ABSTRACT
AIM: To determine if there is a reasonable prospect of success of a re-use liver transplantation. METHODS: We systematically searched for reports of liver graft re-use using electronic searches of PubMed and Web of Knowledge. We performed hand searches of references lists of articles reporting re-use of grafts. RESULTS: A systematic review of the literature reveals 28 liver transplantations using previously transplanted grafts. First and second recipients ranged in age from 4 to 72 years and 29 to 62 years respectively. Liver disease in the first recipient was varied including 5 (18%) patients with fulminant liver failure who died subsequently of cerebral edema. The second transplantation was performed after a median interval of 5 d (one day-13 years). Viral hepatitis was present in 3 (11%) of the initial recipients and in 8 (29%) of final recipients. Hepatocellular carcinoma was present in 6 (21%) of the final recipients. Early survival after the final transplantation was 93%, whereas long-term survival was 78% with a mean follow-up of 23.3 (3-120) mo. CONCLUSION: Outcomes of transplantation using previously transplanted grafts in this select population are similar to those seen with conventional grafts.
ABSTRACT
A genome-wide association screen for primary biliary cirrhosis risk alleles was performed in an Italian cohort. The results from the Italian cohort replicated IL12A and IL12RB associations, and a combined meta-analysis using a Canadian dataset identified newly associated loci at SPIB (P = 7.9 x 10(-11), odds ratio (OR) = 1.46), IRF5-TNPO3 (P = 2.8 x 10(-10), OR = 1.63) and 17q12-21 (P = 1.7 x 10(-10), OR = 1.38).
Subject(s)
Alleles , White People/genetics , Canada , Genome , Genome-Wide Association Study , Humans , Interferon Regulatory Factors , Liver Cirrhosis, Biliary , Meta-Analysis as Topic , Odds RatioABSTRACT
BACKGROUND: Primary biliary cirrhosis is a chronic granulomatous cholangitis, characteristically associated with antimitochondrial antibodies. Twin and family aggregation data suggest that there is a significant genetic predisposition to primary biliary cirrhosis, but the susceptibility loci are unknown. METHODS: To identify genetic loci conferring a risk for primary biliary cirrhosis, we carried out a genomewide association analysis in which DNA samples from 2072 Canadian and U.S. subjects (536 patients with primary biliary cirrhosis and 1536 controls) were genotyped for more than 300,000 single-nucleotide polymorphisms (SNPs). Sixteen of the SNPs most strongly associated with primary biliary cirrhosis were genotyped in two independent replication sets. We carried out fine-mapping studies across three loci associated with primary biliary cirrhosis. RESULTS: We found significant associations between primary biliary cirrhosis and 13 loci across the HLA class II region; the HLA-DQB1 locus (encoding the major histocompatibility complex class II, DQ beta chain 1) had the strongest association (P=1.78x10(-19); odds ratio for patients vs. controls, 1.75). Primary biliary cirrhosis was also significantly and reproducibly associated with two SNPs at the IL12A locus (encoding interleukin-12alpha), rs6441286 (P=2.42x10(-14); odds ratio, 1.54) and rs574808 (P=1.88x10(-13); odds ratio, 1.54), and one SNP at the IL12RB2 locus (encoding interleukin-12 receptor beta2), rs3790567 (P=2.76x10(-11); odds ratio, 1.51). Fine-mapping analysis showed that a five-allele haplotype in the 3' flank of IL12A was significantly associated with primary biliary cirrhosis (P=1.15x10(-34)). We found a modest genomewide association (P<5.0x10(-5)) with the risk of disease for SNPs at the STAT4 locus (encoding signal transducer and activator of transcription 4) and the CTLA4 locus (encoding cytotoxic T-lymphocyte-associated protein 4) and 10 other loci. CONCLUSIONS: Our data show significant associations between primary biliary cirrhosis and common genetic variants at the HLA class II, IL12A, and IL12RB2 loci and suggest that the interleukin-12 immunoregulatory signaling axis is relevant to the pathophysiology of primary biliary cirrhosis. (ClinicalTrials.gov number, NCT00242125.)
Subject(s)
Genes, MHC Class II , HLA-DQ Antigens/genetics , Interleukin-12 Receptor beta 2 Subunit/genetics , Interleukin-12 Subunit p35/genetics , Liver Cirrhosis, Biliary/genetics , Genetic Predisposition to Disease , Genome-Wide Association Study , Genotype , HLA Antigens/genetics , HLA-DQ beta-Chains , Humans , Interleukin-23/genetics , Polymorphism, Single Nucleotide , Receptors, Interleukin-12/geneticsABSTRACT
BACKGROUND: Total immunosuppression withdrawal (TIW) without causing rejection has been reported in stable liver recipients. The role of ursodeoxycholic acid (UDCA) and patient characteristics that predict the success of this tolerance are unclear. There are two goals, to determine: 1) whether TIW is frequently associated with rejection; and 2) whether UDCA decreases the risk of liver disease (both rejection and recurrence) after TIW. METHODS: Twenty-six liver recipients who had been free of rejection while on immunosuppressive agents for a minimum of 2 years were randomized to receive either (15 mg/kg) of UDCA (n=14) or identical placebo (n=12) followed by sequential withdrawal of their immunosuppressive regimen over several months. Endpoints were defined as biochemical and histological evidence of rejection, graft dysfunction without rejection, recurrence of pretransplant disease, or 6 months without immunosuppression and no rejection or dysfunction on repeat liver biopsy. RESULTS: Rejection occurred in 6 of 14 (43%) of the UDCA group and 9 of 12 (75%) of those receiving placebo (P=0.09). Degree of rejection was mild, moderate, and severe in 73%, 20%, and 7% of patients respectively. All responded to rescue therapy and none developed chronic rejection. Nine of the remaining 11 patients (eight of the UDCA recipients and three of controls) who did not develop rejection developed graft dysfunction which responded to reintroduction of immunosuppressive agents in each case. Disease recurrence was most common in patients with underlying immune-mediated disorders of the liver. One year after withdrawal only two patients were free of immunosuppression, 80% were able to discontinue prednisone therapy (steroid free), and 50% were able to reduce their dose of cyclosporine. Age, underlying cause of liver disease, and regimen of immunosuppression were favorable predictors. CONCLUSIONS: The results of this study suggest that TIW: 1) is frequently associated with subsequent rejection, 2) increases the risk of underlying disease recurrence, and 3) is not facilitated by UDCA use and responds properly to the reintroduction of immunosuppressive therapy.
Subject(s)
Cholagogues and Choleretics/therapeutic use , Immunosuppressive Agents/therapeutic use , Liver Transplantation/immunology , Ursodeoxycholic Acid/therapeutic use , Adult , Aged , Cyclosporine/therapeutic use , Drug Administration Schedule , Female , Follow-Up Studies , Graft Rejection/drug therapy , Graft Rejection/epidemiology , Humans , Immunosuppressive Agents/administration & dosage , Liver Diseases/surgery , Male , Middle Aged , Patient Compliance , Placebos , Prednisone/therapeutic use , SafetySubject(s)
Biopsy, Needle/methods , Liver Diseases/diagnosis , Liver/pathology , Biopsy, Needle/adverse effects , Biopsy, Needle/standards , Contraindications , Endoscopy, Gastrointestinal , Fatty Liver/pathology , Hepatitis C/pathology , Humans , Liver Cirrhosis/pathology , Liver Diseases/pathology , Practice Guidelines as TopicABSTRACT
BACKGROUND: Conventional treatment of autoimmune hepatitis consists of either prednisone alone or in combination with azathioprine. Ten to 20% of patients do not respond to or are intolerant of this treatment. Novel drug treatments include immunosuppressive drugs such as tacrolimus (TAC), mycophenolate mofetil (MMF), methotrexate and cyclosporine. We describe a multi-centre Canadian experience with MMF and TAC. OBJECTIVE: To study a multi-centre patient population who had failed conventional therapy and were treated with non-conventional medical therapy for autoimmune hepatitis and document response. METHODS: Members of the Canadian Association for the Study of Liver (CASL) obtained MMF from Hoffmann-La Roche Ltd, as part of a compassionate release program, were contacted for standardized data on patients with AIH who received MMF or TAC. Response definitions based on aminotransferase changes were: Complete response (CR)-sustained normalization, partial response (PR)-improvement by greater than 50%, non-response (NR)-less than 50% improvement and relapse (RP)-initial CR or PR followed by an increase in aminotransferases. RESULTS: A total of 16 patients were identified: six in Ontario, one in Quebec, five in Alberta and four in British Columbia. Three were treated with TAC, eleven with MMF and two with combination MMF and TAC. CR was observed in 50%, PR in 12.5%, RP in 25% and NR occurred in 12.5%. The CR for MMF without TAC was approximately 64%. CONCLUSIONS: MMF is effective and well tolerated by patients with autoimmune hepatitis who do not respond to, or are intolerant of, conventional immunosuppressive agents.
Subject(s)
Hepatitis, Autoimmune/drug therapy , Immunosuppressive Agents/therapeutic use , Mycophenolic Acid/analogs & derivatives , Tacrolimus/therapeutic use , Adult , Aged , Canada , Drug Therapy, Combination , Female , Glucocorticoids/therapeutic use , Hepatitis, Autoimmune/etiology , Hepatitis, Autoimmune/immunology , Humans , Male , Middle Aged , Mycophenolic Acid/therapeutic use , Prednisone/therapeutic use , Retrospective Studies , Secondary Prevention , Transaminases/analysis , Treatment OutcomeABSTRACT
BACKGROUND: The need for immunosuppression in autoimmune hepatitis is established. Previous studies have investigated short-term outcomes in patients who respond to treatment. This study assesses long-term prognosis of patients who fail to respond to standard immunosuppression. METHODS: 163 charts were reviewed, composed of 108 non-transplant patients and 55 patients who required liver transplantation (LT). Clinical endpoints were based on aminotransaminases: early treatment response (ER) was a 50% improvement at 6 months of therapy, Complete remission (CR) was an improvement to <2X normal, Relapse was worsening to >3X normal, Incomplete response (IR) was some response but no CR in 3 years, and No response (NR) was no improvement after 3 years. RESULTS: 85% of non-LT and 25% of LT patients achieved ER, 91% of non-LT and 26% of LT patients achieved CR. 41% of non-LT patients relapsed on maintenance treatment, and 41% of non-LT patients relapsed when withdrawn from treatment. 9% of non-LT and 58% of LT patients had IR. 16% in LT group showed NR, while all non-LT patients showed some response. All paired comparisons were statistically different (P<0.05). Multiple regression analysis revealed that lack of ER predicts need for LT (P=0.0005). 87% of patients who achieved ER did not require LT, whereas 16% of patients who failed ER showed NR and all required LT. Odds ratio of a patient who failed ER proceeding to LT, compared to a patient who achieved ER, was 16.8 (7.5 to 37.7, 95% CI). CONCLUSION: Patients who fail to show a 50% improvement in transaminases at 6 months of standard immunosuppression should be considered for alternate treatment modalities or be referred earlier for LT.
Subject(s)
Azathioprine/therapeutic use , Endpoint Determination/methods , Hepatitis, Autoimmune/diagnosis , Hepatitis, Autoimmune/drug therapy , Immunosuppressive Agents/therapeutic use , Liver Transplantation , Adult , Canada/epidemiology , Drug Therapy, Combination , Female , Hepatitis, Autoimmune/mortality , Hepatitis, Autoimmune/surgery , Humans , Male , Middle Aged , Odds Ratio , Prednisolone/therapeutic use , Prognosis , Recurrence , Remission Induction , Retrospective Studies , Survival Rate , Transaminases/analysis , Treatment OutcomeABSTRACT
Two patients, one with previously undiagnosed liver disease, presenting with right supraclavicular lymphadenopathy were subsequently diagnosed with hepatocellular carcinoma. This presentation has only been previously described once, and the mechanism of this unusual presentation is discussed.
Subject(s)
Carcinoma, Hepatocellular/complications , Liver Neoplasms/complications , Lymphatic Diseases/etiology , Aged , Carcinoma, Hepatocellular/diagnosis , Clavicle , Female , Humans , Liver Neoplasms/diagnosis , Lymphatic Metastasis , MaleABSTRACT
BACKGROUND: There is significant morbidity and mortality related to fungal infections in the solid-organ transplant population. METHODS: A prospective, randomized, double-blind, placebo-controlled, restricted sequential design trial was performed in 71 adults undergoing orthotopic liver transplantation. Patients were randomly assigned to receive either itraconazole (5.0 mg/kg orally, preoperatively, 2.5 mg/kg orally, two times a day, postoperatively) or placebo. Therapy continued for a maximum of 56 days or until patient was discharged from hospital or met a predefined endpoint. Measurements included incidence of fungal colonization, superficial or systemic fungal infections requiring systemic therapy, adverse events, and mortality rate. RESULTS: This trial design supported the superiority of itraconazole in preventing fungal infections; nine patients in the placebo group (24%; 95% confidence interval, 0.118-0.412) and one patient in the itraconazole group (4%; 95% confidence interval, 0.001-0.204) developed fungal endpoints requiring therapy with amphotericin B (P=0.04, Fisher's exact test). At the time of enrollment, fungal colonization occurred in 40% and 37% of itraconazole and placebo patients (P=0.43), respectively. Adverse events were reported by 97% and 100% of the intraconazole and placebo groups, respectively, and one itraconazole and six placebo-group patients died within the study period. There was no relation to trial medication for serious adverse events. CONCLUSION: Prophylaxis with itraconazole reduces fungal infections in patients undergoing orthotopic liver transplantation and is well tolerated.
Subject(s)
Antifungal Agents/therapeutic use , Candidiasis/prevention & control , Itraconazole/therapeutic use , Liver Transplantation/adverse effects , Mycoses/prevention & control , Administration, Oral , Adult , Antifungal Agents/administration & dosage , Candidiasis/epidemiology , Double-Blind Method , Humans , Itraconazole/administration & dosage , Liver Transplantation/mortality , Postoperative Complications/epidemiology , Postoperative Complications/microbiology , Postoperative Complications/prevention & control , Probability , Prospective Studies , Safety , Sample Size , Survival Analysis , Treatment OutcomeABSTRACT
Corticosteroid therapy contributes significant toxicity to liver transplantation. The safety and efficacy of early steroid withdrawal were determined in patients treated with either tacrolimus or microemulsion cyclosporin A (micro-CsA). The primary outcome was the proportion of patients who were steroid-free 1 year posttransplantation. From the seven Canadian adult liver transplant centers, 143 patients were randomly allocated oral treatment with either tacrolimus (n = 71) or micro-CsA (n = 72), together with corticosteroids and azathioprine. Eligibility criteria for steroid withdrawal included freedom from acute rejection for a minimum of 3 months, and prednisone =0.15 mg/kg/d. In eligible patients, the daily steroid dose was reduced by 2.5 mg each month until complete discontinuation was achieved. At 1 year after transplantation, 75% of the tacrolimus patients and 63% of the micro-CsA patients were steroid-free (P =.20). Of all of the patients who became eligible for steroid withdrawal, steroid discontinuation was achieved in over 80%. One-year patient survival was 97% with tacrolimus and 89% with micro-CsA (P =.052). Graft survival was 97% and 86%, respectively (P =.017). The overall incidence of acute rejection during the first year was 35% with tacrolimus and 43% with micro-CsA (P =.26). There was no difference in survival, acute rejection, or rate of steroid withdrawal when adjusting for hepatitis C. All acute rejection episodes experienced during steroid withdrawal were steroid-responsive. Steroid-resistant rejection occurred in 5.6% of the tacrolimus and 9.7% of the micro-CsA patients. One patient, in the micro-CsA group, experienced refractory rejection. Chronic rejection was not observed in either group. The toxicity profiles were similar. Postoperative serum creatinine levels were similar, and dialysis was required in less than 10% of patients in each group. Infectious complications were similar in both groups. Neurotoxicity was a serious adverse event in 13% and 10% of patients receiving tacrolimus and micro-CsA, respectively. Early steroid withdrawal is safe and effective after liver transplantation using either tacrolimus plus azathioprine or micro-CsA plus azathioprine immunoprophylaxis.