Bone histomorphometric changes after liver transplantation for chronic cholestatic liver disease.

Thirty-three patients with cholestatic liver disease underwent histomorphometric assessment of paired bone biopsy specimens at time of orthotopic liver transplantation (OLT) and 4 months thereafter. At 4 months after OLT, bone metabolism improved, with bone formation increasing to normal and no change in bone resorption. Early post-transplant bone loss may be attributed to an additional insult to bone formation early after transplantation. 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.     

Bone mineral density before and after OLT: long-term follow-up and predictive factors.

Fracturing after liver transplantation (OLT) occurs due to the combination of preexisting low bone mineral density (BMD) and early posttransplant bone loss, the risk factors for which are poorly defined. The prevalence and predictive factors for hepatic osteopenia and osteoporosis, posttransplant bone loss, and subsequent bone gain were studied by the long-term posttransplant follow-up of 360 consecutive adult patients with end-stage primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC). Only 20% of patients with advanced PBC or PSC have normal bone mass. Risk factors for low spinal BMD are low body mass index, older age, postmenopausal status, muscle wasting, high alkaline phosphatase and low serum albumin. A high rate of spinal bone loss occurred in the first 4 posttransplant months (annual rate of 16%) especially in those with younger age, PSC, higher pretransplant bone density, no inflammatory bowel disease, shorter duration of liver disease, current smoking, and ongoing cholestasis at 4 months. Factors favoring spinal bone gain from 4 to 24 months after transplantation were lower baseline and/or 4-month bone density, premenopausal status, lower cumulative glucocorticoids, no ongoing cholestasis, and higher levels of vitamin D and parathyroid hormone. Bone mass therefore improves most in patients with lowest pretransplant BMD who undergo successful transplantation with normal hepatic function and improved gonadal and nutritional status. Patients transplanted most recently have improved bone mass before OLT, and although bone loss still occurs early after OLT, these patients also have a greater recovery in BMD over the years following OLT.     

Bone Disease After Liver Transplantation: A Long-Term Prospective Study of Bone Mass Changes, Hormonal Status and Histomorphometric Characteristics

After liver transplantation there is a high incidence of fractures, with important rates of bone loss during the first months. However, the long-term evolution of bone mass and metabolism parameters have been scarcely studied. In order to determine the incidence and risk factors involved in the development of skeletal fractures and to analyze the long-term evolution of bone mass, bone turnover and hormonal status after liver transplantation, a 3-year prospective study was performed in 45 patients following liver transplantation. Serum osteocalcin, parathyroid hormone (PTH), 25-hydroxyvitamin D (25-OH D) and testosterone levels (men), and bone mass at the lumbar spine and femur were measured before and sequentially at different time points during 3 years. Spinal X-rays were obtained during the first year. Histomorphometric analysis of bone biopsies obtained in 24 patients within the first 12 hours after surgery and 6 months after transplantation was performed. Fifteen patients (33%) developed fractures after liver transplantation, and pre- transplant risk factors for fractures were age and low bone mass (odd”s ratio for osteoporosis, 95% confidence interval: 5.69, 1.32–24.53). Serum PTH, osteocalcin, 25-OH D, testosterone and creatinine levels increased after transplantation. Moreover, PTH correlated with creatinine and osteocalcin values. Bone mass decreased during the first 6 months and reached baseline values at the lumbar spine the second year, with posterior significant recovery at the femoral neck. Long term evolution of femoral neck BMD correlated with PTH levels. Six months after transplantation bone histomorphometric data showed an increase in bone formation parameters. After liver transplantation there is a high incidence of fractures, specially in elderly patients and those with osteoporosis. Bone mass decreased in the short-term period and improved, initially at the lumbar spine and later at the femur, according to histomorphometric evidences of an increase in bone formation. The increase in creatinine values induces a secondary hyperparathyroidism that influences the changes in femoral bone mass. Treatment of osteoporosis shortly after liver transplantation may be important in the prevention of bone fractures, particularly in patients with low bone mass. Received: June 2000 / Accepted: November 2000     

The pathogenesis of osteodystrophy after renal transplantation as detected by early alterations in bone remodeling

BACKGROUND: Loss of bone mass after transplantation begins in the early periods after transplantations and may persist for several years, even in patients with normal renal function. While the pathogenesis of these abnormalities is still unclear, several studies suggest that preexisting bone disease, glucocorticoid therapy, and alterations in phosphate metabolism may play important roles. Recent studies indicate that osteoblast apoptosis and impaired osteoblastogenesis play important roles in the pathogenesis of glucocorticoid-induced osteoporosis. OBJECTIVES: To examine the early alterations in osteoblast number and surfaces during the period following renal transplantation. METHODS: Twenty patients with a mean age of 36.5 +/- 12 years were subjected to bone biopsy 22 to 160 days after renal transplantation. In 12 patients, a control biopsy was performed on the day of transplantation. Bone sections were evaluated by histomorphometric analysis and cell DNA fragmentation by the methods of terminal deoxynucleotidyl transferase-mediated uridine triphosphate nick end labeling (TUNEL), using immunoperoxidase and direct immunofluorescence techniques. RESULTS: The main alterations in posttransplant biopsies were a decrease in osteoid and osteoblast surfaces, adjusted bone formation rate, and prolonged mineralization lag time. Peritrabecular fibrosis was markedly decreased. None of the pretransplant biopsies revealed osteoblast apoptosis. In contrast, TUNEL-positive cells in the proximity of osteoid seams or in the medullary space were observed in nine posttransplant biopsies of which four had mixed bone disease, two had adynamic bone disease, one had osteomalacia, one had osteitis fibrosa, and one had mild hyperparathyroid bone disease. Osteoblast number in posttransplant biopsies with apoptosis was lower as compared with posttransplant biopsies without apoptosis. In addition, most of them showed a marked shift toward quiescence from the cuboidal morphology of active osteoblasts. Serum phosphorus levels were lower in patients showing osteoblast apoptosis and correlated positively with osteoblast number and negatively with the number of apoptotic osteoblasts. In addition, posttransplant osteoblast surface correlated positively with parathyroid hormone (PTH) levels and negatively with glucocorticoid cumulative dose. CONCLUSION: The data suggest that impaired osteoblastogenesis and early osteoblast apoptosis may play important roles in the pathogenesis of posttransplant osteoporosis. The possible mechanisms involved in the pathogenesis of theses alterations include posttransplant hypophosphatemia, the use of glucocorticoids, and the preexisting bone disease. PTH seems to have a protective effect by preserving osteoblast survival.     

Effect of Teriparatide on Early Bone Loss After Kidney Transplantation

Kidney transplantation is associated with bone loss and a high risk of fractures. Prophylactic treatment of bone is therefore recommended in the early posttransplant period. As a large number of transplant recipients develop adynamic renal osteodystrophy, recombinant parathyroid hormone (rPTH) could be a promising therapeutic option.
In a 6-month double-blind, randomized trial, 26 kidney transplant recipients were treated with daily subcutaneous injections of 20 μg teriparatide (PTH 1–34) or placebo. Bone mineral density (BMD) of the femoral neck, lumbar spine and radial bone was measured at transplantation and after 6 months. Paired bone biopsies for histomorphometric analysis were obtained in six, and for measurement of bone matrix mineralization in five patients of each group. Serologic bone markers were measured at baseline and every 3 months.
A total of 24 out of 26 patients completed the study. Femoral neck BMD was stable in the teriparatide group, but decreased significantly in the placebo group. Lumbar spine and radial BMD, histomorphometric bone volume and bone matrix mineralization status remained unchanged in both groups. Serologic bone markers were similarly reduced in both groups throughout the study.
We conclude that teriparatide does not improve BMD early after kidney transplantation. Neither histological analysis nor bone markers provide evidence of improved bone turnover or mineralization.     

Bone loss after liver transplantation is not prevented by cyclical etidronate,calcium and alphacalcidol

After orthotopic liver transplantation (OLT) bone mass rapidly declines and vertebral fracture rate increases. We studied bone loss and parameters of bone turnover in 53 consecutive patients. In an attempt to reduce bone loss the patients were prophylactically treated with cyclical etidronate in addition to daily 1-hydroxyvitamin D3 and calcium. During the first 3 months after transplantation median lumbar spinal bone mineral density (BMD) decreased 4.5%; subsequently no significant changes occurred. Median hip BMD continued to fall during the first post-transplantation year and deteriorated 7% over the whole study period. New vertebral fractures were seen in 25% of the patients, which is not lower than previously reported rates in patients not receiving cyclical etidronate. Parathyroid hormone levels increased after OLT (p=0.01), but remained within normal ranges. Urinary hydroxyproline levels were increased and normalized in the second half-year after OLT. Elevated fasting calciuria increased further after OLT. 1,25-Dihydroxy-vitamin D₃ levels were lowered pre-OLT (25 vs 66 pmol/1,p<0.001) and normalized at 3 months after OLT. Serum osteocalcin concentrations remained unchanged and were reduced compared with levels in healthy controls. In summary, increased bone resorption occurs after OLT with persistent decreased bone formation, leading to vertebral fracture in 25% of patients. Etidronate, 1-calcidol and calcium treatment did not prevent bone loss.     

Long-term outcome of bone mineral density in children who underwent a successful liver transplantation

BACKGROUND: It has previously been shown that bone mineral density (BMD) during the first year after orthotopic liver transplantation (OLT) in children with osteodystrophy increases remarkably and according to height. The effect of posttransplant factors possibly influencing bone mass in the long-term after a successful OLT in children is unknown. METHODS: Eighteen patients (9 male), median age 13.3 (range 4.7-23.7) years, median time after OLT 8.3 (1.1-17.3) years were enrolled. Indications for OLT were biliary atresia (8), Alagille (3), hepatoblastoma (2), NonA-NonG acute liver failure (2), intrahepatic cholestasis, cryptogenic cirrhosis, and cholesteryl-ester disease (1 each). At OLT, all were prepubertal and 12 were severely cholestatic. We recorded anthropometric data, immunosuppression, dual-energy x-ray absorptiometry (DXA), biochemical markers of bone metabolism, and liver function. RESULTS: Six children were on steroid therapy, eight were on cyclosporine, nine on tacrolimus. Median L1 to L4 spinal BMD was 0.720 (range 0.524-1.127) g/cm3, Z score -0.70 (-2.2- +2.1), height Z score -0.31 (-1.83- +1.96). Median bone mineral apparent density was 0.112 (0.084-0.142) (normal value 0.10-0.14) g/cm3. Median alanine aminotransferase level was 22 (range 11-79) IU/L, urinary free deoxypyridinolines 20.6 (7.1-62) nmol/mmol creatinine, osteocalcin 14 (2.3-45) microg/L, parathyroid hormone 51 (2-87) ng/L, Vitamin D3 67 (17-102) nmol/L. CONCLUSION: BMD after the first year from a successful pediatric liver transplantation is normal. Our study suggests that normal bone density in this setting is maintained for at least 1 decade.     

The impact of nonalcoholic fatty liver disease and the metabolic syndrome on progression of fibrosis in patients with recurrent HCV after liver transplantation

Nonalcoholic fatty liver disease (NAFLD) and the metabolic syndrome (MS) have been shown to play a role in disease progression and response to therapy in patients with chronic hepatitis C virus (HCV) infection. The primary objective of this study was to evaluate the impact of coexisting NAFLD and MS on the progression of fibrosis in patients with recurrent HCV treated with interferon (IFN)/ribavirin after orthotopic liver transplantation (OLT). From 1998 to 2004, a total of 418 patients underwent OLT in our center for HCV-related cirrhosis. Thirty-five patients with recurrent HCV on IFN/ribavirin treatment, who had at least 2 posttransplant liver biopsies at least 6 months apart, were included in the study. Patients who had MS at the time of their first posttransplant biopsy were identified. The first and last posttransplant biopsies were assessed for the presence and severity of NAFLD, grade of inflammation, and stage of fibrosis. The fibrosis progression rate (FPR) was calculated and expressed in fibrosis units per month (FU/mo). Among 35 patients, 34% were diagnosed with NAFLD in the first posttransplant biopsy. The mean FPR was 0.05+/-0.16 FU/mo in the presence of NAFLD compared to 0.07+/-0.10 FU/mo in its absence (P=.68) and 0.03+/-0.06 FU/mo in the presence of MS versus 0.10+/-0.15 FU/mo in its absence (P=.06). When FPR values were divided into two categories of <0.16 FU/mo or >or=0.16 FU/mo (below/above the 25% upper quartile) or <0.08 FU/mo or >or=0.08 FU/mo (below/above the 50% upper quartile), there was no correlation between FPR categories and the presence of NAFLD with or without MS, only MS, or the absence of both in the first liver transplant biopsy (P=.13). Coexisting NAFLD or MS had no significant effect on the progression of fibrosis after OLT in patients with treated hepatitis C after OLT.     

Vanishing bile-duct syndrome following liver transplantation--is it reversible?

Loss of bile ducts is a characteristic feature of chronic rejection in the liver allograft (also known as irreversible rejection and vanishing bile-duct syndrome). Typically, this occurs as a progressive lesion resulting in irreversible damage and graft failure requiring retransplantation. In this study, we describe 6 patients who developed a transient loss of bile ducts following liver transplantation. This occurred in a series of 138 patients who underwent the first 160 liver transplant operations in the Birmingham Liver Transplant Programme (incidence = 4.4% of patients, 3.7% of grafts). Forty needle biopsies were obtained from the 6 patients between 6 and 1303 days after transplantation. Thirteen specimens, taken between 8 and 1253 days posttransplant (median 98 days) showed an absence of bile ducts in more than 50% of portal tracts. Other histologic features of chronic rejection, inflammatory bile-duct lesions, perivenular cholestasis, and hepatocyte dropout were also seen in these biopsies, and severe cholestasis was present biochemically (median serum bilirubin level 240 mumol/L). The histologic and biochemical changes were thought to be compatible with a diagnosis of chronic/irreversible rejection, but the decision to carry out retransplantation was deferred on the basis of stable and, subsequently, improving biochemistry. Follow-up biopsies showed recovery of duct loss and other histologic abnormalities. All 6 patients are currently alive and well with good graft function. It is concluded that a transient, reversible bile-duct loss can occur after liver transplantation and that cases with this condition are indistinguishable from those who subsequently develop irreversible graft damage. In view of the risks associated with additional immunosuppression and/or retransplantation, caution is advocated in the interpretation of ductopenia in posttransplant liver biopsies. We suggest that the term "early chronic rejection" might be appropriate to describe cases in which a definite diagnosis of irreversible graft damage cannot be made.     

Evidence of continuing bone recovery at a mean of 7 years after liver transplantation.

Patients with end-stage liver disease have low bone-turnover osteoporosis, and there is often further bone loss of 20% to 30% after orthotopic liver transplantation (OLT). Bone recovery after OLT has been reported, but data are limited. We undertook studies to determine whether bone recovery continues in the long term. Twenty-eight adult patients alive at least 5 years after OLT were studied (14 men, 14 women). Bone mineral density (BMD), serum parathyroid hormone (PTH), osteocalcin, and vitamin D levels were measured pretransplantation, at 3 months, 12 months, a mean of 46 months, and a mean of 85 months (range, 63 to 117 months) after transplantation. When BMD is expressed as a z score, the results were as follows: x0.82 +/- 0.22 pre-OLT; -2.04 +/- 0.27 at 3 months; -1.68 +/- 0.24 at 12 months; -1.23 +/- 0.24 at a mean of 46 months; and -1.0 +/- 0.26 at a mean of 85 months after OLT. The results at 46 and 85 months were significantly greater than the measurement at 3 months after OLT (P <.05). Furthermore, mean BMD (expressed as a z score) returns to the pre-OLT level at a mean of 85 months. At final follow-up, 9 of 28 patients had elevated PTH levels, and 14 of 27 patients had elevated osteocalcin levels. Five patients had spontaneous fractures in the first 12 months after transplantation, and 5 more patients had fractures by final follow-up. Even at 7 years after OLT, there was a significant increase in BMD (expressed as a z score) compared with 3 months after transplantation. Elevation of serum PTH and osteocalcin levels in some patients suggests continuing bone remodeling.     

Chronic renal dysfunction after liver transplantation in adult patients: prevalence,risk factors,and impact on mortality

INTRODUCTION: Although chronic renal dysfunction (CRD) is a common complication among patients undergoing liver transplantation (OLT) its prevalence, risk factors, and impact on outcome have not been well defined. We aimed to assess the incidence of CRD, its associated risk factors and its impact on outcome. PATIENTS AND METHODS: The cohort of 289 consecutive adult first liver transplant patients with posttransplant follow-up longer than 6 months received cyclosporine in 230 patients (153 oil-based and 81 microemulsion formulation), tacrolimus in 55. CRD was defined as serum creatinine levels greater than 1.3 mg/dL for more than 6 months. RESULTS: After a mean follow-up of 67 months, 138 patients (47.8%) displayed CRD. The prevalence of CRD was 30.9%, 41.5%, and 38.9% at 1, 5, and 13 years after OLT, respectively. Twelve patients (4.1%) developed end-stage renal failure. Male gender, older recipient age, pretransplant renal dysfunction and hyperuricemia, posttransplant in-hospital renal dysfunction and hyperuricemia, and renal dysfunction during the first 6 months after OLT were each significantly associated with the development of CRD. Survival was significantly lower (63%) among liver transplant patients with CRD than those without this complication (71%, P=.024). CONCLUSIONS: CRD is an important cause of morbidity after OLT, although end-stage renal disease is infrequent. Because early renal dysfunction is associated with the development of CRD, and decreased long-term patient survival, efforts should be made to avoid early renal dysfunction after liver transplantation.     

Local secretion of TNF-α from the liver does not correlate with endotoxin, IL-6, or organ function in the early phase after orthotopic liver transplantation

Hepatic ischemia/reperfusion leads to an excessive release of proinflammatory cytokines, which promotes local and remote cell damage. The value of cytokine measurement in humans for predicting graft function after orthotopic liver transplantation (OLT) remains unclear. Therefore, in this study, tumor-necrosis-factor-α (TNF-α), interleukin-6 (IL-6), and endotoxin (ET) levels were determined in the blood taken from the hepatic veins of 31 patients who underwent OLT. Peak levels of TNF-α in hepatic venous blood were measured shortly after reperfusion and were significantly higher than concentrations in the systemic circulation. IL-6 concentrations, peaking 90 min after reperfusion, only correlated with postoperative pulmonary dysfunction. ET was detectable in 21 patients, but levels did not correlate with either IL-6 or TNF-α concentrations. Additionally, serum cytokine levels did not correlate with the duration of ischemia or with histological changes seen in liver biopsies. In general, our study suggests that local secretion of cytokines does not predict liver function in the early posttransplant phase. Received: 25 October 1999 Revised: 7 July 2000 Accepted: 22 November 2000     

Sequential changes in the metabolic response to orthotopic liver transplantation during the first year after surgery

OBJECTIVE: To quantify the sequential changes in the metabolic response occurring in patients with end-stage liver disease after orthotopic liver transplantation (OLT). SUMMARY BACKGROUND DATA: Detailed quantification of the changes in energy expenditure, body composition, and physiologic function that occur in patients after OLT has not been performed. Understanding these changes is essential for the optimal management of these patients. METHODS: Fourteen patients who underwent OLT for end-stage liver disease had measurements of resting energy expenditure, body composition, and physiologic function immediately before surgery and 5, 10, 15, 30, 90, 180, and 360 days later. RESULTS: Resting energy expenditure was significantly elevated after surgery (24% above predicted), peaking around day 10 after OLT, when it averaged 42% above predicted. A significant degree of hypermetabolism was still present at 6 months, but at 12 months measured resting energy expenditure was close to predicted values. Before surgery, measured total body protein was 82% of estimated preillness total body protein. During the first 10 days after OLT, a further 1.0 kg (10%) of total body protein was lost, mostly from skeletal muscle. Only 54% of this loss was restored by 12 months. Significant overhydration of the fat-free body was seen before OLT, and it was still present 12 months later. Although significant losses of body fat and bone mineral occurred during the early postoperative period, only body fat stores were restored at 12 months. Both subjective fatigue score and voluntary hand grip strength improved rapidly after OLT to exceed preoperative levels at 3 months. At 12 months grip strength was close to values predicted for these patients when well. Respiratory muscle strength improved less markedly and was significantly lower than predicted normal levels at 12 months. CONCLUSIONS: Before surgery, these patients were significantly protein-depleted, overhydrated, and hypermetabolic. After surgery, the period of hypermetabolism was prolonged, restoration of body protein stores was gradual and incomplete, and respiratory muscle strength failed to reach expected normal values. Our measurements indicate that OLT does not normalize body composition and function and imply that a continuing metabolic stress persists for at least 12 months after surgery.     

Steroid-free liver transplantation using rabbit antithymocyte globulin and early tacrolimus monotherapy

BACKGROUND: In 2001, we published early results of a prospective randomized trial of 71 patients who received either steroids or rabbit antithymocyte globulin (RATG) for orthotopic liver transplantation (OLT). We now report follow-up on these patients and additional patients undergoing steroid-free OLT. METHODS: A total of 119 adult OLT recipients were prospectively randomized to receive either methylprednisolone 1,000 mg followed by a 3-month steroid taper or a steroid-free regimen of RATG 1.5 mg/kg during the anhepatic phase followed by a 1.5 mg/kg dose on posttransplant day 1. Maintenance immunosuppression consisted of tacrolimus and mycophenolate mofetil in both groups. Mycophenolate mofetil was weaned over 3 months in the first 71 patients and over 2 weeks in the last 48 patients, achieving tacrolimus monotherapy by 2 weeks posttransplant. Subsequently, a group of 24 sequential OLT recipients received the steroid-free (RATG) protocol. Endpoints of the study were survival, rejection, infectious complications, posttransplant diabetes, and recurrent hepatitis C virus. RESULTS: One-year patient survival was 85% in each group of the prospective randomized trial with a mean follow-up of 18.5 months. One-year graft survival was 82% in the RATG group and 80% in the steroid group (P=not significant). Patient and graft survival of the 24 nonrandomized RATG patients was 96% with a mean follow-up of 3 months. The incidence of rejection was not significantly different; however, 50% of the patients in the steroid group required pulse steroids to reverse the rejection compared with only one patient (1.6%) in the RATG group (P=.03). The incidence of cytomegalovirus infection (P<.05) and posttransplant diabetes was higher in the steroid group (P=.03). There was a trend toward decreased severity of hepatitis C virus in the RATG group. CONCLUSIONS: Steroid-free liver transplantation using RATG and early tacrolimus monotherapy effectively reduces immunosuppression-related complications with excellent survival.     

Hematologic aspects of liver transplantation for Budd-Chiari syndrome with special reference to myeloproliferative disorders

BACKGROUND: Patients who undergo orthotopic liver transplantation (OLT) for Budd-Chiari syndrome (BCS) traditionally have been anticoagulated with warfarin postoperatively. Because a significant proportion of BCS patients are found to have an underlying myeloproliferative disorder (MPD), antiplatelet therapy may be a more rational treatment strategy for this subgroup. METHODS: All patients who underwent OLT for the diagnosis of BCS at our institution through March 2000 were included in this analysis. Posttransplant therapy consisted of hydroxyurea and aspirin for those with MPDs. Standard anticoagulation or no antithrombotic treatment was given to BCS patients with other causes. Major posttransplantation complications (thrombosis and bleeding) and mortality were determined. RESULTS: Seventeen patients underwent OLT for BCS at our institution. The mean follow-up was 68.4 months. Two of seventeen patients died; one patient died of recurrent thrombosis (124 months after OLT) and the other patient died of acute hepatitis B (7 months after OLT). Twelve patients (71%) had evidence of a MPD. Two of the MPD patients were treated with warfarin before the initiation of hydroxyurea and aspirin therapy. The remaining 10 MPD patients were placed on only hydroxyurea and aspirin after OLT. Anagrelide was used in place of hydroxyurea in two patients because of cytopenias caused by the latter agent. The mean follow-up of this group of 10 patients was 59.9 months. Only one patient experienced recurrent thrombosis, which occurred more than 10 years after the original transplant. There were no major bleeding complications and posttransplant liver biopsies were well tolerated. CONCLUSIONS: Antiplatelet therapy that consists of hydroxyurea and aspirin is a safe and effective alternative to anticoagulation to prevent recurrent thrombosis in MPD patients with BCS after liver transplantation. For patients with a hypercoagulable state corrected by OLT, antithrombotic therapy probably is not required. For those patients with conditions not corrected by OLT or with idiopathic BCS, anticoagulation or other therapy to control the hypercoagulable state should be given.     

APRI and FIB-4 Scores Are Useful After Liver Transplantation Independently of Etiology

Noninvasive liver fibrosis scores are evaluated in hepatitis C virus-infected patients but are less known in liver transplant recipients. Fibrosis is a frequent, multifactorial event in these patients. This preliminary retrospective study reviewed the diagnostic performance of 3 simple scores for liver fibrosis in transplant patients: namely, APRI (aspartate aminotransferase to platelet ratio index), FORNS (platelets, γ-glutamyltransferase, patient age, and cholesterol), and FIB-4 (patient age, aspartate aminotransferase, alanine aminotransferase, and platelets). Ninety-four biopsies were collected from 50 liver transplant recipients at a mean period after orthotopic liver transplantation (OLT) of 30.7 months (range, 12–108 months). The indications for OLT were hepatitis C in 23% of cases, hepatitis B in 14%, alcoholic disease in 33%, cholestatic disease in 19%, and others in 11%. According to the Metavir classification, 72% of biopsies revealed no significant histological fibrosis (F0–1 = group 1) and 28% showed significant fibrosis (F2–4 = group 2). A correlation was observed between the histological stage of fibrosis and albumin, γ-glutamyltransferase, aspartate aminotransferase, alanine aminotransferase, and hyaluronic acid levels. APRI and FIB-4 correlated significantly with the histological stage of fibrosis both globally and in the subgroup of nonhepatitis C liver recipients. When APRI and FIB-4 tests were applied to predict fibrosis (area under the receiver operating characteristic curve), the results were 0.87 and 0.78, respectively. Values were not significant with the FORNS test. In conclusion, APRI and FIB-4 enabled accurate prediction of significant fibrosis after OLT. In the nonhepatitis C subgroup, we found similar predictive performances. These simple scores may be applied in clinical practice in the context of follow-up after OLT independent of hepatitis C status.     

Expression of major histocompatibility complex antigens and replacement of donor cells by recipient ones in human liver grafts

The disappearance of certain cell populations of donor origin and their replacement by recipient-specific cells constitutes a possible explanation for the relatively mild course of acute rejection despite lack of MHC compatibility in human orthotopic liver transplantation (OLT). In the present report, graft biopsies of 12 OLT patients from a total of 42 patients were studied for expression of MHC antigens after transplantation using monoclonal antibodies to HLA-ABC and HLA-DR. The patients were selected based upon donor-recipient mismatching for HLA-A2, B7, Drw52, or DQw1. Monoclonal antibodies to these 4 polymorphic HLA antigens and monoclonal antibodies to HLA-ABC and -DR were applied to frozen tissue sections and visualized using an immunoperoxidase technique. Expression of HLA-ABC and -DR on, respectively, hepatocytes and bile duct epithelium were observed in posttransplant graft conditions such as viral infections, cholangitis, and acute rejection. However, no specific pattern of MHC antigen distribution was observed for these various pathological graft conditions. Disappearance of DR-positive Kupffer cells of donor origin and immigration of recipient ones was encountered in the early posttransplant biopsies. This Kupffer cell replacement coincided with a reversible episode of acute rejection. The disappearance of highly immunogenic cellular components as HLA-DR positive Kupffer cells of graft origin may be one of the mechanisms contributing to the mild rejection response observed in human liver transplantation.     

Bronchiolitis obliterans organizing pneumonia in an orthotopic liver transplant patient

A 67-year-old woman was hospitalized for progressive dyspnea on exertion. She had undergone orthotopic liver transplantation (OLT) 15 months before admission. Posttransplant therapy consisted of tacrolimus, trimethoprim/sulfamethoxazole, and prednisone (the latter two were discontinued after 1 year). Physical examination revealed fine bibasilar crackles. High-resolution chest CT demonstrated bilateral, diffuse, interstitial infiltrates. Symptoms persisted on i.v. antibiotics and bronchoscopy was performed demonstrating patchy fibroplastic plugs within air spaces consistent with bronchiolitis obliterans organizing pneumonia (BOOP). Prednisone was initiated and the patient had an uneventful recovery. BOOP was initially described as an idiopathic disease process with clinical, radiographic, pathological, and prognostic features distinguishing it from bronchiolitis obliterans and idiopathic pulmonary fibrosis. BOOP has been recognized as a complication of lung and bone marrow transplantation, but the mechanism is unknown. We report a case of BOOP after OLT to highlight the risk in all transplant patients as well as the protective effect of posttransplant prednisone.     

Prevention of early loss of bone mineral density after liver transplantation by prostaglandin E1

INTRODUCTION: As a result of preexisting chronic liver disease and immunosuppression, the majority of liver transplant patients develop bone mineral density (BMD) loss in the first 3 to 6 months posttransplantation, leading to an increased fracture risk. Using basic prophylaxis and treatment by administration of vitamin D, calcium, and bisphosphonates, BMD loss may be controlled in the long term. In contrast, there is no established medical concept for prevention of early posttransplant BMD loss. MATERIAL AND METHODS: The aim of this trial was to evaluate the effect of prostaglandin E1 on BMD after liver transplantation. Between 1998 and 2004, 29 patients were enrolled in this study. BMD measurement was performed at lumbar spine and femoral neck using dual energy x-ray absorptometry pretransplant, and 3, 6, 12, and 24 months posttransplant. All patients received calcium and vitamin D as basic prophylaxis. In 13 patients, prostaglandin E1 (PGE) was additionally administered for 12 days posttransplant. RESULTS: BMD loss was significantly lower at 3 and 6 months posttransplant in the PGE group (lumbar spine, P < .03; femoral neck, P < .009). Development of BMD loss was comparable between both groups during further follow-up. In the PGE group there was a significantly lower fracture rate compared with the controls (P < .02). CONCLUSION: The application of PGE 1 proved to be beneficial in compensating the early posttransplant BMD loss and in subsequently reducing fracture rate. These positive effects of PGE 1 could be demonstrated in both the femoral neck and lumbar spine.     

Longitudinal Changes in BMD and Fracture Risk in Orthotopic Liver Transplant Recipients Not Using Bone‐Modifying Treatment

Osteoporosis is prevalent in end‐stage liver disease, but data on long‐term changes in bone mineral density (BMD) and related fracture incidence after orthotopic liver transplantation (OLT) are scarce. We evaluated BMD changes up to 5 years in consecutive recipients of a successful OLT at the Leiden University Medical Centre between 2000 and 2011, in whom sequential BMD data were available. Spinal radiographs were available at time of screening and at 6 and 12 months post‐OLT and were assessed for vertebral fractures by two independent observers using Genant's semiquantitative method. Patients were excluded from the study when started on bisphosphonates. A total of 201 patients (71% men), median age 53 years (range, 18–70 years) were included in the study. Most common liver pathology was viral (27%) or alcoholic liver disease (25%). All patients received prednisone for at least 6 months after transplantation and the majority received either tacrolimus or cyclosporine for immunosuppression. At time of screening for OLT, osteoporosis and osteopenia were found in 18% and 36% of patients at the lumbar spine (LS), respectively, and in 9% and 42% at the femoral neck (FN), respectively. T‐scores declined significantly at both sites 6 months after OLT, but increased thereafter at the LS, reaching pretransplantation values at 2 years and remaining stable thereafter. FN T‐scores remained consistently lower than pretransplantation values. The prevalence of vertebral fractures increased from 56% at screening to 71% at 1 year after OLT, with a fracture incidence of 34%. BMD changes did not predict fracture risk. Osteoporosis, osteopenia, and vertebral fractures are prevalent in patients with end‐stage liver disease. An overall decline in BMD is observed within the first 6 months after OLT, with subsequent recovery to pretransplantation values at the LS, but not at the FN. Vertebral fracture risk is high after OLT regardless of changes in BMD. © 2014 American Society for Bone and Mineral Research.