Relazione tra ipovitaminosi D, sindrome metabolica, diabete di tipo 2 e steatosi epatica non alcool-correlata (NAFLD)

Gli studi sperimentali condotti per questa tesi hanno indagato la relazione tra l’ipovitaminosi D e la presenza di malattie del metabolismo come la SM, il T2D e la presenza di NAFLD in diverse popolazioni: soggetti afferenti presso gli ambulatori di Malattie Metaboliche per sospetta SM, con e senza NAFLD, soggetti normopeso e pazienti obesi. Lo studio ha evidenziato la presenza di una forte correlazione tra ridotti livelli sierici di 25(OH)D3 e la presenza e severità di NAFLD, indipendentemente dalla presenza di SM e insulino-resistenza nelle diverse popolazioni studiate. Per approfondire il ruolo del tessuto adiposo nel determinare ipovitaminosi D, legata al possibile sequestro intra-adipocitario di questa molecola lipofilica, è stata selezionata una popolazione adulta di soggetti obesi con o senza SM, confrontabili per sesso, età, BMI, circonferenza vita, circonferenza fianchi e percentuale di massa grassa. Attraverso questo sotto-studio è stato dimostrato che la presenza di ipovitaminosi D si associava alla diagnosi di SM indipendentemente dagli indici antropometrici e dalla massa grassa, suggerendo l’esistenza di un nesso causale tra ipovitaminosi D e fenotipo dismetabolico nelle popolazioni studiate. Per indagare il metabolismo della vitamina D in corso di epatite e comprendere se questa molecola potesse svolgere un’azione diretta sul fegato, è stata studiata l’espressione immunoistochimica delle 25-idrossilasi e del VDR in sede epatica in pazienti con NASH o HCV. Nei soggetti con NASH la presenza di basse concentrazioni sieriche di 25(OH)D3 si associava ad un maggior danno epatocitario e la minore espressione del VDR su colangiociti ed epatociti correlava con un NAS score più severo. Nei pazienti con epatite da HCV stata altresì osservata una correlazione diretta tra l’espressione del VDR e delle 25-idrossilasi negli epatociti e una ridotta espressione di CYP27A1 in presenza di fibrosi severa, indipendentemente dalla concentrazione sierica di vitamina D. Questo studio ha provato per la prima volta che il danno necro-infiammatorio in corso di epatite HCV-correlata è più accentuato nei pazienti con cellule infiammatorie scarsamente positive per il VDR. In conclusione, questo progetto dimostra la presenza di una forte associazione tra ipovitaminosi D e malattie metaboliche associate all’insulino-resistenza. La vitamina D potrebbe rivelarsi, pertanto, un determinante ancora poco indagato della risposta epatica al danno cronico indotto da differenti noxae patogenae e potrebbe influenzare direttamente la patogenesi, la progressione e la prognosi delle epatopatie su base metabolica e virale

Hypovitaminosis D in recent onset rheumatoid arthritis is predictive of reduced response to treatment and increased disease activity: a 12 month follow-up study.

BACKGROUND: Vitamin D displays immunomodulatory activities and has been proposed as a potential player in the pathogenesis of rheumatoid arthritis (RA). A negative association between serum 25(OH) vitamin D levels and RA activity was demonstrated but longitudinal studies investigating the role of vitamin D levels in predicting RA activity and response to treatment are lacking. Therefore, this study was designed to test the hypothesis of an association between serum 25(OH) vitamin D levels at RA diagnosis and disease activity evaluated by clinimetric, laboratory and ultrasound (US) parameters and to detect the prevalence of remission and response to treatment after 12 months follow-up. METHODS: This is a longitudinal, retrospective study on data obtained from thirty-seven patients with early RA treatment-naïve. Serum inflammatory markers, auto-antibodies and 25(OH) vitamin D levels were obtained at baseline. Hypovitaminosis D was diagnosed for 25(OH) vitamin D levels < 20 ng/ml. Tender joint count (TJCs), swollen joint count (SJCs), Visual Analog Scales (VAS), Disease Activity Score (DAS) 28 score were assessed at baseline and 12 months after diagnosis. Joints synovitis and power-Doppler were evaluated at baseline and 12 months later. RESULTS: At baseline mean 25(OH) vitamin D levels were 24.4 ± 11.9 ng/ml; 35% of study subjects had hypovitaminosis D which strongly associated with higher RA activity and lower prevalence of remission and response to treatment (all p-values < 0.001). The percentage of patients not presenting a reduction of the US synovitis score after 12 months from diagnosis was significantly higher among patients with hypovitaminosis D than in those with normal serum 25(OH) vitamin D at baseline. CONCLUSIONS: In patients with early RA and basal hypovitaminosis D after 12 months follow-up reduction of disease activity and percentage of remission and response to treatment were significantly lower than those observed in patients with normal vitamin D levels. These results provide further support to the immunomodulatory action of vitamin D in RA and suggest a role of basal vitamin D status in the prediction of disease evolution. Vitamin D measurement and possibly vitamin D supplementation should be considered an additional option in the management of early RA patients

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

Increased plasma proneurotensin levels identify NAFLD in adults with and without type 2 diabetes

Context Neurotensin (NT), an intestinal peptide released by fat ingestion, promotes lipid absorption; higher circulating NT levels are associated with type 2 diabetes (T2D), obesity, and cardiovascular disease. Whether NT is related to nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) has not been fully investigated. Objective To study the relationship between plasma proneurotensin 1 to 117 (pro-NT), a stable fragment of the NT precursor hormone, and the presence/severity of NAFLD/NASH and to unravel correlates of increased pro-NT levels. Design/Setting/Participants For this cross-sectional study, 60 obese individuals undergoing bariatric surgery for clinical purposes were recruited. The association between pro-NT and NAFLD was further investigated in 260 consecutive subjects referred to our outpatient clinics for metabolic evaluations, including liver ultrasonography. The study population underwent complete metabolic characterization; in the obese cohort, liver biopsies were performed during surgery. Main Outcome Measures Plasma pro-NT levels in relation to NAFLD/NASH. Results Obese subjects with biopsy-proven NAFLD (53%) had significantly higher plasma pro-NT than those without NAFLD (183.6 ± 81.4 vs 86.7 ± 56.8 pmol/L, P &lt; 0.001). Greater pro-NT correlated with NAFLD presence (P &lt; 0.001) and severity (P &lt; 0.001), age, female sex, insulin resistance, and T2D. Higher pro-NT predicted NAFLD with an area under receiver operating characteristic curve of 0.836 [95% confidence interval (CI), 0.73 to 0.94; P &lt; 0.001]. Belonging to the highest pro-NT quartile correlated with increased NAFLD risk (odds ratio, 2.62; 95% CI, 1.08 to 6.40) after adjustment for confounders. The association between higher pro-NT and NAFLD was confirmed in the second cohort independently from confounders. Conclusions Increased plasma pro-NT levels identify the presence/severity of NAFLD; in dysmetabolic individuals, NT may specifically promote hepatic fat accumulation through mechanisms likely related to increased insulin resistance. © 2018 Endocrine Society

Neurotensin is a lipid-induced gastrointestinal peptide associated with visceral adipose tissue inflammation in obesity

Neurotensin (NT) is a 13-amino acid peptide localized in the neuroendocrine cells of the small intestine, which promotes fat absorption and fatty acids translocation in response to lipid ingestion. NT-knock-out mice fed with a high-fat diet are protected from obesity, fatty liver, and the development of insulin-resistance. In humans, higher plasma levels of pro-NT, which is the stable circulating precursor of NT, predict obesity, type 2 diabetes (T2D), and cardiovascular disease. In obesity, the presence of visceral adipose tissue (VAT) inflammation leads to unfavorable metabolic outcomes and is associated with the development of T2D and non-alcoholic fatty liver disease (NAFLD). In this study, we investigated the relationship between plasma pro-NT levels and the presence of VAT inflammation in biopsies from 40 morbidly obese subjects undergoing bariatric surgery. We demonstrated that higher proNT levels are significantly associated with greater macrophages infiltration, HIF-1&alpha;, WISP-1, and UNC5B expression in VAT (all p < 0.01) due to the diagnosis of T2D and NAFLD. The overall results show that, in obesity, pro-NT is a biomarker of VAT inflammation and insulin-resistance. Additionally, NT may be involved in the development of dysmetabolic conditions likely mediated by increased gut fat absorption and the presence of a proinflammatory milieu in the adipose tissue

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

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

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

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

Liver vitamin D receptor, CYP2R1 and CYP27A1 expression related to progression of metabolic and viral chronic liver damage

Background and aim: Low serum 25(OH)vitamin D3 levels were associated with the presence and prognosis of liver diseases [1]. The biological effects of 1,25(OH)2 vitamin D3 are mediated by the vitamin D receptor (VDR) and VDR has been widely detected in liver, but its expression in the course of liver disease has never been investigated [2]. We aimed to evaluate the hepatic expression of VDR and vitamin D 25-hydroxylases in patients with chronic hepatitis C (CHC) or non-alcoholic steatohepatitis (NASH) and its relationship with liver histology and serum 25(OH) vitamin D3 levels. Methods: Patients affected by CHC or NASH who had undergone liver biopsy and subjects without liver disease were included. Expression of VDR, CYP2R1 and CYP27A1 was evaluated by immunohistochemistry. Results: In CHC subjects, fibrosis stage was associated with low hepatic CYP27A1 expression, whereas in patients with VDR-negative inflammatory cells and low VDR expression on hepatocytes, the portal inflammation was significantly higher (p&lt;0.009 and p&lt;0.03). In NASH patients, VDR expression on cholangiocytes was inversely correlated with steatosis severity (p&lt;0.02), lobular inflammation (p&lt;0.01) and NAS score (p&lt;0.03). Conclusions: The liver of patients with viral and metabolic chronic liver disease expresses VDR in a manner inversely proportional to the severity of histological lesions and a role of the vitamin D/VDR system in the progression of chronic liver damage is suggested