Drug-induced autoimmune hepatitis: A minireview

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, Spain	a: Prospective multicentre DILI database, n = 869; b: 1994-2018; c: Median 96-117 d in HC injury	a: Simplified AIH criteria; b: RUCAM (definite, highly probable, probable and possible)	26, 2.9%	843	Culprit drugs: Statins (31%); antimicrobials (23%)
De Boer et al[15], 2015, United States	a: 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 LFT	a: 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, Japan	a: All DILI who underwent liver biopsy, n = 62; b: 1988-2010; c: Median 2290 d	a: Revised IAIHG criteria; b: RUCAM and JDD-W scale	23, NA	39	Culprit 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, Italy	a: 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 immunosuppressants	a: Simplified AIH score ≥ 6; b: RUCAM (definite, highly probable, probable and possible)	12, 8.8%	124	Culprit 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

DIAIH: Drug-induced autoimmune hepatitis; DILI: Drug-induced liver injury; RUCAM: The Roussel Uclaf Causality Assessment Model; NSAIDs: Non-steroidal anti-inflammatory drugs; AIH: Autoimmune hepatitis; IAIHG: International AIH Group; IgG: Immunoglobulin G; CAM: Complementary alternative medicines.

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, Iceland	a: Population based AIH study, n = 71; b: 2006-2018; c: Median 4.8 yr	a: 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)	58	Culprit drugs: Biologics (77%) - 80% were due to infliximab; Nitrofurantoin (15%)
Martínez-Casas et al[34], 2018, Columbia	a: Single centre retrospective review of AIH cases, n = 190; b: 2010-2016; c: Mean 47.4 mo	a: Simplified AIH score; b: RUCAM	12, 6.3%	178	Culprit drugs: Nitrofurantoin (67%); NSAIDs (17%)
Wang et al[20], 2017, China	a: 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)	52	Culprit drugs: CAM, NSAIDs and antibiotics (no breakdown)
Yeong et al[32], 2016, United Kingdom	a: 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%	71	Culprit drugs: Nitrofurantoin (36.4%); Statins (36.4%); CAM (18%)
Weber et al[21], 2019, Germany	a: 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 AIH	a: Simplified AIH score and revised IAIHG criteria; b: RUCAM	22	22	Culprit drugs: NSAIDs (27.3%); Statins (9%); Direct oral anticoagulants (9%)
Björnsson et al[13], 2010, United States	a: Single centre retrospective review of all AIH cases, n = 261; b: 1997-2007	a: Simplified AIH score	24, 9.2% (24/261)	237	Culprit drugs: Minocycline (45.8%); Nitrofurantoin (45.8%)

DIAIH: Drug-induced autoimmune hepatitis; DILI: Drug-induced liver injury; RUCAM: The Roussel Uclaf Causality Assessment Model; NSAIDs: Non-steroidal anti-inflammatory drugs; AIH: Autoimmune hepatitis; IAIHG: International AIH Group; CAM: Complementary alternative medicines.

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 ± SD	57± 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 ± SD	143 ± 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 ± SD	28 ± 19[37]	19 ± 22 (P = 0.0002)[37]
AST × ULN, mean ± SD	24 ± 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 ± SD	19.5 ± 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]

¹Combined comparisons of severity of drug-induced liver injury, mortality, and liver transplantation.

DIAIH: Drug-induced autoimmune hepatitis; DILI: Drug-induced liver injury; ALT: Alanine transaminase; AST: Aspartate transaminase; ULN: Upper limit of normal; CAM: Complementary alternative medicines; Anti-LKM: Anti-liver kidney antibody; SD: Standard deviation; IAIHG: International AIH Group.

Table 4 Comparison between drug-induced autoimmune hepatitis and autoimmune hepatitis

Clinical features	DIAIH	AIH
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 drugs	Positive	Negative
Concurrent AI disease	Unusual[14]	Present in 14%-44%[14]
Biochemical results
ALT (U/L), mean ± SD	548 ± 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]

DIAIH: Drug-induced autoimmune hepatitis; DILI: Drug-induced liver injury; ALT: Alanine transaminase; AST: Aspartate transaminase; RUCAM: The Roussel Uclaf Causality Assessment Model; SD: Standard deviation.