Internal Medicine and Metabolic Diseases

Milano, Italy

Internal Medicine and Metabolic Diseases

Milano, Italy
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Valenti L.,Internal Medicine and Metabolic Diseases | Pelusi S.,Internal Medicine and Metabolic Diseases
Hemodialysis International | Year: 2017

Introduction: in chronic hemodialysis patients, a disruption in iron metabolism ranging from absolute to functional deficiency, with compartmentalization of this metal into macrophages, is often observed. Chronic inflammation indeed often causes an upregulation of the iron hormone hepcidin, thereby reducing iron absorption and availability to the erythron. Methods: we systematically reviewed the literature on the role of genetic risk factors on iron metabolism in hemodialysis. Findings: in this setting, mutations in the HFE gene of hereditary hemochromatosis may confer an adaptive benefit by decreasing hepcidin release, thus improving iron availability to erythropoiesis, anemia control, and the response to erythropoiesis stimulating agents and iron itself, and reducing the side effects of these therapies. The HFE protein together with Transferrin receptor-2 may also have a direct role on erythroid differentiation and iron uptake in erythroid cells. In addition, other genetic determinants of iron status, such as variants in Matriptase-2 (TMPRSS6), have been shown to influence iron metabolism in chronic hemodialysis patients, most likely acting through hepcidin regulation. Discussion: although data must be confirmed in larger prospective studies, this favorable shift in iron metabolism balance possibly results in reduced mortality, in particular because of cardiovascular and infective diseases. Further genetic studies may offer a valuable tool to test these hypotheses and guide personalized clinical management and the research of new therapies. © 2017 International Society for Hemodialysis.


Dongiovanni P.,Internal Medicine and Metabolic Diseases | Valenti L.,Internal Medicine and Metabolic Diseases | Valenti L.,University of Milan
International Journal of Molecular Sciences | Year: 2017

Following the epidemics of obesity due to the consumption of high-calorie diet and sedentary lifestyle, nonalcoholic fatty liver disease (NAFLD) is now the leading cause of liver disease in Western countries. NAFLD is epidemiologically associated with metabolic syndrome and insulin resistance, and in susceptible individuals it may progress to cirrhosis and hepatocellular carcinoma. Genetic factors play a key role in NAFLD predisposition by interacting with nutritional and other environmental factors. To date, there is no drug therapy for the treatment of NAFLD, and the main clinical recommendation is lifestyle modification. In the last years, nutrigenomics is promoting an increased understanding of how nutrition affects the switch from health to disease by altering the expression of an individual’s genetic makeup. The present review tries to summarize the most recent data evidencing how the interactions between nutrients and genetic factors can influence NAFLD development. The final goal should be to develop tools to quantify these complex interactions. The definition of a “nutrigenomic risk score” for each individual may represent a novel therapeutic approach for the management of NAFLD patients. © 2017 by the authors. Licensee MDPI, Basel, Switzerland.


Milano M.,Internal Medicine and Metabolic Diseases | Aghemo A.,Gastroenterology and Hepatology | Mancina R.M.,Gothenburg University | Fischer J.,University of Leipzig | And 18 more authors.
Hepatology | Year: 2015

Steatosis and inherited host factors influence liver damage progression in chronic hepatitis C (CHC). The transmembrane 6 superfamily member 2 (TM6SF2) gene E167K variant increases liver fat and risk of progressive steatohepatitis by interfering with lipoprotein secretion. Our aim was to determine whether the E167K variant affects histological severity of steatosis, necroinflammation, and fibrosis in a cross-sectional cohort of 815 Italian therapy-naïve CHC patients. The association with clinically significant fibrosis was replicated in 645 Swiss/German patients. The TM6SF2 E167K variant was genotyped by TaqMan assays, steatosis graded according to the nonalcoholic fatty liver disease activity score, and necroinflammation and fibrosis graded and staged according to Ishak in Italian, and to Metavir in Swiss/German patients. The E167K variant was detected in 69 (9%) Italian patients and was associated with more severe steatosis, independently of confounders (P=0.038). The association between E167K and steatosis severity was present in patients not infected by genotype 3 (G3) HCV (P=0.031), but not in those infected by G3 HCV (P=0.58). Furthermore, the E167K variant was associated with more severe necroinflammation (Ishak grade; adjusted P=0.037) and nearly associated with more severe fibrosis (Ishak stage; adjusted P=0.058). At multivariate logistic regression analysis, the E167K variant was independently associated with histologically probable or definite cirrhosis (Ishak stage S6; odds ratio [OR]: 2.19; 95% confidence interval [CI]: 1.18-3.93; P=0.010). After further conditioning for steatosis and necroinflammation, the E167K variant remained associated with cirrhosis (OR, 3.15; 95% CI: 1.60-5.99; P<0.001). In Swiss/German patients, the E167K variant was independently associated with clinically significant fibrosis Metavir stage F2-F4 (OR, 1.81; 95% CI: 1.12-3.02; P=0.016). Conclusion: TM6SF2 E167K variant impacts on steatosis severity and is associated with liver damage and fibrosis in patients with CHC. © 2015 by the American Association for the Study of Liver Diseases.


PubMed | University of Turin, University of Verona, Internal Medicine and Metabolic Diseases and Columbia University
Type: Review | Journal: Liver international : official journal of the International Association for the Study of the Liver | Year: 2016

Growing epidemiological evidence suggests that nonalcoholic fatty liver disease (NAFLD) is an early predictor of and determinant for the development of type 2 diabetes and other features of the metabolic syndrome. This finding may have important clinical implications for the diagnosis, prevention and treatment of type 2 diabetes and its chronic complications. However, given the complex and bi-directional relationships between NAFLD, insulin resistance and chronic hyperglycaemia, it is extremely difficult to distinguish whether NAFLD is a cause or a consequence of insulin resistance and type 2 diabetes. Indeed, at the molecular level, hepatic lipogenesis and hepatic glucose production depend on differentially regulated branches of the insulin signalling pathway. Furthermore, genetic studies suggest that excess hepatic fat is associated with progressive liver disease, but does not always increase the risk of incident type 2 diabetes. Here, we will briefly review the epidemiological, pathophysiological and molecular evidence linking NAFLD to the development of type 2 diabetes. We will also discuss some recent genetic and therapeutic advances that seem to challenge a causal role of NAFLD in the pathogenesis type 2 diabetes, and propose a working hypothesis to explain this apparent conundrum. In conclusion, progressive liver disease and type 2 diabetes are divergent though inter-related consequences of insulin resistance and the metabolic syndrome.


Dongiovanni P.,Internal Medicine and Metabolic Diseases | Romeo S.,Gothenburg University | Romeo S.,University of Catanzaro | Valenti L.,Internal Medicine and Metabolic Diseases | Valenti L.,University of Milan
BioMed Research International | Year: 2015

Liver fat accumulation generally related to systemic insulin resistance characterizes nonalcoholic fatty liver disease (NAFLD), which in the presence of nonalcoholic steatohepatitis (NASH) can progress towards cirrhosis and hepatocellular carcinoma. Due to the epidemic of obesity, NAFLD is now the most frequent liver disease in Western countries. Epidemiological, familial, and twin studies provide evidence for a strong genetic component of NAFLD susceptibility. Recently, genome-wide association studies led to the identification of the major inherited determinants of hepatic fat accumulation: patatin-like phospholipase domain-containing 3 (PNPLA3) I148M gene and transmembrane 6 superfamily member 2 (TM6SF2) E167K gene variants, involved in lipid droplets remodelling and very low-density lipoproteins secretion, are the major determinants of interindividual differences in liver steatosis, and susceptibility to progressive NASH. In this review, we aimed to provide an overview of recent insights into the genetics of hepatic fat accumulation and steatohepatitis. © 2015 Paola Dongiovanni et al.


Dongiovanni P.,Internal Medicine and Metabolic Diseases | Valenti L.,University of Milan
Metabolism: Clinical and Experimental | Year: 2015

Epidemiological, familial, and twin studies indicate that non-alcoholic fatty liver disease, now the leading cause of liver damage in developed countries, has a strong heritability. The common I148M variant of PNPLA3 impairing hepatocellular lipid droplets remodeling is the major genetic determinant of hepatic fat content. The I148M variant has a strong impact on the full spectrum of liver damage related to fatty liver, encompassing non-alcoholic steatohepatitis, advanced fibrosis, and hepatocellular carcinoma, and influences the response to therapeutic approaches. Common variants in GCKR enhance de novo hepatic lipogenesis in response to glucose and liver inflammation. Furthermore, the low-frequency E167K variant of TM6SF2 and rare mutations in APOB, which impair very low-density lipoproteins secretion, predispose to progressive fatty liver. Conclusions: These and other recent findings reviewed here indicate that impaired lipid handling by hepatocytes has a major role in the pathogenesis of non-alcoholic fatty liver disease by triggering inflammation, fibrogenesis, and carcinogenesis. These discoveries have provided potential novel biomarkers for clinical use and have revealed intriguing therapeutic targets. © 2015 Elsevier Inc.


Dongiovanni P.,Internal Medicine and Metabolic Diseases | Lanti C.,University of Milan | Riso P.,University of Milan | Valenti L.,Internal Medicine and Metabolic Diseases | Valenti L.,University of Milan
Journal of Nutritional Biochemistry | Year: 2016

Following the epidemics of obesity, nonalcoholic fatty liver disease (NAFLD) has become the leading cause of liver disease in western countries. NAFLD is the hepatic manifestation of metabolic syndrome and may progress to cirrhosis and hepatocellular carcinoma. To date, there are no approved drugs for the treatment of NAFLD, and the main clinical recommendation is lifestyle modification, including increase of physical activity and the adoption of a healthy eating behavior. In this regard, studies aimed to elucidate the effect of dietary interventions and the mechanisms of action of specific food bioactives are urgently needed.The present review tries to summarize the most recent data evidencing the effects of nutrients and dietary bioactive compounds intake (i.e., long-chain PUFA, Vitamin E, Vitamin D, minerals and polyphenols) on the modulation of molecular mechanisms leading to fat accumulation, oxidative stress, inflammation and liver fibrosis in NAFLD patients. © 2015 Elsevier Inc.


PubMed | Internal Medicine and Metabolic Diseases and University of Milan
Type: Journal Article | Journal: Metabolism: clinical and experimental | Year: 2016

Epidemiological, familial, and twin studies indicate that non-alcoholic fatty liver disease, now the leading cause of liver damage in developed countries, has a strong heritability. The common I148M variant of PNPLA3 impairing hepatocellular lipid droplets remodeling is the major genetic determinant of hepatic fat content. The I148M variant has a strong impact on the full spectrum of liver damage related to fatty liver, encompassing non-alcoholic steatohepatitis, advanced fibrosis, and hepatocellular carcinoma, and influences the response to therapeutic approaches. Common variants in GCKR enhance de novo hepatic lipogenesis in response to glucose and liver inflammation. Furthermore, the low-frequency E167K variant of TM6SF2 and rare mutations in APOB, which impair very low-density lipoproteins secretion, predispose to progressive fatty liver.These and other recent findings reviewed here indicate that impaired lipid handling by hepatocytes has a major role in the pathogenesis of non-alcoholic fatty liver disease by triggering inflammation, fibrogenesis, and carcinogenesis. These discoveries have provided potential novel biomarkers for clinical use and have revealed intriguing therapeutic targets.


PubMed | Internal Medicine and Metabolic Diseases and University of Milan
Type: | Journal: The Journal of nutritional biochemistry | Year: 2016

Following the epidemics of obesity, nonalcoholic fatty liver disease (NAFLD) has become the leading cause of liver disease in western countries. NAFLD is the hepatic manifestation of metabolic syndrome and may progress to cirrhosis and hepatocellular carcinoma. To date, there are no approved drugs for the treatment of NAFLD, and the main clinical recommendation is lifestyle modification, including increase of physical activity and the adoption of a healthy eating behavior. In this regard, studies aimed to elucidate the effect of dietary interventions and the mechanisms of action of specific food bioactives are urgently needed. The present review tries to summarize the most recent data evidencing the effects of nutrients and dietary bioactive compounds intake (i.e., long-chain PUFA, Vitamin E, Vitamin D, minerals and polyphenols) on the modulation of molecular mechanisms leading to fat accumulation, oxidative stress, inflammation and liver fibrosis in NAFLD patients.


PubMed | University of Verona, Internal Medicine and Metabolic Diseases and University of Milan
Type: Journal Article | Journal: Liver international : official journal of the International Association for the Study of the Liver | Year: 2016

Dysmetabolic iron overload syndrome (DIOS) is a frequent condition predisposing to metabolic, cardiovascular and hepatic damage, whose pathogenesis remains poorly defined. Aim of this study was to characterize iron metabolism in DIOS.We evaluated 18 patients with DIOS, compared to 18 with nonalcoholic fatty liver and 23 healthy individuals with normal iron status, and 10 patients with hereditary haemochromatosis by a 24-h oral iron tolerance test with hepcidin measurement and iron metabolism modelling under normal iron stores.Dysmetabolic iron overload syndrome patients had higher peak transferrin saturation and area under the-curve of transferrin saturation than subjects with normal iron status, but lower values than haemochromatosis patients (P < 0.05 for all). Conversely, they had higher peak circulating hepcidin levels and area under the curve of hepcidin than the other groups (P < 0.05 for all). This was independent age, sex, haemoglobin, ferritin, and transferrin saturation levels (P = 0.0002). Hepcidin increase in response to the rise in transferrin saturation (hepcidin release index) was not impaired in DIOS patients. Viceversa, the ability of the hepcidin spike to control the rise in transferrin saturation at the beginning of the test (hepcidin resistance index) was impaired in DIOS (P = 0.0002). In DIOS patients, the hepcidin resistance index was correlated with ferritin levels at diagnosis (P = 0.016).Dysmetabolic iron overload syndrome is associated with a subtle impairment in the ability of the iron hormone hepcidin to restrain iron absorption following an iron challenge, suggesting a hepcidin resistance state. Further studies are required to better characterize the molecular mechanism underpinning this new iron metabolism alteration.

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