Hyperbilirubinemia Is Not a Major Contributing Factor to Altered Bone Mineral Density in Patients With Chronic Liver Disease

Reduced bone density is commonly encountered in patients with chronic liver disease. Prior studies have shown that unconjugated bilirubin inhibits osteoblast activity and function in vitro and in animal models of bone mineralization. To determine whether hyperbilirubinemia promotes the development of hepatic osteodystrophy, bone mineral density (BMD) was measured by dual energy X-ray absorptiometry in a cohort of 86 consecutive patients with chronic liver disease referred for liver transplant evaluation. The mean age of the study population was 52 years (range, 22-73), in which 52% were female and 90% were white. Average bone density values were significantly lower than expected for age, race, and sex, with Z-scores for the femoral neck and spine of −0.50 (95% confidence interval [CI] −0.63 to −0.37; p = 0.0003) and −0.69 (95% CI −0.85 to −0.52; p = 0.0001), respectively. Sixty-one subjects (71%) exhibited reduced BMD (T-score of femoral neck or spine ≤ −1 standard deviation [SD] below the young-adult mean), and 18 subjects (21%) met criteria for osteoporosis (T-score < −2.5 SD). Stepwise logistic regression analyses identified significant associations between BMD and serum creatinine, alkaline phosphatase, age, and gender. On the other hand, neither unconjugated, nor conjugated, nor total serum bilirubin levels were found to predict diminished BMD. The lack of association between serum unconjugated bilirubin levels and bone mineralization was validated in hyperbilirubinemic Gunn rats, in which BMD and serum osteocalcin levels were no different than in wild-type rodents. In conclusion, the finding that serum bilirubin levels do not correlate with reduced BMD in patients with end-stage liver disease, and that chronic unconjugated hyperbilirubinemia does not lead to alterations in bone mineralization in Gunn rats, suggests that bilirubin is not a major contributing factor to hepatic osteodystrophy.