Eosinophilia is a distinctive feature of primary biliary cirrhosis (PBC), especially in its early stages. Intriguingly, treatment with ursodeoxycholic acid (UDCA) ameliorates eosinophilia as well as liver tests in patients with PBC. It remains unknown, however, whether eosinophils in PBC patients are functionally activated and whether UDCA inhibits eosinophil activation. In the present study, we systematically examined eosinophil dynamics in the blood and liver in patients with stage I to II PBC before and after UDCA treatment. We determined serum concentrations of eosinophil granule proteins (major basic protein [MBP] and eosinophil-derived neurotoxin [EDN]) by radioimmunoassay and quantitated eosinophil degranulation using computer-assisted morphometry after MBP immunohistochemistry. Before UDCA treatment, patients with PBC (n β«Ψβ¬ 25) showed significantly higher circulating eosinophil counts (P F .05) and serum concentrations of MBP (P F .0005) and EDN (P F .02) compared with patients with chronic viral hepatitis (n β«Ψβ¬ 22), autoimmune hepatitis (n β«Ψβ¬ 10), and obstructive jaundice (n β«Ψβ¬ 12). Four-week UDCA treatment significantly reduced blood eosinophil counts (P F .0001) and serum MBP (P F .0001) and EDN (P F .0001) levels in PBC patients. MBP immunohistochemistry and computer-assisted quantitative morphometry showed infiltration and degranulation of eosinophils in the portal tract in patients with PBC and significant reductions in the number of sites and the area occupied by extracellular MBP deposits after UDCA treatment for 2 years (P F .02) but not in placebo-treated patients. Our results suggest that eosinophils in patients with PBC are not only increased in number, but also release granule proteins, and that UDCA treatment inhibits this eosinophil activation/degranulation. (HEPATOL-OGY 1999;30:71-78.)
Eosinophil activation likely plays an important role in several epithelial diseases including bronchial asthma, atopic dermatitis, and inflammatory bowel disease. 1,2 Activated eosinophils release basic granule proteins such as major basic protein (MBP), eosinophil-derived neurotoxin (EDN), eosinophil cationic protein (ECP), and eosinophil peroxidase. 3 Previous studies have established the cytotoxic properties of the eosinophil granule proteins for epithelial cells. 4,5 Indeed, elevated serum levels of eosinophil granule proteins can serve as markers for eosinophil activation. 6 Primary biliary cirrhosis (PBC) is a chronic cholestatic liver disease characterized by the destruction of biliary epithelial cells (i.e., cholangiocytes), presumably by autoimmune mechanism(s). 7,8 Although lymphocytes play a pivotal role in the pathogenesis of PBC, 9 accumulating evidence also suggests a role for eosinophils. We and others have shown that eosinophilia in the blood 10-12 and liver [13][14][15] is a distinctive feature of PBC, especially in its early stages. Elevated serum ECP levels in PBC patients have been reported. 16 Although the exact mechanism(s) remains unknown, activation of Th2 lymphocytes and mast cells appears to be involved in the pathogenesis of eosinophilia in PBC. 10,15,[17][18][19] Ursodeoxycholic acid (UDCA) is the current mainstay of PBC treatment. 20 This hydrophilic bile acid induces biochemical, histological and prognostic improvement in patients with PBC 20,21 in the virtual absence of adverse reactions. 20,22 UDCA acts as a bile secretagogue 23 and cytoprotective agent. 24 In addition, as recently reviewed elsewhere, 25 UDCA exerts diverse immunomodulatory actions such as suppression of immunoglobulin, interleukin-2 (IL-2), IL-4, and interferon-β₯ production from lymphocytes; 26 attenuation of major histocompatibility complex expression on hepatocytes and cholangiocytes; 27 increase in natural killer cell activity; 28 inhibition of mast cell activation; 29 and activation of the glucocorticoid receptor. 30,31 Intriguingly, we 10 and Wirth et al. 32 have recently shown that UDCA treatment markedly decreases the number of circulating eosinophils in patients with PBC. These data suggest that immunomodulatory actions of UDCA may extend to eosinophils. Here, we systematically examined the effect of UDCA on eosinophil dynamics in the blood and the portal tract of the liver in patients with PBC.