Definition

1. Self-perpetuating hepatic inflammation of unknown cause characterized by interface hepatitis, hypergammaglobulinemia, and liver-associated autoantibodies

2. Exclusion of other conditions that have similar features, including Wilson disease, chronic viral hepatitis, alpha-1 antitrypsin deficiency, hereditary hemochromatosis, drug-induced liver disease (most commonly, minocycline toxicity), celiac disease, nonalcoholic steatohepatitis, primary biliary cirrhosis (PBC), and primary sclerosing cholangitis (PSC) (Table 5.1)

TABLE 5.1 Autoimmune hepatitis: Basic diagnostic tests

Diagnostic tests	Clinical value
Serum AST and ALT, bilirubin, alkaline phosphatase, and γ-globulin levels	Estimate severity of inflammatory activity; characterize pattern of liver injury
Serum albumin level and INR	Estimate impairment of hepatic synthetic function
ANA, SMA, anti-LKM1, and AMA	Document presence and nature of immune activity
Serum immunoglobulin levels	Confirm mainly serum IgG elevation
Liver tissue examination	Document that histologic changes support diagnosis Exclude findings suggestive of other diagnoses
HBsAg, anti-HBc, IgM anti-HAV, and anti-HCV	Document absence of concurrent viral infection
Ceruloplasmin level	Exclude Wilson disease
Alpha-1 antitrypsin phenotype	Exclude alpha-1 antitrypsin deficiency
Serum iron, transferrin, iron saturation and ferritin levels	Exclude hereditary hemochromatosis

AMA, antimitochondrial antibodies; ANA, antinuclear antibodies; anti-HAV, antibody to hepatitis A virus; anti-HBc, antibody to hepatitis B core antigen; anti-HCV, antibody to hepatitis C virus; anti-LKM1, antibodies to liver kidney microsome type 1; AST, aspartate aminotransferase; ALT, alanine aminotransferase; HBsAg, hepatitis B surface antigen; IgG, immunoglobulin G; INR, international normalized ratio; SMA, smooth muscle antibodies.

Nomenclature

1. The designation autoimmune hepatitis replaces terms such as autoimmune liver disease and autoimmune chronic active hepatitis.

2. Type 1 and type 2 autoimmune hepatitis are defined by their principal autoantibody reactivity.

Diagnosis

1. Criteria for definite and probable diagnoses are established by consensus of an international panel (Table 5.2).

2. The requirement for 6 months of disease to establish chronicity is waived, and an acute, rarely severe (fulminant) form, is possible.

3. Interface hepatitis (Fig. 5.1) is required for the diagnosis, but lobular (panacinar) hepatitis (Fig. 5.2) in conjunction with interface hepatitis is within the histologic spectrum.

4. Plasma cell infiltration (Fig. 5.3) is characteristic but not specific or essential for the diagnosis.

5 Centrilobular necrosis is rare and may be an early or acute histologic stage.

6. Prominent cholestatic changes (bile duct injury, ductopenia) or histologic features suggestive of other disease (fat, granulomas, copper or iron) exclude the diagnosis.

7. Conventional serologic markers of autoimmune hepatitis are antinuclear antibodies (ANA), smooth muscle antibodies (SMA), and antibodies to liver kidney microsome type 1 (anti-LKM1).

8. Other nonstandard serologic markers are antibodies to soluble liver antigen (anti-SLA), antibodies to liver cytosol type 1 (anti-LC1), and atypical perinuclear antineutrophil cytoplasmic antibodies (pANCA); they support a probable diagnosis of autoimmune hepatitis if conventional markers are absent.

9. Two scoring systems are used for the diagnosis of difficult cases: (1) the revised original scoring system of the International Autoimmune Hepatitis Group (IAIHG), which is most useful in patients with few or atypical symptoms (Table 5.3); and (2) the simplified scoring system of the IAIHG, which is most useful in patients with other diseases and concurrent autoimmune features (Table 5.4).

10. Gold standard assays for serologic markers of autoimmune hepatitis are based on indirect immunofluorescence (IIF); clinical correlations made by IIF have not been validated against results of enzyme-linked immunosorbent assays (ELISAs) based on recombinant antigens.

TABLE 5.2 International criteria for definite or probable diagnosis of autoimmune hepatitis

Diagnostic features	Definite diagnosis	Probable diagnosis
Exclusion of risk factors for other diseases	Daily alcohol <25 g/day No recent hepatotoxic drugs Normal alpha-1 AT phenotype Normal ceruloplasmin level Normal iron and ferritin levels No active hepatitis A, B, and/or C	Daily alcohol <50 g/day No recent hepatotoxic drugs Heterozygous alpha-1 AT deficiency Abnormal copper or ceruloplasmin level but Wilson disease excluded Nonspecific iron and/or ferritin abnormalities No active hepatitis A, B, and/or C
Inflammatory indices	Serum AST/ALT elevation Minimal-mild cholestatic changes	Serum AST/ALT elevation Minimal-mild cholestatic changes
Autoantibodies	ANA, SMA, or anti-LKM1 >1:80 in adults and >1:20 in children; no AMA	ANA, SMA or anti-LKM1>1:40 in adults; other autoantibodies
Immunoglobulins	Globulin, γ-globulin, or IgG level >1.5 times normal	Hypergammaglobulinemia of any degree
Histologic findings	Interface hepatitis, moderate to severe No biliary lesions, granulomas or prominent changes suggestive of another disease	Interface hepatitis, moderate to severe No biliary lesions, granulomas or prominent changes suggestive of another disease

AMA, antimitochondrial antibodies; ANA, antinuclear antibodies; AT, antitrypsin; anti-LKM1, antibodies to liver kidney microsome type 1; AST, aspartate aminotransferase; ALT, alanine aminotransferase; IgG, immunoglobulin G; SMA, smooth muscle antibodies.

Fig. 5.1 Histopathalogy of interface hepatitis in autoimmune hepatitis. Disruption of the limiting plate of the portal tract by mononuclear inflammatory infiltrate that extends into the acinus is shown (hematoxylin and eosin, ×400).

Fig. 5.2 Histopathology of panacinar hepatitis in autoimmune hepatitis. Mononuclear inflammatory cells line the sinusoidal spaces in association with liver cell degenerative and regenerative changes (hematoxylin and eosin, ×100).

Fig. 5.3 Histopathalogy of plasma cell infiltration in autoimmune hepatitis. Plasma cells typified by perinuclear cytoplasmic haloes contribute to mononuclear inflammatory infiltrate within the portal tract (hematoxylin and eosin, ×400).

TABLE 5.3 Revised original international scoring system for the diagnosis of autoimmune hepatitis

TABLE 5.4 Simplified international scoring system for the diagnosis of autoimmune hepatitis

Variable	Result	Points
Autoantibodies
ANA or SMA	≥1:40	+1
ANA or SMA	≥1:80	+2
anti-LKM1	≥1:40	+2
anti-SLA	Positive	+2
Immunoglobulin level
Immunoglobulin G	>ULN	+1
	>1.1 ULN	+2
Histologic findings
Morphologic features	Compatible	+1
	Typical	+2
Viral disease markers
No viral hepatitis	No viral markers	+2
Pretreatment aggregate score:
Definite diagnosis		≥7
Probable diagnosis		6

ANA, antinuclear antibodies; anti-LKM1, antibodies to liver kidney microsome type 1; anti-SLA, antibodies to soluble liver antigen; SMA, smooth muscle antibodies; ULN, upper limit of normal.