S5894 AMA-Positive Primary Biliary Cholangitis With Normal ALP: A Diagnostic Blind Spot

Introduction: Primary biliary cholangitis (PBC) is an autoimmune cholestatic liver disease associated with intrahepatic bile duct destruction and may manifest as nonspecific fatigue or pruritus. Elevations in alkaline phosphatase (ALP) are a key diagnostic criterion and are an early marker of disease activity that often prompt additional testing with antimitochondrial antibodies (AMA) and/or liver biopsy to establish a diagnosis. However, diagnosis is challenging and frequently delayed even in the presence of elevated ALP levels. While elevated ALP is a hallmark feature of PBC, emerging reports suggest a minority present without biochemical cholestasis. We present a case of AMA+ PBC presenting with normal ALP levels. Case Description/Methods: An asymptomatic 66-year-old Hispanic woman patient was found to have fatty liver on imaging during a hospitalization for sigmoid diverticulitis. Her liver profile on GI follow-up was unremarkable (ALP 89 U/L [upper limit of normal (ULN) 150 U/L], aspartate aminotransferase 25 U/L, TBili 0.4 mg/dL) aside from persistently elevated alanine aminotransferase (ALT) 40 U/L. Serology was positive for AMA and ASMA. Her elevated ALT and positive serologies prompted a liver biopsy to differentiate between autoimmune hepatitis and PBC. This revealed marked steatosis and prominent inflammatory infiltrate with periportal and perisinusoidal fibrosis, consistent with active PBC. She subsequently developed severe pruritus prior to initiation of ursodeoxycholic acid 300 mg twice daily therapy. Discussion: PBC diagnosis requires 2 out of 3 criteria, namely: (1) biochemical evidence of cholestasis (e.g. elevated ALP); (2) positive AMA; and (3) histologic evidence of nonsuppurative destructive cholangitis and interlobular bile duct destruction. Timely identification of PBC is crucial to prevent liver-related morbidity and mortality. ALP levels <1.67× the ULN have been associated with a better prognosis. However, PBC patients without obvious evidence of cholestasis are at high risk of experiencing diagnostic delay. Clinicians should consider PBC in the differential diagnosis of AMA+ patients even in the absence of biochemical cholestasis, particularly when symptoms or serologies are suggestive. Deferring diagnosis due to normal ALP increases the risk of complications, but preemptively initiating therapy in all AMA+ patients may lead to over-treatment. Thus, future studies should investigate biomarkers with better granularity to help better differentiate AMA+ PBC patients with underlying liver damage from those without.