Mariano Malaguarnera

Molecular mechanisms involved in NAFLD progression

Non-alcoholic fatty liver disease (NAFLD) is an emerging metabolic-related disorder characterized by fatty infiltration of the liver in the absence of alcohol consumption. NAFLD ranges from simple steatosis to non-alcoholic steatohepatitis (NASH), which might progress to end-stage liver disease. This progression is related to the insulin resistance, which is strongly linked to the metabolic syndrome consisting of central obesity, diabetes mellitus, and hypertension. Earlier, the increased concentration of intracellular fatty acids within hepatocytes leads to steatosis. Subsequently, multifactorial complex interactions between nutritional factors, lifestyle, and genetic determinants promote necrosis, inflammation, fibrosis, and hepatocellular damage. Up to now, many studies have revealed the mechanism associated with insulin resistance, whereas the mechanisms related to the molecular components have been incompletely characterized. This review aims to assess the potential molecular mediators initiating and supporting the progression of NASH to establish precocious diagnosis and to plan more specific treatment for this disease.

Serum Markers of Hepatocellular Carcinoma

BackgroundThe hepatocellular carcinoma is one of the most common malignant tumors and carries a poor survival rate. The management of patients at risk for developing HCC remains intricate.MethodsA literature search identified potential markers for hepatocellular carcinoma. These markers were analysed and justification was provided for these factors’ inclusion to (or exclusion from) the markers of hepatocellular carcinoma (HCC). A search of the literature was made using cancer literature and the PubMed database for the following keywords: “markers and HCC,” “Lens culinaris agglutinin reactive AFP (AFP-L3) and HCC,” “Des-γ-carboxy prothrombin (DCP) and HCC,” “Glypican-3 and HCC,” “Chromogranin A and HCC,” “Transforming growth factor β1(TGF) and HCC,” “α-l-fucosidase (AFU) and HCC,” “Golgi protein-73 (GP73) and HCC,” “Hepatocyte growth factor (HGF) and HCC,” “Nervous growth factor (NGF) and HCC.”ConclusionsDespite the large number of studies devoted to the immunohistochemistry of HCC, at the present time, the absolute positive and negative markers for HCC are still lacking, and even those characterized by very high sensitivity and specificity do not have an universal diagnostic usefulness. Given the poor response to current therapies, a better understanding of the molecular pathways active in this disease could potentially provide new targets for therapy. However, AFP shows a low sensitivity, therefore other biomarkers have been developed to make an early diagnosis and improve patients’ prognosis.

Bifidobacterium longum with Fructo-Oligosaccharide (FOS) Treatment in Minimal Hepatic Encephalopathy: A Randomized, Double-Blind, Placebo-Controlled Study

Minimal hepatic encephalopathy (MHE) describes patients with chronic liver disease or cirrhosis who have no clinical symptoms of brain dysfunction but perform worse on psychometric tests compared with healthy subjects. The pathogenesis of hepatic encephalopathy is controversial although ammonia has been found to induce cerebral dysfunction. Increased intestinal ammonia production is due to bacterial urease activity and the production of other toxin methabolities, such as mercaptans, thioles. This study assesses the clinical efficacy of Bifidobacterium longum plus fructo-oligosaccharides (FOS) in the treatment of MHE. A total of 60 cirrhotic patients were randomly and equally divided into two groups receiving Bifidobacterium+FOS (17 males, 13 females; mean age, 46±11 years) or placebo (16 males, 14 females; mean age, 45±12 years), respectively. All patients underwent clinical and laboratory assessment psychometric tests and automated EEG analysis: neurophysiological assessment, liver function assessment, amd neuropsychological assessment. After 90 days of treatment, fasting NH4 serum levels were significantly decreased (P=0.003), performance on Trail Making Test-A was significantly decreased (P=0.000), performance on Trail Making Test-B was significantly decreased (P=0.000), performance on the symbol digit modalities test was significantly improved (P<0.05), performance on block design was significantly improved (P=0.000), and performance on the MMSE test was significantly improved (P=0.000). We conclude that the improvement in biochemical and neuropsychological tests of the group treated with Bifidobacterium longum+FOS are interesting and merit further, close examination.

L -Carnitine Supplementation to Diet: A New Tool in Treatment of Nonalcoholic Steatohepatitis — A Randomized and Controlled Clinical Trial

OBJECTIVES:Nonalcoholic steatohepatitis (NASH) is a known metabolic disorder of the liver. No treatment has been conclusively shown to improve NASH or prevent disease progression. The function of L-carnitine to modulate lipid profile, glucose metabolism, oxidative stress, and inflammatory responses has been shown. The aim of this study was to evaluate the effects of L-carnitines supplementation on regression of NASH.METHODS:In patients with NASH and control subjects, we randomly dispensed one 1-g L-carnitine tablet after breakfast plus diet and one 1 g tablet after dinner plus diet for 24 weeks or diet alone at the same dosage and regimen. We evaluated liver enzymes, lipid profile, fasting plasma glucose, C-reactive protein (CRP), tumor necrosis factor (TNF)-α, homeostasis model assessment (HOMA)-IR, body mass index, and histological scores.RESULTS:At the end of the study, L-carnitine-treated patients showed significant improvements in the following parameters: aspartate aminotransferase (P=0.000), alanine aminotransferase (ALT) (P=0.000), γ-glutamyl-transpeptidase (γ-GT) (P=0.000), total cholesterol (P=0.000), low-density lipoprotein (LDL) (P=0.000), high-density lipoprotein (HDL) (P=0.000), triglycerides (P=0.000), glucose (P=0.000), HOMA-IR (P=0.000), CRP (P=0.000), TNF-α (P=0.000), and histological scores (P=0.000).CONCLUSIONS:L-carnitine supplementation to diet is useful for reducing TNF-α and CRP, and for improving liver function, glucose plasma level, lipid profile, HOMA-IR, and histological manifestations of NASH.

B cells in the aged: CD27, CD5, and CD40 expression.

Ageing is characterized by numerous changes in lymphocyte subpopulations. In the present paper we have focused on B cells carrying the surface markers CD27, CD5 and CD40. CD27 is considered a marker of primed (memory) cells and its engagement promotes the differentiation of memory B cells into plasma cells. CD5 is expressed on B1 cells, which are considered to be responsible for T cell-independent antibody production other than autoantibodies. The CD40 molecule binds CD40L (CD154) and is necessary for T-dependent antibody responses. Here we show that the absolute number of CD5+ and CD40+ B cells is decreased in the elderly, while CD27+ B lymphocytes only marginally decrease in centenarians. However, there is a decrease of the percentage of CD5+ B cells, an increase of CD27+ B cells, while CD40 does not change significantly. These data, together with the increased number of NK cells during aging, suggest different regulation of antibody production in the elderly which might be another example of immune remodeling with aging, based on interactions between human B and NK cells.

Elevation of interleukin 6 levels in patients with chronic hepatitis due to hepatitis C virus

Interleukin 6 (IL-6) is a pleiotropic cytokine produced by a wide variety of lymphoid and nonlymphoid tissues. We studied the relationship between IL-6 and the liver in an attempt to elucidate this cytokines role in hepatitis C-induced liver inflammation. We investigated the behavior of serum IL-6 in 25 patients with chronic hepatitis C (divided into three groups depending on severity) and in 27 healthy controls. Our results showed a significant elevation (P<0.0001) in serum IL-6 levels in the patients with chronic hepatitis C, correlated with the histological activity index (HAI) and their HCV-RNA serum levels. This rise may represent the expression of the hepatitis C virusinduced inflammatory state.

Prediction of the response to citalopram and reboxetine in post-stroke depressed patients

Rationale and objectiveDepression is a significant complication of stroke. The effectiveness of antidepressant drugs in the management of post-stroke depression (PSD) has been widely investigated. However, the choice of antidepressant drug is critically influenced by its safety and tolerability and by its effect on concurrent pathologies. Here we investigate the efficacy and safety of a selective serotonin reuptake inhibitor (SSRI), citalopram, and a noradrenaline reuptake inhibitor (NARI), reboxetine, in post-stroke patients affected by anxious depression or retarded depression.MethodsThis was a randomized double-blind study. Seventy-four post-stroke depressed patients were diagnosed as affected by anxious or retarded depression by using a synoptic table. Randomisation was planned so that 50% of the patients in each subgroup were assigned for 16 weeks to treatment with citalopram and the remaining 50% were assigned to treatment with reboxetine. The Beck Depression Inventory (BDI), the Hamilton Depression Rating Scale (HDRS) and a synoptic table were used to score depressive symptoms.ResultsBoth citalopram and reboxetine showed good safety and tolerability. Citalopram exhibited greater efficacy in anxious depressed patients, while reboxetine was more effective in retarded depressed patients.ConclusionsCitalopram or other SSRIs and reboxetine may be of first choice treatment in PSD because of their good efficacy and lack of severe side effects. In addition, PSD patients should be classified according to their clinical profile (similarly to patients affected by primary depression) for the selection of SSRIs or reboxetine as drugs of choice in particular subgroups of patients.

Bifidobacterium combined with fructo-oligosaccharide versus lactulose in the treatment of patients with hepatic encephalopathy

Background Hepatic encephalopathy (HE) is a reversible neuropsychiatric syndrome in patients with liver disease. It was suggested that Bifidobacterium+fructo-oligosaccharides (FOS) may decrease blood and brain ammonia levels. Aim The study was conducted to compare the efficacy of Bifidobacterium+FOS and lactulose in patients with HE. Methods One hundred and twenty-five patients (35 hepatitis B virus infected, 70 hepatitis C virus infected and 20 cryptogenetic cirrhosis) were enrolled in the study. Patients were randomized either to a treatment for 60 days with Bifidobacterium and FOS (group A) or into-group receiving lactulose (group B) in double-blind. Results After 30 days of the study period, the Bifidobacterium+FOS-treated patients compared with lactulose-treated patients showed a significant decrease of Trail Making Test B (TMT B) (P<0.005), and a significant increase of Symbol Digit Modalities Test (P<0.001) and Block Design Test (P<0.001). After 60 days of the study period, the Bifidobacterium+FOS-treated patients compared with lactulose-treated patients showed a significant decrease of NH4 fasting HE1 (P<0.001), TMT A (P<0.05), TMT B (P<0.001), and a significant increase of Symbol Digit Modalities Test (P<0.001) and Block Design Test (P<0.001). Conclusion The treatment with Bifidobacterium+FOS is an alternative to the use of lactulose in patients with cirrhosis, for its usefulness in reducing blood ammonia levels and improvement of psychometric tests.

The management of tumor lysis syndrome

The manifestation of tumor lysis syndrome (TLS) occurs when the destruction of tumor cells releases breakdown products that overwhelm the excretory mechanisms of the body. A cardinal sign is hyperuricemia, leading to uric acid nephropathy. Other signs are hyperkalemia, hyperphosphatemia and secondary hypocalcemia. Conventional management of TLS consists of aggressive intravenous hydration, diuretic therapy, urinary alkalization, and inhibition of urate production by high-dose allopurinol. Urate oxidase has been used in the management of patients at risk for TLS and recently the recombinant urate oxidase rasburicase was developed. Several data indicate that rasburicase is effective and well tolerated in the prevention and treatment of chemotherapy-induced hyperuricemia. Treatment options of hyperkalemia include sodium polystyrene sulfonate, hypertonic glucose and insulin, loop diuretics, and bicarbonate. Treatment of hyperphosphatemia reduces dietary phosphate intake and includes phosphate binders such as aluminum hydroxide and aluminum carbonate. When recurrent hypocalcemia is present, a continuous intravenous infusion of calcium gluconate can be initiated. Hemodialysis should be considered for every patient with excessively elevated uric acid, phosphate and/or potassium and in those patients with acute renal failure to control urinary volume and manage uremia.

Chitotriosidase and inflammatory mediator levels in Alzheimer's disease and cerebrovascular dementia

Inflammation has been reported to be involved in the pathogenesis of cerebrovascular dementias (CvDs). This study investigated the involvement of Chitotriosidase (ChT), a chinolitic enzyme mainly produced by activated macrophages, in the pathophysiology of Alzheimers disease (AD) and ischemic CvD. In addition, the levels of interleukin (IL)‐16, IL‐18, transforming growth factor (TGF) ‐β1 and superoxide anion (O2–) were determined to evaluate the relationship between ChT levels, these cytokines and oxidative stress in both AD and ischemic CvD patients. The levels of ChT and IL‐16, IL‐18, and TGF‐β1 mRNA were investigated using quantitative real‐time polymerase chain reaction on macrophages of peripheral blood of 40 patients with AD, 40 patients with ischemic CvD and 40 non‐demented age‐matched subjects. The results show that ChT, IL‐16 and O2– levels significantly increased in ischemic CvD patients compared with AD patients and were significantly and positively correlated with IL‐18 and O2–. The production of IL‐18 was increased in both AD and ischemic CvD patients. TGF‐β1 expression was higher in AD patients and was inversely correlated with the expression of ChT, IL‐16 and IL‐18, respectively. In non‐demented age‐matched subjects no significant changes in ChT and IL‐16, IL‐18, and TGF‐β1 expression were found. Our results indicate that ChT, IL‐16, IL‐18 and TGF‐β1 are increased in ischemic CvD and AD, confirming that the immune system may play an important role in the development and progression of neurodegenerative disorders. In addition, the present findings suggest that ChT could also play a crucial role in pathological conditions such as CvD in which the inflammatory process is activated.