Comprehensive assessment of frail phenotype determinants in cirrhotic patients evaluated for liver transplantation

BACKGROUND. Frailty is defined as a distinct biologic syndrome of decreasing physiologic reserve and increasing vulnerability to health stressors that predispose affected individuals to health adverse outcomes. So far, frail phenotype in cirrhotic patients has been regarded to a large extent as a manifestation of a wasting disorder, with sarcopenia as the major pathogenic mechanism. However, specific investigations on the pathogeneis of cirrhosis-related frailty are lacking. Therefore, the aim of this study was to perform a comprehensive assessment of potential determinants of frail phenotype, testing known risk factors for cirrhosis-related sarcopenia and exploring other pathogenic mechanisms derived from aging-related frailty METHODS. Observational prospective study on a cohort of cirrhotic patients, aged 50-70 years, who underwent the clinical workup for deceased-donor LT listing at the Hepatology and Liver-Kidney Transplant Unit of the Udine Academic Hospital, from June 2019 to November 2021. Patient physical performance was assessed using the Liver Frail index (LFI) and a LFI≥4.5 was used as diagnostic criteria for frailty. Body mass composition was assessed on cross-sectional computer tomography images at the third lumbar spine level, as follows: skeletal muscle mass index (SMI), visceral adipose tissue index (VATI), subcutaneous adipose tissue index (TATI); total adipose tissue index (VATI+TATI), visceral-to-subcutaneous adipose tissue ratio (VSR) and skeletal muscle radiodensity (SMRD). Osteoporosis was diagnosed based on T score<-2.5 on dual-energy X-ray absorptiometry. For endocrine, inflammatory and metabolic assessment, the following parameters were evaluated on blood samples: thyroid stimulating hormone, freeT4, 17-beta estradiol, testosterone, dehydroepiandrosterone solphate, cortisol and IGF-1 [endocrine profile], neutrophil-to-lymphocyte ratio, C-reactive protein (CRP) and erythrocyte sedimentation rate [inflammatory profile], 25(OH) Vitamin D, prognostic nutritional index, triglyceride, cholesterol HDL, cholesterol LDL, total proteins, albumin, cholinesterase, ammonia, uric acid, creatinine and percent glycated hemoglobin [metabolic profile] RESULTS. One hundred ten patients were assessed. The median LFI was 3.9 [IQR 3.6-4.4], with a frail status prevalence of 23.6% (n=26). Frail patients were not significantly older than non-frail ones but showed a tendency toward an higher prevalence of female sex (46.1% vs 26.2%, p 0.054). Frailty was associated with higher MELD-Na score (median,19 vs 13, p <0.001). Moreover, it was associated with higher NASH prevalence (15.4% vs 0.24%, p 0.027), higher TATI (124.8 cm2/m2 vs 69.7 cm2/m2, p 0.001) and higher metabolic syndrome prevalence (23.1% vs 1.4%, p<0.001). Vitamin D levels were significantly lower, irrespective of pre-existing vitamin D oral supplementation, but frailty was not associated with osteoporosis. Cortisol (431 nMol/L vs 332 nMol/L, p 0.041) as well as CRP (6.5 mg/L vs 3.5 mg/L, p 0.032) levels were significantly higher, while and IGF-1 levels were significantly lower (37 pg/mL vs 45 pg/mL, p 0.032). Frail women specifically showed higher VATI and VSR (0.80 vs 0.41, p 0.27), but comparable SMI and SMRD, as well as significantly lower testosterone (0.7 nMol/L vs 1.4 nMol/L, p<0.001) and estrogen levels (40 pMol/L vs 69 pMol/L, p 0.017). Conversely, frail men showed significantly lower SMI (47.8 cm2/m2 vs 50.9 cm2/m2, p 0.012) and lower SMRD, higher SATI but comparable VSR, with significantly lower testosterone levels (4.5 nMol/L vs 8.7 nMol/L, p<0.001). CONCLUSIONS. Frailty in cirrhotic patients should not be primarily considered as a wasting disorder and the pathogenic role of adipose tissue may be at least as important as that of skeletal muscle. Therefore, beyond sarcopenia and malnutrition, diagnostic and therapeutic interventions should also possibly target obesity, chronic inflammation, hypogonadism, IGF-1 deficiency and vitamin D deficiency.

Hepatocellular Carcinoma: Diagnosis, Therapy and Molecular Investigations

Hepatocellular carcinoma (HCC) is the leading cause of primary liver cancers. Surveillance of individuals at specific risk of developing HCC, early diagnostic markers, and new therapeutic approaches are essential to obtain a reduction in disease-related mortality. In the last decades imaging technologies, statistical models, and standardized diagnostic procedures associated with clinical guidelines for intervention significantly enhanced the success rate and life expectancy of HCC patients. In addition, the work of several research laboratories contributed to the identification of markers and pathways altered in HCC which represent potential biomarkers or molecular targets for therapy. In this short review we describe the current approaches for HCC diagnosis and treatment and the most recent advancements in the characterization of biomolecular mechanisms implicated in the pathogenesis and progression of HCC

Effect of pre‐transplant sarcopenia on the estimation of standard liver volume in living‐donor liver transplant candidates: risk factor for post‐transplant small‐for‐size syndrome? A retrospective study

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The role of antiplatelet therapies on incidence and mortality of hepatocellular carcinoma

Aim To evaluate the impact of antiplatelet therapy (APT)on the incidence of hepatocellular carcinoma (HCC) and mortality following its treatment. Methods A systematic literature search was performed using PubMed and Cochrane Central Register of Controlled Trials Databases. Two HCC clinical settings were explored: (i) incidence, and (ii) death after any HCC treatment. Odds ratios (OR) and 95% confidence intervals (95%CI) were calculated to compare the pooled data between patients who received or did not receive APT. Results A total of 20 studies were identified, of whom 15 focused on HCC incidence, including 2,685,009 patients, and five on post-treatment death, including 3281 patients. APT was associated with an overall reduced risk of HCC incidence (OR: 0.63; 95%CI = 0.51-0.79; p < 0.001) as well as of post-treatment mortality (OR: 0.54; 95%CI = 0.35-0.83; p = 0.006). Conclusions Current data suggest that APT correlated with higher HCC incidence and poor overall survival following tumour treatment

Simultaneous pancreas-kidney transplantation: Initial experience of a center in Japan

Background: Simultaneous pancreas-kidney transplantation (SPK) is an established therapy for diabetes mellitus (DM) patients with associated end stage renal disease. We report the initial results of SPK in our institution afterqualification as transplantation program. Patients and methods: Between September 2017 and July 2018, we performed 3 SPK in type 1 diabetic patientswith end-stage renal disease. All grafts were procured from brain-dead marginal donors according Pittsburgcriteria. Results: The recipients were 2 men and 1 woman with a mean age of 43 ± 5.4 years. Mean time from DMdiagnosis and time on dialysis were 25.7 ± 3.9 years and 19.7 ± 9.1 months. The mean age and HbA1C valueof donor were 56.7 ± 0.5 years and 5.67 ± 0.05%. The pancreatic grafts were transplanted intraperitoneally inthe right iliac fossa. Two patients required a relaparotomy due to arterial anastomotic hemorrhage and twopatients developed acute cellular rejection. With a median follow-up of 13 (6?15) months, patient\u27s and graft\u27ssurvival rate were 100%. All patients showed HbA1C within normal range, but oral glucose tolerance testshowed DM pattern in two patients at 3 months after transplantation. Conclusions: In our initial experience with SPK, mid-term grafts and patient survival appear comparable to theresults reported in literature. Despite the limited availability of donors and the use of grafts from marginaldonors, a quality pancreas transplantation program can be established even in a small-volume centers. Nonetheless further improvement in surgical techniques and meticulous management appear mandatory

Direct-acting antivirals and hepatocellular carcinoma in chronic hepatitis C: A few lights and many shadows

With the introduction of direct-acting antiviral agents (DAA), the rate of sustained virological response (SVR) in the treatment of hepatitis C virus (HCV) has radically improved to over 95%. Robust scientific evidence supports a beneficial role of SVR after interferon therapy in the progression of cirrhosis, resulting in a decreased incidence of hepatocellular carcinoma (HCC). However, a debate on the impact of DAAs on the development of HCC is ongoing. This review aimed to analyse the scientific literature regarding the risk of HCC in terms of its recurrence and occurrence after the use of DAAs to eradicate HCV infection. Among 11 studies examining HCC occurrence, the de novo incidence rate ranged from 0 to 7.4% (maximum follow-up: 18 mo). Among 18 studies regarding HCC recurrence, the rate ranged from 0 to 54.4% (maximum "not well-defined" followup: 32 mo). This review highlights the major difficulties in interpreting data and reconciling the results of the included studies. These difficulties include heterogeneous cohorts, potential misclassifications of HCC prior to DAA therapy, the absence of an adequate control group, short follow-up times and different kinds of follow-up. Moreover, no clinical feature-based scoring system accounts for the molecular characteristics and pathobiology of the tumours. Nonetheless, this review does not suggest that there is a higher rate of de novo HCC occurrence or recurrence after DAA therapy in patients with previous HCV infection. \ua9 2018 The Author(s). Published by Baishideng Publishing Group Inc. All rights reserved

Solid Organ Transplantation During COVID-19 Pandemic: An International Web-based Survey on Resources’ Allocation

Background. Solid organ transplants (SOTs) are life-saving interventions, recently challenged by coronavirus disease 2019 (COVID-19). SOTs require a multistep process, which can be affected by COVID-19 at several phases. Methods. SOT-specialists, COVID-19-specialists, and medical ethicists designed an international survey according to CHERRIES guidelines. Personal opinions about continuing SOTs, safe managing of donors and recipients, as well as equity of resources' allocation were investigated. The survey was sent by e-mail. Multiple approaches were used (corresponding authors from Scopus, websites of scientific societies, COVID-19 webinars). After the descriptive analysis, univariate and multivariate ordinal regression analysis was performed. Results. There were 1819 complete answers from 71 countries. The response rate was 49%. Data were stratified according to region, macrospecialty, and organ of interest. Answers were analyzed using univariate- multivariate ordinal regression analysis and thematic analysis. Overall, 20% of the responders thought SOTs should not stop (continue transplant without restriction); over 70% suggested SOTs should selectively stop, and almost 10% indicated they should completely stop. Furthermore, 82% agreed to shift resources from transplant to COVID-19 temporarily. Briefly, main reason for not stopping was that if the transplant will not proceed, the organ will be wasted. Focusing on SOT from living donors, 61% stated that activity should be restricted only to "urgent"cases. At the multivariate analysis, factors identified in favor of continuing transplant were Italy, ethicist, partially disagreeing on the equity question, a high number of COVID-19- related deaths on the day of the answer, a high IHDI country. Factors predicting to stop SOTs were Europe except-Italy, public university hospital, and strongly agreeing on the equity question. Conclusions. In conclusion, the majority of responders suggested that transplant activity should be continued through the implementation of isolation measures and the adoption of the COVID-19-free pathways. Differences between professional categories are less strong than supposed

Postoperative Trends and Prognostic Values of Inflammatory and Nutritional Biomarkers after Liver Transplantation for Hepatocellular Carcinoma

Preoperative inflammatory biomarkers such as the Platelet-to-Lymphocyte Ratio (PLR) and the Neutrophil-to-Lymphocyte Ratio (NLR) strongly predict the outcome in surgically treated patients with hepatocellular carcinoma (HCC), while nutritional biomarkers such as the Controlling Nutritional Status (CONUT) and the Prognostic Nutritional Index (PNI) show an analogue prognostic value in hepatic resection (HR) but not in liver transplant (LT) cases. Data on the impact of LT on the inflammatory and nutritional/metabolic function are heterogeneous. Therefore, we investigated the post-LT trend of these biomarkers up to postoperative month (POM) 12 in 324 HCC patients treated with LT. Inflammatory biomarkers peaked in the early post-LT period but at POM 3 leveled off at values similar (NLR) or higher (PLR) than pre-LT ones. CONUT and PNI worsened in the early post-LT period, but at POM 3 they stabilized at significantly better values than pre-LT. In LT recipients with an overall survival >1 year and no evidence of early HCC recurrence, 1 year post-LT NLR and PNI independently predicted patient overall survival, while 1 year post-LT PLR independently predicted late tumor recurrence. In conclusion, at 1 year post-LT, the nutritional status of liver-transplanted HCC patients significantly improved while their inflammatory state tended to persist. Consequently, post-LT PLR and NLR maintained a prognostic value for LT outcome while post-LT CONUT and PNI acquired it

Evolution of incidental branch-duct intraductal papillary mucinous neoplasms of the pancreas: A study with magnetic resonance imaging cholangiopancreatography

7AIM: To investigate the type and timing of evolution of incidentally found branch-duct intraductal papillary mucinous neoplasms (bd-IPMN) of the pancreas addressed to magnetic resonance imaging cholangiopancreatography (MRCP) follow-up. METHODS: We retrospectively evaluated 72 patients who underwent, over the period 2006-2016, a total of 318 MRCPs (mean 4.4) to follow-up incidental, presumed bd-IPMN without signs of malignancy, found or confirmed at a baseline MRCP examination. Median follow-up time was 48.5 mo (range 13-95 mo). MRCPs were acquired on 1.5T and/or 3.0T systems using 2D and/ or 3D technique. Image analysis assessed the rates of occurrence over the follow-up of the following outcomes: (1) imaging evolution, defined as any change in cysts number and/or size and/or appearance; and (2) alert findings, defined as worrisome features and/or high risk stigmata (e.g., thick septa, parietal thickening, mural nodules and involvement of the main pancreatic duct). Time to outcomes was described with the Kaplan-Meir approach. Cox regression model was used to investigate clinical or initial MRCP findings predicting cysts changes. RESULTS: We found a total of 343 cysts (per-patient mean 5.1) with average size of 8.5 mm (range 5-25 mm). Imaging evolution was observed in 32/72 patients (44.4%; 95%CI: 32-9-56.6), involving 47/343 cysts (13.7%). There was a main trend towards small ( 0.01). CONCLUSION: Changes in MRCP appearance of incidental bd-IPNM were frequent over the follow-up (44.4%), with relatively rare (8.3%) occurrence of non-malignant alert findings that prompted further diagnostic steps. Changes occurred at a wide interval of time and were unpredictable, suggesting that imaging followup should be not discontinued, though MRCPs might be considerably delayed without a significant risk of missing malignancy.openopenGirometti, Rossano; Pravisani, Riccardo; Intini, Sergio Giuseppe; Isola, Miriam; Cereser, Lorenzo; Risaliti, Andrea; Zuiani, ChiaraGirometti, Rossano; Pravisani, Riccardo; Intini, Sergio Giuseppe; Isola, Miriam; Cereser, Lorenzo; Risaliti, Andrea; Zuiani, Chiar