Role of hyperbilirubinemia in the impairment of osteoblast proliferation associated with cholestatic jaundice.

Abstract

Because the osteoporosis occurring in chronic cholestatic liver disease (CCLD) is associated with decreased bone formation and is reversible by liver transplantation, substances retained in plasma during cholestasis may impair osteoblast function. This hypothesis was tested using a new bioassay that measures plasma mitogenic activity (PMA) for normal human osteoblast-like (hOB) cells. In 29 jaundiced patients, mean PMA was 56.4% (P < 0.001) of that in 29 age-and sex-matched normal subjects, and the decrease in PMA was similar in the 14 with CCLD and the 15 with other causes of jaundice. Bile acids and bilirubin are the two major groups of products retained during cholestasis. The common conjugated bile acids and bilirubin were added to normal human plasma in concentrations simulating those found in patients with CCLD. Various bile salts had no effect on PMA whereas unconjugated bilirubin decreased PMA in a dose-dependent fashion (r = -0.98, P < 0.0001) without affecting cell viability. Relatively selective removal of bilirubin from the plasma by photobleaching normalized the decreased PMA in five jaundiced patients but produced no apparent change in five normal subjects. These data support the hypothesis that hyperbilirubinemia or possibly other photolabile substances impair osteoblast proliferative capacity and thus may play a major role in the pathogenesis of the osteoporosis associated with CCLD. (J. Clin. Invest. 1995.95:2581-2586

Longitudinal evaluation of hepatic osteodystrophy in children and adolescents with chronic cholestatic liver disease

“…These data contrast with in vitro studies demonstrating that serum with hyperbilirubinemia reduced the mitogenic activity of osteoblast-like cells (5). Some clinical studies also showed that osteoporosis is more frequent in cholestatic patients than in non-cholestatic patients with liver disease (18)(19)(20).…”

“…The most relevant factors are nutritional changes, hormonal disorders and the metabolic environment inherent to the progressive deterioration of liver function (1)(2)(3)(4). Regarding this last factor, cholestasis is used as a specific indicator determining bone involvement in chronic liver disease (5).…”

Ectopic and Serum Lipid Levels Are Positively Associated with Bone Marrow Fat in Obesity

“…However, IMCL can also be increased between IHL and BMD in postmenopausal women with nonalcoholic fatty liver disease (9). Potential mechanisms for low BMD in patients with chronic liver disease include decreased levels of insulin-like growth factor 1 (25) and detrimental effects of bilirubin level on osteoblast proliferation (26). In our healthy obese subjects without a history of liver disease, IHL were positively associated with bone marrow fat, even after adjusting for BMI, age, and IR, suggesting that IHL may be involved regression model and IHL, IMCL, triglyceride levels, and BMI were entered as independent variables, serum triglyceride levels were significant predictors of bone marrow fat.…”

Unconjugated bilirubin induces apoptosis in colon cancer cells by triggering mitochondrial depolarization

“…Bilirubin inhibits osteoblast proliferation 19 and stimulates apoptosis in rat brain neurons, 20 -23 astrocytes, 24 fibroblasts 24 and bovine brain endothelial cells. 25 However, many studies of bilirubininduced apoptosis have been conducted at high molar ratios of bilirubin to albumin or under serum-free conditions.…”