Lack of effect of intravenous pamidronate on fracture incidence and bone mineral density after orthotopic liver transplantation

BACKGROUND/AIMS: Increased rates of bone loss and fracture have been reported after liver transplantation. The aim of this study was to investigate the effects of a pre-transplant infusion of pamidronate on fracture incidence and bone loss during the first year after transplantation. METHODS: Ninety-nine adults awaiting orthotopic liver transplantation (OLT) were randomised to pamidronate or no treatment. Spinal X-rays were obtained at baseline and after 12 months. Bone mineral density (BMD) was measured at the lumbar spine (L1-4) and femoral neck at baseline, and 3, 6, and 12 months after OLT. RESULTS: The incidence of fractures in the first year after OLT was 8%, four patients within the pamidronate treated group and two in the untreated group developing fractures (P=0.40). No significant spinal bone loss occurred in either group during the first year. However, significant and sustained bone loss occurred at the femoral neck in both groups. No significant differences were seen between pamidronate treated or untreated groups at either site. CONCLUSIONS: Pamidronate in the regimen used had no significant effect on fracture rate or BMD post-transplant. The low incidence of fracture and absence of spinal bone loss indicate that bone disease after liver transplantation may be less common than previously reported.     

Bone mineral density after allogeneic bone marrow transplantation.

Bone turnover markers and bone mineral density (BMD) were studied in 25 adult patients (14 females, 11 males) who had undergone allogeneic bone marrow transplantation (BMT). The interval from BMT to the first examination was at least 1 year (mean 3, range 1-10). Mean age of the patients at the time of first evaluation was 42 (range 19-54) years. Blood samples and urine collections for evaluation of biochemical factors reflecting skeletal turnover were performed together with the first BMD measurement. BMD was measured from the lumbar vertebrae (L2 to L4) with computed tomography and results were expressed as Z-scores. At the time of the first measurement five patients (20%) had Z-scores <-2.5 s.d. and 12 patients (48%) between -1 and -2.5 s.d. In 12 patients BMD assessments were repeated and it seemed that reduction in BMD had mostly occurred during and shortly after BMT and remained the same during follow-up. The cross-linked carboxyterminal telopeptide of type I collagen (ICTP) correlated negatively with BMD (r = -0.45, P = 0.045) as did bone-specific alkaline phosphatase (BAP; r = -0.64, P = 0.002). No correlation between BMD and time interval from diagnosis to BMT, conditioning regimen, corticosteroid use or hospital stay during transplantation was found. In conclusion, bone disease is common after BMT. Our findings demonstrate an increased collagen and bone turnover and a high risk of osteoporosis. BMD measurements must be repeated regularly and collagen markers such as ICTP and BAP can be beneficial in estimating the activity of bone disease.     

Predicting bone loss following orthotopic liver transplantation

BACKGROUND: Hepatic osteodystrophy occurs in the majority of patients with advanced chronic liver disease with the abnormalities in bone metabolism accelerating following orthotopic liver transplantation (OLT). AIMS: To examine changes in bone mineral density (BMD) following OLT and to investigate factors that lead to bone loss. METHODS: Twelve patients had BMD (at both the lumbar spine (LS) and femoral neck (FN)) and biochemical markers measured preoperatively and for 24 months following OLT. RESULTS: BMD was low in 75% of patients prior to OLT and decreased significantly from baseline at the LS at three months and the FN at six months. BMD began to increase thereafter at both sites, approaching baseline values at the LS by 12 months. Bone formation markers, osteocalcin and procollagen type I carboxy propeptide, decreased immediately post-OLT, with a concomitant increase seen in the resorption markers pyridinoline and deoxypyridinoline. This resulted in a negative uncoupling index early post-OLT, that rebounded to positive values after six months. There was a significant correlation between the change in the uncoupling index between six and three months which preceded the increase in BMD at 12 months. The decrease in BMD recorded early post-OLT correlated with vitamin D levels at three months. CONCLUSIONS: Results suggest that increased resorption and inadequate formation are the major contributors to additional bone loss following OLT. Non-invasive biochemical markers precede later changes in BMD in this patient group following OLT and may have a role in investigating and planning intervention strategies to prevent bone loss in future studies.     

Neurological complications after orthotopic liver transplantation

BACKGROUND: The number of orthotopic liver transplantation performed each year is increasing due to increased safety and logistic facilities. Therefore, the importance of reducing adverse events is progressively growing. AIM: To review present knowledge on the neurological complications of orthotopic liver transplantation. METHODS: The epidemiology, the clinical features and the pathophysiology of the neurological complications of orthotopic liver transplants, resulting from a systematic review of the literature in the last 25 years, are summarized. RESULTS AND CONCLUSIONS: The review highlights that a relevant variety of neurological adverse events can occur in patients undergoing orthotopic liver transplantation. The knowledge of neurological complications of orthotopic liver transplantation is important for transplantation teams to reduce their prevalence and improve their management. In addition, the likelihood of neurological adverse effects provides evidence for the need of a careful cognitive and neurological work up of patients in the orthotopic liver transplantation waiting list, in order to recognize and interpret neurological dysfunction occurring after orthotopic liver transplantation.     

Colorectal cancer after orthotopic liver transplantation

There is an increased incidence of de novo malignancies in post-liver transplant patients, commonly associated with chronic viral infection comprising lymphoproliferative disease and skin cancers, including squamous cell carcinoma and Kaposi's sarcoma. The overall incidence of colorectal cancer however in this population seems to be no different to the age and sex matched general population. In identified high risk patients like those with primary sclerosing cholangitis (PSC) and inflammatory bowel disease (IBD), the incidence of colorectal cancer appears to be higher. In IBD, like other pre-malignant conditions, the risk of developing malignancy increases exponentially with time, raising the question of whether the apparent increase in the incidence of colorectal cancer is the result of liver transplantation and immunosuppression or due to the natural history of IBD. For these PSC recipients, pre-transplant screening with colonoscopy and post-transplant surveillance for malignant change in the large bowel is crucial. The behaviour of inflammatory bowel disease post-liver transplant is largely unpredictable despite immunosuppression. Colorectal cancer when it occurs in the post-liver transplant patient should be managed according to current guidelines, stage for stage as for the population in general coupled with reduction in immunosuppression treatment.     

Bone disease after orthotopic liver transplantation

After orthotopic liver transplantation (OLT), not infrequently a deterioration of bone disease leading to compression fractures of vertebrae is seen. In a consecutive series of 36 adult OLT patients, we studied, clinically and radiologically, the incidence and degree of bone disease before and after OLT; we also studied whether clinical, radiological and laboratory findings were related to the event of postoperative vertebral collapse. Before OLT, radiological signs of mostly slight osteoporosis were seen in a minority of patients. After OLT, 38% of patients developed vertebral collapse, mainly in the second trimester. Collapse occurred in both previously normal and abnormal vertebrae. Of the preoperative parameters sex, age, menopause, intake of prednisolone, duration and diagnosis of liver disease, duration and degree of cholestasis, bone radiology and urinary calcium, only a low urinary calcium was related to postoperative collapse. Of the postoperative parameters duration of cholestasis, urinary calcium, duration of hospital stay, prednisolone dose and outcome in terms of life and death, none was related to collapse. We conclude that vertebral collapse after OLT occurs frequently and is not easily predicted. Early prevention of bone disease in patients with chronic liver disease before OLT and a low steroid-containing immunosuppressive regimen after OLT are advocated.     

Infectious complications after orthotopic liver transplantation

Advances in surgical technique, critical care, immunosuppression, donor and recipient screening, and prophylactic strategies have contributed to the evolving microbiology and epidemiology of infectious complications after liver transplantation. Although decreased overall, infections continue to be a major contributor to graft loss and patient morbidity. Bacterial and candidal infections are less frequent, but antimicrobial resistance has become more common and can potentially limit successful treatment of health care-acquired and surgical site infections. As the transplant population grows, intensivists and pulmonologists are more likely to evaluate liver transplant recipients with infections. Presentations of opportunistic respiratory infections may be atypical in the setting of immunosuppression. Although novel noninvasive diagnostic tools are available for some pathogens, bronchoscopic evaluation may be increasingly helpful in differentiating between certain respiratory pathogens when empirical therapy is plagued by drug interactions and drug toxicities. Knowledge about common postoperative infections and opportunistic respiratory pathogens such as cytomegalovirus and fungi is essential to improving the global care of the liver transplant recipient.     

Tubular function after orthotopic liver transplantation

Renal function after orthotopic liver transplantation (OTL) is very frequently reduced and its level exerts a significant effect on the morbidity and mortality of these subjects. One of the main factors with a negative impact on renal function after OTL is the nephrotoxic action of cyclosporin A (CsA). Renal function after OTL is usually evaluated on the basis of glomerular filtration (GF). As chronic nephrotoxicity of CsA is manifested in the histological picture by significant tubulointerstitial affection, in 75 subjects after OTL the spontaneous concentrating and acidifying capacity of the kidneys was investigated. The value of urine osmolality (UOSM) assessed after noctunal withdrawal of fluids was in 72.7% lower than in healthy subjects and did not reach 600 mOsm/kg H2O, although the serum creatinine concentration (Scr) was still within the normal range. The pH value of the morning urine did not reach in 38.2% the required value of 6.0 although Scr was within the normal range. Between values of UOSM after nocturnal liquid withdrawal and GF assessed on the basis of inulin clearance (Cin) was a significant direct relationship, however the scatter of values was considerable (r = 0.226, p < 0.05). Between pH values of the morning urine and Cin no correlation was found. The assembled results support the idea that the concentrating activity of the kidneys in subjects after OTL treated with CsA is reduced. This reduced concentrating capacity is already apparent on the basis of UOSM of morning urine after nocturnal fluid withdrawal. Although this defect is also frequent in subjects with a normal Scr value, the authors assume that the use of this simple evaluation of the concentrating capacity (it does not burden the patient nor the attending staff) could be useful in the early diagnosis of tubulointerstitial affection.     

Decreased bone mineral density is common after autologous blood or marrow transplantation

Survivors of autologous blood or marrow transplantation (ABMT) are predisposed to decreased bone mineral density (BMD), but data are lacking on the incidence and risk factors for this condition. Therefore, we measured BMD in 64 of 68 consecutive ABMT survivors (35 men and 29 women) attending the University of Toronto ABMT long-term follow-up clinic. Patients were evaluated a median of 4.2 years (range: 4.9 months-11.4 years) after ABMT. Median age at evaluation was 49.6 years (range: 23.5-68.2 years). At the L1-L4 vertebrae, 17 (26%) patients (eight men and nine women) had osteopenia and one male (2%) had osteoporosis. Mean BMD at L1-L4 did not differ from healthy young adults or age and sex matched controls. At the femoral neck, 30 patients (46%) (18 men and 12 women) had osteopenia and five (8%) (two men and three women) had osteoporosis. Mean BMD at the femoral neck was significantly lower than in healthy young adults and age- and sex-matched controls. By regression analysis, patients with decreased BMD were older than those with normal BMD (P = 0.02). Gender, body mass index, time from BMT to evaluation and presence of hypogonadism were not associated with decreased BMD. Treatment of decreased bone density was instituted and follow-up data were obtained 1 year after treatment in 22 of 39 patients with reduced BMD. Nineteen (86%) patients had stabilization or improvement of their bone density at follow-up. We conclude that, after ABMT, over half of the patients have evidence of osteopenia or osteoporosis. Men and women were equally affected. In our study, only older age at evaluation was predictive for loss of BMD. We recommend the measurement of BMD as an integral component to the follow-up of ABMT patients.     

Successful twin pregnancy after orthotopic liver transplantation

AIM: Report of a case of successful twin pregnancy following liver transplantation. PATIENT AND METHOD: A 42-year-old nulliparous-woman was subjected to an orthotopic liver transplantation due to Budd-Chiari syndrome. Sixteen months after the transplantation, an ultrasonography revealed twin pregnancy. Her prenatal course was uneventful, except for mild arterial hypertension. The immunosuppressive agents used during pregnancy were cyclosporine and prednisone. RESULT: The patient gave birth to two healthy girls at 37 weeks of gestation. The patient's postpartum course was uneventful with normal liver and renal function tests. CONCLUSION: Following successful pregnancy, women may become pregnant and give birth to normal children, including twins     

Composition of bile after orthotopic liver transplantation

In 20 adult patients undergoing orthotopic liver transplantation (OLT), we studied longitudinally for the first 3 weeks after OLT the composition of bile with regard to differences between surviving and non-surviving patients and between patients with more or less rejection and the relation between bile and serum concentrations. The analyzed biliary components were bilirubin, cholesterol, bile acids, phospholipids, copper, iron, glucose, urea, creatinine, ammonia, protein, sodium, potassium, chloride, pH, bicarbonate, calcium and phosphate. After the 1st day the composition of bile was often different from reference values. In most patients deviations of the hepatic excretion function were found. Especially, a sharp fall was noticed in the biliary concentrations of cholesterol and copper. The composition of bile was not helpful in predicting the histologic degree of rejection or the ultimate outcome of the patients. Changes in bile glucose, electrolyte, urea, and creatinine concentrations were positively related to serum concentrations. We conclude that for the compounds analyzed the composition of bile after OLT is not only influenced by the state of the liver but also by the overall metabolic state of the patient.     

Biliary complications after deceased-donor orthotopic liver transplantation

A wide range of potential biliary complications can occur after orthotopic liver transplantation (OLT). The most common biliary complications are bile leaks, anastomotic and intrahepatic strictures, stones, and ampullary dyfunction, which may occur in up to 20%–40% of OLT recipients. Leaks predominate in the early posttransplant period; stricture formation typically develops gradually over time. However, with the advent of new techniques, such as split-liver, reduced-size, and living-donor liver transplantation, the spectrum of biliary complications has changed. Risk factors for biliary complications comprise technical failure; T-tube or stent-related complications; hepatic artery thrombosis; bleeding; ischemia/reperfusion injury; and other immunological, nonimmunological, and infectious complications. Noninvasive diagnostic methods have been established and treatment modalities have been modified towards a primarily nonoperative, endoscopy-based strategy. Besides, the management of biliary complications after OLT requires a multidisciplinary approach, in which interventional and endoscopic treatment options have to be weighed up against surgical treatment options. The etiology and spectrum of bile duct complications, their diagnosis, and their treatment will be reviewed in this article.     

Gut perforation after orthotopic liver transplantation in adults

AIM： To describe cases of gut perforation after orthotopic liver transplantation.
METHODS： Data were colleted from our center database and medical records. Six of 187 patients （3.2%）who underwent orthotopic liver transplantation from January to December 2005 developed gut perforation.All patients were male with an average age of 46 years.Modified piggyback liver transplantation was performed at the Organ Transplantation Center, First Affiliated Hospital, Sun Yat-Sen University.RESULTS： Previous operation, steroid therapy, and prolonged portal venous cross clamp time, poor nutritional status and iatrogenic injury were found to be its ecological factors. The patients with gut perforation were found to have fever, increased leukocytes, mild abdominal pain and tenderness. The median portal venous clamp time was 63 min （range 45-72 min）,median cold ischaemia time was 11.3 h （range 7-15 h）.Median intraoperative blood loss was 500 mL （range 100-1200 mL） and median operation time was 8.8 h （range 6-12 h）. None of the six patients developed acute cellular rejection. White cell count was above 18 × 10^9/L in five patients （neutrophilic leukocytes were above 90%） and 1.5 × 10^9/L in one patient. Bacterial culture in drainage liquid revealed enterococci in five patients. Of the 6 patients undergoing orthotopic liver transplantation, 3 survived and 3 died after modified piggyback liver transplantation.
CONCLUSION： Gut perforation occurs after orthotopic liver transplantation in adults. A careful and minimal dissection during OLT, longer retention of the stomach tube, and reducing the portal clamp time and steroid dose should be taken into consideration. If gut perforation is not prevented, then early diagnosis,preferably through detection of enterococci may ensure better survival.     

Grading of cellular rejection after orthotopic liver transplantation

All 684 post-orthotopic liver transplantation (OLT) liver biopsies performed at the Royal Free Hospital (RFH) between 1988 and 1993, from 120 patients, were reviewed in order to try to define the relative importance of the histological features of immunosuppressionresponsive cellular rejection. Twenty histological features considered to be possible contributors to the diagnosis of cellular rejection were documented in a binary (presentlabsent) fashion. These features in 106 biopsy specimens obtained 1 to 8 days after OLT were analyzed using stepwise logistic discriminant analysis. All clinical and treatment records were reviewed, and each biopsy specimen was assigned to a diagnostic category depending on these records and follow-up information. Important determinants of the histological diagnosis of cellular rejection (which occurred in 84 of the 106 cases) were moderate/severe mixed portal inflammation, eosinophils, endotheliitis, and bile duct damage. When these all occurred together, the odds of rejection increased 3.6-fold. The original histological diagnosis was recorded, and each biopsy specimen showing cellular rejection was regraded according to the specific criteria of Snover et al., Demetris et al., and a novel RFH scoring system. The latter consists of evaluating portal inflammation, endotheliitis, eosinophils, and bile duct damage, each on a 0 to 3 scale (none, mild, moderate, or severe, respectively) and summation. The resulting cellular rejection score thus can range from 0 to 12. The agreement between the different scoring systems was analyzed using K statistics, and there was good concordance (K, 0.64 to 0.78), despite different histological criteria being used to derive each score. Each system showed a similar degree of sensitivity (87% to 96%). The specificity ranged from 59% to 77%. We conclude that the histological diagnosis of cellular rejection relies mainly on the previously described features of mixed portal inflammation, endotheliitis, eosinophils, and duct damage. There is scope for unification and simplification of the existing grading systems, which depend on differing criteria, and we suggest one such scheme.     

原位肝移植术后肝脓肿的诊断和治疗

目的 探讨原位肝移植术(OLT)后肝脓肿的病因、诊断、治疗和预防措施。方法自1993年1月至2003年6月，本中心共行OLT274例，术后并发肝脓肿6例(2．2％)。患者主要临床表现有发热、寒战、腹痛、身目黄染、肝功能损害、低蛋白血症、贫血、白细胞及中性粒细胞比例增高等。诊断主要根据临床表现及超声或CT检查。治疗方法主要包括脓肿抽吸引流、清除胆泥．抗炎和支持治疗。结果6例中2例治愈，3例放弃再次肝移植术，2例死于严重全身感染，治愈率为33．3％。结论OLT后肝脓肿病因较复杂，可能与肝动脉血栓或狭窄、甲基强的松龙冲击治疗、胆管炎症和介入治疗等有关。OLT后肝脓肿的预后较差．应加强预防措施防止其发生。     

Ischemic-type biliary complications after orthotopic liver transplantation.

Nonanastomotic biliary strictures that involve only the biliary tree of the graft occur after orthotopic liver transplantation in patients with hepatic artery thrombosis, chronic ductopenic rejection and ABO blood group incompatibility. This complication may also occur in the absence of these known risk factors. The major focus of our study was to evaluate the risk factors for nonanastomotic biliary stricturing of unknown cause after orthotopic liver transplantation. Results demonstrate that the development of biliary strictures is strongly associated with the duration of cold ischemic storage of allografts in both Euro-Collins solution and University of Wisconsin solution. Results also demonstrate that strictures are not associated with the type of biliary reconstruction, the primary liver disease, cytomegalovirus infection, allograft rejection or the presence of a positive lymphocytotoxic crossmatch. More recently, we have markedly reduced the occurrence of nonanastomotic biliary stricturing by decreasing the ischemia time of our allografts. Thus nonanastomotic biliary strictures appear to be the result of the ischemia/reperfusion-induced tissue injury associated with the harvest and implantation of allografts.     

受体骨髓间质干细胞在大鼠原位肝移植中对免疫排斥的影响

目的:观察受体骨髓间质干细胞(BM-MSCs)在大鼠原位肝移植后体内的分布与作用.方法:以Wistar大鼠为供体,SD大鼠为受体采用双袖套法制作原位肝移植模型,密度梯度离心法分离与贴壁法富集受体BM-MSCs.CFSE标记术后经门静脉注入,荧光显微镜分别观测术后1wk,2 wk,1mo肝脾肺肾组织中BM- MSCs的分布及各时间点检测肝功能及肝组织免疫排斥情况.结果:密度梯度离心所得到的BM-MSCs为比较一致的球形单个核细胞,台盼蓝染色细胞活力达98%左右,其他细胞少见.BM-MSCs体外分离培养扩增至第3代后较为纯化.应用CFSE可快速高效的标记贴壁BM-MSCs.移植的BM-MSCs主要在受体肝脏中聚集,1mo后略有减少,而脾肺肾组织内BM-MSCs在1mo后仅有极少分布.B组无BM-MSCs输入与C组有BM-MSCs输入肝功能比较,C组肝功能有明显好转,B,C组间差异有显著意义(F=63.179,P<0.01),B,C组各时段肝功能差异有显著性意义(F=221.026,P<0.01).C组肝组织免疫排斥反应明显减轻.结论:原位肝移植术后输注受体BM-MSCs可有效缓解免疫排斥反应.