[Show abstract][Hide abstract] ABSTRACT: The aim of the present study was to describe the histopathologic features of hepatic iron accumulation in patients with chronic hepatitis C (CH-C) infection, the relation between HFE mutations and hepatic iron location and among iron distribution, HFE, and hepatic damage. We studied 206 patients with CH-C infection. Of 101 patients with hemosiderin deposits, 90.1% had iron deposits in hepatocytes (alone or with sinusoidal and/or portal involvement). The hepatic iron score increased significantly as iron accumulation involved sinusoidal and portal tract compartments and according to HFE genotypes. Severe fibrosis and cirrhosis were associated more markedly with the presence of hemosiderin iron in the 3 hepatic compartments, HFE mutations, and high alcohol intake. We suggest that part of the iron accumulation in CH-C infection derives from increased iron absorption and release from storage cells and that the amount and distribution of hepatic iron deposits is related to hepatic damage. HFE mutations favor both processes, but other factors, genetic or acquired, are involved.
American Journal of Clinical Pathology 01/2006; 124(6):846-53. · 2.88 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The A16V mitochondrial targeting sequence polymorphism influences the antioxidant activity of MnSOD, an enzyme involved in neutralising iron induced oxidative stress. Patients with hereditary haemochromatosis develop parenchymal iron overload, which may lead to cirrhosis, diabetes, hypogonadism, and heart disease. The objective of this study was to determine in patients with haemochromatosis whether the presence of the Val MnSOD allele, associated with reduced enzymatic activity, affects tissue damage, and in particular heart disease, as MnSOD knockout mice develop lethal cardiomyopathy. We studied 217 consecutive unrelated probands with haemochromatosis, and 212 healthy controls. MnSOD polymorphism was evaluated by restriction analysis. The frequency distribution of the polymorphism did not differ between patients and controls. Patients carrying the Val allele had higher prevalence of cardiomyopathy (A/A 4%, A/V 11%, V/V 30%, p = 0.0006) but not of cirrhosis, diabetes, or hypogonadism, independently of age, sex, alcohol misuse, diabetes, and iron overload (odds ratio 10.1 for V/V, p = 0.006). The frequency of the Val allele was higher in patients with cardiomyopathy (0.67 v 0.45, p = 0.003). The association was significant in both C282Y+/+ (p = 0.02), and in non-C282Y+/+ patients (p = 0.003), and for both dilated (p = 0.01) and non-dilated stage (p = 0.04) cardiomyopathy, but not for ischaemic heart disease. In patients with hereditary haemochromatosis, the MnSOD genotype affects the risk of cardiomyopathy related to iron overload and possibly to other known and unknown risk factors and could represent an iron toxicity modifier gene.
Journal of Medical Genetics 01/2005; 41(12):946-50. · 5.70 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We evaluated the effect of venesections and restricted diet on iron and metabolic indices and liver function tests in patients with insulin-resistance hepatic iron overload (IR-HIO).
Patients were divided in three groups: (a) patients without any therapy who were followed-up for 36+28 months; (b) patients venesected; and (c) patients on dietary treatment. In each group baseline and end-point levels of serum iron and metabolic indices, and liver function tests were compared by Student's paired t-test and the relationship between serum ferritin and the other variables during treatment was evaluated by linear regression analysis.
In the follow-up group, iron and metabolic indices did not change over time. Serum alanine aminotransferase, gamma-glutamyl transferase, cholesterol and triglycerides significantly decreased after iron depletion. Serum glucose, cholesterol, triglyceride, ferritin and liver function tests significantly decreased after dietary treatment. Transferrin saturation decreased below 20% during phlebotomy treatment in 52% of the patients. In conclusion, our results show that IR-HIO patients had relatively low amount of iron overload that seems not to increase even after a long follow-up period. Both venesections and diet improved iron, metabolic and hepatic indices. Data suggest a relationship between hepatic iron overload and insulin resistance, and a role for both iron overload and insulin resistance in hepatocellular damage. The behaviour of iron indices during venesections suggests an impaired iron release from hepatic cells.
Liver international: official journal of the International Association for the Study of the Liver 11/2004; 24(5):471-6. · 3.87 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Type 3 hemochromatosis is a rare autosomal recessive disorder due to mutations of the TFR2 gene. We describe clinical, biochemical and histopathologic findings of a patient with type 3 hemochromatosis at presentation and during a follow-up of more than 20 yr and we evaluate the effect of an associated beta-thalassemia trait on phenotypic expression. At the age of 33 yr the patient showed a marked iron overload and severe iron-related complications. After removal of 26 g of iron by subcutaneous deferoxamine infusion a marked clinical improvement was observed. Liver biopsies, performed at the age of 34 and 49 yr, indicate that in type 3 hemochromatosis there is a progressive hepatocellular iron accumulation from Rappaport's zone 1-3 and that iron loading in sinusoidal and portal macrophages occurs only in the more advanced stage. As observed in HFE hemochromatosis, the beta-thalassemia trait seems to aggravate the clinical picture of patients lacking TFR2, favoring higher rates of iron accumulation probably by activation of the erythroid iron regulator.
European Journal Of Haematology 06/2004; 72(5):370-4. · 2.55 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Insulin-resistance-associated hepatic iron overload syndrome (IRHIO) is characterized by high serum ferritin and presence of metabolic alterations that are part of insulin-resistance syndrome (IRS). Thus, clinical conditions characterized by a high prevalence of IRS may also be characterized by a high prevalence of IRHIO.
We studied 88 consecutive patients with essential hypertension, 62 patients with IRHIO and 102 healthy normotensive controls. Hemochromatosis, other conditions able to induce secondary iron overload or serum ferritin increase unrelated to body iron stores were excluded. Iron indices, metabolic profiles and hepatic tests in hypertensive with or without increased serum ferritin and in IRHIO with and without hypertension were studied. Metabolic variables, serum iron indices, liver function tests and hepatic ultrasound data were analysed. Data were compared by non-parametric tests.
In men with hypertension, increased serum ferritin was more frequent than in controls (21 versus 0%, P = 0.001). Hypertensive men with increased serum ferritin had more frequent and pronounced metabolic alterations than those with normal serum ferritin, the metabolic abnormalities and serum ferritin being frequently positively correlated. In hypertensive men with increased serum ferritin, metabolic and iron data were similar to those of IRHIO patients with hypertension.
In males, hypertension is characterized by a higher prevalence of increased iron stores and metabolic abnormalities that are part of the IRHIO syndrome. This finding may have clinical implications due to the increased risk of IRHIO patients to develop hepatic cirrhosis and also for the role of iron in early atherogenesis.
Journal of Hypertension 09/2002; 20(8):1513-8. · 4.22 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Endothelial function is noninvasively assessed by measuring nitric oxide-dependent increase in radial artery diameter accompanying the elevation in shear stress induced by increasing blood flow through a short-lasting ischemia of the hand. However, shear stress also depends on blood viscosity, whose changes might thus affect nitric oxide increase in a manner that is not properly reflected by blood flow changes. In 12 subjects with hemochromatosis, we measured ultrasonographically radial artery diameter and blood flow responses to a 4-minute ischemia of the hand. This was done also after removing 500 mL of blood (and concomitantly infusing 500 mL of saline), which significantly (P<0.01) reduced hemoglobin concentration and hematocrit. The increase in blood flow induced by the 4-minute ischemia was similar before and after blood removal (+76% and +80%), which, in contrast, markedly attenuated the accompanying increase in radial artery diameter (+25% versus +13%, P<0.01). Thus, in humans, blood viscosity is involved in the endothelial response to an increase in shear stress. This implies that this response may not be accurately assessed and compared by quantifying the stimulus only through an increase in blood flow.
[Show abstract][Hide abstract] ABSTRACT: Severe iron overload has been reported in patients with the beta-thalassaemia trait. Studies performed before the discovery of the haemochromatosis gene (HFE) have yielded conflicting results: some suggest that iron overload might arise from the interaction of the beta-thalassaemia trait with heterozygosity for haemochromatosis, some with homozygosity for haemochromatosis and others that it was unrelated to haemochromatosis. We have studied the clinical phenotype, iron indices and HFE genotypes of 22 unrelated patients with the beta-thalassaemia trait and haemochromatosis, the inheritance of chromosome 6p and 1q haplotypes in families of non-homozygous C282Y probands and serum measures of iron status in relatives heterozygous for C282Y with or without the beta-thalassaemia trait. We demonstrate that the beta-thalassaemia trait aggravates the clinical picture of C282Y homozygotes, favouring higher rates of iron accumulation and the development of severe iron-related complications. We suggest that the coexistence of the beta-thalassaemia trait might also increase the risk of iron overload in patients with HFE genotypes at a mild risk of haemochromatosis. Our findings do not support the hypothesis that the association of the beta-thalassaemia trait with a single C282Y or H63D allele might lead to iron overload and suggest that other non-HFE-related inherited factors are present in haemochromatosis patients with incomplete HFE genotypes.
British Journal of Haematology 01/2001; 111(3):908-14. · 4.94 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Severe iron overload has been reported in patients with the β-thalassaemia trait. Studies performed before the discovery of the haemochromatosis gene (HFE) have yielded conflicting results: some suggest that iron overload might arise from the interaction of the β-thalassaemia trait with heterozygosity for haemochromatosis, some with homozygosity for haemochromatosis and others that it was unrelated to haemochromatosis. We have studied the clinical phenotype, iron indices and HFE genotypes of 22 unrelated patients with the β-thalassaemia trait and haemochromatosis, the inheritance of chromosome 6p and 1q haplotypes in families of non-homozygous C282Y probands and serum measures of iron status in relatives heterozygous for C282Y with or without the β-thalassaemia trait. We demonstrate that the β-thalassaemia trait aggravates the clinical picture of C282Y homozygotes, favouring higher rates of iron accumulation and the development of severe iron-related complications. We suggest that the coexistence of the β-thalassaemia trait might also increase the risk of iron overload in patients with HFE genotypes at a mild risk of haemochromatosis. Our findings do not support the hypothesis that the association of the β-thalassaemia trait with a single C282Y or H63D allele might lead to iron overload and suggest that other non-HFE-related inherited factors are present in haemochromatosis patients with incomplete HFE genotypes.
British Journal of Haematology 11/2000; 111(3):908 - 914. · 4.94 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Iron overload is believed to have an adverse influence on the cardiovascular system and animal studies have shown that iron may be involved in the events that lead to atherosclerosis via an enhancement of smooth muscle cell proliferation, lipid oxidation, and free radical production. There are no data on the effect of iron overload on arterial structural and mechanical properties in humans. We measured wall thickness and distensibility (D) by ultrasonography of the radial artery in 12 patients with uncomplicated genetic hemochromatosis (GH) who were normotensive and without atherosclerotic plaques. Twelve age- and sex-matched patients were taken as controls. Nine patients were evaluated also after iron depletion. Wall thickness was greater in patients with GH than in controls (+50%, P <.01) whereas D was slightly reduced in the former group compared with the latter group, though the difference was not statistically significant. After iron depletion, a significant reduction of wall thickness and a significant increase in D were observed (-24% and +33%, P <.05 for both). Thus, in patients with hemochromatosis, arterial wall thickness is increased before the onset of cardiovascular complications. This alteration is reverted by iron depletion, which also can improve the initial and modest radial artery wall stiffening associated with this condition. Thus, functional and structural alterations in midsize muscle arteries may be an early abnormality of hemochromatosis.
[Show abstract][Hide abstract] ABSTRACT: Most hemochromatosis patients of Northern European descent are homozygous for the C282Y mutation of HFE gene. In Italy, many patients with iron overload are not homozygous for C282Y, and the presence of other mutations or other genetic determinant has been suggested.
Five unrelated Italian patients heterozygous for C282Y with the classic hemochromatosis phenotype were studied. The entire coding sequence and the exon-intron boundaries of the HFE gene were analyzed. Chromosome 6p haplotypes were defined in each patient by analysis of D6S265, D6S105, and D6S1281 microsatellites.
Two novel nonsense HFE mutations were identified in exon 3 in the C282Y negative chromosome. The first one, a G-to-T transition at codon 168, was detected in 3 probands; the second, a G-to-A transition at codon 169, was detected in the others.
The 2 nonsense mutations in the compound heterozygous state with C282Y result in the classic hemochromatosis phenotype in several unrelated Italian patients. This confirms that hemochromatosis in Italy is not as homogeneous as in northern Europe and suggests that other mutations can exist in C282Y or H63D heterozygotes with iron overload. These findings have practical implications for diagnostic and screening strategies for hemochromatosis.
[Show abstract][Hide abstract] ABSTRACT: Hepatic iron overload is a common but still poorly characterized finding in patients with chronic viral hepatitis.
To evaluate lobular and cellular distribution of iron in patients with chronic viral hepatitis, the relation between hepatic iron distribution, grading and staging, and the frequency of haemochromatosis gene mutations.
Thirty-four patients with chronic viral hepatitis and iron overload; 34 matched chronic viral hepatitis controls without iron overload; 139 healthy controls.
Hepatic iron was assessed by hepatic iron concentration and Deugnier's score, histological grading and staging by Ishak's score, and frequency of haemochromatosis gene mutations by polymerase chain reaction-restriction assays.
Iron deposits were found in hepatocytes (94% of the patients), sinusoidal tracts (88%) and portal cells (59%). In 41%, iron deposits were homogeneously distributed in the hepatic specimen. Hepatocytic iron showed a decreasing gradient from Rappaport's zone 1 to 3. Heavy alcohol intake influenced the distribution rather than the amount of hepatic iron by increasing sinusoidal iron. Haemochromatosis gene mutations were more frequent in chronic viral hepatitis patients with iron overload than in those without iron overload and in healthy controls suggesting they contribute to pathogenesis of hepatic iron accumulation. The correlation between hepatic fibrosis and portal iron supports the fibrogenetic role of iron in chronic viral hepatitis.
Italian journal of gastroenterology and hepatology 01/1999; 31(5):395-400.