An ‘alcohol contract’ has no significant effect on return to drinking after liver transplantation for alcoholic liver disease

Return to drinking after liver transplantation for alcoholic liver disease (ALD) remains a source of unease with varying reported rates of return to drinking and impact this has on graft function. In 2005, the UK Transplant liver advisory group recommended an ‘alcohol contract’ in which ALD patients listed for transplantation confirmed in writing their commitment to abstinence. We aimed to measure the rates and consequences of return to drinking alcohol in a UK transplant programme and assess the effect of the ‘alcohol contract’. Consecutive patients transplanted for ALD during 1996–2011 were included. Every patient listed after Feb 2007 signed up to the ‘alcohol contract’. We compared rates and pattern of return to drinking and survival before and after the introduction of the contract. Overall, 52 (37%) patients returned to drinking alcohol; 37 (39%) before and 15 (34%) after the contract. There was no significant difference in the rate of return or pattern of drinking. Median survival was 176 months (145–207 95% CI). There was no significant difference in survival, mortality rates, or in the causes of death in either group. We report high rates of return to drinking alcohol in a UK liver transplant programme. Despite this, the impact on patient and graft survival is low. There is no evidence that an ‘alcohol contract’ has had any effect on alcohol consumption.     

Are preoperative patterns of alcohol consumption predictive of relapse after liver transplantation for alcoholic liver disease?

Predictive factors for alcoholic relapse after liver transplantation (LT) performed for alcoholic liver disease (ALD) have been assessed in numerous studies, often with contradictory results. The aim of the study was to assess pretransplantation alcohol consumption characteristics on alcoholic relapse after LT. Patients transplanted for ALD for at least 6 months were included. An anonymous questionnaire assessed socio-demographic characteristics, medical history, and alcohol consumption before and after LT. Relapse was defined as any alcohol use after LT. Severe relapse was defined by heavy drinking: more than 21 units/week for males and 14 units/week for females. A total of 61 patients were studied. The mean follow up after LT was 49 +/- 34 months. Alcoholic relapse occurred in 32 of 61 patients (52%) and severe relapse in eight of 61 patients (13%). Risk factors for severe relapse were: length of abstinence before LT (P = 0.0001), more than one alcohol withdrawal before LT (P = 0.001), alcohol dependence (P = 0.05), alcohol abuse in first relatives (P = 0.05), and younger age (P = 0.05). Information on previous alcohol consumption (dependence, number of withdrawals, family history) helps to predict severe relapse after LT in patients with ALD, allowing early awareness and specific postoperative care.     

Improved detection of alcohol consumption using the novel marker phosphatidylethanol in the transplant setting: results of a prospective study

Phosphatidylethanol (PEth) is a new, highly specific alcohol marker. The aim of this study was to assess its diagnostic value in the liver transplant setting. In 51 pre‐ and 61 post‐transplant patients with underlying alcoholic liver disease PEth, ethanol, methanol, carbohydrate‐deficient transferrin (CDT), and ethyl glucuronide in urine (uEtG) and hair (hEtG) were tested and compared with patients’ questionnaire reports. Twenty‐eight (25%) patients tested positive for at least one alcohol marker. PEth alone revealed alcohol consumption in 18% of patients. With respect to detection of alcohol intake in the preceding week, PEth showed a 100% sensitivity. PEth testing was more sensitive than the determination of ethanol, methanol, CDT or uEtG alone [sensitivity 25% (confidence interval (CI) 95%, 7–52%), 25% (7–52%), 21% (6–45%) and 71% (41–91%), respectively], or ethanol, methanol and uEtG taken in combination with 73% (45–92%). Specificity of all markers was 92% or higher. Additional testing of hEtG revealed alcohol consumption in seven patients, not being positive for any other marker. Phosphatidylethanol was a highly specific and sensitive marker for detection of recent alcohol consumption in pre‐ and post‐transplant patients. The additional determination of hEtG was useful in disclosing alcohol consumption 3–6 months retrospectively.     

Negative outcomes after liver transplantation in patients with alcoholic liver disease beyond the fifth post‐transplant year

Although up to 50% of patients with alcoholic liver disease (ALD) resume alcohol consumption after liver transplantation (LT), numerous studies indicate that long‐term results are not compromised. This study focused on evaluating the impact of ALD on outcomes up to and beyond the fifth year after LT. Among the 432 primary LT recipients included in this study, 97 underwent transplantation for ALD. Alcohol relapse rate at 10 yr was 33.5%, with younger recipient age being the only independent predictor (p = 0.019). Survival of patients with ALD (77.0%) was similar to those without (79.0%) up to the fifth post‐transplant year (p = 0.655) but worse during the five subsequent years among the five‐yr survivors (70.6% vs. 92.9%; p = 0.002). ALD was an independent risk factor for poorer survival beyond the fifth post‐transplant year (p = 0.049), but not earlier (p = 0.717). Conversely, alcohol relapse increased the risk of death only during the first five post‐transplant years (p = 0.039). There were no significant differences regarding graft failure incidence between ALD and non‐ALD recipients up to the fifth post‐transplant year (7.3% vs. 11.6%; p = 0.255) and beyond (12.9% vs. 5.0%; p = 0.126). In conclusion, pre‐transplant diagnosis of ALD yields negative effects on post‐transplant outcomes beyond the fifth post‐transplant year, not attributable to recidivism.     

Combined liver–kidney transplantation versus liver transplant alone based on KDIGO stratification of estimated glomerular filtration rate: data from the United Kingdom Transplant registry – a retrospective cohort study

Patient selection for combined liver–kidney transplantation (CLKT) is a current issue on the background of organ shortage. This study aimed to compare outcomes and post‐transplant renal function for patients receiving CLKT and liver transplantation alone (LTA) based on native renal function using estimated glomerular filtration rate (eGFR) stratification. Using the UK National transplant database (NHSBT) 6035 patients receiving a LTA (N = 5912; 98%) or CLKT (N = 123; 2%) [2001–2013] were analysed, and stratified by KDIGO stages of eGFR at transplant (eGFR group‐strata). There was no difference in patient/graft survival between LTA and CLKT in eGFR group‐strata (P > 0.05). Of 377 patients undergoing renal replacement therapy (RRT) at time of transplantation, 305 (81%) and 72 (19%) patients received LTA and CLKT respectively. A significantly greater proportion of CLKT patients had severe end‐stage renal disease (eGFR < 30 ml/min/1.73 m²) at 1 year post‐transplant compared to LTA (9.5% vs. 5.7%, P = 0.001). Patient and graft survival benefit for patients on RRT at transplantation was favouring CLKT versus LTA (P = 0.038 and P = 0.018, respectively) but the renal function of the long‐term survivors was not superior following CLKT. The data does not support CLKT approach based on eGFR alone, and the advantage of CLKT appear to benefit only those who are on established RRT at the time of transplant.     

Expanded living‐donor liver transplantation criteria for patients with hepatocellular carcinoma based on the Japanese nationwide survey: the 5‐5‐500 rule ‐ a retrospective study

Expansion of the liver transplantation indication criteria for patients with hepatocellular carcinoma (HCC) has long been debated. Here we propose new, expanded living‐donor liver transplantation (LDLT) criteria for HCC patients based on a retrospective data analysis of the Japanese nationwide survey. A total of 965 HCC patients undergoing LDLT were included, 301 (31%) of whom were beyond the Milan criteria. Here, we applied the Greenwood formula to investigate new criteria enabling the maximal enrollment of candidates while securing a 5‐year recurrence rate (95% upper confidence limit) below 10% by examining various combinations of tumor numbers and serum alpha‐fetoprotein values, and maintaining the maximal nodule diameter at 5 cm. Finally, new expanded criteria for LDLT candidates with HCC, the 5‐5‐500 rule (nodule size ≤5 cm in diameter, nodule number ≤5, and alfa‐fetoprotein value ≤500 ng/ml), were established as a new regulation with a 95% confidence interval of a 5‐year recurrence rate of 7.3% (5.2–9.3) and a 19% increase in the number of eligible patients. In addition, the 5‐5‐500 rule could identify patients at high risk of recurrence, among those within and beyond the Milan criteria. In conclusion, the new criteria – the 5‐5‐500 rule – might provide rational expansion for LDLT candidates with HCC.     

Intra‐operative cardiac arrests during liver transplantation – a retrospective review of the first 15 yr in Asian population

Although many report intra‐operative cardiac arrests (ICAs) in liver transplantation (LT), the incidence, major causes, and outcome remain unclear. We aimed to investigate retrospectively, the incidence, nature, and outcome of ICA in Asian population and to identify risk factors for ICA. Consecutive 1071 LTs in an institution during 1996–2011 (adult 920, pediatric 151/living donor liver transplantation, LDLT 841, deceased donor liver transplantation, DDLT 230) were reviewed. ICA occurred in 14 adult LTs (1.5%), but none in pediatrics. ICA occurred 1.0% and 3.3% in LDLT and DDLT, respectively. Stages of ICA incidence were three at pre‐anhepatic, one at anhepatic, and 10 at neohepatic stage. Post‐reperfusion syndrome (PRS) with hyperkalemia and bleeding were the major causes of ICA. While LDLT showed miscellaneous causes for ICA at various stages, DDLT incurred ICAs at neohepatic stage only. Interestingly, we did not find pulmonary thromboembolism (PTE) to incur ICA. Risk factor analysis showed no association of pre‐operative patient condition, donor types, and intra‐operative parameters. In this review, the incidence of ICA was low in Asian population with LDLT predominance, and while PTE was not the cause of ICA, the neohepatic stage with PRS and bleeding was the most vulnerable period to anticipate ICA.     

Downstaging prior to liver transplantation for hepatocellular carcinoma: advisable but at the price of an increased risk of cancer recurrence – a retrospective study

The use of downstaging prior to liver transplantation for hepatocellular carcinoma (HCC) still needs refinement. This study included patients with HCC listed for transplantation according to the Total Tumour Volume (TTV) ≤115 cm³ and alpha fetoprotein (AFP) ≤400 ng/ml criteria, with and without previous downstaging. Overall, 455 patients were listed, and 286 transplanted. Post‐transplant follow‐up was 38.5 ± 1.7 months. Patients downstaged to TTV115/AFP400 (n = 29) demonstrated similar disease‐free survivals (DFS, 74% vs. 80% at 5 years, P = 0.949), but a trend to more recurrences (14% vs. 5.8%, P = 0.10) than those always within TTV115/AFP400 (n = 257). Similarly, patients downstaged to Milan criteria (n = 80) demonstrated similar DFS (76% vs. 86% at 5 years, P = 0.258), but more recurrences (11% vs. 1.7%, P = 0.001) than those always within Milan (n = 177). Among patients downstaged to Milan, those originally beyond TTV115/AFP400 (n = 27) had similar outcomes as those originally beyond Milan, but within TTV115/AFP400 (n = 53). However, the likelihood of being within Milan at transplant was lower for patients with more advanced original HCCs (P < 0.0001). Overall, despite an expected increase in post‐transplant HCC recurrence, similar survivals can be achieved with and without downstaging, using the TTV115/AFP400 transplantation criteria, and including patients with advanced original HCCs. Downstaging should continue to be performed.     

Steroid‐free living donor liver transplantation for HCV – a multicenter prospective cohort study in Japan

This prospective, non‐randomized, multicenter cohort study analyzed the safety and efficacy of a steroid‐free immunosuppressive (IS) protocol for hepatitis C virus (HCV)‐positive living donor liver transplant (LDLT) recipients in Japan. Of 68 patients enrolled from 13 transplant centers, 56 fulfilled the inclusion/exclusion criteria; 27 were assigned the steroid‐free IS protocol (Fr group) and 29 the traditional steroid‐containing IS protocol (St group). Serum HCV RNA levels increased over time and were higher in the St group until postoperative day 90 (POD 14, p = 0.013). Preemptive anti‐HCV therapy was started in a higher percentage of recipients (59.3%) in the Fr group than in the St group (31.0%, p = 0.031), mainly due to early HCV recurrence. The incidence of HCV recurrence at one yr was lower in the Fr group (22.2%) than in the St group (41.4%; p = 0.066). The incidence of acute cellular rejection was similar between groups. New onset diabetes after transplant, cytomegalovirus infection, and renal dysfunction were significantly less frequent in the Fr group than in the St group (p = 0.022, p < 0.0001, p = 0.012, respectively). The steroid‐free IS protocol safely reduced postoperative morbidity and effectively suppressed both the HCV viral load in the early post‐transplant period and HCV recurrence in HCV‐positive LDLT recipients.     

Transplant oncology: assessment of response and tolerance to systemic chemotherapy for metastatic colorectal cancer after liver transplantation – a retrospective study

Solid organ recipients have a 2–5 fold increased risk of malignancy compared to the general population. Because of the broader indications for transplantation, it is anticipated that an increasing number of organ graft recipients will present with malignancy. There are limited data about responses and tolerance to chemotherapy in solid organ transplanted patients. Twenty‐three of 46 colorectal cancer (CRC) patients with nonresectable liver metastases who had undergone liver transplantation (LT) in three different studies were included. All patients had received chemotherapy both prior to LT and after LT, at recurrence of metastatic CRC (mCRC). Adverse reactions (grades 3–4) and clinical and radiological outcome were retrospectively registered. Overall survival was determined from start of palliative chemotherapy after LT. No graft rejection was observed. Chemotherapy for mCRC was overall well‐tolerated and there was no increased bone marrow toxicity registered after LT; however, mucositis and diarrhea were more frequent in post‐LT chemotherapy. Median overall survival from start of palliative chemotherapy after LT was 13 months. No graft loss was observed when chemotherapy for mCRC was given to LT recipients who had developed nonresectable metastases. Overall, the chemotherapy for mCRC was well‐tolerated, induced responses, and long‐term survival was obtained in some patients.     

A staged approach for a lung–liver transplant patient using ex vivo reconditioned lungs first followed by an urgent liver transplantation

Combined lung–liver transplantation is a logistically challenging procedure hampered by shortage of organ donors. We describe the case of a young patient with end‐stage lung disease due to of cystic fibrosis and liver cirrhosis who needed combined lung–liver transplantation. The long waiting for this caused an interesting clinical dilemma. We decided to change our policy in this situation by listing him only for the lung transplantation and to apply for a high urgent liver transplantation if the liver failed after the lung transplantation. This strategy enabled us to use lungs treated with ex vivo lung perfusion (EVLP) from an unsuitable donor after circulatory death. After conditioning for 4 h via EVLP, the pO₂ was 59.7 kPa. The lungs were transplanted successfully. He developed an acute‐on‐chronic liver failure for which he received a successful liver transplantation 19 days after the lung transplantation.     

Multicentric evaluation of model for end‐stage liver disease‐based allocation and survival after liver transplantation in Germany – limitations of the ‘sickest first’‐concept

Since the introduction of model for end‐stage liver disease (MELD) in 2006, post‐orthotopic liver transplantation (OLT) survival in Germany has declined. The aim of this study was to evaluate risk factors and prognostic scores for outcome. All adult OLT recipients in seven German transplant centers after MELD implementation (December 2006–December 2007) were included. Recipient data were analyzed for their influence on 1‐year outcome. A total of 462 patients (mean calculated MELD = 20.5, follow‐up: 1 year) were transplanted for alcoholic cirrhosis (33.1%), hepatocellular carcinoma (26.6%), Hepatitis‐C (17.1%), Hepatitis‐B (9.5%), primary sclerosing cholangitis (5.6%) and late graft‐failure after first OLT before December 2006 (8.7%). 1‐year patient survival was 75.8% (graft survival 71.2%) correlating with MELD parameters and serum choline esterase. MELD score >30 [odds ratio (OR) = 4.17, confidence interval: 2.57–6.78, 12‐month survival = 52.6%, c‐statistic = 0.669], hyponatremia (OR = 2.07), and pre‐OLT hemodialysis (OR = 2.35) were the main death risk factors. In alcoholic cirrhosis (n = 153, mean MELD = 21.1) and hepatocellular carcinoma (n = 123, mean MELD = 13.5), serum bilirubin and the survival after liver transplantation score were independent outcome parameters, respectively. MELD >30 currently represents a major risk factor for outcome. Risk factors differ in individual patient subgroups. In the current German practice of organ allocation to sicker patients, outcome prediction should be considered to prevent results below acceptable standards.     

Pre‐operative trans‐catheter arterial chemo‐embolization increases hepatic artery thrombosis after liver transplantation – a retrospective study

Little is known about nonsurgical risk factors for hepatic artery thrombosis (HAT ) after liver transplantation (LT ). We determined risk factors for HAT occurring within 90 days post‐LT and analysed the effect of HAT on graft and patient survival. Donor and recipient demographics, surgery‐related data and outcome in transplants complicated by thrombosis (HAT +) and their matched controls (HAT ?) were compared. Risk factors were assessed by univariate logistic regression. Median (IQR ) is given. A total of 25 HAT occurred among 1035 adult LT (1/1997–12/2014) and 50 controls were manually matched. Donor and recipient demographics were similar. Pre‐LT trans‐catheter arterial chemo‐embolization (TACE ) was more frequent in HAT + (HAT + 20% vs. HAT ? 4%, P = 0.037). HAT + had longer implantation [HAT + 88 min (76–108) vs. HAT ? 77 min (66–93), P = 0.028] and surgery times [HAT + 6.25 h (5.18–7.47) vs. HAT ? 5.25 h (4.33–6.5), P = 0.001]. Early graft dysfunction and sepsis were more frequent in HAT + and hospitalization longer. TACE had the greatest odds ratio in unadjusted analysis (OR : 6, 95% CI : 1.07–33.53, P = 0.03). All but seven grafts were lost after HAT (HAT + 72% vs. HAT ? 36%, P = 0.003); however, patient survival was unaffected (HAT + 79.8% vs. HAT ? 76%, P = 0.75). LT candidates undergoing TACE are at risk of developing HAT early after transplant.     

Improved survival outcomes in patients with non‐alcoholic steatohepatitis and alcoholic liver disease following liver transplantation: an analysis of 2002–2012 United Network for Organ Sharing data

There is an increasing trend of patients with hepatocellular carcinoma (HCC) and non‐alcoholic fatty liver disease undergoing liver transplantation in the US. Our study utilized data from the 2002 to 2012 United Network for Organ Sharing registry to evaluate model for end‐stage liver disease era trends in US liver transplantations focused on patients with non‐alcoholic steatohepatitis (NASH), hepatitis C (HCV), alcoholic liver disease (ALD), and HCC. Survival outcomes were stratified by liver disease etiology and compared across time periods using Kaplan–Meier and Cox proportional hazards models. Patients with NASH were more likely to be women, had higher body mass index (BMI), and had higher prevalence of diabetes and cardiac disease. However, overall long‐term survival was significantly higher in patients with NASH and ALD (p < 0.001). Compared to HCV, patients with NASH had significantly higher post‐transplantation survival (HR 0.69, 95% CI 0.63–0.77), and lower risk of graft failure (HR 0.76, 95% CI 0.69–0.83). Despite having higher BMI and higher prevalence of diabetes and cardiac disease, patients with NASH had better post‐liver transplantation survival compared to patients with HCV or HCC. Patients with ALD also had superior survival outcomes. However, these survival differences were limited to patients without HCC that underwent liver transplantation.