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1.
Eur J Intern Med ; 26(8): 635-9, 2015 Oct.
Article in English | MEDLINE | ID: mdl-26293833

ABSTRACT

BACKGROUND: Increased levels of adiponectin, a major adipokine with insulin sensitizing properties showing a strong sexual dimorphism, have been reported in individuals with chronic HCV infection (CHC), but data are limited by small samples and lack of control for the genetic background and hepatic fibrosis. The aim of this study was to compare adiponectin levels between CHC patients and accurately matched controls. METHODS: We considered 184 CHC patients, matched (1:1) for age, gender, body mass index, and Adiponectin genotype (ADIPOQ) with healthy individuals. To control for the severity of liver disease, a second control group consisting of 95 patients with histological nonalcoholic fatty liver disease (NAFLD) further matched (1:1) for severe fibrosis was exploited. ADIPOQ genotype was evaluated by Taqman assays, serum adiponectin measured by ELISA. RESULTS: Serum adiponectin was higher in CHC patients than in healthy individuals (9.0±5.0 µg/ml vs. 7.3±4.0 µg/ml; p=0.001; adjusted estimate +1.8, 1.7-2.9; p=0.001), and than in NAFLD patients (8.3±4.5 µg/ml vs. 6.0±4.2 µg/ml; p<0.001; adjusted estimate +0.8, 0.2-1.4, p=0.006). After stratification for sex, serum adiponectin was higher in males with CHC than in healthy individuals and NAFLD patients (p<0.005 for both), whereas the difference was not significant in females. CONCLUSIONS: CHC is associated with increased serum adiponectin independently of age, body mass, diabetes, ADIPOQ genotype, and of severe liver fibrosis, particularly in men.


Subject(s)
Adiponectin/blood , Hepatitis C, Chronic/blood , Adiponectin/genetics , Case-Control Studies , Female , Genotype , Humans , Male , Middle Aged , Non-alcoholic Fatty Liver Disease/blood , Severity of Illness Index , Sex Factors
2.
PLoS One ; 7(11): e48804, 2012.
Article in English | MEDLINE | ID: mdl-23144979

ABSTRACT

BACKGROUND & AIMS: Hepatic iron accumulation due to altered trafficking is frequent in patients with nonalcoholic fatty liver disease (NAFLD), and is associated with more severe liver damage and hepatocellular carcinoma. The p.Ala736Val TMPRSS6 variant influences iron metabolism regulating the transcription of the hepatic hormone hepcidin, but its role in the pathogenesis of iron overload disorders is controversial. Aim of this study was to evaluate the whether the TMPRSS6 p.Ala736Val variant influences hepatic iron accumulation in a well-characterized series of Italian patients with histological NAFLD. METHODS: 216 patients with histological NAFLD. TMPRSS6 and HFE variants were assessed by allele specific PCR, liver histology by the NAFLD activity score and Perls' staining for iron. RESULTS: Homozygosity for the p.736Val allele previously linked to higher hepcidin did not influence transferrin saturation (TS), but was associated with lower hepatic iron stores (p = 0.01), and ferritin levels (median 223 IQR 102-449 vs. 308 IQR 141-618 ng/ml; p = 0.01). Homozygosity for TMPRSS6 p.736Val was nearly associated with lower ballooning (p = 0.05), reflecting hepatocellular damage related to oxidative stress. The influence of TMPRSS6 on hepatic iron accumulation was more marked in patients negative for HFE genotypes predisposing to iron overload (p.Cys282Tyr + and p.His63Asp +/+; p = 0.01), and the p.736Val variant was negatively associated with hepatic iron accumulation independently of age, gender, HFE genotype, and beta-thalassemia trait (OR 0.59, 0.39-0.88). CONCLUSIONS: The p.Ala736Val TMPRSS6 variant influences secondary hepatic iron accumulation in patients with NAFLD.


Subject(s)
Fatty Liver/genetics , Iron Overload/genetics , Membrane Proteins/genetics , Polymorphism, Genetic , Serine Endopeptidases/genetics , Amino Acid Substitution , Body Mass Index , Dyslipidemias/complications , Dyslipidemias/genetics , Fatty Liver/complications , Ferritins/metabolism , Genetic Predisposition to Disease , Genotype , Hemochromatosis Protein , Histocompatibility Antigens Class I/genetics , Humans , Iron/metabolism , Iron Overload/complications , Membrane Proteins/chemistry , Non-alcoholic Fatty Liver Disease , Risk Factors , Serine Endopeptidases/chemistry
3.
BMC Gastroenterol ; 12: 111, 2012 Aug 16.
Article in English | MEDLINE | ID: mdl-22898488

ABSTRACT

BACKGROUND: Reduced adiponectin is implicated in the pathogenesis of nonalcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH), and the I148M Patatin-like phospholipase domain-containing 3 (PNPLA3) polymorphism predisposes to NAFLD and liver damage progression in NASH and chronic hepatitis C (CHC) by still undefined mechanisms, possibly involving regulation of adipose tissue function. Aim of this study was to evaluate whether the I148M PNPLA3 polymorphism influences serum adiponectin in liver diseases and healthy controls. METHODS: To this end, we considered 144 consecutive Italian patients with NAFLD, 261 with CHC, 35 severely obese subjects, and 257 healthy controls with very low probability of steatosis, all with complete clinical and genetic characterization, including adiponectin (ADIPOQ) genotype. PNPLA3 rs738409 (I148M) and ADIPOQ genotypes were evaluated by Taqman assays, serum adiponectin by ELISA. Adiponectin mRNA levels were evaluated by quantitative real-time PCR in the visceral adipose tissue (VAT) of 35 obese subjects undergoing bariatric surgery. RESULTS: Adiponectin levels were independently associated with the risk of NAFLD and with the histological severity of the disease. Adiponectin levels decreased with the number of 148 M PNPLA3 alleles at risk of NASH both in patients with NAFLD (p = 0.03), and in healthy subjects (p = 0.04). At multivariate analysis, PNPLA3 148 M alleles were associated with low adiponectin levels (<6 mg/ml, median value) independently of NAFLD diagnosis, age, gender, BMI, and ADIPOQ genotype (OR 1.67, 95% c.i. 1.07-2.1 for each 148 M allele). The p.148 M PNPLA3 variant was associated with decreased adiponectin mRNA levels in the VAT of obese patients (p < 0.05) even in the absence of NASH. In contrast, in CHC, characterized by adiponectin resistance, low adiponectin was associated with male gender and steatosis, but not with PNPLA3 and ADIPOQ genotypes and viral features. CONCLUSIONS: The I148M PNPLA3 variant is associated with adiponectin levels in patients with NAFLD and in healthy subjects, but in the presence of adiponectin resistance not in CHC patients. The I148M PNPLA3 genotype may represent a genetic determinant of serum adiponectin levels. Modulation of serum adiponectin might be involved in mediating the susceptibility to steatosis, NASH, and hepatocellular carcinoma in carriers of the 148 M PNPLA3 variant without CHC, with potential therapeutic implications.


Subject(s)
Adiponectin/blood , Fatty Liver/blood , Fatty Liver/genetics , Lipase/genetics , Membrane Proteins/genetics , Polymorphism, Genetic/genetics , Adult , Aged , Alleles , Case-Control Studies , Fatty Liver/epidemiology , Female , Genetic Predisposition to Disease/genetics , Genotype , Hepatitis C, Chronic/blood , Hepatitis C, Chronic/genetics , Humans , Male , Middle Aged , Multivariate Analysis , Obesity/blood , Obesity/genetics , Risk Factors
4.
World J Nephrol ; 1(6): 166-76, 2012 Dec 06.
Article in English | MEDLINE | ID: mdl-24175256

ABSTRACT

The anemia of chronic kidney disease and hemodialysis is characterized by chronic inflammation and release of cytokines, resulting in the upregulation of the iron hormone hepcidin, also increased by iron therapy and reduced glomerular filtration, with consequent reduction in iron absorption, recycling, and availability to the erythron. This response proves advantageous in the short-term to restrain iron availability to pathogens, but ultimately leads to severe anemia, and impairs the response to erythropoietin (Epo) and iron. Homozygosity for the common C282Y and H63D HFE polymorphisms influence iron metabolism by hampering hepcidin release by hepatocytes in response to increased iron stores, thereby resulting in inadequate inhibition of the activity of Ferroportin-1, inappropriately high iron absorption and recycling, and iron overload. However, in hemodialysis patients, carriage of HFE mutations may confer an adaptive benefit by decreasing hepcidin release in response to iron infusion and inflammation, thereby improving iron availability to erythropoiesis, anemia control, the response to Epo, and possibly survival. Therefore, anti-hepcidin therapies may improve anemia management in hemodialysis. However, HFE mutations directly favor hemoglobinization independently of hepcidin, and reduce macrophages activation in response to inflammation, whereas hepcidin might also play a beneficial anti-inflammatory and anti-microbic action during sepsis, so that direct inhibition of HFE-mediated regulation of iron metabolism may represent a valuable alternative therapeutic target. Genetic studies may offer a valuable tool to test these hypotheses and guide the research of new therapies.

5.
J Hepatol ; 53(5): 927-33, 2010 Nov.
Article in English | MEDLINE | ID: mdl-20739079

ABSTRACT

BACKGROUND & AIMS: Parenchymal liver siderosis is associated with increased fibrosis in patients with non-alcoholic fatty liver disease (NAFLD). The aim of this study was to assess whether a panel of genetic variants previously reported to influence iron metabolism, including the C282Y/H63D HFE, the PiZ/PiS alpha1-antitrypsin, the IVS1-24 ferroportin polymorphisms, and the beta-thalassemia trait, may be able to predict the presence of parenchymal siderosis and of progressive fibrosis in NAFLD. METHODS: We considered 274 Italian patients with biopsy-proven NAFLD. Genetic polymorphisms were searched for by sequence allele specific-polymerase chain reaction and restriction analysis, whereas beta-trait was determined according to blood count and HbA(2) determination. RESULTS: Parenchymal iron deposition was predominantly observed in 32 (11.7%) patients. Heterozygosity for the C282Y (OR 1.87, 95% CI 1.04-3.25), homozygosity for the H63D HFE (OR 2.31, 95% CI 1.04-4) mutations, and the beta-thalassemia trait (OR 2.57 95% CI 1.49-4.47) were all predominantly associated with parenchymal siderosis, independently of age, sex, body mass index, alcohol intake, ferritin, and transferrin saturation. Sixty-three percent of patients with hepatocellular siderosis were positive for at least one of the aforementioned genetic variants. The beta-thalassemia trait had the highest positive and the lowest negative likelihood ratios for predominantly parenchymal iron accumulation (5.05 and 0.74, respectively), and was independently associated with moderate/severe fibrosis (OR 2.50, 95% CI 1.26-5.19). CONCLUSIONS: In patients with NAFLD, predominant hepatocellular iron deposition is often related to genetic factors, among which beta-globin mutations play a major role, predisposing to parenchymal iron accumulation and to progressive liver fibrosis.


Subject(s)
Iron Overload/genetics , Liver Cirrhosis/genetics , Mutation , beta-Globins/genetics , Adult , Aged , Fatty Liver/complications , Fatty Liver/genetics , Female , Ferritins/blood , Humans , Iron/metabolism , Iron Overload/etiology , Liver Cirrhosis/etiology , Male , Middle Aged , Non-alcoholic Fatty Liver Disease
6.
Gastroenterology ; 138(3): 905-12, 2010 Mar.
Article in English | MEDLINE | ID: mdl-19931264

ABSTRACT

BACKGROUND & AIMS: Mutations in the hemochromatosis gene (HFE) (C282Y and H63D) lead to parenchymal iron accumulation, hemochromatosis, and liver damage. We investigated whether these factors also contribute to the progression of fibrosis in patients with nonalcoholic fatty liver disease (NAFLD). METHODS: We studied clinical, histologic (liver biopsy samples for hepatocellular iron accumulation), serologic (iron and enzyme levels), and genetic (HFE genotype) data from 587 patients from Italy with NAFLD and 184 control subjects. RESULTS: Iron accumulation predominantly in hepatocyes was associated with a 1.7-fold higher risk of a fibrosis stage greater than 1 (95% confidence interval [CI]: 1.2-2.3), compared with the absence of siderosis (after adjustment for age, body mass index, glucose tolerance status, and alanine aminotransferase level). Nonparenchymal/mixed siderosis was not associated with moderate/severe fibrosis (odds ratio, 0.72; 95% CI: 0.50-1.01). Hepatocellular siderosis was more prevalent in patients with HFE mutations than in those without; approximately one third of patients with HFE mutations had parenchymal iron accumulation (range, 29.8%-35.7%, depending on HFE genotype). Predominantly hepatocellular iron accumulation occurred in 52.7% of cases of patients with HFE mutations. There was no significant association between either the presence of HFE mutations or specific HFE genotypes and the severity of liver fibrosis. CONCLUSIONS: Iron deposition predominantly in hepatocyes is associated with more severe liver damage in patients with NAFLD. However, HFE mutations cannot be used to identify patients with hepatocellular iron accumulation.


Subject(s)
Fatty Liver/etiology , Hemochromatosis/genetics , Histocompatibility Antigens Class I/genetics , Iron/metabolism , Liver Cirrhosis/etiology , Liver/metabolism , Membrane Proteins/genetics , Mutation , Adult , Biopsy , Case-Control Studies , Disease Progression , Fatty Liver/genetics , Fatty Liver/metabolism , Fatty Liver/pathology , Female , Gene Frequency , Genetic Predisposition to Disease , Hemochromatosis/complications , Hemochromatosis/metabolism , Hemochromatosis/pathology , Hemochromatosis Protein , Humans , Italy , Liver/pathology , Liver Cirrhosis/genetics , Liver Cirrhosis/metabolism , Liver Cirrhosis/pathology , Logistic Models , Male , Middle Aged , Odds Ratio , Phenotype , Risk Assessment , Risk Factors , Severity of Illness Index
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