Autoimmune hepatitis, one disease with many faces: Etiopathogenetic, clinico-laboratory and histological characteristics

Table 1 Differential diagnosis of autoimmune hepatitis

Other autoimmune liver diseases

Primary biliary cirrhosis

Primary sclerosing cholangitis (including small duct sclerosing cholangitis)

Variants syndromes

Chronic viral hepatitis

Chronic hepatitis B with or without hepatitis delta

Chronic hepatitis C

Chronic hepatitis non A to E

Cholangiopathy due to human immunodeficiency virus infection

Alcoholic liver disease

Drug-induced hepatitis

Granulomatous hepatitis

Hemochromatosis

Non-alcoholic steatohepatitis

α1-antitrypsin deficiency

Wilson's disease

Systemic lupus erythematosus

Celiac disease

Table 2 Clinical features of autoimmune hepatitis

Characteristic
Age at presentation	Any age of both sexes and all ethnic groups; bimodal distribution usually with peaks around puberty and between 4th and 6th decades although a considerable number of patients are even older (above 65 years of age)
Types of disease onset	Broad range from asymptomatic (‘‘en passant’’ diagnosis) to acute/severe or even fulminant hepatitis
	Most common clinical phenotype of the disease (two thirds of patients) is characterized by an insidious onset with unspecific symptoms, such as fatigue, right upper quadrant pain, lethargy, malaise, anorexia, nausea, pruritus, fluctuating jaundice and polyarthralgia without arthritis, sometimes dating back years
	Acute onset of AIH does exist and contains two different clinical entities (the acute exacerbation of chronic AIH and the true acute AIH without histological findings of chronic liver disease)
	One third of patients at diagnosis have already developed cirrhosis irrespective of the presence of symptoms or not, suggesting a delay in diagnosis due to unfamiliar clinicians, histopathologists and/or laboratories
Physical findings	Depends on the clinical status of the disease, ranging from completely normal to signs and symptoms of chronic liver disease and/or portal hypertension
Clinical features in special conditions	Presentation of AIH during pregnancy or more frequently after delivery
	Development of AIH after liver transplantation for other liver diseases (de novo AIH or post-transplant plasma cell hepatitis)
	Development of AIH after drugs, supplements or herbals (drug-induced AIH, nitrofurantoin and minocycline implicated in 90% of cases)
Specific characteristics	Frequent presence in the patient or first-degree relatives of other autoimmune or immune-mediated diseases like Hashimoto thyroiditis, Grave’s disease, vitiligo, alopecia, rheumatoid arthritis, diabetes mellitus type-1, inflammatory bowel disease, psoriasis, systemic lupus erythematosus, Sjögren’s syndrome and celiac disease
	An unusual form of AIH has been reported in 10%-18% of patients with APECED, also known as APS-1
Complications	HCC development in AIH is less common than other liver diseases but it does exist and is associated with cirrhosis, suggesting surveillance in all cirrhotic patients with AIH
	Drug-related complications are also significant in 10%-25% of patients; these complications are most commonly related to long-term corticosteroid use or azathioprine toxicity and/or intolerance

AIH: Autoimmune hepatitis; HCC: Hepatocellular carcinoma; APECED: Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy; APS-1: Autoimmune polyglandular syndrome type 1.

Table 3 Simplified criteria for the diagnosis of autoimmune hepatitis

Feature/parameter	Discriminator	Score
ANA or SMA +	≥ 1:40	+11
ANA or SMA+	≥ 1:80	+21
or LKM +	≥ 1:40	+21
or SLA/LP +	Any titer	+21
IgG or γ-globulins level	> upper limit of normal	+1
	> 1.1 × upper limit	+2
Liver histology (evidence of hepatitis is a necessary condition)	Compatible with AIH	+1
	Typical of AIH	+2
	Atypical	0
Absence of viral hepatitis	No	0
	Yes	+2

¹Addition of points achieved for all autoantibodies (maximum, 2 points). Definite autoimmune hepatitis: ≥ 7; Probable autoimmune hepatitis: ≥ 6. Typical liver histology for autoimmune hepatitis = each of the following features had to be present, namely interface hepatitis, lymphocytic/lymphoplasmocytic infiltrates in portal tracts and extending into the lobule, emperipolesis (active penetration by one cell into and through a larger cell) and hepatic rosette formation. Compatible liver histology for autoimmune hepatitis = chronic hepatitis with lymphocytic infiltration without all the features considered typical. Atypical = showing signs of another diagnosis, like steatohepatitis. ANA: Antinuclear antibodies; SMA: Smooth muscle autoantibodies; LKM: Liver/kidney microsomal; SLA/LP: Soluble liver antigen or liver pancreas; AIH: Autoimmune hepatitis.

Table 4 Subdivision of autoimmune hepatitis according to the autoantibodies detected

Types of AIH	Characteristic autoantibodies
AIH-1	ANA, SMA, p-ANCA (p-ANNA), anti-ASGP-R, anti-SLA/LP (specific antibody; molecular target: SepSecS)
AIH-2	Anti-LKM1 (molecular target: CYP2D6), anti-LKM3 (molecular target: UGT1), anti-LC1 (liver specific antibody, molecular target: FTCD), anti-ASGP-R
AIH as component of APECED	ANA, anti-LC (molecular target: unknown), anti-LKM (molecular target: CYP2A6, CYP1A1, CYP2B6), anti-LM (liver specific antibody; molecular target: CYP1A2)

AIH-1: Autoimmune hepatitis type 1; AIH-2: Autoimmune hepatitis type 2; APECED: Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy; ANA: Antinuclear antibodies; SMA: Smooth muscle antibodies; p-ANCA: Perinuclear antineutrophil cytoplasmic antibodies; p-ANNA: Peripheral antineutrophil nuclear antibodies; Anti-ASGP-R: Antibodies against asialoglycoprotein receptor; Anti-SLA/LP: Antibodies against soluble liver antigen/liver pancreas; SEpSEcS: Synthase-converting O-phosphoseryl-tRNA to selenocysteinyl-tRNA; anti-LKM1: Anti-liver kidney microsomal antibodies type 1; CYP2D6: Cytochrome P450 2D6; Anti-LKM3: Anti-liver kidney microsomal antibodies type 3; UGT1: UDP-glucuronosyltransferases; Anti-LC1: Anti-liver cytosol antibodies type 1; FTCD: Formiminotransferase cyclodeaminase; CYP2A6: Cytochrome P450 2A6; CYP1A1: Cytochrome P450 1A1; CYP2B6: Cytochrome P450 2B6; Anti-LM: Antibodies against liver membrane; CYP1A2: Cytochrome P450 1A2.

Table 5 Differential diagnosis of liver diseases according to autoantibodies against molecularly defined autoantigens of cytochrome P450

Anti-CYP2D6	Anti-CYP1A2	Anti-CYP2A6	Chronic liver disease
Pos	Neg	Neg	AIH-2 (94%-100%); Hepatitis C (0%-10%)
Neg	Neg	Pos	Hepatitis C; APECED with or without hepatitis
Neg	Pos	Neg	AIH in APECED
			dihydralazine-induced hepatitis
Pos	Neg	Pos	Hepatitis C (0%-7%)
Neg	Pos	Pos	AIH in APECED

Pos: Positive; Neg: Negative; APECED; Autoimmune polyendocrinopathy-candidiasis ectodermal dystrophy syndrome.