Relationship between adipose tissue dysfunction, Vitamin D deficiency and the pathogenesis of non-alcoholic fatty liver disease

Non-alcoholic fatty liver disease ( NAFLD) is the most common chronic liver disease worldwide. Its pathogenesis is complex and not yet fully understood. Over the years many studies have proposed various pathophysiological hypotheses, among which the currently most widely accepted is the "multiple parallel hits" theory. According to this model, lipid accumulation in the hepatocytes and insulin resistance increase the vulnerability of the liver to many factors that act in a coordinated and cooperative manner to promote hepatic injury, inflammation and fibrosis. Among these factors, adipose tissue dysfunction and subsequent chronic low grade inflammation play a crucial role. Recent studies have shown that vitamin D exerts an immune-regulating action on adipose tissue, and the growing wealth of epidemiological data is demonstrating that hypovitaminosis D is associated with both obesity and NAFLD. Furthermore, given the strong association between these conditions, current findings suggest that vitamin D may be involved in the relationship between adipose tissue dysfunction and NAFLD. The purpose of this review is to provide an overview of recent advances in the pathogenesis of NAFLD in relation to adipose tissue dysfunction, and in the pathophysiology linking vitamin D deficiency with NAFLD and adiposity, together with an overview of the evidence available on the clinical utility of vitamin D supplementation in cases of NAFLD

Phenotypical heterogeneity linked to adipose tissue dysfunction in patients with type 2 diabetes

Adipose tissue (AT) inflammation leads to increased free fatty acid (FFA) efflux and ectopic fat deposition, but whether AT dysfunction drives selective fat accumulation in specific sites remains unknown. The aim of the present study was to investigate the correlation between AT dysfunction, hepatic/pancreatic fat fraction (HFF, PFF) and the associated metabolic phenotype in patients with Type 2 diabetes (T2D). Sixty-five consecutive T2D patients were recruited at the Diabetes Centre of Sapienza University, Rome, Italy. The study population underwent clinical examination and blood sampling for routine biochemistry and calculation of insulin secretion [homoeostasis model assessment of insulin secretion (HOMA-β%)] and insulin-resistance [homoeostasis model assessment of insulin resistance (HOMA-IR) and adipose tissue insulin resistance (ADIPO-IR)] indexes. Subcutaneous (SAT) and visceral (VAT) AT area, HFF and PFF were determined by magnetic resonance. Some 55.4% of T2D patients had non-alcoholic fatty liver disease (NAFLD); they were significantly younger and more insulin-resistant than non-NAFLD subjects. ADIPO-IR was the main determinant of HFF independently of age, sex, HOMA-IR, VAT, SAT and predicted severe NAFLD with the area under the receiver operating characteristic curve (AUROC)=0.796 (95% confidence interval: 0.65-0.94, P=0.001). PFF was independently associated with increased total adiposity but did not correlate with AT dysfunction, insulin resistance and secretion or NAFLD. The ADIPO-IR index was capable of predicting NAFLD independently of all confounders, whereas it did not seem to be related to intrapancreatic fat deposition; unlike HFF, higher PFF was not associated with relevant alterations in the metabolic profile. In conclusion, the presence and severity of AT dysfunction may drive ectopic fat accumulation towards specific targets, such as VAT and liver, therefore evaluation of AT dysfunction may contribute to the identification of different risk profiles among T2D patients

Palliation with Oesophageal Metal Stent of Pseudoachalasia from Gastric Carcinoma at the Cardia: A Case Report

We present an 82-year-old woman with a 3-month history of progressive dysphagia and a normal initial upper gastrointestinal endoscopy. The diagnosis of pseudoachalasia was suspected by oesophageal manometric and barium swallow studies, and confirmed by biopsies revealing an intestinal type carcinoma of the stomach at a repeated endoscopy. In view of the history of heart disease, diabetes, and old age, this patient was treated by a partially covered Ultraflex self-expanding metal stent (Boston Scientific, Natick, MA, USA) placed into the oesophageal body with no direct complications and obtaining the relief from dysphagia. During the 11-month follow-up she was treated for an iron deficiency anaemia due to reflux oesophagitis with ulcerations in the oesophageal body and died from myocardial infarction. According to the localization of the cancer, the old age, and the presence of comorbidities, we should recommend the insertion of a partially covered self-expanding metal stent as a reasonable palliative treatment in selected subjects with pseudoachalasia

Strong association between non alcoholic fatty liver disease (NAFLD) and low 25(OH) vitamin D levels in an adult population with normal serum liver enzymes

<p>Abstract</p> <p>Background</p> <p>Hypovitaminosis D has been recently recognized as a worldwide epidemic. Since vitamin D exerts significant metabolic activities, comprising free fatty acids (FFA) flux regulation from the periphery to the liver, its deficiency may promote fat deposition into the hepatocytes. Aim of our study was to test the hypothesis of a direct association between hypovitaminosis D and the presence of NAFLD in subjects with various degree of insulin-resistance and related metabolic disorders.</p> <p>Methods</p> <p>We studied 262 consecutive subjects referred to the Diabetes and Metabolic Diseases clinics for metabolic evaluation. NAFLD (non-alcoholic fatty liver disease) was diagnosed by upper abdomen ultrasonography, metabolic syndrome was identified according to the Third Report of National Cholesterol Education Program/Adult Treatment Panel (NCEP/ATPIII) modified criteria. Insulin-resistance was evaluated by means of HOMA-IR. Fatty-Liver-Index, a recently identified correlate of NAFLD, was also estimated. Serum 25(OH)vitamin D was measured by colorimetric method.</p> <p>Results</p> <p>Patients with NAFLD (n = 162,61.8%) had reduced serum 25(OH) vitamin D levels compared to subjects without NAFLD (14.8 ± 9.2 vs 20.5 ± 9.7 ng/ml, p < 0.001, OR 0.95, IC 95% 0.92-0.98). The relationship between NAFLD and reduced 25(OH)vitamin D levels was independent from age, sex, triglycerides, high density lipoproteins (HDL) and glycaemia (p < 0.005) and Fatty Liver Index inversely correlated with low 25(OH) vitamin D regardless sex, age and HOMA-IR (p < 0.007).</p> <p>Conclusions</p> <p>Low 25(OH)vitamin D levels are associated with the presence of NAFLD independently from metabolic syndrome, diabetes and insulin-resistance profile.</p

No effects of oral vitamin D supplementation on non-alcoholic fatty liver disease in patients with type 2 diabetes: a randomized, double-blind, placebo-controlled trial

Background: Non-alcoholic fatty liver disease (NAFLD) is the most common hepatic disorder worldwide, reaching prevalence up to 90 % in obese patients with type 2 diabetes (T2D), and representing an independent risk factor for cardiovascular mortality. Furthermore, the coexistence of T2D and NAFLD leads to higher incidence of diabetes’ complications and additive detrimental liver outcomes. The existence of a close association between NAFLD and hypovitaminosis D, along with the anti-inflammatory and insulin-sensitizing properties of vitamin D, have been largely described, but vitamin D effects on hepatic fat content have never been tested in a randomized controlled trial. We assessed the efficacy and safety of 24-week oral high-dose vitamin D supplementation in T2D patients with NAFLD. Methods: This randomized, double-blind, placebo-controlled trial was carried out at the Diabetes Centre of Sapienza University, Rome, Italy, to assess oral treatment with cholecalciferol (2000 IU/day) or placebo in T2D patients with NAFLD. The primary endpoint was reduction of hepatic fat fraction (HFF) measured by magnetic resonance; as hepatic outcomes, we also investigated changes in serum transaminases, CK18-M30, N-terminal Procollagen III Propeptide (P3NP) levels, and Fatty Liver Index (FLI). Secondary endpoints were improvement in metabolic (fasting glycaemia, HbA1c, lipids, HOMA-IR, HOMA-β, ADIPO-IR, body fat distribution) and cardiovascular (ankle-brachial index, intima-media thickness, flow-mediated dilatation) parameters from baseline to end of treatment. Results: Sixty-five patients were randomized, 26 (cholecalciferol) and 29 (placebo) subjects completed the study. 25(OH) vitamin D significantly increased in the active treated group (48.15 ± 23.7 to 89.80 ± 23.6 nmol/L, P &lt; 0.001); however, no group differences were found in HFF, transaminases, CK18-M30, P3NP levels or FLI after 24 weeks. Vitamin D neither changed the metabolic profile nor the cardiovascular parameters. Conclusions: Oral high-dose vitamin D supplementation over 24 weeks did not improve hepatic steatosis or metabolic/cardiovascular parameters in T2D patients with NAFLD. Studies with a longer intervention period are warranted for exploring the effect of long time exposure to vitamin D

Hypovitaminosis D is independently associated with metabolic syndrome in obese patients

Background: Metabolic syndrome (MS) and hypovitaminosis D represent two of the most diffuse condition worldwide, reaching pandemic proportions in industrialized countries, and are both strongly associated with obesity. This study set out to evaluate the presence of an independent association between hypovitaminosis D and MS in an adult population of obese subjects with/without MS. Methods: We recruited 107 consecutive obese subjects, 61 with MS (age(mean +/- SD) 45.3 +/- 13.3 years, BMI(mean +/- SD): 43.1 +/- 8.3 kg/m(2)) and 46 without MS (age: 41.8 +/- 11.5, p = n.s., BMI: 41.6 +/- 6.5 kg/m(2), p = n.s.) comparable for sex, BMI, waist circumference and body fat mass, evaluated by bioimpedentiometry. 25(OH) vitamin D-3 levels were measured by colorimetric method. Insulin resistance was estimated by fasting blood insulin, HOMA-IR and ISI. Results: Serum 25(OH) D3 levels were significantly lower in MS obese patients than in obese subjects without MS (median(range) 13.5(3.3-32) vs 17.4(5.1-37.4), p&lt;0.007). Low 25(OH)D-3 levels correlated with glycaemia (p&lt;0.007), phosphate (p&lt;0.03), PTH (p&lt;0.003) and the MS (p&lt;0.001). Multivariate model confirmed that low 25(OH)D-3 levels were associated with the diagnosis of MS in obese patients independently from gender, age, serum PTH and body fat mass. After stratifying the study population according to 25(OH)D-3 concentrations, patients in the lowest quartile showed a markedly increased prevalence of MS compared to those in the highest quartile (OR = 4.1, CI 1.2-13.7, p = 0.02). Conclusions: A powerful association exists between hypovitaminosis D and MS in obese patients independently from body fat mass and its clinical correlates. This indicates that the association between low 25(OH)D-3 levels and MS is not merely induced by vitamin D deposition in fat tissue and reinforces the hypothesis that hypovitaminosis D represent a crucial independent determinant of MS.Background:Metabolic syndrome (MS) and hypovitaminosis D represent two of the most diffuse condition worldwide, reaching pandemic proportions in industrialized countries, and are both strongly associated with obesity. This study set out to evaluate the presence of an independent association between hypovitaminosis D and MS in an adult population of obese subjects with/without MS.Methods:We recruited 107 consecutive obese subjects, 61 with MS (age(mean±SD) 45.3±13.3 years, BMI(mean±SD): 43.1±8.3 kg/m2) and 46 without MS (age: 41.8±11.5, p = n.s., BMI:41.6±6.5 kg/m2, p = n.s.) comparable for sex, BMI, waist circumference and body fat mass, evaluated by bioimpedentiometry. 25(OH) vitamin D3 levels were measured by colorimetric method. Insulin resistance was estimated by fasting blood insulin, HOMA-IR and ISI.Results:Serum 25(OH)D3 levels were significantly lower in MS obese patients than in obese subjects without MS (median(range) 13.5(3.3-32) vs 17.4(5.1-37.4), p&lt;0.007). Low 25(OH)D3 levels correlated with glycaemia (p&lt;0.007), phosphate (p&lt;0.03), PTH (p&lt;0.003) and the MS (p&lt;0.001). Multivariate model confirmed that low 25(OH)D3 levels were associated with the diagnosis of MS in obese patients independently from gender, age, serum PTH and body fat mass. After stratifying the study population according to 25(OH)D3 concentrations, patients in the lowest quartile showed a markedly increased prevalence of MS compared to those in the highest quartile (OR = 4.1, CI 1.2-13.7, p = 0.02).Conclusions:A powerful association exists between hypovitaminosis D and MS in obese patients independently from body fat mass and its clinical correlates. This indicates that the association between low 25(OH) D3 levels and MS is not merely induced by vitamin D deposition in fat tissue and reinforces the hypothesis that hypovitaminosis D represent a crucial independent determinant of MS. © 2013 Barchetta et al

Toll-like receptor-4 is involved in hepatic fibrogenesis in the course of non-alcoholic fatty liver disease

Toll-like receptor-4 (TLR4) is actively involved in liver in the response to injury from a variety of etiologies. Recently TLR4 expression by hepatic progenitor cells (HPC) and biliary epithelial cells has been associated to the progression of liver damage in chronic HCV-related hepatitis (1). HPC compartment activation in ductular reaction (DR) is a feature of progressive disease also in non-alcoholic fatty liver disease (NAFLD) (2). We aimed to investigate the association among TLR4 expression, HPC compartment activation and histopathologic features of fibrotic disease progression in NAFLD. Seventy-four patients who had undergone liver biopsy were included and immunohistochemistry for TLR4 was performed on hepatic tissue samples. CK-7 was used to evaluate HPC, bile ducts (BD)/ductules of DR and intermediate hepatocytes; α-smooth muscle actin was used to quantify the activation of hepatic stellate cells (HSC) and of portal/septal myofibroblasts (MF). HPC in BD/DR were responsible for the highest TLR4 intensity of staining. TLR4-positive HPC and BD/ DR correlated with fibrosis (p&lt;0.01 and p&lt;0.05), activity of MF (p&lt;0.001 and p&lt;0.05) and HSC (p&lt;0.001 and p&lt;0.001), portal and interface chronic inflammation (p&lt;0.01 and p=0.01). The present study indicates the activation of the TLR4 expressing HPC compartment as important determinant of the progressive liver damage in NAFLD. TLR4 stimulation could represent one of the mechanisms directly linking the activation of HPC to inflammation and fibrosis in NAFLD

Portal and interface chronic inflammation are associated with the progenitor cell compartment activation during NAFLD

Background and aim: During nonalcoholic fatty liver disease (NAFLD), portal and interface chronic inflammation (PCI and ICI) are strongly associated with fibrosis by activation of hepatic stellate cell (HSC)s (Brunt et al., 2009; Vespasiani-Gentilucci et al., 2014). However, the determinants of PCI and ICI observed in NAFLD remain to be elucidated. Since portal and periportal ductular reaction is related to disease progression, we aimed to investigate if PCI and ICI are associated with hepatic progenitor cell (HPC) compartment activation. Methods: Fifty-two NAFLD patients were studied. NAFLD activity score, fibrosis, PCI and ICI were histologically evaluated. HPCs, intermediate hepatobiliary cells and bile ductules/interlobular bile ducts were evaluated by immunohistochemistry for CK-7, CK-19 and EpCAM. HSC and myofibroblast (MF) activity were determined by immunohistochemistry for α-SMA. Results: PCI and ICI strongly correlated with HPC compartment activation and with the activity of MFs (p≤0.001). Lobular inflammation, ballooning and HPC compartment activation were all associated with both PCI (p&lt;0.01) and ICI (p&lt;0.05) by univariate analysis. In the multivariate models, HPC compartment activation was independently associated with PCI and ICI (OR 4.4, 1.7-11.5; OR 3.4, 1.5-7.9, respectively). Conclusions: During NAFLD, PCI and ICI are strongly associated with HPC compartment activation and this association is likely one determinant subtending the strong association between PCI/ICI and fibrosis

Global diversity in the TAS2R38 bitter taste receptor: Revisiting a classic evolutionary PROPosal

The ability to taste phenylthiocarbamide (PTC) and 6-n-propylthiouracil (PROP) is a polymorphic trait mediated by the TAS2R38 bitter taste receptor gene. It has long been hypothesized that global genetic diversity at this locus evolved under pervasive pressures from balancing natural selection. However, recent high-resolution population genetic studies of TAS2Rs suggest that demographic events have played a critical role in the evolution of these genes. We here utilized the largest TAS2R38 database yet analyzed, consisting of 5,589 individuals from 105 populations, to examine natural selection, haplotype frequencies and linkage disequilibrium to estimate the effects of both selection and demography on contemporary patterns of variation at this locus. We found signs of an ancient balancing selection acting on this gene but no post Out-Of-Africa departures from neutrality, implying that the current observed patterns of variation can be predominantly explained by demographic, rather than selective events. In addition, we found signatures of ancient selective forces acting on different African TAS2R38 haplotypes. Collectively our results provide evidence for a relaxation of recent selective forces acting on this gene and a revised hypothesis for the origins of the present-day worldwide distribution of TAS2R38 haplotypes

Reelin expression in liver and pancreas and its correlation with liver fibrosis

Reelin is an extracellular glycoprotein secreted by a variety of cell types in both embryonic and adult tissue and plays a critical role during brain development (1,2). Reelin is up-regulated in experimental liver cirrhosis of rats in hepatic stellate cell(HSC)s, the cell type mainly implicated in liver fibrogenesis, supporting that reelin is involved in the pathogenesis of liver fibrosis (3). Pancreatic stellate cell(PSC)s share similar morphology and function to HSCs, in pancreatic fibrosis setting (4). Currently, the role of reelin in human liver and pancreas is still unclear. We investigated reelin expression in different stages of chronic liver disease in 81 liver biopsies of HCV affected patients and in pancreatic tissue near to tumoral lesions. The expression of Reelin, HSC markers (CRBP1, alpha-SMA) and Dab1, a Reelin adaptor protein, was investigated by immunohistochemistry and immunofluorescence. Reelin protein was expressed by HSCs and a strong correlation was found between Reelin expression and liver fibrosis stage (