Histological evaluation of the intrahepatic biliary tree in intrahepatic cholesterol stones, including immunohistochemical staining against apolipoprotein A-1

Abstract

Apolipoprotein A-1 is known to be one of inhibiting factors of cholesterol nucleation in bile, and decreased activity of apolipoprotein A-1 is considered to predispose cholesterol-supersaturated bile to formation of cholesterol crystals. To study the pathogenesis of the intrahepatic formation of cholesterol stones, we examined surgically resected liver specimens from six patients with intrahepatic cholesterol stones and compared the characteristic histopathological features with those of intrahepatic calcium bilirubinate stones, using morphological examination and immunohistochemical staining against apolipoprotein A-1. Morphologically, in all six patients with cholesterol stones the severity of chronic proliferative cholangitis with proliferation of the mucus-producing glandular elements in the walls of the large bile duct or periductal tissues was less extensive than that seen with calcium bilirubinate stones, and cholesterol crystals had formed in the septal and interlobular bile ducts. Immunohistochemically, unlike the normal liver and calcium bilirubinate stone-containing lobes, the hepatocytes and the epithelial lining of the bile ducts and peribiliary glands of the cholesterol stone-containing lobes did not react completely (some of the epithelial cells reacted only faintly) with apolipoprotein A-1 antibody. These findings suggest that an abundance of mucous substance and bacterial infection of the biliary tree may not be necessary for the formation of cholesterol stones, compared with findings in cases of calcium bilirubinate stones. We suggest that cholesterol crystals may be produced in the septal and interlobular bile ducts in the microenvironment of cholesterol-supersaturated bile and decreased activity of apolipoprotein A-1.

Etiologic significance of defects in cholesterol, phospholipid, and bile acid metabolism in the liver of patients with intrahepatic calculi

“…10 Recently, an increased number of primary cholesterol stones in the intrahepatic bile ducts has also been reported. 11,12 The formation of cholesterol-rich brown pigment stones as well as cholesterol stones in the intrahepatic bile ducts suggests the possibility that these stones are caused by underlying metabolic defects, such as those occurring in cholesterol gallstone disease. 13 Seeking metabolic factors that might promote the formation of cholesterol supersaturated bile, we have first reported increased cholesterogenesis and decreased bile acid synthesis in the liver of patients with intrahepatic calculi.…”

Cultured gallbladder epithelial cells synthesize apolipoproteins A-I and E

“…This study is the first to document that GBEC are capable of synthesizing and secreting apoA-I and -E. The source of biliary apoA-I has been presumed to be the hepatocyte, although the intrahepatic biliary tree also expresses apoA-I mRNA and protein (40,41). Given the complexities of apolipoprotein function, additional studies are needed to define the roles of these apolipoproteins in the GB.…”

The significance of hepatectomy for primary intrahepatic stones

“…Moreover, the bile duct on the upstream side was filled with cholesterol crystals, which suggests that cholesterol crystals tend to be deposited in the peripheral bile duct. 7,8 The migration of deposited cholesterol crystals supposedly results in the formation of cholesterol stones; however, it is impossible to remove all the cholesterol crystals existing in the peripheral bile duct. Even if they are able to be successfully removed, the recurrence of cholesterol crystal deposition and cholesterol stone formation is likely to occur.…”