Autoimmune Hepatitis

GENERAL PRINCIPLES

Autoimmune hepatitis (AIH) is a chronic inflammation of the liver of unknown cause, associated with circulating autoantibodies and hyperglobulinemia.

• Women are affected more than men (gender ratio 4:1).

• Extrahepatic manifestations may be found in 30%-50% of patients and include synovitis, celiac disease, Coombs-positive hemolytic anemia, autoimmune thyroiditis, Graves disease, rheumatoid arthritis, ulcerative colitis (UC), and other immune-mediated processes.

Two types of AIH have been proposed based on differences in their immunologic markers. They have a good response to corticosteroid therapy.

• Type IAIH is the most common form of the disease and constitutes 80% of AIH cases. It is associated with antinuclear antibodies (ANA) and anti-smooth muscle antibodies.

• Type 2 AIH is characterized by antibodies to liver/kidney microsome type 1 and/or liver cytosol type 1. This type is predominately seen in children and young adults.

DIAGNOSIS

Clinical Presentation

• AST and ALT elevations are usually more marked than those of bilirubin and ALP, although a cholestatic pattern can occur.

• Elevated serum globulins, particularly #947;-globulins (IgG), are characteristic of AIH. Hyperglobulinemia is generally associated with circulating autoantibodies, which are helpful in identifying AIH.

• In approximately 30%-40% of cases, the clinical presentation is similar to acute viral hepatitis. A smaller percentage of patients may present in ALF or with asymptomatic elevation of serum ALT. It presents with cirrhosis in at least 25% of patients.

• The most common symptoms at presentation include fatigue, jaundice, myalgias, anorexia, diarrhea, acne, abnormal menses, and right upper quadrant abdominal discomfort.

• Patients with AIH may overlap with clinical and histologic findings consistent with other liver diseases (e.g., PBC, PSC, Wilson disease [WD], and autoimmune cholangitis).

• The International Autoimmune Hepatitis Group developed a diagnostic scoring system. The scoring system accounts for sex, LFTs, elevated IgG, antibodies such as ANA/SMA, HLA genetic variants and history of other autoimmune disease, histologic features, treatment response, and likelihood of an etiology other than AIH.¹¹

Diagnostic Testing

Liver biopsy is recommended for definitive diagnosis.

• “Piecemeal necrosis” or interface hepatitis with lobular or panacinar inflammation (Iymphoplasmacytic infiltration) is the histologic hallmark of AIH.

• Histologic changes, such as ductopenia or destructive cholangitis, may indicate overlap syndromes with AIH and primary sclerosing cholangitis, PBC, or autoimmune cholangitis.

TREATMENT

Begin treatment in patients with serum AST and ALT levels gt; 10 times the ULN, IgG gt;2 times the ULN, and histologic features of interface hepatitis, bridging necrosis or multiacinar necrosis. Those with lower level transaminase elevations should be considered for treatment if the serum AST and ALT levels gt; two times the ULN along with symptoms, elevated IgG level, elevated conjugated bilirubin, and interface hepatitis on biopsy.

Medications

• Therapy consists of prednisone (50-60 mg/d PO) monotherapy or prednisone at a lower dose (30 mg/d PO) with azathioprine (AZA; 50 mg or up to 1-2 mg/kg). The dose of prednisone is tapered down over weeks to months. Tapering patients off corticosteroids within weeks to a few months is an option, especially if the liver tests normalize. The AZA dose can be increased if the liver tests fail to improve. AZA is usually continued long term. Some patients may achieve remission with cessation of AZA. However, stopping immunosuppressive therapy increases the risk of a disease flare, necessitating reinstitution of therapy.

• The combination of prednisone and AZA decreases corticosteroid-associated side effects; however, AZA should be used with caution in patients with pretreatment cytopenias or thiopurine methyltransferase (TPMT) deficiency.

• TPMT phenotyping should be obtained prior to initiating treatment.

• Budesonide (6-9 mg/d PO), in combination with AZA (1-2 mg/kg/d PO), may also result in normalization of AST and ALT, with fewer steroid-specific side effects, in noncirrhotic adults with AIH.¹²

• Second-line treatments for suboptimal response or treatment failures include mycophenolate mofetil, tacrolimus, cyclosporine, and budesonide.

Treatment Failure

• Consider liver transplantation in patients with ESLD and those with AIH-mediated fulminant hepatic failure (FHF).

• After transplantation, recurrent AIH is seen in approximately 15% of patients. De novo AIH or immunologically mediated hepatitis, defined as hepatitis with histologic features similar to AIH in patients transplanted for nonautoimmune diseases, has been described in about 5% of transplant recipients.¹³

Monitoring and Follow-Up

• About 90% of adults have improvements in the serum aminotransferase, bilirubin, and #947;-globulin levels within the first 2 weeks of treatment.

• Histologic improvement lags behind clinical and laboratory improvement by 3-8 months.

OUTCOME AND PROGNOSIS

• The overall goal of treatment is normalization of aminotransferases, hyperglobulinemia (IgG), and liver histology.

• Remission is achieved in 65% and 80% of patients within 1.5-3 years of treatment, respectively.

• Relapses occur in at least 20%-50% of patients after cessation of therapy and require retreatment.