Platelet-to-lymphocyte ratio in the setting of liver transplantation for hepatocellular cancer. A systematic review and meta-analysis

AIM: To perform a systematic review and meta-analysis on platelet-to-lymphocyte ratio (PLR) as a risk factor for post-transplant hepatocellular cancer (HCC) recurrence. METHODS: A systematic literature search was performed using PubMed. Participants of any age and sex, who underwent liver transplantation for HCC were considered following these criteria: (1) studies comparing pre-transplant low vs high PLR values; (2) studies reporting post-transplant recurrence rates; and (3) if more than one study was reported by the same institute, only the most recent was included. The primary outcome measure was set for HCC recurrence after transplantation. RESULTS: A total of 5 articles, published between 2014 and 2017, fulfilled the selection criteria. As for the quality of the reported studies, all the investigated articles presented an overall high quality. A total of 899 cases were investigated: 718 cases (80.0%) were males. Three studies coming from European countries and one from Japan presented HCV as the main cause of cirrhosis. On the opposite, one Chinese study presented a greater incidence of HBV-related cirrhotic cases. In all the studies apart one, the PLR cut-off value of 150 was reported. At meta-analysis, high PLR value was associated with a significant increase in recurrence after transplantation (OR = 3.33; 95%CI: 1.78-6.25; p < 0.001). A moderate heterogeneity was observed among the identified studies according to the Higgins I 2 statistic value. CONCLUSION: Pre-transplant high PLR values are connected with an increased risk of post-operative recurrence of hepatocellular cancer. More studies are needed for better clarify the biological mechanisms of this results

Specific issues concerning the management of patients on the waiting list and after liver transplantation

The present document is a second contribution collecting the recommendations of an expert panel of transplant hepatologists appointed by the Italian Association for the Study of the Liver (AISF) concerning the management of certain aspects of liver transplantation, including: the issue of prompt referral; the management of difficult candidates; malnutrition; living related liver transplants; hepatocellular carcinoma; and the role of direct acting antiviral agents before and after transplantation. The statements on each topic were approved by participants at the AISF Transplant Hepatology Expert Meeting organized by the Permanent Liver Transplant Commission in Mondello on 12-13 May 2017. They are graded according to the GRADE grading system

Rifaximin reduces risk of all-cause hospitalization in cirrhotic liver transplant candidates with hepatic encephalopathy

In cirrhotic patients listed for liver transplantation (LT) with a history of hepatic encephalopathy (HE), rifaximin reduces the number of hospitalizations, but whether it influences the time to first hospitalization is unknown. Aims: to evaluate the time-dependent impact of rifaximin on the risk of all-cause hospitalization and dropout in patients on the LT waiting list. Methods: Consecutive patients listed for LT were retrospectively enrolled. After balancing populations with and without rifaximin treatment using the inverse probability therapy weighting analysis, Fine-Gray multivariable competing risk analyses were run to explore risk factors for the first episode of hospitalization and dropout. Results: When comparing 92 patients taking rifaximin to the untreated group of 152, rifaximin treatment was not associated with any of the study outcomes. In the subset of patients with a history of HE at waitlist entry (N = 81 rifaximin-treated and N = 39 untreated), rifaximin intake was independently associated with a lower risk of hospitalization for all causes (SHR 0.638; 95.0% CI 0.418-0.973; p = 0.037) and for HE (SHR 0.379; 95.0% CI 0.207-0.693; p = 0.002). Conclusions: cirrhotic LT candidates with a prior history of HE rifaximin treatment are associated with a lower risk of time-dependent all-cause hospitalization, likely due to its unique effect on gut microbiome composition/function

New Diagnostic and Prognostic Models for the Development of Alcoholic Cirrhosis Based on Genetic Predisposition and Alcohol History

Liver cirrhosis development is a multifactorial process resulting from a combination of environmental and genetic factors. The aim of the study was to develop accurate non-invasive diagnostic and prognostic models for alcoholic cirrhosis. Consecutive subjects with at-risk alcohol intake were retrospectively enrolled (110 cirrhotic patients and 411 non-cirrhotics). At enrollment, the data about lifetime drinking history were collected and all patients were tested for Patatin-like phospholipase domain-containing protein 3 (PNPLA3) rs738409, Transmembrane 6 Superfamily 2 (TM6SF2) rs58542926, and hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13) rs72613567 variants. In cross-sectional analyses, models for the diagnosis of cirrhosis were developed using multivariate logistic regression. A predictive score for cirrhosis development over 24 years was built by evaluating time-dependent AUC curves. The best diagnostic accuracy was demonstrated by the model, which also includes daily alcohol consumption, duration of hazardous alcohol use, and genetic variants, with AUCs of 0.951 (95% CI 0.925–0.977) and 0.887 (95% CI 0.925–0.977) for cirrhosis and compensated cirrhosis, respectively. The predictive model for future cirrhosis development (AUC of 0.836 95% CI: 0.769–0.904) accounted for age at onset of at-risk alcohol consumption and the number of PNPLA3 and HSD17B13 variant alleles. We have developed accurate genetic and alcohol consumption models for the diagnosis of alcoholic cirrhosis and the prediction of its future risk

Severity of Hepatocyte Damage and Prognosis in Cirrhotic Patients Correlate with Hepatocyte Magnesium Depletion

We aimed to evaluate the magnesium content in human cirrhotic liver and its correlation with serum AST levels, expression of hepatocellular injury, and MELDNa prognostic score. In liver biopsies obtained at liver transplantation, we measured the magnesium content in liver tissue in 27 cirrhotic patients (CIRs) and 16 deceased donors with healthy liver (CTRLs) by atomic absorption spectrometry and within hepatocytes of 15 CIRs using synchrotron-based X-ray fluorescence microscopy. In 31 CIRs and 10 CTRLs, we evaluated the immunohistochemical expression in hepatocytes of the transient receptor potential melastatin 7 (TRPM7), a magnesium influx chanzyme also involved in inflammation. CIRs showed a lower hepatic magnesium content (117.2 (IQR 110.5–132.9) vs. 162.8 (IQR 155.9–169.8)  g/g; p < 0.001) and a higher percentage of TRPM7 positive hepatocytes (53.0 (IQR 36.8–62.0) vs. 20.7 (10.7–32.8)%; p < 0.001) than CTRLs. In CIRs, MELDNa and serum AST at transplant correlated: (a) inversely with the magnesium content both in liver tissue and hepatocytes; and (b) directly with the percentage of hepatocytes stained intensely for TRPM7. The latter also directly correlated with the worsening of MELDNa at transplant compared to waitlisting. Magnesium depletion and overexpression of its influx chanzyme TRPM7 in hepatocytes are associated with severity of hepatocyte injury and prognosis in cirrhosis. These data represent the pathophysiological basis for a possible beneficial effect of magnesium supplementation in cirrhotic patients

Reduced lysosomal acid lipase activity in blood and platelets is associated with nonalcoholic fatty liver disease

OBJECTIVES: To investigate whether blood total lysosomal acid lipase activity (BT-LAL) levels are uniquely associated with the noncirrhotic and cirrhotic stages of nonalcoholic fatty liver disease (NAFLD) and with protection from NAFLD in metabolically/genetically predisposed subjects and a normal liver. To clarify which enzyme-carrying circulating cells are involved in reduced BT-LAL of NAFLD.METHODS: In a cross-sectional study, BT-LAL was measured by a fluorigenic method in patients with NAFLD (n = 118), alcoholic (n = 116), and hepatitis C virus-related disease (n = 49), in 103 controls with normal liver and in 58 liver transplant recipients. Intracellular platelet and leukocyte LAL was measured in 14 controls and 28 patients with NAFLD.RESULTS: Compared with controls, (i) BT-LAL and LAL in platelets, but not in leukocytes, were progressively reduced in noncirrhotic NAFLD and in nonalcoholic steatohepatitis-related cirrhosis; (ii) platelet and leukocyte counts did not differ in patients with noncirrhotic NAFLD; and (iii) BT-LAL did not differ in alcoholic and hepatitis C virus noncirrhotic patients. BT-LAL progressively increased in controls with metabolic syndrome features according to their PNPLA3 rs738409 steatosis-associated variant status (II vs IM vs MM), and their BT-LAL was higher than that of noncirrhotic NAFLD, only when carriers of the PNPLA3 unfavorable alleles were considered. Liver transplant recipients with de novo NAFLD compared with those without de novo NAFLD had lower BT-LAL.DISCUSSION: LAL in blood and platelets is progressively and uniquely reduced in NAFLD according to disease severity. High BT-LAL is associated with protection from NAFLD occurrence in subjects with metabolic and genetic predisposition. Low LAL in platelets and blood could play a pathogenetic role in NAFLD

Superiority of the new sex-adjusted models to remove the female disadvantage restoring equity in liver transplant allocation

Background and Aims: Model for End-stage Liver Disease (MELD) and MELDNa are used worldwide to guide graft allocation in liver transplantation (LT). Evidence exists that females are penalized in the present allocation systems. Recently, new sex-adjusted scores have been proposed with improved performance respect to MELD and MELDNa. GEMA-Na, MELD 3.0, and sex-adjusted MELDNa were developed to improve the 90-day dropout prediction from the list. The present study aimed at evaluating the accuracy and calibration of these scores in an Italian setting. Methods: The primary outcome of the present study was the dropout from the list up to 90 days because of death or clinical deterioration. We retrospectively analysed data from 855 adults enlisted for liver transplantation in the Lazio region (Italy) (2012–2018). Ninety-day prediction of GEMA-Na, MELD 3.0 and sex-adjusted MELDNa with respect to MELD and MELDNa was analysed. Brier score and Brier Skill score were used for accuracy, and the Greenwood-Nam- D'Agostino test was used to evaluate the calibration of the models. Results: GEMA-Na (concordance = .82, 95% CI = .75–. 89), MELD 3.0 (concordance = .81, 95% CI = .74–. 87) and sex-adjusted MELDNa (concordance = .81, 95% CI = .74–.88) showed the best 90-day dropout prediction. GEMA-Na showed a higher increase in accuracy with respect to MELD (p = .03). No superiority was shown with respect to MELDNa. All the tested scores showed a good calibration of the models. Using GEMA-Na instead of MELD would potentially save one in nine dropouts and could save one dropout per 285 patients listed

Managing chronic pain in elderly patients requires a CHANGE of approach

Peer reviewe

Pain in the cancer patient : different pain characteristics CHANGE pharmacological treatment requirements

Peer reviewe

Microbiota intestinale e modulazione del profilo metabolico lipico e glucidico

Studi recenti hanno ipotizzato un ruolo del microbiota intestinale come possibile mediatore della perdita di peso e del miglioramento del profilo metabolico dopo chirurgia bariatrica. Al fine di valutare gli effetti della sleeve gastrectomy (SG) sul microbiota intestinale, sono stati arruolati nello studio una coorte longitudinale di 36 pazienti che sono stati valutati pre-SG e a 6 e 18 mesi pot-SG. I pazienti sono stati sottoposti a valutazioni metaboliche con meal test con Oxepa® e curva da carico di glucosio oltre alla raccolta di un campione fecale ad ogni valutazione. E’ stato arruolato nello studio anche un gruppo cross-sectional di pazienti a 4 anni dalla SG. I pazienti in seguito all’intervento hanno mostrato un miglioramento non solo del peso corporeo (BMI pre-SG vs 6 mesi post-SG: 44,5±6,8 vs 32,7±5,5 kg/m2, p<0.001) ma anche del profilo metabolico in particolare di quello glucidico: durante carico di glucosio AUC della glicemia pre-SG vs 6 mesi post-SG: 16598±3678 vs 13143±3505, p<0,001. L’analisi del microbiota ha evidenziato che la sleeve gastrectomy induce un aumento della biodiversità del microbiota staticamente significativa e un aumento delle funzioni geniche che esso svolge. Dall’analisi effettuata si evince che il 57% e il 48% delle funzionalità geniche che si sono modificate nel primi 6 mesi post-SG rimangono modificate rispettivamente a 18 mesi post-SG e nel gruppo cross-sectional a 4 anni indicando che una consistente parte delle modificazioni precoci indotte dall’intervento chirurgico si mantengono nel tempo. Di particolare interesse metabolico appare l’aumento degli Actinobatteri, dei produttori di acetato (Proteobatteri) e dei produttori di acido lattico (Streptococcus, Lactobacillus e Enterococcus) con concomitante riduzione dei Clostridium cluster XIVa (Clostridium, Coprococcus, Dorea, Eubacterium e Ruminococcus). Tali modificazioni hanno portato alla variazione anche della metabolomica del microbiota intestinale per cui si verifica un aumento del metabolismo del carbonio, citrato e glicossilato e una concomitante riduzione del metabolismo dei solfuri e della sintesi degli aminoacidi in particolare quelli a catena ramificata la cui riduzione è associata al miglioramento del profilo glucidico, come già descritto in letteratura. Per individuare il ruolo svolto dal microbiota intestinale è stato eseguito un ulteriore esperimento in topi conventionally-raised e germ-free. Entrambi sono stati sottoposti a SG ma solo nel gruppo dei topi conventionally-raised è stato documentato il miglioramento del metabolismo glucidico statisticamente significativo (p<0.010). Questo ad indicare che il microbiota intestinale è fondamentale per determinare i miglioramenti osservati. Al fine di verificare se fossero le modificazioni del microbiota a determinare le variazioni metaboliche osservate è stato eseguito un trapianto di feci in topi germ free dei campioni fecali pre-SG e 18 mesi post-SG di due pazienti arruolate nello studio. L’esperimento ha mostrato come il miglioramento del profilo glucidico osservato a 18 mesi post-SG sia replicabile nei topi germ-free attraverso il trapianto delle feci raccolte al medesimo timing. Al fine di individuare il meccanismo alla base dei cambiamenti osservati sono stati dosati gli acidi biliari durante meal test ed è stato evidenziato un aumento statisticamente significativo delle AUC a 6 mesi post-SG rispetto al pre-SG degli acidi biliari secondari (328858±392137 vs 102043±92835, p=0,001, rispettivamente) e di FGF19 (20,13±14,85 vs 12,50±6,97; p=0,029, rispettivamente) con concomitante riduzione della AUC del C4 (8634±5909 vs 4301±4245, p<0,0001, rispettivamente). Alla luce di tali dati è stato misurato l’FGF15 (analogo murino di FGF19) nei topi germ-free sottoposti a trapianto di feci (18M), nei topi conventionally-raised e germ-free sottoposti a SG. L’attivazione significativa di FGF15 è stata evidenziata solo primi due gruppi ma non nei topi germ free sottoposti a SG. In conclusione la SG provoca una modificazione del microbiota intestinale che induce una modificazione del metabolismo degli acidi biliari e quindi del signaling prodotto dagli stessi attraverso FXR. L’attivazione selettiva di FXR nel piccolo intestino potrebbe quindi rappresentare un pathway metabolico utile per mimare gli effetti della chirurgia bariatrica