Autoimmune hepatitis in human immunodeficiency virus-infected patients: A case series and review of the literature

Table 1 Prevalence and incidence of autoimmune hepatitis among different countries in the world¹

Country	Prevalence	Incidence	Study period
Asia-Pacific
Taiwan[7]	NA	0.5	2000 -2004
India[8]	1.5	NA	1999 -2002
Singapore[9]	4.0	NA	1990 -1996
South Korea[10]	4.8	1.1	2009 -2013
Brunei Darussalam[11]	5.6	NA	NA
Australia[12]	8.0	NA	NA
Israel[13]	11.0	0.7	1995 -2010
Japan[14]	23.4	2.2	2004 -2014
New Zealand[15]	24.5	2.0	2001 -2008
Europe and America
Spain[6]	NA	1.1	2003
Finland[3]	14.3	1.1	1995 -2015
Norway[16]	16.9	1.9	1986 -1995
Sweden[2]	17.3	1.2	1989 -2011
Netherlands[5]	18.3	1.1	1967 -2011
Denmark[4]	23.9	1.7	1994 -2012
United States (Alaska)[17]	42.9	NA	1984 -2000

¹Unit of prevalence and incidence: per 100000 population. NA: Not available.

Table 2 Baseline characteristics of 13 human immunodeficiency virus-infected patients at the time of autoimmune hepatitis diagnosis

Case	Sex	Age	HIV status				Presentation, duration (mo)	Lab values1									AIH score
			Duration (yr)	Current ART regimen, duration (year or month)	Viral load, duration (year or month)	CD4+ count in 2 and 1 years ago and at AIH presentation		AST	ALT	ALP	TB	Albumin	Globulin	ANA titer	ASMA	IgG
1	M	47	7	TDF/FTC/EFV, 4 yr	< 40, 3 yr	761, 885, 963	Rising ALT, 10 mo	121	263	145	0.8	4.4	4.8	1:80	+	2930	7
2	M	44	21	TDF/FTC/EFV, 1 yr	< 40, 5 yr	588, 669, 798	Rising ALT, 2 mo	130	172	172	0.4	4.5	4	1:80	-	1310	5
3	M	61	10	TDF/FTC/EFV, 8 yr	< 40, 6 yr	496, -, 646	Rising ALT, 31 mo	168	177	189	0.8	4.0	4.8	> 1280	-	1890	6
4	M	26	1	TDF/3TC/EFV, 6 mo	< 40, 1 mo	-, -, 82	Rising ALT, 7 mo	199	197	106	0.8	4.6	4.6	< 1:40	-	1920	5
5	F	30	7	TDF/3TC/EFV, 6 yr	< 40, -	-, -, 772	Rising ALT, 9 mo	236	157	191	0.4	3.6	5.9	> 1:1280	-	4100	7
6	F	29	6	TDF/FTC/EFV, 6 yr	< 40, -	-, -, 731	Rising ALT, 10 mo	108	133	125	1.0	4.1	3.7	1:320	-	1710	5
7	F	57	25	TDF/3TC/EFV, 8 yr	< 40, 7 yr	583, 477, 384	Rising ALT, 24 mo	106	49	357	0.6	3.7	6.5	1:2560	-	2333	7
8	F	40	10	TDF/3TC/EFV, 6 yr	< 40, 5 yr	-, 415, 480	Rising ALT, 4 mo	269	353	237	0.7	4.1	3.9	< 1:40	+	1860	5
9	F	46	6	TDF/FTC/EFV, 3 yr	< 40, -	-, -, 451	Rising ALT, 20 mo	178	230	262	1.4	3.8	4.2	> 1:1280	+	2050	7
10	F	34	2	TDF/FTC/EFV, 1 yr	< 40, 10 mo	-, 377, 557	Rising ALT, 11 mo	191	205	112	1.3	3.8	4.1	1:320	+	2580	7
11	F	31	2	TDF/FTC/EFV, 6 mo	< 40, 1 mo	-, -, 563	Jaundice, 1 mo	393	266	133	6.3	3.1	5.1	1:320	+	3710	7
12	F	40	13	TDF/FTC/EFV, 3 yr	< 40, 3 yr	320, 298, 216	Rising ALT, 6 mo	314	150	304	2.0	3.3	6.8	> 1:2560	-	5050	7
13	M	39	4	ABC/RPV/3TC, 1 yr	< 40, 2 yr	-, 52, 310	Rising ALT, 23 mo	63	124	100	0.7	4.1	4.4	1:80	-	2250	7

¹Unit of labs: AST, ALT, and ALP – U/L, TB and IgG – mg/dL, albumin and globulin – g/dL. 3TC: Lamivudine; ABC: Abacavir; EFV: Efavirenz; RPV: Rilpivirine; TDF: Tenofovir; AIH: Autoimmune hepatitis; HIV: Human immunodeficiency virus.

Table 3 Treatment and outcome of autoimmune hepatitis in human immunodeficiency virus-infected patients

	Induction regimen		Time to ALT normalization (mo)	Maintenance regimen		Outcome	Follow up duration (mo)	Last CD4 count	Last HIV VL (copies/mL)
	Prednisolone (mg/d)	Azathioprine (mg/d)		Prednisolone (mg/d)	Azathioprine (mg/d)
1	30	0	9.5	5	50	Minor flare	43.4	775	< 40
2	20	0	7.6	15	100	No relapse	12.8	799	< 40
3	30	0	8.2	0	50	No relapse	35.4	451	< 40
41	-	-	-	-	-	-	-	-	-
5	40	0	1.0	2.5	0	No relapse	10.3	772	< 40
6	30	0	2.6	10	100	No relapse	5.4	1841	< 40
7	15	25	0.9	0	MMF 1000 mg/day	No relapse	30.2	444	< 40
8	30	50	2.3	0	50	No relapse	65.8	513	< 40
9*	-	-	-	-	-	-	-	-	-
10	20	0	1.4	0	50	No relapse	22.6	632	< 40
11	30	0	7.6	0	50	No relapse	24.9	630	< 40
12	20	0	3.0	5	75	No relapse	19.7	176	< 40
13	30	0	Remain in the induction phase			-	4.9	-		-

¹Patients were initiated treatment at their primary hospitals. MMF: Mycophenolate mofetil.

Table 4 Baseline characteristics at autoimmune hepatitis presentation of previously reported human immunodeficiency virus cases

No.	Sex, age (yr)	HIV status				Presentation	ANA titer	ASMA titer	Treatment	Outcome
		HIV Duration	ART duration	Viral load	CD4
1[21]	NA	NA	NA	< 48	1011	NA	1:640	1:40	P+ Z	Remission
2[21]	NA	NA	NA	< 48	456	NA	Neg	1:20	P+ Z	Remission
3[21]	NA	NA	NA	< 48	783	NA	1:40	1:320	P+ Z	Remission
4[21]	NA	NA	NA	< 48	688	Acute liver failure	1:640	1:160	LT	Relapse at 4 yr after LT
5[21]	NA	NA	NA	< 48	653	n/a	1:1280	1:20	P+ Z	Remission
6[22]	M, 54	NA	3 yr	5104	357	↑ ALT*	1:40	1:640	P+ Z	Remission
7[22]	F, 55	NA	NA	< 50	174	↑ ALT	Neg	1:40	P+ Z	Relapse
8[22]	F, 49	NA	NA	69318	286	↑ ALT	Neg	Neg	P+ Z	Died
9[22]	F, 56	NA	NA	232734	331	↑ ALT	1:40	1:20	P	Died
10[23]	M, 21	Newly diagnosed	0	7900	753	Jaundice	Neg	Neg	P	Relapse
11[23]	F, 59	n/a	7 mo	-	504	↑ ALT	Pos	Pos	P+ Z	Remission
12[24]	M, 26	3 yr	1 yr	-	NA	Jaundice	1:160	Neg	P+ Z	Relapse
13[25]	M, 40	8 yr	8 yr	ND	832	↑ ALT	Neg	1:60	P+ Z	Relapse
14[25]	F, 44	20 yr	7 yr	ND	823	Acute hepatitis*	1:640	1:180	P	Remission
15[26]	M, 52	7 yr	7	ND	641	↑ ALT	1:2560	NA	P	Remission
16[27]	F, 44	9 mo	9 mo	ND	526	↑ ALT	1:160	1:160	P+ Z	Minor flare during taper steroid
17[28]	M, 29	Newly diagnosed	0	7122	259	↑ ALT	Neg	Neg	none	Resolved spontaneously
18[28]	F, 45	2 yr	7 mo	ND	297	↑ ALT	1:640	Neg	P+Z	Remission
19[28]	F, 65	10 yr	n/a	ND	922	↑ ALT	1:160	1:320	P+Z → MMF	Flare
20[29]	M, 38	2 yr after AIH diagnosed	0	81000	216	↑ ALT	1:320	1:40	ART	ALT improved after ART initiaion
21[30]	F, -	15 yr	12 yr	ND	634	Acute hepatitis	1:20000	Neg	P	Remission
22[31]	F, 48	20 yr	NA	ND	> 250	Acute hepatitis	1:80	1:300	P	Died
23[32]	F, 23	NA	8 mo	ND	523	↑ Jaundice and ALT*	Pos	Neg	P ± Z	Remission
24[32]	F, 31	NA	7 mo	< 40	277		Pos	Neg
25[32]	F, 42	NA	10 mo	-	593		Pos	Pos
26[32]	F, 45	NA	6 mo	< 40	253		Neg	Pos
27[32]	F, 35	NA	41 mo	ND	339		Neg	Pos
28[32]	M, 39	NA	77 mo	ND	416		Neg	Pos
29[32]	F, 39	NA	4 mo	ND	357		Neg	Pos
30[32]	F, 43	NA	4 mo	ND	876		Pos	Neg
31[32]	F, 36	NA	17 mo	ND	693		Neg	Pos
32[33]	F, 42	20 yr	NA	ND	232	Acute hepatitis	1:1280	Neg	P	Remission
33[34]	F, 51	NA	11 mo	94	417	Acute liver failure	1:256	1:80	P	Died
34[35]	F, 38	13 yr	NA	6392	436	NA	1:400	Pos	B	Remission
35[36]	M, 38	2 yr	0	8072	762	Acute hepatitis	1:640	1:160	P+Z	Remission
36[37]	F, 70	32 yr	24 yr	< 50	938	Decompensated cirrhosis*	1:640	NA	P	Remission
37[38]	M, 43	13 yr	2 yr	ND	900	↑ ALT	1:160	NA	P	Remission
38[39]	F, 43	4 yr	18 mo	ND	425	Acute hepatitis	1:8000	Neg	P+Z	Flare during tapering steroid

ART: Antiretroviral therapy; B: Budesonide; M: Mycophenolate mofetil, P: Prednisolone; Z: Azathioprine; LT: Liver transplantation; NA: Not available.

Table 5 Demographics of non-human immunodeficiency virus infected patients with autoimmune hepatitis

Country	n	Female (%)	Age at onset	Cirrhosis1	Disease onset	ANA+	ASMA+	IgG > ULN
Asia-Pacific
South Korea[10]	4085	86	60-69	32.3%	-	-	-	-
Japan[46]	1682	87	60-69	6.7% (P)	11.7% acute hepatitis 79.6% chronic hepatitis	90.7%	40.9%	n/a
South Korea[47]	343	-	-	23%	46.4% acute onset 30.6% asymptomatic	94.2%	23.0%	78.2%
New Zealand[15]	138	71	50-59	36% (P, R)	-	56%	57%	97%
Israel[13]	100	95	48	22.3% (P)	35% asymptomatic	91%	55%	n/a
Taiwan[7]	48	77	58	35.4% (P)	12.5% asymptomatic 41.7% acute onset 45.8% insidious onset	97.8%	18.2%	72.9%
Japan[14]	48	-	-	8.3% (C+R)	68.8% acute onset 31.2% chronic onset	100%	22.9%	79.2%
Australia[12]	42	74	53	24% (P)	-	n/a	65.8%	n/a
India[8]	38	89	30	34.2% (C±P)	13.1% acute hepatitis 39.4% acute onset 50% chronic onset	39.4%	63.1%	n/a
Singapore[9]	24	92	63	42% (C)	2/3 insidious onset	79.2%	20.8%	n/a
Brunei Darussalam[11]	19	79	52	21.1% (P)	53% asymptomatic	100%	47.4%	n/a
Europe and America
Denmark[4]	1721	72	70	28.3% (P)	-	-	-	-
Netherlands[5]	1313	78	Middle age	12% (P)	-	49%	58%	83%
Finland[3]	887	76	55-64	-	-	-	-	-
Sweden[2]	634	73	50-60	28.1%	-	-	-	-
Alaska[48]	71	-	-	-	-	79.1%	60%	66%
United States (Alaska)[17]	49	92	52	0%	34.7% acute hepatitis 65.3% asymptomatic	-	-	-
Norway[16]	25	80	68	28% (P)	-	68%	40%	n/a
Spain[6]	19	95	45-54	-	-	-	-	-

¹(P, C, R) – Diagnosis of cirrhosis at AIH presentation was made by pathological, clinical or radiological features, respectively.

Table 6 Simplified diagnostic scoring system of autoimmune hepatitis

Parameters		Score
I Seroimmunological test (maximum 2 points)
ANA or SMA +	≥ 1:40	+1
ANA or SMA +	≥ 1:80	+2
LKM +	≥ 1:40	+2
SLA +	Any titer	+2
II IgG or immunoglobulin level	> ULN	+1
	> 1.1 × ULN	+2
III Histological finding	Compatible	+1
	Typical	+2
IV Absence of viral hepatitis	No	0
	Yes	+2

≥ 6 points - probable AIH; ≥ 7 points - definite AIH. AIH: autoimmune hepatitis; ANA: Antinuclear antibody; LKM: Liver kidney microsomal antibody; SLA: Soluble liver antigen.