Frequency and significance of the variant syndromes of autoimmune hepatitis

Abstract

The variant syndromes of autoimmune hepatitis (AIH) have features of AIH and primary biliary cirrhosis (AIH/PBC), AIH and primary sclerosing cholangitis (AIH/PSC), and autoimmune cholangitis (AC). AIMS: To evaluate the frequency and nature of the variant syndromes of AIH and to determine their distinguishing characteristics and prognostic significance. METHODS: Two hundred twenty-six patients with the clinical diagnoses of AIH (162 patients), PBC (37 patients) and PSC (27 patients) were graded by the scoring system of the International Autoimmune Hepatitis Group for probable and definite diagnoses of AIH. Patients in the clinical category of AIH who were graded as probable or no AIH were scrutinized further for variant features. Patients who were graded as probable or definite AIH in the clinical categories of PBC and PSC were regarded as variant syndromes. RESULTS: Variant syndromes of AIH, including those with features of PBC (15 patients), PSC (15 patients) and AC (11 patients), were present in 41 of the 226 patients with autoimmune liver disease (18%). Patients with AC had fewer features of AIH than the other variants and the lowest autoimmune score compared to definite AIH (10.4 _+ 0.8 vs 18.5 _+ 0.2, p<0.0001). In contrast, patients with AIH/PBC had the most features in common with definite AIH, including similar serum aspartate aminotransferase (565 _+ 159 U/L vs 519 _+ 38 U/L), bilirubin, and alkaline phosphatase (433 _+ 68 U/L/vs 360_+ 26 U/L) levels. They differed mainly by having antimitochondrial antibodies (p<0.0001), higher IgM levels (p=0.0006), and a lower frequency of the A1-BS-DR3 phenotype (p=0.02). Patients with AIH/PSC were distinguished from definite AIH by their male predominance (67%), low occurrence of autoantibodies (p=0.004), increased alkaline phosphatase levels (p<0.0001), and low prevalence of HLA DR4 (p=0.01). Only patients with AC failed to respond to corticosteroids. Remission occurred less frequently in these patients than in those with definite AIH (0% vs 55%, p=0.003). Similarly, remission occurred less often in patients with AIH/PSC than in definite AIH (2% vs 55%, p=0.01) and they more commonly experienced an adverse outcome (70% vs 22%, p=0.003). In contrast, patients with AII-I/PBC responded as well to corticosteroids as those with definite AIH. The principal finding associated with corticosteroid responsiveness among all variants was a serum alkaline phosphatase level of less than twofold normal (p=0.0009). CONCLUSIONS: Variant syndromes of AIH are common. AIH/PBC is the variant that most closely resembles AIH and it frequently improves with corticosteroid therapy. AC is an outlier variant and it may be a separate disease. Steroid responsiveness is associated with low serum alkaline phosphatase levels.