Liver transplantation and non-alcoholic fatty liver disease

Non-alcoholic fatty liver disease(NAFLD) is an important health problem worldwide. NAFLD encompasses a histological spectrum ranging from bland liver steatosis to severe steatohepatitis(nonalcoholic steatohepatitis, NASH) with the potential of progressing to cirrhosis and its associated morbidity and mortality. NAFLD is thought to be the hepatic manifestation of insulin resistance(or the metabolic syndrome); its prevalence is increasing worldwide in parallel with the obesity epidemic. In many developed countries, NAFLD is the most common cause of liver disease and NASH related cirrhosis is currently the third most common indication for liver transplantation. NASH related cirrhosis is anticipated to become the leading indication for liver transplantation within the next one or two decades. In this review, we discuss how liver transplantation is affected by NAFLD, specifically the following:(1) the increasing need for liver transplantation due to NASH;(2) the impact of the increasing prevalence of NAFLD in the general population on the quality of deceased and live donor livers available for transplantation;(3) the long term graft and patient outcomes after liver transplantation forNASH,and finally;and(4)the de novo occurrence of NAFLD/NASH after liver transplantation and its impact on graft and patient outcomes.

Links between donor macrosteatosis,interleukin-33 and complement after liver transplantation

BACKGROUND As prevalence of nonalcoholic fatty liver disease increases in the population,livers with steatosis will continue to infiltrate the donor pool.Safe utilization of these extended criteria grafts is paramount given the increased risk associated with their use in transplantation.Prognostic factors that can predict liver dysfunction immediately after transplantation with macrosteatotic grafts are lacking.AIM To understand the relationship between interleukin-33(IL-33)and complement in recipients immediately following liver reperfusion as a marker of liver dysfunction.METHODS Cohort consisted of patients who received a liver transplant from September 2016–September 2019 at our institution.Clinical variables were retrospectively extracted from the electronic medical record.Back-table donor biopsies were obtained with donor steatosis percentage retrospectively determined by a boardcertified pathologist.Blood samples were available immediately following liver transplantation.Quantification of plasma IL-33 and complement proteins,C3a and C5a,were determined by enzyme-linked immunosorbent assay.For mRNA expression,RNA was extracted from donor biopsies and used against a 780 gene panel.RESULTS Cohort consisted of 99 donor and recipients.Donor median age was 45 years and 55%male.Recipients had a median age of 59 years with 62%male.The main etiologies were alcoholic hepatitis,nonalcoholic steatohepatitis,and hepatocellular carcinoma.Median MELD-Na at transplant was 21.Donors were grouped based on moderate macrosteatosis(≥30%).Recipients implanted with moderate macrosteatotic grafts had significantly higher peak alanine aminotransferase/aspartate aminotransferase(P<0.001 and P<0.004),and increased incidence of early allograft dysfunction(60%compared to 18%).Circulating IL-33 levels were significantly elevated in recipients of≥30%macrosteatotic grafts(P<0.05).Recipients with detectable levels of circulating IL-33 immediately following reperfusion had significantly higher alanine aminotransferase/aspartate aminotransferase(P<0.05 and P<0.01).Activated complement(C3a and C5a)were elevated in recipients implanted with moderate macrosteatotic grafts.RNA expression analysis of donor biopsies revealed moderate steatotic grafts upregulated genes inflammatory processes while downregulated hepatocyte-produced complement factors.CONCLUSION Circulating IL-33 and activated complement levels immediately following liver reperfusion in recipients of moderate macrosteatotic grafts may identify which patients are at risk of early allograft dysfunction.

Evaluation of the updated definition of early allograft dysfunction in donation after brain death and donation after cardiac death liver allografts

BACKGROUND:An updated definition of early allograft dysfunction(EAD) was recently validated in a multicenter study of 300 deceased donor liver transplant recipients.This analysis did not differentiate between donation after brain death(DBD) and donation after cardiac death(DCD) allograft recipients.METHODS:We reviewed our prospectively entered database for all DBD(n=377) and DCD(n=38) liver transplantations between January 1,2006 and October 30,2011.The incidence of EAD as well as its ability to predict graft failure and survival was compared between DBD and DCD groups.RESULTS:EAD was a valid predictor of both graft and patient survival at six months in DBD allograft recipients,but in DCD allograft recipients there was no significant difference in the rate of graft failure in those with EAD(11.5%) compared with those without EAD(16.7%)(P=0.664) or in the rate of death in recipients with EAD(3.8%) compared with those without EAD(8.3%)(P=0.565).The graft failure rate in the first 6 months in those with international normalized ratio ≥1.6 on day 7 who received a DCD allograft was 37.5% compared with 6.7% for those with international normalized ratio <1.6 on day 7(P=0.022).CONCLUSIONS:The recently validated definition of EAD is a valid predictor of patient and graft survival in recipients of DBD allografts.On initial assessment,it does not appear to be a useful predictor of patient and graft survival in recipients of DCD allografts,however a study with a larger sample size of DCD allografts is needed to confirm these findings.The high ALT/AST levels in most recipients of DCD livers as well as the predisposition to biliary complications and early cholestasis make these parameters as poor predictors of graft failure.An alternative definition of EAD that gives greater weight to the INR on day 7 may be more relevant in this population.

Implication of the intestinal microbiome in complications of cirrhosis

The intestinal microbiome(IM) is altered in patients with cirrhosis,and emerging literature suggests that this impacts on the development of complications.The Pub Med database was searched from January 2000 to May 2015 for studies and review articles on the composition,pathophysiologic effects and therapeutic modulation of the IM in cirrhosis.The following combination of relevant text words and MeS H terms were used,namely intestinal microbiome,microbiota,or dysbiosis,and cirrhosis,encephalopathy,spontaneous bacterial peritonitis,hepatorenal syndrome,variceal bleeding,hepatopulmonary syndrome,portopulmonary hypertension and hepatocellular carcinoma.The search results were evaluated for pertinence to the subject of IM and cirrhosis,as well as for quality of study design.The IM in cirrhosis is characterized by a decreased proportion of Bacteroides and Lactobacilli,and an increased proportion of Enterobacteriaceae compared to healthy controls.Except for alcoholic cirrhosis,the composition of the IM in cirrhosis is not affected by the etiology of the liver disease.The percentage of Enterobacteriaceae increases with worsening liver disease severity and decompensation and is associated with bacteremia,spontaneous bacterial peritonitis and hepatic encephalopathy.Lactulose,rifaximin and Lactobacillus-containing probiotics have been shown to partial y reverse the cirrhosis associated enteric dysbiosis,in conjunction with improvement in encephalopathy.The IM is altered in cirrhosis,and this may contribute to the development of complications associated with end-stage liver disease.Therapies such as lactulose,rifaximin and probiotics may,at least partially,reverse the cirrhosisassociated changes in the IM.This,in turn,may prevent or alleviate the severity of complications.

A comparison of survival and pathologic features of non-alcoholic steatohepatitis and hepatitis C virus patients with hepatocellular carcinoma

AIM:To compare the clinical outcome and pathologic features of non-alcoholic steatohepatitis(NASH) patients with hepatocellular carcinoma(HCC) and hepatitic C virus(HCV) patients with HCC(another group in which HCC is commonly seen) undergoing liver transplantation.METHODS:Patients transplanted for HCV and NASH at our institution from January 2000 to April 2011 were analyzed.All explanted liver histology and pre-transplant liver biopsies were examined by two specialist liver histopathologists.Patient demographics,disease free survival,explant liver characteristics and HCC features(tumour number,cumulative tumour size,vascular invasion and differentiation) were compared between HCV and NASH liver transplant recipients.RESULTS:A total of 102 patients with NASH and 283 patients with HCV were transplanted.The incidence of HCC in NASH transplant recipients was 16.7%(17/102).The incidence of HCC in HCV transplant recipients was 22.6%(64/283).Patients with NASH-HCC were statistically older than HCV-HCC patients(P < 0.001).A significantly higher proportion of HCV-HCC patients had vascular invasion(23.4% vs 6.4%,P = 0.002) and poorly differentiated HCC(4.7% vs 0%,P < 0.001) compared to the NASH-HCC group.A trend of poorer recurrence free survival at 5 years was seen in HCV-HCC patients compared to NASH-HCC who underwent a Liver transplantation(P = 0.11).CONCLUSION:Patients transplanted for NASH-HCC appear to have less aggressive tumour features compared to those with HCV-HCC,which likely in part accounts for their improved recurrence free survival.

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 transplanta-tion 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.

Liver transplantation for unresectable colorectal metastasis:a new hope

Despite recent advances in medical and surgical treatments,surgical resection remains the only curative option for patients with colorectal liver metastasis(CRLM).Unfortunately,only a minority of patients with CRLM are candidates for liver resection.The 5-year survival of patients with liver-only disease and deemed unresectable is difficult to quantify but likely ranges around 5 to 10%.Since 2013,a few studies have shown that liver transplantation(LT)is feasible for selected patients with unresectable CRLM(1,2).Recently,the Oslo University Hospital LT group has published their latest results with modified selection criteria and should be congratulated for their efforts.Nevertheless,the evidence available is still developing.For example,currently,there is a lack of robust evidence supporting the widespread use of LT for CRLM outside Norway,a particular region in terms of graft scarcity.

Prognostic risk scores for liver transplantation: game changers or statistical artworks?

Several prognostic liver transplant-related risk scores for hepatocellular carcinoma(HCC)have been developed in recent years.The most prominent scores,displayed in Table 1,are based exclusively on HCC-related variables(1-6).Given that non-HCC-related variables can also influence post-transplant outcomes,Goldberg et al.sought to develop a continuous risk score predicting post-transplant survival for patients using both HCC-and non-HCC-related variables(1).