310 IRON OVERLOAD AND HEMOCHROMATOSIS (HFE) MUTATION CORRELATE WITH CLINICAL OUTCOMES IN AN OSTEOARTHRITIS COHORT

The role of oxidative stress in the initiation and progression of myelodysplastic syndromes (MDS) as a consequence of iron overload remains unclear. In this study we have simultaneously quantified plasma low-molecular-weight aminothiols, malondialdehyde, nitrite, and nitrate and have studied their correlation with serum iron/ferritin levels, patient treatment (chelation therapy), and clinical outcomes. We found significantly elevated plasma levels of total, oxidized, and reduced forms of cysteineP<0.001, homocysteineP<0.001, and cysteinylglycineP<0.006and significantly depressed levels of total and oxidized forms of glutathioneP<0.03and nitriteP<0.001in MDS patients compared to healthy donors. Moreover, total(P=0.032)and oxidized cysteinylglycine(P=0.029)and nitrite(P=0.021)differed significantly between the analyzed MDS subgroups with different clinical classifications. Malondialdehyde levels in plasma correlated moderately with both serum ferritin levels(r=0.78, P=0.001)and serum free iron levels(r=0.60, P=0.001)and were significantly higher in patients with iron overload. The other analyzed compounds lacked correlation with iron overload (represented by serum iron/ferritin levels). For the first time our results have revealed significant differences in the concentrations of plasma aminothiols in MDS patients, when compared to healthy donors. We found no correlation of these parameters with iron overload and suggest the role of oxidative stress in the development of MDS disease.

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Dietary and Sentinel Factors Leading to Hemochromatosis

Nutrients ◽

10.3390/nu11051047 ◽

2019 ◽

Vol 11 (5) ◽

pp. 1047 ◽

Cited By ~ 2

Author(s):

Chang-Kyu Oh ◽

Yuseok Moon

Keyword(s):

Iron Overload ◽

Clinical Outcomes ◽

Iron Metabolism ◽

Iron Transport ◽

Hereditary Hemochromatosis ◽

External Factors ◽

Present Review ◽

Chronic Complications ◽

Nutritional Interventions ◽

External Stresses

Although hereditary hemochromatosis is associated with the mutation of genes involved in iron transport and metabolism, secondary hemochromatosis is due to external factors, such as intended or unintended iron overload, hemolysis-linked iron exposure or other stress-impaired iron metabolism. The present review addresses diet-linked etiologies of hemochromatosis and their pathogenesis in the network of genes and nutrients. Although the mechanistic association to diet-linked etiologies can be complicated, the stress sentinels are pivotally involved in the pathological processes of secondary hemochromatosis in response to iron excess and other external stresses. Moreover, the mutations in these sentineling pathway-linked genes increase susceptibility to secondary hemochromatosis. Thus, the crosstalk between nutrients and genes would verify the complex procedures in the clinical outcomes of secondary hemochromatosis and chronic complications, such as malignancy. All of this evidence provides crucial insights into comprehensive clinical or nutritional interventions for hemochromatosis.

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IDENTIFIKASI MUTASI H63D GEN HFE PADA KELAINAN HBE

INDONESIAN JOURNAL OF CLINICAL PATHOLOGY AND MEDICAL LABORATORY ◽

10.24293/ijcpml.v22i2.1123 ◽

2018 ◽

Vol 22 (2) ◽

pp. 176

Author(s):

Yanuarita Tursinawati ◽

Nyoman Suci Widyastiti ◽

Moedrik Tamam

Keyword(s):

Iron Overload ◽

Allele Frequency ◽

Gene Frequency ◽

Total Sample ◽

Cross Sectional Study ◽

Sectional Study ◽

Cross Sectional ◽

H63d Mutation ◽

Indonesian Population ◽

Hfe Mutation

The H63D HFE mutation has been reported to be responsible for primary haemochromatosis. The allele frequency in Indonesianpopulation is about 2.8%. Co inheritance between H63D mutation and hemoglobin disorders such as Thalassemia may increase theseverity of iron overload. Nevertheless, the coinheritance of this mutation with HbE disorder is the most common hemoglobin disorderin Indonesia and the gene frequency have not been reported especially in Javanese ethnic. To identify the presence and the frequency ofH63D HFE mutation in HbE disorder among Javanese ethnic. A cross sectional study involved 24 Javanese individuals who consist of21 HbE heterozygotes (HbAE) and 3 HbE homozygotes (HbEE) subjects. The subjects were screened for H63D mutation by digestion ofPCR products with MbO I restriction endonuclease. The genotype frequency for wt/wt was 95.24% in HbAE, 100% in HbEE and for wt/H63D was 4.76% in HbAE. The allele frequency for H63D HFE mutation was 2.08% in total sample of HbE. The allele frequencies inHbAE and HbEE individual were 2.38% and 0%, respectively. H63D HFE mutation is found in 24 Javanese ethnic individual with HbEdisorder. However, the allele frequency of H63D HFE mutation is low and almost similar to the allele frequency of H63D HFE mutationin Indonesian population.

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Incidence of HFE Gene Mutations in Chinese Patients with Myelodysplastic Syndrome and Aplastic Anemia

Blood ◽

10.1182/blood.v112.11.5085.5085 ◽

2008 ◽

Vol 112 (11) ◽

pp. 5085-5085

Author(s):

Ling Nie ◽

Lin Yang ◽

Qinghua Li ◽

Jianxiang Wang ◽

Zhijian Xiao

Keyword(s):

Myelodysplastic Syndrome ◽

Iron Overload ◽

Aplastic Anemia ◽

Gene Mutations ◽

Chinese Patients ◽

Hfe Gene ◽

Genotype Distribution ◽

Chi Square ◽

Hfe Gene Mutations ◽

Hfe Mutation

Abstract The C282Y and H63D mutations of HFE gene responsible for hereditary hemochromatosis lead to absorption of excess dietary iron, tissue iron deposition and occurrence of clinical complications such as congestive heart failure, arrhythmia, hepatocellular cirrhosis, insulin resistance and diabetes. Iron overload is one important clinical feature in patients with myelodysplastic syndrome (MDS) and aplastic anemia(AA). However, the conflict has been existing about influence of HFE gene mutations on iron overload in MDS patients. In the present study, we analyzed the incidence of the C282Y and H63D mutations of HFE gene in 271 MDS patients, 402 AA patients and 1615 healthy controls by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). No C282Y mutations and compound heterozygote were observed in the entire cohort. The genotype distribution of H63D heterozygous and homozygous did not differ significantly in AA cases from those in controls(9.7%vs. 10.2%, 0.25%vs. 0.24% respectively, Pearson Chi-square p both >0.05). While the frequency of the H63D heterozygous in MDS patients was significantly lower than controls (4.1%vs. 10.7%, Pearson Chi-square p=0.002). H63D homozygous was not found in MDS patients. The incidence of C282Y and H63D mutations of HFE gene in Chinese MDS cases is lower than those reported in the literature. Comparing the pretransfusion serum ferritin(SF), serum iron concentration(SI) and transferrin saturation values(TS) between HFE-mutation and HFE-wild MDS groups, we did not find a significant difference (all P>0.05); However, Only SI values were significantly higher in the HFE-mutation AA cases than those in HFE-wild ones[42.6(24.6–60.4)umol/Lvs. 32.0(8.4–63.3)umol/L, P=0.011]. We further estimated the function of important organs in MDS and AA patients. There is no significantly difference in Alanine amino transferase (ALT), Aspartate amino transferase (AST), fasting blood sugar, and electrocardiogram(ECG) between HFE-mutation and HFE-wild MDS and AA groups irrespective of the red blood cell transfusion history. The results suggest that the distribution of C282Y and H63D mutations has ethnic and genetic differences, and is very rare in Chinese population. The mutations of HFE gene are not main factors of iron overload in Chinese patients with myelodysplastic syndrome and aplastic anemia.

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The overlapping of local iron overload and HFE mutation in venous leg ulcer pathogenesis

Free Radical Biology and Medicine ◽

10.1016/j.freeradbiomed.2006.01.026 ◽

2006 ◽

Vol 40 (10) ◽

pp. 1869-1873 ◽

Cited By ~ 43

Author(s):

Paolo Zamboni ◽

Marcello Izzo ◽

Silvia Tognazzo ◽

Sergio Carandina ◽

Massimiliano De Palma ◽

...

Keyword(s):

Iron Overload ◽

Leg Ulcer ◽

Venous Leg Ulcer ◽

Hfe Mutation

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Commentary on “The overlapping of local iron overload and HFE mutation in venous leg ulcer pathogenesis”

Free Radical Biology and Medicine ◽

10.1016/j.freeradbiomed.2006.03.005 ◽

2006 ◽

Vol 40 (10) ◽

pp. 1700-1701

Author(s):

Leo R. Zacharski ◽

Cocav A. Engman

Keyword(s):

Iron Overload ◽

Leg Ulcer ◽

Venous Leg Ulcer ◽

Hfe Mutation

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Clinico-Immunobiologic Study By a Prospective Open-Label Clinical Trial of Deferasirox before & after Allogeneic HSCT in Adult Patients with AML - Preliminary Analysis Focusing on Outcomes with Immunocyte Subsets (I) -

Blood ◽

10.1182/blood.v124.21.2543.2543 ◽

2014 ◽

Vol 124 (21) ◽

pp. 2543-2543

Author(s):

Heeje Kim ◽

Jae-Ho Yoon ◽

Seung-Ah Yahng ◽

Sung-Eun Lee ◽

Seung-Hwan Shin ◽

...

Keyword(s):

Iron Overload ◽

Clinical Outcomes ◽

Induction Chemotherapy ◽

Serum Ferritin ◽

Treg Cells ◽

Adult Patients ◽

Effector Memory ◽

Allogeneic Hsct ◽

Post Induction ◽

Before And After

Abstract Background: The ferritin contents in immature myeloid cells could be detected in both iron overload and in AML. Ferritin itself in leukemic cells could be regarded as an important marker for leukemic activity. Serialreports have shown that the serum ferritin level in patients with acute leukemia and myelodysplastic syndrome is a critical prognostic factor after hematopoietic stem cell transplantation (HSCT). However, the exact mechanism itself is not clear. Methods: We evaluated the iron chelating efficacy and the immunomodulatory effect of deferasirox therapy as assessed by regular monitoring of serum ferritin levels and immunocyte subsets from the post-induction period to post-HSCT. In addition, we tried to reveal the effects of deferasirox on various clinical outcomes in patients with adult AML who were expected to receive allogeneic HSCT. A total of sixty-six consecutive adult patients with de novo AML who received allogeneic HSCT were prospectively enrolled during the period 2009 to 2011. Serum ferritin levels were monitored from initial diagnosis to the post-HSCT period from both the iron-chelated group (IC, n=28) and the non-treated group (NT, n=38) of patients. Among the patients of the IC group, the final 20 AML patients were followed and were collected peripheral blood samples until minimum 6 months post-HSCT. The overall median follow-up for total survivors (IC) was 58 months (range: 48~66). Deferasirox treatment was initiated at the outpatient clinic both after induction chemotherapy and post-HSCT 1 month. Various clinical outcomes in association with multiple parameters including serum ferritin levels and multiple immunocyte subsets of CD4, CD8, CD16, CD56, invariant NKT, Treg, central/effector memory T cells were simultaneously analyzed, mainly in the IC group of patients, with the usage of the multi-color flow cytometer at pre- and post-HSCT periods. Results: The median duration of total (pre- + post-HSCT) medication in IC group of patients was 241 days (109-452). The median ferritin levels at diagnosis (IC, 651 ng/mL vs. NT, 667 ng/mL) and at peak levels (IC, 3,090 ng/mL vs. NT, 3,685 ng/mL) during chemotherapy did not differ significantly between groups. However, pre-HSCT levels were different between groups, as the median level of 1,555 ng/mL (335-3,800) (IC) vs. 964 ng/mL (229-7,360) (NT). The 5-year overall survival (OS) and event-free survival (EFS) rates of total AML patients were 63.6% and 60.6%, respectively. The Kaplan-Meier estimates of OS/EFS rates were all significantly different in pre-HSCT ferritin levels (P=0.0247, 0.0212) and duration of deferasirox treatment both pre- (P=0.028, 0.0166) and post-HSCT (P=0.0102, 0.0064). The levels of CD4+CD62L-CD44+ (P=0.027) and CD8+CD62L-CD44+ cells (P=0.006) post-induction chemotherapy were significantly associated with the duration of deferasirox treatment before HSCT. To note, the levels of CD4+ cells at 1 month post-HSCT deferasirox treatment (P=0.017), CD4+ effector memory T (TEM)-cells pre-HSCT (P=0.029), and CD8+CD62L-CD44+ cells post-HSCT 1 month (P=0.003) and 6 months (P=0.021) were closely related to the relapse of AML. Most of all, regulatory T (Treg) cells both pre-HSCT (P=0.002) and post-HSCT (P <0.001) periods after deferasirox therapy showed a very close correlation with various clinical outcomes, specifically with lower rates of relapse in patients with low levels of Treg after at least 120 days in total use of deferasirox before and after HSCT. Interestingly, patients who received deferasirox therapy for a sufficient duration showed consistently lower levels of Treg cells as well as higher levels of CD16+ NK cells along the timeline of chemotherapy and HSCT compared to those who did not. Furthermore, we found a marginal significance in the increased levels of CD4+CD161+ NKT cells at post-induction chemotherapy when patients received deferasirox before HSCT (P=0.056). Conclusion: Our data suggest that despite small sample numbers, iron-chelation therapy for adult AML patients with hyperferritinemia pre- and post-HSCT is very closely related to the outcomes of allogeneic HSCT, and that it is especially associated with the modulation of immunobiologic properties during the period of immune reconstitution. Therefore, more cautious approaches to reduce iron overload by using iron chelating agents, such as deferasirox, may be warranted both before and after allogeneic HSCT. Disclosures Kim: Novartis Korea: Research Funding.

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HFE MUTATIONS AND IRON OVERLOAD IN PATIENTS WITH ALCOHOLIC LIVER DISEASE

Arquivos de Gastroenterologia ◽

10.1590/s0004-28032013000100008 ◽

2013 ◽

Vol 50 (1) ◽

pp. 35-41 ◽

Cited By ~ 16

Author(s):

Luís COSTA-MATOS ◽

Paulo BATISTA ◽

Nuno MONTEIRO ◽

Pedro HENRIQUES ◽

Fernando GIRÃO ◽

...

Keyword(s):

Liver Disease ◽

Liver Fibrosis ◽

Iron Overload ◽

Serum Ferritin ◽

Hfe Gene ◽

Healthy Controls ◽

Liver Iron ◽

Iron Stores ◽

Hfe Mutations ◽

Hfe Mutation

ContextAlcoholic liver disease (ALD) is generally associated with iron overload, which may contribute to its pathogenesis, through increased oxidative stress and cellular damage. There are conflicting reports in literature about hemochromatosis (HFE) gene mutations and the severity of liver disease in alcoholic patients.ObjectivesTo compare the prevalence of mutations in the hemochromatosis (HFE) gene between patients with ALD and healthy controls; to assess the relation of HFE mutations with liver iron stores and liver disease severity.MethodsLiver biopsy specimens were obtained from 63 ALD patients (during routine treatment) and 52 healthy controls (during elective cholecystectomy). All individuals underwent routine liver function tests and HFE genotyping (to detect wild-type sequences and C282Y, H63D, S65C, E168Q, E168X, V59M, H63H, P160delC, Q127H, Q283P, V53M and W164X mutations). Associations between HFE mutations and risk of excessive liver iron stores, abnormal serum ferritin, liver fibrosis, or necroinflammatory activity were assessed by multivariate logistic regression analysis.ResultsALD patients had significantly higher serum ferritin and transferrin saturation than controls (both P<0.05), but the distribution of HFE mutations was similar between the two groups. For ALD patients, the odds ratio for having at least one HFE mutation and excessive liver iron stores was 17.23 (95% confidence interval (CI): 2.09-142.34, P = 0.008). However, the presence of at least one HFE mutation was not associated with an increased risk of liver fibrosis or necroinflammatory activity. Active alcohol ingestion showed the strongest association to increased serum ferritin (OR = 8.87, 95% CI: 2.11-34.78, P = 0.003).ConclusionsALD patients do not present with a differential profile of HFE mutations from healthy controls. In ALD patients, however, the presence of at least one HFE mutation increases the risk of having excessive liver iron stores but has no detectable effects on liver disease activity or severity.

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Hereditary Hyperferritinemia-Cataract Syndrome in 3 Generations of a Family in East Tennessee

Case Reports in Hematology ◽

10.1155/2020/2837573 ◽

2020 ◽

Vol 2020 ◽

pp. 1-3

Author(s):

Heidi A. Worth ◽

Zachary Marlette ◽

David Aljadir ◽

Ronald Lands

Keyword(s):

Iron Deficiency ◽

Iron Overload ◽

Cataract Surgery ◽

Medical History ◽

No Reduction ◽

Clinical Course ◽

Genetic Disorder ◽

Past Medical History ◽

Invasive Evaluation ◽

Hfe Mutation

Hereditary hyperferritinemia and cataracts syndrome (HHCS) without iron overload is a syndrome first identified less than 3 decades ago. While investigators have dissected the gene where several responsible mutations reside, it remains a relatively unknown genetic disorder to clinicians. The result is often an expensive, invasive evaluation for iron overload, followed by a well-intended prescription for a series of phlebotomies that delivers morbidity instead of benefit. We present a father with an elevated ferritin and heterozygosity for H63D HFE mutation whose clinical course followed this path. His treatment rendered him symptomatic from iron deficiency with no reduction in his ferritin. On re-evaluation, a review of his past medical history clarified the cataract surgery noted in his record had occurred at a young age. Furthermore, one of his daughters required cataract surgery as a teenager. With this information, we strongly suspected HHCS. His phlebotomies were discontinued, and within weeks, his iatrogenic iron deficiency resolved and his health returned to normal.

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