Immunosuppressive and postoperative effects of orthotopic liver transplantation on bone metabolism

Bone loss occurs early after orthotopic liver transplantation (OLT) in all liver transplant recipients and leads to postoperative fractures, especially in cholestatic patients with the lowest bone mass. Little is known about the underlying changes in bone metabolism after OLT or about the etiology of these changes. Histomorphometric analysis of bone biopsies, a method that allows assessment of bone volume, resorption, and formation, has shown improved bone metabolism at 4 months after OLT. It has further suggested that accelerated posttransplant hone loss occurs in the first 1-2 months after OLT, probably by an additional insult to bone formation. This study attempts to correlate the histomorphometric bone changes in paired bone biopsies (OLT and 4 months after OLT) of 33 patients undergoing OLT for chronic cholestatic liver disease with the many clinical and biochemical changes in these patients over the same period. Cumulative steroid dosage early after OLT is shown to be important, presumably by decreasing bone formation rates. The actual effect of calcineurin inhibitors on this early phase of bone loss is less clear, although posttransplant histomorphometric findings suggest that tacrolimus-treated patients have an earlier recovery of bone metabolism and trabecular structure compared with cyclosporine patients. Other factors important in the recovery of bone metabolism after the early phase of bone loss are recovery of liver and gonadal function and better calcium balance

Bone metabolism in advanced cholestatic liver disease: Analysis by bone histomorphometry

Despite the clinical importance of cholestatic osteopenia, little is known about its pathophysiologic mechanism. By tetracycline-labeled histomorphometric analysis of bone biopsies taken at the time of liver transplantation, we prospectively evaluated bone resorption and formation in 50 consecutive patients with advanced primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC). Histomorphometric analysis confirmed low bone volume parameters, consistent with the mean T-score of the lumbar spine of -1.9 by dual energy x-ray absorptiometry. Dynamic (bone formation rates, adjusted apposition rates) and static (osteoid markers, osteoblast number) parameters of bone formation were decreased in cholestatic patients with no abnormalities in mineralization. Increased osteoclast numbers and increased eroded surface areas suggested increased bone resorption, and this was supported in female patients by increased trabecular separation and decreased trabecular number. Male cholestatic patients, however, did not have significant increases in resorption parameters, although they were as osteopenic as female patients and had low bone formation markers. Bone histomorphometric changes were similar in PBC and PSC, suggesting an etiologic effect of chronic cholestasis rather than the individual diseases. Cancellous bone volume and osteoid markers correlated with bone mineral density measurements but no correlations were found between histomorphometric parameters and biochemical markers of bone metabolism. In conclusion, cholestatic osteopenia appears to result from a combination of decreased bone formation and increased resorption, especially in female patients, but the relative importance of these two abnormalities and their actual etiology remain to be elucidated

Bone histomorphometric changes after liver transplantation for chronic cholestatic liver disease

Introduction: Patients with advanced liver disease, especially chronic cholestasis, often have osteopenia, which worsens early after orthotopic liver transplantation (OLT) before starting to recover. The changes in bone metabolism leading to this rapid loss of bone after OLT, and to its recovery, are poorly defined. Materials and Methods: In thirty-three patients with advanced chronic cholestatic liver disease, tetracycline-labeled bone biopsy specimens were analyzed prospectively at time of OLT and at 4 months after OLT, as part of a randomized trial to study the efficacy of calcitonin on post-transplant bone loss. Hierarchical cluster analysis of histomorphometric parameters was performed in an attempt to establish the functional grouping of individual histomorphometric parameters before and after OLT. Results and Conclusions: Results showed that from the time of OLT to 4 months after OLT, bone mineral density of the lumbar spine and histomorphometric parameters of bone volume decreased, consistent with early post-transplant bone loss. Histomorphometric resorption parameters were increased before OLT, with no change after OLT. Histomorphometric formation parameters increased from low values before OLT to normal values at 4 months after OLT, with the exception of mean wall thickness values, which further decreased after OLT, suggesting an additional insult to bone formation during the study period. Histomorphometric changes after OLT were similar in female and male patients, pre- and postmenopausal women, and in patients treated and not treated with calcitonin. Hierarchical cluster analysis suggested that before OLT, bone resorption was functioning independently of bone formation, but that by 4 months after OLT, their coupled relationship had improved. Therefore, despite post-transplant bone loss, by 4 months after OLT, bone metabolism had improved, with increased bone formation and more coupled bone balance, as suggested by hierarchical cluster analysis

Risk factors for and clinical course of non-anastomotic biliary strictures after liver transplantation

Non-anastomotic biliary stricture (NAS) formation is : major complication of liver transplantation. We prospectively determined the time to development of responsiveness to treatment, and clinical outcomes following NAS formation. In addition, an extensive analysis of the association of recipient, donor, and clinical variables with NAS formation was performed. A total of 749 consecutive patients was studied in a prospective, protocol-based fashion. Seventy-two patients (9.6%) developed NAS at a mean of 23.6 +/- 34.2 weeks post-transplantation. Non-anastomotic biliary stricture formation resolved in only 6% of affected patients. Although patient survival was not affected, retransplantation and graft loss rates were significantly greater in recipients who developed NAS. In contrast to previous reports, a pretransplant diagnosis of HCV was associated with a low frequency of NAS formation. The incidence of NAS was independently associated with pretransplant diagnoses of PSC and autoimmune hepatitis. Hepatic artery thrombosis, and prolonged warm and cold ischemia times were also independent risk factors for NAS formation. We conclude that NAS developed in similar to10% of primary liver transplant recipients. A pretransplant diagnosis of autoimmune hepatitis has been identified as a novel independent risk factor for NAS formation. Development of NAS significantly attenuates graft but not patient survival