tacrolimus and Hepatic-Veno-Occlusive-Disease

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 Tacrolimus was withdrawn and the progression of HVOD was reversed..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

To determine how well tacrolimus (FK506) and cyclosporin A (CsA) are tolerated after HLA-identical blood stem cell transplantation, we performed a retrospective review of 87 adults transplanted consecutively who received FK506 (n = 40) or CsA (n = 47) in a nonrandomized fashion in combination with methylprednisolone for graft-versus-host disease (GVHD) prophylaxis and compared the incidences of complications potentially related to the immunosuppressive agents. Pre-transplant demographic characteristics, drug compliance and rates of acute GVHD were comparable for the two groups. Following first discharge, fewer patients in the FK506 group required antihypertensive therapy (32 vs 59%, P = 0.022), but more required insulin (34 vs 10%, P = 0.014). There was also a trend for more hyperkalemia and less moderate-to-severe venoocclusive disease in the FK506 group. However, nephrotoxicity, neurotoxicity, hemolytic-uremic syndrome, and cytomegaloviral or fungal infections through the first 100 days post-transplant did not differ significantly between the two groups. We conclude that for allogeneic blood stem cell transplant recipients, the incidence of complications related to FK506 and CsA in equally effective dose schedules in combination with methylprednisolone are similar with the exception of the risks of hypertension and hyperglycemia.

Topics: Acute Kidney Injury; Adolescent; Adult; Chemical and Drug Induced Liver Injury; Cyclosporine; Female; Hematopoietic Stem Cell Transplantation; Hepatic Veno-Occlusive Disease; Humans; Hyperglycemia; Hyperkalemia; Hypertension; Immunosuppressive Agents; Incidence; Infections; Male; Methylprednisolone; Middle Aged; Patient Compliance; Retrospective Studies; Seizures; Tacrolimus; Transplantation Conditioning; Transplantation, Homologous; Treatment Outcome; Whole-Body Irradiation

A calcineurin inhibitor combined with methotrexate is the standard prophylaxis for graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (HSCT). Everolimus, a derivative of sirolimus, seems to mediate antileukemia effects. We report on a combination of everolimus and tacrolimus in 24 patients (median age, 62 years) with either myelodysplastic syndrome (MDS; n = 17) or acute myeloid leukemia (AML; n = 7) undergoing intensive conditioning followed by HSCT from related (n = 4) or unrelated (n = 20) donors. All patients engrafted, and only 1 patient experienced grade IV mucositis. Nine patients (37%) developed acute grade II-IV GVHD, and 11 of 17 evaluable patients (64%) developed chronic extensive GVHD. Transplantation-associated microangiopathy (TMA) occurred in 7 patients (29%), with 2 cases of acute renal failure. The study was terminated prematurely because an additional 6 patients (25%) developed sinusoidal obstruction syndrome (SOS), which was fatal in 2 cases. With a median follow-up of 26 months, the 2-year overall survival rate was 47%. Although this new combination appears to be effective as a prophylactic regimen for acute GVHD, the incidence of TMA and SOS is considerably higher than seen with other regimens.

Topics: Adult; Aged; Anemia, Hemolytic; Everolimus; Female; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Hepatic Veno-Occlusive Disease; Humans; Leukemia, Myeloid, Acute; Male; Middle Aged; Myelodysplastic Syndromes; Sirolimus; Survival Rate; Tacrolimus; Transplantation, Homologous

Topics: Hematopoietic Stem Cell Transplantation; Hepatic Veno-Occlusive Disease; Humans; Immunosuppressive Agents; Liver Transplantation; Tacrolimus

Topics: Graft Rejection; Hepatic Veno-Occlusive Disease; Humans; Immunosuppressive Agents; Liver Transplantation; Mycophenolic Acid; Pharmaceutical Preparations; Tacrolimus

Topics: Adult; End Stage Liver Disease; Female; Hepatic Veno-Occlusive Disease; Humans; Immunosuppressive Agents; Liver Transplantation; Male; Middle Aged; Tacrolimus

Sinusoidal obstruction syndrome (SOS), previously known as hepatic veno-occlusive disease, is a rare disorder in solid organ transplant patients, and is an uncommon complication after liver transplantation. Severe SOS with hepatic failure causes considerable mortality. Tacrolimus has been reported to be an offending agent, which potentially plays a role in the pathophysiological process of SOS. SOS due to tacrolimus has been reported in lung and pancreatic transplantations, but has never been described in a liver transplant recipient. Herein, we present a case of SOS after liver transplantation, which was possibly related to tacrolimus. A 27-year-old man developed typical symptoms of SOS with painful hepatomegaly, ascites and jaundice after liver transplantation, which regressed following withdrawal of tacrolimus. By excluding other possible predisposing factors, we concluded that tacrolimus was the most likely cause of SOS.

Topics: Adult; Biopsy; Cyclosporine; Drug Substitution; Hepatic Veno-Occlusive Disease; Humans; Immunosuppressive Agents; Liver Transplantation; Male; Predictive Value of Tests; Risk Factors; Tacrolimus; Tomography, X-Ray Computed; Treatment Outcome

Hepatic veno-occlusive disease (HVOD) describes the nonthrombotic, fibrous obliteration of the small centrilobular hepatic veins by connective tissue and centrilobular necrosis in zone 3 of the acini. Occlusion of the terminal venules of the liver might result in HVOD with the characteristic clinical findings of painful hepatomegaly, ascites, jaundice, and weight gain for more than 5% of patients. It is mainly observed after hematopoietic stem cell transplantation (SCT) and is responsible for significant morbidity and mortality. The incidence of HVOD is much lower after solid organ transplantation than after SCT and seems to differ from one organ to another. It has been sporadically reported after lung, renal, and liver transplantation, but has never been reported after pancreas transplantation. In general, HVOD is presumably attributed to azathioprine or tacrolimus used in solid organ transplantation. Here we describe a case of HVOD occurring after pancreas transplantation, in which tacrolimus might have played a causative role because complete recovery was observed after discontinuation of tacrolimus. Pancreas transplantation physicians should raise the suspicion of HVOD when a recipient presents with hepatomegaly, ascites, or jaundice.

Topics: Adult; Female; Hepatic Veno-Occlusive Disease; Humans; Immunosuppressive Agents; Pancreas Transplantation; Tacrolimus

Hepatic veno-occlusive disease is defined as nonthrombotic fibrous obliterative endophlebitis of small centrilobular hepatic venules. Clinically, patients present with elevated liver enzymes and a triad of jaundice, hepatomegaly and ascites. Although reported as a complication of other solid organ and stem cell transplantation, there have been no reported cases to date of veno-occlusive disease following lung transplantation. The present authors report a case of veno-occlusive disease following single-lung transplantation in a patient on a triple-drug immunosuppressive regimen composed of tacrolimus, mycophenolate mofetil and prednisone. The diagnosis was established by transjugular liver biopsy and by discontinuing tacrolimus; there was clinical regression of symptoms and serological return to baseline.

Topics: Female; Hepatic Veno-Occlusive Disease; Humans; Immunosuppressive Agents; Lung Transplantation; Middle Aged; Tacrolimus

Liver injury is a common complication in allogeneic hematopoietic stem cell transplantation. Its major causes comprise graft-versus-host disease (GVHD), infection, and toxicities of preparative regimens and immunosuppressants; however, we have little information on liver injuries after reduced intensity cord blood transplantation (RICBT). We reviewed medical records of 104 recipients who underwent RICBT between March 2002 and May 2004 at Toranomon Hospital. Preparative regimen and GVHD prophylaxis comprised fludarabine/melphalan/total body irradiation and cyclosporine or tacrolimus. We assessed the etiology of liver injuries based on the clinical presentation, laboratory results, comorbid events, and imaging studies in 85 patients who achieved primary engraftment. The severity of liver dysfunction was assessed according to the National Cancer Institute Common Toxicity Criteria version 2.0. Hyperbilirubinemia was graded according to a report by Hogan et al (Blood. 2004;103:78-84). Moderate to very severe liver injuries were observed in 36 patients. Their causes included cholestatic liver disease (CLD) related to GVHD or sepsis (n = 15), GVHD (n = 7), cholangitis lenta (n = 5), and others (n = 9). Median onsets of CLD, GVHD, and cholangitis lenta were days 37, 40, and 22, respectively. Frequencies of grade 3-4 alanine aminotransferase elevation were comparable across the 3 types of hepatic injuries. Serum gamma-glutamil transpeptidase was not elevated in any patients with cholangitis lenta, whereas 27% and 40% of patients with CLD and GVHD, respectively, developed grade 3-4 gamma-glutamil transpeptidase elevation. Multivariate analysis identified 2 risk factors for hyperbilirubinemia; grade II-IV acute GVHD (relative risk, 2.23; 95% confidential interval, 1.11-4.47; P = .024) and blood stream infection (relative risk, 3.77; 95% confidential interval, 1.91-7.44; P = .00013). In conclusion, the present study has demonstrated that the hepatic injuries are significant problems after RICBT, and that GVHD and blood stream infection contribute to their pathogenesis.

Topics: Adolescent; Adult; Aged; Anti-Bacterial Agents; Bacterial Infections; Busulfan; Chemical and Drug Induced Liver Injury; Cholangitis; Cord Blood Stem Cell Transplantation; Cyclosporine; Female; Hematologic Diseases; Hematologic Neoplasms; Hepatic Veno-Occlusive Disease; Humans; Hyperbilirubinemia; Immunosuppressive Agents; Incidence; Infant, Newborn; Liver Diseases; Liver Function Tests; Male; Melphalan; Middle Aged; Postoperative Complications; Risk Factors; Tacrolimus; Tissue Donors; Transplantation Conditioning; Vidarabine; Whole-Body Irradiation

Tacrolimus is widely used for the prophylaxis and treatment of graft-versus-host disease after allogeneic hematopoietic stem cell transplantation (HSCT) and graft rejection in solid organ transplantation. The metabolism of tacrolimus has been reported to be impaired in association with liver dysfunction, mostly as documented in liver transplant recipients. Hepatic veno-occlusive disease (VOD) is one of the serious complications after allogeneic HSCT. It is characterized by jaundice, fluid retention, and painful hepatomegaly, caused by endothelial cell injury resulting from the toxicity of the conditioning regimen. The impaired metabolism of tacrolimus in hepatic VOD has not previously been reported in the literature. Here, we report the notable alteration in the metabolism of tacrolimus in two patients with hepatic VOD, in whom the half-lives of tacrolimus were markedly prolonged (288 and 146 h).

Topics: Cord Blood Stem Cell Transplantation; Endothelium, Vascular; Female; Hepatic Veno-Occlusive Disease; Humans; Immunosuppressive Agents; Liver; Liver Diseases; Male; Middle Aged; Myelodysplastic Syndromes; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Tacrolimus; Transplantation Conditioning

Topics: Adult; Female; Hepatic Veno-Occlusive Disease; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Tacrolimus

Tacrolimus is an immunosuppressant commonly used in the prevention of graft-versus-host disease (GVHD) following allogeneic HCT. Unfortunately, the use of tacrolimus is associated with variable immunosuppression and toxicity. The purpose of this study was to describe tacrolimus population pharmacokinetic parameters, to identify relationships between clinical covariates and pharmacokinetic estimates, and to develop a model to predict tacrolimus clearance in HCT patients. Steady-state whole blood tacrolimus concentrations (n = 1625) obtained during intravenous and oral therapy were analyzed in 122 patients. Population clearance (CL) was 5.22 l/h and bioavailability (F) was 0.28. The influence of clinical covariates on population estimates of CL and F of tacrolimus were tested with nonlinear mixed effects models (NONMEM). CL was significantly reduced by elevations in total bilirubin 2.0-9.9 mg/dl (CL * 0.797), bilirubin > or = 10 mg/dl (CL * 0.581), serum creatinine > or = 2 mg/dl (CL * 0.587), grade III/IV graft-versus-host disease (CL * 0.814) and veno-occlusive disease (CL 0.814). No covariates were predictive of oral F. The interindividual variabilities in CL and F were 33% and 44%, respectively. Residual variability was 27.5% and 16.8% at tacrolimus concentrations of 10 microg/l and 20 microg/l, respectively. These models may be used to predict tacrolimus clearance and doses in adult patients following HCT.

Topics: Administration, Oral; Adolescent; Adult; Biological Availability; Creatinine; Female; Graft vs Host Disease; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Hepatic Veno-Occlusive Disease; Humans; Hyperbilirubinemia; Immunosuppressive Agents; Infusions, Intravenous; Male; Metabolic Clearance Rate; Middle Aged; Models, Biological; Patient Compliance; Retrospective Studies; Tacrolimus; Transplantation, Homologous

A 40-year-old man with chronic myelogenous leukemia in chronic phase received an allogeneic marrow graft from his HLA identical brother. He was conditioned with busulfan (16 mg/kg) and cyclophosphamide (120 mg/kg). Graft-versus-host disease (GVHD) prophylaxis was attempted with cyclosporine A (CYA) and methotrexate. On day 30, weight gain, ascites and hepatomegaly developed in addition to an elevation of total bilirubin (TB). He was diagnosed as having veno-occlusive disease (VOD) and treated conservatively. The TB level increased up to 20.1 mg/dl on day 66, then reduced to 2.1 mg/dl on day 129. By that time ascites and hepatomegaly also had completely resolved. However, on day 134. The TB level started to increase again, when the lesions of chronic GVHD were observed in the eye, the mouth, and the skin. CYA was started on day 142, and FK506 was substituted for CYA on day 161. Despite the improvement of oral and skin lesions, TB level continued to rise, and he died of respiratory failure due to ARDS on day 186. Autopsy revealed both acute and old hepatic VOD lesions, suggesting the occurrence of late-onset VOD which probably contributed to the liver dysfunction observed after clinical resolution of the first episode of VOD.

Topics: Adult; Bone Marrow Transplantation; Busulfan; Chronic Disease; Cyclophosphamide; Cyclosporine; Graft vs Host Disease; Hepatic Veno-Occlusive Disease; Humans; Immunosuppressive Agents; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Male; Methotrexate; Recurrence; Respiratory Distress Syndrome; Tacrolimus