tacrolimus and Liver-Diseases--Alcoholic

Topics: Hepatitis B; Hepatitis C; Humans; Immunosuppressive Agents; Liver Diseases, Alcoholic; Liver Transplantation; Tacrolimus; Tissue Donors

Post-transplant diabetes mellitus (PTDM) is a serious and frequent metabolic complication after the transplantation of solid organs. PTDM incidence 12 months after the transplantation is 2.5%-25%.. It is a retrospective analysis with 6-month follow-up of patients after liver transplantation without diabetes mellitus type 1 or 2 at the time of transplantation. We recorded all known risk factors for PTDM; however, only patients with tacrolimus in standard immunosuppression protocol were included in the analysis.. The PTDM incidence in the group of 102 patients was 18.6%. We identified following independent risk factors for PTDM: alcohol-related liver disease (Hazard Ratio 1.8261 [1.2246-2.723], P = .0031) and average level of tacrolimus ≥ 10 ng/mL (2.5482 [1.1592-5.6019], P = .0199). PTDM was diagnosed in average 2.5 months after the liver transplantation.. PTDM leads to infections, cardiovascular disease, and decreased survival. The mechanism by which alcohol-related liver disease influences the development of PTDM remains unclear.

Topics: Adult; Diabetes Mellitus, Type 2; Female; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Incidence; Liver Diseases, Alcoholic; Liver Transplantation; Male; Middle Aged; Postoperative Complications; Retrospective Studies; Risk Factors; Tacrolimus

Alcohol-related liver disease (ALD) is one of the main indications for liver transplantation (LT). For 20 years, tacrolimus (Tac) is the cornerstone immunosuppressive drug used after LT and is very efficient for the prevention of rejection. Nevertheless, the major drawback of long-term use of Tac is the risk for developing dose-dependent adverse effects.. The aim of the present study was to assess the impact of Tac exposure (trough concentrations and concentration/dose (C/D) ratio) during the first year after LT, on short- and long-term complications after LT for ALD.. All patients who underwent a LT for ALD at Lyon Edouard Herriot Hospital from October 1990 to September 2010, and who were treated with Tac for at least one year after LT, were analyzed.. The study population consisted in 251 patients, mean age 53.4 ± 7.3 years, and followed during 11.6 ± 4.8 years. Post-LT complications included severe infectious events (44.6%), malignancies (41.4%), arterial hypertension (49.4%) dyslipidemia (44.2%), diabetes (18.7%) and cardiovascular events (15.5%). De novo hypertension, cardiovascular event, CMV infection, non-melanoma skin cancers and HCC recurrence after transplantation were significantly associated with higher Tac trough blood concentration. In addition, Tac fast-metabolizers (defined as C/D < 1.8) had significantly more impaired renal function at 1, 5, and 10 years and more cardiovascular events, PTLD, diabetes and hypertension than slow-metabolizers.. Our results strongly support that, in addition to blood trough concentrations, Tac metabolism, as estimated by the simple C/D ratio, could be an efficient parameter in daily practice to identify LT patients at risk to develop long term general complications of Tac.

Topics: Cytomegalovirus Infections; Drug-Related Side Effects and Adverse Reactions; Female; Follow-Up Studies; France; Humans; Hypertension; Immunosuppressive Agents; Liver Diseases, Alcoholic; Liver Transplantation; Male; Middle Aged; Postoperative Complications; Risk; Skin Neoplasms; Tacrolimus; Time Factors

Despite improvements in patient management and extensive use of therapeutic drug monitoring (TDM), the rate of acute cellular rejection (ACR) remains high in patients treated with tacrolimus (TAC). Moreover, some patients experienced ACR while their whole-blood (WB) concentrations were maintained within the therapeutic range meaning that TDM in WB misrepresents the drug effect. Thus, monitoring TAC directly inside of its effect compartment (intracellular concentrations) or monitoring directly the inhibitory effect on the target protein (calcineurin activity) could be more relevant. The aim of the present study was to explore, in 10 de novo liver transplant recipients, the relationship between TAC whole-blood concentrations, TAC intracellular concentrations and TAC-induced intracellular calcineurin inhibition at day 1 and day 7 after treatment initiation.. Prospective monocentric observational pharmacokinetic (WB and intracellular concentrations)-pharmacodynamic (calcineurin activity) study.. Full intracellular TAC pharmacokinetic as well as calcineurin activity steady-state profiles is presented in the study. The main result of this study is the lack of relationship between TAC pharmacokinetics (WB and leukocytes) and calcineurin activity in leukocytes at day 1 and day 7 after the graft implantation.. Drug monitoring of TAC intracellular concentrations and determination of the calcineurin activity are among future potential biomarkers of acute rejection in transplant recipients. A better knowledge of the relationship between TAC whole blood and intracellular concentrations and calcineurin activity appears necessary before planning clinical trials to evaluate their potential interest as predictive biomarkers.

Topics: Aged; Area Under Curve; Calcineurin; Female; Graft Rejection; Humans; Immunosuppressive Agents; Leukocytes, Mononuclear; Liver Diseases, Alcoholic; Liver Transplantation; Male; Middle Aged; Prospective Studies; Tacrolimus; Tissue Distribution; Treatment Outcome

The aim of this paper was to report the case of type 2 diabetes and significant insulin resistance that improved dramatically after removal of a pheochromocytoma in a liver transplant recipient , and to provide a review of the relevant literature. We describe the clinical presentation, diagnostic results and management of the patient. In addition, we performed a PubMed search for related English language articles, to provide an overview of the pertinent literature. A 53 year old woman with a history of an orthotopic liver transplantation and insulin-requiring type 2 diabetes was admitted to the hospital with fever, diaphoresis, tachycardia and hypertension. A pheochromocytoma was diagnosed and removed. The patient subsequently developed hypoglycemia and required no further insulin therapy. Pheochromocytomas have been described to lead to hyperglycemia and diabetes, due to the suppression of insulin release and increased insulin resistance. Furthermore, a review of the literature revealed only 3 other reported cases of pheochromocytomas in organ transplant recipients. None of these pheochromocytomas were believed to have occurred de novo after transplantation. This is the first report of a pheochromocytoma in a liver transplant recipient and possibly the first case of a de novo pheochromocytoma in any organ transplant recipient. Moreover, this case showcases pheochromocytomas as a rare cause of diabetes mellitus.

Topics: Adrenal Gland Neoplasms; Adrenalectomy; Diabetes Mellitus, Type 2; Female; Glipizide; Glucocorticoids; Humans; Hypertension; Hypoglycemic Agents; Immunosuppressive Agents; Insulin; Insulin Resistance; Insulin Secretion; Liver Diseases, Alcoholic; Liver Transplantation; Middle Aged; Pheochromocytoma; Postoperative Complications; Remission Induction; Tachycardia; Tacrolimus

Hepatitis C virus (HCV)-induced cirrhosis is the most common indication for liver transplantation (LT). However, graft reinfection is nearly universal. The choice of immunosuppression, including the calcineurin inhibitor (CNI), may have some effect on severity of recurrence and graft survival. In addition, HCV recurrence may have some impact on metabolism of immunosuppressive drugs. In this retrospective study, we examined the dose and blood levels of tacrolimus (TAC) and cyclosporin A (CYA) in HCV patients consecutively undergoing transplantation (TAC, n = 44; CYA, n = 60) and surviving 12 months post-LT. In addition, we examined the CNI dose and blood levels in an age- and gender-matched comparison group of patients who were transplanted for alcoholic liver disease (ALD) (TAC, n = 44; CYA, n = 47). During the 12-month period of observation, TAC levels were significantly higher for HCV than for ALD patients (P = 0.002). The dose of TAC decreased over time for both HCV and ALD patients (P < 0.001), but the reduction was greater for HCV patients (P = 0.03). CYA dose decreased over time for both groups (P < 0.001) but a greater reduction was observed for the HCV group (P = 0.007). For both HCV and ALD patients, CYA levels decreased over time (P < 0.001) but there was no significant difference between HCV and ALD patients. Thus, to maintain comparable blood levels, a greater reduction of dose was required for HCV than for ALD patients. In conclusion, our observations demonstrate a likely effect of HCV infection on CNI metabolism, an effect that is not clearly due to graft damage. Physicians need to be alert to this interaction and to the need to respond quickly to changes in CNI levels that may be associated with HCV infection and with HCV clearance during antiviral therapy.

Topics: Adult; Aged; Biopsy; Cyclosporine; Dose-Response Relationship, Drug; Female; Follow-Up Studies; Graft Rejection; Hepatitis C, Chronic; Humans; Immunosuppressive Agents; Liver Cirrhosis; Liver Diseases, Alcoholic; Liver Transplantation; Male; Middle Aged; Recurrence; Retrospective Studies; Tacrolimus; Treatment Outcome

Liver transplant recipients are at risk of chronic renal failure (CRF), customarily considered to be secondary to CsA/FK506 nephrotoxicity. We have examined renal biopsies from 26 liver transplant recipients with CRF. Before OLT, 5 patients had CRF, 8 were diabetic and 9 hypertensive. Renal biopsies were performed at a mean of 5 years after liver transplantation. Mean SCr was then 212 micromol/L, proteinuria was 1 g/24 h. Twelve patients were diabetic and 25 hypertensive. Histology revealed impressive renal destruction, with a mean of 45% interstitial fibrosis and 45% glomerular sclerosis. All biopsies showed severe arteriosclerosis. CRF can be attributed to four associated primary lesions: (i) specific chronic CsA/FK506 arteriolopathy; (ii) typical diabetic nephropathy; (iii) acute or chronic thrombotic microangiopathy attributed to CsA/FK506 or alpha-IFN and (iv) tubular changes related to administration of hydroxyethylstarch. At the end of the follow-up, after a mean of 6.4 years, 12 patients required dialysis, 13 had CRF and only 1 had normal renal function. Thus, CRF in OLT recipients is more complex than originally thought and should not be classified as anti-calcineurin nephrotoxicity without further investigations, including renal histology. These investigations have therapeutic potential, that is, they may lead to a more aggressive treatment of hypertension and/or diabetes.

Topics: Adult; Aged; Biopsy; Diabetes Mellitus; Female; Glomerulonephritis, IGA; Graft Survival; Hepatitis; Humans; Hydroxyethyl Starch Derivatives; Hypertension; Immunosuppressive Agents; Interferon-alpha; Kidney; Kidney Diseases; Kidney Failure, Chronic; Kidney Transplantation; Liver; Liver Diseases, Alcoholic; Liver Transplantation; Male; Middle Aged; Postoperative Complications; Renal Insufficiency; Risk; Tacrolimus; Time Factors

Liver transplantation (LTx) for alcohol-related liver disease (ALD) is an accepted modality of treatment and is one of the most common indications for LTx in the United States. The present report examines the long-term patient survival, graft survival, rates of recidivism, and development of de novo cancers in this group, and compares these results with a contemporaneous group of patients who were transplanted for non-ALD indications.. Between August 1989 and December 1992, 185 adults received LTx for ALD (group I). During the same time interval, 649 adults received LTx for non-ALD (group II). The mean follow-up time was 94+/-10.7 months for group I vs. 92+/-11 months for group II. Kaplan-Meier survival estimates and the incidence of cancers using Surveillance Epidemiologic End Result data were compared in both groups.. At 5 years after orthotopic LTx, the overall patient survival and graft survival for group I were 72.0% and 66.5% vs. 66.5% and 60.3% for group II, respectively. After 5 years, the patient survival and graft survival for the alcoholic group were significantly lower (P=0.001) compared to the non-alcoholic group. The rate of de novo oropharyngeal cancer and lung cancer was 25.5 times and 3.7 times higher, respectively, in ALD group compared with the general population matched for age, sex, and length of follow-up (P=0.001), whereas this was not higher in the non-ALD group. Prior pretransplant length of sobriety and alcohol rehabilitation was not associated with the rate of post-LTx rate of recidivism, which was 20%. Out of 79 deaths in group I, only 1 was attributed to recidivism and 3 to noncompliance with recidivism. The other deaths occurred from de novo cancer (n=13), posttransplant lymphoproliferative disorder (n=5), age-related complications (n=23), and other infection or miscellaneous causes (n=34).. Patient and graft survival past 5 years after orthotopic LTx is significantly lower for ALD for a variety of reasons (P=0.001). The rate of upper airway malignances was significantly higher in ALD patients than for non-ALD post-LTx patients and the general public. Graft loss/death related to recidivism or chronic rejection was extremely low. More attention is needed for early diagnosis of de novo cancer and prevention of cardiorespiratory and cerebrovascular complications.

Topics: Adult; Aged; Carcinoma, Hepatocellular; Female; Follow-Up Studies; Graft Survival; Humans; Immunosuppressive Agents; Liver Diseases, Alcoholic; Liver Neoplasms; Liver Transplantation; Male; Middle Aged; Survival Rate; Tacrolimus; Time Factors

Blood transfusions are common in patients with end-stage liver disease (ESLD), and their effects on sensitization, rejection, and liver graft survival are not well known. These effects were examined in 121 recipients of primary liver grafts, surviving > or = 30 days. Ninety-six (79%) patients received transfusions before transplantation. Transfusion recipients had significantly fewer severe or recurrent rejection episodes (18%), compared with patients who did not receive transfusions (42%, P=0.006), if the first transfusion was > or = 90 days before the transplant. Patients with alcoholic ESLD (n=49) had significantly fewer severe rejection episodes when compared with the nonalcoholic (n=72) patients (12% vs. 35%, P=0.004). The transfusion benefit was, however, more apparent and significant in the nonalcoholic (26% vs. 56% in nontransfused, P=0.02) than among the alcoholic recipients (6% vs. 25%, P=0.1). This finding is, most likely, due to a combination of a higher rate of severe rejection and the statistical power of the larger number of recipients in the nonalcoholic group. This finding is further corroborated by a multivariate analysis in which blood transfusions retained their benefit (P<0.05) independent of recipient's age and diagnosis. Graft and patient survival were not significantly different in the transfused versus nontransfused groups. Transfusion recipients had a higher panel antibody (11.4+/-23.4 vs. 2.7+/-8.1, P<0.02) but no increased risk of a positive crossmatch. In liver recipients, blood transfusions diminish the risk of rejection independent of recipient's age and the cause of ESLD.

Topics: Adult; Blood Transfusion; Chronic Disease; Cyclosporine; Female; Graft Rejection; Humans; Immunosuppressive Agents; Intraoperative Period; Liver Diseases, Alcoholic; Liver Failure; Liver Transplantation; Male; Middle Aged; Tacrolimus; Time Factors