Investigations
1st investigations to order
aspartate transaminase
Test
Indicator of inflammatory activity in the liver. Raised in patients with AIH at initial presentation.
Raised in other liver diseases. Not specific to liver disease.
Higher values in fulminant forms.
Result
values averaging 200 to 300 international units/L
alanine transaminase
Test
Indicator of inflammatory activity in the liver. Raised in patients with AIH at initial presentation.
Raised in other liver diseases. Not specific to liver disease.
Higher values in fulminant forms.
Result
values averaging 200 to 300 international units/L
bilirubin
Test
Increased in most patients with AIH.
Also raised in other liver diseases, Gilbert's syndrome and other inherited disorders of bilirubin transport and metabolism, haemolysis (usually an unconjugated hyperbilirubinaemia), and ineffective erythropoiesis.
Higher levels of conjugated bilirubin in cholestatic forms (rare).[1]
Result
mildly to moderately increased
gamma glutamyl transferase (gamma-GT)
Test
When levels of gamma-GT and alkaline phosphatase are markedly raised, or the alkaline phosphatase:aminotransferase ratio is greater than 3, bile duct injury should be suspected. A diagnosis of sclerosing cholangitis or AIH-sclerosing cholangitis overlap syndrome should be considered in this setting.
Gamma-GT levels are also raised by alcohol abuse, intra-hepatic or extra-hepatic cholestasis and biliary obstruction, hepatocellular disease of other origin, and hepatic malignancies.
Higher levels in cholestatic forms (rare) and overlap syndromes.
Result
mildly to moderately increased
alkaline phosphatase
Test
Only 21% of patients have alkaline phosphatase levels that exceed 2-fold normal and none with classical disease have levels that exceed 4-fold normal.[13] When levels of gamma glutamyl transferase and alkaline phosphatase are markedly raised, or the alkaline phosphatase:aminotransferase ratio is more than 3, bile duct injury should be suspected and a diagnosis of sclerosing cholangitis or AIH-sclerosing cholangitis overlap syndrome should be considered.
Levels are also raised by intra-hepatic or extra-hepatic cholestasis, hepatocellular disease of other origin, and some bone diseases.
Higher levels in cholestatic forms (rare) and overlap syndromes.[13]
Result
mildly to moderately increased
serum globulin
Test
Gamma-globulin levels are usually 1.2 to 3.0 times normal; more marked elevation is seen in patients with type 1 than type 2 AIH.[3] Hyperglobulinaemia is associated with circulating auto-antibodies. Increased levels of gamma-globulins are found in approximately 85% of patients.[26] However, normal globulin or immunoglobulin G (IgG) levels cannot exclude a diagnosis of AIH.
The presence of high IgG levels is a very distinctive feature (IgA and IgM levels are usually normal). Increased IgA or IgM levels suggest different diseases such as alcoholic steatohepatitis and primary biliary cholangitis (PBC), respectively.[26]
The test is not specific to liver disease; raised levels are often seen in Hodgkin's disease, chronic lymphocytic leukaemia, and lymphoma. Venous blood sample should be drawn after patients have not eaten for at least 8 hours before the test.[3]
Result
markedly increased in patients with untreated AIH (IgG-predominant polyclonal hypergammaglobulinaemia); IgA and IgM levels usually normal
serum albumin
Test
Good indicator of hepatocellular function. Serum albumin levels are reduced in most forms of chronic liver disease, particularly cirrhosis.
Decreased also in nephrotic syndrome, malnutrition and malabsorption, chronic infection, and loss from bloodstream (haemorrhage, burns, exudates) or gastrointestinal tract (protein-losing enteropathies).
Result
decreased
prothrombin time
Test
Good indicator of hepatocellular function. Prolonged in cirrhosis or fulminant liver failure of other causes, genetic abnormalities of the coagulation factors (congenital factor VII deficiency), or use of anti-coagulants (warfarin therapy).
Result
prolonged
Investigations to consider
antinuclear antibodies (ANAs)
Test
ANAs are not disease-specific and abnormal results can occur in systemic lupus erythematosus, scleroderma, mixed connective tissue disease, Sjogren's syndrome, primary biliary cirrhosis, primary sclerosing cholangitis, non-alcoholic steatohepatitis, hepatitis C, tuberculosis, pulmonary interstitial fibrosis, and necrotising vasculitis. Found in 43% of patients with type 1 AIH.[26]
Titres are usually more than 1:160, but low titres (1:40 to 1:80) do not preclude the diagnosis in patients with other compatible features.
Five percent of the normal population may have a titre between 1:160 and 1:320.[3][18]
Result
titres 1:80 or higher in adults (1:40 or higher in children) are associated with type 1 AIH
smooth muscle antibodies (SMAs)
Test
SMAs are not disease-specific and abnormal results can occur in drug-induced hepatitis, cryptogenic cirrhosis, transient viral infection, and other liver diseases.
Result
titres 1:80 or higher in adults (1:40 or higher in children) are associated with type 1 AIH
anti-soluble liver antigens or liver/pancreas (anti-SLA/LP)
Test
They are highly specific markers of AIH. A 50-kDa cytosolic protein is the target antigen.[2] Found in approximately 10% to 30% of all patients with AIH.[28][29] Anti-SLA/LP is the only disease-specific auto-antibody and therefore has high diagnostic value. This has led to the development of reliable commercial assays for anti-SLA/LP detection (enzyme-linked immunosorbent assay [ELISA] and dot-blot).[26]
Result
may be positive in patients with type 1 AIH
perinuclear anti-neutrophil cytoplasmic antibodies (pANCA)
Test
In patients who are seronegative for ANA/SMA or anti-SLA/LP, it is useful to test for atypical pANCA to aid diagnosis.[1] The prevalence of pANCA, traditionally associated with primary sclerosing cholangitis and inflammatory bowel disease, is 40% to 95% of patients with type 1 AIH.[2][3]
Result
atypical pANCA can be found in patients with type 1 AIH
antibodies against single-stranded DNA (anti-ssDNA)
Test
Patients with antinuclear antibody (ANA)-positive type 1 AIH may also have anti-ssDNA antibodies.[27]
Result
positive in some patients with type 1 AIH
antibodies against double-stranded DNA (anti-dsDNA antibodies)
Test
Patients with antinuclear antibody (ANA)-positive type 1 AIH may also have anti-dsDNA.[27]
Also positive in systemic lupus erythematosus, rheumatoid arthritis, Sjogren's syndrome, scleroderma, and Raynaud's disease.
Result
positive in some patients with type 1 AIH
antibodies to liver/kidney microsome type 1 antigen (anti-LKM-1 antibodies)
Test
Characteristic serological marker for the diagnosis of type 2 AIH.[1]
Result
titres 1:80 or higher in adults (1:20 or higher in children) are associated with type 2 AIH
antibodies to liver/kidney microsome type 3 antigen (anti-LKM-3)
antibodies to liver cytosol 1 antigen (anti-LC1)
Test
Anti-LC1 antibody is a specific marker of type 2 AIH, together with anti-LKM-1 auto-antibodies.
Anti-LC1 antibodies are present in 32% of patients with anti-LKM-1, occurring mainly in children with severe disease.[1]
Result
positive in some patients with type 2 AIH
anti-mitochondrial antibodies (AMAs)
Test
Isolated elevation of AMA is virtually diagnostic for primary biliary cirrhosis, except in rare instances of AIH/primary biliary cirrhosis overlap syndrome.
Result
rarely positive in AIH, usually accompanying antinuclear antibodies (ANAs), soluble liver antigen antibodies (SLAs), and/or smooth muscle autoantibodies (SMAs)
antibodies against asialoglycoprotein receptor (anti-ASGP-R)
Test
Determination of anti-ASGP-R may be particularly useful for the identification of patients who are seronegative for traditional markers, although they can co-exist with antinuclear antibodies (ANAs), smooth muscle autoantibodies (SMAs), or anti-LKM-1.[2]
Also found in some patients with primary biliary cirrhosis, chronic viral hepatitis B and C, and alcoholic liver disease, although at lower frequency and lower titres.
Result
detected in up to 90% of patients with AIH
IgM antibodies to hepatitis A virus (IgM anti-HAV)
Test
Test of exclusion for alternative diagnosis: hepatitis A.
Result
negative
hepatitis B surface antigen (HBsAg)
Test
Test of exclusion for alternative diagnosis: hepatitis B.
Result
negative
antibodies to hepatitis B core antigen (anti-HBc)
Test
Test of exclusion for alternative diagnosis: hepatitis B.
Result
negative
hepatitis C antibodies and viral RNA
Test
Test of exclusion for alternative diagnosis: hepatitis C.
Result
negative
ceruloplasmin
Test
Test of exclusion for alternative diagnosis: Wilson's disease.
Result
normal
alpha-1 antitrypsin
Test
Test of exclusion for alternative diagnosis: alpha-1 antitrypsin deficiency.
Result
normal
serum iron and total iron binding capacity
Test
Test of exclusion for alternative diagnosis: haemochromatosis.
Result
normal
thiopurine methyltransferase (TPMT) activity
Test
Not a diagnostic test in AIH, but used to determine treatment regimen.
Azathioprine is contraindicated in patients with reduced TPMT activity.
Result
may be reduced
abdominal ultrasound
Test
Most patients who have elevated liver enzymes will have an abdominal ultrasound. There are no characteristic imaging features for AIH; however, ultrasound can evaluate for extra-hepatic biliary obstruction, abnormalities in liver morphology, and changes associated with portal hypertension such as splenomegaly.[30][31]
Result
no characteristic imaging features for AIH; biliary dilatation may be seen if cholestatic picture; features of portal hypertension (e.g., splenomegaly may be present in chronic disease)
liver biopsy
Test
Essential to establish the diagnosis, evaluate disease severity, and determine the need for treatment.[1]
The percutaneous route is generally not considered safe if the INR is more than 1.5 or the platelet count is less than 50,000/mm³.
The transjugular route is preferred in patients with coagulopathy, severe thrombocytopenia, or ascites.[32]
Possible complications include bleeding, bowel perforation, and pneumothorax. Risk of mortality is very low (0.01%).[33]
Result
characterised by a periportal lesion or interface hepatitis (a portal mononuclear and plasma cell infiltrate)
Emerging tests
Transient elastography (TE)
Test
Ultrasound-based TE can be performed to stage liver fibrosis using liver stiffness measurements, similar to FibroScan/vibration-controlled TE (VCTE). It may play some role in monitoring AIH after at least 6 months of immunosuppressive therapy but its role has not yet been clearly defined. TE cannot accurately stage fibrosis at time of diagnosis because hepatic inflammation is a known confounding factor that can lead to over-estimation of liver stiffness, independent of fibrosis.[37]
Result
more advanced fibrosis stages are associated with higher liver stiffness measurement values
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