Intrahepatic calculi is characterized by an intractable course and frequent recurrences, requiring multiple operative interventions. Chronic proliferative cholangitis, an active and long-standing inflammation of the stonecontaining bile ducts with the hyperplasia of epithelia and the proliferation of the duct-associated mucus glands, may underlie the complex nature of the disease. In terms of the pathophysiology, interest has been focused on the role of secretory low-molecular-weight phospholipases A 2 (sPLA 2 s) as inflammatory mediators or factors modulating cell functions via their specific sPLA 2 -receptor, and also on the production and secretion of altered mucin molecules from the inflamed bile ducts. In search of factors involving chronic proliferative cholangitis, the sPLA 2 isoforms in the bile such as the pancreatic-type sPLA 2 (group IB sPLA 2 ) and the arthritic-type sPLA 2 (group IIA sPLA 2 ), were assayed to correlate protein masses of the sPLA 2 s with alterations in biliary composition. Furthermore, the steady-state messenger RNA (mRNA) levels of the sPLA 2 s, the membranebound sPLA 2 -receptor, cystic fibrosis transmembrane conductance regulator (CFTR), and mucin core polypeptide (MUC) genes in the bile ducts were assayed by reversetranscriptase polymerase chain reaction (RT-PCR). Immunoreactive sPLA 2 -IB and sPLA 2 -IIA levels were significantly higher in the bile from the stone-containing hepatic ducts (2315 ؎ 677 for sPLA 2 -IB; 281 ؎ 42 for sPLA 2 -IIA ng/dL, mean ؎ SEM; n ؍ 20) than in the ductal bile from gallbladder stone patients (609 ؎ 92, P F .01; 22 ؎ 2, P F .01; n ؍ 24). The increased sPLA 2 levels were associated with a concomitant increase in lysophosphatidylcholine, prostaglandin E 2 (PGE 2 ), and total mucin concentrations. The affected bile ducts showed an increased mRNA level of sPLA 2 -IB and sPLA 2 -IIA compared with the ducts from control subjects, in whom the mRNAs of the sPLA 2 -receptor and other sPLA 2 isoforms, such as groups V and X sPLA 2 s, were coincidently expressed. Reflecting the increased amounts of total biliary mucins, the affected ducts showed an increase in mRNA levels of CFTR as well as MUC2, MUC3, MUC5AC, MUC5B, and MUC6 compared with the ducts from control subjects. In intrahepatic calculi, an enhanced expression of the sPLA 2 s and their possible cross-talk via sPLA 2 -receptor may be of pathophysiological significance for the chronic proliferative cholangitis, in association with the enhanced CFTR expression and the alterations in mucin gene expression in the bile ducts, probably through potentiating arachidonate metabolism with associated biliary alterations favoring growth of preexisting stones and even further progressions. (HEPATOLOGY 1999;29:1026-1036.) Hepatolithiasis, or intrahepatic calculi, is prevalent in the Far East including Japan, although the disease is extremely rare in Western countries. 1,2 The distinctive feature is an intractable course requiring multiple operative interventions with frequent recurrence. Most intrahepatic calcul...