tacrolimus and Cholestasis

Pediatric donor (PD) livers have been allocated to adult transplant recipients in certain situations despite size discrepancies. We compared data on adults (age > or = 19 years) who underwent primary liver transplantation using livers from either PDs (age < 13 years; n = 70) or adult donors (ADs; age > or = 19 years; n = 1,051). We also investigated the risk factors and effect of prolonged cholestasis on survival in the PD group. In an attempt to determine the minimal graft volume requirement, we divided the PD group into 2 subgroups based on the ratio of donor liver weight (DLW) to estimated recipient liver weight (ERLW) at 2 different cutoff values: less than 0.4 (n = 5) versus 0.4 or greater (n = 56) and less than 0.5 (n = 21) versus 0.5 or greater (n = 40). The incidence of hepatic artery thrombosis (HAT) was significantly greater in the PD group (12.9%) compared with the AD group (3.8%; P =.0003). Multivariate analysis showed that preoperative prothrombin time of 16 seconds or greater (relative risk, 3.206; P =.0115) and absence of FK506 use as a primary immunosuppressant (relative risk, 4.477; P =.0078) were independent risk factors affecting 1-year graft survival in the PD group. In the PD group, transplant recipients who developed cholestasis (total bilirubin level > or = 5 mg/dL on postoperative day 7) had longer warm (WITs) and cold ischemic times (CITs). Transplant recipients with a DLW/ERLW less than 0.4 had a trend toward a greater incidence of HAT (40%; P <.06), septicemia (60%), and decreased 1- and 5-year graft survival rates (40% and 20%; P =.08 and.07 v DLW/ERLW of 0.4 or greater, respectively). In conclusion, the use of PD livers for adult recipients was associated with a greater risk for developing HAT. The outcome of small-for-size grafts is more likely to be adversely affected by longer WITs and CITs. The safe limit of graft volume appeared to be a DLW/ERLW of 0. 4 or greater.

Topics: Adolescent; Adult; Cholestasis; Graft Survival; Hepatic Artery; Humans; Immunosuppressive Agents; Liver; Liver Transplantation; Multivariate Analysis; Organ Size; Postoperative Complications; Prothrombin Time; Risk Factors; Safety; Tacrolimus; Thrombosis; Tissue Donors

In patients after orthotopic liver transplantation, treatment with the novel immunosuppressant FK 506 may lead to elevated levels of alkaline phosphatase, gamma glutamyl transferase and bilirubin. Up to now it was unclear whether the excretory capacity of the liver in such patients is impaired.. We measured quantitatively the secretion of bile acids, phospholipids and cholesterol using the duodenal perfusion method, which allows assessment of biliary secretion without interruption of the enterohepatic circulation. Six healthy volunteers served as controls.. All patients studied after orthotopic liver transplantation had elevated concentrations of serum alkaline phosphatase and gamma glutamyl transferase, whereas only half of them had slightly abnormal serum bilirubin levels. On average, the FK 506-treated patients excreted 1.23 +/- 0.27 mmol/h bile acids, 0.23 +/- 0.04 mmol/h phospholipids and 0.11 +/- 0.02 mmol/h cholesterol, which was not significantly different from the healthy controls.. The normal secretion rates of biliary bile acids and lipids in FK 506-treated patients with elevated serum alkaline phosphatase and gamma glutamyl transferase indicate that the excretory capacity of the transplanted liver has completely recovered 2-3 months after surgery. In addition, in the majority of these patients elevated serum levels of alkaline phosphatase, gamma glutamyl transferase and bilirubin do not reflect impaired biliary secretion.

Topics: Adult; Bile; Biomarkers; Cholestasis; Female; Humans; Liver Transplantation; Male; Middle Aged; Reproducibility of Results; Tacrolimus

Topics: Allografts; Biopsy; Carcinoma, Hepatocellular; Cholestasis; Cyclosporine; Graft Rejection; Hepatitis; Humans; Immunosuppressive Agents; Liver; Liver Cirrhosis; Liver Neoplasms; Liver Transplantation; Male; Middle Aged; Tacrolimus; Ultrasonography, Doppler

Topics: Antibodies, Monoclonal; Antigens, CD20; ATP Binding Cassette Transporter, Subfamily B, Member 11; ATP-Binding Cassette Transporters; Bile Acids and Salts; Cholestasis; Female; Humans; Immunosuppressive Agents; Infant; Jaundice; Liver; Liver Transplantation; Male; Tacrolimus

Although the development of de novo autoimmune liver disease after liver transplantation (LT) has been described in both children and adults, autoimmune hepatitis (AIH)-primary biliary cirrhosis (PBC) overlap syndrome has rarely been seen in liver transplant recipients. Here, we report a 50-year-old man who underwent LT for decompensated liver disease secondary to alcoholic steatohepatitis. His liver function tests became markedly abnormal 8 years after LT. Standard autoimmune serological tests were positive for anti-nuclear and anti-mitochondrial antibodies, and a marked biochemical response was observed to a regimen consisting of prednisone and ursodeoxycholic acid added to maintain immunosuppressant tacrolimus. Liver biopsy showed moderate bile duct lesions and periportal lymphocytes infiltrating along with light fibrosis, which confirmed the diagnosis of AIH-PBC overlap syndrome. We believe that this may be a case of post-LT de novo AIH-PBC overlap syndrome; a novel type of autoimmune overlap syndrome.

Topics: Cholagogues and Choleretics; Cholestasis; Fatty Liver, Alcoholic; Hepatitis, Autoimmune; Humans; Immunosuppressive Agents; Liver Cirrhosis, Biliary; Liver Function Tests; Liver Transplantation; Male; Middle Aged; Prednisone; Tacrolimus; Treatment Outcome; Ursodeoxycholic Acid

The role of Interleukin 28B (IL-28B) genetic polymorphisms in influencing the occurrence of biliary complications after liver transplantation has never been evaluated. This study aimed to investigate whether IL-28B rs12979860C/T polymorphisms associate with the occurrence of biliary complications after liver transplantation and if these complications may influence survival.. One hundred seventy one recipients (133 males) who underwent liver transplantation were recruited. To confirm the mechanical etiology of cholestasis, endoscopic cholangio pancreatography, percutaneous and/or trans-Kehr cholangiography or cholangio magnetic resonance were performed. Two main clinical pictures were identified: biliary strictures and biliary leakage. Immunosuppressive therapy was based on cyclosporine (N = 54) or tacrolimus (N = 117), in association with steroids during the first month after operation. IL-28B rs12979860C/T genotypes were detected by means of polymerase chain reaction.. Forty patients (23.4%) presented anastomotic strictures, 7 (4.1%) non-anastomotic strictures, 10 (5.8%) leakage, 8 (4.7%) leakage plus anastomotic strictures. IL-28B rs12979860C/C genotype in association with cyclosporin was found to be an independent predictor of anastomotic strictures occurrence (p = 0.008). A significant difference in 5 years survival was observed between patients with viral etiology of liver disease experiencing either anastomotic or non-anastomotic strictures (16/23) and the remaining patients (104/112, p = 0.001).. In recipients carrying rs12979860 IL-28B C/C genotype the use of cyclosporine seems to contribute to enhance the probability of developing biliary complications which in hepatitis B and C positives appear to reduce patient survival. If confirmed in larger studies the use of cyclosporine in these patients could be revised.

Topics: Adult; Aged; Anastomotic Leak; Cholestasis; Cyclosporine; Female; Genetic Variation; Genotype; Hepatitis B, Chronic; Hepatitis C, Chronic; Humans; Immunosuppressive Agents; Interferons; Interleukins; Liver Transplantation; Male; Middle Aged; Retrospective Studies; Risk Factors; Tacrolimus

Hepatotoxicity, including cholestasis, is a rare but significant complication of treatment with calcineurin inhibitors. Timely life-saving therapy with revision of immunosuppression is mandatory. A 43-year-old woman with pulmonary hypertension was found to have severe cholestasis (serum bilirubin up to 35 mg/dL) after a living-donor lobar lung transplantation. Calcineurin-inhibitor cholestasis markedly improved after withdrawal of the calcineurin inhibitor, initiation of sirolimus, and interleukin-2 receptor blockade. Awareness of the diagnostic criteria of this rare posttransplant complication is important to initiate timely therapy.

Topics: Adult; Calcineurin; Calcineurin Inhibitors; Cholestasis; Disease Progression; Fatal Outcome; Female; Graft Rejection; Humans; Hypertension, Pulmonary; Immunosuppressive Agents; Living Donors; Lung Transplantation; Methylprednisolone; Pneumonia, Bacterial; Postoperative Complications; Pseudomonas Infections; Risk Assessment; Sirolimus; Tacrolimus; Transplantation Immunology

Transient hyperphosphatasemia was found in a 3-year-old male liver transplant recipient. The condition was associated with diarrheal disease due to the Epstein-Barr virus (EBV). Immunosuppression was tapered and valganciclovir prescribed for 3 months, after which the diarrhea resolved and the EBV polymerase chain reaction assays became negative. After 6 months, alkaline phosphatase levels normalized. Isolated elevation of alkaline phosphatase in conjunction with enteric infection is a rare condition. No further diagnostic or therapeutic interventions except treatment of the underlying infection are needed, as this has been shown to be a benign, transient condition.

Topics: Adult; Child, Preschool; Cholestasis; Enteritis; Epstein-Barr Virus Infections; Family; Humans; Immunosuppressive Agents; Liver Transplantation; Living Donors; Male; Phosphoric Monoester Hydrolases; Phosphorus Metabolism Disorders; Postoperative Complications; Tacrolimus; Treatment Outcome

Several factors may contribute to post-transplant cholestatic complications after liver transplantation. These include ischemic reperfusion injury, hypoperfusion, bile duct strictures, and hepatotoxic drugs. Up to now, there have been no publications on tacrolimus cholestatic toxicity in clinical transplantation when the drug was used in therapeutic doses. We describe six pediatric liver graft recipients in whom cholestatic complications developed under a tacrolimus-based immunosuppression following liver transplantation and all of them suffered from previous steroid-resistant graft rejection. The overall incidence of cholestatic syndrome was 5.4% in children receiving tacrolimus. The immunosuppression was switched back to cyclosporine and prednisolone in all six patients resulting in completely resolved clinical signs and laboratory findings. We conclude from our observations that a cholestatic syndrome following pediatric liver transplantation may be caused by tacrolimus therapy following steroid-resistant graft rejection, even if given in therapeutic doses.

Topics: Adolescent; Child; Cholestasis; Cyclosporine; Graft Rejection; Humans; Immunosuppressive Agents; Infant; Liver; Liver Transplantation; Postoperative Complications; Pruritus; Retrospective Studies; Tacrolimus

Metabolic bone disease is one of the major long-term complications in liver transplant recipients, but it remains unclear which patients are at highest risk for developing severe bone disease following transplantation.. A total of 46 consecutive, adult patients with chronic liver disease accepted for a liver transplantation waiting list were prospectively included in the study. The patients were classified into two groups: group A--chronic cholestatic liver disease (n = 28), and group B--chronic non-cholestatic liver disease (n = 18). Bone mineral density (BMD) was measured at acceptance for the waiting list and at 3, 12 and 36 months following transplantation. Markers of bone turnover (serum-bone specific alkaline phosphatases (bALP), s-osteocalcin, s-1-collagen-C-terminal telopeptide (1-CTP) and urine N-terminal telopeptides u-Ntx) were measured at acceptance and at 3, 6, 12, 24 and 36 months following transplantation. BMD and markers of bone turnover were compared with similar values in a matched control group of 42 healthy individuals.. BMD decreased significantly during the early post-transplantation period (median bone loss femoral neck (FN) 3 months post-transplant 8.5%). BMD levels declined slightly from 3 to 12 months following transplantation and increased thereafter. The relative bone loss was greatest among group B patients (relative bone loss FN 3 months post-transplant: group A, 8% versus group B, 13%; P = 0.04). At 36 months, 8/17 group A and 2/9 group B patients had BMD levels that exceeded the pretransplant levels (P = 0.12). The early bone loss was positively correlated with an increase in resorption markers (s-1-CTP and u-Ntx). Group B had higher levels of both s-1-CTP and u-Ntx at 3 and 6 months post-transplant than group A patients (P = 0.03). Bone formation markers increased slowly from 6 months post-transplant and onwards. Relative bone loss was positively correlated to total glucocorticoid dose during the first 3 months post-transplant. There were no differences in BMD between patients receiving tacrolimus versus those receiving cyclosporin A.. Bone loss following liver transplantation is considerable in patients with both cholestatic and non-cholestatic liver disease, the first group has the poorest starting-point while the latter group has the greatest bone loss following transplantation. Bone loss is closely correlated with biochemical markers of bone resorption and total dose of glucocorticoids given post-transplant.

Topics: Adult; Aged; Alkaline Phosphatase; Biomarkers; Bone Density; Bone Resorption; Cholestasis; Collagen; Collagen Type I; Cyclosporine; Female; Femur Neck; Follow-Up Studies; Forearm; Fractures, Bone; Glucocorticoids; Humans; Immunosuppressive Agents; Liver Diseases; Liver Transplantation; Longitudinal Studies; Lumbar Vertebrae; Male; Middle Aged; Norway; Osteocalcin; Osteoporosis; Peptide Fragments; Peptides; Postoperative Complications; Survival Analysis; Tacrolimus; Treatment Outcome; Waiting Lists

FK506 is an immunosuppressant for organ transplantation in the same clinical settings as cyclosporine (CsA). In the management of liver transplantation, FK506 has advantages over CsA, in terms of rejection and corticosteroid requirements. Recent clinical findings in liver transplant patients indicate that FK506, but not CsA, stimulates choleresis, suggesting that FK506 treatment may accelerate recovery from cholestatic dysfunction through its choleretic action. Recently, we demonstrated in rats that exogenous treatment with insulin-like growth factor I (IGF-I) results in an increase in bile flow and also that FK506 has the potential to increase hepatic production of IGF-I. However, circulating levels of IGF-I in FK506-treated rats were only 30% higher than in nontreated rats. In this study, we evaluated the combined effect of treatment with both IGF-I and FK506 on bile flow in rats to explore the possibility that combination treatment in liver transplant patients could enhance the choleretic action of FK506, benefiting the transplanted liver. Combination treatment of IGF-I with FK506 resulted in a potent and long-lasting increase in bile flow. Overall, this study demonstrated that IGF-I treatment enhanced the choleretic action of FK506, providing potential clinical utility for combination therapy using these two drugs, in treatment after liver transplantation.

Topics: Animals; Cholagogues and Choleretics; Cholestasis; Drug Synergism; Humans; Immunosuppressive Agents; Insulin-Like Growth Factor I; Rats; Recombinant Proteins; Tacrolimus

Topics: Bile Duct Diseases; Bile Ducts, Intrahepatic; Carbamazepine; Child, Preschool; Cholestasis; Hepatitis B; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Male; Methylprednisolone; Pancreatitis; Stevens-Johnson Syndrome; Tacrolimus

The new immunosuppressive agent sirolimus is combined in transplant patients with the cholestatic substances cyclosporin and tacrolimus. Nothing is known about possible cholestatic effects of these combinations. Therefore, we compared their effects on bile flow and on important bile parameters in an acute bile fistula model in rats. Cyclosporin reduced bile flow, biliary excretion of bile salts, cholesterol, and GSH to 20-40% of basal values. Sirolimus decreased bile flow to 50% and excretion of GSH to 30% of the initial conditions but had no effect on cholesterol and bile salt excretion. In contrast, tacrolimus increased bile flow to 120% and GSH excretion to 220% of the basal levels. Sirolimus/cyclosporin decreased bile flow and bile parameters to the same extent as cyclosporin alone. Sirolimus/tacrolimus reversed sirolimus-induced reduction of bile flow and GSH excretion and resulted in a normal bile salt and cholesterol excretion, thus it may be the better alternative in cholestatic patients.

Topics: Animals; Bile Acids and Salts; Biliary Fistula; Biliary Tract; Cholestasis; Cyclosporine; Disease Models, Animal; Drug Combinations; Immunosuppressive Agents; Male; Rats; Rats, Wistar; Sirolimus; Tacrolimus

Tacrolimus, an immunosuppressive agent, is metabolized mainly in the liver and has shown large intra- and interindividual pharmacokinetic variability. We investigated the effect of liver dysfunctions on the pharmacokinetics of tacrolimus in rats with experimental liver diseases. Experimental hepatic failure was induced by CCl4-treatment or bile duct ligation. Tacrolimus (1 or 0.3 mg/kg) was administered intravenously or intraportally to the rats (n = 5-6 per group), and blood samples were collected over a 240-min period. The tacrolimus concentrations in the blood were then measured by a high-performance liquid chromatography-enzyme immunoassay. In the normal rats, the hepatic extraction ratio of tacrolimus (EH) was dose-independent, ranging from 0.556-0.598 at 0.3 and 1.0 mg/kg doses. The EH were dose-dependent in the CCl4-treated rats and in the bile duct-ligated rats: the EH at 1.0 mg/kg dose were 0.158-0.170 and those at 0.3 mg/kg dose were 0.329-0.394. The intermediate EH of tacrolimus suggested that the clearance of tacrolimus depends not only on hepatic intrinsic clearance but also on hepatic blood flow. The present pharmacokinetic study also suggested that the decrease of EH and the dose-dependence of EH contribute to the elevation of blood tacrolimus concentrations and to the large variability in the pharmacokinetics of tacrolimus after oral administration in hepatic dysfunctions.

Topics: Animals; Carbon Tetrachloride Poisoning; Chemical and Drug Induced Liver Injury; Cholestasis; Chromatography, High Pressure Liquid; Immunoenzyme Techniques; Immunosuppressive Agents; Male; Rats; Rats, Wistar; Tacrolimus

Tacrolimus (FK506) is an immunosuppressive agent used for the prevention of allograft rejection after organ transplantation. The aim of this study was to investigate the effects of chronic tacrolimus treatment on bile secretion in rats.. Tacrolimus was administered intraperitoneally at doses of 0.2, 0.5, and 0.8 mg/kg/day for 6 weeks.. Bile flow was significantly reduced at doses of 0.5 mg/kg and 0.8 mg/kg (-25% and -32%, respectively). Bile acid secretion was not significantly modified, but bicarbonate secretion decreased at doses of 0.5 mg/kg and 0.8 mg/kg (-23% and -29%, respectively). Glutathione secretion was significantly reduced at doses of 0.5 mg/kg (-29%) and 0.8 mg/kg (-49%). Liver glutathione concentration was reduced at the higher dose (-17%). Liver gamma-glutamyl-cysteinyl synthetase activity was elevated (+22%, +10, and +15%) and gamma-glutamyl transpeptidase activity was reduced (-18%, -40%, and -25%) at all doses. Dichlorofluorescein and thiobarbituric acid-reactive substance concentrations were not significantly modified. Liver glutathione peroxidase activity increased at doses of 0.5 mg/kg (+65%) and 0.8 mg/kg (+56%). Kidney concentration of thiobarbituric acid-reactive substances was significantly increased at doses of 0.5 mg/kg (+17%) and 0.8 mg/kg (+12%).. Our data indicate that tacrolimus at high doses induces cholestasis by inhibiting primarily biliary excretion of glutathione and, to a lesser extent, bicarbonate. The decrease in biliary glutathione secretion is not due to a lower synthesis or degradation and could be related to its increased sinusoidal efflux.

Topics: Animals; Bile; Cholestasis; Glutathione; Immunosuppressive Agents; Liver; Male; Rats; Rats, Wistar; Tacrolimus

Acute vanishing bile duct syndrome is a rare but established cause of progressive cholestasis in adults, is most often drug or toxin related, and is of unknown pathogenesis. It has not been reported previously in children. Stevens-Johnson syndrome is a well-recognized immune complex-mediated hypersensitivity reaction that affects all age groups, is drug or infection induced, and has classic systemic, mucosal, and dermatologic manifestations. A previously healthy child who developed acute, severe, rapidly progressive vanishing bile duct syndrome shortly after Stevens-Johnson syndrome is described; this was temporally associated with ibuprofen use. Despite therapy with ursodeoxycholic acid, prednisone, and then tacrolimus, her cholestatic disease was unrelenting, with cirrhosis shown by biopsy 6 months after presentation. This case documents acute drug-related vanishing bile duct syndrome in the pediatric age group and suggests shared immune mechanisms in the pathogenesis of both Stevens-Johnson syndrome and vanishing bile duct syndrome.

Topics: Acute Disease; Adult; Bile Duct Diseases; Biopsy; Child; Cholestasis; Female; Humans; Ibuprofen; Liver; Liver Cirrhosis; Prednisone; Stevens-Johnson Syndrome; Tacrolimus; Time Factors; Ursodeoxycholic Acid

Intestinal transplants using cadaver donors have become an alternative to total parenteral nutrition (TPN) for the treatment of irreversible intestinal failure. Intestinal transplants using living-related donors have rarely been attempted, and the surgical technique has not been standardized.. We performed a living-related intestinal transplant for a paraplegic, 16-year-old boy with life-threatening TPN complications, including lack of vascular access, recurrent line infections, and intermittent liver dysfunction.. A four antigen-matched donor (father) underwent resection of 200 cm of the ileum on a vascular pedicle comprising the ileocolic artery and vein. This resection left the donor with 300 cm of proximal small bowel, 20 cm of the most distal terminal ileum, the ileocecal valve, and all of the large intestine. The donor's ileocolic artery and vein were anastomosed to the recipient's infrarenal aorta and cava; bowel continuity was restored with an end-to-end anastomosis between the recipient's jejunum and the donor's ileum. Both donor and recipient had uneventful postoperative courses. Recipient maintenance immunosuppression has been with tacrolimus, mycophenolate mofetil, and prednisone. One year after transplant, urine methylmalonic acid indicates good vitamin B12 absorption in both the donor and recipient. The recipient has been completely off TPN since discharge (posttransplant day 21), has gained 20 kg, and has had no evidence of rejection, infection, or graft-versus-host disease.. Intestinal transplants from living-related donors can be lifesaving for selected patients with chronic intestinal failure and can be done with minimal risk to the donor.

Topics: Adolescent; Anastomosis, Surgical; Cholestasis; Histocompatibility Testing; Humans; Immunosuppressive Agents; Intestines; Living Donors; Male; Methylmalonic Acid; Middle Aged; Paraplegia; Parenteral Nutrition, Total; Short Bowel Syndrome; Tacrolimus

Topics: Administration, Oral; Biopsy; Cholestasis; Cyclosporine; Humans; Immunosuppression Therapy; Intestinal Absorption; Liver Transplantation; Male; Middle Aged; Postoperative Complications; Tacrolimus

FK 506 plasma levels were analyzed in 89 liver-grafted patients under FK 506-based immunosuppression. Plasma levels were found to be influenced by the patients' liver function: compared to patients without major liver dysfunction, those with cholestasis had higher plasma levels and these plasma levels were able to differentiate between rejection and toxicity. In patients with stable liver function, no clear difference was observed with regard to the plasma levels detectable during toxicity or rejection. We conclude that plasma levels can be used to determine the FK 506 dose but only in patients with cholestasis (i.e., during the early post-transplant course, or in patients with cholestatic rejection). In patients with stable liver function, plasma levels are only of limited clinical relevance.

Topics: Cholestasis; Graft Rejection; Humans; Immunoenzyme Techniques; Infusions, Intravenous; Kidney; Liver Function Tests; Liver Transplantation; Tacrolimus

We report two cases of recurrence of primary biliary cirrhosis (PBC) in the transplanted liver whilst maintained on a FK506-based immunosuppressive regime, the first to be described. One patient experienced symptoms in association with the development of cholestasis. In both there was a persistence of serological markers of PBC and liver histology revealed florid bile duct destruction and a granulomatous reaction.

Topics: Adult; Cholestasis; Female; Humans; Liver Cirrhosis, Biliary; Liver Transplantation; Male; Middle Aged; Recurrence; Tacrolimus