ABSTRACT
BACKGROUND: Venesection is the key therapy in haemochromatosis, but it remains controversial in hyperferritinaemia with moderate iron accumulation. There is substantial evidence that the results of HFE genotyping are routinely misinterpreted, while elevated serum ferritin has become more frequent in recent years in white adult populations following the increase of obesity and metabolic traits. AIMS: To examine the reasons for prescribing venesection in 1,059 French patients during the period 2012-2015, determine the true prevalence of HFE-related haemochromatosis, and compare iron overload profiles between haemochromatosis and non-haemochromatosis patients. RESULTS: Only 258 of the 488 patients referred for haemochromatosis had the p.[Cys282Tyr];[Cys282Tyr] disease causative genotype (adjusted prevalence: 24.4%). Of the 801 remaining patients, 112 (14.0%) had the debated p.[Cys282Tyr];[His63Asp] compound heterozygote genotype, 643 (80.3%) had central obesity, 475 (59.3%) had metabolic syndrome (MetS) and 93 (11.6%) were heavy drinkers. The non-haemochromatosis patients started therapeutic venesection 9 years later than haemochromatosis patients (P < 0.001). Despite similar serum ferritin values, they had lower transferrin saturation (41.1% vs 74.3%; P < 0.001), lower amounts of iron removed by venesection (1.7 vs 3.2 g; P < 0.001) and lower hepatic iron concentrations (107 vs 237 µmol/g; P < 0.001). CONCLUSIONS: Haemochromatosis is over-diagnosed and is no longer the main reason for therapeutic venesection in France. Obesity and other metabolic abnormalities are frequently associated with mild elevation of serum ferritin, the MetS is confirmed in ~50% of treated patients. There is a minimal relationship between serum ferritin and iron overload in non-p.Cys282Tyr homozygotes. Our observations raise questions about venesection indications in non-haemochromatosis patients.
Subject(s)
Hemochromatosis , Hyperferritinemia , Iron Overload , Adult , Hemochromatosis/epidemiology , Hemochromatosis/genetics , Hemochromatosis Protein/genetics , Humans , Iron Overload/epidemiology , Iron Overload/genetics , Phlebotomy , PrevalenceABSTRACT
BACKGROUND: HFE hemochromatosis is an inborn error of iron metabolism linked to a defect in the regulation of hepcidin synthesis. This autosomal recessive disease typically manifests later in women than men. Although it is commonly stated that pregnancy is, with menses, one of the factors that offsets iron accumulation in women, no epidemiological study has yet supported this hypothesis. The aim of our study was to evaluate the influence of pregnancy on expression of the predominant HFE p.[Cys282Tyr];[Cys282Tyr] genotype. METHODS: One hundred and forty p.Cys282Tyr homozygous women enrolled in a phlebotomy program between 2004 and 2011 at a blood centre in western Brittany (France) were included in the study. After checking whether the disease expression was delayed in women than in men in our study, the association between pregnancy and iron overload was assessed using multivariable regression analysis. RESULTS: Our study confirms that women with HFE hemochromatosis were diagnosed later than men cared for during the same period (52.6 vs. 47.4 y., P < 0.001). Compared to no pregnancy, having at least one pregnancy was not associated with lower iron markers. In contrast, the amount of iron removed by phlebotomies appeared significantly higher in women who had at least one pregnancy (eß = 1.50, P = 0.047). This relationship disappeared after adjustment for confounding factors (eß = 1.35, P = 0.088). CONCLUSIONS: Our study shows that pregnancy status has no impact on iron markers level, and is not in favour of pregnancy being a protective factor in progressive iron accumulation. Our results are consistent with recent experimental data suggesting that the difference in disease expression observed between men and women may be explained by other factors such as hormones.
Subject(s)
Hemochromatosis , Iron/blood , Phlebotomy , Pregnancy Complications, Hematologic , Adult , Alcohol Drinking/epidemiology , Alcohol Drinking/physiopathology , Body Mass Index , Female , Ferritins/blood , France/epidemiology , Hemochromatosis/diagnosis , Hemochromatosis/genetics , Hemochromatosis/physiopathology , Hemochromatosis/therapy , Hemochromatosis Protein/genetics , Homozygote , Humans , Iron Overload/diagnosis , Iron Overload/etiology , Male , Menopause/blood , Middle Aged , Phlebotomy/methods , Phlebotomy/statistics & numerical data , Pregnancy , Pregnancy Complications, Hematologic/diagnosis , Pregnancy Complications, Hematologic/genetics , Pregnancy Complications, Hematologic/physiopathology , Pregnancy Complications, Hematologic/therapy , Regression Analysis , Risk Factors , Sex FactorsSubject(s)
Hemochromatosis/blood , Hemochromatosis/genetics , Histocompatibility Antigens Class I/genetics , Homozygote , Iron Overload/blood , Iron, Dietary/metabolism , Membrane Proteins/genetics , Adult , Cohort Studies , Female , Hemochromatosis/diagnosis , Hemochromatosis Protein , Humans , Iron Overload/diagnosis , Iron, Dietary/administration & dosage , Male , Middle AgedABSTRACT
Despite type I haemochromatosis (HC) is mainly associated with the HFE C282Y/C282Y genotype, a second genotype -C282Y/H63D- has mostly been described in other patients. Its association with HC, apart from any associated co-morbid factors, remains unclear and complex to interpret for physicians. This study assesses the weight of this genotype and the role of co-morbid factors in the occurrence of iron overload. This prospective study included the C282Y/C282Y (nâ=â172) and C282Y/H63D (nâ=â58) patients enrolled in a phlebotomy program between 2004 and 2007 in a blood centre of western Brittany (Brest, France), where HC is frequent. We compared prevalence of these two genotypes, as well as patients' profile regarding degree of iron overload and prevalence of co-morbid factors. First, we confirmed the obvious deficit of C282Y/H63D compound heterozygotes among patients cared by phlebotomies. This genotype was 3.0 times less frequent than the C282Y/C282Y genotype among those patients (18.9% vs. 56.0%) whereas it was 4.9 times more frequent in the general population (4.3% vs. 0.9%; p<0.0001). Despite a similar level of hyperferritinaemia, the C282Y/H63D patients who came to medical attention had a milder plasma iron overload, reflected by a lower transferrin saturation median (52.0% vs. 84.0%; p<0.0001). They also exhibited more frequently co-morbid factors, as heavy drinking (26.0% vs. 13.9%; pâ=â0.0454), overweight (66.7% vs. 39.4%; pâ=â0.0005) or both (21.3% vs. 2.6%; p<0.0001). Ultimately, they required a lower amount of iron removed to reach depletion (2.1 vs. 3.4 g; p<0.0001), clearly reflecting their lower tissue iron. This study confirms that H63D is a discrete genetic susceptibility factor whose expression is most visible in association with other co-factors. It highlights the importance of searching for co-morbidities in these diagnostic situations and of providing lifestyle and dietary advice.
Subject(s)
Histocompatibility Antigens Class I/genetics , Membrane Proteins/genetics , Overweight/epidemiology , Overweight/genetics , Phlebotomy , Polymorphism, Genetic , Alcoholism/epidemiology , Comorbidity , Female , Genotype , Hemochromatosis Protein , Humans , Iron Overload/epidemiology , Male , Overweight/therapy , Prospective StudiesABSTRACT
BACKGROUND: Hereditary hemochromatosis (HH) is a common inherited disorder of iron metabolism in Northern European populations. The discovery of a candidate gene in 1996 (HFE), and of its main mutation (C282Y), has radically altered the way to diagnose this disease. The aim of this study was to assess the impact of the HFE gene discovery on the clinical presentation and epidemiology of HH. METHODS: We studied our cohort of 415 patients homozygous for the C282Y allele and included in a phlebotomy program in a blood centre in western Brittany, France. RESULTS: In this cohort, 56.9% of the patients were male and 21.9% began their phlebotomy program before the implementation of the genetic test. A significant decrease in the sex ratio was noticed following implementation of this DNA test, from 3.79 to 1.03 (p < 10(-5)), meaning that the proportion of diagnosed females relatives to males greatly increased. The profile of HH patients at diagnosis changed after the DNA test became available. Serum ferritin and iron values were lower and there was a reduced frequency of clinical signs displayed at diagnosis, particularly skin pigmentation (20.1 vs. 40.4%, OR = 0.37, p < 0.001) and hepatomegaly (11.0 vs. 22.7%, OR = 0.42, p = 0.006). In contrast, fatigue became a more common symptom at diagnosis (68.0 vs. 51.2%, OR = 2.03, p = 0.004). CONCLUSION: This study highlights the importance of the HFE gene discovery, which has simplified the diagnosis of HH and modified its clinical presentation and epidemiology. This study precisely measures these changes. Enhanced diagnosis of HFE-related HH at an early stage and implementation of phlebotomy treatment are anticipated to maintain normal life expectancy for these patients.
Subject(s)
Hemochromatosis/epidemiology , Hemochromatosis/genetics , Histocompatibility Antigens Class I/genetics , Membrane Proteins/genetics , Molecular Epidemiology/trends , Adolescent , Adult , Aged , Amino Acid Substitution/genetics , Cohort Studies , Cysteine/genetics , Female , France , Genetic Testing , Genotype , Hemochromatosis/diagnosis , Hemochromatosis Protein , Humans , Male , Middle Aged , Molecular Diagnostic Techniques/methods , Molecular Epidemiology/methods , Sex Ratio , Tyrosine/geneticsABSTRACT
Hereditary hemochromatosis is a common inherited disorder characterized by iron overload. A single mutation (C282Y) in the HFE gene is present in 80-95% of cases in populations of northern European extraction. The disorder presents a large phenotypic heterogeneity, and its expression can be influenced by environmental factors. This 1977-2002 study aimed to identify the influence of alcohol consumption on expression of the disease. The authors retrospectively registered 378 C282Y-homozygous patients treated in a blood center of western Brittany, France. In this cohort, 33 patients reported excessive alcohol consumption (8.7%). Those subjects presented significantly increased iron parameters (serum ferritin: 1745.2 vs. 968.7 microg/liter, p< 0.0001; serum iron: 39.9 vs. 36.0 micromol/liter, p = 0.0040; transferrin saturation: 87.1 vs. 80.1%, p = 0.0071) and elevated liver enzymes (alanine aminotransferase: 66.3 vs. 41.1 IU/liter, p = 0.0003; aspartate aminotransferase: 56.2 vs. 34.9 IU/liter, p = 0.0002). Their risk of skin pigmentation was also higher (odds ratio = 3.4, p = 0.0006). Results remained unchanged after adjustment. This study provides precise quantitative data about the impact of alcohol on expression of hereditary hemochromatosis in C282Y-homozygous patients. Excessive alcohol consumption accentuates disease expression and therefore the risk of cirrhosis and cancer. Consequently, these patients should be encouraged to consume very moderate quantities of alcohol.