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

Numerical Analysis Results of Debonding Damage Effects for an SHM System Application on a Typical Composite Beam

In the aeronautical field, the damage that occurs to a carbon-fibre-reinforced polymer (CFRP) structure analysis is a crucial point for further improving its capability and performance. In the current the state of the art, in fact, many issues are linked to the certification process more than to technological aspects. For the sake of clarity, it should be added that regulations call for technological solutions that are invasive (in terms of weight and manufacturing costs) or exploit technologies that are not fully mature. Thus, the truth is in between the above statements. One of the possible solutions to bypass this issue is the assessment of a structural health monitoring system (SHM) that is sufficiently reliable to provide a full-state representation of the structure, automatically, perhaps in real-time, with a minimum intervention of specialized technicians, and that can raise an alert for safe maintenance whenever necessary. Among the different systems that have been proposed in the scientific and technological literature, SHM systems based on strain acquisitions seem very promising: they deduce the presence of flaws by analysing the variations of the intimate response of the structure. In this context, the SHM using fibre optics, supported by a dedicated algorithm, seems to be able to translate the effects of the damage reading the strain field. This means that is necessary to have a full comprehension of the flaws’ effects in terms of strain variation to better formulate a strategy aimed at highlighting these distortions. It should be remarked that each type of damage is distinct; imperfections of the bonding line are herein targeted since the quality of the latter is of paramount importance for ensuring the correct behaviour of the referred structure. This presents paper focuses on a deep investigation on the strain field peculiarities that arise after the imposition of irregularities in the adhesive region. The aim is to explore the damage dimension versus its effect on the strain map, especially when bonding connects different parts of a complex composite beam. By means of finite element method applied on a typical aeronautical beam, a parametric numerical simulation was performed in order to establish the influence of a debonding dimension on a reference strain map. This work provides evidence that these effects on strain flaw decrease the distancing itself of the damage. The knowledge of these effects can be highly helpful during the design of a preliminary phase of an SHM system in order to choose the most suitable sensor in terms of reading sensitivity error, the number to be used, and their location

De-Bonding Numerical Characterization and Detection in Aeronautic Multi-Element Spars

Structural health monitoring has multifold aims. Concerning composite structures, the main objectives are perhaps reducing costs by shifting from scheduled to on-demand maintenance and reducing weight by removing redundant precautions as the insertion of chicken fasteners to for ensuring joint safety in cases of bonding layer fail. Adhesion defects may be classified along different types, for instance distinguishing between glue deficiency or de-bonding. This paper deals with a preliminary numerical characterization of adhesive layer imperfections on a representative aircraft component. The multipart composite spar is made of two plates and two corresponding C-beams, bonded together to form an almost squared boxed section beam. A numerical test campaign was devoted to extract relevant information from different defect layouts and to try to assess some parameters that could describe their peculiarities. A focus was then given to macroscopic evidence of fault effects behavior, as localization, reciprocal interference, impact on structural response, and so on. A proprietary code was finally used to retrieve the presence and size of the imperfections, correlating numerical outcomes with estimations. Activities were performed along OPTICOMS, a European project funded within the Clean Sky 2 Joint Technology Initiative (JTI)

Drug induced liver injury: from pathogenesis to liver transplantation

Drug induced liver injury (DILI) is a necro-inflammatory liver disease caused by several drugs commonly used in clinical practice, herbs and dietary supplements prescribed for medical purposes. Despite its rarity, it represents the major cause of acute liver failure (ALF) requiring liver transplantation in USA and its frequency is increasing in Europe too. Two types of drug induced liver injury have been recognized: intrinsic and idiosyncratic. Predisposing factors may be classified in environmental, drugs- and individual- related risk factors, with the latter further distinguished in genetics and non-genetics. The liver injury canpresent with a hepatocellular, cholestatic or mixed pattern of disease. A definitive diagnosis of DILI is, nowadays, one of the main challenging issue in the management of these patients. Diagnosis often is based on suspicion derived from clinical history, biochemical exams and eventually on histological examination from liver biopsy. Score system may be helpful in these setting and new markers are gaining more prominence. Evaluation for liver transplantation is indicated when spontaneous resolution does not occur or in cases of ALF. Overall, the 1-year survival rate following liver transplantation is lower than that seen in patients who have been transplanted for chronic liver failure; however long-term survival is higher compared to other indications

Preliminary Results of a Structural Health Monitoring System Application for Real-Time Debonding Detection on a Full-Scale Composite Spar

The present paper reports the outcomes of activities concerning a real-time SHM system for debonding flaw detection based on ground testing of an aircraft structural component as a basis for condition-based maintenance. In this application, a damage detection method unrelated to structural or load models is investigated. In the reported application, the system is applied for real-time detection of two flaws, kissing bond type, artificially deployed over a full-scale composite spar under the action of external bending loads. The proposed algorithm, local high-edge onset (LHEO), detects damage as an edge onset in both the space and time domains, correlating current strain levels to next strain levels within a sliding inner product proportional to the sensor step and the acquisition time interval, respectively. Real-time implementation can run on a consumer-grade computer. The SHM algorithm was written in Matlab and compiled as a Python module, then called from a multiprocess wrapper code with separate operations for data reception and data elaboration. The proposed SHM system is made of FBG arrays, an interrogator, an in-house SHM code, an original decoding software (SW) for real-time implementation of multiple SHM algorithms and a continuous interface with an external operator

Current and future perspective on targeted agents and immunotherapies in hepatocellular carcinoma

Hepatocellular carcinoma (HCC) represents the sixth most commonly diagnosed cancer and the fourth leading cause of cancer-related death worldwide. HCC occurs predominantly in patients with underlying chronic liver disease and cirrhosis, and it presents a poor prognosis in advanced stage. Since its approval, for the following 10 years, sorafenib remained the only systemic agent with proven clinical efficacy for patients with advanced HCC. Recently, more drugs have been studied and several advances in first-line and second-line treatment options should yield significant improvements in survival. Lenvatinib, another tyrosine-kinase inhibitor, was found to be non-inferior to sorafenib in terms of overall survival (OS). with significantly better progression-free survival and objective response rate (ORR). The tyrosinekinase inhibitors, regorafenib and cabozantinib, were shown to significantly improve survival in the second-line setting after sorafenib failure. Ramucirumab, a VEGF inhibitor, can also improve survival in the second-line setting among patients with AFP >= 400 ng/dL. Moreover, good efficacy was seen in phase I/II trials of immune checkpoint inhibitors as monotherapy. Ongoing trials are evaluating combination immune checkpoint inhibitor and tyrosine-kinase inhibitors or VEGF inhibitors for increasing overall survival in this patient population with advanced HCC

Hepatocellular carcinoma risk in patients with HBV-related liver disease receiving antiviral therapy

Hepatitis B virus (HBV) is a major health problem worldwide, with approximatively 240 million people living with a chronic HBV infection. HBV chronic infection remains the major cause of hepatocellular carcinoma worldwide, with more than half of HCC patients being chronic HBV carriers, even if underlying mechanisms of tumorigenesis are not totally understood. HBV-related HCC can be prevented by reducing the exposure to HBV by vaccination or by treatment of CHB infection. Current treatment of CHB are Peg-IFN alpha and oral NUCs. Treating HBV infection, either with IFN or NUCs, substantially reduces the risk of HCC development, even if antiviral therapy fails to completely eliminate MCC risk. Among treated patients, cirrhosis, HBeAg negative at baseline and failure to remain in virological remission were associated with an increased risk of HCC. The reduction of the risk of developing HCC during antiviral therapy is largely dependent upon the maintenance of virological remission, since viral load is found to be the most important factor leading to cirrhosis and its complications, including liver cancer development. The question whether Peg-IFN-alpha is superior to NUCs and whether there is a superior agent among NUCs is still controversial. Several studies demonstrated that antiviral therapy with NUCs could reduce the risk of HCC recurrence after curative treatment of HBV-related HCC

Management of portal hypertension severe complications

Portal hypertension is a clinical syndrome characterized by an increase in the portal pressure gradient, defined as the gradient between the portal vein at the site downstream of the site of obstruction and the inferior vena cava. The most frequent cause of portal hypertension is cirrhosis. In patients with cirrhosis, portal hypertension is the main driver of cirrhosis progression and development of hepatic decompensation (ascites, variceal hemorrhage, and hepatic encephalopathy), which defines the transition from compensated to decompensated stage. In decompensated patients, treatments aim at lowering the risk of death by preventing further decompensation and/or development of acute-on-chronic liver failure. Decompensated patients often pose a complex challenge which typically requires a multidisciplinary approach. The aims of the present review are to discuss the current knowledge regarding interventional treatments for patients with portal hypertension complications as well as to highlight useful information to aid hepatologists in their clinical practice. Specifically, we discuss indications and contraindications of transjugular intra-hepatic portosystemic shunt (TIPS) and balloon-occluded transvenous retrograde obliteration (BRTO) for the treatment of gastro-esophageal variceal hemorrhage in patients with decompensated cirrhosis (first section), we review the use of interventional treatments in patients with hepatic vein obstruction (Budd-Chiari syndrome) and in those with portal vein thrombosis (second section), and we briefly comment on the most frequent applications of selective splenic embolization in patients with and without underlying cirrhosis (third section)

The impact of sarcopenia on the outcome of patients with cirrhosis with and without hepatocellular carcinoma who undergo liver transplantation

Background: The impact of sarcopenia on the outcome of patients with cirrhosis who undergo liver transplantation (LT) has been analysed in heterogeneous cohorts with mixed results. We sought to determine the prevalence and the impact of pre-LT sarcopenia on morbidity and mortality after LT in a cohort of patients with cirrhosis with and without hepatocellular carcinoma (HCC).Methods: Patients with cirrhosis who underwent LT between 2010 and 2016 at Padua University Hospital were retrospectively evaluated. Using image software analysis, cross-sectional area of skeletal muscle at 3rd lumbar vertebra was measured and skeletal muscle index (SMI) was calculated. Sarcopenia was defined by SMI < 50 cm2/m2 in males and < 39 cm2/m2 in females, respectively. Primary outcome was post-LT survival. Secondary outcomes included hospitalization length and post-LT complications.Results: 197 patients were included, of whom, 122 (62%) had sarcopenia. Demographics and severity of cirrhosis were comparable in patients with vs. without sarcopenia. Overall survival was similar between the groups. When survival analysis was adjusted for severity of liver disease, sarcopenia was associated with a significantly reduced survival in decompensated (80% vs. 91%, 1-year post-LT; P = 0.04) but not in compensated (93% vs. 90%, 1-year post-LT; P = 0.7) patients. In patients with HCC, sarcopenia was associated with a trend towards lower survival but only in those with HCC beyond Milan criteria. Among secondary outcomes, bacterial infections were more frequent in patients with vs. without sarcopenia (50% vs. 35%; P = 0.02), whereas hospitalization length and other complications were comparable between the groups.Conclusion: Sarcopenia is a common finding in patients awaiting LT and, in those with decompensated cirrhosis, it is associated with reduced survival after transplantation