Hereditary hemochromatosis in a Brazilian university hospital in São Paulo State (1990-2000)

Hereditary hemochromatosis (HH) is the most common genetic disease among individuals of European descent. Two mutations (845G-->A, C282Y and 187C-->G, H63D) in the hemochromatosis gene (HFE gene) are associated with HH. About 85-90% of patients of northern European descent with HH are C282Y homozygous. The prevalence of HH in the Brazilian population, which has a very high level of racial admixture, is unknown. The aims of the present study were to identify individuals with diagnostic criteria for HH among patients with a body iron overload attended at the university hospital of the Faculty of Medicine of Ribeirao Preto from 1990 to 2000, and to evaluate the prevalence of HFE mutations. We screened first-degree relatives for HFE mutations. Four of 72 patients (three men and one woman, mean age 47 years) fulfilled the criteria for HH. HFE mutations were studied in three patients [two C282Y homozygotes (patients 1 and 2) and one H63D heterozygote]. Patient 1 had four children (all C282Y heterozygotes with no iron overload) and seven brothers and sisters: two sisters (66 and 76 years old) were C282Y homozygotes and both had an iron overload (a liver biopsy in one showed severe iron deposits), one sister (79 years old) was a compound heterozygote with no iron overload, one brother (78 years old) was a C282Y heterozygote with no iron overload, two individuals were H63D heterozygotes (one brother, 49 years old, obese, with a body iron overload and abnormal liver enzymes - a biopsy showed non-alcoholic steatohepatitis, and one 70-year-old sister with no iron overload). Patient 2 had two children (22 and 24 years old who were C282Y heterozygotes with no iron overload) but no brothers or sisters. These results showed that HH was uncommon among individuals attended at our hospital, although HFE mutations were found in all patients. Familial screening is valuable for the early diagnosis of individuals at risk since it allows treatment to be initiated before the onset of the clinical manifestations of organ damage associated with HH

Factor XIII val34leu and the risk of myocardial infarction.

BACKGROUND AND OBJECTIVE: Recent studies have suggested an association between a genetic variation in the coagulation factor XIII (FXIII Val34Leu) and decreased risk of vascular thrombosis. DESIGN AND METHODS: We investigated the frequency of the FXIII Val34Leu polymorphism in 150 consecutive, unrelated and relatively young (<55 years) survivors of myocardial infarction (MI) with angiographically-proven severe coronary atherosclerosis and in 150 age-, gender- and race-matched controls. RESULTS: FXIII Val34Leu was detected in 54/150 patients and 73/150 controls, yielding an overall odds ratio (OR) for MI of 0.6 (CI95: 0.4-0.9). Homozygosity for FXIII Val34Leu was found in 4/150 patients and in 12/150 controls, yielding an OR for MI of 0.26 (CI95: 0.08-0.9). The OR for heterozygotes was 0.65 (CI95: 0.4-1.1). FXIII Val34Leu carriership decreased the risk of MI related to metabolic risk factors (RF) (hypertension, diabetes, dyslipidemia, and obesity): non-carriers in the presence of a metabolic RF had a 13.9-fold higher risk of MI, whereas in carriers with a metabolic RF the risk was reduced to 6.8. FXIII Val34Leu also attenuated the risk of MI among smokers. Non-carrier smokers had a 6.1-fold higher risk (CI95: 3.1-11.9), whereas the risk among smokers carrying FXIII Val34Leu was 3.9 (CI95: 1.9-8.1). INTERPRETATION AND CONCLUSIONS: FXIII Val34Leu confers a significant protective effect against the occurrence of MI in relatively young patients. FXIII Val34Leu exhibits a gene dosage effect: the protective effect was particularly strong in homozygous carriers, and heterozygosity conferred moderate protection. Finally, FXIII Val34Leu seems to reduce the risk of MI related to major cardiovascular risk factors.

Porphyria cutanea tarda in Brazilian patients: association with hemochromatosis C282Y mutation and hepatitis C virus infection.

OBJECTIVE: Porphyria cutanea tarda (PCT) is commonly associated with iron overload and hepatitis C virus (HCV) infection. Association between hemochromatosis C282Y or H63D mutations and PCT has been observed, although not uniformly, and iron overload is also commonly found in chronic HCV hepatitis. The aim of the present study was to investigate the frequency of C282Y and H63D mutations and HCV infection in Brazilian patients with PCT and their relationship with iron overload. METHODS: Twenty-three patients (19 men) aged 39.6 +/- 11.1 yr were studied. All had dermatological lesions of PCT and high levels of urinary uroporphyrin. HCV infection and iron overload were investigated. DNA samples were analyzed for the presence of HFE mutations. RESULTS: The frequency of C282Y was significantly higher in PCT patients than in 278 healthy individuals (17.4% vs 4%, odds ratio = 5.1, 95% confidence interval 1.5-17.6, p = 0.02), whereas no difference was observed regarding the H63D mutation (30.4% vs 31%, odds ratio = 1, 95% confidence interval 0.4-2.4, p = 1). Biochemical tests in PCT patients showed iron overload with transferrin saturation = 47.3 +/- 20.7% and ferritin = 566.8 +/- 425 ng/ml. Fifteen of 23 (65.2%) patients had HCV infection and alcohol ingestion was observed in 17 of 23 (73.9%). CONCLUSIONS: PCT patients exhibited evidence of iron overload, a high frequency of HCV, and an association with C282Y mutation. These data further support the notion that both acquired and inherited factors contribute to the occurrence of PCT, and indicate that screening for C282Y may be justified in PCT patients.

Heterogeneous ethnic distribution of the 844ins68 in the cystathionine beta-synthase gene.

A novel mutation in the cystathionine beta-synthase (CBS) gene (a 68-bp insertion in the coding region of exon 8: 844ins68) was recently described, but its prevalence in different human populations is unknown. We analyzed the prevalence of the 68-bp insertion in the CBS gene in 405 unrelated individuals (810 chromosomes) of European, African, Asian and Amerindian origins. PCR amplification of a DNA fragment containing exon 8 of the CBS gene was employed. In addition, screening for the T833C CBS mutation by BsrI digestion was carried out in all samples bearing the 844ins68 mutation, since both mutations were previously reported to be associated in cis. The insertion was found in heterozygosity in 14 out of 104 whites (13.5%), was absent among Asians, and was found solely in 1 out of 220 Amerindian chromosomes analyzed, whereas a much higher prevalence was observed among blacks (37.7% of heterozygotes and 4% of mutant homozygotes). Furthermore, the T833C CBS mutation was found to cosegregate in cis with 844ins68 in all carriers of the insertion. The finding of the double mutant among blacks and Caucasians suggests that it antedated the racial divergence between Africans and non-Africans, and provides evidence for a partly or completely neutralizing effect conferred by the 68-bp insertion, since it allows the skipping of the T833C mutation. Our study represents the first analysis of the 844ins68 insertion in the CBS gene in different human populations, and reveals an extensive ethnic and geographic variability associated with this mutation.

Hormonal-induced changes on the lipid composition and DPH fluorescence anisotropy of erythrocyte ghost from pre- and postmenopausal women.

Fluorescence anisotropy determinations were performed on hypotonically lysed red blood cells from 12 healthy, free living, premenopausal and 10 postmenopausal women fed a self-selected diet. Fatty acid composition of phospholipids and cholesterol esters, lipid/lipid and lipid/protein ratios were also determined in erythrocyte ghosts along the menstrual cycle or during hormonal replacement therapy. The postmenopausal women were treated with transdermal 17-beta estradiol (approx, delivery rate of 50 micrograms/day) for a 5-week period and with a combination of percutaneous administration of estradiol and orally administered medroxyprogesterone acetate (5 mg/day) for 5 weeks more. Premenopausal women were studied in the mid-follicular and mid-luteal phases of their menstrual cycles. Membrane fluidity in cells from the luteal phase was greater than that observed in the follicular phase. After estradiol treatment, postmenopausal women exhibited a significant raise in the fluorescence anisotropy. The association with progesterone prevented the estrogen-induced increase of the anisotropy values. Estrogen administration also produced an increment in the relative content of cholesterol and membrane proteins that was reverted by progesterone addition. Changes induced by estradiol treatment in the fatty acid pattern of phospholipids and cholesterol esters were characterized by an increment in the monoenoic/saturated fatty acid ratio and linoleic relative content, with a concomitant decrease in the proportion of arachidonic and docosatetraenoic acids. These results suggest that the modification of the desaturase activities may be involved in a mechanism by which these hormonal-induced changes take place. The present study demonstrated that human erythrocyte fluidity is under hormonal control subjected through changes in the proportion and quality of the membrane lipids.

Hormonal-induced changes on lipidi composition and DPH fluorescence anisotropy of erithrocyte ghost from pre-and postmenopausal women

Fluorescence anisotropy determination were performed on hypotonically lysed red blood cells from 12 healthy, free living, premenopausal and 10 postmenopausal women fed a self-selected diet. Fatty acid composition of phospholipids and cholesterol esters, lipid/lipid and lipid/protein ratios were also determined in erythrocyte ghosts along the menstrual cycle or during hormonal replacemente therapy. The postmenopausal women were treated with transdermal 17-beta estradiol (approx. delivery rate of 50 mug/day) for a 5-week period and with a combination of percutaneous administration of estradiol and orally administered medroxyprogesterone acetate (5 mg/day) for 5 weeks more. Premenopausal women were studied in the mid-follicular and mid-luteal phases of their menstrual cycles. Membrane fluidity in cells from the luteal phase was greater than that observed in the follicular phase. After estradiol treatment, postmenopausal women exhibited a significant raise in the fluorescence anisotropy. The association with progesterone prevented the estrogen-induced increase of the anisotropy values. Estrogen administration also produced an increment in the relative content of cholesterol and membrane proteins that was reverted by progesterone addition. Changes induced by estradiol treatment in the fatty acid pattern of phospholipids and cholesterol esters were characterized by an increment in the monoenoic/saturated fatty acid ratio and linoleic relative content, with a concomitant decrease in the proportion of arachidonic and docosatetraenoic acids. These results suggest that the modification of the desaturase activities may be involved in a mechanism by which these hormonal-induced changes take place. The present study demonstrated that human erythrocyte fluidity is under hormonal control subjected through changes in the proportion and quality of the membrane lipids.

Factibilidad de la implementación de un registro de infarto de miocardio en el contexto de un programa de prevención / Feasibility of myocardial infarction record on a prevention program

Se realizó un registro de infarto piloto en la ciudad de La Plata con el fin de analizar su factibilidad de implementación en el marco de un progama de prevención de factores de riesgo. El estudio se llevó a cabo en diez centros de recolección de datos (Unidades Coronarias) de dicha ciudad. La propuesta de realizar un Registro de Infarto en el área de demostración de un proyecto de prevención primaria y a través de un modelo estandarizado, basado en el MONICA, y en el marco de un proyecto de prevención primaria permitiría la obtenció de data genuina tanto de infarto de miocardio como de los factores de riesgo implicados

Probucol modifica la composición en acidos grasos en pacientes con hypertrigliceridemicos con control de ingestas grasas / Probucol modify the fatty acid composition in patients hypertriglyceridemic whith control consumption fat

Se estudio el efecto de probucol sobre los parametros lipídicos tradicionales: colesterol total, colesterol HDL y trigliceridos, y no tradicionales apolipoproteinas AI, AII, B, CIII y E, así como la composición en ácidos grasos de trigliceridos fosfolípidos y ésteres de colesterol plasmático en seis pacientes hipertrigliceridemicos, cuya dieta fue estrictamente controlada. Se observo la disminución estadisticamente significativa del contenido de ácido aratidónico en los ésteres de colesterol y del ácido miristico en los fosfolípidos, así como el aumento significativo del contenido de ácido palmitoleico en los triglicéridos. No se observaron variaciones significativas en las concentraciones de lípidos tradicionales ni apolipoproteinas plasmáticas. Los resultados indican que probucol fue capaz de madificar el perfil de ácidos grasos de distintas fracciones lipídas plasmáticas que habitualmente se utilizan para medir el impacto del consumo graso.

La terapia hormonal sustitutiva modifica la composición en ácidos grasos de fosfolípidos de HDL / Hormone replacement therapy modifies the fatty-acid composition of HDL phospholipids

Las mujeres postmenospáusicas tienen un riesgo aumentado de padecer enfermedad coronaria en comparación con las premenospáusicas. Sin embargo, el riesgo disminuye cuando se realiza terapia hormonal sustitutiva. El objetivo de este estudio es investigar el posible efecto de la terapia con 17 ß Estradiol (E2) o de la combinación de 17 ß Estradiol y Acetato de Medroxiprogesterona (AMP), sobre las concentraciones plásmicas de colesterol total, colesterol HDL, colesterol LDL, colesterol VLDL y triglicéridos, fracciones de conocida participación en la aterogénesis. También se estudió la composición de ácidos grasos de fosfolípidos de la fracción no retenida obtenida por cromatografía de afinidad con Concanavalina A. Al cabo de 30 días de tratamiento con E2, el colesterol total disminuyó desde 226,0 ñ 54,4 mg/dl hasta 202,0 ñ 51,7 mg/dl; los niveles de triglicéridos descendieron desde 106,3 ñ 31,3 mg/dl hasta 80,6 ñ 13,9 mg/dl (p < 0,05), posiblemente a expensas de la fracción VLDL (21,3 ñ 6,2 mg/dl vs. 16,9 ñ 2,5 mg/dl); los fosfolípidos de la fracción no retenida de Concanavalina A mostraron una disminución de los ácidos grasos mirístico, palmítico y esteárico, y un aumento concomitante de los ácidos grasos oleico y linoleico. Los cambios observados con la administración de E2 tendieron a anularse cuando se agregó Acetato de Medroxiprogesterona

ß-Thalassemia intermedia and ivs-1 NT6 homozygosis in Brazil

The molecular abnormality of a patient with thalassemia intermedia was identified by DNA amplification (PCR) combined with the of synthetic oligonucleotide probes. The patient is a homozygote for the T===>C substitution at position 6 of the first intervening sequence (IVS1-6) of the ß globin gene. On the basis of this finding, the family, which had been previously reported by us to be a carrier of an unusually mild ß-thalassemia gene, was actually the first example reported of the clinical and biochemical features of ß-thalassemia-Portuguese type

Deletion type alpha-thelassemia among brazilian patients with sickle cell anemia

A frequência de alfa-talassemia determinada entre 41 pacientes com anemia falciforme, empregando análise de DNA com enzimas de restriçäo, demonstrou 9 (22%) heterozigotos alfa+ - talassêmicos (genótipo alfa-/alfa alfa), o que indica uma frequência gênica de 0,126. A comparaçäo dos dois grupos de pacientes com anemia falciforme, com três ou com quatro genes de globina alfa, mostrou VCM menor no primeiro grupo, ao passo que näo foram detectadas diferencas nos valores de HbF, HbA2 e hemoglobina total. Estes dados indicam uma elevada prevalência de alfa-talassemia na populaçäo negróide brasileira