Elsevier

Clinics in Liver Disease

Volume 12, Issue 1, February 2008, Pages 173-185
Clinics in Liver Disease

Anti-Mitochondrial Antibody–Negative Primary Biliary Cirrhosis

https://doi.org/10.1016/j.cld.2007.11.008Get rights and content

The recent development in the authors' laboratory of a sensitive bead assay able to detect AMA in 20% of otherwise AMA-negative sera seems to support the hypothesis that many AMA-negative cases of primary biliary cirrhosis (PCB) are secondary to limits in the methods used and do not represent an independent clinical entity. Clinical data demonstrate that patients without detectable serum AMA do not differ in their natural history from their seropositive counterparts. Anti-nuclear antibodies have been associated repeatedly with more severe disease and are helpful tools in the management of patients who have PBC, particularly those lacking AMA.

Section snippets

Autoantibodies in primary biliary cirrhosis

As in most autoimmune diseases, noninvasive tests for autoantibodies are the cornerstone of the diagnostic process in patients suspected of having PBC. Ideally, serum hallmarks should be 100% specific and sensitive, but this state is seldom achieved in everyday practice. The case of serum AMA in PBC comes close to this ideal scenario, but several gray spots remain and warrant clarification for the clinical practitioner and the basic scientist alike.

Serum AMA at titers higher than 1:40 are

Autoantigens in primary biliary cirrhosis

Thanks to the earlier work of Gershwin and colleagues [37], it now is established that AMA are directed against components of the 2-oxoacid dehydrogenase complex (2-OADC) family, including the E2 subunit of the pyruvate dehydrogenase complex (PDC-E2), the branched chain 2-oxo-acid dehydrogenase complex (BCOADC-E2), and the oxoglutarate dehydrogenase complex (OGDC-E2), as well as the dihydrolipoamide dehydrogenase (E3)-binding protein (E3BP) and the E1α subunit of pyruvate dehydrogenase complex

The significance of anti-mitochondrial antibodies in primary biliary cirrhosis

AMA are clinically important in both the diagnosis and management of PBC. A positive result from a routine AMA test strongly suggests the diagnosis of PBC even before the appearance of biochemical cholestasis. Although longitudinal data from large populations are lacking, AMA are believed to appear in asymptomatic individuals decades before the onset of PBC [47]. Metcalf and colleagues [47] reported that 76% of asymptomatic individuals who have serum AMA eventually develop symptoms of PBC over

Are anti-mitochondrial antibodies the “body of evidence” for autoimmunity?

The autoimmune pathogenesis of PBC has been established, but among the issues still to be resolved are the lack of clinical benefit from immune suppressants and the absence of direct proof of AMA pathogenicity. Further, the presence of as many as 10% of patients who have elevated alkaline phosphatase levels and compatible liver histology but without evidence of serum AMA could be taken either as a proof of nonpathogenicity or as a sign of inaccurate testing. As mentioned earlier, AMA are not

The significance of anti-nuclear antibodies in primary biliary cirrhosis

Sera from a subgroup of patients who had PBC, representing up to 30% of the investigated series, manifest disease-specific ANA. It had been suggested that ANA at IIF might be unmasked (and thus be more prevalent) in AMA-negative sera, but the authors' laboratory experience does not support this assumption (M.E. Gershwin, unpublished data). A number of nuclear structures have been recognized as specific targets of ANA in PBC, including Sp100, PML, and two components of the nuclear pore complex,

Autoimmune cholangitis: coming to terms with clinicians

The term “autoimmune cholangitis” was introduced to indicate cases of AMA-negative PBC with detectable serum ANA. More recently, a broader definition has been suggested that includes (1) serum ANA and/or smooth muscle (SMA) positivity and/or hypergammaglobulinemia, (2) serum AMA negativity by IIF, (3) biochemical and/or histologic features of cholestatic and hepatocellular injury, and (4) exclusion of chronic viral, metabolic, or toxic liver disease [62]. This definition was coined to include

Are all cases of primary biliary cirrhosis created equal?

Ultimately, autoimmune cholangitis is considered a disease of unknown cause that typically has serum ANA with or without SMA in serum and cholestatic clinical, laboratory, and/or histologic changes in the absence of AMA, that is, AMA-negative PBC. It is likely that autoimmune cholangitis is a cholestatic liver disease with a natural history similar to AMA-positive PBC despite differences in serology [26]. The medical management of autoimmune cholangitis is the same as that for its AMA-positive

New anti-mitochondrial antibody kits on the block

The authors recently proposed a novel bead-based assay that uses recombinant antigens to reduce further the prevalence of AMA-negative sera among otherwise established PBC cases [64]. Because PBC may constitute a diagnostic challenge in cases that lack AMA at IIF and do not have conclusive liver histology, they wanted to develop a diagnostic assay to offer a valid, fast, and reliable alternative for the diagnosis of PBC. The design improves the sensitivity associated with spatial presentation,

What is preventing the perfect game?

Whether AMA-negative PBC (or autoimmune cholangitis) is a distinct clinical entity or represents the limits of current serology methods can only be hypothesized. Given the known stability of AMA titers over long observation periods [69] and their positivity long before disease onset [47], it is unlikely that autoantibodies have yet to appear in these patients who have otherwise typical PBC. Accordingly, the authors are convinced that evolving AMA tests eventually will provide a method of

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