This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Metabolic bone disease is a frequent and significant complication of chronic liver disease in children and adults. Osteopenia that develops during cholestasis culminates in fractures of long bones, which responds poorly to medical treatment and becomes an indication for liver transplantation in many patients. A factor related to bone metabolism during cholestatic liver disease that has recently received attention is magnesium homeostasis. A deficiency of magnesium may interfere with parathyroid hormone secretion and subsequent bone mineralization. It is postulated that dietary magnesium is malabsorbed secondary to the steatorrhea caused by cholestasis, which leads to the formation of magnesium soaps with unabsorbed fatty acids. Magnesium deficiency is associated with decreased bone mineral density in children with chronic cholestatic liver disease and that repletion with magnesium will be associated with improvement of bone mineral density. Other factors have been implicated in the pathogenesis of impaired bone formation that occurs in other clinical situations; Elevated concentrations of inflammatory cytokines (IL-1, IL-6 and TNF alpha) have been shown to inhibit osteoblast synthesis of bone; IGF-1 is also instrumental in normal osteoblast function and bone accretion. Suppressed serum levels of IGF-1 have been reported in children with chronic liver disease. A major goal of this proposal is to determine the relationship of circulating cytokines, IGF-1 and IGF-1 binding proteins (IGFBP) to bone mineral density in children with chronic cholestatic and non-cholestatic liver disease. The evaluation of these factors in children with both cholestatic and non-cholestatic liver disease will allow for the differentiation of the effects of chronic cholestasis vs. that of chronic liver disease on bone formation. Once identified, children with magnesium deficiency will undergo magnesium repletion and its effect on bone mineral density will be evaluated over 2 years. Subjects will be recruited into three groups; those with cholestatic liver disease, those with non-cholestatic liver disease, and normal controls. Repletion of magnesium in deficient subjects may have therapeutic benefit for metabolic bone disease, which may improve the care of patients with liver disease.
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