Autoimmune Hepatitis Differential Diagnoses

Updated: Jun 11, 2019
  • Author: David C Wolf, MD, FACP, FACG, AGAF, FAASLD; Chief Editor: BS Anand, MD  more...
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Diagnostic Considerations

Because autoimmune hepatitis is a potentially treatable condition, a missed diagnosis can have serious consequences. The diagnosis should be considered in all patients with hepatitis, especially females. Untreated autoimmune hepatitis can result in death due to liver failure.

Similarly, a wrong diagnosis of autoimmune hepatitis can expose the patient to unnecessary complications of immunosuppressant therapy, which can be serious and life threatening.

Regardless of the mode of presentation (ie, acute vs chronic), autoimmune hepatitis always becomes chronic, making it unnecessary to wait 6 months to prove the chronic nature of the disease.

Differential diagnoses for autoimmune hepatitis should include many causes of chronic liver disease, including α1 -antitrypsin deficiency, Wilson disease, viral hepatitis, hepatotoxic drugs, and excessive alcohol consumption.

Autoimmune hepatitis must also be differentiated from autoimmune polyendocrine syndrome type I (APS-1), autoimmunity in hepatitis C virus (HCV) infection, immune-mediated drug-induced hepatitis, cryptogenic hepatitis, and overlap syndrome.

Autoimmune hepatitis and hepatitis C

HCV has several important associations with autoimmune hepatitis. The prevalence rate of HCV infection in patients with autoimmune hepatitis is similar to that in the general population. This implies that HCV is not an important factor in the etiology of autoimmune hepatitis.

However, patients who are seropositive for liver-kidney microsomal type 1 (LKM-1) antibodies frequently are infected with HCV. These patients have predominant features of chronic viral hepatitis and frequently lack antibodies to cytochrome P-450 IID6. Such patients respond to treatment with interferon. They should be distinguished from anti–LKM-1-positive patients who have a positive anti–P-450 IID6 test, are seronegative for anti-HCV, and are responsive to steroid therapy. [40]

False-positive results on anti-HCV enzyme-linked immunoassay (ELISA) tests are described in the setting of hypergammaglobulinemia, including that observed in patients with autoimmune hepatitis. In patients with antinuclear antibody (ANA) and/or anti–smooth muscle antibody (ASMA) seropositivity and positive anti-HCV serology, a false-positive reaction to HCV should be excluded by performing a test for HCV RNA using the polymerase chain reaction (PCR).

In general, patients with definite autoimmune hepatitis have median serum titers of ASMA and ANA of 1:160 and 1:320, respectively. In contrast, these titers may be in the range of 1:80 or less in patients with true chronic viral hepatitis.

Although autoimmune hepatitis and chronic HCV have similar histologic features, moderate-to-severe plasma cell infiltration of the portal tracts is more common in patients with autoimmune hepatitis. Portal lymphoid aggregates, steatosis, and bile duct damage are more common in patients with chronic HCV.

Overlap syndromes

Patients with autoimmune hepatitis may present with features that overlap with those classically associated with patients with primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC).

About 7% of patients with autoimmune hepatitis have a disease that overlaps with PBC. They may have detectable antimitochondrial antibody (usually in low titer), histologic findings of bile duct injury and/or destruction, and the presence of hepatic copper. The natural history of the disease tends to echo type 1 autoimmune hepatitis. Patients with the autoimmune hepatitis–PBC overlap syndrome may improve with steroid therapy.

About 6% of patients with autoimmune hepatitis have a disease that overlaps with PSC. Patients with the autoimmune hepatitis–PSC overlap syndrome frequently have concurrent inflammatory bowel disease. The liver biopsy findings reveal bile duct injury. Findings from cholangiograms are abnormal. Such patients usually have mixed hepatocellular and cholestatic liver chemistries and typically are resistant to steroid therapy. Treatment with ursodiol should be considered. The natural history of autoimmune hepatitis–PSC is not well studied.

One article assessed 41 consecutive patients with PSC, 34 patients with classical PSC and 7 patients with the autoimmune hepatitis-PSC overlap syndrome. [41] The mean follow-up period was 14 years. Patients with autoimmune hepatitis–PSC tended to present at a younger age and had more elevated aminotransferases and serum immunoglobulin G (IgG) measurements than patients with classical PSC. They also appeared to have a better chance for transplant-free survival.

One case of cholangiocarcinoma, no deaths, and 1 transplant were reported among the 7 patients with autoimmune hepatitis–PSC, as compared to 5 cases of cholangiocarcinoma, 9 deaths, and 6 transplants among the 34 patients with classical PSC.

Autoimmune cholangitis is characterized by mixed hepatic and cholestatic liver chemistries, positive ANA and/or ASMA, negative AMA, antibodies to carbonic anhydrase, and histology that resembles PBC. Some authors contend that this condition is AMA-negative PBC. Patients may have an unpredictable response to therapy with steroids or ursodiol.

Cryptogenic autoimmune hepatitis is characterized by a clinical picture that is indistinguishable from autoimmune hepatitis. Here, the diagnosis is made by liver biopsy. ANA, ASMA, and anti–LKM-1 are negative at disease onset and may appear late in the disease course, as might anti-SLA. The disease usually is responsive to steroid therapy.

Differential Diagnoses