IgG subclass levels in referred hemochromatosis probands with HFE p.C282Y/p.C282Y.

BACKGROUND: IgG subclass levels in hemochromatosis are incompletely characterized. METHODS: We characterized IgG subclass levels of referred hemochromatosis probands with HFE p.C282Y/p.C282Y (rs1800562) and human leukocyte antigen (HLA)-A and -B typing/haplotyping and compared them with IgG subclass levels of eight published cohorts of adults unselected for hemochromatosis. RESULTS: There were 157 probands (82 men, 75 women; mean age 49±13 y). Median serum ferritin, mean body mass index (BMI), median IgG4, and median phlebotomy units to achieve iron depletion were significantly higher in men. Diabetes, cirrhosis, and HLA-A*03,-B*44, -A*03,B*07, and -A*01,B*08 prevalences and median absolute lymphocyte counts in men and women did not differ significantly. Mean IgG subclass levels [95% confidence interval] were: IgG1 5.31 g/L [3.04, 9.89]; IgG2 3.56 g/L [1.29, 5.75]; IgG3 0.61 g/L [0.17, 1.40]; and IgG4 0.26 g/L [<0.01, 1.25]. Relative IgG subclasses were 54.5%, 36.6%, 6.3%, and 2.7%, respectively. Median IgG4 was higher in men than women (0.34 g/L [0.01, 1.33] vs. 0.19 g/L [<0.01, 0.75], respectively; p = 0.0006). A correlation matrix with Bonferroni correction revealed the following positive correlations: IgG1 vs. IgG3 (p<0.01); IgG2 vs. IgG3 (p<0.05); and IgG2 vs. IgG4 (p<0.05). There was also a positive correlation of IgG4 vs. male sex (p<0.01). Mean IgG1 was lower and mean IgG2 was higher in probands than seven of eight published adult cohorts unselected for hemochromatosis diagnoses. CONCLUSIONS: Mean IgG subclass levels of hemochromatosis probands were 5.31, 3.56, 0.61, and 0.26 g/L, respectively. Median IgG4 was higher in men than women. There were positive associations of IgG subclass levels. Mean IgG1 may be lower and mean IgG2 may be higher in hemochromatosis probands than adults unselected for hemochromatosis.

HFE Mutations in Neurodegenerative Disease as a Model of Hormesis.

Common variants in the iron regulatory protein HFE contribute to systematically increased iron levels, yet the effects in the brain are not fully characterized. It is commonly believed that iron dysregulation is a key contributor to neurodegenerative disease due to iron's ability to catalyze reactive oxygen species production. However, whether HFE variants exacerbate or protect against neurodegeneration has been heavily debated. Some claim that mutated HFE exacerbates oxidative stress and neuroinflammation, thus predisposing carriers to neurodegeneration-linked pathologies. However, H63D HFE has also been shown to slow the progression of multiple neurodegenerative diseases and to protect against environmental toxins that cause neurodegeneration. These conflicting results showcase the need to further understand the contribution of HFE variants to neurodegenerative disease heterogeneity. Data from mouse models consistently demonstrate robust neuroprotection against toxins known to increase the risk of neurodegenerative disease. This may represent an adaptive, or hormetic, response to increased iron, which leaves cells better protected against future stressors. This review describes the current research regarding the contribution of HFE variants to neurodegenerative disease prognosis in the context of a hormetic model. To our knowledge, this is the first time that a hormetic model for neurodegenerative disease has been presented.

Clinical characteristics of HFE C282Y/H63D compound heterozygotes identified in a specialty practice: key differences from HFE C282Y homozygotes.

BACKGROUND: Patients with p.C282Y homozygous (p.C282Y) HFE mutations are more likely to develop hemochromatosis (HC) than p.C282Y/p.H63D compound heterozygotes (p.C282Y/H63D). RESEARCH DESIGN AND METHODS: We conducted a retrospective chart review of 90 p.C282Y and 31 p.C282Y/H63D patients at a referral practice to illustrate the differences in the natural history of the disease in these two HC cohorts. RESULTS: Over a median follow-up of 17 years, p.C282Y had higher mean serum ferritin (1105 mg/dL vs. 534 mg/dL, p = 0.001) and transferrin saturations (75.3% vs. 49.5%, p = 0.001) at diagnosis. p.C282Y underwent more therapeutic phlebotomies (TP) till de-ironing (mean 24 vs. 10), had higher mean mobilized iron stores (4759 mg vs. 1932 mg), and required more annual maintenance TP (1.9/year vs. 1.1/year, p = 0.039). p.C282Y/H63D were more likely to have obesity (45.2% vs. 20.2%, p = 0.007) at diagnosis, with a non-significant trend toward consuming more alcohol. There was no significant difference in the development of HC-related complications between the two cohorts. CONCLUSIONS: p.C282Y have a higher mobilizable iron and require more TP. p.C282Y/H63D likely require additional insults such as obesity or alcohol use to develop elevated ferritin. De-ironing may mitigate the risk of developing HC-related complications.

HFE genotypes, haemochromatosis diagnosis and clinical outcomes at age 80 years: a prospective cohort study in the UK Biobank.

OBJECTIVES: HFE haemochromatosis genetic variants have an uncertain clinical penetrance, especially to older ages and in undiagnosed groups. We estimated p.C282Y and p.H63D variant cumulative incidence of multiple clinical outcomes in a large community cohort. DESIGN: Prospective cohort study. SETTING: 22 assessment centres across England, Scotland, and Wales in the UK Biobank (2006-2010). PARTICIPANTS: 451 270 participants genetically similar to the 1000 Genomes European reference population, with a mean of 13.3-year follow-up through hospital inpatient, cancer registries and death certificate data. MAIN OUTCOME MEASURES: Cox proportional HRs of incident clinical outcomes and mortality in those with HFE p.C282Y/p.H63D mutations compared with those with no variants, stratified by sex and adjusted for age, assessment centre and genetic stratification. Cumulative incidences were estimated from age 40 years to 80 years. RESULTS: 12.1% of p.C282Y+/+ males had baseline (mean age 57 years) haemochromatosis diagnoses, with a cumulative incidence of 56.4% at age 80 years. 33.1% died vs 25.4% without HFE variants (HR 1.29, 95% CI: 1.12 to 1.48, p=4.7×10-4); 27.9% vs 17.1% had joint replacements, 20.3% vs 8.3% had liver disease, and there were excess delirium, dementia, and Parkinson's disease but not depression. Associations, including excess mortality, were similar in the group undiagnosed with haemochromatosis. 3.4% of women with p.C282Y+/+ had baseline haemochromatosis diagnoses, with a cumulative incidence of 40.5% at age 80 years. There were excess incident liver disease (8.9% vs 6.8%; HR 1.62, 95% CI: 1.27 to 2.05, p=7.8×10-5), joint replacements and delirium, with similar results in the undiagnosed. p.C282Y/p.H63D and p.H63D+/+ men or women had no statistically significant excess fatigue or depression at baseline and no excess incident outcomes. CONCLUSIONS: Male and female p.C282Y homozygotes experienced greater excess morbidity than previously documented, including those undiagnosed with haemochromatosis in the community. As haemochromatosis diagnosis rates were low at baseline despite treatment being considered effective, trials of screening to identify people with p.C282Y homozygosity early appear justified.

Serum ferritin level is associated with liver fibrosis and incident liver-related outcomes independent of HFE genotype in the general population.

BACKGROUND & AIMS: Hyperferritinemia reflects iron accumulation in the body and has been associated with metabolic disturbances and alcohol use, and is also a common finding in individuals diagnosed with liver disease. The major genetic regulator of iron metabolism is the HFE gene. METHODS: The aim of this this study was to investigate the association between serum ferritin and liver fibrosis using the enhanced liver fibrosis (ELF) test, and the association between ferritin and liver-related outcomes in a Finnish population-based cohort of 6194 individuals (45% male, mean [± standard deviation] age, 52.9 ± 14.9 years; body mass index 26.9 ± 4.7 kg/m2). The effects of HFE variants on these associations were also evaluated. RESULTS: Serum ferritin levels were significantly associated with liver fibrosis, as estimated by enhanced liver fibrosis (ELF) test in weighted linear regression analysis. Serum ferritin was significantly associated with both all liver-related outcomes (n = 92) and severe liver-related outcomes (n = 54) in weighted Cox regression analysis (hazard ratio [HR] per 1 SD, 1.11 [95% confidence interval (CI) 1.02-1.21]; p = 0.012 and HR 1.11 [95% CI 1.02-1.21]; p = 0.013, respectively). However, there was association neither between HFE risk variants and ELF test nor between HFE risk variants and liver-related outcomes. CONCLUSION: Serum ferritin levels were associated with liver fibrosis and incident liver disease, independent of HFE genotype in the general population. Furthermore, data demonstrated that metabolic disturbances and alcohol use were major risk factors for hyperferritinemia.

Penetrance, cancer incidence and survival in HFE haemochromatosis-A population-based cohort study.

BACKGROUND AND AIMS: Haemochromatosis is characterized by progressive iron overload affecting the liver and can cause cirrhosis and hepatocellular carcinoma. Most haemochromatosis patients are homozygous for p.C282Y in HFE, but only a minority of individuals with this genotype will develop the disease. The aim was to assess the penetrance of iron overload, fibrosis, hepatocellular carcinoma and life expectancy. METHODS: A total of 8839 individuals from the Austrian region of Tyrol were genotyped for the p.C282Y variant between 1997 and 2021. Demographic, laboratory parameters and causes of death were assessed from health records. Penetrance, survival, and cancer incidence were ascertained from diagnosed cases, insurance- and cancer registry data. Outcomes were compared with a propensity score-matched control population. RESULTS: Median age at diagnosis in 542 p.C282Y homozygous individuals was 47.8 years (64% male). At genotyping, the prevalence of iron overload was 55%. The cumulative penetrance of haemochromatosis defined as the presence of provisional iron overload was 24.2% in males and 10.5% in females aged 60 years or younger. Among p.C282Y homozygotes of the same ages, the cumulative proportion of individuals without fibrosis (FIB-4 score < 1.3) was 92.8% in males and 96.7% in females. Median life expectancy was reduced by 6.8 years in individuals homozygous for p.C282Y when compared with population-matched controls (p = .001). Hepatocellular carcinoma incidence was not significantly higher in p.C282Y homozygotes than in controls matched for age and sex. CONCLUSION: Reduced survival and the observed age-dependent increase in penetrance among p.C282Y homozygotes call for earlier diagnosis of haemochromatosis to prevent complications.

Haemochromatosis in children: A national retrospective cohort promoted by the A.I.E.O.P. (Associazione Italiana Emato-Oncologia Pediatrica) study group.

Haemochromatosis (HC) encompasses a range of genetic disorders. HFE-HC is by far the most common in adults, while non-HFE types are rare due to mutations of HJV, HAMP, TFR2 and gain-of-function mutations of SLC40A1. HC is often unknown to paediatricians as it is usually asymptomatic in childhood. We report clinical and biochemical data from 24 paediatric cases of HC (10 cases of HFE-, 5 TFR2-, 9 HJV-HC), with a median follow-up of 9.6 years. Unlike in the adult population, non-HFE-HC constitutes 58% (14/24) of the population in our series. Transferrin saturation was significantly higher in TFR2- and HJV-HC compared to HFE-HC, and serum ferritin and LIC were higher in HJV-HC compared to TFR2- and HFE-HC. Most HFE-HC subjects had relatively low ferritin and LIC at the time of diagnosis, so therapy could be postponed for most of them after the age of 18. Our results confirm that HJV-HC is a severe form already in childhood, emphasizing the importance of early diagnosis and treatment to avoid the development of organ damage and reduce morbidity and mortality. Although phlebotomies were tolerated by most patients, oral iron chelators could be a valid option in early-onset HC.

Hereditary hemochromatosis with homozygous C282Y HFE mutation: possible clinical model to assess effects of elevated reactive oxygen species on the development of cardiovascular disease.

Hereditary hemochromatosis with the homozygous C282Y HFE mutation (HH-282H) is a genetic condition which causes iron overload (IO) and elevated reactive oxygen species (ROS) secondary to the IO. Interestingly, even after successful iron removal therapy, HH-282H subjects demonstrate chronically elevated ROS. Raised ROS are also associated with the development of multiple cardiovascular diseases and HH-282H subjects may be at risk to develop these complications. In this narrative review, we consider HH-282H subjects as a clinical model for assessing the contribution of elevated ROS to the development of cardiovascular diseases in subjects with fewer confounding clinical risk factors as compared to other disease conditions with high ROS. We identify HH-282H subjects as a potentially unique clinical model to assess the impact of chronically elevated ROS on the development of cardiovascular disease and to serve as a clinical model to detect effective interventions for anti-ROS therapy.

Height of non-Hispanic white adults with homeostatic iron regulator HFE genotypes p.C282Y/p.C282Y and wt/wt.

BACKGROUND: We sought to evaluate height in white adults with hemochromatosis. METHODS: We analyzed the height of (1) post-screening examination participants with HFE p.C282Y/p.C282Y (rs1800562) and wt/wt (absence of p.C282Y and p.H63D (rs1799945)) and (2) referred hemochromatosis probands with p.C282Y/p.C282Y. RESULTS: There were 762 participants (270 p.C282Y/p.C282Y, 492 wt/wt; 343 men, 419 women) and 180 probands (104 men, 76 women). Median height of male participants with p.C282Y/p.C282Y or wt/wt was 177.8 cm. Median height of female participants was greater in those with p.C282Y/p.C282Y than wt/wt (165.1 cm vs 162.6 cm, respectively; p = 0.0298). Median height of p.C282Y/p.C282Y participants and probands was the same (men 177.8 cm; women 165.1 cm). Regressions on height of male and female participants revealed no associations with HFE genotype and inverse and positive associations with age and weight, respectively. Height of female participants was positively and inversely associated with transferrin saturation and serum ferritin, respectively. Regressions on height of male and female probands revealed positive associations with weight. CONCLUSIONS: The height of men with HFE p.C282Y/p.C282Y and wt/wt does not differ significantly. The height of female participants was greater in those with p.C282Y/p.C282Y than wt/wt. We found no independent association of HFE genotype with the height of men or women.

Frequency Evaluation of the Interleukin-6 -174G>C Polymorphism and Homeostatic Iron Regulator (HFE) Mutations as Disease Modifiers in Patients Affected by Systemic Lupus Erythematosus and Rheumatoid Arthritis.

Autoimmune diseases are generally characterized by a multifactorial etiology and are often associated with a genetic predisposition. Both iron metabolism and the inflammatory cytokine system have been shown to play a pivotal role in the dysregulation of the immune response in many different autoimmune conditions, rheumatologic diseases included. The purpose of this work was to analyze the frequency of mutations altering the expression of IL-6 or influencing iron metabolism in patients affected by autoimmune diseases such as Rheumatoid Arthritis (RA) and Systemic Lupus Erythematosus (SLE). In this study, 144 patients were enrolled: 77 and 67 patients were affected by RA and SLE, respectively. In these cohorts, the frequency of the IL-6 polymorphism -174G>C located in the IL-6 gene promoter was tested. Moreover, the frequencies of the three HFE gene variations associated with iron overload were analyzed: p.His63Asp, p.Ser65Cys and p.Cys282Tyr. The two mutations p.His63Asp and p.Ser65Cys in the HFE gene did not reach statistical significance in any of the comparisons, regardless of the statistical model, cohorts of patients and control populations analyzed. The frequencies of the p.Cys282Tyr mutation and the IL-6 polymorphism -174G>C were found to be overall significantly decreased in RA and SLE patients when the Dominant model and Allele contrast were adopted with both the Odds Ratio and Chi-square. Although further investigation is needed, the examination of the frequencies of the -174G>C IL-6 promoter polymorphism and HFE mutations may add some valuable information on the interplay linking iron metabolism, inflammation and immunity in autoimmune diseases such as SLE and RA.

Differences in bone microarchitecture between genetic and secondary iron-overload mouse models suggest a role for hepcidin deficiency in iron-related osteoporosis.

Iron overload is one of the secondary osteoporosis etiologies. Cellular and molecular mechanisms involved in iron-related osteoporosis are not fully understood. AIM: The aim of the study was to investigate the respective roles of iron excess and hepcidin, the systemic iron regulator, in the development of iron-related osteoporosis. MATERIAL AND METHODS: We used mice models with genetic iron overload (GIO) related to hepcidin deficiency (Hfe-/- and Bmp6-/- ) and secondary iron overload (SIO) exhibiting a hepcidin increase secondary to iron excess. Iron concentration and transferrin saturation levels were evaluated in serum and hepatic, spleen, and bone iron concentrations were assessed by ICP-MS and Perl's staining. Gene expression was evaluated by quantitative RT-PCR. Bone micro-architecture was evaluated by micro-CT. The osteoblastic MC3T3 murine cells that are able to mineralize were exposed to iron and/or hepcidin. RESULTS: Despite an increase of bone iron concentration in all overloaded mice models, bone volume/total volume (BV/TV) and trabecular thickness (Tb.Th) only decreased significantly in GIO, at 12 months for Hfe-/- and from 6 months for Bmp6-/- . Alterations in bone microarchitecture in the Bmp6-/- model were positively correlated with hepcidin levels (BV/TV (ρ = +.481, p < .05) and Tb.Th (ρ = +.690, p < .05). Iron deposits were detected in the bone trabeculae of Hfe-/- and Bmp6-/- mice, while iron deposits were mainly visible in bone marrow macrophages in secondary iron overload. In cell cultures, ferric ammonium citrate exposure abolished the mineralization process for concentrations above 5 µM, with a parallel decrease in osteocalcin, collagen 1, and alkaline phosphatase mRNA levels. Hepcidin supplementation of cells had a rescue effect on the collagen 1 and alkaline phosphatase expression level decrease. CONCLUSION: Together, these data suggest that iron in excess alone is not sufficient to induce osteoporosis and that low hepcidin levels also contribute to the development of osteoporosis.

Testing and Management of Iron Overload After Genetic Screening-Identified Hemochromatosis.

Importance: HFE gene-associated hereditary hemochromatosis type 1 (HH1) is underdiagnosed, resulting in missed opportunities for preventing morbidity and mortality. Objective: To assess whether screening for p.Cys282Tyr homozygosity is associated with recognition and management of asymptomatic iron overload. Design, Setting, and Participants: This cross-sectional study obtained data from the Geisinger MyCode Community Health Initiative, a biobank of biological samples and linked electronic health record data from a rural, integrated health care system. Participants included those who received a p.Cys282Tyr homozygous result via genomic screening (MyCode identified), had previously diagnosed HH1 (clinically identified), and those negative for p.Cys282Tyr homozygosity between 2017 and 2018. Data were analyzed from April 2020 to August 2023. Exposure: Disclosure of a p.Cys282Tyr homozygous result. Main Outcomes and Measures: Postdisclosure management and HFE-associated phenotypes in MyCode-identified participants were analyzed. Rates of HFE-associated phenotypes in MyCode-identified participants were compared with those of clinically identified participants. Relevant laboratory values and rates of laboratory iron overload among participants negative for p.Cys282Tyr homozygosity were compared with those of MyCode-identified participants. Results: A total of 86 601 participants had available exome sequences at the time of analysis, of whom 52 994 (61.4%) were assigned female at birth, and the median (IQR) age was 62.0 (47.0-73.0) years. HFE p.Cys282Tyr homozygosity was disclosed to 201 participants, of whom 57 (28.4%) had a prior clinical HH1 diagnosis, leaving 144 participants who learned of their status through screening. There were 86 300 individuals negative for p.Cys282Tyr homozygosity. After result disclosure, among MyCode-identified participants, 99 (68.8%) had a recommended laboratory test and 36 (69.2%) with laboratory or liver biopsy evidence of iron overload began phlebotomy or chelation. Fifty-three (36.8%) had iron overload; rates of laboratory iron overload were higher in MyCode-identified participants than participants negative for p.Cys282Tyr homozygosity (females: 34.1% vs 2.1%, P < .001; males: 39.0% vs 2.9%, P < .001). Iron overload (females: 34.1% vs 79.3%, P < .001; males: 40.7% vs 67.9%, P = .02) and some liver-associated phenotypes were observed at lower frequencies in MyCode-identified participants compared with clinically identified individuals. Conclusions and Relevance: Results of this cross-sectional study showed the ability of genomic screening to identify undiagnosed iron overload and encourage relevant management, suggesting the potential benefit of population screening for HFE p.Cys282Tyr homozygosity. Further studies are needed to examine the implications of genomic screening for health outcomes and cost-effectiveness.

Common Mutation in the HFE Gene Modifies Recovery After Intracerebral Hemorrhage.

BACKGROUND: Intracerebral hemorrhage (ICH) is characterized by bleeding into the brain parenchyma. During an ICH, iron released from the breakdown of hemoglobin creates a cytotoxic environment in the brain through increased oxidative stress. Interestingly, the loss of iron homeostasis is associated with the pathological process of other neurological diseases. However, we have previously shown that the H63D mutation in the homeostatic iron regulatory (HFE) gene, prevalent in 28% of the White population in the United States, acts as a disease modifier by limiting oxidative stress. The following study aims to examine the effects of the murine homolog, H67D HFE, on ICH. METHODS: An autologous blood infusion model was utilized to create an ICH in the right striatum of H67D and wild-type mice. The motor recovery of each animal was assessed by rotarod. Neurodegeneration was measured using fluorojade-B and mitochondrial damage was assessed by immunofluorescent numbers of CytC+ (cytochrome C) neurons and CytC+ astrocytes. Finally, the molecular antioxidant response to ICH was quantified by measuring Nrf2 (nuclear factor-erythroid 2 related factor), GPX4 (glutathione peroxidase 4), and FTH1 (H-ferritin) levels in the ICH-affected and nonaffected hemispheres via immunoblotting. RESULTS: At 3 days post-ICH, H67D mice demonstrated enhanced performance on rotarod compared with wild-type animals despite no differences in lesion size. Additionally, H67D mice displayed higher levels of Nrf2, GPX4, and FTH1 in the ICH-affected hemisphere; however, these levels were not different in the contralateral, non-ICH-affected hemisphere. Furthermore, H67D mice showed decreased degenerated neurons, CytC+ Neurons, and CytC+ astrocytes in the perihematomal area. CONCLUSIONS: Our data suggest that the H67D mutation induces a robust antioxidant response 3 days following ICH through Nrf2, GPX4, and FTH1 activation. This activation could explain the decrease in degenerated neurons, CytC+ neurons, and CytC+ astrocytes in the perihematomal region, leading to the improved motor recovery. Based on this study, further investigation into the mechanisms of this neuroprotective response and the effects of the H63D HFE mutation in a population of patients with ICH is warranted.

Iron homeostasis in mice: does liver lobe matter?

The liver plays a crucial role in maintaining systemic iron homeostasis through iron storage, sensing of systemic iron needs, and production of the iron-regulatory hormone hepcidin. While mice are commonly used as models for studying human iron homeostasis, their liver structure differs significantly from humans. Since the mouse liver is structured in six separated lobes, often, the analysis of a single defined lobe is preferred due to concerns over data reproducibility between experimental cohorts. In this study, we compared iron-related parameters in distinct liver lobes of C57BL/6 wild-type mice across different ages. We found that the non-heme iron levels, as well as the mRNA and protein expression of iron storage protein Ferritin and the iron importer Transferrin Receptor 1, were similar between liver lobes. Additionally, the mRNA expression of Hepcidin, as well as its regulators, Bmp2 and Bmp6, and iron importers Zip8 and Zip14 were comparable. Minor differences were observed in Ferroportin mRNA levels of 24-wk-old mice; however, this did not correlate with altered iron content. The findings in wild-type mice were reproduced in Hfe knock-out mice - a well-established genetic model of the most prevalent form of hemochromatosis. Overall, our results indicate that C57BL/6 mouse liver lobes can be used interchangeably for assessing iron content and expression of iron-related genes. Understanding if these findings are applicable to other mouse developmental stages, strains, or models of (iron-related) disorders will be key to promote reduction of experimental animal numbers and facilitate resource sharing among research groups studying liver iron homeostasis.NEW & NOTEWORTHY This study reveals that, despite being structurally separated, liver lobes from C57BL/6 wild-type and iron-overloaded mice can be used interchangeably for the evaluation of iron content and expression of iron-related genes.

Platelet counts in HFE p.C282Y/p.C282Y and wt/wt post-screening clinical evaluation participants.

Our aim was to document the effects of genotype HFE p.C282Y/p.C282Y and hemochromatosis-associated laboratory and clinical manifestations on platelet counts (PC). We compiled genotype (p.C282Y/p.C282Y or HFE wt/wt (absence of p.C282Y and p.H63D (rs1799945)), age, sex, body mass index, presence/absence of chronic fatigue, swelling/tenderness of second/third metacarpophalangeal joints, and hyperpigmentation, transferrin saturation (TS), serum ferritin (SF), hemoglobin levels, absolute neutrophil, lymphocyte, and monocyte counts, C-reactive protein levels, and PC of non-Hispanic white participants in a hemochromatosis and iron overload post-screening clinical examination. There were 171 men and 254 women (141 p.C282Y/p.C282Y, 284 wt/wt) of median age 53 y. Median TS and SF were higher in p.C282Y/p.C282Y than wt/wt participants grouped by sex (p < .0001, all comparisons). Median PC by genotype was lower in men than women (p < .0001, both comparisons). Regression on PC using 14 independent variables identified these significant positive associations: absolute neutrophil, lymphocyte, and monocyte counts and C-reactive protein levels and these significant inverse associations: age, TS, and hemoglobin levels. We conclude that PC is significantly associated with absolute neutrophil, lymphocyte, and monocyte counts, and C-reactive protein (positive) and age, TS, and hemoglobin (inverse), after adjustment for other variables. HFE genotypes we studied were not significantly associated with PC.

What is the context? Hemochromatosis is typically associated with inheritance of two copies of p.C282Y, a common mutation of the HFE gene on chromosome 6p that regulates iron absorption.Platelet counts, age, and serum levels of liver enzymes have been used to estimate risks of cirrhosis in adults with hemochromatosis.Lower platelet counts in Europeans are significantly associated with a mutation in CARMIL1, a gene on chromosome 6p close to HFE.Clinical and laboratory associations of normal platelet counts in adults with HFE p.C282Y/p/C282Y and wt/wt uncomplicated by cirrhosis are unreported.What is new? We studied normal platelet counts in 425 white adults who participated in a primary care-based hemochromatosis screening program. These participants did not have cirrhosis or other conditions that often influence platelet counts.Our analyses of 14 variables identified these significant positive associations with platelet counts, after adjustment for other variables: absolute neutrophil, lymphocyte, and monocyte counts and C-reactive protein levels; and these significant inverse associations: age, TS, and hemoglobin levels.What is the impact? Laboratory and clinical factors significantly associated with platelet counts in adults with HFE p.C282/p.C282Y or wt/wt are similar to those in persons unselected for HFE genotypes or hemochromatosis.It is unlikely that genes that influence platelet counts are closely linked to HFE on chromosome 6p.Adults with hemochromatosis and HFE p.C282/p.C282Y who have abnormal platelet counts should be evaluated for cirrhosis or non-iron platelet disorders.

Hereditary hemochromatosis: An update vision of the laboratory diagnosis.

Haemochromatosis (HC) is an inherited disorder of iron metabolism. The 85-90% of Hereditary hemochromatosis cases are caused by mutations in HFE gene (HC type 1). The remaining 10-15% of HC cases are caused by mutations in other non-HFE genes (HJV, HAMP, TRF2, SLC40A1, BMP6). The study of patients for the diagnosis of HC has an important laboratory approached: analysis of biochemical parameters and genetic studies. To confirm a case, it is necessary to carry out a genetic study of the C282Y and H63D mutations. The presence of C282Y mutation in homozygosis is compatible with the diagnosis of HC type 1. Due to the incomplete penetrance of this mutation and the variable phenotypic expression, the severe forms of the disease are relatively rare. The study of variants in non-HFE genes allows more detailed study of both non-classic HC cases and those with more severe clinical expression. The genotype characterization of a patient not always justified the phenotype expression of the symptoms in this disease. All laboratory clinicians must consider recommendation provide by the experts in the Materia.

Hfe Actions in Kupffer Cells Are Dispensable for Hepatic and Systemic Iron Metabolism.

Mutations in the HFE/Hfe gene cause Hereditary Hemochromatosis (HH), a highly prevalent genetic disorder characterized by elevated iron deposition in multiple tissues. HFE acts in hepatocytes to control hepcidin expression, whereas HFE actions in myeloid cells are required for cell-autonomous and systemic iron regulation in aged mice. To address the role of HFE specifically in liver-resident macrophages, we generated mice with a selective Hfe deficiency in Kupffer cells (HfeClec4fCre). The analysis of the major iron parameters in this novel HfeClec4fCre mouse model led us to the conclusion that HFE actions in Kupffer cells are largely dispensable for cellular, hepatic and systemic iron homeostasis.

The ancestral haplotype markers HLA -A3 and B7 do not influence the likelihood of advanced hepatic fibrosis or cirrhosis in HFE hemochromatosis.

Advanced hepatic fibrosis occurs in up to 25% of individuals with C282Y homozygous hemochromatosis. Our aim was to determine whether human leukocyte antigen (HLA)-A3 and B7 alleles act as genetic modifiers of the likelihood of advanced hepatic fibrosis. Between 1972 and 2013, 133 HFE C282Y homozygous individuals underwent clinical and biochemical evaluation, HLA typing, liver biopsy for fibrosis staging and phlebotomy treatment. Hepatic fibrosis was graded according to Scheuer as F0-2 (low grade hepatic fibrosis), F3-4 (advanced hepatic fibrosis), and F4 cirrhosis. We analysed associations between the severity of fibrosis and HLA-A3 homozygosity, heterozygosity or absence, with or without the presence of HLA-B7 using categorical analysis. The mean age of HLA-A3 homozygotes (n = 24), heterozygotes (n = 65) and HLA-A3 null individuals (n = 44) was 40 years. There were no significant differences between the groups for mean(± SEM) serum ferritin levels (1320 ± 296, 1217 ± 124, 1348 ± 188 [Formula: see text]g/L), hepatic iron concentration (178 ± 26, 213 ± 22, 199 ± 29 [Formula: see text]mol/g), mobilizable iron stores (9.9 ± 1.5, 9.5 ± 1.5, 11.5 ± 1.7 g iron removed via phlebotomy), frequency of advanced hepatic fibrosis (5/24[12%], 13/63[19%], 10/42[19%]) or cirrhosis (3/24[21%], 12/63[21%], 4/42[24%]), respectively. The presence or absence of HLA-B7 did not influence the outcome. Thus, HLA-A3 and HLA-B7 alleles are not associated with the risk of advanced hepatic fibrosis or cirrhosis in C282Y hemochromatosis.