Autoimmune Hepatitis

Autoimmune hepatitis (AIH) is a chronic, progressive, inflammatory liver disease of unknown etiology, and the most common form of autoimmune liver disease (ALD). Autoimmune hepatitis can co-occur with other autoimmune diseases; these conditions are labeled overlap syndromes (eg, primary biliary cholangitis [PBC]-AIH).

Quick Answers for Clinicians

Which testing algorithms are related to this topic?

Autoimmune Liver Disease Testing Algorithm

Diagnosis

Indications for Testing

Persistently elevated alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) in the absence of other liver disease, especially in presence of hypergammaglobulinemia (European Association for the Study of the Liver [EASL], 2015)
Cirrhosis of undetermined etiology

Criteria for Diagnosis

Diagnosis of exclusion – rule out other more common etiologies of liver disease, including toxins, infections, and hereditary diseases

International clinical scoring system may be helpful in establishing diagnosis

Simplified scoring system of the International Autoimmune Hepatitis Group

Simplified Scoring System of the International Autoimmune Hepatitis Group
Autoantibodies	Test Results	Test Score
ANA or SMA	≥1:40	+1
ANA or SMA	≥1:80	+2
Antibodies to LKM-1	≥1:40	+2
Antibodies to SLA	Positive	+2
Absent autoantibodies	None	0
Immunoglobulin level
Immunoglobulin G	>ULN	+1
	>1.1 ULN	+2
	Normal	0
Histological findings
Morphological features of AIH	Compatible	+1
	Typical	+2
	Incompatible	0
Viral disease
Absence of viral hepatitis	No viral markers	+2
Absence of viral hepatitis	Viral markers present	0
Pretreatment aggregate score
Definite diagnosis		≥7
Probable diagnosis		6
ANA, antinuclear antibodies; LKM-1, liver-kidney microsome-1; SLA, soluble liver antigen; SMA, smooth muscle antibodies; ULN, upper limit of normal range Source: Hennes, International Autoimmune Hepatitis Group, 2008

Laboratory Testing

Liver function testing – transaminases (AST and ALT) usually elevated
- Elevation in both bilirubin and alkaline phosphatase (cholestatic pattern) is unusual and warrants evaluation for other etiologies or overlap syndromes
Hepatitis testing – important to rule out acute or chronic hepatitis (hepatitis A virus [HAV], hepatitis B virus [HBV], hepatitis C virus [HCV])
Quantitative immunoglobulins – IgG usually elevated
Antibody testing – consider the following
- Antinuclear antibody (ANA)
- Antineutrophil cytoplasmic antibody (ANCA)
- Antismooth muscle antibody (anti-SMA)
- Anti-F-actin (smooth muscle) antibody
- Antimitochondrial antibody (AMA)
- Antisoluble liver antigen antibody (anti-SLA)
- Antiliver-kidney microsomal-1 antibody (anti-LKM-1; cytochrome P450 2D6)
- Antiliver cytosol (anti-LC-1)
  - Serum titers of antibodies do not appear to correlate with disease activity
  - Titers may vary during course of disease without activity correlation

Antibody patterns

Associated Autoantibody Profile
Disease	ANA Pattern	ANCA Pattern	SMA	F-actin	AMA (M2)	LKM-1	LC-1	SLA
AIH-1	Homogenous pattern most common		+	+	Uncommon	-	-	+/- More common in children
AIH-2	-	Rare	-	-	-	+	+	+/- More common in children
PSC	+	Atypical p-ANCA	+/-	-	-	-	-	+/-
PBC	Nuclear dot or nuclear envelope pattern on HEp-2 cell substrate	-	-	-	+	-	-	-
M2, mitochondrial antigen 2 (PDH-E2); p-ANCA, perinuclear antineutrophil cytoplasmic antibody; PSC, primary sclerosing cholangitis Sources: Liberal, 2013, 2014; Czaja, 2015

Testing to rule out other conditions (see Differential Diagnosis)
Histopathology
- Tissue evaluation helps to exclude other disease processes, but features are not disease specific
- Typically demonstrates interface hepatitis with plasma cell and lymphocytic infiltrates
  - Significantly progressed disease may only reveal cryptogenic cirrhosis

Prognosis

Antibodies That May Prognosticate
Autoantibody	Associations
Anti-SLA	More severe histological changes Increased risk of relapse after drug withdrawal Increased risk for liver transplantation
Anti-actin	Younger age at onset Treatment dependence in children Increased risk for liver transplantation
Anti-LC-1	Severe liver inflammation Increased risk for rapid progression to cirrhosis Correlation of antibody titers with disease activity
Anti-ASGPR	Increased, more severe interface hepatitis Increased risk of relapse after treatment
Anti-LKM-1	Younger age at presentation Fulminant hepatic failure
ASGPR, asialoglycoprotein receptor Sources: Czaja, 2010; Liberal, 2014

Differential Diagnosis

Infection
- Viral
  - Cytomegalovirus
  - Epstein-Barr virus
  - Herpes simplex virus
  - Varicella-zoster virus
  - Hepatitis A, B, C, D, or E
- Bacterial
  - Leptospira spp
  - Coxiella burnetii
  - Rickettsia rickettsii
  - Treponema pallidum (secondary)
  - Sepsis
  - Rickettsia typhi
  - Mycobacterium tuberculosis
- Parasitic
  - Liver trematodes
  - Echinococcus spp
  - Parasitic diarrhea
  - Toxocara spp
Drug or toxin exposure
- Acetaminophen
- Antiseizure medications
- Isoniazid (Nydrazid)
- Oral contraceptives
- Rifampin (Rifadin)
- Sulfonamides
- Alcohol abuse
- Tetrachloride
Nonalcoholic acute steatohepatitis (NASH)
Other autoimmune diseases
- Primary biliary cholangitis
- Primary sclerosing cholangitis
- Systemic lupus erythematosus
- Autoimmune cholangitis
Genetic diseases
Granulomatous disease (eg, Sarcoidosis)
Hepatic ischemia

Monitoring

Patients with cirrhosis – monitor for hepatocellular carcinoma
Patients receiving glucocorticoids for treatment – monitor for adverse effects of long-term therapy

Background

Epidemiology

Incidence – 0.85-1.9/100,000 per year for adults of white northern European ancestry (Czaja, 2015)
Prevalence – 15-25/100,000; higher in some populations, eg, Alaskan natives (EASL, 2015)
Sex – M<F, 1:4 (type 1), 1:10 (type 2) (Heneghan, 2013)

Classification

AIH type 1 (AIH-1)
- Most common
- Characterized by ANA and/or SMA (EASL, 2015)
- Age – bimodal peaks
  - 10-30 years
  - 40-50 years
- Broad spectrum of disease from mild liver disease to cirrhosis
AIH type 2 (AIH-2)
- Rare – ~4% of patients with AIH in the U.S.
- Characterized by anti-LKM-1, anti-LC-1, and, rarely, anti-LKM-3 (EASL, 2015)
- Most common in children or young adults
- Disease has a more rapid onset and progression than type 1
- Associated with
  - IgA deficiency
  - Chronic hepatitis C infection
AIH type 3 (AIH-3) (EASL, 2015)
- Controversial subclassification
- Characterized by presence of anti-SLA, also called antiliver-pancreas (anti-LP)
- May predict more severe disease and need for lifelong immunosuppression

Genetics

AIH-1 – DRB1*0301, DRB1*0401
AIH-2 – DQB1*0201, DRB1*07, DRB1*03

Clinical Presentation

~25% of patients are asymptomatic when AIH is detected by liver function testing (Liberal, 2014)
Nonspecific symptoms – fatigue, lethargy, anorexia, malaise
Gastrointestinal – nausea, abdominal pain, jaundice, hepatomegaly, upper abdominal discomfort
Musculoskeletal – arthralgias
Extrahepatic associations
- AIH-1 – thyroiditis, celiac disease, ulcertive colitis, rheumatoid arthritis, Sjögren, mixed connective tissue disease, CREST
- AIH-2 – diabetes mellitus, thyroiditis, vitiligo
Overlap syndromes
- The two most common syndromes are AIH with either primary biliary cholangitis (PBC) or primary sclerosing cholangitis (PSC)

Select AIH overlap syndromes with common features

Select AIH Overlap Syndromes with Common Features
AIH Combined with	Criteria	Features
Autoimmune cholangitis	Predominant AIH phenotype AMA negative Bile duct injury or loss Normal cholangiography	IAIHG score for AIH Likely mixed syndrome – AMA-negative PBC and small-duct PSC
AMA-negative PSC	Same as autoimmune cholangitis	IAIHG score for AIH
Autoimmune sclerosing cholangitis	Same as AIH with PSC	Affects children Corticosteroid responsive
IgG4 cholangitis	>5 IgG4+ plasma cells per high-power field in liver tissue Abnormal biliary cholangiogram	Corticosteroid responsive Variable serum IgG4 level
PBC	Both AIH and PBC criteria AIH criteria (2 of 3) ALT ≥5 ULN IgG ≥2 ULN or SMA Interface hepatitis PBC criteria (2 of 3) Alk phos ≥2 ULN or GGT ≥5 ULN AMA Florid duct lesions	AIH predominant phenotype IAIHG score for AIH Alk phos ≥2 ULN AMA positive frequently Bile duct destruction or loss
PSC	AIH predominant AMA-negative phenotype Bile duct injury or loss Biliary sclerosis	IAIHG score for AIH Concurrent inflammatory bowel disease possible Bile duct abnormalities
Alk phos, alkaline phosphatase; GGT, gamma-glutamyl transpeptidase; IAIHG, International Autoimmune Hepatitis Group; PSC, primary sclerosing cholangitis Source: Czaja, 2013

AIH antibody-negative disease
- No other etiology found for cirrhosis – key to this diagnosis
- Same clinical and histological presentation as antibody-positive disease
AIH complications
- Liver failure/cirrhosis
- Increased risk of hepatocellular carcinoma

ARUP Lab Tests

Primary Tests

Recommended first-line panel for the evaluation of ALD

Negative results do not rule out disease

All interpretation of antibody patterns must be performed in conjunction with clinical presentation

3002479

Autoimmune Liver Disease Reflexive Panel 3002479

Method

Semi-Quantitative Enzyme-Linked Immunosorbent Assay/Semi-Quantitative Indirect Fluorescent Antibody

Components include mitochondrial M2 antibody, IgG; LKM-1 antibody, IgG; F-actin (smooth muscle) antibody, IgG with reflex to SMA, IgG titer; soluble liver antigen antibody, IgG; ANA with HEp-2 substrate, IgG

Initial test in conjunction with ALD panel for evaluation of ALD

Panel detects ANCA, myeloperox (MPO), and serine proteinase 3 (PR3) antibodies

Negative antibody testing does not rule out ALD

All interpretation of antibody patterns must be performed in conjunction with clinical presentation

There may be overlap between diseases and antibodies detected

No single test shows absolute specificity

Concurrent ALD panel testing recommended

2006480

ANCA-Associated Vasculitis Profile (ANCA/MPO/PR3) with Reflex to ANCA Titer 2006480

Method

Semi-Quantitative Indirect Fluorescent Antibody/Semi-Quantitative Multiplex Bead Assay

Use to evaluate for AIH of unknown etiology

Use in combination with LKM-1 antibody, IgG

Consider if other serological tests in ALD panel are negative, or in combination with specific tests, such as ANA, F-actin, SMA

Negative antibody testing does not rule out ALD

All interpretation of antibody patterns must be performed in conjunction with clinical presentation – overlap may occur between diseases and antibodies detected

Neither LKM-1 nor LC-1 has absolute diagnostic sensitivity for AIH-2

2010711

Liver Cytosolic Antigen Type 1 (LC-1) Antibody, IgG 2010711

Method

Qualitative Immunoblot

Related Tests

Order to evaluate viral etiology in patients with acute hepatitis

Not recommended for screening asymptomatic patients

0020457

Hepatitis Panel, Acute with Reflex to HBsAg Confirmation 0020457

Method

Qualitative Chemiluminescent Immunoassay

Panel includes HAV IgM, HBV core antibody IgM, HBV surface antigen (HBsAg), HCV antibody

Initial screening for hepatobiliary inflammation

0020416

Hepatic Function Panel 0020416

Method

Quantitative Enzymatic/Quantitative Spectrophotometry

Panel includes albumin; alkaline phosphatase; aspartate aminotransferase; alanine aminotransferase; bilirubin, total; protein, total; and bilirubin, direct

Initial test in the workup of immunoglobulin disorders

0050630

Immunoglobulins (IgA, IgG, IgM), Quantitative 0050630

Method

Quantitative Nephelometry

Aid in initial diagnosis of connective tissue disease

0050080

Antinuclear Antibodies (ANA), IgG by ELISA with Reflex to ANA, HEp-2 Substrate, IgG by IFA 0050080

Method

Qualitative Enzyme-Linked Immunosorbent Assay/Semi-Quantitative Indirect Fluorescent Antibody

Differential evaluation of ALD of unknown etiology, especially AIH of childhood onset

Use in combination with LC-1 IgG testing when evaluating for AIH-2

More likely to be positive than LC-1

Negative antibody testing does not rule out ALD

All interpretation of antibody patterns must be performed in conjunction with clinical presentation – overlap may occur between diseases and antibodies detected

Neither LKM-1 nor LC-1 has absolute diagnostic sensitivity for AIH-2

0055241

Liver-Kidney Microsome - 1 Antibody, IgG 0055241

Method

Semi-Quantitative Enzyme-Linked Immunosorbent Assay

Differential evaluation of ALD of unknown etiology, especially AIH of childhood onset

Use in combination with LC-1 IgG testing when evaluating for AIH-2

Test does not differentiate among the four types of LKM antibodies (LKM-1, LKM-2, LKM-3, and a fourth type that recognizes CYP1A2 and CYP2A6 antigens)

0099270

Liver-Kidney Microsome Antibody, IgG 0099270

Method

Semi-Quantitative Indirect Fluorescent Antibody

Recommended for the evaluation of ALD or hepatitis of unknown etiology

0055235

Soluble Liver Antigen Antibody, IgG 0055235

Method

Semi-Quantitative Enzyme-Linked Immunosorbent Assay

May be helpful in evaluating for ALD

For more comprehensive reflex panel, refer to ALD evaluation with reflex to SMA, IgG by IFA

0051174