Anti-Mitochondrial Antibody–Negative Primary Biliary Cirrhosis
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
References (71)
- et al.
Genetic polymorphisms of toll-like receptor 9 influence the immune response to CpG and contribute to hyper-IgM in primary biliary cirrhosis
J Autoimmun
(2005) - et al.
IL-2 receptor alpha deficiency and features of primary biliary cirrhosis
J Autoimmun
(2006) - et al.
T cell targeting and phagocytosis of apoptotic biliary epithelial cells in primary biliary cirrhosis
J Autoimmun
(2006) - et al.
Identification of 2-nonynoic acid, a cosmetic component, as a potential trigger of primary biliary cirrhosis
J Autoimmun
(2006) - et al.
The X and why of xenobiotics in primary biliary cirrhosis
J Autoimmun
(2007) - et al.
Balancing autoaggressive and protective T cell responses
J Autoimmun
(2007) - et al.
Incomplete penetrance of susceptibility genes for MHC-determined immunoglobulin deficiencies in monozygotic twins discordant for type 1 diabetes
J Autoimmun
(2006) - et al.
Familial clustering of autoimmune diseases in patients with type 1 diabetes mellitus
J Autoimmun
(2006) - et al.
The regulatory T cell gene FOXP3 and genetic susceptibility to thyroid autoimmunity: an association analysis in Caucasian and Japanese cohorts
J Autoimmun
(2007) - et al.
Epidemiology of autoimmune diseases in Denmark
J Autoimmun
(2007)
Clearance deficiency and systemic lupus erythematosus (SLE)
J Autoimmun
Sjogren's syndrome in the NOD mouse model is an interleukin-4 time-dependent, antibody isotype-specific autoimmune disease
J Autoimmun
Anti-MBL autoantibodies in patients with rheumatoid arthritis: prevalence and clinical significance
J Autoimmun
Antiphospholipid antibodies: lessons from the bench
J Autoimmun
The role of the innate immune response in autoimmune diseases
J Autoimmun
Repertoire-dependent immunopathology
J Autoimmun
Death, adaptation, and regulation: the three pillars of immune tolerance restrict the risk of autoimmune disease caused by molecular mimicry
J Autoimmun
Regulatory T cells in the prevention of mucosal inflammatory diseases: patrolling the border
J Autoimmun
Primary biliary cirrhosis in monozygotic and dizygotic twins: genetics, epigenetics, and environment
Gastroenterology
Gender as risk factor for autoimmune diseases
J Autoimmun
Clinical and biochemical expression of the histopathological lesions of primary biliary cirrhosis
J Hepatol
Mucosal immunity and primary biliary cirrhosis: presence of antimitochondrial antibodies in urine
Hepatology
T cell immunity and primary biliary cirrhosis
Autoimmun Rev
Antimitochondrial and other autoantibodies
Clin Liver Dis
Antibody titer to gp210-C terminal peptide as a clinical parameter for monitoring primary biliary cirrhosis
J Hepatol
Phylogenetic and immunological definition of four lipoylated proteins from Novosphingobium aromaticivorans, implications for primary biliary cirrhosis
J Autoimmun
Autoreactivity to lipoate and a conjugated form of lipoate in primary biliary cirrhosis
Gastroenterology
Natural history of early primary biliary cirrhosis
Lancet
Detection of antimitochondrial autoantibodies in immunofluorescent AMA-negative patients with primary biliary cirrhosis using recombinant autoantigens
Hepatology
Use of a designer triple expression hybrid clone for three different lipoyl domain for the detection of antimitochondrial autoantibodies
Hepatology
Role of anti-DNA antibodies in the pathogenesis of lupus nephritis
Autoimmun Rev
Patients with primary biliary cirrhosis react against a ubiquitous xenobiotic-metabolizing bacterium
Hepatology
Lack of immunological or molecular evidence for a role of mouse mammary tumor retrovirus in primary biliary cirrhosis
Gastroenterology
Heterogeneous response of antimitochondrial autoantibodies and bile duct apical staining monoclonal antibodies to pyruvate dehydrogenase complex E2: the molecule versus the mimic
Hepatology
Penetration and co-localization in MDCK cell mitochondria of IgA derived from patients with primary biliary cirrhosis
J Autoimmun
Cited by (33)
Inflammatory Hepatobiliary Diseases
2019, Clinical Immunology: Principles and PracticePrimary biliary cholangitis
2019, The Autoimmune DiseasesPractical guidelines for examination of adults with asymptomatic hypertransaminasaemia
2017, Gastroenterologia y HepatologiaThe diagnosis of antimitochondrial antibody-negative primary biliary cholangitis
2016, Clinics and Research in Hepatology and GastroenterologyCitation Excerpt :It detects AMAs and ANAs altogether, so it is regarded as a screening test [19]. On the other hand, IF has also some limitations which may lead to false negative results, such as labour intensive technical steps, the use of old and misprepared tissue extract, using only kidney extract (cheap), and interpretation error (underrecognition of AMA or falsely reported as liver kidney microsome [LKM-1] instead of AMA) [21–23]. ELISA and IB detect pre-selected M2 antigen(s).
Antimitochondrial Antibodies
2014, Autoantibodies, Third Edition