Diagnosis of autoimmune hepatitis in any patient who has
acute hepatitis or acute liver failure (defined by the new onset of
coagulopathy include the following assays:
·
Serum antinuclear antibody (ANA)
·
Anti–smooth muscle antibody (ASMA)
·
Liver-kidney microsomal type 1 (LKM-1) antibody
·
Serum protein electrophoresis (SPEP)
·
Quantitative immunoglobulins
Urgent liver biopsy, transjugular if appropriate, may help
to confirm the clinical suspicion of autoimmune hepatitis.
Laboratory findings in autoimmune hepatitis include the
following:
·
Elevated serum aminotransferase levels (1.5-50
times reference values)
·
Elevated serum immunoglobulin levels, primarily
immunoglobulin G (IgG)
·
Seropositive results for ANAs, SMAs, or LKM-1 or
anti–liver cytosol 1 (anti-LC1) antibodies
In 50% of patients, abnormal results on liver function tests
include decreased albumin levels and prolonged prothrombin time.
Autoantibody Assays
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 - Antibodies to soluble liver antigen
(anti-SLA)
SMAs are present in 90%-100% of patients with autoimmune
hepatitis type 1 (AIH-1). ANAs are present in 10% of patients with AIH-1 and in
association with SMAs in 40%-60% of patients with AIH-1. Titers range from
1:100-500,000. SMAs occur in low titers in healthy children and patients with
viral hepatitis and other diseases that do not affect the liver.
LKM-1 antibodies are present in 40%-45% of patients with
AIH-2 and are associated with anti-LC1 antibodies in 50% of patients. Anti-LC1
antibodies occur alone in 30% of patients with AIH-2; these antibodies
recognize formiminotransferase cyclodeaminase, a liver-specific 58kD metabolic
enzyme. Anti-asialoglycoprotein receptor antibodies occur more often in
patients with AIH-1 and may serve as a marker of inflammatory activity.
Other autoantibodies may be evident. Atypical perinuclear
antineutrophil cytoplasmic antibodies (pANCA) are frequently present. Czaja et
al have shown that patients with autoimmune hepatitis who have positive test
results for actin antibody are younger, more commonly test positive for human
leukocyte antigen (HLA)–DR3, and required transplantation more frequently than
patients with ANAs who test negative for actin antibody
Serum Proteins and
Immunoglobulins
An IgG-predominant polyclonal hypergammaglobulinemia is a
common finding in patients with untreated autoimmune hepatitis. Gamma globulin
values typically range from 3-4 g/dL and frequently are as high as 5-6 g/dL.
Cases of hyperviscosity syndrome secondary to high IgG levels are 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 AIH-2 commonly have partial immunoglobulin A
(IgA) deficiency.
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 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 3-6 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 values are mildly
to moderately increased in 80%-90% of patients. A sharp increase in the
alkaline phosphatase values during the course of autoimmune disease might
reflect the development of 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
active disease or decompensated cirrhosis.
Complete Blood 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
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.
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 ultrasound or abnormal contrast
enhancement on abdominal CT imaging may suggest the presence of active
inflammation or necrosis.
The appearance of an irregular nodular liver may confirm the
presence of cirrhosis. Furthermore, these imaging studies may be used to rule
out the presence of hepatocellular carcinoma, a potential complication of
autoimmune hepatitis–induced cirrhosis.
When alkaline phosphatase levels are 7-8 times reference
values or gamma glutamyl transferase levels are 2-3 times reference values, a
patient with autoimmune hepatitis and ulcerative colitis may require endoscopic
retrograde cholangiopancreatography (ERCP) to rule out coexisting primary
sclerosing cholangitis (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 ultrasound 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 or if the liver is small, shrunken, and 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. As an 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's
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 cirrhosis, and PSC. [43]
Autoimmune hepatitis is characterized by a portal
mononuclear cell infiltrate that invades the limiting plate surrounding the
portal triad and permeates the surrounding lobule (ie, periportal infiltrate)
and beyond. A plasma cell infiltrate sometimes occurs, which, in the past, led
to the use of the term plasma cell hepatitis.
Biopsies may show evidence for interface hepatitis (ie,
piecemeal necrosis), bridging necrosis, and fibrosis. Interface hepatitis
essentially spares the biliary tree but may involve most of the lobule. Lobular
collapse, best identified by reticulin staining, is a common finding.
Interface hepatitis does not predict a progressive disease
course. By contrast, a strong likelihood exists that cirrhosis will develop
when bridging necrosis is present. The presence or absence of cirrhosis on
liver biopsy is an important determinant of the patient's prognosis.
Fibrosis is present in most patients with autoimmune
hepatitis. Without effective therapy, fibrosis starts to connect the portal and
central areas, which ultimately leads to cirrhosis.
In 1999, the International Autoimmune Hepatitis Group
established a scoring system that is particularly helpful in establishing the
diagnosis of autoimmune hepatitis in problematic cases. [44, 45]
Histopathologic findings in patients with autoimmune
hepatitis are characteristic but nonspecific; autoimmune hepatitis has findings
in common with chronic viral hepatitis, drug-associated chronic hepatitis, and
several other chronic liver disorders. Multinucleated giant hepatocytes are
found in 10%-20% of biopsy specimens; their occurrence after the neonatal
period may suggest a diagnosis of autoimmune hepatitis.
Tucker et al indicate that the presence of characteristic
hyaline droplets in the cytoplasm of Kupffer cells on routine hematoxylin and
eosin (H&E) from biopsy specimens in pediatric patients with autoimmune
hepatitis may provide a useful diagnostic clue to distinguish this disease from
other forms of chronic hepatitis.
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