2E1, NAT2, GSTM1, GSTT1 / 89 / 2155 / INH+RMP+PZA+EMB+/SM / ALT/AST/bilirubin>2×ULN / Increased risk of ATDH in NAT2*5 C/T genotype
(Yamada et al. 2010) / Mixed / CYP2E1, NAT2 / 23 / 147 / INH / AST >2 ×ULN / No risk factors of ATDH
(Yimer et al. 2011) / Ethiopian / NAT2, CYP2B6, CYP3A5, ABCB1, UGT2B7, SLCO1B1 / 41 / 160 / RIF and anti-HIV drugs / ALT⩾5×ULN or equal to threefold elevation and TBIL⩾2×ULN / Increased risk of ATDH in NAT2 slow acetylators and ABCB1 3435T/T genotype
(Zaverucha-do-Valle et al. 2014) / Brazilian / CYP2E1, CYP3A4, NAT2 / 52 / 79 / INH+RMP+PZA / ALT>2×ULN / Increased risk of ATDH in NAT2 slow acetylators
(Zhu et al. 2011) / Chinese / GSTM1, GSTT1 / 228 / 300 / INH+RMP+PZA+EMB / AST and/or ALT>2×ULN or elevated AST/ALT with hyperbilirubinaemia / No risk factors of ATDH
NR: Not report
Abbreviations：
ALT / Alanine aminotransferase
AP / Alkaline phosphatase
ART / Antiretroviral therapy
ASP / Asparaginic acid
AST / Aspartate transaminase
ATDH / Anti-tuberculosis drug-induced hepatotoxicity
CBIL / Conjugated bilirubin
EMB / Ethambutol
HIV / Human immunodeficiency virus
IBIL / Indirect bilirubin
INH / Isoniazid
NR / Not Report
PZA / Pyrazinamide
RMP / Rifampicin
SM / Streptomycin
TB / Tuberculosis
TBIL / Total bilirubin
ULN / Upper limit of normal
References
An H-r, Wu X-q, Wang Z-y (2012a) [The relationship between the polymorphism of MnSOD gene and antituberculosis drug-induced liver injury]. Chinese Journal of Antibiotics 37(11):1-4 doi:10.3969/j.issn.1001-8689.2012.11.018