Antimitochondrial Antibody—Negative Chronic Nonsuppurative Destructive Cholangitis

Abstract

We investigated whether autoimmune cholangitis (AC) has specific features that constitute an entity other than primary biliary cirrhosis (PBC). We compared clinical, laboratory, and liver biopsy features; response to treatment; and the follow-up of two groups of patients. The first group comprised seven patients with AC criteria-PBC with negative antimitochondrial antibodies (AMAs) and positive antinuclear antibodies (ANAs)-termed the PBC AMA-negative group; the second was made up of another seven PBC patients with positive AMA, labeled the PBC AMA-positive group. We found that the PBC AMA-negative group had, besides negative AMAs and positive ANAs, a significantly higher incidence of asthenia, a higher and earlier incidence of liver failure, and higher ANA titers and serum immunoglobulin G levels than the PBC AMA-positive group. There were no significant differences in the other laboratory tests, although the PBC AMA-negative group showed higher serum bilirubin and aminotransferase and lower serum alkaline phosphatase and immunoglobulin M levels. Liver histological data were similar in both groups. Patients in the PBC AMA-negative group, with more markedly abnormal liver tests, responded to immunosuppressive therapy. We concluded that patients with criteria for PBC but with negative AMAs and positive ANAs have a few specific features that fall between PBC and autoimmune chronic hepatitis. This finding suggests that these patients have a different disease, for which autoimmune cholangitis seems to be an appropriate name.

Positive markers in AMA-negative PBC

“…Viral infectious in animals have provided suitable infectious disease models for the induction of autoimmune destruction of ␤ islet cell, and infections with enteroviruses, such as echovirus 9 and Coxsackie B3 and B4 virus, have been linked with type I diabetes in children and young adolescents (3)(4)(5)(6). Genome scanning studies have shown that the human leukocyte antigens (HLA) genes within the major histocompatibility complex provide the most prominent linkage associated with type I diabetes; the extended haplotype DR4, DQA3, DQB3/2 reportedly provides a 5-to 35-fold increased relative risk for disease (7). In addition, polymorphisms in the promoter region of the insulin gene are associated with the development of type I diabetes (8).…”

Autoimmune overlap syndromes

“…40 Over subsequent years, increasing numbers of patients with similar presentations have been described as "primary autoimmune cholangitis," 13,41,42 "autoimmune cholangiopathy," 43 or AMA-negative PBC. 14,44,45 The principal discriminant from classical PBC in all of these studies is the lack of AMA. In one study 32% of patients with PBC were found to be AMA negative 13 ; however, this is probably skewed by the specialist referral practice of the Ishak.…”

“…13,14,41,44 A total of 13 patients with AMA-negative PBC or "autoimmune cholangitis" 14,110,111 were treated with UDCA, and showed biochemical improvements indistinguishable from those of similarly treated AMA-positive PBC patients. However, in other reported series, immunosuppression has been given in view of the high ANA titers with improved clinical and biochemical markers in 2 studies 43,44 that included 7 patients in total, but with only transient biochemical improvement in 1 of 13 patients combined from 2 other series. 39,41 In only 4 patients were follow-up biopsies available after immunosuppressive treatment, and showed diminished hepatitic features but no improvement of bile duct damage.…”

Autoimmune cholangitis within the spectrum of autoimmune liver disease

“…Indeed, autoimmune cholangitis has been variously categorized as a variant of primary biliary cirrhosis (PBC) 4,[6][7][8] or autoimmune hepatitis (AIH), 5,9 a hybrid of both, 10 and a separate disease entity. 2,3,11 Patients with autoimmune cholangitis have been distinguished from patients with PBC by having higher serum levels of aspartate transaminase (AST) and lower serum concentrations of immunoglobulin M. 2 They also have been characterized by the presence of antibodies to carbonic anhydrase in serum, 12 HLA risk factors that are different from PBC, 13 and clonal expansion of liver-infiltrating lymphocytes that express V␤5.1 T-cell receptors. 14 These findings have suggested that autoimmune cholangitis is an entity distinct from PBC and not an ''AMA-negative'' variant.…”