Minireviews
Copyright ©The Author(s) 2022.
World J Gastroenterol. Jun 28, 2022; 28(24): 2654-2666
Published online Jun 28, 2022. doi: 10.3748/wjg.v28.i24.2654
Table 1 Studies comparing drug-induced autoimmune hepatitis and drug-induced liver injury
Ref.
a: Study population; b: Study period; c: Follow-up period
a: Definition of DIAIH; b: Causality tool assessment
No. of DIAIH cases, % of all DILI
No. of DILI cases
Key findings for DIAIH (in addition to Table 3)
Stephens et al[37], 2021, Spaina: Prospective multicentre DILI database, n = 869; b: 1994-2018; c: Median 96-117 d in HC injurya: Simplified AIH criteria; b: RUCAM (definite, highly probable, probable and possible)26, 2.9% 843Culprit drugs: Statins (31%); antimicrobials (23%)
De Boer et al[15], 2015, United Statesa: National prospective DILI database (n = 1322), subgroup of DILI secondary to Nitrofurantoin, hydralazine, Minocycline and methyldopa (n = 88); b: 2004-2014; c: 6 mo, 12 mo or 24 mo until normalization of LFTa: Autoimmune (AI) DILI–AI score based on seropositivity for AIH antibodies and raised IgG); b: RUCAM (definite, highly probable and probable)47, 3.6%Two groups: (a) 18 non-AI DILI due to 4 drugs; (b) 67 (reference cohort, DILI due to Augmentin, Isoniazid, Diclofenac)Similar HLA-DRB1*03:01 (15%) and HLADRB1*04:01 (9%) percentage in patients with DILI compared to population controls from National Marrow Donor Program (12% and 9%, respectively)
Hisamochi et al[22], 2016, Japana: All DILI who underwent liver biopsy, n = 62; b: 1988-2010; c: Median 2290 da: Revised IAIHG criteria; b: RUCAM and JDD-W scale23, NA39Culprit drugs: CAM (69.6%); NSAIDs (8.7%). IgG reduction in 87%. 50% (8/16) relapsed (4 not treated with steroids, 2 previously received steroids and 2 on tapering dose of steroid dosage). Median time to relapse 283 d (range, 47-1090 d). Rise in IgG with relapse
Licata et al[16], 2014, Italya: Single centre hospitalized patients with DILI, n =136 (44 with liver biopsy); b: 2000-2011; c: Mean 26 mo (12-84 mo), at least 1 yr after stopping immunosuppressantsa: Simplified AIH score ≥ 6; b: RUCAM (definite, highly probable, probable and possible)12, 8.8%124Culprit drugs: NSAIDs (50%) - (Nimesulide/ketoprofen); Antimicrobials (25%) (Augmentin/Ceftriaxone); CAM (17%). 38.2% of all DILI patients had positive AIH antibodies but only 42.9% with positive antibodies have DIAIH. All DIAIH were treated with corticosteroids and all achieved remission at 15 mo. 58.3% (7/12) had addition of Azathioprine. One patient had a flare while on tapering prednisolone. In 41% (5/12), immunosuppressant was stopped after 2 yr, with no relapse
Table 2 Studies comparing drug-induced autoimmune hepatitis and autoimmune hepatitis
Ref.
a: Study population; b: Study period; c: Follow-up period
a: Definition of DIAIH/AIH; b: Causality tool assessment
No. of DIAIH cases, % of all AIH
No. of AIH cases
Key findings for DIAIH (in addition to Table 4)
Valgeirsson et al[14], 2019, Icelanda: Population based AIH study, n = 71; b: 2006-2018; c: Median 4.8 yra: Simplified AIH score, if not fulfilled, Revised IAIHG score is used; or received corticosteroids; b: RUCAM score (highly probable, probable and possible)13, 18% (9/13 had liver biopsy)58Culprit drugs: Biologics (77%) - 80% were due to infliximab; Nitrofurantoin (15%)
Martínez-Casas et al[34], 2018, Columbiaa: Single centre retrospective review of AIH cases, n = 190; b: 2010-2016; c: Mean 47.4 moa: Simplified AIH score; b: RUCAM12, 6.3%178Culprit drugs: Nitrofurantoin (67%); NSAIDs (17%)
Wang et al[20], 2017, Chinaa: Single centre retrospective review of AIH and DILI patients; b: 2010-2014; c: NA a: DILI with positive antibody; simplified AIH score; b: NA (DILI due to drugs/CAM within 6 mo of hospitalization)18 (12.4% of all DILI with positive antibody)52Culprit drugs: CAM, NSAIDs and antibiotics (no breakdown)
Yeong et al[32], 2016, United Kingdoma: Single centre retrospective AIH cases, n = 82; b: 2005-2013; c: Median 86.3 mo (14.6% < 18 mo)a: Revised IAIHG criteria; b: RUCAM (highly probable, probable)11, 13.4%71Culprit drugs: Nitrofurantoin (36.4%); Statins (36.4%); CAM (18%)
Weber et al[21], 2019, Germanya: Single centre cohort of 288 acute liver injury patients who received corticosteroid for DILI/AIH, n = 44; b: 2013-2018; c: Median 19 mo in DILI; 23 mo in AIHa: Simplified AIH score and revised IAIHG criteria; b: RUCAM2222Culprit drugs: NSAIDs (27.3%); Statins (9%); Direct oral anticoagulants (9%)
Björnsson et al[13], 2010, United Statesa: Single centre retrospective review of all AIH cases, n = 261; b: 1997-2007a: Simplified AIH score24, 9.2% (24/261)237Culprit drugs: Minocycline (45.8%); Nitrofurantoin (45.8%)
Table 3 Comparison between drug-induced autoimmune hepatitis and drug-induced liver injury
Clinical features
DIAIH
DILI
Demographics
Female, %62%[37]48% (P = 0.162)[37]
Age (yr), mean ± SD57± 17[37]; 59 ± 17[22]54 ± 18 (P = 0.550)[37]; 47 (P = 0.002)[22]
Clinical presentation
Jaundice, %69%[37]; 68%[15]; 66%[16]69% (P = 0.953)[37]; 56% (P = 0.4)[15]; 40%-47.6% (P = 0.2)[16]
Rash, %4.5%[37]; 19%[15]7.9% (P = 1.000)[37]; 22% (P = 0.7)[15]
Hepatocellular injury, %92%[37]57% (P = 0.002)[37]
Latency period (d), median (range) 65 (27-274)[37]; 277 (8-7032)[15]; 4 (1-9)[16]27 (8-64) (P = 0.004)[37]; 100 (13-1572) (P = 0.03)[15]; 7-10 (5-50) (P = 0.7)[16]
Latency period (d), mean ± SD143 ± 188[22]32 ± 120 (P = 0.000)[22]
Culprit drug due to CAM, %70%[22]25% (P = 0.000)[22]
Biochemical results
ALT × ULN, mean ± SD28 ± 19[37]19 ± 22 (P = 0.0002)[37]
AST × ULN, mean ± SD24 ± 17[37]15 ± 21 (P = 0.0001)[37]
Autoimmune antibodies and serology
Detectable ANA, %88%[37]; 72%[15]; 52%[22]12 (P < 0.001)[37]; 22[15]; 15 (P = 0.003)[22]
Detectable ASMA, %44%[37]; 60%[15]8.9% (P < 0.001)[37]; 13%[15]
Detectable AMA, %4%[37]1.9% (P = 0.397)[37]
Detectable anti-LKM-1, %0%[37]1.1% (P = 1.000)[37]
Elevated IgG, %39%[15]; (25% > 1.1 × ULN)[15]9%[15]
Serum IgG (g/L), mean ± SD19.5 ± 10.7[37]; 1.07 × ULN ± 0.51[22]11.9 ± 4.6 (P < 0.001)[37]; 0.69 × ULN ± 0.28 (P = 0.000)[22]
Histopathology
Liver biopsy[16]
Severe portal inflammation, %100%56.2%-62.5%
Prominent portal plasma cells, %58.3%6.3%-12.5%
Rosette formation, %66.7%6.3%-12.5%
Severe focal necrosis, %66%6.3%-25%
Treatment and response to treatment
Corticosteroid therapy, %43%[15]61% (P = 0.3)[15]
Immunosuppressive therapy, (corticosteroid/Azathioprine), %58%[37]; 60.8%[22]9.9% (P < 0.001)[37]; 10.3% (P = 0.000)[22]
Outcomes
Mild/mod/severe DILI, %35%/45%/7.7%[37]31%/59%/6.2% (P = 0.784)1[37]
Outcomes (liver transplant/death), %3.8%/0%[37]; 6%/4%[15]2.1%/1.5% (P = 0.784)1[37]; 0/0 (P = 0.6 for liver transplant, P = 1.0 for death)[15]
Chronicity rate, %17%[15]21% (P = 0.70)[15]
Table 4 Comparison between drug-induced autoimmune hepatitis and autoimmune hepatitis
Clinical featuresDIAIHAIH
Demographics
Female, %82%[32]; 91%[34]80% (P = 0.635)[32]; 92% (P = 0.95)[34]
Clinical presentation
Acute presentation> 60%[14]; 55%[32]; 83%[34]< 20%[14]; 47% (P = 0.618)[32]; 35% (P < 0.001)[34]
Hypersensitivity reaction (fever, rash, eosinophilia)Up to 30%[14]Unusual[14]
Cirrhosis at presentation, %0%[34]34.8% (P = 0.07)[34]
Temporal relationship with drugsPositiveNegative
Concurrent AI diseaseUnusual[14]Present in 14%-44%[14]
Biochemical results
ALT (U/L), mean ± SD548 ± 335[20]227 ± 121 (P = 0.021)[20]
AST (U/L), mean ± SD 460 ± 321[20]202 ± 57 (P = 0.018)[20]
Serology
IgG, mean ± SD (g/L)13.4 g/L[14]; 21.4 ± 7.5[34]18.6 g/L (P value non-significant)[14]; 24.3 ± 11.2 (P = 0.422)[34]
Pre-treatment score
RUCAM score, median (range)6 (3-10)[21]3.5 (0-7) (P < 0.01)[21]
Revised IAIHG score, median (range)9.5 (4-14)[21]13 (9-18)[21]
Simplified AIH score, median (range)4 (2-6)[21]5 (1-7) (P = 0.385)[21]
Histopathology
F3-F4, %33.3%[34] 54.4% (P = 0.15)[34]
Typical histology (portal inflammation, interface hepatitis, plasma cells infiltrates)18.2%[20]54%[20]
Treatment and response to treatment
Time to biochemical remission, mean (mo)2[34]16.8 (P <0.001)[34]
Treatment with Azathioprine or Mycophenolic acid in addition to corticosteroids, %57%[13]; 15%[14]; 28%[20]; 20%[21]86% (P = 0.024)[13]; 83% (P < 0.001)[14]; 90% (P = 0.023)[20]; 85% (P < 0.01)[21]
Biochemical remission, %95%[21]77.3% (P = 0.08)[21]
Treatment discontinuation, %69%[14]; 100%[20]; 85%[21]; 25%[34]26% (P < 0.02)[14]; 25% (P = 0.013)[20]; 5% (P < 0.1)[21]; 3% (P < 0.001)[34]
Relapse rate, %0%[14]; 15%[21]; 60%[32]; 0%[34]43% (P = 0.022)[14]; 70% (P < 0.01)[21]; 83% (P = 0.538)[32]; 18% (P = 0.10)[34]
Time to relapse (wk), median (range)131 (37-216)[34]14 (1-155) (P = 0.033)[34]
Outcomes
Liver transplant/death, %0%/0%[32,34]2.8%/7% (P = 0.748 for liver transplant; p = 0.65 for death)[32]; 5.6%/2.8% (P = 0.40 for liver transplant; P = 0.55 for death)[34]