tacrolimus and Liver-Cirrhosis--Alcoholic

Hepatic vein occlusive disease (HVOD) is a rare complication after liver transplantation, which is characterized by nonthrombotic, fibrous obliteration of the small centrilobular hepatic veins by connective tissue and centrilobular necrosis in zone 3 of the acini. HVOD after solid organ transplantation has been reported; recently, most of these reports with limited cases have documented that acute cell rejection and immunosuppressive agents are the major causative factors. HVOD is relatively a rare complication of liver transplantation with the incidence of approximately 2%.. A 59-year-old male patient with alcoholic liver cirrhosis underwent liver transplantation in our center. He suffered ascites, renal impairment 3 months after the surgery while liver enzymes were in normal range.. Imagining and pathology showed no evidence of rejection or vessels complications. HVOD was diagnosed with pathology biopsy.. Tacrolimus was withdrawn and the progression of HVOD was reversed.. Now, this patient has been followed up for 6 months after discharge with normal liver graft function.. The use of tacrolimus in patients after liver transplantation may cause HVOD. Patients with jaundice, body weight gain, and refractory ascites should be strongly suspected of tacrolimus related HVOD.

Topics: Graft Rejection; Hepatic Veins; Hepatic Veno-Occlusive Disease; Humans; Immunosuppressive Agents; Liver; Liver Cirrhosis, Alcoholic; Liver Transplantation; Male; Middle Aged; Tacrolimus; Tomography, X-Ray Computed; Ultrasonography, Doppler

We evaluate 5-year results of a prospective randomized trial that compared cyclosporine microemulsion (CsA-me) and Tacrolimus (Tac) for primary immunosuppression. One hundred one adult patients undergoing liver transplantation were randomized to receive Tac (n = 50) or CsA-me (n = 51). The most frequent indication for the procedure was cirrhosis due to virus C followed by alcoholism. Survival rates at 1, 3, and 5 years were 86%, 75%, and 72%, respectively; there was no significant difference between CsA-me versus Tac arms. Acute rejection occurred in 30 cases (30%), independent of the type of primary immunosuppression. Serious adverse events were reported significantly more among patients under CsA-me (48 episodes) than under Tac (32 episodes). Nineteen patients were switched to the other calcineurin inhibitor. The switch was much more frequent from CsA-me to Tac (n = 15; 29.4%), mainly because of lack of efficacy (n = 10; 19.6%). There were no cases of chronic rejections in the Tac arm. Four patients were switched from Tac to CsA-me for side effects; only 1 remains alive, after treatment was changed from CsA-me to an antimetabolite. There were no statistical differences in renal dysfunction, diabetes, hypertension, neurologic disorders, new-onset malignancies, or infections. There were no differences in survival or rejection among the intention-to-treat groups. Serious adverse events, total patients with switch of calcineurin inhibitor, as well as switches due to lack of efficacy, were statistically more frequent under CsA-me. Tacrolimus seems to be a more appropriate drug to be used for primary immunosuppression in liver transplantation.

Topics: Cyclosporine; Emulsions; Follow-Up Studies; Humans; Immunosuppressive Agents; Liver Cirrhosis, Alcoholic; Liver Transplantation; Postoperative Period; Reoperation; Survival Analysis; Tacrolimus; Time Factors

Tacrolimus (FK506, Prograf), marketed for the prophylaxis of organ rejection following allogenic liver or kidney transplantation, is virtually completely metabolized. The major metabolic pathways are P450 3A4-mediated hydroxylation and demethylation. Since P450 hepatic drug-metabolizing enzymes may be impaired in hepatic dysfunction, a study was conducted to characterize oral and intravenous tacrolimus pharmacokinetics in 6 patients with mild hepatic dysfunction and compared with parameters to those from normal subjects obtained in a separate study. Patients received two treatments: a single 0.020 mg/kg ideal body weight (IBW) i.v. dose infused over 4 hours and approximately 0.12 mg/kg IBW orally; normal subjects were dosed at 0.02 mg/kg 4-hour i.v. and 5 mg (0.065 mg/kg) p.o. Mean blood pharmacokinetic parameters with mild hepatic dysfunction were as follows: clearance = 0.035 L/h/kg, terminal exponential volume of distribution = 2.59 L/kg, terminal exponential half-life = 60.6 hours (i.v.), p.o. maximum blood concentration = 48.2 ng/mL, time of p.o. maximum blood concentration = 1.5 hours, and absolute bioavailability = 22.3%. The respective parameters in normal subjects were as follows: 0.040 L/h/kg, 1.91 L/kg, 34.2 hours (i.v.), 29.7 ng/mL, 1.6 hours, and 17.8%. Inasmuch as clearance and bioavailability were not substantially different from that in normal subjects, patients with mild hepatic impairment may initially be treated with conventional tacrolimus doses, with subsequent dosage adjustments based on response, toxicity, and therapeutic drug monitoring.

Topics: Body Weight; Cholelithiasis; Cross-Over Studies; Drug Administration Routes; Female; Humans; Immunosuppressive Agents; Liver; Liver Cirrhosis, Alcoholic; Male; Middle Aged; Tacrolimus; Time Factors

Topics: Adult; Cyclosporine; Humans; Liver Cirrhosis; Liver Cirrhosis, Alcoholic; Liver Transplantation; Survival Analysis; Tacrolimus

The incidence and impact of anti-human leukocyte antigen donor-specific alloantibodies (DSAs) developing after liver transplantation (LT) remains controversial and not extensively studied. The aim of the present study was to assess the incidence of DSAs, to identify risk factors for the development of DSAs, and to understand the impact of DSAs in a large population of adult LT recipients. This single-center retrospective study included all adult patients who underwent a first LT between 2000 and 2010 in our center. The study population mainly consisted of male patients, the mean age was 52.4 years, and the main indication was alcoholic cirrhosis (54.1%). From the 297 patients included in the cross-sectional study, 14 (4.7%) had preformed DSAs, and 59 (19.9%) presented de novo DSAs (12.2% at 1 year, 13.4% at 5 years, and 19.5% at 10 years). Multivariate analysis found that female donor sex (hazard ratio [HR], 1.50; 95% confidence interval [CI], 1.12-2.01; P = 0.01) and delay between LT and DSA screening (HR, 1.10; 95% CI, 1.01-1.20; P = 0.03) were associated with occurrence of de novo DSAs. From the 190 patients included in the subgroup longitudinal analysis, exposure to tacrolimus (mean trough level during the periods 0-2 years and 0-3 years) was significantly lower for patients having DSAs at 5 years. Concerning histology, only acute rejection (P = 0.04) and portal fibrosis ≥2 (P = 0.02) were more frequent at 1 year for patients with DSAs. Patient survival and graft survival were not significantly different according to the presence or not of DSAs at 1 year. Among the 44 patients who had de novo or persistent preformed DSAs, the diagnosis of antibody-mediated rejection was made in 4 (9.1%) patients after 1, 47, 61, and 74 months following LT. In conclusion, the results of the present study suggest that DSAs are observed in a minority of LT adult patients, with limited overall impact on graft and patient outcome.

Topics: Adult; Cross-Sectional Studies; Female; Follow-Up Studies; Graft Rejection; Graft Survival; HLA Antigens; Humans; Immunosuppressive Agents; Incidence; Isoantibodies; Liver Cirrhosis, Alcoholic; Liver Transplantation; Male; Middle Aged; Postoperative Complications; Prevalence; Retrospective Studies; Risk Factors; Survival Analysis; Tacrolimus; Transplant Recipients; Treatment Outcome

Nocardiosis is usually a disseminated disease seen in immunocompromised individuals. We herein present a rare case of isolated Nocardia liver abscess post liver transplantation. The patient responded well to treatment and is on long-term antibiotics for Nocardia infection.

Topics: Anti-Bacterial Agents; End Stage Liver Disease; Glucocorticoids; Humans; Immunocompromised Host; Immunosuppression Therapy; Immunosuppressive Agents; Liver Abscess; Liver Cirrhosis, Alcoholic; Liver Transplantation; Male; Middle Aged; Mycophenolic Acid; Nocardia; Nocardia Infections; Paracentesis; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Tacrolimus; Tomography, X-Ray Computed; Trimethoprim, Sulfamethoxazole Drug Combination; Ultrasonography, Doppler; Ultrasonography, Interventional

Topics: Delayed Diagnosis; Herpesvirus 8, Human; Humans; Immunocompromised Host; Immunosuppressive Agents; Liver Cirrhosis, Alcoholic; Liver Transplantation; Male; Middle Aged; Mycophenolic Acid; Postoperative Complications; Sarcoma, Kaposi; Skin Neoplasms; Tacrolimus; Thorax

Topics: Adult; Hemorrhage; Humans; Immunosuppressive Agents; Liver Cirrhosis, Alcoholic; Liver Transplantation; Magnetic Resonance Imaging; Male; Retinal Vein; Retinal Vein Occlusion; Risk Factors; Tacrolimus; Vision Disorders; Vision, Ocular

We report our experience with a 61-year-old patient with alcoholic and hepatitis C cirrhosis who underwent liver transplantation. On the 3rd postoperative day he presented a mediastinitis secondary to esophageal perforation produced by a Linton tube. An esophagectomy with jejunostomy was performed. Tacrolimus granules for oral suspension (Modigraf) were administered through the jejunostomy. This case report highlights the use of Modigraf and the absence of secondary effects. We observed biochemical parameters during the jejunostomy period. We discuss the administration strategy applied and whether tacrolimus granules for oral suspension by jejunostomy affect the bioavailability and its side effects.

Topics: Administration, Oral; Biological Availability; Carcinoma, Hepatocellular; Chemistry, Pharmaceutical; Esophageal Perforation; Esophagectomy; Hepatitis C; Humans; Immunosuppressive Agents; Jejunostomy; Liver Cirrhosis; Liver Cirrhosis, Alcoholic; Liver Neoplasms; Liver Transplantation; Male; Mediastinitis; Middle Aged; Tacrolimus; Tomography, X-Ray Computed; Treatment Outcome

We present the case of a liver transplant recipient with alcoholic liver cirrhosis and early-stage hepatocellular carcinoma who developed biopsy-proven acute steroid-resistant rejection 3 months after liver transplantation. After the failure of immunosuppressive therapy with intravenous boluses of 6-methyl-prednisolone and switching of the immunosuppressive regimen to tacrolimus plus mycophenolate mofetil, two doses of intravenous basiliximab were administered four days apart. Clinical, analytical, and biopsy-proven histological response was complete. No basiliximab-related adverse events were detected. Basiliximab may represent an alternative in liver transplantation immunosuppression to treat acute steroid-resistant rejection, without increasing the incidence of infections, neoplasms, or other adverse events, as shown by this case.

Topics: Acute Disease; Antibodies, Monoclonal; Basiliximab; Carcinoma, Hepatocellular; Cyclosporine; Drug Resistance; Graft Rejection; Humans; Immunosuppressive Agents; Liver Cirrhosis, Alcoholic; Liver Function Tests; Liver Neoplasms; Liver Transplantation; Male; Methylprednisolone; Middle Aged; Mycophenolic Acid; Pregnenediones; Receptors, Interleukin-2; Recombinant Fusion Proteins; Tacrolimus

Nephrotoxicity is one of the most common side effects of long-term immunosuppressive therapy with calcineurin inhibitors. We describe a case of distal renal tubular acidosis secondary to tacrolimus administration. A 43-year-old man with end-stage liver disease due to hepatitis C and B virus infections and alcoholic cirrhosis received a liver transplantation under immunosuppressive treatment with tacrolimus and mycophenolate mofetil. In the postoperative period, the patient developed hyperkalemic hyperchloremic metabolic acidosis, with a normal serum anion gap and a positive urinary anion gap, suggesting distal renal tubular acidosis. We excluded other causes of hyperkalemia. Administration of intravenous bicarbonate, loop diuretics, and oral resin exchanger corrected the acidosis and potassium levels. Distal renal tubular acidosis is one of several types of nephrotoxicity induced by tacrolimus treatment, resulting from inhibition of potassium secretion in the collecting duct. Treatment to correct the acidosis and hyperkalemia should be promptly initiated, and the tacrolimus dose adjusted when possible.

Topics: Acidosis, Renal Tubular; Administration, Oral; Adult; Bicarbonates; Cation Exchange Resins; Drug Therapy, Combination; Humans; Hyperkalemia; Immunosuppressive Agents; Liver Cirrhosis, Alcoholic; Liver Transplantation; Male; Mycophenolic Acid; Polystyrenes; Sodium Potassium Chloride Symporter Inhibitors; Tacrolimus; Treatment Outcome

Liver transplantation is the only curative treatment in patients with end-stage liver disease. Neurological complications (NC) are increasingly reported to occur in patients after cadaveric liver transplantation. This retrospective cohort study aims to evaluate the incidence and causes of NC in living donor liver transplant (LDLT) patients in our transplant center. Between August 1998 and December 2005, 121 adult LDLT patients were recruited into our study. 17% of patients experienced NC, and it occurred significantly more frequently in patients with alcoholic cirrhosis (42%) and autoimmune hepatitis (43%) as compared with patients with hepatitis B or C (9/10%, P = 0.013). The most common NC was encephalopathy (47.6%) followed by seizures (9.5%). The choice of immunosuppression by calcineurin inhibitor (Tacrolimus or Cyclosporin A) showed no significant difference in the incidence of NC (19 vs. 17%). The occurrence of NC did not influence the clinical outcome, since mortality rate, median ICU stay and length of hospital stay were similar between the two groups. Most patients who survived showed a nearly complete recovery of their NC. NCs occur in approximately 1 in 6 patients after LDLT and seem to be predominantly transient in nature, without major impact on clinical outcome.

Topics: Brain Diseases; Cohort Studies; Cyclosporine; Female; Hepatitis B; Hepatitis C; Hepatitis, Autoimmune; Humans; Immunosuppressive Agents; Incidence; Liver Cirrhosis, Alcoholic; Liver Diseases; Liver Transplantation; Male; Middle Aged; Nervous System Diseases; Retrospective Studies; Seizures; Tacrolimus; Treatment Outcome

T(H)17 cells have been recently described to be involved in inflammatory and immune-mediated diseases, but there is no evidence of their role in human liver transplantation. Interleukin (IL)-23 is considered an inducer cytokine, whereas IL-17 is the main cytokine released by T(H)17 cells. The aim of our study was to measure the serum levels of IL-17 and IL-23 in stable liver transplant recipients and examine the influence of immunosuppressant concentrations.. Serum levels of IL-23 and IL-17 were determined in 38 healthy subjects and 35 stable hepatic transplant recipients who were free of rejection episodes for at least 8 years. The results were analyzed according to the simultaneous blood levels of cyclosporine (n = 20) or tacrolimus (n = 15).. No significant differences were observed in the serum levels of IL-17 and IL-23 between healthy subjects and transplanted patients. In addition, patients with low blood levels of tacrolimus (<6 ng/mL), but not cyclosporine, showed significantly lower serum levels of the 2 cytokines.. These preliminary results suggested a lack of activation of the T(H)17 pathway, which was more pronounced among the patient subgroup treated with tacrolimus.

Topics: Aged; Cohort Studies; Cyclosporine; Female; Humans; Immunosuppressive Agents; Interleukin-17; Interleukin-23; Liver Cirrhosis, Alcoholic; Liver Diseases; Liver Transplantation; Male; Middle Aged; Reference Values; Tacrolimus; Th1 Cells; Th2 Cells

Posterior leukoencephalopathy due to calcineurin-inhibitor-related neurotoxicity is a rare but severe complication that results from treatment with immunosuppressive agents (primarily those administered after a liver or kidney transplant). The pathophysiologic mechanisms of that disorder remain unknown.. We report the case of a 46-year-old woman who received a liver transplant in our center as treatment for alcoholic cirrhosis and in whom either a fulminant course of posterior leukoencephalopathy or posterior reversible encephalopathy syndrome developed 110 days after transplant. After an initially uneventful course after the transplant, the patient rapidly fell into deep coma.. Cerebral MRI scan showed typical signs of enhancement in the pontine and posterior regions. Switching the immunosuppressive regimen from tacrolimus to cyclosporine did not improve the clinical situation. The termination of treatment with any calcineurin inhibitor resulted in a complete resolution of that complication.. Posterior reversible encephalopathy syndrome after liver transplant is rare. We recommend a complete cessation of any calcineurin inhibitor rather than a dose reduction.

Topics: Calcineurin Inhibitors; Coma; Cyclosporine; Female; Humans; Immunosuppressive Agents; Liver Cirrhosis, Alcoholic; Liver Transplantation; Magnetic Resonance Imaging; Middle Aged; Mycophenolic Acid; Posterior Leukoencephalopathy Syndrome; Prednisolone; Tacrolimus; Time Factors

The occurrence of an oesophageal squamous cell carcinoma following liver transplantation is very infrequent. Such an event has been related to a history of alcohol-induced cirrhosis, as in other squamous cell tumours of the oropharynx. We report the case of a 64-year-old male patient diagnosed as having oesophageal squamous cell carcinoma six years after having had a liver transplant due to alcohol-induced cirrhosis. The tumour was treated surgically and consisted of an Ivor-Lewis oesophagectomy. The patient is disease-free 17 months after surgery. A review of the cases reported in the literature indicated treatment with chemotherapy and radiation therapy, and with excision in some cases. Generally, despite aggressive treatment the prognosis is poor.

Topics: Alcoholism; Carcinoma, Squamous Cell; Cardia; Deglutition Disorders; Esophageal Neoplasms; Esophageal Stenosis; Esophagectomy; Humans; Immunocompromised Host; Immunosuppression Therapy; Immunosuppressive Agents; Liver Cirrhosis, Alcoholic; Liver Transplantation; Male; Middle Aged; Neoplasms, Multiple Primary; Postoperative Complications; Remission Induction; Stomach Neoplasms; Tacrolimus

De novo hepatitis B was diagnosed in a 47-year-old man 15 months after liver transplantation for end-stage alcoholic cirrhosis. Serum antibodies to hepatitis B core antigen (anti-HBc) were negative, and remained undetectable over 20 months of follow-up. The possible causes of negative serum anti-HBc despite of active hepatitis B virus infection are reviewed. Immunosuppression may underlie this phenomenon in similar cases.

Topics: Antibody Formation; DNA, Viral; False Negative Reactions; Follow-Up Studies; Graft Rejection; Hepatitis B; Hepatitis B Antibodies; Hepatitis B Antigens; Hepatitis B virus; Humans; Immunosuppressive Agents; Liver Cirrhosis, Alcoholic; Liver Transplantation; Male; Methylprednisolone; Middle Aged; Postoperative Complications; Tacrolimus; Viremia

Topics: Adult; Brain Edema; Cerebral Hemorrhage; Fatal Outcome; Female; Graft Rejection; Humans; Hypercholesterolemia; Hypertension; Liver Cirrhosis, Alcoholic; Liver Transplantation; Magnetic Resonance Imaging; Myelin Sheath; Postoperative Complications; Seizures; Tacrolimus

Topics: Adult; Biopsy; Graft vs Host Disease; Humans; Immunosuppressive Agents; Liver Cirrhosis, Alcoholic; Liver Transplantation; Male; Tacrolimus; Time Factors; Treatment Outcome

Oral ulcers have may possible causes, including immunosuppression and drug therapy. Severe cases of oral ulceration merit special consideration because the ulcers may become large enough to alter the quality of life of the patient. The present case involves a male patient who in 1994 received an orthotopic liver transplantation because of alcoholic cirrhosis. The initial immunosuppressive regimen was induced with tacrolimus (4 mg/d) and prednisone (20 mg/d). Ten months after orthotopic liver transplantation, the patient complained of multiple recurrent oral ulcers, dysphagia, and severe oral pain, which did not respond to any of the treatments over a 3-year period. Approximately 3(1/4) years after these unresponsive ulcers appeared, the reduction of the oral dosage of tacrolimus resulted in the total remission of the ulcers. A retrospective analysis demonstrated that appearance of the ulcers coincided with a dose of 9 mg/d of tacrolimus (whole blood levels of 12 ng/mL); the ulcers did not disappear until the dose was reduced to 4 mg/d (whole blood level of 6.6 ng/mL).

Topics: Administration, Oral; Deglutition Disorders; Follow-Up Studies; Humans; Immunosuppressive Agents; Liver Cirrhosis, Alcoholic; Liver Transplantation; Male; Middle Aged; Oral Ulcer; Recurrence; Retrospective Studies; Tacrolimus; Treatment Outcome

Because of the donor shortage, there are concerns for liver transplantation in patients with alcoholic cirrhosis. We therefore analyzed patients transplanted for alcoholic cirrhosis at our center with respect to patient and graft survival, recurrence of disease, and postoperative complications. Out of 1000 liver transplantations performed in 911 patients, 167 patients were transplanted for alcoholic cirrhosis; 91 patients received CsA- and 76 patients FK506-based immunosuppression. Recurrence was diagnosed by patient's or relative's declaration, blood alcohol determination, and delirium. Diagnosis and treatment of acute and chronic rejection was performed as previously described. One- (96.8% versus 91.3%) and 9-year patient survival (83.3% versus 80%) compared well with other indications. Five of 15 patients died due to disease recurrence. Recurrence of disease was significantly related to the duration of alcohol abstinence prior to transplantation. In patients who were abstinent for less than 6 months (17.1%), recurrence rate was 65%, including four of the five patients who died of recurrence. Recurrence rate decreased to 11.8%, when abstinence time was 6-12 months and to 5.5%, when the abstinence times was > 2 years. Next to duration of abstinence, alcohol relapse was significantly related to sex, social environment, and psychological stability. The incidence of acute rejection compared well with other indications (38.1%); CsA: 40.1% versus 33.3% in FK506 patients. In all, 18.2% of CsA patients experienced steroid-resistant rejection compared with 2.6% of FK506 patients. Seven patients (7.6%) in the CsA group and one patient (1.3%) in the FK506 group developed chronic rejection. A total of 57.1% developed infections; 5.7% were life-threatening. CMV infections were observed in 14.3% (versus 25% for other indications). New onset of insulin-dependent diabetes was observed in 8.6% and hypertension in 32.4%. In conclusion, alcoholic cirrhosis is a good indication for liver transplantation with respect to graft and patient survival and development of postoperative complications. FK506 therapy was favourable to CsA treatment. Patient selection is a major issue and established criteria should be strictly adhered to. Patients with alcohol abstinence times shorter than 6 months should be excluded, since recurrence and death due to recurrence was markedly increased in this group of patients.

Topics: Adult; Alcoholism; Cyclosporine; Female; Graft Rejection; Humans; Immunosuppressive Agents; Liver Cirrhosis, Alcoholic; Liver Transplantation; Male; Middle Aged; Postoperative Complications; Recurrence; Retrospective Studies; Survival Rate; Tacrolimus; Temperance; Time Factors

Topics: Cyclosporine; Electrocardiography; Female; Follow-Up Studies; Heart Rate; Humans; Immunosuppressive Agents; Liver Cirrhosis; Liver Cirrhosis, Alcoholic; Liver Transplantation; Long QT Syndrome; Male; Tacrolimus

Topics: Cyclosporine; Electrocardiography; Female; Humans; Immunosuppressive Agents; Liver Cirrhosis; Liver Cirrhosis, Alcoholic; Liver Transplantation; Male; Tacrolimus

Topics: Cyclosporine; Drug Monitoring; Graft Rejection; Hepatitis B; Hepatitis C; Humans; Immunosuppression Therapy; Incidence; Liver Cirrhosis; Liver Cirrhosis, Alcoholic; Liver Cirrhosis, Biliary; Liver Transplantation; Muromonab-CD3; Retrospective Studies; Survival Rate; Tacrolimus; Time Factors

Topics: Cyclosporine; Enzyme-Linked Immunosorbent Assay; Female; Hemiplegia; Humans; Liver Cirrhosis, Alcoholic; Liver Transplantation; Methylprednisolone; Middle Aged; Prednisolone; Seizures; Tacrolimus