Reuse of liver grafts following the brain death of the initial recipient.

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.

Genome-wide meta-analyses identify three loci associated with primary biliary cirrhosis.

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).

Primary biliary cirrhosis associated with HLA, IL12A, and IL12RB2 variants.

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.)

Randomized controlled trial of total immunosuppression withdrawal in liver transplant recipients: role of ursodeoxycholic acid.

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.

Transplant immunosuppressive agents in non-transplant chronic autoimmune hepatitis: the Canadian association for the study of liver (CASL) experience with mycophenolate mofetil and tacrolimus.

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.

Hepatocellular carcinoma presenting as right supraclavicular lymphadenopathy.

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.