Hemochromatosis Gene Mutations Research Articles

SGLT2i-Induced Erythrocytosis Unveiling Heterozygous Hereditary Hemochromatosis (HH) Gene Mutation in an Individual with CKD

SGLT2i-Induced Erythrocytosis Unveiling Heterozygous Hereditary Hemochromatosis (HH) Gene Mutation in an Individual with CKD

HFE hemochromatosis gene polymorphism and porphyria cutanea tarda

Purpose. To study the frequency of genotypes and alleles of C282Y and H63D mutations in the HFE gene in patients with porphyria cutanea tarde of the West Siberian region and their influence on the clinical and biochemical characteristics of the disease. Materials and methods. We observed 14 patients with porphyria cutanea tarde (PCT), who underwent a comprehensive general clinical and instrumental examination. The indicators of the excretory profile of porphyrin metabolism indicators were purposefully determined, a molecular genetic examination was carried out to determine the genotypes and alleles of the C282Y and H63D mutations of the hemochromatosis gene HFE. Results and discussion. Molecular genetic research found that the HFE gene mutation was found in 7 patients (50.0%). Polymorphism for the C282Y allele was found in 2 (14.3%) patients, and for the H63D allele - in 5 patients (35.7%). Risk factors for the manifestation of PCT included frequent alcohol consumption and chronic HCV infection. Genotype 1b was recorded more often (9 people), less often - genotype 3a (4 people). The excretory profile of porphyrin metabolism indices in patients of both groups exceeded the control values. Porphyrin metabolism parameters in patients without HFE gene mutations were significantly higher than those in patients without HFE gene mutations. Conclusions. Polymorphism of the hemochromatosis gene HFE in PCT was detected in 50% of patients. The most common mutation was the H63D allele. The level of porphyrin metabolism disorders in patients with HFE hemochromatosis gene mutations is significantly lower. The clinical picture of PCT in all observed patients did not differ. Chronic viral hepatitis C is assessed as a risk factor for the manifestation of PCT.

Elevated erythroferrone distinguishes erythrocytosis with inherited defects in oxygen-sensing pathway from primary familial and congenital polycythaemia.

Congenital erythrocytoses represent a heterogenous group of rare defects of erythropoiesis characterized by elevated erythrocyte mass. We performed molecular-genetic analysis of 21 Czech patients with congenital erythrocytosis and assessed the mutual link between chronic erythrocyte overproduction and iron homoeostasis. Causative mutations in erythropoietin receptor (EPOR), hypoxia-inducible factor 2 alpha (HIF2A) or Von Hippel-Lindau (VHL) genes were detected in nine patients, including a novel p.A421Cfs*4 EPOR and a homozygous intronic c.340+770T>C VHL mutation. The association and possible cooperation of five identified missense germline EPOR or Janus kinase 2 (JAK2) variants with other genetic/non-genetic factors in erythrocytosis manifestation may involve variants of Piezo-type mechanosensitive ion channel component 1 (PIEZO1) or Ten-eleven translocation 2 (TET2), but this requires further research. In two families, hepcidin levels appeared to prevent or promote phenotypic expression of the disease. No major contribution of heterozygous haemochromatosis gene (HFE) mutations to the erythrocytic phenotype or hepcidin levels was observed in our cohort. VHL- and HIF2A-mutant erythrocytosis showed increased erythroferrone and suppressed hepcidin, whereas no overproduction of erythroferrone was detected in other patients regardless of molecular defect, age or therapy. Understanding the interplay between iron metabolism and erythropoiesis in different subgroups of congenital erythrocytosis may improve current treatment options.

P1556: HYPER -FERRITINEMIA IN PEDIATRIC ONCOLOGY PATIENTS SECONDARY TO TREATMENT: DIAGNOSTIC APPROACH AND OUTCOME

Background: Multiple red blood cell transfusions during cancer therapy are the leading cause of iatrogenic hyper- ferritinemia which of notice is often overlooked. Patients with genetic predisposition for hemochromatosis have a higher chance of developing hyper-ferritinemia, with a potential to promote significant organ dysfunction. Aims: The aim of this study was to identify pediatric oncology patients with high levels of ferritin post cancer treatment, and refer their management and outcome. Methods: Selected patients’ charts of our Department were retrospectively reviewed. Patient and treatment characteristics, ferritin levels and their progression over time, genetic testing for hemochromatosis genes, treatment and outcome were recorded and analyzed. Results: Twelve (12) patients were identified with increased (>600 ng/ml) ferritin levels, diagnosed with Acute Lymphoblastic Leukemia (N=5), Acute Myeloid Leukemia (N=1), Non-Hodgkin Lymphoma (N=1), Neuroblastoma (N =2), Medulloblastoma (N=1), Rhabdomyosarcoma (N=2) from 1995 to 2020. Mean patient age at diagnosis was 7.1 years (range 3.0-15.2 years). Three patients had undergone Hematopoietic Stem Cell Transplantation, 2 of them twice. Mean blood transfusions per patient were 42 (range: 9-62), with 6 patients receiving more than 50 transfusions each (10-15 ml/kg). Of 6 patients tested for hemochromatosis genes, 2 were negative for the common mutations of HFE, TfR2 FPN1 genes, 1 was found double heterozygote for the His63Asp and Cys282Tyr HFE mutations and 1 patient carried the HFE H63D mutation. Eight (8/12) patients were observed only, and ferritin reduction of 5.7% to 69.7% was observed, within 12 months of follow-up, but none normalized ferritin levels, the lowest value being 560 ng/ml (Image). One patient received chelation therapy (deferasinox po) for 13 months, 1 patient (heterozygous for beta-thalassemia trait) received 37 phlebotomy sessions and 2 received combination of chelation (deferasirox only or with deferoxamine) and short-course phlebotomies. Out of the later intervention group of patients, none achieved normal ferritin levels after an observation period of 12 months. With a mean follow up of 3.7 years for all patients (range 1,1-15,7 years), mean ferritin levels after cancer therapy and at +12 months, were 2056 ng/ml (range: 621-4750 ng/ml) and 1227 ng/ml (range: 590-3550 ng/ml), respectively. Only 1 patient achieved ferritin levels under 500 ng/ml following 3-years of phlebotomies, and she has remained so, for another 4 years of follow-up (b-thalassemia heterozygote and Η63D HFE heterozygote for the hemochromatosis genes). Image:Summary/Conclusion: Iatrogenic iron overload post antineoplastic therapy in pediatric patients is a common and often overlooked diagnosis. Prompt evaluation and appropriate treatment is necessary. Patients presenting with hyper-ferritinemia for extended time period could bear hemochromatosis gene mutations. Since the symptoms are absent initially, pediatric patients after cancer treatment should be screened for ferritin levels. If persistently high levels are documented, evaluation of relevant mutations and appropriate treatment is necessary. The long-term effect of high Ferritin levels is not fully documented, but it has the potential to promote significant organ dysfunction. Further research is necessary in this field.

Abstract #1152223: Hereditary Hemochromatosis Gene Mutation in Patients Developing Erythrocytosis on Combined Testosterone Replacement and SGLT-2 Inhibitor Therapy: A Case Series

Recent reports have demonstrated that male patients with type 2 diabetes (T2D) and hypogonadism receiving combined testosterone replacement therapy (TRT) and sodium-glucose cotransporter-2 inhibitor (SGLT2i) prescription may be at increased risk for erythrocytosis (E). We investigated if the incident E is associated with pathogenic mutation in common HFE genes known to result in hereditary hemochromatosis (HH).

Unmasking hereditary hemochromatosis with CFTR modulator therapy

Cystic Fibrosis (CF) is a genetic condition affecting the ability to excrete chloride, resulting in multi-system organ damage. Liver disease is one co-morbidity that affects 20-40% of people with CF. This case describes a 16-year-old male with CF (F508Del and Q493X mutations) who was started one lexacaftor/tezacaftor/ifacaftortriple CF Transmembrane Regulator (CFTR) modulator therapy. Prior to starting treatment, it was noted that he had transaminitis (AST 69, ALT 120, Total bilirubin 0.4). His liver enzymes continued to increase with therapy and at week 8 of treatment he complained of abdominal pain, body aches, and fatigue warranting further evaluation. At that time, AST and ALT were elevated at 5- and 13-times the Upper Limits of Normal (ULN) and creatinine kinase was elevated at 12-times ULN. A dose reduction led to a decrease in AST and ALT to 2 and 4-times ULN, but total and direct bilirubin increased to 2.2 mg/dl and 0.5 mg/dl, warranting a liver ultrasound and biopsy. Pathology showed fatty liver and hepatocyte iron deposition, but no indications of cirrhosis. Iron studies and genetic testing confirmed a diagnosis of HH (Homozygous HIS63ASP gene mutation). After stopping triple CFTR modulator therapy, AST and ALT continued to rise, prompting further evaluation by hepatology and hematology. Upon discontinuation of drug therapy, his lung function dropped significantly back to baseline values and respiratory symptoms returned. Discussion: Hereditary hemochromatosis gene mutations have been shown to have a gene modulating impact on CFTR gene mutations that can affect CF disease phenotype, which negatively affects pulmonary function and gastrointestinal disease. In this case, the introduction of a new medication instigated further work-up leading to the discovery of a potential alternative cause of hepatic dysfunction while attempting to optimize medications to sustain improvements in pulmonary function. Although elevated hepatic transaminases can be expected from CF and CFTR modulator therapy, further investigation may be indicated in patients with persistent elevations despite medication adjustments. This workup may lead to important considerations in balancing liver function with lung function. Keywords: cystic fibrosis; elexacaftor; tezacaftor; ivacaftor; liver transaminases; hereditary hemochromatosis.

Hemochromatosis Gene Mutation in Persons Developing Erythrocytosis on Combined Testosterone and SGLT-2 Inhibitor Therapy.

In clinical trials, sodium-glucose cotransporter-2 inhibitors (SGLT-2i) use alone in persons with type 2 diabetes (T2D) or testosterone replacement therapy (TRT) prescription alone in men with hypogonadism was shown to lead to a modest but significant increase in red blood cell mass. Recent evidence indicates that combined use of TRT and SGLT-2i in persons with T2D may be associated with risk of erythrocytosis. However, factor(s) that may lead to the development of erythrocytosis in these patients is unknown. We describe here 5 consecutive patients with hypogonadism on chronic TRT who developed erythrocytosis following addition of SGLT-2i empagliflozin for optimization of T2D management. In addition to the careful review of medical history, all patients underwent genetic screening for hereditary hemochromatosis. We have found that none of the patients had C282Y mutation in the HFE (Homeostatic Iron Regulator) gene and 4 out of 5 patients had heterozygosity in the H63D allele. Upon TRT discontinuation or its dose reduction or referral for scheduled phlebotomy, patients showed resolution of erythrocytosis. Our study reaffirms that practitioners should monitor for changes in hematocrit following the initiation of SGLT-2i in persons with T2D and hypogonadism on chronic TRT. Also, for the first time, we showed that in some of the patients receiving combined TRT and SGLT-2i H63D heterozygosity in the HFE gene may mediate the development of new-onset erythrocytosis.

Clinicopathologic Characteristic and Natural History of Patients with Non Hereditary, Non Polycythemia Vera (NH/NPV) Persistent Polycythemia

Introduction;Polycythemia Vera (PV), is one of the most common Philadelphia chromosome negative myeloproliferative disorders. The identification of Janus Kinase (JAK) 2 mutations and the publication of 2016 revision of WHO classification of myeloid neoplasms has improved diagnostic accuracy of PV. The lower cut-off values of Hemoglobin (Hb) and hematocrit (Hct) used in WHO diagnostic criteria, however, resulted in increased number of adult patients undergoing further evaluation for PV leading to identification of patients with acquired, idiopathic Persistent polycythemia (PP) who not meet WHO criteria for PV despite extensive work up. The clinicopathologic features, disease course, treatment and outcomes of these patients has not been well characterize. This study seeks to described clinicopathologic and molecular profile of cohort of adult patients with Non Hereditary, Non-Polycythemia Vera (NHNPV) Persistent Polycythemia.Methodology;Patients with PP diagnosed and followed up in Fresno community regional medical center/University of San Francisco (UCSF) Fresno, from January 2010 to December 2020 were reviewed. Patients who didn't meet WHO diagnostic criteria for PV after full evaluation including bone marrow biopsies were included in the study. Those with incomplete evaluation, clearly attributable secondary causes of polycythemia or erythropoietin (EPO) level above institutional laboratory reference range (2-18), were excluded from the study. Patients with polycythemia diagnosed at pediatric age were also excluded. The study was approved by institutional review board of UCSF Fresno.Results;129 subjects with JAK 2 Negative PP were reviewed of which 63 had EPO levels within or below the normal range (2-18).Of 36 patients who met the study inclusion and exclusion criteria, majority were males (70% N= 28) and non-Hispanic (56% N=20) with median age at diagnosis of 48.5 years (range 18-70 years). Half of the patients (N=18) have no identifiable etiology of PP. In patients with associated conditions, the most common is non-oxygen requiring clinical OSA (36%) and tobacco smoking (19.4%). Of note, all these patients have EPO level less than 10 which represents the median value of the local institutional defined normal range for EPO. Four (11%) patients have non-iron overloaded hemochromatosis gene mutation (1 Homozygous H63D HFE gene, 2 heterozygous mutation and one with unspecified mutation type).Average Hb and Hct at diagnosis was (17.26+/- 2.23) and (49.76+/- 6.34) respectively. Mean EPO level 7.05+/-2.75 with less than third of patients 8 (22%) with level less or equal to in 5 units. There is no statistically significance difference between mean diagnostic EPO level between males and females in the study (7.20+/-2.89 vs.6.51+/-2.26) and so is the Hct though males have numerically higher levels.The most common bone marrow morphology includes normocellularity (51.76+/-10.36) with erythroid hyperplasia (25%) or megakaryocyte hyperplasia without dysplasia (17%) and grade 1/3 fibrosis 6/36.Abnormal mutations were identified in 17 patients whose bone marrow biopsies were evaluated with limited or extensive next generation sequencing (NGS). Of those patients with available results, 6 patients (35% out of those with NGS) have identifiable previously well described genetic mutations {FANCA S1311fs*1, HGF R134H, TP53 splice site 97-2A>G, KMT2A (Gain), MLL3 (KMT2C) and AFF4, ASXL1 c.1934dupG/TrpfsX12 (p. Gly646)}.9 patients had variance of unknown significant (VUS) mutations (Table 1) with average of 6.2 mutation per patient. Only 1 VUS (TSC1 K587R) was reported in 2 different patients (#7, #9)Mild Myeloproliferative neoplasia (MPN) associated symptoms was reported in 22% of patient with Intermittent phlebotomy (72% N= 26) and aspirin (75% N=27) was the treatment for majority of patients. One patient died during the follow up period. No patient progressed to other MPN, myelofibrosis or AML during the study period.Conclusion;With improved diagnostic criteria and accuracy of PV, increased number of patients are diagnosed with NHNPV Persistent polycythemia. None of the mutation or VUS identified from extensive evaluation is recurrent in our cohort of patient. Longer follow up is needed to delineate clinical significance and prognosis of these mutation in patients with NHNPV persistent Polycythemia. [Display omitted] DisclosuresAbdulhaq: BMS, Alexion, Oncopeptides, Morphosys, Pfizer, Norvartis: Honoraria; Oncopeptides, Alexion, Amgen: Speakers Bureau; Morphosys, BMS, Amgen: Membership on an entity's Board of Directors or advisory committees.

Frequency of hereditary hemochromatosis gene mutations and their effects on iron overload among beta thalassemia patients of Chennai residents

<abstract> <p>Hereditary Hemochromatosis (HH) is an autosomal recessive disorder of iron metabolism associated with <italic>HFE</italic> 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 <italic>HFE</italic> variants among beta thalassemia cases and their effect on iron overload. The frequency of three <italic>HFE</italic> 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 <italic>HFE</italic> 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 <italic>HFE</italic> variant was absent in the present study. Iron overload was completely absent in the control cases among all three <italic>HFE</italic> genotypes. Hence it is inferred from the present investigation, analysis of <italic>HFE</italic> 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.</p> </abstract>

Association of frequency of hereditary hemochromatosis (HFE) gene mutations (H63D and C282Y) with iron overload in beta-thalassemia major patients in Pakistan.

Objectives:To evaluate any association between the frequency of hereditary hemochromatosis (HFE) gene mutation (H63D and C282Y) and iron overload in beta-thalassemia major (BTM) patients.Methods:The case-control study was conducted from June 2016 to February 2018. Blood samples from 204 BTM patients and 204 normal controls were taken from the Sundas Foundation Blood Bank.These samples were analyzed for serum ferritin assay and HFE mutation. Ferritin level was measured on the ARCHITECT 1000SR. Both patient and control samples were analyzed for mutations using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP).Results:Serum ferritin levels for all patients were >1000ng/mL. The p.H63D mutation was observed in 23 (11.3%) cases, out of which 19 cases were heterozygous for p.H63D and 4 cases were homozygous. In control samples, 4 cases (2%) were found heterozygous for the p.H63D, and no homozygous mutation was found. Significantly high serum ferritin levels were found in BTM patients with the H63D mutation (p=0.00). In the case of p.C282Y, neither homozygous nor heterozygous mutation was found in patients or in controls.Conclusion:H63D polymorphism is associated with iron overload in BTM patients. Larger-scale research is required to give an elaborated view of the association of the HFE mutation with iron overload in these patients and to confirm our conclusion.

Hepcidin is a useful biomarker to evaluate hyperferritinemia associated with metabolic syndrome.

Investigation of hyperferritinemia in metabolic syndrome patients represents a diagnostic challenge, but it is essential for the identification of individuals with iron overload. Hepcidin negatively regulates iron absorption and release. An increase in hepcidin occurs when iron levels are sufficient or in inflammatory states, conditions often associated with hyperferritinemia. Hemochromatosis causes hyperferritinemia due to iron overload, but frequently has low hepcidin levels. Our aim was to evaluate biochemical and molecular parameters related to iron metabolism in patients with metabolic syndrome. We evaluated 94 patients with metabolic syndrome according to the International Diabetes Federation criteria in a cross-sectional study. Anthropometric data and diagnostic criteria for metabolic syndrome, iron dosage, ferritin, transferrin saturation, hepcidin, and the C282Y and H63D mutations in the HFE hemochromatosis gene were evaluated. Prevalence of hyperferritinemia in the study population was 27.7% and was higher in males (46.2%) than in females (14.5%). Increase in transferrin saturation correlated with mutations in the hemochromatosis gene. Hyperferritinemia was associated to transferrin saturation and hepcidin after logistic regression analysis. In conclusion, hyperferritinemia is a frequent finding in metabolic syndrome patients, most frequently in men; and hepcidin assessment can be useful for the investigation of ferritin increase in those subjects.

- 174 G>C IL-6 polymorphism and primary iron overload in male patients.

Primary iron overload (IO) is commonly associated with mutations in the hereditary hemochromatosis gene (HFE). Nonetheless, other genetic variants may influence the development of IO beyond HFE mutations. There is a single nucleotide polymorphism (SNP) at - 174 G>C of the interleukin (IL)-6 gene which might be associated with primary IO. Our aim was to study the association between the SNP - 174 G>C gene promoter of IL-6 and primary IO in middle-aged male patients. We studied 37 men with primary IO diagnosed by liver histology. Controls were age-matched male volunteers (n = 37). HFE mutations and the SNP - 174 G>C gene promoter of IL-6 were evaluated by PCR-RFLP. Logistic regression was used to evaluate the association between primary IO and SNP - 174 G>C gene promoter of IL-6. Patients and control subjects were in Hardy-Weinberg equilibrium for the SNP - 174 G>C gene promoter of IL-6 (p = 0.17). Significantly different genotype frequencies were observed between patients (43% CC, 43% CG, and 14% GG) and control subjects (10% CC, 41% CG, and 49% GG) (OR = 4.09, 95% CI = 2.06-8.13; p < 0.0001). The multiple logistic regression analysis showed that IO was significantly associated with CC homozygosis in the SNP - 174 G>C gene promoter of IL-6 (OR = 6.3, 95% CI = 1.9-21.4; p < 0.005) in a model adjusted by age and body mass index. In conclusion, CC homozygosis in the SNP - 174 G>C gene promoter of IL-6 can be proposed as one of the gene variants influencing iron accumulation in male adults with HFE mutations. Studies in larger cohorts are warranted.

The Correlation of Cardiac and Hepatic Hemosiderosis as Measured by T2*MRI Technique with Ferritin Levels and Hemochromatosis Gene Mutations in Iranian Patients with Beta Thalassemia Major.

Organ-specific hemosiderosis and iron overload complications are more serious and more frequent in some patients with beta thalassemia major (BTM) compared with others. We investigated whether coinheritance of HFE H63D or C282Y gene mutations in patients with BTM contributes to the phenotypic variation of iron overload complications and assessed the correlation of cardiac and hepatic hemosiderosis with plasma ferritin levels. We studied 60 patients with BTM with a mean age of 17.5±9.1 years from the Northwest of Iran. HFE gene mutations were analyzed using the polymerase chain reaction-restriction fragment length polymorphism method. Cardiac and hepatic hemosiderosis was assessed using T2*magnetic resonance imaging (MRI). Ferritin levels were measured using the enzyme immunoassay method. Ferritin levels showed a strong inverse correlation with hepatic T2*MRI values (r = -0.631, p = 0.001) but a poor correlation with cardiac T2*MRI values (r = -0.297, p = 0.044). The correlation between cardiac T2*MRI values and hepatic T2*MRI values was poor and insignificant (r = 0.287, p = 0.058). Genotype and allele distribution of HFE H63D and C282Y mutation did not differ significantly between patients with and without hepatic or cardiac hemosiderosis (p > 0.050). However, carriers of HFE 63D allele had significantly higher ferritin levels compared with non-carriers (1 903±993 vs. 992±683, p < 0.001). Cardiac T2*MRI values showed a poor correlation with hepatic T2*MRI values and ferritin levels. Accurate assessment of cardiac iron overload in patients with BTM can only be done using the T2*MRI technique. Additionally, HFE H63D is a significant determinant factor for elevated ferritin levels in BTM patients.

Hemochromatosis Gene Mutation and Erythrocytosis

Hemochromatosis Gene Mutation and Erythrocytosis

HFE gene mutation and iron overload in Egyptian pediatric acute lymphoblastic leukemia survivors: a single-center study

ABSTRACTBackground: Hereditary hemochromatosis gene (HFE) mutations have a role in iron overload in pediatric acute lymphoblastic leukemia (ALL) survivors. We aimed to evaluate the genotype frequency and allelic distribution of the two HFE gene mutations (C282Y and H63D) in a sample of Egyptian pediatric ALL survivors and to detect the impact of these two mutations on their iron profile.Patients and methods: This study was performed on 35 ALL survivors during their follow-up visits to the Hematology and Oncology Unit, Pediatric Department, Menoufia University Hospitals. Thirty-five healthy children of matched age and sex were chosen as controls. After completing treatment course, ALL survivors were screened for the prevalence of these two mutations by polymerase chain reaction-restriction fragment length polymorphism. Serum ferritin levels were measured by an enzyme-linked immunosorbent assay technique (ELISA).Results: C282Y mutation cannot be detected in any of the 35 survivors or the 35 controls. The H63D heterozygous state (CG) was detected in 28.6% of the survivors group and in 20% of controls, while the H63D homozygous (GG) state was detected in 17.1% of survivors. No compound heterozygosity (C282Y/H63D) was detected at both groups with high G allele frequency (31.4%) in survivors more than controls (10%). There were significant higher levels of iron parameters in homozygote survivors than heterozygotes and the controls.Conclusion: H63D mutation aggravates the iron overload status in pediatric ALL survivors.

Beyond Human Leukocyte Antigen Class I Antigens: Hereditary Hemochromatosis Gene Mutations in Recurrent Aphthous Oral Ulcers and Behçet Disease in the South of Tunisia

Objective: The aim of this work was to establish human leukocyte antigen (HLA) class I and hereditary hemochromatosis gene (HFE) mutation associations with recurrent aphthous oral ulcers (RAOU) and Behçet disease (BD) in a cohort of Southern Tunisian patients. Subjects and Methods: A total of 232 patients with RAOU and 123 healthy controls (HCs) were enrolled in this study. The patients were divided into 2 groups based on the presence (BD+: n = 62) or absence of BD (BD−, n = 170). In the BD+ group, 28 patients had severe manifestations of BD. In the BD- group, RAOU was isolated in 81 patients, associated with mucocutaneous manifestations in 58 and with joint symptoms in 25. Complement-dependent microlymphocytotoxicity assay and polymerase chain reaction-restriction fragment length polymorphism were used to study HLA class I polymorphism and HFE mutations, respectively. Results: HLA-B51 was positively associated with BD, particularly in those with severe manifestations. No association was detected with HLA class I polymorphism among the BD group. Based on stratification to clinical manifestations, the isolated RAOU was negatively associated with HLA-A1 with a difference close to significance (12 [14.81%] vs. 32 [26.02%] in HCs; p = 0.06). Furthermore, patients with mucocutaneous features had a higher frequency of HLA-B51 (14, 24.14%) than patients without mucocutaneous involvement (11, 11.37%). Considering HFE mutations, patients with isolated RAOU had a higher frequency of H63D when compared with other subgroups, especially after limiting the comparison to 27 patients of at least 5 years of follow-up. Conclusion: This study showed that, unlike BD, RAOU were not associated with HLA-B51. Moreover, we suggest that H63D mutation was positively associated with isolated RAOU.

Frequency of Hereditary Hemochromatosis (HFE) Gene Mutations in Egyptian Beta Thalassemia Patients and its Relation to Iron Overload.

AIM:This study aimed to detect the most common HFE gene mutations (C282Y, H63D, and S56C) in Egyptian beta thalassemia major patients and its relation to their iron status.SUBJECTS AND METHODS:The study included 50 beta thalassemia major patients and 30 age and sex matched healthy persons as a control group. Serum ferritin, serum iron and TIBC level were measured. Detection of the three HFE gene mutations (C282Y, H63D and S65C) was done by PCR-RFLP analysis. Confirmation of positive cases for the mutations was done by sequencing.RESULTS:Neither homozygote nor carrier status for the C282Y or S65C alleles was found. The H63D heterozygous state was detected in 5/50 (10%) thalassemic patients and in 1/30 (3.3%) controls with no statistically significant difference between patients and control groups (p = 0.22). Significantly higher levels of the serum ferritin and serum iron in patients with this mutation (p = 001).CONCLUSION:Our results suggest that there is an association between H63D mutation and the severity of iron overload in thalassemic patients.

Late Cardiotoxicity: Issues for Childhood Cancer Survivors.

Cardiovascular-related morbidity is a substantial health burden in survivors of childhood cancers. This burden is gaining importance as this population increases through advancements in therapy. Anthracyclines are commonly used agents that are known to cause late cardiotoxicity. Cardiotoxicity is also increased by other risk factors, such as concurrent radio- or chemotherapy, younger age at diagnosis, female sex, comorbidities, lifestyle factors, and genetic factors, such as hemochromatosis gene mutations. Treatment of late cardiotoxicity depends on the type of cardiac abnormalities and consists of pharmacotherapy, mechanical support, or heart transplantation. Because cardiotoxicity is progressive and often irreversible, prevention, risk reduction, and early detection are of utmost importance. The cardioprotectant dexrazoxane decreases anthracycline cardiotoxicity. Screening for other risk factors at the time of diagnosis may identify risk that when present, if used to tailor therapy, may reduce the severity of cardiac damage. The effects of exercise and other lifestyle changes in reducing the cardiovascular diseases in cancer survivors are unclear. However, it may be beneficial to encourage survivors to engage in physical activity tailored to survivor medical status, but with close monitoring.

Hemochromatosis gene mutations may affect the survival of patients with myelodysplastic syndrome

Objectives: The recent availability of potent oral iron chelators is renewing an interest in the assessment of the possible impact of HFE genetics in MDS.Methods: Thirty six newly diagnosed patients with MDS were studied for parameters of iron metabolism in addition to C282Y and H63D mutations of the HFE gene.Results: Mutations were present in 11 out of 36 patients (31%), which were not different from our general population and were equally distributed among MDS subtypes. Mutated patients had higher ferritin levels (P = 0.039) and lower TIBC (P = 0.018). Ferritin was found to be higher for the untransfused mutated patients (P = 0.017), but not for transfusion-dependent patients in whom ferritin levels correlated significantly with the number of blood units received (P = 0.04). There was no difference in the number of blood units received between the mutated and wild type patients. A new observation made was that the mutated patients had a lower overall survival in addition to a poorer leukemia free survival (LFS) (P = 0.004 and P = 0.003, respectively).Discussion: The HFE gene mutations are not more frequent in MDS patients. Iron overload in mutated patients was higher but there was no correlation found using supportive therapy for anemia. The effect of mutations on survival could be mediated by changes in iron metabolism.Conclusion: The HFE genotype may predict MDS prognosis and there is a need for further studies. It remains a challenging question if HFE mutated MDS patients should be considered for potent iron chelation therapy.

Hemochromatosis gene mutations in chronic hepatitis “C” patients

Hepatitis C virus (HCV) infection is a significant global health problem. Elevated hepatic iron concentration has often been found in patients with chronic hepatitis C, and this excess iron increases oxidative stress, which can accelerate the progression of fibrosis and may promote hepatic carcinogenesis. The current study aimed to determine the prevalence of C282Y (exchange of cysteine to tyrosine at amino acid 282) and H63D (exchange of histidine to aspartic acid at amino acid 63) in hereditary hemochromatosis gene (HFE) mutations among chronic HCV patients and to find whether elevation of serum iron indices is related to HFE gene mutations in patients with chronic hepatitis C. The study population was 80 chronic HCV patients divided into two groups: group I included 40 patients with serum iron overload, and group II included 40 patients without iron overload. HFE gene mutation was studied by PCR-restriction fragment length polymorphism (RFLP). The C282Y mutation was not found in any of the 80 patients, while the H63D mutation was present in 18.7 % of the entire study sample. Comparing the two studied groups, H63D mutation was found in 20 % of the iron overload group and 17.5 % of the non-iron overload group. Statistically, there was no significant difference between the two study groups. Regarding iron studies, results of the current study revealed no significant difference between chronic HCV patients with iron overload and those with normal iron profile regarding any of the HFE mutations. In conclusion, the current work emphasizes that the C282Y mutation is absent in our community, while H63D mutation presence does not differ greatly from other Caucasian races especially in Europe. The current study did not detect any effect of HFE mutation on increasing serum iron overload.