Antimitochondrial Antibody–Negative Primary Biliary Cirrhosis

There is a subset of patients who have biochemical and histologic features consistent with primary biliary cirrhosis (PBC) who lack antimitochondrial antibodies (AMA). This entity is usually referred to as AMA-negative PBC or alternatively autoimmune cholangitis. Patients who have AMA-negative PBC are believed to have a similar clinical course, response to treatment, and prognosis as their AMA-positive counterparts. As more sensitive and specific serologic tests are developed to detect serum AMA, it is possible we may find that these patients initially believed to be AMA-negative are indeed AMA-positive, suggesting a single disease process.

Primary biliary cirrhosis (PBC) is a chronic cholestatic liver disease of unclear cause. It is characterized histologically by nonsuppurative destruction of the bile ducts and serologically by the presence of antimitochondrial antibodies (AMA). Several reports indicate that in approximately 5% of patients serologic evidence of AMA is absent, even though these patients share similar clinical, biochemical, and histologic features of PBC with those who are AMA-positive .

There is some controversy as to whether autoimmune cholangitis (AIC), AMA-negative PBC, and AMA-positive PBC represent the same entities clinically and immunologically. According to Czaja and colleagues AIC cannot be assimilated into a single diagnostic category. It may represent variant forms of different autoimmune liver diseases, a transition stage between two autoimmune disorders, or a separate entity with varying manifestations.

The advent of more sensitive and specific techniques other than indirect immunofluorescence, such as ELISA or immunoblotting, to determine the presence of AMA in patients suspected to have PBC have disclosed that as many as 79% of patients initially considered AMA-negative are in fact AMA-positive , strengthening the suspicion that the two are indeed one single condition.

This article reviews the clinical, biochemical, serologic, and histopathologic features and treatment approach and outcomes in patients who have AMA-negative PBC. The term AMA-negative PBC is used in preference to AIC.

Clinical and Biochemical Features

AMA-negative PBC, like AMA-positive PBC, occurs predominantly in middle-aged women and is commonly asymptomatic. When symptoms are present, fatigue, pruritus, and symptoms of sicca syndrome are common initial features, whereas jaundice is usually a late finding. Elevation of the alkaline phosphatase is the typical biochemical feature, with transaminases being only mildly elevated. Several studies comparing the clinical and laboratorial findings between patients who have AMA-negative PBC and classic PBC have been published and there is no disagreement that the two entities behave similarly . Table 1 summarizes the most important studies comparing the various features of AMA-negative and -positive PBC.

Table 1

Studies comparing patients who have antimitochondrial antibody–negative and antimitochondrial antibody–positive primary biliary cirrhosis

Michieletti, et al Lacerda, et al Invernizzi, et al Kim, et al Nakajima, et al
No. of patients 17 17 35 180 24 273 8 89 23 71
Age (y) 51.1 55.0 52 ± 11 53 ± 9 52 ± 11 54 ± 11 57.9 ± 7.2 54.2 ± 9.5 53.3 ± 13.7 52.3 ± 9.4
Female gender (%) Matched All 21(8) 244(89) 80(100) 81(91) 23(100) 63(89)
No. of asymptomatic (%) No difference NA No difference NA Higher in AMA−
8(47) 6(35) 17(71) 166(61) 21(91) 48(68)
Complications of cirrhosis NA NA No difference NA NA
3(13) 22(8)
Histologic findings Slightly less portal inflammation in AMA− NA No difference in proportion of patients who had stage II–IV NA NA
ALP No difference No difference No difference NA Lower in AMA−
AST Lower in AMA− No difference NA No difference No difference
ALT No difference NA No difference NA No difference
TB Matched No difference No difference No difference Lower in AMA−
Number with +ANA Higher in AMA− Higher in AMA− Higher in AMA− NA Higher in AMA−
Number with +SMA Lower in AMA− No difference Higher in AMA− NA Higher in AMA−
IgM Lower in AMA− Lower in AMA− Lower in AMA− NA Lower in AMA−
Response to UDCA treatment NA No difference (biochemical and Mayo risk score) No difference (biochemical) No difference (biochemical and clinical outcome—death or OLT) NA

Abbreviations: ALP, alkaline phosphatase; ALT, alanine aminotransferase; ANA, antinuclear antibodies; AST, aspartate aminotransferase; NA, not assessed; OLT, orthotopic liver transplantation; SMA, smooth muscle antibodies; TB, total bilirubin; UDCA, ursodeoxycholic acid.

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Feb 26, 2017 | Posted by in GASTROENTEROLOGY | Comments Off on Antimitochondrial Antibody–Negative Primary Biliary Cirrhosis

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