tacrolimus and Hepatic-Encephalopathy

Advances in liver transplantation (LT), particularly in immunosuppression and intensive care treatment have had increased the number of long-term survivors following liver transplantation. In order of more long-term survivors, reports about neurological complication following liver transplantation are increasing. Neurological complications are not uncommon in liver transplant recipients, which contribute to a longer ICU- and in-hospital stay. Every effort should be focused on early detection to prevent the patient from this life-threatening event, which is often associated with poor life quality.

Topics: Brain; Calcineurin; Calcineurin Inhibitors; Cyclosporine; Early Diagnosis; Hepatic Encephalopathy; Humans; Immunosuppressive Agents; Liver Transplantation; Neurotoxicity Syndromes; Postoperative Complications; Tacrolimus

Patient and primary graft survival for 2,090 patients who received primary liver transplants at the University of Pittsburgh from 1984 through 1990 are presented. Observed (actual) 3- and 12-month patient and primary graft survival rates were compared for 3 periods: 1) January 1984 to September 1987 (cyclosporine, OKT3, and Euro-Collins preservation period); 2) October 1987 to December 1988 (University of Wisconsin solution preservation period); and 3) January 1989 to December 1990 (FK506 period). Data for results according to age group, medical urgency, and primary diagnosis are provided. In addition, estimated survivor and cumulative hazard functions (life-table method) for patient and primary graft survival out to 60 months after transplantation are presented. Overall results have improved significantly in recent experience. Most notable are the improved results seen in liver transplantation for patients with biliary atresia (especially in infants), primary sclerosing cholangitis, fulminant hepatic failure, and chronic active hepatitis B. For all but a few conditions, most of the mortality after liver transplantation occurred in the first 3 months after surgery. Less than 2% of patients were lost in each 6-month interval beyond the first 6 months after transplantation. Outcome was related to patient condition at the time of surgery. Observed survival rates at 3 and 12 months for patients called in the hospital to receive a transplant were 88.6% and 86.5%, respectively, compared with 81.9% and 73.7% for patients in critical condition. The continuing shortage of organs for transplantation, which often forces patients to wait longer for an organ than they can afford to, continues to impose a significant penalty.

Topics: Adolescent; Age Factors; Body Weight; Child; Child, Preschool; Cyclosporine; Graft Survival; Hepatic Encephalopathy; Humans; Immunosuppression Therapy; Infant; Liver Function Tests; Liver Transplantation; Postoperative Complications; Prednisone; Reoperation; Survival Rate; Tacrolimus

There is paucity of data on neurological complications (NCs) and its predisposing factors, in pediatric liver transplant (PLT) recipients.. Records of seventy-one children who underwent LT between October 2018 and November 2019 were reviewed. Patients were categorized into group A: with NC and group B: without NC in the post-LT period. Various risk factors contributing to NC were studied.. In total, 15 (21.1%) had NC (group A) and 56 (78.9%) had no NC in the post-LT period. NC included cerebrovascular accident (n = 1), seizures (n = 5; 4 generalized, 1 focal), central pontine myelolysis (CPM) (n = 1), diaphragmatic palsy (n = 2), peripheral neuropathy (n = 1), extrapyramidal movements (n = 3), and encephalopathy beyond 96 h (n = 2). The median onset of NC was at 8.5 days post-LT (1-58 days). Ten (66.7%) patients in group A had grades 2-4 hepatic encephalopathy (HE) prior to LT. Eight (14.3%) patients in group B also had pre-LT neurological issues including HE in six, epilepsy and spastic diplegia in one each. On univariate analysis, pre-existing HE, high PELD/MELD score, pre-LT ventilation, pre-LT infection, higher day 1 post-operative bilirubin (all p < .05), and higher tacrolimus were found to predict post-operative NC whereas on multivariate analysis, pre-LT HE was the only predictive factor. Median follow-up was 15.5 months. Four patients died in each group (survival log-rank p = .369). All the surviving patients in group A (n = 11) fully recovered from the NC.. Pre-transplant HE was the single most significant predisposing factor for post-LT neurological complications.

Topics: Child; Hepatic Encephalopathy; Humans; Liver Transplantation; Postoperative Complications; Retrospective Studies; Risk Factors; Seizures; Tacrolimus

Many papers have reported on pregnancy and delivery after liver transplantation, but there have been no reports on pregnancy after ABO-incompatible liver transplantation. This paper reports the first successful pregnancy and delivery of a newborn after ABO-incompatible liver transplantation for fulminant hepatic failure. The patient was a 39-year-old female. She had an ABO-incompatible liver transplantation, donated from her husband, due to subacute fulminant hepatitis of unknown etiology. She was taking tacrolimus, methylprednisolone, and mizoribine orally for the maintenance of immunosuppression at the time of discharge. She was discharged uneventfully on postoperative day 38 without any rejection episodes. At 1 year and 6 mo after transplantation, she indicated a wish to become pregnant. Therefore, treatment with mycophenolate mofetil was interrupted at that time. After two miscarriages, she finally became pregnant and delivered transvaginally 3 years after the transplantation. All of the pregnancies were conceived naturally. The newborn was female with a birth weight of 3146 g; the Apgar scores were 9 and 10. Delivery was performed smoothly, and the newborn exhibited no malformations. The mother and the newborn were discharged uneventfully. We suggest that pregnancy is possible for recipients after ABO-incompatible liver transplantation.

Topics: ABO Blood-Group System; Administration, Oral; Adult; Apgar Score; Biopsy; Blood Group Incompatibility; Delivery, Obstetric; Female; Hemodiafiltration; Hepatic Encephalopathy; Hepatitis; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Infant, Newborn; Liver Transplantation; Living Donors; Methylprednisolone; Pregnancy; Ribonucleosides; Rituximab; Spouses; Tacrolimus

To determine risk factors for early neurologic complications (NCs) after liver transplantation from perspective of recipient, donor, and surgeon.. In all, 295 adult recipients were enrolled consecutively between August 2001 and February 2014 from a single medical center in Taiwan. Any NC in the first 30 d post-liver transplantation, and perioperative variables from multiple perspectives were collected and analyzed. The main outcome was a 30-d NC. Generalized additive models were used to detect the non-linear effect of continuous variables on outcome, and to determine cut-off values for categorizing risk. Risk factors were identified using multiple logistic regression analysis.. In all, 288 recipients were included, of whom 142 (49.3%) experienced at least one NC, with encephalopathy being the most common 106 (73%). NCs prolonged hospital stay (35.15 ± 43.80 d vs 20.88 ± 13.58 d, P < 0.001). Liver recipients' age < 29 or ≥ 60 years, body mass index < 21.6 or > 27.6 kg/m(2), Child-Pugh class C, history of preoperative hepatoencephalopathy or mental disorders, day 7 tacrolimus level > 8.9 ng/mL, and postoperative intra-abdominal infection were more likely associated with NCs. Novel risk factors for NCs were donor age < 22 or ≥ 40 years, male-to-male gender matching, graft-recipient weight ratio 0.9%-1.9%, and sequence of transplantation between 31 and 174.. NCs post- liver transplantation occurs because of factors related to recipient, donor, and surgeon. Our results provide a basis of risk stratification for surgeon to minimize neurotoxic factors during transplantation.

Topics: Adrenal Cortex Hormones; Adult; Age Factors; Body Mass Index; Brain Diseases; Case-Control Studies; Consciousness Disorders; Delirium; Female; Graft Rejection; Hepatic Encephalopathy; Humans; Immunosuppressive Agents; Intraabdominal Infections; Length of Stay; Liver Transplantation; Male; Mental Disorders; Middle Aged; Mycophenolic Acid; Myelinolysis, Central Pontine; Neurotoxicity Syndromes; Posterior Leukoencephalopathy Syndrome; Postoperative Complications; Preoperative Period; Psychotic Disorders; Risk Assessment; Risk Factors; Seizures; Sex Factors; Stroke; Tacrolimus; Taiwan; Tissue Donors

Topics: Acetaminophen; Adolescent; Adult; Allografts; Ammonia; Analgesics, Non-Narcotic; Biopsy; Female; Graft Rejection; Hepatectomy; Hepatic Artery; Hepatic Encephalopathy; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Liver; Liver Failure, Acute; Liver Transplantation; Portacaval Shunt, Surgical; Portal Vein; Prednisolone; Tacrolimus; Tomography, X-Ray Computed; Transplantation, Homologous; Ultrasonography, Doppler; Vena Cava, Inferior

Early calcineurin inhibitor-induced neurotoxicity (ECIIN) is considered when neurological symptoms occur within 4 weeks after liver transplantation (LT). Risk factors and clinical outcome of ECIIN remain largely unknown. We sought to estimate the incidence, risk factors, and outcome of ECIIN after LT. We retrospectively evaluated 158 patients that underwent LT in a 2-year period and received immunosuppression with calcineurin inhibitors (CNI) and prednisone. ECIIN was considered when moderate/severe neurological events (after excluding other etiologies) occurred within 4 weeks after LT and improved after modification of CNI. Demographic and clinical variables were analyzed as risk factors. Twenty-eight (18%) patients developed ECIIN and the remaining 130 patients were analyzed as controls. History of pre-LT hepatic encephalopathy (OR 3.16, 95% CI 1.29-7.75, P = 0.012), post-LT hyponatremia (OR 3.34, 95% CI 1.38-9.85, P = 0.028), and surgical time >7 h (OR 2.62, 95% CI 1.07-6.41, P = 0.035) were independent factors for ECIIN. Acute graft rejection and infections were more frequent in the ECIIN group. In addition, length of stay was longer in ECIIN patients. In conclusion, pre-LT hepatic encephalopathy, surgical time >7 h, and post-LT hyponatremia are risk factors for ECIIN. Clinical complications and a longer hospital stay are associated with ECIIN development.

Topics: Acute Disease; Aged; Calcineurin Inhibitors; Female; Graft Rejection; Hepatic Encephalopathy; Humans; Hyponatremia; Immunosuppression Therapy; Immunosuppressive Agents; Liver; Liver Transplantation; Male; Middle Aged; Postoperative Complications; Retrospective Studies; Risk Factors; Tacrolimus; Time Factors

Diabetes mellitus (DM) is a frequent and serious complication in patients with liver diseases. We aimed to assess the prevalence and consequences of post-transplant DM (PTDM) in Chinese patients with HBV-related liver diseases and to determine the possible risk factors.. Altogether 165 patients with HBV infection and undergoing cadaveric related liver transplantation (LT) were enrolled. The clinical data of patients with (PTDM group) and without PTDM (non-PTDM group) were compared.. Of the 165 patients, 28 had DM and 12 had impaired fasting glucose (IFG) before LT. Patients with pre-transplant DM or IFG had a survival rate similar to that of the others. Forty patients (24.2%) developed PTDM with a mean time of 36+/-17 days (range 2-300 days) after LT. Of those, 32 developed PTDM within 3 months post-LT and 29 needed insulin treatment. Pre-transplant hepatic encephalopathy and tacrolimus application were found more frequently in the PTDM group than in the non-PTDM group. The plasma tacrolimus levels were notably higher at 1 and 3 months post-LT in the PTDM group than those in the non-PTDM group. Compared to the non-PTDM group, the PTDM group showed remarkably poorer survival and tumor-free survival in patients with hepatocellular carcinoma, and significantly higher incidence of sepsis, fungal infection, chronic kidney diseases and biliary complications after LT.. Pre-transplant DM did not affect the patient survival after LT. Since PTDM is common, it has a negative impact on outcome and may contribute to tumor recurrence. Pre-transplant hepatic encephalopathy, a tacrolimus-based regimen, and high levels of tacrolimus are clearly associated with the occurrence of PTDM.

Topics: Adolescent; Adult; Aged; China; Diabetes Mellitus; Female; Hepatic Encephalopathy; Hepatitis B; Humans; Hypoglycemic Agents; Immunosuppressive Agents; Insulin; Liver Transplantation; Male; Middle Aged; Prevalence; Retrospective Studies; Risk Factors; Tacrolimus; Time Factors; Young Adult

Five cases that were referred to the Division of Transplantation at NYU School of Medicine for consideration for liver transplantation were discussed among a panel of hepatitis B and liver transplant experts. Opinions were obtained on the management at every stage of treatment of patients with the following initial information: Case one: young Asian woman in stage IV hepatic coma; intubated; prothrombin time (PT): 30 s; serum glutamic oxaloacetic transaminase (SGOT): 8,000 IU; total bilirubin: 25 mg/dL; hepatitis B surface antigen (HBsAg) positive. Case two: 70-yr-old woman, native of Greece; decompensated cirrhosis with encephalopathy; Child-Pugh Class C; HBsAg positive; hepatitis B surface antibody (HBsAb) negative; hepatitis B e antigen (HBeAg) positive; hepatitis B e antibody (HBeAb) negative; hepatitis B virus (HBV) DNA titer: 10,000. Case three: Muscular detective working full-time; cirrhosis; Child Pugh Class B; ascites controlled with spironolactone and furosemide; PT: 19s; HBsAg positive; HBsAb negative; HBV DNA titer: 50,000; low platelet count. Case four: 45-yr-old baker; cirrhosis and resectable 4-cm hepatoma; Child-Pugh Class B; PT: 16 s; Blood type O; United Network for Organ Sharing (UNOS) 2B; HBV DNA titer: 3,000. Case five: 40-yr-old Indian man; 300 pounds with massive ascites; Child Pugh Class C; PT: 17 s; HBsAg positive; HBV DNA titer: 22,000; transplanted with intra-operative hypotension; tacrolimus; graft functioning; HBIg 10,000 IU intra-operative and around the clock during the first post-operative week; required huge doses of hepatitis B immune globulin (HBIg) to maintain adequate HBsAb level; daily loss of 5 6 L of ascites fluid; post-operative day 8: anuric, blood urea nitrogen (BUN) 127, creatinine 3, mental status changes.

Topics: Adult; Aged; Antiviral Agents; Ascites; Carcinoma, Hepatocellular; Female; Hepatic Encephalopathy; Hepatitis B; Humans; Immunization, Passive; Immunoglobulins; Immunosuppressive Agents; Liver Cirrhosis; Liver Neoplasms; Liver Transplantation; Middle Aged; Tacrolimus

Newer surgical techniques and immunosuppressive therapies have resulted in paediatric liver transplantation being available for most children with end-stage liver disease and has resulted in a greater than 80% 5-year survival rate. The most common indications for paediatric liver transplantation are biliary atresia (43%), metabolic disease (13%) and acute hepatic necrosis (11%). For approximately 75% of children with acute hepatic failure, the cause is unknown. Timing of liver transplantation not only affects survival rate, but may influence neurodevelopmental outcome. Fortunately, numerous types of donors, such as reduced-sized, living related or unrelated and blood-type mismatched, have reduced the mortality of children who are waiting for liver transplantation. However, the mortality and morbidity before and after liver transplantation remain high for children who have fulminant hepatic failure or are less than 5 months of age at the time of transplantation. The principle medical complications after liver transplantation are rejection and infection. Although use of newer immunosuppressive regimens has reduced the rate of rejection, Epstein-Barr virus infection with associated lymphoproliferative disorder remains the principle cause for morbidity and mortality after the initial 3 months post-liver transplant.

Topics: Adolescent; Adult; Age Factors; Biliary Atresia; Child; Child, Preschool; Cyclosporine; Hepatic Encephalopathy; Herpesviridae Infections; Herpesvirus 4, Human; Humans; Immunosuppressive Agents; Liver Transplantation; Lymphoproliferative Disorders; Postoperative Complications; Tacrolimus

Topics: Amino Acid Metabolism, Inborn Errors; Biliary Atresia; Child; Child, Preschool; Contraindications; Drug Interactions; Erythromycin; Female; Hepatic Encephalopathy; Humans; Liver Transplantation; Male; Propionates; Rifampin; Tacrolimus

The authors established a new experimental model of fulminant hepatic failure (FHF) with prolonged hepatocellular necrosis and impaired liver regeneration, and evaluated the immunological mechanisms related to the impaired liver regeneration in this model. A novel lipid A analogue, FS-112, was injected intravenously into male Balb/c mice, followed by a 70% partial hepatectomy 2 days later. Serum levels of T.Bil. and ALT rose 7 days after the partial hepatectomy, as compared with controls. In mice pretreated with FS-112, labeling indices of both BrdU and PCNA 36 hrs after the partial hepatectomy were significantly lower than those in the controls. Splenic lymphocytes harvested from the FHF mice 1-5 days after the partial hepatectomy showed a cytotoxic activity against regenerating hepatocytes with a peak effect on day 5. Cytotoxic activity against YAC-1 cells was also found up to 5 days after the partial hepatectomy, and resembled that directed against the regenerating hepatocytes. On the 5th day of FS-112 administration, there was a marked rise in the production of IFN-gamma from splenocytes. When FK-506, an immunosuppressive agent, was given intracutaneously daily for 7 days, serum levels of T.Bil. and ALT significantly decreased, as compared with controls. Furthermore, the PCNA-labeling index 36 hrs after the partial hepatectomy was enhanced by the administration with FK-506 in the FHF mice. These results strongly suggest that the NK cells activated by IFN-gamma may be involved in killing the regenerating liver cells, and thus play a role in the pathogenesis of the impaired liver regeneration in FHF.2+ recovery from the impaired liver regeneration in FHF.

Topics: Animals; Cytotoxicity, Immunologic; Hepatic Encephalopathy; Interferon-gamma; Killer Cells, Natural; Liver; Liver Regeneration; Male; Mice; Mice, Inbred BALB C; Necrosis; Spleen; Tacrolimus

Liver grafting is now established as the optimal treatment for patients with end-stage parenchymal liver disease. Twenty-three years of experience at a single center is presented. The 1-year actuarial patient survival rate for all cases transplanted in Cambridge has now risen from 10% in 1968 to 1970 to 80% in 1990 to 1991. Increasing numbers of patients are being referred for transplantation with an ever-increasing range of indications being developed. Many inborn errors of metabolism can now be cured by liver grafting. There is still, however, considerable scope for improvement in many areas of patient treatment from operative and postoperative care to long-term immunosuppressive management. Much remains to be done to minimize early sepsis- and rejection-related deaths and late immunosuppression-related morbidity.

Topics: Actuarial Analysis; Adolescent; Adult; Aged; Azathioprine; Child; Child, Preschool; Cross-Cultural Comparison; Cyclosporine; England; Female; Follow-Up Studies; Graft Survival; Hepatic Encephalopathy; Humans; Immunosuppression Therapy; Infant; Infant, Newborn; Liver Transplantation; Male; Middle Aged; Postoperative Complications; Reoperation; Survival Rate; Tacrolimus; Tissue Donors