Approach Considerations
Clinicians must consider the diagnosis of autoimmune hepatitis in any patient who presents with abnormal liver chemistries, acute hepatitis, or acute liver failure (defined by the new onset of coagulopathy and hepatic encephalopathy).
In addition to aminotransferase levels and other liver function studies (albumin, bilirubin, alkaline phosphatase, international normalized ratio [INR]), the workup of such patients should include the following assays:
-
Serum antinuclear antibody (ANA)
-
Anti–smooth muscle antibody (ASMA)
-
Anti-mitochondrial antibody (AMA)
-
Quantitative immunoglobulins (IgG, IgA, IgM)
Additional testing may include the following:
-
Liver-kidney microsomal type 1 (LKM-1) antibody
-
Anti-soluble liver antigen (anti-SLA): This test should be considered if tests for ASMA and AMA are negative.
-
Serum protein electrophoresis (SPEP)
Other tests that may be considered, particularly in the setting of acute severe autoimmune hepatitis include the following:
-
Anti-hepatitis A virus (anti-HAV) total and IgM
-
Hepatitis B core (HBc) IgG and IgM, hepatitis B surface Ag (HBsAg), hepatitis B surface Ab (HBsAb)
-
Anti-HCV, HCV RNA [Note: One-time anti-HCV testing is now recommended by the Centers for Disease Control and Prevention (CDC) for all US adults]
-
Anti-hepatitis E virus (anti-HEV) IgM (and HEV RNA if anti-HEV IgM results are positive)
-
Anti-herpes simplex virus (anti-HSV) IgM
-
Epstein Barr Virus (EBV) DNA
-
Cytomegalovirus (CMV) DNA
-
Anti-varicella zoster virus (anti-VZV) IgM
-
Parvovirus B19 IgG and IgM
Laboratory findings in autoimmune hepatitis include the following:
-
Elevated serum aminotransferase levels (1.5-50 times reference values)
-
Elevated serum immunoglobulin levels, primarily IgG
-
Seropositive results for ANA, ASMA, anti-LKM-1, anti-SLA, or anti–liver cytosol 1 (anti-LC1)
While serologic tests may help the clinician make a correct a diagnosis of autoimmune hepatitis, it should be recalled that liver biopsy plays a pivotal role in the evaluation. The 2019 American Association for the Study of Liver Diseases (AASLD) practice guideline states: “The diagnosis of autoimmune hepatitis cannot be made without liver biopsy and compatible histologic findings.” [3]
Autoantibody Assays
Tests for antibodies to liver-kidney microsome type 1 (anti-LKM-1), soluble liver antigen (anti-SLA), and liver cytosol type 1 (anti-LC1) may be helpful if antinuclear antibody (ANA) and anti–smooth muscle antibody (ASMA) test results are negative.
Autoimmune hepatitis is characterized by positive findings on autoantibody tests, as follows:
-
AIH-1: ASMA and ANA
-
AIH-2: Anti-LKM-1 antibody
-
AIH-3: Anti-SLA
The 2019 AASLD Practice Guidelines indicate the following findings in White North American adults at time of presentation with autoimmune hepatitis [3] :
-
ANA is positive in 80%. Note that ANA may be positive in other chronic liver diseases and in healthy adults.
-
ASMA is positive in 63%. Note that ASMAs occur in low titers in healthy children and patients with viral hepatitis and other diseases that do not affect the liver.
-
Anti-LKM1 is positive in 3%.
-
Anti-SLA is positive in 7-22%.
In patients with type 2 autoimmune hepatitis, note the following:
-
Anti-LKM1 antibodies are positive in 40-45%.
-
Anti-LC1 antibodies occur alone in 30% of patients with autoimmune hepatitis type 2 (AIH-2).
Other autoantibodies may be evident. Atypical perinuclear antineutrophil cytoplasmic antibodies (pANCA) are frequently present. Anti-asialoglycoprotein receptor antibodies (anti-ASGPR) occur more often in patients with AIH-1 and may serve as a marker of inflammatory activity.
Of the multiple forms of ASMAs, antibodies against filamentous (F) actin may have the highest sensitivity for identifying patients with autoimmune hepatitis. They are seen in upward of 86% of patients. [55]
Serum Proteins and Immunoglobulins
An immunoglobulin G (IgG)-predominant polyclonal hypergammaglobulinemia is a common finding in patients with untreated autoimmune hepatitis. Gamma globulin values typically range from 3 to 4 g/dL and frequently are as high as 5-6 g/dL. Cases of hyperviscosity syndrome secondary to high IgG levels have been reported. Autoimmune hepatitis is an unlikely diagnosis in patients who have acute hepatitis without hypergammaglobulinemia.
The gamma globulin or the IgG level may be followed on a regular basis as a marker of disease responsiveness to therapy.
Patients with autoimmune hepatitis type 2 (AIH-2) commonly have partial IgA deficiency. [53]
Aminotransferases
Serum aminotransferases (aspartate aminotransferase [AST] and alanine aminotransferase [ALT]) are elevated in 100% of patients at initial presentation, with average values of 200-300 U/L. Aminotransferase values correlate poorly with the degree of hepatic necrosis; however, values in the thousands may indicate acute severe autoimmune hepatitis or a severe flare of preexisting disease.
Continued elevation of the aminotransferases in the face of continuing therapy is a reliable marker for ongoing inflammatory activity in the liver. Normalization of the aminotransferase levels during therapy is an encouraging sign, but active liver inflammation is present in more than 50% of patients with normalized liver chemistries. Indeed, biochemical remission may precede true histologic remission by 3-8 months.
Typically, patients are treated for at least 1 year after documentation of normal liver chemistries. Liver biopsy is recommended by some experts to confirm that the patient is in histologic remission. Drug withdrawal may be attempted at this time (see Treatment).
Worsening of aminotransferase levels in a patient undergoing treatment or in a patient who is in remission may signal a resurgence of disease activity.
Other liver chemistries
Serum bilirubin and alkaline phosphatase (ALP) values are mildly to moderately increased in 80-90% of patients. Marked hyperbilirubinemia can be seen in patients with acute severe autoimmune hepatitis. A sharp increase in the ALP values over the course of autoimmune disease might reflect the development of primary sclerosing cholangitis (PSC) or the onset of hepatocellular carcinoma as a complication of cirrhosis.
Hypoalbuminemia and prolongation of the prothrombin time are markers of severe hepatic synthetic dysfunction, which may be observed in severe acute autoimmune hepatitis or decompensated cirrhosis.
Complete Blood Cell Count and Other Blood Studies
Other hematologic abnormalities may include the following:
-
Mild leukopenia
-
Normochromic anemia
-
Coombs-positive hemolytic anemia
-
Thrombocytopenia
-
Elevated erythrocyte sedimentation rate (ESR)
Eosinophilia is uncommon, but counts ranging from 9% to 48% are described. Autoimmune hepatitis has even been described as the sole presenting feature of idiopathic hypereosinophilic syndrome (HES).
Hepatic Imaging Studies
Imaging studies, in general, are not helpful in reaching a definitive diagnosis of autoimmune hepatitis. However, the presence of heterogeneous hepatic echotexture on abdominal ultrasonography or abnormal contrast enhancement on abdominal computed tomography (CT) imaging may suggest the presence of active inflammation or necrosis.
The appearance of an irregular, nodular liver may confirm the presence of cirrhosis. Patients with suspected cirrhosis due to autoimmune hepatitis should undergo routine surveillance to rule out the development of hepatocellular carcinoma as a complication of cirrhosis. Typically, this involves the performance of a hepatic sonogram every 6 months, as well as blood testing for alpha fetoprotein (AFP). Abdomen CT scanning or magnetic resonance imaging (MRI) should be performed if a liver mass is discovered on ultrasonography.
Primary sclerosing cholangitis (PSC) needs to be ruled out in autoimmune hepatitis patients with either a rising alkaline phosphatase (ALP) level or a concomitant diagnosis of ulcerative colitis. MRI with MR cholangiopancreatography (MRCP) is an excellent noninvasive test to investigate the possibility of PSC.
Liver Biopsy
Liver biopsy is the most important diagnostic procedure in patients with autoimmune hepatitis. This procedure can be performed percutaneously, with or without ultrasonographic guidance, or by the transjugular route. The latter is preferred if the patient has coagulopathy or severe thrombocytopenia. A transjugular liver biopsy also may be preferable if ascites is present, if the liver is small and shrunken, or if the liver is difficult to reach percutaneously.
Liver biopsy routinely is performed in the outpatient setting to investigate abnormal liver chemistries. Liver biopsy should be performed as early as possible in patients with acute hepatitis who are thought to have autoimmune hepatitis. Confirmation of the diagnosis enables initiation of treatment at an early stage in the disease process.
The role of biopsy in patients presenting with well-established cirrhosis secondary to autoimmune hepatitis is less clear. For example, the initiation of treatment in a patient with cirrhosis, normal aminotransferase levels, and a minimally elevated gamma globulin level is not expected to influence the disease outcome.
Histologic Findings
Histopathologic findings on liver biopsy specimens are crucial to determining the diagnosis of autoimmune hepatitis and the disease severity. Liver biopsy findings can help to differentiate autoimmune hepatitis from chronic hepatitis C virus (HCV) infection, alcohol-induced hepatitis, drug-induced liver disease, primary biliary cholangitis (PBC), and primary sclerosing cholangitis (PSC). [56]
Key histologic features defined in the 2008 “simplified criteria” published by the International Autoimmune Hepatitis Group (IAHIG) include the following [57] :
-
Interface hepatitis: Lymphocytes and plasma cells infiltrate the portal tract and expand beyond its limiting plate to permeate the surrounding liver lobule. The infiltrate is commonly plasma cell predominant.
-
Emperipolesis: Lymphocytes may penetrate the cytoplasm of damaged hepatocytes.
-
Hepatocyte rosette formation: Small groups of hepatocytes appear to be arranged around a small central lumen.
Lobular hepatitis and perivenulitis (involving the terminal hepatic venule) also may be seen.
Fibrosis is present in most patients with autoimmune hepatitis. Without effective therapy, fibrosis starts to connect the portal and central areas, ultimately leading to cirrhosis.
Simplified criteria for making a diagnosis of autoimmune hepatitis
The IAHIG published its initial diagnostic scoring system for making a diagnosis of autoimmune hepatitis in 1993. [10] The system was initially designed for research purposes. A revised version was published in 1999, but it was still felt to be cumbersome by some users. [58, 59] The simplified system was introduced in 2008 and was found to be highly reliable. [57]
The simplified IAHIG diagnostic scoring system is as follows [57] :
-
If the antinuclear antibody (ANA) or smooth muscle antibody (SMA) cutoff is ≥1:40, assign 1 point
-
If the ANA or SMA cutoff is ≥1:80 ---
-
Or, soluble liver antigen (SLA) is positive ---
-
Or, if the liver-kidney microsome (LKM) cutoff is ≥1:40, assign 2 points (addition of points achieved for all autoantibodies, for a maximum of 2 points)
-
If immunoglobulin G (IgG) is over the upper limit of normal (ULN), assign 1 point; if it is over 1.10 times the ULN, assign 2 points
-
If the liver histology (evidence of hepatitis is required) is compatible with autoimmune hepatitis, assign 1 point; if it is typical of autoimmune hepatitis, assign 2 points
-
If viral hepatitis is absent, assign 2 points
If the total score is at least 6 points, autoimmune hepatitis is probable. If it is at least 7, then autoimmune hepatitis is definite.
Tables
Clinical Features |
Type 1 |
Type 2 |
Type 3 |
Diagnostic autoantibodies |
ASMA ANA Anti-actin |
Anti-LKM P-450 IID6 Synthetic core motif peptides 254-271 |
Soluble liver-kidney antigen Cytokeratins 8 and 18 |
Age |
10 y - elderly |
Pediatric (2-14 y) Rare in adults |
Adults (30-50 y) |
Women (%) |
78 |
89 |
90 |
Concurrent immune disease (%) |
41 |
34 |
58 |
Gamma globulin elevation |
+++ |
+ |
++ |
Low IgA |
No |
Occasional |
No |
HLA association |
B8, DR3, DR4 |
B14, Dr3, C4AQO |
Uncertain |
Steroid response |
+++ |
++ |
+++ |
Progression to cirrhosis (%) |
45 |
82 |
75 |
ANA = antinuclear antibody; anti-LKM = anti-liver-kidney microsomal antibody; ASMA = anti-smooth muscle antibody; HLA = human leukocyte antigen; IgA = immunoglobulin A. |
|||
Absolute Indications |
Relative Indications |
Serum aspartate transaminase (AST) ≥10-fold the upper limit of normal (ULN) |
Symptoms (eg, fatigue, arthralgia, jaundice) |
Serum AST ≥5-fold the ULN and gamma-globulin level ≥2-fold the ULN |
Serum AST and/or gamma-globulin less than absolute criteria |
Bridging necrosis or multiacinar necrosis on histologic examination |
Interface hepatitis |
|
Prednisone Only (mg/d) |
Combination Therapy |
|
Prednisone (mg/d) |
Azathioprine (mg/d) |
||
Week 1 |
60 |
30 |
50 |
Week 2 |
40 |
20 |
50 |
Week 3 |
30 |
15 |
50 |
Week 4 |
30 |
15 |
50 |
Maintenance until end point |
20 |
10 |
50 |
Reasons for preference |
Cytopenia
Thiopurine methyltransferase deficiency
Pregnancy
Malignancy
Short course (≤6 months) |
Postmenopausal state
Osteoporosis
Brittle diabetes
Obesity
Acne
Emotional lability
Hypertension |
|
Initial Regimen |
Maintenance Regimen |
End Point |
Prednisone, 1-2 mg/kg/day (up to 60 mg/day), for 2 weeks, either alone or in combination with azathioprine, 1-2 mg/kg/day |
a. Prednisone taper over 6-8 weeks to 0.1-0.2 mg/kg daily or 5 mg daily
b. Azathioprine at constant dose if added initially
c. Continue daily prednisone dose with or without azathioprine, or switch to alternate day prednisone dose adjusted to response with or without azathioprine |
a. Normal liver tests for 1-2 years during treatment
b. No flare during entire interval
c. Liver biopsy examination discloses no inflammation |
