Relative carcinogenicity of tacrolimus vs mycophenolate after solid organ transplantation and its implications for liver transplant care

BACKGROUND De novo malignancy is a leading cause of late morbidity and mortality in liver transplant recipients.Cumulative immunosuppression has been shown to contribute to post-transplant malignancy(PTM)risk.There is emerging evidence on the differential carcinogenic risk profile of individual immunosuppressive drugs,independent of the net effect of immunosuppression.Calcineurin inhibitors such as tacrolimus may promote tumourigenesis,whereas mycophenolic acid(MPA),the active metabolite of mycophenolate mofetil,may limit tumour progression.Liver transplantation(LT)is relatively unique among solid organ transplantation in that immunosuppression monotherapy with either tacrolimus or MPA is often achievable,which makes careful consideration of the risk-benefit profile of these immunosuppression agents particularly relevant for this cohort.However,there is limited clinical data on this subject in both LT and other solid organ transplant recipients.AIM To investigate the relative carcinogenicity of tacrolimus and MPA in solid organ transplantation.METHODS A literature search was conducted using MEDLINE and Embase databases using the key terms“solid organ transplantation”,“tacrolimus”,“mycophenolic acid”,and“carcinogenicity”,in order to identify relevant articles published in English between 1st January 2002 to 11th August 2022.Related terms,synonyms and explosion of MeSH terms,Boolean operators and truncations were also utilised in the search.Reference lists of retrieved articles were also reviewed to identify any additional articles.Excluding duplicates,abstracts from 1230 records were screened by a single reviewer,whereby 31 records were reviewed in detail.Full-text articles were assessed for eligibility based on pre-specified inclusion and exclusion criteria.RESULTS A total of 6 studies were included in this review.All studies were large population registries or cohort studies,which varied in transplant era,type of organ transplanted and immunosuppression protocol used.Overall,there was no clear difference demonstrated between tacrolimus and MPA in de novo PTM risk following solid organ transplantation.Furthermore,no study provided a direct comparison of carcinogenic risk between tacrolimus and MPA monotherapy in solid organ transplantation recipients.CONCLUSION The contrasting carcinogenic risk profiles of tacrolimus and MPA demonstrated in previous experimental studies,and its application in solid organ transplantation,is yet to be confirmed in clinical studies.Thus,the optimal choice of immunosuppression drug to use as maintenance monotherapy in LT recipients is not supported by a strong evidence base and remains unclear.

Statin, aspirin and metformin use and risk of hepatocellular carcinoma related outcomes following liver transplantation: A retrospective study

BACKGROUND Liver transplantation(LT)is a potentially curative therapy for patients with hepatocellular carcinoma(HCC).HCC-recurrence following LT is associated with reduced survival.There is increasing interest in chemoprophylaxis to improve HCC-related outcomes post-LT.AIM To investigate whether there is any benefit for the use of drugs with proposed chemoprophylactic properties against HCC,and patient outcomes following LT.METHODS This was a retrospective study of adult patients who received Deceased Donor LT for HCC from 2005-2022,from a single Australian centre.Drug use was defined as statin,aspirin or metformin therapy for≥29 days,within 24 months post-LT.A cox proportional-hazards model with time-dependent covariates was used for survival analysis.Outcome measures were the composite-endpoint of HCC-recurrence and all-cause mortality,HCC-recurrence and HCC-related mortality.Sensitivity analysis was performed to account for immortality time bias and statin dosing.RESULTS Three hundred and five patients were included in this study,with 253(82.95%)males with a median age of 58.90 years.Aetiologies of liver disease were 150(49.18%)hepatitis C,73(23.93%)hepatitis B(HBV)and 33(10.82%)non-alcoholic fatty liver disease(NAFLD).56(18.36%)took statins,51(16.72%)aspirin and 50(16.39%)metformin.During a median follow-up time of 59.90 months,34(11.15%)developed HCC-recurrence,48(15.74%)died,17(5.57%)from HCC-related mortality.Statin,aspirin or metformin use was not associated with statistically significant differences in the composite endpoint of HCC-recurrence or all-cause mortality[hazard ratio(HR):1.16,95%CI:0.58-2.30;HR:1.21,95%CI:0.28-5.27;HR:0.61,95%CI:0.27-1.36],HCC-recurrence(HR:0.52,95%CI:0.20-1.35;HR:0.51,95%CI:0.14-1.93;HR 1.00,95%CI:0.37-2.72),or HCC-related mortality(HR:0.32,95%CI:0.033-3.09;HR:0.71,95%CI:0.14-3.73;HR:1.57,95%CI:0.61-4.04)respectively.Statin dosing was not associated with statist-ically significant differences in HCC-related outcomes.CONCLUSION Statin,metformin or aspirin use was not associated with improved HCC-related outcomes post-LT,in a largely historical cohort of Australian patients with a low proportion of NAFLD.Further prospective,multicentre studies are required to clarify any potential benefit of these drugs to improve HCC-related outcomes.

Intrahepatic cholestasis of pregnancy:When should you look further?

Pruritis with abnormal liver function tests is the classical presentation of intrahepatic cholestasis of pregnancy(ICP),a condition associated with significant fetal complications.Although the etiology of ICP is unclear in many cases,certain features of the clinical presentation should alert the practitioner to the possibility of an underlying metabolic defect, which may not only affect subsequent pregnancies, but may be an indicator of more serious subsequent liver disease.We report a kindred of Anglo-Celtic descent,among whom many members present with ICP,gallstones or cholestasis related to use of oral contraception.Genetic studies revealed a novel mutation in the ABCB4 gene,which codes for a phospholipid transport protein.The clinical significance of this mutation and the importance of identifying such patients are discussed.

Clinical outcomes of patients with two small hepatocellular carcinomas

BACKGROUND Management of single small hepatocellular carcinoma(HCC)is straightforward with curative outcomes achieved by locoregional therapy or resection.Liver transplantation is often considered for multiple small or single large HCC.Management of two small HCC whether presenting synchronously or sequentially is less clear.AIM To define the outcomes of patients presenting with two small HCC.METHODS Retrospective review of HCC databases from multiple institutions of patients with either two synchronous or sequential HCC≤3 cm between January 2000 and March 2018.Primary outcomes were overall survival(OS)and transplant-free survival(TFS).RESULTS 104 patients were identified(male n=89).Median age was 63 years(interquartile range 58-67.75)and the most common aetiology of liver disease was hepatitis C(40.4%).59(56.7%)had synchronous HCC and 45(43.3%)had sequential.36 patients died(34.6%)and 25 were transplanted(24.0%).1,3 and 5-year OS was 93.0%,66.1% and 62.3% and 5-year post-transplant survival was 95.8%.1,3 and 5-year TFS was 82.1%,45.85% and 37.8%.When synchronous and sequential groups were compared,OS(1,3 and 5 year synchronous 91.3%,63.8%,61.1%,sequential 95.3%,69.5%,64.6%,P=0.41)was similar but TFS was higher in the sequential group(1,3 and 5 year synchronous 68.5%,37.3% and 29.7%,sequential 93.2%,56.6%,48.5%,P=0.02)though this difference did not remain during multivariate analysis.CONCLUSION TFS in patients presenting with two HCC≤3 cm is poor regardless of the timing of the second tumor.All patients presenting with two small HCC should be considered for transplantation.