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Surgical Treatment Strategies and Prognosis of Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC is the fifth most common cause of mortality worldwide and the third cancer related cause and is responsible for about 1 million deaths yearly [1]. The ageadjusted worldwide incidence is 5.5-14.9 per 100.000 population. In some areas of the world, such as sub-Saharan Africa and Southeast Asia, HCC represents the first cause of cancer death with an incidence of 52 per 100.000. Furthermore, in Europe and USA, HCC incidence has progressively raised in the past decade representing a burden problem. HCC is one of the few cancers for which a number of risk factors are known in great detail [2, 3]. HCC is almost always (80%) associated with cirrhosis, at least in developed countries, and chronic hepatitis C and B infection, alcoholic cirrhosis and haemocromatosis are some of the established risk factors [4]. The metabolic syndrome related to hypertension, central obesity, diabetes and obesity has been identified as a new risk factor. As a result, screening programs have developed, with the use of ultrasound and \u3b1-fetoprotein (AFP), with a hope to increase the chances of diagnosing small HCC and unltimately increase the rate of curability. Definitive diagnosis relies on the demonstration of a typical vascular pattern per liver imaging techniques (triple-phase CT-scan or MRI) of tumors larger than 2 cm with arterial hypervascularity and venous wash- out. Nodules, smaller than 2 cm, should be rechecked every six months or, if highly suspect, subjected to needle biopsy. It\u2019s likely that the study of tumor-specific tissue markers with prognostic value could introduce a systematic use of needle biopsy. Over the past 20 years, surgical treatment of hepatocellular carcinoma has seen an immense boost and improvement, with good survival outcomes and reduced morbidity and mortality.Liver resection (LR) and orthotopic liver transplantation (OLT) and ablative therapies are now considered the only potentially curative treatments for this cancer. LR has achieved improvement in survival within the past decade as a result of advances in diagnosis, surgical management of HCC and perioperative care. However, the long-term prognosis remains poor, and the 5-year overall survival rate ranges between 33% and 44%, with a 5-year cumulative recurrence rate of 80% to 100%. OLT could be viewed as the optimal treatment for HCC that is accompanied by advanced cirrhosis because of the widest possible resection margins for tumour and for a definitive cure of cirrhosis and its related complications. OLT for HCC performed within well-defined oncologic criteria (Milan criteria \u201creference\u201d) has shown long-term results comparable with those of transplantation for non-HCC patients. However, the critical shortage of available donated organs, together with the increasing number of patients awaiting transplantation, makes this therapeutic option available to only a small percentage of patients. Owing to the limited organ supply, many liver transplant centers usually make a selection to resect patients with compensated liver cirrhosis, defined as Child\u2013Pugh A chronic liver disease and resectable tumor and to reserve transplantation for those with impaired liver function (Child-Pugh class B-C) and small oligonodular HCC considered within the currently accepted criteria for transplantation. Radiofrequency and microwave ablation are relatively new percutaneous techniques in clinical use for HCC, that can produce tumour necrosis. Complete response rates are high in large series if tumour is less that 3 cm in diameter. This chapter will consider the main surgical techniques for the treatment of HCC in the light of the major guidelines currently available and of personal experience. Also, we will review HCC prognostic factors, and the particular situation of \u201clarge\u201d HCC and the strategy for liver tumours located at the hepato-caval confluence

Serum Soluble Vascular-Cell Adhesion Molecule-1 (VCAM-1) in Patients with Acute and Chronic Liver Diseases

Our ai m was to ascertai n the degree of variation of serum soluble vascular cell adhesion moleculeI (VCAM-1) concentrations according to the nature and the severity of an underl ying liver disease . One-hundred forty sera collected from 123 patients (83 male, 40 female) with acute hepatitis (n=14). mi Id chronic Ii ver disease (n=52) or cirrhosis (n=57) of different etiologies as well as from 17 healthy blood donors (8 male, 9 female) were studied. Soluble VCAM-I concentration was measured immunoenzymatically. One-way analysis of variance revealed a significant variability of the mean values of soluble VCAM-1 among groups (F=80.02, p <0.000 I). All groups of patients had higher soluble VCAM-I than controls; moreover, patients with acute hepatitis and patients with cirrhosis had higher soluble VCAM-1 levels than patients with mild chronic liver disease (Bonferroni's test. p <0.(1). These results did not change after stratification of patients according to the etiology (viral or toxic) of liver disease (two-way analysis of variance: grouping factor diagnosis, F=60.39, p <0.000 I; grouping factor etiology. F= 1.73, p NS). Cholinesterase, total bilirubin, circulating thrombocytes and blood urea nitrogen were the independent predictors of the concentration of soluble VCAM-1. In conclusion, patients with liver disease have high serum soluble VCAM-1, which seems to reflect more the severity of impairment of liver function rather than the etiologic nature of the disease

Serum Soluble Vascular-Cell Adhesion Molecule-1 (VCAM-1) in Patients with Acute and Chronic Liver Diseases

Our ai m was to ascertai n the degree of variation of serum soluble vascular cell adhesion moleculeI (VCAM-1) concentrations according to the nature and the severity of an underl ying liver disease . One-hundred forty sera collected from 123 patients (83 male, 40 female) with acute hepatitis (n=14). mi Id chronic Ii ver disease (n=52) or cirrhosis (n=57) of different etiologies as well as from 17 healthy blood donors (8 male, 9 female) were studied. Soluble VCAM-I concentration was measured immunoenzymatically. One-way analysis of variance revealed a significant variability of the mean values of soluble VCAM-1 among groups (F=80.02, p <0.000 I). All groups of patients had higher soluble VCAM-I than controls; moreover, patients with acute hepatitis and patients with cirrhosis had higher soluble VCAM-1 levels than patients with mild chronic liver disease (Bonferroni's test. p <0.(1). These results did not change after stratification of patients according to the etiology (viral or toxic) of liver disease (two-way analysis of variance: grouping factor diagnosis, F=60.39, p <0.000 I; grouping factor etiology. F= 1.73, p NS). Cholinesterase, total bilirubin, circulating thrombocytes and blood urea nitrogen were the independent predictors of the concentration of soluble VCAM-1. In conclusion, patients with liver disease have high serum soluble VCAM-1, which seems to reflect more the severity of impairment of liver function rather than the etiologic nature of the disease

Obesity Modifies the Performance of Fibrosis Biomarkers in Nonalcoholic Fatty Liver Disease

Context: Guidelines recommend blood-based fibrosis biomarkers to identify advanced nonalcoholic fatty liver disease (NAFLD), which is particularly prevalent in patients with obesity. Objective: To study whether the degree of obesity affects the performance of liver fibrosis biomarkers in NAFLD. Design: Cross-sectional cohort study comparing simple fibrosis scores [Fibrosis-4 Index (FIB-4); NAFLD Fibrosis Score (NFS); aspartate aminotransferase to platelet ratio index; BARD (body mass index, aspartate-to-alanine aminotransferase ratio, diabetes); Hepamet Fibrosis Score (HFS)] and newer scores incorporating neo-epitope biomarkers PRO-C3 (ADAPT, FIBC3) or cytokeratin 18 (MACK-3). Setting: Tertiary referral center. Patients: We recruited overweight/obese patients from endocrinology (n = 307) and hepatology (n = 71) clinics undergoing a liver biopsy [median body mass index (BMI) 40.3 (interquartile range 36.0-44.7) kg/m(2)]. Additionally, we studied 859 less obese patients with biopsy-proven NAFLD to derive BMI-adjusted cutoffs for NFS. Main Outcome Measures: Biomarker area under the receiver operating characteristic (AUROC), sensitivity, specificity, and predictive values to identify histological stage >= F3 fibrosis or nonalcoholic steatohepatitis with >= F2 fibrosis [fibrotic nonalcoholic steatohepatitis (NASH)]. Results: The scores with an AUROC >= 0.85 to identify >= F3 fibrosis were ADAPT, FIB-4, FIBC3, and HFS. For fibrotic NASH, the best predictors were MACK-3 and ADAPT. The specificities of NFS, BARD, and FIBC3 deteriorated as a function of BMI. We derived and validated new cutoffs for NFS to rule in/out >= F3 fibrosis in groups with BM Is = 40.0 kg/m(2). This optimized its performance at all levels of BMI. Sequentially combining FIB-4 with ADAPT or FIBC3 increased specificity to diagnose >= F3 fibrosis. Conclusions: In obese patients, the best-performing fibrosis biomarkers are ADAPT and the inexpensive FIB-4, which are unaffected by BMI. The widely used NFS loses specificity in obese individuals, which may be corrected with BMI-adjusted cutoffs.Peer reviewe

Rare ATG7 genetic variants predispose patients to severe fatty liver disease

Non-alcoholic fatty liver disease (NAFLD) is the leading cause of liver disorders and has a strong heritable component. The aim of this study was to identify new loci that contribute to severe NAFLD by examining rare variants

A simple in silico strategy identifies candidate biomarkers for the diagnosis of liver fibrosis in morbidly obese subjects

Background &amp; aims: Non-alcoholic fatty liver disease (NAFLD) is a chronic liver disorder, tightly associated with obesity. The histological spectrum of the disease ranges from simple steatosis to steatohepatitis, with different stages of fibrosis, and fibrosis stage is the most significant predictor of mortality in NAFLD. Liver biopsy continues to be the gold standard for its diagnosis and reliable non-invasive diagnostic tools are unavailable. We investigated the accuracy of candidate proteins, identified by an in silico approach, as biomarkers for diagnosis of fibrosis. Methods: Seventy-one morbidly obese (MO) subjects with biopsy-proven NAFLD were enrolled, and the cohort was subdivided according to minimal (F0/F1) or moderate (F2/F3) fibrosis. The plasmatic level of CD44 antigen (CD44), secreted protein acidic and rich in cysteine (SPARC), epidermal growth factor receptor (EGFR) and insulin-like growth factor 2 (IGF2) were determined by ELISA. Significant associations between plasmatic levels and histological fibrosis were determined by correlation analysis and the diagnostic accuracy by the area under receiver operating characteristic curves (AUROC). Results: Eighty-two percentage of the subjects had F0/F1 and 18% with F2/F3 fibrosis. Plasmatic levels of IGF2, EGFR and their ratio (EGFR/IGF2) were associated with liver fibrosis, correlating inversely for IGF2 (P &lt; .006) and directly (P &lt; .018; P &lt; .0001) for EGFR and EGFR/IGF2 respectively. The IGF2 marker had the best diagnostic accuracy for moderate fibrosis (AUROC 0.83), followed by EGFR/IGF2 ratio (AUROC 0.79) and EGFR (AUROC 0.71). Conclusions: Our study supports the potential utility of IGF2 and EGFR as non-invasive diagnostic biomarkers for liver fibrosis in morbidly obese subjects.Facultad de Ciencias Exacta

Impact of safety-related dose reductions or discontinuations on sustained virologic response in HCV-infected patients: Results from the GUARD-C Cohort

BACKGROUND: Despite the introduction of direct-acting antiviral agents for chronic hepatitis C virus (HCV) infection, peginterferon alfa/ribavirin remains relevant in many resource-constrained settings. The non-randomized GUARD-C cohort investigated baseline predictors of safety-related dose reductions or discontinuations (sr-RD) and their impact on sustained virologic response (SVR) in patients receiving peginterferon alfa/ribavirin in routine practice. METHODS: A total of 3181 HCV-mono-infected treatment-naive patients were assigned to 24 or 48 weeks of peginterferon alfa/ribavirin by their physician. Patients were categorized by time-to-first sr-RD (Week 4/12). Detailed analyses of the impact of sr-RD on SVR24 (HCV RNA <50 IU/mL) were conducted in 951 Caucasian, noncirrhotic genotype (G)1 patients assigned to peginterferon alfa-2a/ribavirin for 48 weeks. The probability of SVR24 was identified by a baseline scoring system (range: 0-9 points) on which scores of 5 to 9 and <5 represent high and low probability of SVR24, respectively. RESULTS: SVR24 rates were 46.1% (754/1634), 77.1% (279/362), 68.0% (514/756), and 51.3% (203/396), respectively, in G1, 2, 3, and 4 patients. Overall, 16.9% and 21.8% patients experienced 651 sr-RD for peginterferon alfa and ribavirin, respectively. Among Caucasian noncirrhotic G1 patients: female sex, lower body mass index, pre-existing cardiovascular/pulmonary disease, and low hematological indices were prognostic factors of sr-RD; SVR24 was lower in patients with 651 vs. no sr-RD by Week 4 (37.9% vs. 54.4%; P = 0.0046) and Week 12 (41.7% vs. 55.3%; P = 0.0016); sr-RD by Week 4/12 significantly reduced SVR24 in patients with scores <5 but not 655. CONCLUSIONS: In conclusion, sr-RD to peginterferon alfa-2a/ribavirin significantly impacts on SVR24 rates in treatment-naive G1 noncirrhotic Caucasian patients. Baseline characteristics can help select patients with a high probability of SVR24 and a low probability of sr-RD with peginterferon alfa-2a/ribavirin