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Background: Hereditary hemochromatosis (HH) is a genetic condition with fatigue as an essential but not precisely assessed symptom. While some well-specified scales for fatigue assessment in some pathologies exist, data on their usefulness in HH need to be collected. This research aimed to evaluate fatigue in HH using the Fatigue Assessment Scale (FAS), Fatigue Severity Scale (FSS), and Chalder Fatigue Scale (CFQ). Methodology: Seventy-nine HH patients underwent a questionnaire containing items about detailed medical history and the FAS, FSS, and CFQ scales. Twenty-five sex- and age-matched healthy persons constituted the control group (controls); additionally, thirty blood donors (donors) were compared. Results: The fatigue indices were significantly worse in the HH patients than in the controls and donors (HH vs. controls p-value: FAS = 0.003, FSS < 0.001, and CFQ = 0.003; HH vs. donors p-value: FAS = 0.025, FSS < 0.001, and CFQ = 0.041). There were no differences between the severity of fatigue and the specific genotype or the age of the patients. The HH women presented more severe fatigue than the men. High internal consistency and reliability for each scale were revealed: the Cronbach alpha values were as follows: FAS 0.92, FSS 0.95, and CFQ 0.93. Additionally, the construct validity and factorial validity of the implemented scales were confirmed. Conclusions: The HH patients exhibited significantly worse fatigue across all the scales. The FAS, FSS, and CFQ are simple and reliable diagnostic tools for assessing and quantifying fatigue for clinical and research purposes. [ABSTRACT FROM AUTHOR]

Hereditary hemochromatosis (HH) is an autosomal recessive inherited iron-loading disorder and is characterized by chronic hepatitis, cirrhosis, diabetes, and bronze skin. The hemochromatosis gene (C282Y homozygosity)-related hemochromatosis is the most common form of HH. The prevalence of HH is varied. Here, we defined six cases with C282Y homozygosity-related HH in a single center in Turkiye. [ABSTRACT FROM AUTHOR]

Hereditary hemochromatosis (HH) causes unbalanced iron deposition in many organs including the joints leading to severe cartilage loss and bone damage in the metacarpophalangeal joints (MCPJ). High-resolution peripheral quantitative computed tomography (HR-pQCT) and its joint space width (JSW) quantification algorithm quantifies in vivo 3D joint morphology. We therefore aimed to (i) determine feasibility and performance of the JSW algorithm in HH, (ii) quantify joint space morphology, and (iii) investigate the relationship between morphological and clinical parameters in HH. Here, we performed an exploratory study on 24 HH patients and sex- and age-matched controls using HR-pQCT imaging of MCPJ. Mineralized bone structure was automatically segmented from the grayscale image data and periosteal surface bone masks and joint space masks were generated. Mean, minimal, and maximal joint space width (JSW; JSW.MIN; JSW.MAX), JSW heterogeneity (JSW.SD), JSW asymmetry (JSW.AS), and joint space volume (JSV) were computed. Demographics and, for HH patients, disease-specific parameters were recorded. Segmentation of JS was very good with 79.7% of MCPJs successfully segmented at first attempt and 20.3% requiring semi-manual correction. HH men showed larger JSV at all MCPs (+ 25.4%

Introduction: Oxylipins are mediators of oxidative stress. To characterize the underlying inflammatory processes and phenotype effect of iron metabolism disorders, we investigated the oxylipin profile in hereditary hemochromatosis (HH) and dysmetabolic iron overload syndrome (DIOS) patients. Methods: An LC-MS/MS-based method was performed to quantify plasma oxylipins in 20 HH and 20 DIOS patients in fasting conditions and 3 h after an iron-rich meal in HH patients. Results: Principal component analysis showed no separation between HH and DIOS, suggesting that the clinical phenotype has no direct impact on oxylipin metabolism. 20-HETE was higher in DIOS and correlated with hypertension (p = 0.03). Different oxylipin signatures were observed in HH before and after the iron-rich meal. Discriminant oxylipins include epoxy fatty acids derived from docosahexaenoic acid and arachidonic acid as well as 13-HODE and 9-HODE. Mediation analysis found no major contribution of dietary iron absorption for 16/22 oxylipins significantly affected by the meal. Discussion: The oxylipin profiles of HH and DIOS seemed similar except for 20-HETE, possibly reflecting different hypertension prevalence between the two groups. Oxylipins were significantly affected by the iron-rich meal, but the specific contribution of iron was not clear. Although iron may contribute to oxidative stress and inflammation in HH and DIOS, this does not seem to directly affect oxylipin metabolism. [ABSTRACT FROM AUTHOR]

Hereditary hemochromatosis (HH) is a common autosomal recessive disorder. This disease affects gut iron transport, leading to iron overload, which affects immune function, coagulation mechanics, and bone health. Within the spine, HH contributes to decreased bone mineral density and accelerated intervertebral disc degeneration. The purpose of this study was to discover the differences in the rates of common 90-day postoperative complications and 1-year and 2-year surgical outcomes in patients with and without HH after anterior cervical discectomy and fusion (ACDF). Using the PearlDiver database, patients with active diagnoses of HH before ACDF were matched to patients without HH using a 1:5 ratio on the basis of age, sex, body mass index, and comorbidities. Postoperative complications were assessed at 90 days, and 1-year and 2-year surgical outcomes were assessed. All outcomes and complications were analyzed using multivariate logistic regression with significance achieved at P < 0.05. Patients with HH had significantly higher rates of 1-year and 2-year reoperation rates compared with patients without HH (29.19% vs. 3.94% and 37.1% vs. 5.93%, respectively; P < 0.001). The rates of 90-day postoperative complications significantly increased in patients with HH including dysphagia, pneumonia, cerebrovascular accident, deep vein thrombosis, acute kidney injury, urinary tract infection, hyponatremia, surgical site infection, iatrogenic deformity, emergency department visit, and hospital readmission. Patients with HH undergoing ACDF showed increased 90-day postoperative complications and significantly increased rates of 1-year and 2-year reoperation compared with patients without HH. These findings suggest that iron overload may contribute to adverse outcomes in patients with HH undergoing 1-level and 2-level ACDF. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

This is not surprising to detect iron overload in chronic liver diseases and end-stage liver diseases since Kupffer cells scavenge necrotic hepatocytes during the course of liver damage, leading to an increased serum iron level and transferrin saturation compatible with iron overload even in the absence of a genetic mutation suggestive of hereditary hemochromatosis. Therewith, a relative association has been found between some sorts of chronic liver diseases like non-alcoholic steatohepatitis and hepatitis C with human homeostatic iron regulator protein (HFE: High Fe2+) gene mutations. Moreover, impairment of ceruloplasmin ferroxidase activity in the course of Wilson's disease (WD), leading to the accumulation of ferrous ions just like what is expected in aceruloplasminemia, is another known reason for iron overload accompanied by chronic liver disease. Of chronic liver diseases, autoimmune hepatitis (AIH), and cholestatic liver diseases are less related to iron overload. Accordingly, the coexistence of WD, AIH, and hereditary hemochromatosis when there exist clinical features, laboratory tests, genetic confirmation, and histological evaluations indicative of the three mentioned diseases is exceedingly rare. Here, we present a 55-year-old man referred with progressive generalized icterus accompanied by loss of appetite and significant weight loss. The presented case was not an appropriate candidate for liver biopsy due to recent coronary angioplasty and the urgent need for dual antiplatelet therapy. However, medical follow-ups were highly suggestive of concomitant WD, hereditary hemochromatosis, and AIH. The attempts failed for the treatment of hereditary hemochromatosis and WD with chelating agents until the completion of the course of treatment with immunosuppressants targeting components of the AIH-related immune system. [ABSTRACT FROM AUTHOR]

Purpose: Hereditary hemochromatosis (HH) may cause iron deposition in cardiac tissue. We aimed to describe the echocardiographic findings in patients with HH and identify risk factors for cardiac dysfunction. Methods: In this retrospective study, we included patients with HH who underwent transthoracic echocardiography at our tertiary care center between August 2000 and July 2022. We defined three primary outcomes for cardiac dysfunction: 1) left ventricular ejection fraction (LVEF) < 55%, 2) ratio between early mitral inflow velocity and mitral annular early diastolic velocity (E/e') > 15, and 3) global longitudinal strain (GLS) < 18. Multivariable logistic regression was utilized to identify predictors of cardiac dysfunction. Results: 582 patients (median age 57 years, 61.2% male) were included. The frequency of LVEF < 55%, E/e' > 15 and GLS < 18 was 9.0% (52/580), 9.6% (51/534) and 20.2% (25/124), respectively. In multivariable analysis, non-White race, age, and hypertension were associated with E/e' > 15. No specific HFE genetic mutation was associated with LVEF < 55%. A history of myocardial infarction was strongly associated with both LVEF < 55% and E/e' > 15. In patients with LVEF ≥ 55%, the C282Y/H63D genetic mutation was associated with reduced likelihood of E/e' > 15, p = 0.024. Patients with C282Y/H63D had a higher frequency of myocardial infarction. Smoking and alcohol use were significantly associated with GLS < 18 in unadjusted analysis. Conclusion: We found the traditional risk factors of male sex, and history of myocardial infarction or heart failure, were associated with a reduced LVEF, irrespective of the underlying HFE genetic mutation. Patients with a C282Y/H63D genetic mutation had a higher frequency of myocardial infarction, yet this mutation was associated with reduced odds of diastolic dysfunction compared to other genetic mutations in patients with a normal LVEF. [ABSTRACT FROM AUTHOR]

Aims: Hereditary hemochromatosis (HH) is the most common inherited disease in European populations. It is particularly common in people of Irish heritage, approximately 2% of whom will be at risk of iron overload as a result of human homoeostatic iron regulator protein (HFE) gene mutations. We aimed to evaluate the utility of screening for HH in newly referred patients with DM of Irish heritage in a prospective study. Methods: Of 575 patients newly referred between March 2018 and March 2021, 556 attended for blood testing, to include fasting transferrin saturations, prior to their first clinic visit. Patients with elevated transferrin saturations were further screened for hereditary hemochromatosis (HH) with HFE gene analysis. Results: Transferrin saturations were elevated in 13 of 556 patients (2.3%), 3 of whom had a preexisting diagnosis of HH. Of the remaining 10 patients, 7 had HFE gene mutations suggestive of HH (2 C282Y homozygous, 3 C282Y/H63D compound heterozygous, and 2 H63D homozygous), 1 was a HH carrier (C282Y heterozygous), and 2 had normal genetics. Conclusions: The prevalence of HH of 1.8% in this screened DM population is lower than the reported incidence of HH in the Irish population, suggesting a limited utility of routine screening for HH in newly referred patients with DM.

The human hemochromatosis protein HFE is encoded by the HFE gene and participates in iron regulation. The aim of this study was to detect the most frequent HFE gene mutations in a control population and in β-thalassemia trait (BTT) carriers, and to study their relationship with iron metabolism. Total blood count, hemoglobin electrophoresis at alkaline pH, HbA2 quantification, iron (Fe), total Fe binding capacity and ferritin were assayed. HFE gene mutations were analyzed by real-time PCR. A total of 119 individuals (69 normal and 50 BTT) were examined. In the control group, 9% (6/69) presented a codon 282 heterozygous mutation (C282Y), and 19% a codon 63 mutation (H63D) (13/69, 11 heterozygotes and 2 homozygotes). In the BTT group, 3 carriers (6%) were heterozygous for C282Y, 14 (28%) for H63D, 1 (2%) for a codon 65 mutation and 1 (2%) was H63D and C282Y double heterozygous. Control group Fe metabolism did not show significant differences (p > 0.05) according to whether or not they carried an HFE gene mutation; while the BTT group with and without HFE mutation showed higher Fe and ferritin than the control group (p < 0.05). However, no increases in iron parameters were detected in BTT carriers that simultaneously exhibited an H63D mutation compared to BTT subjects without a mutation. Therefore, the iron metabolism alterations observed in BTT carriers could not be attributed to the presence of HFE gene mutations. It is likely that BTT individuals have other genetic modifiers that affect their iron balance.

Background: Hereditary hemochromatosis (HH) is characterized by iron overload that can cause multiple organ dysfunction primarily due to uncontrolled iron-mediated oxidative stress. Although HH leads to muscular weakness, disorder, and fatigue, the mechanism by which HH affects skeletal muscle physiology is largely unknown. Methods: Using Hfe knockout mice (6–7 months old), a well-defined mouse model of HH, we examined iron status in the skeletal muscle, as well as other organs. As mitochondria are key organelle for muscular function, this study also explored how molecular markers for mitochondrial function and related systems are regulated in the HH skeletal muscle using western blots. Results: Although iron overload was evident at the systemic level, only mild iron overload was observed in the skeletal muscle of HH. Of note, mitochondrial electron transport chain complex I was upregulated in the HH skeletal muscle, which was accompanied by enhanced autophagy. However, these molecular changes were not associated with oxidative stress, suggesting altered mitochondrial metabolism in the muscle in response to iron overload. Conclusions: These early adaptive responses may be important for supporting mitochondrial health before fully developing skeletal muscle dysfunction in HH. More studies are needed to determine the role of autophagy in the HH-related muscle mitochondrial dysfunction. [ABSTRACT FROM AUTHOR]

The human hemochromatosis protein HFE is encoded by the HFE gene and participates in iron regulation. The aim of this study was to detect the most frequent HFE gene mutations in a control population and in β-thalassemia trait (BTT) carriers, and to study their relationship with iron metabolism. Total blood count, hemoglobin electrophoresis at alkaline pH, HbA2 quantification, iron (Fe), total Fe binding capacity and ferritin were assayed. HFE gene mutations were analyzed by real-time PCR. A total of 119 individuals (69 normal and 50 BTT) were examined. In the control group, 9% (6/69) presented a codon 282 heterozygous mutation (C282Y), and 19% a codon 63 mutation (H63D) (13/69, 11 heterozygotes and 2 homozygotes). In the BTT group, 3 carriers (6%) were heterozygous for C282Y, 14 (28%) for H63D, 1 (2%) for a codon 65 mutation and 1 (2%) was H63D and C282Y double heterozygous. Control group Fe metabolism did not show significant differences (p > 0.05) according to whether or not they carried an HFE gene mutation; while the BTT group with and without HFE mutation showed higher Fe and ferritin than the control group (p < 0.05). However, no increases in iron parameters were detected in BTT carriers that simultaneously exhibited an H63D mutation compared to BTT subjects without a mutation. Therefore, the iron metabolism alterations observed in BTT carriers could not be attributed to the presence of HFE gene mutations. It is likely that BTT individuals have other genetic modifiers that affect their iron balance. [ABSTRACT FROM AUTHOR]

BackgroundHereditary hemochromatosis (HH) is a genetic disease that leads to increased iron accumulation in several organs. Cardiomyocytes are highly susceptible to this damage owing to their high iron uptake, and cardiovascular complications account for 1/3 of the deaths in the natural course of HH. Additionally, excess iron intake and associated oxidative stress may accelerate the aging of the cardiovascular system, regardless of the age of patients with HH. We aimed to investigate the role of standard and speckle-tracking echocardiography (STE) in revealing heart differences in patients with HH considering the disease stage and the patient age.MethodologyConsecutive patients with HH (n = 58) without heart pathologies (except hypertension) and 29 age- and sex-matched healthy individuals underwent echocardiography. Patients were compared according to the time since HH diagnosis (the recently diagnosed HH group [31 patients] with diagnosed HH for less than 6 months and had no more than one venesection; the medium group [11 patients] with diagnosed HH between 6 and 24 months; and the long-lasting group [16 patients] with diagnosed HH for more than 2 years) and the quartile contribution of their age.ResultsStandard echocardiography revealed differences in diastolic parameters between patients with HH and controls, which were the most prominent between healthy and long-lasting HH patients. Regarding systolic function, left ventricular ejection fraction was lower in HH patients, with the most evident differences between the healthy and recently diagnosed HH patients. STE revealed additional differences in systolic parameters, with LV rotation the worst in recently diagnosed patients and its increase in patients with medium and long-lasting HH. Significantly worse peak systolic longitudinal strain values were observed in all patients with HH. Analyses of the results according to the age quartiles of patients with HH revealed that some changes ocurred earlier than expected according to age.ConclusionsEchocardiography can reveal possible heart damage in HH patients at different stages of the disease and highlight potential features of accelerated myocardial aging in these patients.

Abstract Backgrounds Hereditary hemochromatosis (HH) is mainly caused by homozygous p.C282Y mutations in HFE in the Caucasians. We recently reported non-HFE mutations constitute the major cause of HH in Chinese. However, there is still a relatively high proportion of cases with primary iron overload from unexplained causes. We aimed to explore novel non-HFE mutations in Chinese patients with primary iron overload. Methods Whole exome sequence was conducted to screen mutations in novel HH-related genes in the 9 cases with unexplained primary iron overload. Then the representative candidate genes were screened for mutations in another cohort of 18 HH cases. The biological function of the selected genes and variants were analyzed in vitro. Results Whole exome sequencing of 9 cases with unexplained primary iron overload identified 42 missense variants in 40 genes associated with iron metabolism pathway genes such as UBE2O p.K689R and PCSK7 p.R711W. Subsequent Sanger sequencing of the UBE2O and PCSK7 genes in the 27 cases with primary iron overload identified p.K689R in UBE2O, p.R711W and p.V143F in PCSK7 at frequency of 2/27,1/27 and 2/27 respectively. In vitro siRNA interference of UBE2O and PCSK7 resulted in down-regulated HAMP mRNA expression. Adenovirus generation of UBE2O p.K689R in cell lines resulted in increased expression of SMAD6 and SMAD7 and downregulation of p-SMAD1/5 and HAMP expression, and the reduction of hepcidin level. Conclusions Our study identified a series of novel candidate non-HFE mutations in Chinese patients with HH. These may provide insights into the genetic basis of unexplained primary iron overload.

Abstract Hereditary Hemochromatosis is a disorder characterized by iron deposition in several organs and hyperferritinemia. The most studied variants are linked to the HFE gene. In Brazil, surveys that characterize this population are scarce, with no sampling in the state of Rio Grande do Sul. Our objective is to carry out a data collection focusing on the profile of this population and the influence of the most frequently HFE variants. Two centers were enrolled: Hospital de Clínicas de Porto Alegre and Hospital São Vicente de Paulo. Patients with hyperferritinemia and undergoing phlebotomy were invited. Clinical data were collected, including HFE investigation. Among the descriptive data, the allele frequency of the C282Y variant (0.252) stands out, which differs from the national scenario. Systemic arterial hypertension was the most cited comorbidity. Differences between centers were observed, highlighting higher frequency of H63D cases in HSVP (p

Abstract Background Human hepcidin, produced by hepatocytes, regulates intestinal iron absorption, iron recycling by macrophages, and iron release from hepatic storage. Recent studies indicate that hepcidin deficiency is the underlying cause of the most known form of hereditary hemochromatosis. Case presentation A 44-year-old Asian man who developed type 2 diabetes mellitus had elevated serum ferritin levels (10,191 ng/mL). Liver biopsy revealed remarkable iron deposition in the hepatocytes and relatively advanced fibrosis (F3). Chromosomal analysis confirmed the presence of transferrin receptor type 2 mutations (c.1100T>G, c.2008_9delAC, hereditary hemochromatosis type 3 analyzed by Kawabata). The patient received intravenous infusions of Laennec (672 mg/day, three times/week) or oral administration with Porcine (3.87 g/day) for 84 months as an alternative to repeated phlebotomy. At the end of the treatment period, serum ferritin level decreased to 428.4 ng/mL (below the baseline level of 536.8 ng/mL). Hemoglobin A1c levels also improved after treatment with the same or lower dose of insulin (8.8% before versus 6.8% after). Plural liver biopsies revealed remarkable improvements in the grade of iron deposition and fibrosis (F3 before versus F1 after) of the liver tissue. Conclusion The discovery of hepcidin and its role in iron metabolism could lead to novel therapies for hereditary hemochromatosis. Laennec (parenteral) and Porcine (oral), which act as hepcidin inducers, actually improved iron overload in this hereditary hemochromatosis patient, without utilizing sequential phlebotomy. This suggests the possibility of not only improving the prognosis of hereditary hemochromatosis (types 1, 2, and 3) but also ameliorating complications, such as type 2 diabetes, liver fibrosis, and hypogonadism. Laennec and Porcine can completely replace continuous venesection in patients with venesection and may improve other iron-overloading disorders caused by hepcidin deficiency.

Objectives: We developed a natural polyphenol supplement that strongly chelates iron in vitro and assessed its effect on non-heme iron absorption in patients with hereditary hemochromatosis (HH). Methods: We performed in vitro iron digestion experiments to determine iron precipitation by 12 polyphenol-rich dietary sources, and formulated a polyphenol supplement (PPS) containing black tea powder, cocoa powder and grape juice extract. In a multi-center, single-blind, placebo-controlled cross-over study, we assessed the effect of the PPS on iron absorption from an extrinsically labelled test meal and test drink in patients (n = 14) with HH homozygous for the p.C282Y variant in the HFE gene. We measured fractional iron absorption (FIA) as stable iron isotope incorporation into erythrocytes. Results: Black tea powder, cocoa powder and grape juice extract most effectively precipitated iron in vitro. A PPS mixture of these three extracts precipitated ~ 80% of iron when 2 g was added to a 500 g iron solution containing 20 µg Fe/g. In the iron absorption study, the PPS reduced FIA by ~ 40%: FIA from the meal consumed with the PPS was lower (3.01% (1.60, 5.64)) than with placebo (5.21% (3.92, 6.92)) (p = 0.026)), and FIA from the test drink with the PPS was lower (10.3% (7.29 14.6)) than with placebo (16.9% (12.8 22.2)) (p = 0.002). Conclusion: Our results indicate that when taken with meals, this natural PPS can decrease dietary iron absorption, and might thereby reduce body iron accumulation and the frequency of phlebotomy in patients with HH. Trial registry: clinicaltrials.gov (registration date: 9.6.2019, NCT03990181). [ABSTRACT FROM AUTHOR]

Hereditary hemochromatosis (HH) is a rather frequent, preventable disease because the progressive iron overload affecting many organs can be effectively reduced by phlebotomy. Even before the discovery of the major gene, HFE, in 1996, hemochromatosis was seen as a candidate for population-wide screening programmes. A US Centers of Disease Control and the National Human Genome Research Institute expert panel convened in 1997 to consider genotype-based HH population-wide screening and decided that the scientific evidence available at that time was insufficient and advised against. In spite of a large number of studies performed within the last 25 years, addressing all aspects of HH natural history, health economics, and social acceptability, no professional body worldwide has reverted this decision, and HH remains a life-threatening condition that often goes undetected at a curable stage. [ABSTRACT FROM AUTHOR]

Hereditary hemochromatosis (HH) is a genetic disorder in which mutations affect systemic iron homeostasis. Most subtypes of HH result in low hepcidin levels and iron overload. Accumulation of iron in various tissues can lead to widespread organ damage and to various complications, including liver cirrhosis, arthritis, and diabetes. Osteoporosis is another frequent complication of HH, and the underlying mechanisms are poorly understood. Currently, it is unknown whether iron overload in HH directly damages bone or whether complications associated with HH, such as liver cirrhosis or hypogonadism, affect bone secondarily. This review summarizes current knowledge of bone metabolism in HH and highlights possible implications of metabolic dysfunction in HH-driven bone loss. We further discuss therapeutic considerations managing osteoporosis in HH. Hereditary hemochromatosis (HH) is a disease associated with iron overload caused by mutations in genes regulating the hepcidin/ferroportin regulatory axis. Toxic iron accumulation in tissues is responsible for multiple pathologies. HH is associated with skeletal complications and an increased fracture risk. Skeletal complications in HH may be the result of direct effects of iron on bone; effects of mutated iron regulatory genes expressed in bones; or effects secondary to HH-associated endocrinopathies, including hypogonadism and diabetes. HH therapy aims to reduce iron accumulation. Bone health should be considered and monitored. [ABSTRACT FROM AUTHOR]

Atrial and ventricular arrhythmias are common in patients with Infiltrative heart diseases. This review discusses ablative techniques for arrhythmias in amyloidosis, sarcoidosis, hemochromatosis, and glycogen storage disorders, primarily focusing on atrial fibrillation (AF). A thorough literature review was conducted on the MEDLINE database to synthesize current knowledge and propose future research directions. AF is the most common arrhythmia identified in patients with amyloidosis due to cellular infiltration and atrial dilation. While catheter ablation is associated with a significantly lower rate of all-cause mortality and admission rate, conflicting data exist regarding the higher risk of pericardial effusion, in-hospital mortality, length of stay, and cost of hospitalization. Cardiac sarcoid predisposes AF due to granulomas, atrial dilation, and scarring. Studies demonstrate encouraging outcomes and low recurrence rates in these patients who undergo ablation for AF, with no difference in complications compared to those without sarcoidosis. AF is the most common arrhythmia in hereditary hemochromatosis (HH), secondary to increased myocardial iron stores and elevated oxidative stress, and is primarily managed by chelation. Scant reports regarding ablation are described for HH and glycogen storage disorders. Catheter ablation is a safe and effective modality for the treatment of AF in infiltrative cardiomyopathy. Future large-scale trials are needed to confirm these findings., (© 2024 Wiley Periodicals LLC.)

Juvenile hemochromatosis (JH) is a subtype of hereditary hemochromatosis, a genetic disorder characterized by excessive iron absorption and deposition in various organs, leading to cardiomyopathy, cirrhosis, and diabetes. Endocrine dysfunction is a common manifestation and may appear years before end-organ damage. This report describes a rare case of JH, emphasizing the consequences of delayed diagnosis. A 28-year-old woman with a history of hypogonadotropic hypogonadism presented with cardiac arrest complicated by acute renal failure and cerebral vascular accidents. She initially exhibited signs of severe cardiomyopathy and multiorgan failure, which led to workup for an underlying cause. Laboratory values showed significantly elevated ferritin and transferrin saturation. Subsequent genetic screening revealed HJV gene pathogenic variants consistent with juvenile hemochromatosis. Treatment involved aggressive iron chelation therapy and outpatient referral for cardiac transplant. This case calls for heightened awareness and early screening of JH, particularly among patients with unexplained endocrine dysfunction. Early diagnosis and treatment are paramount in preventing irreversible organ damage and improving patient outcomes., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society.)

Hereditary Hemochromatosis (HH) is an autosomal recessive disorder of iron metabolism associated with HFE gene mutations, characterized by increased iron absorption and accumulation leading to multi-organ damage caused by iron overload toxicity. Beta thalassemia is caused by a mutation in the human beta globin gene. Imbalanced production of globin chain results in beta thalassemia, where the unpaired alpha chains precipitates in red cell precursors leading to ineffective erythropoiesis and reduced RBC survival. Both HH and beta thalassemia condition results in rapid accumulation of iron lead to iron overload in tissues and organs. The study aims to analyze the frequency of HFE variants among beta thalassemia cases and their effect on iron overload. The frequency of three HFE variants C282Y, H63D, S65C was analyzed by PCR RFLP method among Beta Thalassemia Trait (BTT) (n = 203), Beta Thalassemia Major (BTM) (n = 19) and age and sex-matched control samples (n = 200). The present study furnished allele frequency of H63D variant in BTT, BTM and controls 8.13, 15.8 and 6% respectively. Ten out of 33 heterozygous H63D variants exhibited iron overload with higher ferritin levels indicating HFE variant might aggravate the absorption of iron. The C282Y variant was present in heterozygous state in 1 case among beta thalassemia carriers. The C282Y variant was absent among BTM and control cases. S65C HFE variant was absent in the present study. Iron overload was completely absent in the control cases among all three HFE genotypes. Hence it is inferred from the present investigation, analysis of HFE genes and iron status will remarkably help to reason out the probable reason behind the iron status and support in proper management of beta thalassemia cases.

Backgrounds: Hereditary hemochromatosis (HH) is mainly caused by homozygous p.C282Y mutations in HFE in the Caucasians. We recently reported non-HFE mutations constitute the major cause of HH in Chinese. However, there is still a relatively high proportion of cases with primary iron overload from unexplained causes. We aimed to explore novel non-HFE mutations in Chinese patients with primary iron overload.Methods: Whole exome sequence was conducted to screen mutations in novel HH-related genes in the 9 cases with unexplained primary iron overload. Then the representative candidate genes were screened for mutations in another cohort of 18 HH cases. The biological function of the selected genes and variants were analyzed in vitro.Results: Whole exome sequencing of 9 cases with unexplained primary iron overload identified 42 missense variants in 40 genes associated with iron metabolism pathway genes such as UBE2O p.K689R and PCSK7 p.R711W. Subsequent Sanger sequencing of the UBE2O and PCSK7 genes in the 27 cases with primary iron overload identified p.K689R in UBE2O, p.R711W and p.V143F in PCSK7 at frequency of 2/27,1/27 and 2/27 respectively. In vitro siRNA interference of UBE2O and PCSK7 resulted in down-regulated HAMP mRNA expression. Adenovirus generation of UBE2O p.K689R in cell lines resulted in increased expression of SMAD6 and SMAD7 and downregulation of p-SMAD1/5 and HAMP expression, and the reduction of hepcidin level.Conclusions: Our study identified a series of novel candidate non-HFE mutations in Chinese patients with HH. These may provide insights into the genetic basis of unexplained primary iron overload. [ABSTRACT FROM AUTHOR]

Arthropathy or joint disease leads to significant pain and disability irrespective of etiology. Clinical and experimental evidence point to the presence of considerable links between arthropathy and iron overload. Previous work has suggested that iron accumulation in the joints is often associated with increased oxidative stress, disrupted matrix metabolism, and cartilage degeneration. However, key issues regarding the role of iron overload in the pathogenesis of arthropathy remain ambiguous. For example, significant gaps in our knowledge of the primary cellular targets of iron overload‐induced damage and the exact molecular mechanism through which disrupted iron homeostasis leads to joint damage still exist. The exact signaling pathway that links iron metabolism and cellular damage in arthropathy also remains largely unmapped. In this review, we focus on the relationship between iron overload and arthropathy with special emphasis on the adversarial relationship between iron that accumulates in the joints over time and cartilage homeostasis. A better understanding of the mechanisms and pathways underlying iron‐induced cartilage degeneration may help in defining new prognostic markers and therapeutic targets in arthropathy. [ABSTRACT FROM AUTHOR]

Background and aimWomen who are homozygous for the p.C282Y mutation in the HFE gene are at much lower risk of iron overload-related disease than p.C282Y homozygous men, presumably because of the iron-depleting effects of menstruation and pregnancy. We used data from a population cohort study to model the impact of menstruation cessation at menopause on serum ferritin (SF) levels in female p.C282Y homozygotes, with p.C282Y/p.H63D simple or compound heterozygotes and those with neither p.C282Y nor p.H63D mutations (HFE wild types) as comparison groups.MethodsA sample of the Melbourne Collaborative Cohort Study was selected for the "HealthIron" study (n = 1438) including all HFE p.C282Y homozygotes plus a random sample stratified by HFE-genotype (p.C282Y and p.H63D). The relationship between the natural logarithm of SF and time since menopause was examined using linear mixed models incorporating spline smoothing.ResultsFor p.C282Y homozygotes, SF increased by a factor of 3.6 (95% CI (1.8, 7.0), P

IntroductionCo-inheritance of hereditary hemochromatosis (HFE) gene variants p. C282Y and p.H63D worsen iron overload in transfusion-dependent thalassemia. Data on the HFE gene variants in Sri Lankan patients with thalassemia have not been extensively studied. This study aimed to analyze the p.C282Y and p.H63D variants in transfusion-dependent beta (β) and HbE/β-thalassemia patients and establish an association between these variants and their serum ferritin levels.Materials and MethodsA total of 125 transfusion-dependent β-thalassemia major and HbE/β thalassemia patients were tested for the c.845G>A (p.C282Y) and c.187C>G (p.H63D) HFE gene variants using the multiplex Amplification Refractory Mutation System Polymerase Chain Reaction method. For phenotype-genotype correlation, serum ferritin levels, the erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) levels were measured. The standard descriptive statistics were used for data analysis.ResultsThe study cohort consisted of transfusion-dependent 123 β-thalassemia and 2 HbE/β-thalassemia patients. The p.C282Y variant was not detected in any patient; allele frequency for the wild type (c.845GG) was 100%. Twenty-three patients were heterozygous for the p.H63D variant allele, and the allele frequencies were c.187CC 91.8%, c.187CG 9.2%, and c.187GG 0%. The mean serum ferritin level was relatively higher (mean level 4,987 ng/ml) in the p.H63D heterozygous (c.187CG) group compared to the wild type (c.187CC) group (mean level 4,571 ng/ml), but the difference was statistically not significant (p = 0.865). Among the total study population, CRP, ESR, and serum glutamine aspartate transaminase (SGPT) were elevated in 9 (7.2%), 65 (52%), and 82 (65.6%) patients, respectively. Among the p.H63D c.187CG group, elevated CRP, ESR, and SGPT were present in 5 (5%), 15 (12%), and 18 (14.4%) patients, respectively. The detected sample number was low to correlate with the confounding effect of inflammatory disorders and liver damage on the serum ferritin levels.ConclusionsThe HFE gene variant p.C282Y is unlikely to cause iron overload in the Asian β-thalassemia patients; the rarity of this variant in the study cohort replicates the findings of other South Asian population studies of this variant. The presence of the p.H63D variant could be a potential risk factor for iron overload in the β-thalassemia patients. A more extensive cohort study is required to validate this finding.

In a newborn with very precocious liver failure, cholestatic jaundice, and low γ-glutamyl transpeptidase, progressive hepatosplenomegaly induced a progressively worsening respiratory distress, that was successfully treated with steroids. Laboratory and genetic tests did not find any disease usually associated with neonatal cholestasis. However, the patient was positive for a homozygous mutation of the HFE gene, which is associated with hereditary hemochromatosis, a disease with typical onset in adulthood. Although no firm conclusions can be drawn from a single clinical case, this experience suggests that hereditary hemochromatosis could have played a role in the induction of this serious cholestasis, probably already arisen in the uterus. We suggest that hereditary hemochromatosis ought to be included in the panel of the possible causes of neonatal cholestasis and that steroids ought to be added to the pharmacological armamentarium for treating specific conditions which cause cholestasis in newborns.

Abstract Background Hereditary hemochromatosis is a heterogenous group of inherited iron-overload conditions that is characterized by increased intestinal absorption and deposition in vital organs. Hepcidin is a soluble regulator that acts to attenuate both intestinal iron absorption and iron release from reticuloendothelial macrophages through internalization of ferroportin-1, an iron exporter. Ferroportin disease is hereditary hemochromatosis which is affected by SLC40A1, a gene coding ferroportin-1, and phenotypically classified into two forms (classical and nonclassical). In nonclassical form, ferroportin mutations are responsible for a gain of function with full iron export capability but insensitivity to downregulation by hepcidin. Here, we report a case of nonclassical ferroportin disease. Case presentation A 46-year-old Japanese man showed elevated serum iron (284 μg/dl), ferritin (1722 ng/ml), transferrin saturation ratio (91.3%), and hepcidin-25 level (139.6 ng/ml). Magnetic resonance imaging (MRI) demonstrated a marked reduction in the signal intensity of the liver in T1- and T2-weighted images. The liver histology exhibited a large amount of iron that had accumulated predominantly in hepatocytes. We identified a heterozygous 1520A > G (p.H507R) mutation in the SLC40A1 gene. Phlebotomy (400 ml at a time) was monthly performed for 3 years in this patient. Importantly, the serum hepcidin level (1.0 ng/ml) was normal when the serum ferritin level was normal and hepatic iron accumulation was remarkably reduced after 3 years of phlebotomy. Conclusions The present case demonstrated for the first time that there was a correlation between hepatic iron levels as measured by MRI and serum hepcidin levels through long-term phlebotomy in a patient with ferroportin disease with the p.H507R mutation of in SLC40A1.

Type 3 hereditary hemochromatosis (HH) is a rare form of HH characterized by genetic mutation in the TFR2 gene. Clinical features reported in patients with type 3 HH include abnormal liver function, liver fibrosis, cirrhosis, diabetes, hypogonadism, cardiomyopathy, and skin pigmentation. Since its original description in 2000, 33 pathogenic TFR2 mutations associated with HH have been described until now. Here, we first reported a Chinese pedigree of TFR2 -related hemochromatosis with a novel compound heterozygous mutation c.1288G > A (p.G430R)/c.960T > A (p.Y320X). Interestingly, different phenotypes were reported although the proband and his sister shared the same gene mutation. This inconsistency between genotypes and phenotypes indicates multifactorial etiology contributing to the development of HH. Our report broadens the mutation spectrum of the TFR2 gene associated with HH. [ABSTRACT FROM AUTHOR]

Abstract Background Hereditary hemochromatosis is an autosomal recessive disorder where the clinical phenotype of skin pigmentation and organ damage occurs only in homozygotes. Simple heterozygotes, that is, just C282Y, typically do not develop iron overload. Here we present a case where a simple heterozygote in combination with alcoholism developed high ferritin and high transferrin saturation levels indicative of iron overload. Though alcoholism alone could explain her presentation, we hypothesize that an inflammatory cocktail of iron and alcohol probably caused our patient to succumb to acute liver failure at a very young age. Case presentation A 29-year-old Caucasian woman presented to the hospital with progressively worsening yellowish discoloration of her eyes and skin associated with anorexia, nausea, vomiting, diffuse abdominal discomfort, increasing abdominal girth, dark urine and pale stools for about 2 weeks. Family history was significant for hereditary hemochromatosis. Her father was a simple heterozygote and her grandmother was homozygous for C282Y. Physical examination showed scleral icterus, distended abdomen with hepatomegaly and mild generalized tenderness. Lab test results showed an elevated white blood cell count, ferritin 539 ng/dL, transferrin saturation 58.23%, elevated liver enzymes, elevated international normalized ratio (INR), low albumin, Alcoholic Liver Disease/Nonalcoholic Fatty Liver Disease (ALD/NAFLD) Index (ANI) of 2.6, suggesting a 93.2% probability of alcoholic liver disease, and phosphatidyl ethanol level of 537ng/ml. Genetic testing showed that the patient was heterozygous for human homeostatic iron regulator protein (HFE) C282Y mutation and the normal allele. Computed tomography (CT) of the abdomen revealed hepatomegaly, portal hypertension and generalized anasarca. Magnetic resonance cholangiopancreatography (MRCP) showed negative results for bile duct pathology. Workup for other causes of liver disease was negative. A diagnosis of acute alcoholic hepatitis was made, with Maddrey’s discriminant function of > 32, so prednisolone was started. Her bilirubin and INR continued to increase despite steroids, and the patient unfortunately died. Conclusion Our case highlights the importance of considering hemochromatosis in the differential diagnosis of young patients presenting with liver failure, including cases suggestive of alcoholism as the likely etiology. Larger studies are needed to investigate the role of non-iron factors like alcohol and viral hepatitis in the progression of liver disease in simple heterozygotes with hereditary hemochromatosis, given the high prevalence of this mutation in persons of Northern European descent.

A 51-year-old woman, clinically diagnosed with Xeroderma pigmentosum (XP), showed abnormalities in liver enzymes, high ferritin and transferrin saturation levels, with ultrasonographic features of chronic liver disease, in addition to skin hyperpigmentation. Genetic testing confirmed the clinical hypothesis of hereditary hemochromatosis (HH). Due to the known proximity of HFE (6p22.2) and POLH (6p21.1) genes, accountable for HH and the XP-V variant, respectively, a genetic test was offered and a rare variant of the POLH gene was identified. We report the first confirmed case, to our knowledge, of a patient diagnosed both with XP and HH, in whom two mutated neighbor genes – POLH and HFE – were identified, possibly the result of genetic linkage.

Jubran Alqanatish,1– 3 Banan Alsowailmi,1 Haneen Alfarhan,1 Albandari Alhamzah,1 Talal Alharbi1,2,4 1King Saud Bin Abdulaziz University for Health Sciences (KSAU-HS), Riyadh 14611, Saudi Arabia; 2King Abdullah International Medical Research Center (KAIMRC), Riyadh 14611, Saudi Arabia; 3Department of Pediatrics, King Abdullah Specialist Children’s Hospital and King Abdulaziz Medical City, Ministry of National Guard Health Affairs, Riyadh, Saudi Arabia; 4Department of Pediatric Hematology/Oncology, King Abdullah Specialist Children’s Hospital and King Abdulaziz Medical City, Ministry of National Guard Health Affairs, Riyadh, Saudi ArabiaCorrespondence: Jubran AlqanatishKing Saud Bin Abdulaziz University for Health Sciences (KSAU-HS), PO Box 22490, Riyadh 11426, Saudi ArabiaTel +966 118011111 Ext 53501Email qanatishj@ngha.med.saAbstract: Hereditary hemochromatosis (HH) is an inherited iron overload. The most common form of HH is type 1 hereditary hemochromatosis (HFE-related), which is associated with mutation of the HFE gene located on chromosome 6 and inherited in an autosomal recessive pattern. Type 2 hereditary hemochromatosis or juvenile hemochromatosis is less frequent autosomal recessive disease that results from mutations in the HJV gene on chromosome 1 (type2a) or the HAMP gene on chromosome19 (type2b). Mutation of type 2 transferrin receptor gene and mutation of the ferroportin gene result in hemochromatosis type 3 and hemochromatosis type 4, respectively. Juvenile hemochromatosis is characterized by an early onset of excess accumulation of iron in various organs. It could affect the liver, heart, pancreas and joints, resulting in arthropathy. Most juvenile hemochromatosis cases exhibit severe symptoms due to early onset. Cardiac and hypogonadism are the dominating features of the disease. Prevalence of arthropathy in juvenile hemochromatosis is higher than classic HH. Early diagnosis and intervention of juvenile hemochromatosis may prevent irreversible organ damage. The diagnosis can be made based on laboratory testing (of increased transferrin saturation, serum iron and ferritin levels), liver biopsy, imaging or genotype. According to international guidelines, treatment of HH is indicated when serum ferritin concentrations are above the upper limit of normal. We report two sisters who presented to the rheumatology clinic with arthralgia, which was subsequently found to have a homozygous mutation variant of unknown significance in the HFE2 gene: c.497A>G;p.(His166Arg) and has been treated with deferasirox (Exjade®). Musculoskeletal symptoms completely resolved in both patients in two months and remained so for one year on treatment.Keywords: hereditary hemochromatosis, HFE gene, arthritis, deferasirox

Abstract β‐thalassemia heterozygosity can cause significant iron overload when accompanied by HFE gene mutations and inappropriate iron supplementation.

Type 3 hereditary hemochromatosis (HH) is a rare form of HH characterized by genetic mutation in the TFR2 gene. Clinical features reported in patients with type 3 HH include abnormal liver function, liver fibrosis, cirrhosis, diabetes, hypogonadism, cardiomyopathy, and skin pigmentation. Since its original description in 2000, 33 pathogenic TFR2 mutations associated with HH have been described until now. Here, we first reported a Chinese pedigree of TFR2-related hemochromatosis with a novel compound heterozygous mutation c.1288G > A (p.G430R)/c.960T > A (p.Y320X). Interestingly, different phenotypes were reported although the proband and his sister shared the same gene mutation. This inconsistency between genotypes and phenotypes indicates multifactorial etiology contributing to the development of HH. Our report broadens the mutation spectrum of the TFR2 gene associated with HH.

Introduction: For the maintenance treatment of patients with hereditary hemochromatosis (HH), it is advised to keep the transferrin saturation (TSAT) <70% to prevent formation of non‐transferrin‐bound iron and labile plasma iron. The period of the initial iron depletion may last up to 1 year or longer and during this period, the patient is exposed to elevated TSAT levels. Therapeutic erythrocytapheresis (TE) is a modality which has proven to reduce treatment duration of patients with iron overload from HH. In this study, we investigated the time to reach TSAT <70% for both treatment modalities. Methods: From a previous randomized controlled trial comparing erythrocytaphereses with phlebotomies (PBMs), we performed an analysis in a subgroup of patients who presented with TSAT >70%. Mann‐Whitney U tests were performed to compare the number of treatments and the number of weeks to reach the interim goal of a persistent level of <70% for TSAT between TE and PBM. Results: The period to reach TSAT levels of <70% was statistically significant shorter for the TE group compared to the PBM treatment group (median treatment procedures [IQR] 2.0 (5) vs 16.0 (23), P‐value: <.001, and median treatment duration [IQR]: 5.5 (11) vs 19.0 (29) weeks, P‐value:.007). Conclusion: Patients with HH reach a safe TSAT <70% significantly sooner and with less treatment procedures with TE compared to PBM. [ABSTRACT FROM AUTHOR]

Background: Human hepcidin, produced by hepatocytes, regulates intestinal iron absorption, iron recycling by macrophages, and iron release from hepatic storage. Recent studies indicate that hepcidin deficiency is the underlying cause of the most known form of hereditary hemochromatosis. Case presentation: A 44-year-old Asian man who developed type 2 diabetes mellitus had elevated serum ferritin levels (10,191 ng/mL). Liver biopsy revealed remarkable iron deposition in the hepatocytes and relatively advanced fibrosis (F3). Chromosomal analysis confirmed the presence of transferrin receptor type 2 mutations (c.1100T>G, c.2008_9delAC, hereditary hemochromatosis type 3 analyzed by Kawabata). The patient received intravenous infusions of Laennec (672 mg/day, three times/week) or oral administration with Porcine (3.87 g/day) for 84 months as an alternative to repeated phlebotomy. At the end of the treatment period, serum ferritin level decreased to 428.4 ng/mL (below the baseline level of 536.8 ng/mL). Hemoglobin A1c levels also improved after treatment with the same or lower dose of insulin (8.8% before versus 6.8% after). Plural liver biopsies revealed remarkable improvements in the grade of iron deposition and fibrosis (F3 before versus F1 after) of the liver tissue. Conclusion: The discovery of hepcidin and its role in iron metabolism could lead to novel therapies for hereditary hemochromatosis. Laennec (parenteral) and Porcine (oral), which act as hepcidin inducers, actually improved iron overload in this hereditary hemochromatosis patient, without utilizing sequential phlebotomy. This suggests the possibility of not only improving the prognosis of hereditary hemochromatosis (types 1, 2, and 3) but also ameliorating complications, such as type 2 diabetes, liver fibrosis, and hypogonadism. Laennec and Porcine can completely replace continuous venesection in patients with venesection and may improve other iron-overloading disorders caused by hepcidin deficiency. [ABSTRACT FROM AUTHOR]

Infectious mononucleosis is a largely benign disease process that occurs secondary to infection with the Epstein-Barr virus. However, it can also present with more serious complications, including auto-immune hemolytic anemia and acute liver failure. Hereditary hemochromatosis is a genetic disorder that leads to organ damage via increased iron uptake and deposition. This case report describes a 25-year-old man who presented with acute liver failure and severe hemolytic anemia. Workup revealed that not only did he have a rare presentation of Epstein-Barr virus-induced acute liver failure and C3-positive IgG-negative hemolytic anemia, he also had previously undiagnosed hereditary hemochromatosis. This combined presentation of these pathologies presents a unique opportunity to study their interaction and possible synergistic pathophysiology. Furthermore, the evolving understanding of the disease mechanisms behind these disease processes is described.

Abstract Background Hereditary hemochromatosis (HH) is an autosomal recessive genetic disorder with increased intestinal iron absorption and therefore iron Overload. iron overload leads to increased levels of toxic non-transferrin bound iron which results in oxidative stress and lipid peroxidation. The impact of iron on lipid metabolism is so far not fully understood. The aim of this study was to investigate lipid metabolism including lipoproteins (HDL, LDL), neutral (triglycerides, cholesterol) and polar lipids (sphingo- and phospholipids), and PNPLA3 polymorphism (rs738409/I148M) in HH. Methods We conducted a cohort study of 54 subjects with HH and 20 healthy subjects. Patients were analyzed for their iron status including iron, ferritin, transferrin and transferrin saturation and serum lipid profile on a routine follow-up examination. Results HH group showed significantly lower serum phosphatidylcholine (PC) and significantly higher phosphatidylethanolamine (PE) compared to healthy control group. The ratio of PC/PE was clearly lower in HH group indicating a shift from PC to PE. Triglycerides were significantly higher in HH group. No differences were seen for HDL, LDL and cholesterol. Hepatic steatosis was significantly more frequent in HH. PNPLA3 polymorphism (CC vs. CG/GG) did not reveal any significant correlation with iron and lipid parameters including neutral and polar lipids, grade of steatosis and fibrosis. Conclusion Our study strengthens the hypothesis of altered lipid metabolism in HH and susceptibility to nonalcoholic fatty liver disease. Disturbed phospholipid metabolism may represent an important factor in pathogenesis of hepatic steatosis in HH.

Abstract Introduction Hereditary hemochromatosis is an inherited disorder of iron metabolism, characterized by excessive iron deposition in major organs of the body, leading to multi-organ dysfunction. It is a genetically heterogeneous disease caused by mutations in one or more different genes, the most common being mutations in the HFE gene. HFE hereditary hemochromatosis is mostly found in Europeans and is almost always a result of two mutations: C282Y and H63D. The H63D mutation is not as penetrant as the C282Y mutation, but there are rare reported cases of hereditary hemochromatosis with homozygous H63D genotype. While the C282Y mutation is primarily confined to persons of Northern European origin, the H63D mutation is spread worldwide. Other types of hereditary hemochromatosis are rare and broadly defined as non-HFE hereditary hemochromatosis and include mutations in the hemojuvelin gene, hepcidin (HAMP gene), transferrin receptor 2 gene, and ferroportin gene. Hereditary hemochromatosis is commonly found in populations of European origin; in contrast, it is rare and less well understood in Asia. It can be masked by the presence of concurrent iron deficiency or secondary iron overload in thalassemias. Case presentation We report the case of a 42-year-old Sri Lankan man investigated for fatigue during a brief upper respiratory tract infection and found to have high liver transaminases and high serum ferritin, which persisted even after complete resolution of the infection. Homozygosity for H63D mutation in the HFE gene was detected. Liver enzymes, serum ferritin, and transferrin saturation normalized following venesections. Conclusion This case adds to the literature on the importance of being vigilant and investigating patients suspected for iron overload, including genetic studies for hereditary hemochromatosis, even though it is a rare clinical entity in Asians.

Abstract Background Detection of brain-MRI T2/T2* gradient echo images (T2*GRE)-hypointensity can be compatible with iron accumulation and leads to a differential diagnosis work-up including neurodegeneration with brain iron accumulation (NBIA) and Wilson Disease. Idiopathic or secondary brain calcification can be also associated with neurological involvement and brain-MRI T2/T2*GRE-hypointensity. Hereditary hemochromatosis (HH), characterized by systemic iron loading, usually does not involve the CNS, and only sporadic cases of neurological abnormalities or brain-MRI T2/T2*GRE-hypointensity have been reported. Case presentation A 59-year-old man came to our observation after a diagnosis of HH carried out in another hospital 2 years before. First-level genetic test had revealed a homozygous HFE p.Cys282Tyr (C282Y) mutation compatible with the diagnosis of HFE-related HH, thus phlebotomy treatment was started. The patient had a history of metabolic syndrome, type-2 diabetes, autoimmune thyroiditis and severe chondrocalcinosis. Brain-MRI showed the presence of bilateral T2*GRE hypointensities within globus pallidus, substantia nigra, dentate nucleus and left pulvinar that were considered expression of cerebral siderosis. No neurological symptoms or family history of neurological disease were reported. Neurological examination revealed only mild right-sided hypokinetic-rigid syndrome. Vitamin D–PTH axis, measurements of serum ceruloplasmin and copper, and urinary copper were within the normal range. A brain computed tomography (CT) was performed to better characterize the suspected and unexplained brain iron accumulation. On the CT images, the hypointense regions in the brain MRI were hyperdense. DNA sequence analysis of genes associated with primary familial brain calcification and NBIA was negative. Conclusions This report highlights the importance of brain CT-scan in ambiguous cases of suspected cerebral siderosis, and suggests that HH patients with a severe phenotype, and likely associated with chondrocalcinosis, may display also brain calcifications. Further studies are needed to confirm this hypothesis. So far, we can speculate that iron and calcium homeostasis could be reciprocally connected within the basal ganglia.

Hereditary hemochromatosis (HH) is recognized as a progressive iron-storage disorder, and leading to severe organ impairments, including liver cirrhosis. Hereditary hemochromatosis type 3 arises from mutations in the transferrin receptor 2 (TFR2) gene. However, HH type 3 is rare in Asia, and information regarding genetic mutations and associated phenotypes remains limited. Here, we reported the case of a Japanese patient with HH type 3, with a novel homozygous mutation of the TFR2 gene. A 69-year-old woman presented to our hospital with hand joint pain and was referred due to liver impairment. Viral hepatitis and autoimmune liver diseases were ruled out. However, the transferrin saturation was 92.2%, and the serum ferritin level was 1611.8 ng/mL. Additionally, abdominal computed tomography showed diffuse increased density of the liver parenchyma. Abdominal magnetic resonance imaging also suggested iron deposition. There is no history of prior treatments involving blood transfusions or iron agents. Her parents were involved in a consanguineous marriage, prompting genetic testing. She had a homozygous novel mutation, c.1337G>A (p.G446E), in the TFR2 gene. Serum hepcidin-25 level was decreased to 2.9 ng/mL. According to the American Society of Medical Genetics and Genomics guideline, the mutation was classified as likely pathogenic, leading to the diagnosis of HH type 3. Following phlebotomy, her arthritis resolved, and serum transaminase levels were normalized. This case marks the first demonstration of homozygous mutation, c.1337G>A (p.G446E), in the TFR2 gene in patients with HH type 3., (© 2024 The Author(s). Hepatology Research published by John Wiley & Sons Australia, Ltd on behalf of Japan Society of Hepatology.)

Hereditary Hemochromatosis (HH) is an autosomal recessive disorder of iron metabolism associated with HFE gene mutations, characterized by increased iron absorption and accumulation leading to multi-organ damage caused by iron overload toxicity. Beta thalassemia is caused by a mutation in the human beta globin gene. Imbalanced production of globin chain results in beta thalassemia, where the unpaired alpha chains precipitates in red cell precursors leading to ineffective erythropoiesis and reduced RBC survival. Both HH and beta thalassemia condition results in rapid accumulation of iron lead to iron overload in tissues and organs. The study aims to analyze the frequency of HFE variants among beta thalassemia cases and their effect on iron overload. The frequency of three HFE variants C282Y, H63D, S65C was analyzed by PCR RFLP method among Beta Thalassemia Trait (BTT) (n = 203), Beta Thalassemia Major (BTM) (n = 19) and age and sex-matched control samples (n = 200). The present study furnished allele frequency of H63D variant in BTT, BTM and controls 8.13, 15.8 and 6% respectively. Ten out of 33 heterozygous H63D variants exhibited iron overload with higher ferritin levels indicating HFE variant might aggravate the absorption of iron. The C282Y variant was present in heterozygous state in 1 case among beta thalassemia carriers. The C282Y variant was absent among BTM and control cases. S65C HFE variant was absent in the present study. Iron overload was completely absent in the control cases among all three HFE genotypes. Hence it is inferred from the present investigation, analysis of HFE genes and iron status will remarkably help to reason out the probable reason behind the iron status and support in proper management of beta thalassemia cases. [ABSTRACT FROM AUTHOR]