Antimitochondrial antibodies in acute liver failure: Implications for primary biliary cirrhosis

Abstract

In our previous work, including analysis of more than 10,000 sera from control patients and patients with a variety of liver diseases, we have demonstrated that with the use of recombinant autoantigens, antimitochondrial autoantibodies (AMAs) are only found in primary biliary cirrhosis (PBC) and that a positive AMA is virtually pathognomonic of either PBC or future development of PBC. Although the mechanisms leading to the generation of AMA are enigmatic, we have postulated that xenobiotic-induced and/or oxidative modification of mitochondrial autoantigens is a critical step leading to loss of tolerance. This thesis suggests that a severe liver oxidant injury would lead to AMA production. We analyzed 217 serum samples from 69 patients with acute liver failure (ALF) collected up to 24 months post-ALF, compared with controls, for titer and reactivity with the E2 subunits of pyruvate dehydrogenase, branched chain 2-oxo-acid dehydrogenase, and 2-oxo-glutarate dehydrogenase. AMAs were detected in 28/69 (40.6%) ALF patients with reactivity found against all of the major mitochondrial autoantigens. In addition, and as further controls, sera were analyzed for autoantibodies to gp210, Sp100, centromere, chromatin, soluble liver antigen, tissue transglutaminase, and deaminated gliadin peptides; the most frequently detected nonmitochondrial autoantibody was against tissue transglutaminase (57.1% of ALF patients). Conclusion: The strikingly high frequency of AMAs in ALF supports the thesis that oxidative stress-induced liver damage may lead to AMA induction. The rapid disappearance of AMAs in these patients provides further support for the contention that PBC pathogenesis requires additional factors, including genetic susceptibility. (HEPATOLOGY 2007;46:1436-1442

Probable Bexarotene Hepatotoxicity Associated With Transient Serum Antimitochondrial Antibodies

“…Nonetheless, this case provides further evidence that bexarotene can induce liver injury in susceptible individuals. It also suggests that various types of liver damage could potentially lead to the generation of antimitochondrial antibodies but, as hypothesized by Leung et al [7], the pathogenesis of primary biliary cirrhosis requires additional factors.…”

“…Approximately one year after discontinuing bexarotene, serum antimitochondrial antibodies were no longer detectable. Serum antimitochondrial antibodies are detected in approximately 40% of subjects with acute liver failure from a variety of causes, with disappearance in most subjects within one year after resolution [7]. Transiently detectable serum antimitochondrial antibodies have also been reported in subjects with liver damage presumably induced by Teucrium chamaedrys (germander) [8] and an anticonvulsant [9].…”

Primary biliary cirrhosis: From bench to bedside

“…Moreover, AMAs is not a specific finding in PBC, since they are occasionally present in other autoimmune and non-autoimmune liver diseases. Therefore loss of tolerance to PDC-E2 alone does not seem to be sufficient to cause autoimmune cholangitis [73,74] . Against the pathogenetic role of AMAs is also the presence of the clinical condition of the so called autoimmune cholangitis or better AMA-negative PBC, a disease clinically and histologically identical to PBC but without detectable AMA.…”

Autoimmune liver serology: Current diagnostic and clinical challenges

“…Anti-LKM1 and anti-LC1 are reported in a proportion of adult (0%-6%) or pediatric (0%-11%) cases with chronic hepatitis C infection [36,[105][106][107] . AMA are present (expectedly) in patients with AIH/PBC overlap syndrome, and also in chronic hepatitis C virus infected patients [1] , and most recently were described in patients with acute liver failure [108] ; AMA occur also in various rheumatological disorders which may co-exist with PBC notably Sjögren's syndrome and systemic sclerosis [1,48,[108][109][110][111] and are described in non-liver related conditions with asymptomatic recurrent bacteriuria in women, pulmonary tuberculosis and leprosy [112][113][114] . However we would submit that in the index disease (AIH or PBC) the frequency and titre of the relevant liver-related autoantibody is substantially higher than for the contrast disease.…”