Liver transplant selection criteria and outcomes in critically ill patients with ACLF.

Background & Aims: Retrospective studies have reported good results with liver transplantation (LTx) for acute-on-chronic liver failure (ACLF) in selected patients. The aim of this study was to evaluate the selection process for LTx in patients with ACLF admitted to the intensive care unit (ICU) and to assess outcomes. Methods: This prospective, non-interventional, single high-volume center study collected data on patients with ACLF admitted to the ICU between 2017-2020. Results: Among 200 patients (mean age: 55.0 ± 11.2 years and 74% male), 96 patients (48%) were considered potential candidates for LTx. Unfavourable addictology criteria (n = 76) was the main reason for LTx ineligibility. Overall, 69 patients were listed for LTx (34.5%) and 50 were transplanted (25% of the whole population). The 1-year survival in the LTx group was significantly higher than in the non-transplanted group (94% vs. 15%, p <0.0001). Among patients eligible for LTx, mechanical ventilation during the first 7 days of ICU stay and an increase in the number of organ failures at day 3 were associated with the absence of LTx or death (odds ratio 9.58; 95% CI 3.29-27.89; p <0.0001 for mechanical ventilation and odds ratio 1.87; 95% CI 1.08-3.24; p <0.027 for increasing organ failures). The probability of not being transplanted in patients with ACLF under mechanical ventilation is >85.4% in those experiencing an increase of 2 organ failures since admission or >91% if experiencing an increase >2 organ failures, at which point futility could be considered. Conclusion: This prospective analysis of outcomes of patients with ACLF admitted to the ICU highlights the drastic nature of selection in this setting. Unfavourable addictology criteria, mechanical ventilation and increasing number of organ failures since admission were predictive of absence of LTx, futility and death. Impact and implications: Liver transplantation (LT) is the best therapeutic option in selected cirrhotic patients admitted to the ICU with acute on chronic liver failure. However, the selection criteria are poorly described and based on retrospective studies. This is the first prospective study that aimed to describe the selection process for LT in a transplant center. Patients with ACLF should be admitted to the ICU and evaluated within a short period of time for LT. In the context of organ shortage, eligibility for LT and either absence of LT, futility of care or death are better clarified in our study. These are mainly determined by prolonged respiratory failure and worsening of organ failures since ICU admission. Considering worldwide variations in the etiology and definition of ACLF, transplant availability and a narrow therapeutic window for transplant further prospective studies are awaited.

A Low Daily Intake of Simple Sugars in the Diet Is Associated with Improved Liver Function in Cirrhotic Liver Transplant Candidates.

(1) Background: We investigated, for the first time, whether dietary simple sugar intake affects MELD score changes over time in a cohort of cirrhotic liver transplant candidates. (2) Methods: the MELD score, dietary habits using a 3-day food diary, and visceral adipose tissue index (VATI) measured with CT scan were assessed in 80 consecutive outpatient cirrhotic patients at baseline, after counseling to follow current nutritional guidelines. The MELD score was reassessed after six months and the DELTA-MELD was calculated as the MELD at the second assessment minus the MELD at baseline. (3) Results: Compared with the baseline, the MELD score of cirrhotic patients at the end of the study was decreased, stable, or increased in 36%, 8% and 56% of patients, respectively. In separate multiple linear regression models, DELTA-MELD was positively and independently correlated with the daily intake of simple sugars expressed in g/kg body weight (p = 0.01) or as a percentage of total caloric intake (p = 0.0004) and with the number of daily portions of fruit, added sugar, jam, and honey (p = 0.003). These associations were present almost exclusively in patients with VATI above the median value. (4) Conclusions: In cirrhotic patients with high amounts of visceral adipose tissue the consumption of simple sugars and fructose should be limited to improve their clinical outcome.

Advanced epithelioid hemangioendothelioma of the liver: could lenvatinib offer a bridge treatment to liver transplantation?

In this article, we describe the case of a 34-year-old woman presenting a multifocal and metastatic epithelioid hemangioendothelioma (HEHE) of the liver. Under classical chemotherapy using cyclophosphamide, there was a fast tumor progression in liver and extra-hepatic metastatic sites (lungs and mediastinal lymph node). Taking into account the patient's age and the natural history of the HEHE, our goal was to try to bring her to liver transplantation (LT) and lenvatinib was an acceptable candidate for this reason. Shortly after the initiation of lenvatinib before LT and surgery, we observed the enlargement of large devascularized necrotic areas in most of the liver HEHE masses, suggesting a good response. The patient was finally transplanted 6 months after initiation of lenvatinib treatment. Eight months after LT, progression occurred (ascites, peritoneal recurrence, and mediastinal lymph node). After restarting lenvatinib, ascites disappeared and the lymph node decreased in size, suggesting a good response, more than 1 year after her transplantation. This is the first case report to our knowledge that illustrates the benefit of lenvatinib as a neoadjuvant bridge until LT for a multifocal and metastatic HEHE. In addition, this drug has also shown a benefit in term of disease control after a late recurrence of the tumor. We suggest that lenvatinib should be proposed as a bridge to the LT for nonresectable HEHE. Moreover, this drug was also beneficial in the treatment of late recurrence after LT. The absence of pharmacologic interactions between classical immunosuppressive drugs and lenvatinib may allow its use as an early adjuvant approach when the risk of recurrence is high. The strength of our case consists in the long follow-up and the innovative message allowing changing palliative strategies into curative ones in case of advanced HEHE.

Donor Small-Droplet Macrovesicular Steatosis Affects Liver Transplant Outcome in HCV-Negative Recipients.

Background: No data are available on liver transplantation (LT) outcome and donor liver steatosis, classified as large droplet macrovesicular (Ld-MaS), small-droplet macrovesicular (Sd-MaS), and true microvesicular (MiS), taking into account the recipient Hepatitis C virus (HCV) status. Aim: We investigate the impact of allograft steatosis reclassified according to the Brunt classification on early graft function and survival after LT. Methods: We retrospectively reviewed 204 consecutive preischemia biopsies of grafts transplanted in our center during the period 2001-2011 according to recipient HCV status. Results: The median follow-up after LT was 7.5 years (range: 0.0-16.7). In negative recipients (n=122), graft loss was independently associated with graft Sd-MaS, in multivariable Cox regression models comprehending only pre-/intraoperative variables (HR=1.03, 95%CI=1.01-1.05; P=0.003) and when including indexes of early postoperative graft function (HR=1.04, 95%CI=1.02-1.06; P=0.001). Graft Sd-MaS>15% showed a risk for graft loss > 2.5-folds in both the models. Graft Sd-MaS>15% was associated with reduced graft ATP content and, only in HCV- recipients, with higher early post-LT serum AST peaks. Conclusions: In HCV-negative recipients, allografts with >15% Sd-MaS have significantly reduced graft survival and show low ATP and higher AST peaks in the immediate posttransplant period. Donors with >15% Sd-MaS have significantly higher BMI, longer ICU stays, and lower PaO2.

A two gene-based risk score predicts alcoholic cirrhosis development in males with at-risk alcohol consumption.

Background: Alcoholic cirrhosis represents 1% of all cause-of-deaths worldwide. Its incidence is higher in males and results from the combination of environmental and genetic factors. Among all the genetic determinants of alcoholic cirrhosis, the patatin-like phospholipase domain protein 3 (PNPLA3) rs738409 represents the most widely validated determinant. Recent cross-sectional studies on alcohol abusers identified transmembrane-6 superfamily member 2 (TM6SF2) rs58542926, membrane bound O-acyltransferase domain containing 7 (MBOAT7) rs641738, and cluster of differentiation 14 (CD14) rs2569190 as new genetic risk factors for alcoholic cirrhosis. We aimed to develop a gene-based risk score to predict the incidence of alcoholic cirrhosis in males with at-risk alcohol consumption. Materials and methods: A total of 416 male at-risk alcohol drinkers were retrospectively examined. The association between alcoholic cirrhosis incidence and PNPLA3, CD14, TM6SF2, and MBOAT7 variants was tested. Age at onset of at-risk alcohol consumption, age, and body mass index (BMI) were included as covariates to determine the prediction score for alcoholic cirrhosis incidence by evaluating time-dependent receiver operating characteristic curves. Results: We found that PNPLA3, CD14, and TM6SF2 were associated with alcoholic cirrhosis prevalence. PNPLA3 and CD14 were also associated with its incidence. The best predictive score formula was (age at onset of at-risk alcohol consumption × 0.1) + (number of CD14 allele T) + (number of PNPLA3 allele M) + (BMI × 0.1). A threshold of 7.27 was identified as cutoff for the predictive risk of alcoholic cirrhosis development in 36 years from the onset of at-risk alcohol consumption with 70.1% sensitivity and 78.7% specificity. Conclusion: We developed the first score for alcoholic cirrhosis prediction that combines clinical and genetic factors.

The multidisciplinary support in preventing alcohol relapse after liver transplantation: A single-center experience.

BACKGROUND AND AIM: Alcoholic liver disease (ALD) represents a frequent indication for liver transplantation (LT). Since 2004, we have adopted a program of multidisciplinary support(MS) to assist patients undergoing LT for ALD. We aimed at analyzing the relapse rate and the risk factors for relapse. The relapse rate was also compared with that of a historical group of patients who underwent transplantation. Their survival rate was also analyzed. PATIENTS AND METHODS: Consecutive patients with ALD transplanted from 2004 were included. The most important demographic, psychosocial, and clinical characteristics known to be associated with alcohol relapse were recorded. RESULTS: Sixty-nine patients underwent MS: 8.7% presented alcohol relapse. At multivariate analysis female gender (sHR 9.02, 95% CI 1.71-47.56, P = .009), alcohol withdrawal syndrome (sHR 5.89, 95% CI 1.42-24.46, P = .015) and a shorter time of MS program before LT (sHR 0.928 per month, 95% CI 0.870-0.988, P = .021) were identified as independent risk factors for relapse. The rate of alcohol relapse was significantly lower than that of the historical group who did not undergo MS (sHR 0.21, 95% CI: 0.06-0.68; P = .009). CONCLUSION: This study shows that a MS program may contribute to alcohol relapse prevention after LT in ALD patients. However, the relevance of this support needs to be confirmed by clinical trials.

Fluctuations of Estimated Glomerular Filtration Rate Outside Kidney Disease Improving Global Outcomes Diagnostic Criteria for Acute Kidney Injury in End-Stage Liver Disease Outpatients and Outcome Postliver Transplantation.

BACKGROUND: Renal dysfunction in end-stage liver disease (ESLD) results from systemic conditions that affect both liver and kidney with activation of vasoconstrictor systems. In this setting, estimated glomerular filtration rate (eGFR) may undergo variations often outside Kidney Disease Improving Global Outcomes criteria for acute kidney injury (AKI) diagnosis, whose meaning is not clear. The aim of this study was to evaluate eGFR variations in ESLD outpatients listed for liver transplant (liver Tx) and the association with post-Tx outcome. METHODS: Fifty-one patients with ESLD were retrospectively evaluated from listing to transplant (L-Tx time), intraoperatively (Tx time), and up to 5 years post-Tx time. Variations between the highest and the lowest eGFR occurring in more than 48 hours, not satisfying Kidney Disease Improving Global Outcomes guideline, were considered as fluctuations (eGFR-F). Fluctuations of eGFR greater than 50% were defined as eGFR drops (DeGFR). Early graft dysfunction, AKI within 7 days, chronic kidney disease, and short- and long-term patient survivals were considered as outcomes. RESULTS: All patients presented eGFR-F, whereas DeGFR were observed in 18 (35.3%) of 51 (DeGFR+ group). These patients presented higher levels of Model for End-stage Liver Disease score, pre-Tx bilirubin and significantly greater incidence of post-Tx AKI stages 2 to 3 compared with patients without drops (DeGFR-). DeGFR was the only independent predictive factor of the occurrence of post-Tx AKI. The occurrence of AKI post-Tx was associated with the development of chronic kidney disease at 3 months and 5 years post-Tx. CONCLUSIONS: Drops of eGFR are more frequently observed in patients with a worse degree of ESLD and are associated with a worse post-Tx kidney outcome.

MELDNa score is associated with psychopathology and reduced quality of life in cirrhotic patients with a liver transplant perspective.

Psychopathological symptoms and reduced health related quality of life (HRQoL) are frequent in cirrhotics, but no data on their association with cirrhosis prognosis assessed by the MELDNa score are available. Prospective data on the long-term effect of deceased donor liver transplantation (LT) on psychopathological symptoms are needed. Before entering the LT waiting list, 44 consecutive LT cirrhotic candidates without a major psychiatric disorder underwent a psychopathological assessment, including Symptom Checklist-90-revised (SCL-90-R) and Defense Style Questionnaire (DSQ). HRQoL was measured by Short Form 36 Health Survey (SF-36). Abnormal performance at each questionnaire was defined by using 44 age, gender, BMI and education-matched healthy subjects. Separate binary logistic regression models were used to test the association of the Child-Pugh, MELD and MELDNa scores with abnormal performance at each questionnaire. Fourteen patients repeated the battery tests 3 years after LT. Before LT, increasing MELDNa was the only prognostic score independently associated with an abnormal SCL-90-R global psychopathological score index (OR: 1.207; 95% CI: 1.026-1.420; P = 0.02) and the best independent predictor of reduced HRQoL. After LT, compared to status prior to LT, performance at SF-36 general health perception scale ameliorated (P = 0.02), performance at SCL-90-R somatization scale (P = 0.001) and global psychopathological score index (P < 0.001) worsened and the negative correlation between the psychopathological global score index and HRQoL disappeared. The severity of cirrhosis in LT candidates should be monitored by the MELDNa score to better establish the right psychological counselling. Psychopathology, and in particular somatization, worsens after LT and should be carefully investigated.

Hepatic encephalopathy expands the predictivity of model for end-stage liver disease in liver transplant setting: Evidence by means of 2 independent cohorts.

Despite its documented prognostic relevance, hepatic encephalopathy (HE) is not considered in liver transplantation (LT) due to its possible poor objectivity. To override this problem, we aimed to analyze if an objective diagnosis of HE may confer additional mortality risk beyond MELD. Study and validation cohorts of patients with cirrhosis were considered in Italy and Canada, respectively. Patients were considered to be HE+ if an episode of overt HE was documented in a hospitalization. Of the 486 patients enrolled in Italy, 184 (38%) were HE+. During the 6-month follow-up, 77 patients died and 50 underwent transplantation. The 6-month mortality of HE+ versus HE- patients was significantly higher (P < 0.001). Model for End-Stage Liver Disease (MELD; subdistribution hazard ratio [sHR], 1.2; 95% confidence interval [CI], 1.1-1.2; P < 0.001), HE+ (sHR, 3.6; 95% CI, 1.8-7.1; P < 0.001), and sodium (sHR, 0.9; 95% CI, 0.8-0.9; P < 0.001) were independent predictors of 6-month mortality. In HE+ patients, short-term mortality increased across the entire MELD spectrum (range, 6-40). The results were unchanged by including or excluding patients with hepatocellular carcinoma or stratifying patients according to HE characteristics. The higher 6-month mortality of HE+ versus HE- patients was confirmed also in the Canadian cohort (P < 0.001; n = 300, 33% HE+; 33 died, 104 transplanted). A similar and statistically significant C-index increase derived by the incorporation of HE in MELD was observed both in the Italian (from 0.67 to 0.75) and Canadian (from 0.69 to 0.74) cohorts. A score based on MELD plus 7 points (95% CI, 4-10) for HE+ patients optimally predicted 6-month mortality in the 2 cohorts. According to the net reclassification index, by not considering HE, 29% of overall patients were misclassified by MELD score. In conclusion, the incorporation of HE in MELD score might improve the listing and allocation policy in LT. Liver Transplantation 22 1333-1342 2016 AASLD.

Risk Factors for Immediate and Delayed-Onset Fever After Percutaneous Transhepatic Biliary Drainage.

OBJECTIVES: To prospectively investigate the pre and intra-procedural risk factors for immediate (IF) and delayed-onset (DOF) fever development after percutaneous transhepatic biliary drainage (PTBD). METHODS: Institutional review board approval and informed patient consent were obtained. Between February 2013 and February 2014, 97 afebrile patients (77 at the Sapienza University of Rome, Italy and 20 at the Sun Yat-sen University of Guangzhou, China) with benign (n = 31) and malignant (n = 66) indications for a first PTBD were prospectively enrolled. Thirty pre- and intra-procedural clinical/radiological characteristics, including the amount of contrast media injected prior to PTBD placement, were collected in relation to the development of IF (within 24 h) or DOF (after 24 h). Fever was defined as ≥37.5 °C. Binary logistic regression analysis was used to assess independent associations with IF and DOF. RESULTS: Fourteen (14.4%) patients developed IF and 17 (17.5%) developed DOF. At multivariable analysis, IF was associated with pre-procedural absence of intrahepatic bile duct dilatation (OR 63.359; 95% CI 2.658-1510.055; P = 0.010) and low INR (OR 4.7 × 10(-4); 95% CI 0.000-0.376; P = 0.025), while DOF was associated with unsatisfactory biliary drainage at the end of PTBD (OR 4.571; 95% CI 1.161-17.992; P = 0.030). CONCLUSIONS: The amount of contrast injected is not associated with post-PTBD fever development. Unsatisfactory biliary drainage at the end of PTBD is associated with DOF, suggesting that complete biliary tree decompression should be pursued within the first PTBD. Patients with unsatisfactory drainage and those with the absence of pre-procedural intrahepatic bile duct dilatation, which is associated with IF, require tailored post-PTBD management.

Plasma fatty acid lipidome is associated with cirrhosis prognosis and graft damage in liver transplantation.

BACKGROUND: Knowledge regarding the plasma fatty acid (FA) pattern in patients with liver cirrhosis is fragmentary. OBJECTIVE: We evaluated plasma FA lipidome and its association with the prognosis of cirrhosis and severity of liver graft damage after transplantation. DESIGN: In this observational study, plasma FA lipidome was investigated in 51 cirrhotic patients before liver transplantation and in 90 age- and sex-matched healthy control subjects. In addition, we studied ischemia-reperfusion damage in the liver of 38 patients for whom a graft biopsy was available at transplantation. With the use of logistic regression, we modeled the presence of cirrhosis, the dichotomized model for end-stage liver disease score below and above the median, and the presence of severe liver graft ischemia-reperfusion damage. RESULTS: The FA pattern was markedly altered in cirrhotic patients, who showed, compared with healthy controls, higher monounsaturated FAs, lower n-6 and n-3 polyunsaturated FAs, and undetectable cerotic acid. Plasma di-homo-γ-linolenic acid was independently associated with the presence of cirrhosis (OR: 0.026; 95% CI: 0.004, 0.196; P < 0.0001), severity of its prognosis (OR: 0.041; 95% CI:0.005, 0.376; P = 0.006), postreperfusion graft hepatocellular necrosis (OR: 0.921; 95% CI: 0.851, 0.997; P = 0.043), and sinusoidal congestion (OR: 0.954; 95% CI: 0.912, 0.998; P = 0.039). Associations of di-homo-γ-linolenic acid with the presence of cirrhosis and severity of its prognosis were confirmed also after false discovery rate correction. CONCLUSIONS: Cerotic and di-homo-γ-linolenic acids may serve as markers of disease and prognosis in liver cirrhosis. Dietary supplementation with di-homo-γ-linolenic acid could be a reasonable interventional strategy to delay disease progression in liver cirrhosis.

Recipient perioperative cholesterolaemia and graft cholesterol metabolism gene expression predict liver transplant outcome.

BACKGROUND & AIMS: We analysed for the first time whether recipient perioperative serum total cholesterol (sTC) concentration is associated with liver transplantation outcome. METHODS: We studied noncholestatic cirrhotics submitted to primary deceased-donor liver transplantation in a prospective group (n=140) from Rome and in a validation retrospective cohort (n=157) from Udine, Italy. Pre-ischaemia and post-reperfusion cholesterol metabolism gene mRNA was measured by RT-PCR in 74 grafts of the study group. RESULTS: At Cox regression analysis, independently from confounders including recipient MELD score, the recipient pre-operative sTC pooled quintiles 2-5, compared with the lowest quintile showed HR (95% CI) and significances for overall graft loss (GL) of 0.215 (0.104-0.444) P<0.001 in the study group and 0.319 (0.167-0.610) P=0.001 in the validation cohort. Analysing sTC as a continuous variable, the risk of overall GL for every 10-mg/dl decrease in pre-operative sTC increased by 13% and by 9% in the study group and in the validation cohort respectively. In the study group, independent associations at multivariate analyses were: (a) high graft pre-ischaemia expression of INSIG-1, which indicates hepatocellular cholesterol depletion, with post-reperfusion graft necrosis; (b) GL with inadequate graft post-reperfusion response to cholesterol depletion, shown by a failure to reduce the PCSK9 to LDLR expression ratio; (c) GL with a relative increase of sTC on post-operative day-7, selectively because of the LDL fraction, which indirectly suggests poor cholesterol uptake from blood. CONCLUSIONS: Low recipient pre-transplant sTC concentration, its post-operative day-7 increase and a genetically determined low graft cholesterol availability predict poor liver transplant outcome.

Beneficial effect of sulphate-bicarbonate-calcium water on gallstone risk and weight control.

AIM: To investigate the effect of drinking sulphate-bicarbonate-calcium thermal water (TW) on risk factors for atherosclerosis and cholesterol gallstone disease. METHODS: Postmenopausal women with functional dyspepsia and/or constipation underwent a 12 d cycle of thermal (n = 20) or tap (n = 20) water controlled drinking. Gallbladder fasting volume at ultrasound, blood vitamin E, oxysterols (7-ß-hydroxycholesterol and 7-ketocholesterol), bile acid (BA), triglycerides, total/low density lipoprotein and high density lipoprotein cholesterol were measured at baseline and at the end of the study. Food consumption, stool frequency and body weight were recorded daily. RESULTS: Blood lipids, oxysterols and vitamin E were not affected by either thermal or tap water consumption. Fasting gallbladder volume was significantly (P < 0.005) smaller at the end of the study than at baseline in the TW (15.7 ± 1.1 mL vs 20.1 ± 1.7 mL) but not in the tap water group (19.0 ± 1.4 mL vs 19.4 ± 1.5 mL). Total serum BA concentration was significantly (P < 0.05) higher at the end of the study than at baseline in the TW (5.83 ± 1.24 µmol vs 4.25 ± 1.00 µmol) but not in the tap water group (3.41 ± 0.46 µmol vs 2.91 ± 0.56 µmol). The increased BA concentration after TW consumption was mainly accounted for by glycochenodeoxycholic acid. The number of pasta (P < 0.001), meat (P < 0.001) and vegetable (P < 0.005) portions consumed during the study and of bowel movements per day (P < 0.05) were significantly higher in the TW than in the tap water group. Body weight did not change at the end of the study as compared to baseline in both groups. CONCLUSION: Sulphate-bicarbonate-calcium water consumption has a positive effect on lithogenic risk and intestinal transit and allows maintenance of a stable body weight despite a high food intake.