Clinical significance of the fluctuation of primary biliary cirrhosis-related autoantibodies during the course of the disease

Abstract

Primary biliary cirrhosis (PBC) is a chronic cholestatic disease characterized by the presence of antimitochondrial antibodies (AMA). PBC-specific antinuclear antibodies (ANA) have been characterized and associated with disease progression and outcome. We evaluated the clinical significance of the presence and serial changes in titers of AMA, PBC-specific ANA (anti-gp210, anti-sp100) and anti-chromatin antibodies. Over a median (IQR) period of 35 (36) months, 512 specimens were collected from 110 patients. Autoantibodies were detected by commercial ELISAs (INOVA Diagnostics). Biochemical, clinical, and histological status were included at initial presentation and during follow-up visits. The Mayo risk score was calculated as a prognostic index at each time point. Liver biopsy findings were classified according to Ludwig's classification and biochemical response to ursodeoxycholic acid was evaluated according to Pares. At baseline, AMA IgG and IgA, anti-gp210 IgG, anti-sp100 IgG and anti-chromatin IgG were detected in 92/110 (83.6%), 57/110 (51.8%), 5/110 (4.5%), 14/110 (12.7%), and 0/110 (0%) patients, respectively. Positivity for all autoantibodies apart from anti-chromatin, at baseline visit (n = 110 patients), in all tested sera (n = 512) as well as increased autoantibodies titers during follow-up were associated with biochemically and/or histologically advanced disease. A decrease of anti-sp100 titers but not of anti-gp210 titers during follow-up was associated with improvement of Mayo risk score (p = 0.025) and response to ursodeoxycholic acid (p = 0.016). These results suggest that detection of AMA and PBC-specific ANA was correlated with disease severity. Serial changes of anti-sp100 titers and not of anti-gp210 titers might prove useful for monitoring the disease course and treatment outcome.

Primary biliary cirrhosis in HBV and HCV patients: Clinical characteristics and outcome

“…These data suggest that existence mostly of biochemical indices of cholestasis should prompt physicians to sick for AMA with various sensitive techniques as well as for PBC-specific ANA irrespective of the presence or not of other liver diseases [12,20,22,25,29] . Since the discovery of AMA, their subsequent inclusion in "routine" autoantibody testing, has led to PBC being more frequently diagnosed at an earlier stage of disease progression being mainly asymptomatic [7,12,19,20,25] .…”

“…Since the discovery of AMA, their subsequent inclusion in "routine" autoantibody testing, has led to PBC being more frequently diagnosed at an earlier stage of disease progression being mainly asymptomatic [7,12,19,20,25] . Indeed, up to 60% of PBC patients are reported to be asymptomatic at diagnosis with less severe disease in terms of liver biochemistry and histology compared to symptomatic patients [7,12,19,20,22,26,30] . In accordance with this, the repetitive presence of AMA in our patients, who were mostly asymptomatic, may well signify that PBC was in its early stages.…”

“…In all but two patients with chronic HBV and HCV infections described in our study PBC was diagnosed during the follow-up period for viral hepatitis. The diagnosis of PBC was based in all patients on the presence of elevated cholestatic enzymes and AMA identified either by IIF and immunoblot or by a sensitive MIT3-based ELISA (IgG and IgA) and immunoblot, in those being AMA negative by IIF [12,19,20,22] . In addition, ANA specific for PBC, identified in two of these patients, could serve not only as diagnostic tools for PBC but also as prognostic markers of the disease [12,25,29] .…”

“…A liver biopsy was performed in 12 of 17 patients and had PBC features in 3 of them. In terms of AMA positivity, 14 patients were AMA positive by IIF confirmed by immunoblot, while 3 patients being persistently AMA negative by IIF were found to be repeatedly anti-M2 positive tested by the enhanced performance MIT3-based ELISA and immunoblot [20,22] . Two out of 17 patients had also ANA with reactivity against multiple nuclear dots (MND), which is considered specific for PBC [12,25] .…”

“…According to internationally accepted criteria and to previous publications from our group [12,[19][20][21] , patients with PBC met at least two of the following criteria: (1) positivity for antimitochondrial antibody (AMA; positive titre ≥ 1/40) either by IIF on in-house rodent tissue substrates confirmed by Western blot using in-house mitochondrial subfraction of rat livers, or by enhanced performance M2 ELISA (M2 EP (MIT3) ELISA, Quanta Lite, INOVA Diagnostics, San Diego, CA), which was shown to have higher sensitivity compared to the conventional anti-M2 [20,22] ; (2) elevated cholestatic enzymes and (3) histological lesions of PBC (when a liver biopsy had been performed). The presence of other liver diseases and in particular of AIH has been appropriately excluded [8,23] .…”