tacrolimus and Fatty-Liver

BACKGROUND Progressive familial intrahepatic cholestasis (PFIC) is an autosomal recessive inherited disease that disrupts the genes for bile formation. Liver transplantation (LT) is the only effective treatment for PFIC patients with end-stage liver disease. We describe our experience in terms of clinical characteristics, complications, and outcome of LT for PFIC. CASE REPORT The data of 5 pediatric PFIC patients recipients (3 PFIC1, 1 PFIC2, and 1 PFIC3) who received LT at our Liver Transplant Center from June 2013 to February 2017 were retrospectively analyzed. Four patients received liver transplantation from donation after cardiac death (DCD) donors. One patient received a living donor liver transplantation (LDLT). All the LT recipients received an immunosuppressive regimen of tacrolimus (FK 506) + methylprednisolone + mycophenolate mofetil (MMF). Diarrhea did not improve in 2 PFIC1 patients after LT, and they both developed steatohepatitis several months after LT. The other PFIC1 patient received ABO blood group incompatible LT and developed biliary complications and a severe Epstein-Barr virus infection; this patient underwent endoscopic retrograde cholangiopancreatography. She recovered after treatment with ganciclovir and reduction of tacrolimus dosage. The PFIC2 patient had abnormal liver function 19 months after LT, and recovered after administration of increased dosage of immunosuppressant agents. Liver function in the PFIC3 patient was normal during 2-year follow-up. CONCLUSIONS Liver transplantation is an effective treatment in PFIC patients. However, PFIC1 patients may develop aggravated diarrhea and steatohepatitis after LT. PFIC2 and PFIC3 patients have good outcomes after LT.

Topics: Child; Child, Preschool; Cholestasis, Intrahepatic; Diarrhea; Disease Progression; Fatty Liver; Female; Humans; Immunosuppressive Agents; Liver Transplantation; Living Donors; Male; Methylprednisolone; Mycophenolic Acid; Postoperative Complications; Retrospective Studies; Tacrolimus; Treatment Outcome

Recurrence of chronic hepatitis C and progressive fibrosis in liver transplants is frequent and impairs both graft and patient survival. Whether or not the choice of immunosuppression affects progression of fibrosis remains unclear. The aim of the present study was to compare the potential of the commonly used immunosuppressants to halt experimental liver fibrosis progression.. To induce liver fibrosis, rats underwent bile duct ligation and treatment with sirolimus (2mg/kg), everolimus (3mg/kg), tacrolimus (1mg/kg), and cyclosporin A (10mg/kg) daily for 5 weeks. Fibrosis, inflammation, and portal pressure were evaluated by histology, hydroxyproline levels, morphometry, hemodynamics, and hepatic gene expression.. Sirolimus and everolimus decreased fibrosis up to 70%, improved portal pressure, reduced ascites, and showed potent down-regulation of pro-fibrogenic genes, paralleled by a strong increase in matrix degradation (collagenase) activity; in contrast, tacrolimus and cyclosporine A had no or even aggravating effects on liver fibrosis in rats.. mTOR inhibition by sirolimus and everolimus in experimental liver fibrosis associates with significantly less fibrosis progression and portal hypertension than treatment with calcineurin inhibitors tacrolimus and cyclosporine A. These data suggest that the selection of the immunosuppressant could impact the recurrence of fibrosis in liver allografts.

Topics: Animals; Bile Ducts; Calcineurin Inhibitors; Cyclosporine; Disease Progression; Everolimus; Fatty Liver; Immunosuppressive Agents; Ligation; Liver Cirrhosis, Experimental; Male; Matrix Metalloproteinases; Non-alcoholic Fatty Liver Disease; Portal Pressure; Rats; Rats, Wistar; RNA, Messenger; Sirolimus; Tacrolimus; TOR Serine-Threonine Kinases; Triglycerides

Hepatic steatosis and insulin resistance are factors that aggravate the progression of liver disease caused by hepatitis C virus (HCV) infection. In the pathogenesis of liver disease and metabolic disorders in HCV infection, oxidative stress due to mitochondrial respiratory chain dysfunction plays a pivotal role. Tacrolimus (FK506) is supposed to protect mitochondrial respiratory function. We studied whether tacrolimus affects the development of HCV-associated liver disease using HCV core gene transgenic mice, which develop hepatic steatosis, insulin resistance, and hepatocellular carcinoma. Administration of tacrolimus to HCV core gene transgenic mice three times per week for 3 months led to a significant reduction in the amounts of lipid in the liver as well as in serum insulin. Tacrolimus treatment also ameliorated oxidative stress and DNA damage in the liver of the core gene transgenic mice. Tacrolimus administration reproduced these effects in a dose-dependent manner in HepG2 cells expressing the core protein. The intrahepatic level of tumor necrosis factor-alpha, which may be a key molecule for the pathogenesis in HCV infection, was significantly decreased in tacrolimus-treated core gene transgenic mice. Tacrolimus thus reversed the effect of the core protein in the pathogenesis of HCV-associated liver disease. These results may provide new therapeutic tools for chronic hepatitis C, in which oxidative stress and abnormalities in lipid and glucose metabolism contribute to liver pathogenesis.

Topics: Animals; Antioxidants; Cyclosporine; Disease Models, Animal; Dose-Response Relationship, Drug; Fatty Liver; Gene Expression Regulation; Glucose; Hep G2 Cells; Humans; Insulin Resistance; Lipid Metabolism; Liver; Mice; Mice, Transgenic; NAD; Oxidative Stress; Reactive Oxygen Species; RNA, Messenger; Tacrolimus; Viral Core Proteins

Ischemia-reperfusion (I-R) injury is poorly tolerated by fatty livers, most probably secondary to reduced cellular adenosine triphosphate (ATP) levels. We investigated the effectiveness of tacrolimus pretreatment on fatty liver I-R injury in obese Zucker rats. Tacrolimus (0.3 mg/kg, intravenously) was injected 24 hours before a 75-minute ischemic period and rats were sacrificed 6 hours later. Tacrolimus modified the response to I-R observed in obese Zucker rats, when compared to nontreated obese rats: a significant reduction in hepatocyte necrosis was associated with a significant increase in hepatocyte apoptosis. In addition, cell necrosis and apoptosis were significantly and inversely correlated in lean nontreated and treated obese Zucker rats following I-R. Tacrolimus also significantly increased the hepatic ATP levels, reduced in nontreated obese rats, toward values found in lean Zucker rat livers. This protective effect of tacrolimus was further confirmed in vivo by a significantly improved survival following pretreatment with tacrolimus, 24 hours prior to ischemia. In conclusion, in obese Zucker rat livers, tacrolimus pretreatment reversed the I-R injury toward the one found in lean Zucker rats. The correlations between ATP levels and the opposite changes in necrosis and apoptotic pathways strongly suggest a cause-effect relationship between tacrolimus and changes in ATP levels.

Topics: Animals; Biopsy, Needle; Body Weight; Disease Models, Animal; Fatty Liver; Immunohistochemistry; Liver Circulation; Liver Function Tests; Liver Regeneration; Male; Necrosis; Probability; Random Allocation; Rats; Rats, Zucker; Reference Values; Reperfusion Injury; Statistics, Nonparametric; Survival Rate; Tacrolimus; Time Factors

The aim of this study was to determine whether the minimum necessary volume of a moderate fatty liver graft was similar to the normal liver volume and to elucidate means for improving the function of the transplanted fatty liver if it were inferior in volume to a normal liver under conditions of permissible cold preservation. Nine-week-old male Wistar rats were used. Normal rat chow was fed to the normal liver group, and fat-enriched rat chow was fed to the fatty liver group for 4 weeks to induce a moderately fatty liver. Liver transplantation with various volumes of reduced-size grafts, including whole liver graft (100%LT), 70% volume graft (70%LT), and 30% volume graft (30%LT), was performed with both groups of rats as donors. All procedures were performed under the conditions of 2-hour cold preservation. All rats with an implanted normal liver were surviving at 7 days after the operation regardless of the graft volume (100%LT, 5 of 5; 70%LT, 5 of 5; 30%LT, 5/5). In contrast, the survival rates decreased according to the graft volume in rats implanted with fatty livers (100%LT, 8 of 8; 70%LT, 5 of 8; 30%LT, 2/8). To improve the survival of 30%LT with fatty liver, we employed two potent inhibitors of ischemia-reperfusion injury: FK506 and prostaglandin E1. Though FK506 had no advantageous effect, prostaglandin E1 significantly improved the survival rate and diminished serum levels of alanine aminotransferase and hyaluronic acid. In conclusion, the volume of graft necessary for successful transplantation is larger in fatty livers than in normal livers in permissible cold preservation. Also, prostaglandin E1 protects grafts against ischemia-reperfusion injury and improves the functioning of a transplanted fatty liver.

Topics: Alanine Transaminase; Alprostadil; Animals; Fatty Liver; Hyaluronic Acid; Immunosuppressive Agents; Liver; Liver Transplantation; Male; Models, Animal; Organ Preservation; Rats; Rats, Wistar; Reperfusion Injury; Tacrolimus

Steatosis of the liver, demonstrating itself as the acute liver failure during the third trimester of pregnancy (Acute Fatty Liver of Pregnancy--AFLP) is a rarely observed liver pathology. Herewith we describe the case of a 19-years old pregnant patient with this rare disease. The authors present the clinical course, dynamics, diagnostics, and outcome of treatment in this unique case. In this patient the ultimate treatment chosen was the liver transplantation. The opinions, concerning liver transplantation in AFLP (expressed in the world literature) are somewhat controversial. This paper presents the first case of AFLP treatment with orthotopic liver transplantation (OLTx) in Poland.

Topics: Acute Disease; Adrenal Cortex Hormones; Adult; Fatty Liver; Female; Humans; Immunosuppressive Agents; Liver Transplantation; Pregnancy; Pregnancy Complications; Tacrolimus; Treatment Outcome