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Lichtman MA. The 50th anniversary of Blood Cells, Molecules and Diseases, 1975-2024. Blood Cells Mol Dis 2024; 108:102854. [PMID: 39034060 DOI: 10.1016/j.bcmd.2024.102854] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/23/2024]
Abstract
The journal Blood Cells was initiated in 1975 by Marcel Bessis, a French hematologist and cell biologist, as a vehicle for the publication of papers and discussions presented at an international blood club meeting he convened at L' Institut de Pathologie Cellulaire on the campus of Hôpital Bicétre in Kremlin Bicétre, France, a commune on the southern border of Paris. The group met at the Institute for the first time in October 1972. After the first meeting, Bessis published the articles describing the presentations in the Nouvelle Revue d'Hématologie Française, France's principal journal for articles on the science and practice of hematology of which he was the editor. The refusal of the Nouvelle Revue d'Hématologie Française to continue publishing the papers from the meeting of the blood club in English prompted Bessis to start a new journal, Blood Cells, in 1975. Blood Cells, also, began to accept individual submitted papers unrelated to the blood club meeting and, thus, it evolved into a standard journal. A decade later, when Bessis became ill, he asked Brian Bull, a hematopathologist and professor at Loma Linda University School of Medicine in California to assume the position as the second editor-in-chief. He and Bessis had become scientific collaborators and good friends in the preceding years. In 1995, Ernest Beutler, Chair of Molecular and Experimental Medicine at Scripps Research Institute, assumed the editor-in-chief position and transformed the Journal by making three consequential changes. He expanded its title to Blood Cells, Molecules and Diseases, converted its editorial board to past presidents of the American Society of Hematology plus a few additional experimental hematologists of note, a few from abroad, and he converted the Journal to a digital format, hosted on the Scripps Research Institute server. The Journal was the first published solely in a digital format. It, subsequently, was bought by Academic Press, then Harcourt and, then, by Elsevier. The next three editors-in-chief were (i) Marshall A. Lichtman, then Professor of Medicine (Hematology) and of Biochemistry and Biophysics and former Dean of the School of Medicine and Dentistry at the University of Rochester Medical Center, editor from 2000 to 2013, (ii) Mohandas Narla, then Vice President for Research and Director of The Laboratory of Red Cell Physiology at the New York Blood Center, editor from 2014 to 2021 and (iii) Lionel Blanc, Professor of Molecular Medicine and Pediatrics, Center for Autoimmune, Musculoskeletal and Hematopoietic Diseases, Institute of Molecular Medicine, The Feinstein Institutes for Medical Research and the Les Nelkin Professor of Pediatric Oncology Donald and Barbara Zucker School of Medicine at Hofstra-Northwell from 2022 to the present. Although the Journal publishes papers on any aspect of hematology, it has developed a focus on disorders of red cells, erythropoiesis and hematopoiesis. In October 2024, it celebrates its 50th anniversary as a vehicle for the publication of papers in the discipline of hematology.
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Affiliation(s)
- Marshall A Lichtman
- Department of Medicine and the James P. Wilmot Cancer Institute, University of Rochester Medical Center, 601 Elmwood Avenue, Rochester, NY 14642, USA.
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2
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Banta CW, Zonna X, Lott R, Jaisawal P, Elsisi A. Drug-Resistant Parkinson's Disease in a Patient With Hereditary Hemochromatosis: A Case Report. Cureus 2023; 15:e44530. [PMID: 37790065 PMCID: PMC10544707 DOI: 10.7759/cureus.44530] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/31/2023] [Indexed: 10/05/2023] Open
Abstract
A 55-year-old male, with a strong family history of hereditary hemochromatosis, presented with progressively worsening right-sided tremor and Parkinsonian symptoms. He was diagnosed with hereditary hemochromatosis based on genetic testing and started undergoing regular phlebotomies to reduce his blood iron levels. Despite extensive trials of different pharmaceutical therapies, including levodopa-carbidopa, his Parkinsonian symptoms were not relieved and continued to worsen. This report serves to highlight the importance of early disease identification and intervention in patients with hereditary hemochromatosis to prevent the development of neurological sequelae, as well as a need for further research into effective therapies in such patients.
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Affiliation(s)
- Conor W Banta
- Internal Medicine, Geisinger Commonwealth School of Medicine, Scranton, USA
| | - Xavier Zonna
- Internal Medicine, Lake Erie College of Osteopathic Medicine, Erie, USA
| | - Ronald Lott
- Internal Medicine, Lake Erie College of Osteopathic Medicine, Erie, USA
| | - Pooja Jaisawal
- Internal Medicine, Guthrie Robert Packer Hospital, Sayre, USA
| | - Amr Elsisi
- Internal Medicine, Guthrie Robert Packer Hospital, Sayre, USA
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3
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Reutemann B, Gordon FD. Evaluation of the Patient with Markedly Abnormal Liver Enzymes. Clin Liver Dis 2023; 27:1-16. [PMID: 36400459 DOI: 10.1016/j.cld.2022.08.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Liver enzyme tests are very commonly ordered by physicians, and when they return as abnormal, they can pose a clinical challenge to the provider. Markedly abnormal liver enzymes indicate severe hepatic injury and require immediate evaluation. There are various causes for abnormal liver tests, including infectious, autoimmune, genetic, metabolic, drug, and vascular causes. An understanding of the patterns of aminotransferase and alkaline phosphatase elevations is useful in narrowing the differential diagnosis. A thorough history and physical examination, appropriate blood testing, and imaging are typically key to evaluating the patient with abnormal liver enzymes.
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Affiliation(s)
- Bethany Reutemann
- Dartmouth Hitchock Medical Center, 100 Hitchcock Way, Manchester, NH 03104, USA.
| | - Fredric D Gordon
- Tufts Medical Center, 800 Washington St. #40, South Building, 4th floor, Boston, MA 02111, USA
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Barton JC, Edwards CQ, Acton RT. HFE hemochromatosis in African Americans: Prevalence estimates of iron overload and iron overload-related disease. Am J Med Sci 2023; 365:31-36. [PMID: 36096187 DOI: 10.1016/j.amjms.2022.08.015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2021] [Revised: 05/03/2022] [Accepted: 08/10/2022] [Indexed: 01/12/2023]
Abstract
BACKGROUND Little is known about the prevalence of HFE (homeostatic iron regulator) hemochromatosis in African Americans (AA). METHODS We defined AA as self-identified AA, blacks, or non-Hispanic blacks. We defined hemochromatosis-associated HFE genotypes as p.C282Y/p.C282Y and p.C282Y/p.H63D. We compiled prevalences of these genotypes in AA using published population and cohort data and numbers of men and women ≥18 y in 2018 U.S. Census estimates. We defined iron overload (IO) and IO-related disease by genotype as previously reported in population and cohort studies of hemochromatosis in whites of European ancestry. We used these definitions to estimate prevalences and numbers of AA with IO and IO-related disease associated with hemochromatosis-associated HFE genotypes. RESULTS There were ∼16,287,599 men and ∼17,644,898 women. HFE genotypes and their respective prevalences were: p.C282Y/p.C282Y, 0.00017 (6/34,905) [95% confidence interval 0.000034, 0.00031] and p.C282Y/p.H63D, 0.0012 (41/33,596) [0.000084, 0.0016]. IO prevalences were: men 0.000076 [0.000072, 0.000081] and women 0.0000061 [0.0000050, 0.0000073]. IO-related disease prevalences were: men 0.000063 [0.000059, 0.000067] and women 0.0000021 [0.0000014, 0.0000027]. There were ∼1021 [961, 1091] men and ∼36 [25, 48] women with IO-related disease. CONCLUSIONS We conclude that ∼1/25,061 AA >18 y have a hemochromatosis-associated HFE genotype and IO and that ∼1/32,103 AA >18 y have a hemochromatosis-associated HFE genotype and IO-related disease.
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Affiliation(s)
- James C Barton
- Southern Iron Disorders Center, Birmingham, AL, USA; Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.
| | - Corwin Q Edwards
- Department of Medicine, Intermountain Medical Center and University of Utah, Salt Lake City, UT, USA
| | - Ronald T Acton
- Southern Iron Disorders Center, Birmingham, AL, USA; Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL, USA
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Twenty-Five Years of Contemplating Genotype-Based Hereditary Hemochromatosis Population Screening. Genes (Basel) 2022; 13:genes13091622. [PMID: 36140790 PMCID: PMC9498654 DOI: 10.3390/genes13091622] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2022] [Revised: 09/07/2022] [Accepted: 09/08/2022] [Indexed: 11/22/2022] Open
Abstract
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.
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Shahandeh A, Bui BV, Finkelstein DI, Nguyen CTO. Effects of Excess Iron on the Retina: Insights From Clinical Cases and Animal Models of Iron Disorders. Front Neurosci 2022; 15:794809. [PMID: 35185447 PMCID: PMC8851357 DOI: 10.3389/fnins.2021.794809] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2021] [Accepted: 12/17/2021] [Indexed: 01/19/2023] Open
Abstract
Iron plays an important role in a wide range of metabolic pathways that are important for neuronal health. Excessive levels of iron, however, can promote toxicity and cell death. An example of an iron overload disorder is hemochromatosis (HH) which is a genetic disorder of iron metabolism in which the body’s ability to regulate iron absorption is altered, resulting in iron build-up and injury in several organs. The retina was traditionally assumed to be protected from high levels of systemic iron overload by the blood-retina barrier. However, recent data shows that expression of genes that are associated with HH can disrupt retinal iron metabolism. Thus, the effects of iron overload on the retina have become an area of research interest, as excessively high levels of iron are implicated in several retinal disorders, most notably age–related macular degeneration. This review is an effort to highlight risk factors for excessive levels of systemic iron build-up in the retina and its potential impact on the eye health. Information is integrated across clinical and preclinical animal studies to provide insights into the effects of systemic iron loading on the retina.
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Affiliation(s)
- Ali Shahandeh
- Department of Optometry and Vision Sciences, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Parkville, VIC, Australia
| | - Bang V. Bui
- Department of Optometry and Vision Sciences, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Parkville, VIC, Australia
| | - David I. Finkelstein
- Florey Department of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC, Australia
| | - Christine T. O. Nguyen
- Department of Optometry and Vision Sciences, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Parkville, VIC, Australia
- *Correspondence: Christine T. O. Nguyen,
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Halcrow PW, Lynch ML, Geiger JD, Ohm JE. Role of endolysosome function in iron metabolism and brain carcinogenesis. Semin Cancer Biol 2021; 76:74-85. [PMID: 34139350 PMCID: PMC8627927 DOI: 10.1016/j.semcancer.2021.06.013] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Revised: 06/10/2021] [Accepted: 06/11/2021] [Indexed: 02/07/2023]
Abstract
Iron, the most abundant metal in human brain, is an essential microelement that regulates numerous cellular mechanisms. Some key physiological roles of iron include oxidative phosphorylation and ATP production, embryonic neuronal development, formation of iron-sulfur clusters, and the regulation of enzymes involved in DNA synthesis and repair. Because of its physiological and pathological importance, iron homeostasis must be tightly regulated by balancing its uptake, transport, and storage. Endosomes and lysosomes (endolysosomes) are acidic organelles known to contain readily releasable stores of various cations including iron and other metals. Increased levels of ferrous (Fe2+) iron can generate reactive oxygen species (ROS) via Fenton chemistry reactions and these increases can damage mitochondria and genomic DNA as well as promote carcinogenesis. Accumulation of iron in the brain has been linked with aging, diet, disease, and cerebral hemorrhage. Further, deregulation of brain iron metabolism has been implicated in carcinogenesis and may be a contributing factor to the increased incidence of brain tumors around the world. Here, we provide insight into mechanisms by which iron accumulation in endolysosomes is altered by pH and lysosome membrane permeabilization. Such events generate excess ROS resulting in mitochondrial DNA damage, fission, and dysfunction, as well as DNA oxidative damage in the nucleus; all of which promote carcinogenesis. A better understanding of the roles that endolysosome iron plays in carcinogenesis may help better inform the development of strategic therapeutic options for cancer treatment and prevention.
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Affiliation(s)
- Peter W Halcrow
- Department of Biomedical Sciences, University of North Dakota School of Medicine and Health Sciences, Grand Forks, ND, United States
| | - Miranda L Lynch
- Hauptman-Woodward Medical Research Institute, Buffalo, NY, United States
| | - Jonathan D Geiger
- Department of Biomedical Sciences, University of North Dakota School of Medicine and Health Sciences, Grand Forks, ND, United States
| | - Joyce E Ohm
- Department of Cancer Genetics and Genomics, Roswell Park Cancer Institute, Buffalo, NY, United States.
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Asif S, Begemann M, Raza S. Polycythemia in Patients With Hereditary Hemochromatosis: Real or Myth? J Clin Med Res 2019; 11:422-427. [PMID: 31143309 PMCID: PMC6522237 DOI: 10.14740/jocmr3816] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2019] [Accepted: 04/09/2019] [Indexed: 11/28/2022] Open
Abstract
Background Hereditary hemochromatosis (HH) is an autosomal recessive disorder affecting iron metabolism, resulting in iron accumulation in tissue parenchymal cells. Missense mutations result in homozygosity or heterozygosity for substitutions in the HFE gene, with the most common being C282Y and H63D. Methods With an aim to evaluate an association between polycythemia and HH, retrospective chart review was performed for 152 patients with known HFE mutations. Parameters reviewed included individual HFE genotypes, gender distribution, hemoglobin (Hgb) and hematocrit (Hct) levels, median ferritin levels and whether or not phlebotomy was required. Results Of 152 patients, 96 (63.2%) were men and 56 (36.8%) were women. Median Hgb and Hct were noted to be higher in men compared to women irrespective of HFE status. Mean age was 60.5 years (range 22 - 93 years). Regarding HFE mutation, 44 (28.9%) patients were C282Y/C282Y, 10 (6.6%) were H63D/H63D and 27 (17.8%) had one copy of each mutation. One patient in the study group was H63D/S65C. Median Hgb and Hct were noted to be 15.5 g/dL and 44.9% respectively in C282Y/C282Y subjects, 16.0 g/dL and 47% in H63D/H63D subjects, 15.8 g/dL and 46% in C282Y/H63D subjects, 16g/dL and 47% in those with single C282Y mutation and 16.6g/dL and 48% in those with single H63D mutation. A total of 67.1% subjects received phlebotomy. A total of 21.7% patients in this cohort were active tobacco users and only 8.6% had an established pulmonary diagnosis, including obstructive sleep apnea (OSA) and chronic obstructive pulmonary disease (COPD). Elevated Hgb levels were noted despite absence of an established reason for secondary polycythemia. Anemia was not encountered despite concurrent medical conditions that would usually be associated with anemia, including gastrointestinal bleeding or end-stage renal disease (ESRD). Conclusions Elevated Hgb and Hct levels in HH may be secondary to increased iron uptake by erythroid cell precursors in the bone marrow, in setting of increased availability of both transferrin-bound as well as non-transferrin-bound iron (NTBI). Additional studies need to be pursued to explore the association between HFE mutations and secondary polycythemia.
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Affiliation(s)
- Samia Asif
- Saint Luke's Cancer Institute, Kansas City, MO 64111, USA.,University of Missouri, Kansas City, MO 64111, USA
| | - Madeline Begemann
- Saint Luke's Cancer Institute, Kansas City, MO 64111, USA.,University of Missouri, Kansas City, MO 64111, USA
| | - Shahzad Raza
- Saint Luke's Cancer Institute, Kansas City, MO 64111, USA.,University of Missouri, Kansas City, MO 64111, USA
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Nowak A, Giger RS, Krayenbuehl PA. Higher age at diagnosis of hemochromatosis is the strongest predictor of the occurrence of hepatocellular carcinoma in the Swiss hemochromatosis cohort: A prospective longitudinal observational study. Medicine (Baltimore) 2018; 97:e12886. [PMID: 30335010 PMCID: PMC6211894 DOI: 10.1097/md.0000000000012886] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Hereditary hemochromatosis (HH) is the most common genetic disease in Caucasians which is characterized by an increased intestinal iron absorption, resulting into a progressive accumulation of iron in organs including liver, heart, and pancreas, leading to their progressive dysfunction. Hepatocellular carcinoma (HCC) is a long-term complication of HH, which contributes to increased mortality.We evaluated the risk factors of HCC in a prospective cohort of Swiss hemochromatosis patients with a long-term follow-up.We included 147 patients with the mean age at diagnosis of 48 years, in whom 70% were men. Overall, 9% of the patients developed HCC during the mean follow-up time of 14 years (range 1-40 years). Patients with HCC had higher age at diagnosis (61 ± 11 vs 47 ± 13 years, P = .003), more frequently liver cirrhosis on biopsy (90% vs 37.5%, P = .004), and higher serum ferritin levels [3704 (Q1:2025, Q3:4463) vs 1338 (Q1:691, Q3:2468) μg/L, P < .001], they needed more iron removed by phlebotomy until its depletion [8.9 (Q1:7.2, Q3:10.1) vs 3.8 (Q1:1.6, Q3:8.9) g, P = .029], compared to non-HCC patients. After adjustment for possible confounders, only higher age at diagnosis remained significantly associated with HCC development (odds ratio 1.19, 95% CI 0.056-0.397, P = .001, per year).Higher age at diagnosis showed the strongest association with the occurrence of HCC in Swiss hemochromatosis patients. Patients who were diagnosed at a higher age and with a high iron overload (serum ferritin levels >1000 μg/L) require regular screening even if they have no liver cirrhosis.
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Affiliation(s)
- Albina Nowak
- Department of Endocrinology and Clinical Nutrition, University Hospital Zurich
- Department of Internal Medicine, Psychiatric University Hospital Zurich, University of Zurich
| | - Rebekka S. Giger
- Department of Internal Medicine, University Hospital Zurich, Zurich
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Pericleous M, Kelly C, Vijay C. The clinical management of hereditary haemochromatosis. Frontline Gastroenterol 2018; 9:110-114. [PMID: 29588838 PMCID: PMC5868443 DOI: 10.1136/flgastro-2017-100872] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/13/2017] [Revised: 08/04/2017] [Accepted: 08/19/2017] [Indexed: 02/04/2023] Open
Abstract
Hereditary haemochromatosis is an autosomal recessive disorder with variable penetrance. Most patients are C282Y homozygotes while heterozygotes or patients who are homozygous with other mutations are uncommonly affected. The true genotype to phenotype expression remains unclear. Treatment with phlebotomy is highly effective and cost-efficient while liver transplantation confers a curative option.
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Affiliation(s)
- Marinos Pericleous
- Department of Gastroenterology & Hepatology, Royal Surrey County Hospital NHS Foundation Trust, Guildford, Surrey, UK
- Department of Clinical & Experimental Medicine, University of Surrey, Guildford, Surrey, UK
| | - Claire Kelly
- Department of Gastroenterology & Hepatology, Royal Surrey County Hospital NHS Foundation Trust, Guildford, Surrey, UK
- Department of Clinical & Experimental Medicine, University of Surrey, Guildford, Surrey, UK
| | - Charles Vijay
- Department of Gastroenterology & Hepatology, Royal Surrey County Hospital NHS Foundation Trust, Guildford, Surrey, UK
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Herta T, Fischer J, Berg T. Genetik metabolischer und viraler Lebererkrankungen. DER GASTROENTEROLOGE 2017; 12:16-31. [DOI: 10.1007/s11377-016-0128-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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12
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Gerhard GS, Jin Q, Paynton BV, Popoff SN. The Anatomy to Genomics (ATG) Start Genetics medical school initiative: incorporating exome sequencing data from cadavers used for Anatomy instruction into the first year curriculum. BMC Med Genomics 2016; 9:62. [PMID: 27716216 PMCID: PMC5053090 DOI: 10.1186/s12920-016-0223-4] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2016] [Accepted: 09/24/2016] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND The increasing use of next generation DNA sequencing in clinical medicine is exposing the need for more genetics education in physician training. We piloted an initiative to determine the feasibility of incorporating exome sequencing data generated from DNA obtained from cadavers used for teaching Anatomy into a first year medical student integrated block-style course. METHODS We optimized the procedure to obtain DNA for exome sequencing by comparing the quality and quantity of DNA isolated from several tissues by two different extraction methods. DNA was sequenced using exome capture and analyzed using standard methods. Single nucleotide variants (SNVs), as well as small insertions/deletions, with potential functional impact were selected by faculty for student teams to independently investigate and prepare presentations on their findings. RESULTS A total of seven cadaver DNAs were sequenced yielding high quality results. SNVs were identified that were associated, with known physical traits and disease susceptibility, as well as pharmacogenomic phenotypes. Students presented findings based on correlation with known clinical information about the cadavers' diseases and traits. CONCLUSION Exome sequencing of cadaver DNA is a useful tool to integrate Anatomy with Genetics and Biochemistry into a first year medical student core curriculum.
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Affiliation(s)
- Glenn S. Gerhard
- Lewis Katz School of Medicine at Temple University , Philadelphia, PA 19140 USA
- Department of Medical Genetics and Molecular Biochemistry, 960 Medical Education and Research Building (MERB), Lewis Katz School of Medicine at Temple University , 3500 N. Broad Street, Philadelphia, PA 19140 USA
| | - Qunyan Jin
- Lewis Katz School of Medicine at Temple University , Philadelphia, PA 19140 USA
| | - Barbara V. Paynton
- Lewis Katz School of Medicine at Temple University , Philadelphia, PA 19140 USA
| | - Steven N. Popoff
- Lewis Katz School of Medicine at Temple University , Philadelphia, PA 19140 USA
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Porto G, Brissot P, Swinkels DW, Zoller H, Kamarainen O, Patton S, Alonso I, Morris M, Keeney S. EMQN best practice guidelines for the molecular genetic diagnosis of hereditary hemochromatosis (HH). Eur J Hum Genet 2016; 24:479-95. [PMID: 26153218 PMCID: PMC4929861 DOI: 10.1038/ejhg.2015.128] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2014] [Revised: 04/29/2015] [Accepted: 05/06/2015] [Indexed: 12/14/2022] Open
Abstract
Molecular genetic testing for hereditary hemochromatosis (HH) is recognized as a reference test to confirm the diagnosis of suspected HH or to predict its risk. The vast majority (typically >90%) of patients with clinically characterized HH are homozygous for the p.C282Y variant in the HFE gene, referred to as HFE-related HH. Since 1996, HFE genotyping was implemented in diagnostic algorithms for suspected HH, allowing its early diagnosis and prevention. However, the penetrance of disease in p.C282Y homozygotes is incomplete. Hence, homozygosity for p.C282Y is not sufficient to diagnose HH. Neither is p.C282Y homozygosity required for diagnosis as other rare forms of HH exist, generally referred to as non-HFE-related HH. These pose significant challenges when defining criteria for referral, testing protocols, interpretation of test results and reporting practices. We present best practice guidelines for the molecular genetic diagnosis of HH where recommendations are classified, as far as possible, according to the level and strength of evidence. For clarification, the guidelines' recommendations are preceded by a detailed description of the methodology and results obtained with a series of actions taken in order to achieve a wide expert consensus, namely: (i) a survey on the current practices followed by laboratories offering molecular diagnosis of HH; (ii) a systematic literature search focused on some identified controversial topics; (iii) an expert Best Practice Workshop convened to achieve consensus on the practical recommendations included in the guidelines.
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Affiliation(s)
- Graça Porto
- Center for Predictive and Preventive Genetics (CGPP), Institute of Molecular and Cellular Biology (IBMC), Porto, Portugal
- Clinical Haematology, Hospital Santo António (CHP-HAS) and Department of Molecular Pathology and Immunology, Abel Salazar Institute for Biomedical Sciences (ICBAS), University of Porto, Porto, Portugal
| | - Pierre Brissot
- Liver Disease Unit, Pontchaillou University Hospital, University of Rennes, and National Reference Centre for Rare Iron Overload Diseases of Genetic Origin, Rennes, France
| | - Dorine W Swinkels
- Department of Laboratory Medicine, Radboud University Medical Centre, Nijmegen, The Netherlands
| | - Heinz Zoller
- Department of Medicine II, Gastroenterology and Hepatology, Medical University of Innsbruck, Innsbruck, Austria
| | | | - Simon Patton
- European Molecular Quality Network (EMQN), Manchester, UK
| | - Isabel Alonso
- Center for Predictive and Preventive Genetics (CGPP), Institute of Molecular and Cellular Biology (IBMC), Porto, Portugal
| | - Michael Morris
- European Molecular Quality Network (EMQN), Manchester, UK
- Synlab, Lausanne, Switzerland
| | - Steve Keeney
- European Molecular Quality Network (EMQN), Manchester, UK
- Molecular Diagnostics Centre (Haematology), Manchester Royal Infirmary, Manchester, UK
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Ryan E, Ryan JD, Russell J, Coughlan B, Tjalsma H, Swinkels DW, Stewart S, Crowe JP. Correlates of hepcidin and NTBI according to HFE status in patients referred to a liver centre. Acta Haematol 2014; 133:155-61. [PMID: 25277871 DOI: 10.1159/000363490] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2014] [Accepted: 05/08/2014] [Indexed: 12/21/2022]
Abstract
BACKGROUND/AIMS Innately low hepcidin levels lead to iron overload in HFE-associated hereditary haemochromatosis. METHODS This study compared hepcidin and non-transferrin bound iron (NTBI) levels in untreated iron-loaded and non-iron-loaded C282Y homozygotes to levels in C282Y/H63D compound heterozygotes and individuals with other HFE genotypes associated with less risk of iron overload. RESULTS As the genotypic risk for iron overload increased, transferrin saturation and serum NTBI levels increased while serum hepcidin levels decreased. Overweight and obese male C282Y homozygotes had significantly higher hepcidin levels than male C282Y homozygotes with a normal BMI. Pearson product-moment analysis showed that serum hepcidin levels significantly correlated with HFE status, serum ferritin, age, NTBI, transferrin saturation, gender and BMI. Subsequent multiple regression analysis showed that HFE status and serum ferritin were significant independent correlates of serum hepcidin levels. CONCLUSIONS In summary, this study has shown that while serum ferritin and HFE status are the most important determinants of hepcidin levels, factors such age, gender, BMI, transferrin saturation and NTBI all interact closely in the matrix of homeostatic iron balance.
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Affiliation(s)
- Eleanor Ryan
- Liver Centre, Mater Misericordiae University Hospital, Dublin, Ireland
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Shaked O, Gonzalez A, Bahirwani R, Furth E, Siegelman E, Shaked A, Olthoff K, Reddy KR. Donor hemosiderosis does not affect liver function and regeneration in the setting of living donor liver transplantation. Am J Transplant 2014; 14:216-20. [PMID: 24354876 DOI: 10.1111/ajt.12504] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2013] [Revised: 09/03/2013] [Accepted: 09/10/2013] [Indexed: 01/25/2023]
Abstract
Living donor liver transplantation (LDLT) demands a careful assessment of abnormal findings discovered during the evaluation process to determine if there will be any potential risks to the donor or recipient. Varying degrees of elevated hepatic iron levels are not uncommonly seen in otherwise healthy individuals. We questioned whether mild expression of hemosiderin deposition presents a safety concern when considering outcomes of living donation for both the donor and the recipient. We report on three LDLT patients who were found to have low- to moderate-grade hemosiderin deposition on liver biopsy. All other aspects of their evaluation proved satisfactory, and the decision was made to proceed with donation. There were no significant complications in the donors, and all demonstrated complete normalization of liver function postoperatively, with appropriate parenchymal regeneration. The recipients also had unremarkable postoperative recovery. We conclude that these individuals can be considered as potential donors after careful evaluation.
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Affiliation(s)
- O Shaked
- Department of Surgery, Division of Transplantation, Hospital of the University of Pennsylvania, Philadelphia, PA
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16
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Abstract
Hereditary hemochromatosis is an inherited iron overload disorder caused by inappropriately low hepcidin secretion leading to increased duodenal absorption of dietary iron, most commonly in C282Y homozygous individuals. This can result in elevated serum ferritin, iron deposition in various organs and ultimately end-organ damage, although there is incomplete biochemical and clinical penetrance and variable phenotypic expression of the HFE mutation in hereditary hemochromatosis. An elevated SF >1000 mg/l [corrected] is associated with an increased risk of cirrhosis and mortality in C282Y homozygotes.Conversely, a SF <1000 µg/l is associated with a very low likelihood of cirrhosis, making liver biopsy unnecessary among C282Y homozygotes in the absence of concomitant risk factors for liver disease. Phlebotomy remains the mainstay of treatment and new treatments being studied include erythrocytapheresis and 'mini-hepcidins'. Iron overload is being recognized to play a carcinogenic role in hepatocellular carcinoma and other cancers, possibly supporting iron depletion in these patients.
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Affiliation(s)
- Pushpjeet Kanwar
- Liver Center for Excellence, Digestive Disease Institute, Virginia Mason Medical Center, Seattle, WA, USA
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Khusainova RI, Khusnutdinova NN, Litvinov SS, Khusnutdinova EK. Analysis of H63D mutation in hemochromatosis (HFE) gene in populations of Central Eurasia. RUSS J GENET+ 2013. [DOI: 10.1134/s1022795412120046] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
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Hattori A, Miyajima H, Tomosugi N, Tatsumi Y, Hayashi H, Wakusawa S. Clinicopathological study of Japanese patients with genetic iron overload syndromes. Pathol Int 2013; 62:612-8. [PMID: 22924847 DOI: 10.1111/j.1440-1827.2012.02848.x] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
In addition to hemochromatosis, aceruloplasminemia and ferroportin disease may be complicated by iron-induced multiple organ damage. Therefore, clinicopathological features should be evaluated in a wider range of genetic iron disorders. This study included 16 Japanese patients with genetic iron overload syndromes. The responsible genes were CP in four, HAMP in one, HJV in three, TFR2 in five, and SLC40A1 in three patients. No phenotype dissociation was observed in patients with the CP, TFR2, or HAMP genotypes. Two of the three patients with the HJV genotype displayed classic hemochromatosis instead of the juvenile type. Patients with the SLC40A1 genotype were affected by mild iron overload (ferroportin A) or severe iron overload (ferroportin B). Transferrin saturation was unusually low in aceruloplasminemia patients. All patients, except those with ferroportin disease, displayed low serum hepcidin-25 levels. Liver pathology showed phenotype-specific changes; isolated parenchymal iron loading in aceruloplasminemia, periportal fibrosis associated with heavy iron overload in both parenchymal and Kupffer cells of ferroportin B, and parenchyma-dominant iron-loading cirrhosis in hemochromatosis. In contrast, diabetes occurred in all phenotypes of aceruloplasminemia, hemochromatosis, and ferroportin disease B. In conclusion, clinicopathological features were partially characterized in Japanese patients with genetic iron overload syndromes.
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Affiliation(s)
- Ai Hattori
- Department of Medical Technology, Nagoya University Graduate School of Health Sciences, Nagoya, Japan.
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Trieß C, von Figura G, Stuhrmann M, Butzeck B, Krayenbuehl PA, Strnad P, Kulaksiz H. Diagnosis of hereditary hemochromatosis in the era of genetic testing. Dig Dis Sci 2012; 57:2988-94. [PMID: 22674401 DOI: 10.1007/s10620-012-2243-z] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/11/2011] [Accepted: 05/03/2012] [Indexed: 12/15/2022]
Abstract
BACKGROUND Homozygous C282Y mutation in HFE gene is responsible for the majority of hereditary hemochromatosis cases. Since 1996 this mutation can be identified by a simple genetic test. AIMS To determine the clinical presentations in patients with homozygous HFE C282Y mutation and the impact of genetic testing on the time needed for diagnosis. METHODS A total of 414 patients diagnosed with C282Y homozygous hereditary hemochromatosis before and after the introduction of genetic testing were evaluated regarding symptoms and clinical findings at diagnosis as well as first hemochromatosis-related clinical features in their past medical history. RESULTS At the time of diagnosis, the predominant symptom was joint pain, in particular of the hands/wrists. Those patients presenting with hand/wrist arthralgia had significantly higher ferritin levels than patients without this joint involvement (p = 0.0005 for males and p < 0.0001 for females). After the introduction of the HFE genetic test an earlier diagnosis after first onset of hemochromatosis-associated clinical features was observed between 2006 and 2009 vs. 2000-2005 p = 0.01). CONCLUSIONS Arthralgia, in particular of the hands/wrists, is a hallmark of hereditary hemochromatosis and its presence is associated with higher ferritin levels. Despite the availability of a genetic test, it often takes more than 6 years from the first onset of clinical features to diagnose hereditary hemochromatosis. This underlines the importance of raising the awareness of hemochromatosis and its typical clinical presentations.
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Affiliation(s)
- Christiane Trieß
- Department of Internal Medicine I, University Hospital Ulm, Ulm, Germany
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20
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Abstract
Hereditary haemochromatosis (HH) is a common autosomal recessive disorder of iron overload in Caucasian populations. Clinical manifestations usually occur in individuals homozygous for the C282Y mutation in the HFE gene product and who have developed significant iron loading. Current screening methods can detect affected individuals either prior to or early during disease evolution, enabling early introduction of phlebotomy treatment that can normalise life expectancy. Evaluation of possible iron overload, via measurement of serum transferrin saturation and ferritin level, is the most appropriate initial test for those subjects presenting clinically for evaluation. HFE genotyping, when combined with serum biochemical measurements, defines the presence of likely iron overload and the underlying genetic disorder and is the preferred initial screening modality for families of an affected individual. Definitive proof of iron overload requires measurement of hepatic iron concentration or total iron burden via therapeutic phlebotomy; elevated serum ferritin level alone is not adequate. We now recognise that the natural history of HH is not as discrete as previously believed, because genetic and environmental modifiers of disease penetrance are increasingly identified as influencing the clinical expression of HH. In fact, a minority of C282Y homozygotes develop classical 'iron overload disease', although it has recently emerged that the disorder may predispose to breast and colorectal cancer. Uncertainties as to the true clinical impact of the condition at a population level lead to current recommendations of cascade screening of families of affected patients, case-finding in high-risk groups, such as patients with clinical manifestations consistent with the diagnosis, and a high level of clinical awareness in the community to facilitate early diagnosis. Generalised population screening is not presently recommended.
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21
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Kohane IS, Hsing M, Kong SW. Taxonomizing, sizing, and overcoming the incidentalome. Genet Med 2012; 14:399-404. [PMID: 22323072 DOI: 10.1038/gim.2011.68] [Citation(s) in RCA: 88] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
PURPOSE With the advent of whole-genome sequencing made clinically available, the number of incidental findings is likely to rise. The false-positive incidental findings are of particular clinical concern. We provide estimates on the size of these false-positive findings and classify them into four broad categories. METHODS Whole-genome sequences (WGS) of nine individuals were scanned with several comprehensive public annotation databases and average estimates for the number of findings. These estimates were then evaluated in the perspective of various sources of false-positive annotation errors. RESULTS At present there are four main sources of false-positive incidental findings: erroneous annotations, sequencing error, incorrect penetrance estimates, and multiple hypothesis testing. Of these, the first two are likely to be addressed in the near term. Conservatively, current methods deliver hundreds of false-positive incidental findings per individual. CONCLUSION The burden of false-positives in whole-genome sequence interpretation threatens current capabilities to deliver clinical-grade whole-genome clinical interpretation. A new generation of population studies and retooling of the clinical decision-support approach will be required to overcome this threat.
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Affiliation(s)
- Isaac S Kohane
- Children's Hospital Informatics Program, Children's Hospital, Boston, Massachusetts, USA.
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Jain S, Agarwal S, Tamhankar P, Verma P, Choudhuri G. Lack of association of primary iron overload and common HFE gene mutations with liver cirrhosis in adult Indian population. Indian J Gastroenterol 2011; 30:161-5. [PMID: 21822737 DOI: 10.1007/s12664-011-0109-5] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/18/2010] [Accepted: 07/02/2011] [Indexed: 02/04/2023]
Abstract
AIM To find out the association of common HFE mutations (viz., C282Y and H63D) with primary iron overload (PIL) in liver cirrhosis (CLD) patients of Indian origin. METHODS Polymerase chain reaction-restriction fragment length polymorphism method was used for screening C282Y and H63D mutation in 496 CLD patients (hepatitis B virus associated cirrhosis (HBVc) = 74, hepatitis C virus associated cirrhosis (HCV) = 50, alcoholic cirrhosis with hepatitis (ALcW) = 38, alcoholic cirrhosis without hepatitis (ALc) = 92, cryptogenic cirrhosis (CC) = 242) and 502 healthy controls. Transferrin saturation of >45 or serum ferritin of >300 ng/mL (males)/>200 ng/mL (females) with normal total exogenous iron intake was suggestive of PIL. Histological liver iron grading was done by Perl's Prussian blue stain. RESULTS Of 496 patients, 13 (2.6; 9 CC, 2 ALc, 1 HBVc, 1 AlcW) had PIL. However, only two (15.3) of 13 patients (1 CC and 1 HBVc) were positive for H63D heterozygous mutation. All the subjects were found to be C282Y wild type, except a single case of double heterozygous (C282Y/H63D) who however, did not have PIL. Overall frequency of H63D allele in patients and controls was not significantly different (5.95 and 4.58 respectively, p = 0.17). A highly significant H63D allele frequency (p < 0.005) was observed in HBVc (10.82) and ALcW (11.84) groups but they were not associated with PIL. CONCLUSION The frequency of PIL, and the HFE gene mutaion (C282Y) are both rare in Indian patients and explain why hemochromatosis is a rare cause of liver cirrhosis in India. A highly significant H63D allele frequency in HBV and alcohol-related cirrhosis suggest a possible predisposing role for liver fibrosis of this allele.
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Affiliation(s)
- Shalu Jain
- Department of Medical Genetics, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
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Sirlin CB, Reeder SB. Magnetic resonance imaging quantification of liver iron. Magn Reson Imaging Clin N Am 2011; 18:359-81, ix. [PMID: 21094445 DOI: 10.1016/j.mric.2010.08.014] [Citation(s) in RCA: 151] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Iron overload is the histologic hallmark of hereditary hemochromatosis and transfusional hemosiderosis but also may occur in chronic hepatopathies. This article provides an overview of iron deposition and diseases where liver iron overload is clinically relevant. Next, this article reviews why quantitative noninvasive biomarkers of liver iron would be beneficial. Finally, we describe current state-of-the-art methods for quantifying iron with MR imaging and review remaining challenges and unsolved problems.
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Affiliation(s)
- Claude B Sirlin
- Liver Imaging Group, Department of Radiology, University of California San Diego, 408 Dickinson Street, San Diego, CA 92103-8226, USA.
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Aguilar-Martinez P, Grandchamp B, Cunat S, Cadet E, Blanc F, Nourrit M, Lassoued K, Schved JF, Rochette J. Iron overload in HFE C282Y heterozygotes at first genetic testing: a strategy for identifying rare HFE variants. Haematologica 2011; 96:507-14. [PMID: 21228038 DOI: 10.3324/haematol.2010.029751] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023] Open
Abstract
BACKGROUND Heterozygotes for the p.Cys282Tyr (C282Y) mutation of the HFE gene do not usually express a hemochromatosis phenotype. Apart from the compound heterozygous state for C282Y and the widespread p.His63Asp (H63D) variant allele, other rare HFE mutations can be found in trans on chromosome 6. DESIGN AND METHODS We performed molecular investigation of the genes implicated in hereditary hemochromatosis in six patients who presented with iron overload but were simple heterozygotes for the HFE C282Y mutation at first genetic testing. Functional impairment of new variants was deduced from computational methods including molecular modeling studies. RESULTS We identified four rare HFE mutant alleles, three of which have not been previously described. One mutation is a 13-nucleotide deletion in exon 6 (c.1022_1034del13, p.His341_Ala345 > LeufsX119), which is predicted to lead to an elongated and unstable protein. The second one is a substitution of the last nucleotide of exon 2 (c.340G > A, p.Glu114Lys) which modifies the relative solvent accessibility in a loop interface. The third mutation, p.Arg67Cys, also lies in exon 2 and introduces a destabilization of the secondary structure within a loop of the α1 domain. We also found the previously reported c.548T > C (p.Leu183Pro) missense mutation in exon 3. No other known iron genes were mutated. We present an algorithm at the clinical and genetic levels for identifying patients deserving further investigation. Conclusions Our results suggest that additional mutations in HFE may have a clinical impact in C282Y carriers. In conjunction with results from previously described cases we conclude that an elevated transferrin saturation level and elevated hepatic iron index should indicate the utility of searching for further HFE mutations in C282Y heterozygotes prior to other iron gene studies.
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Gerhard GS, Chokshi R, Still CD, Benotti P, Wood GC, Freedman-Weiss M, Rider C, Petrick AT. The influence of iron status and genetic polymorphisms in the HFE gene on the risk for postoperative complications after bariatric surgery: a prospective cohort study in 1,064 patients. Patient Saf Surg 2011; 5:1. [PMID: 21219652 PMCID: PMC3031214 DOI: 10.1186/1754-9493-5-1] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2010] [Accepted: 01/10/2011] [Indexed: 01/22/2023] Open
Abstract
BACKGROUND Gastric bypass surgery is a highly effective therapy for long-term weight loss in severely obese patients, but carries significant perioperative risks including infection, wound dehiscence, and leaks from staple breakdown. Iron status can affect immune function and wound healing, thus may influence peri-operative complications. Common mutations in the HFE gene, the gene responsible for the iron overload disorder hereditary hemochromatosis, may impact iron status. METHODS We analyzed 1064 extremely obese Caucasian individuals who underwent open and laparoscopic Roux-n-Y gastric bypass surgery at the Geisinger Clinic. Serum iron, ferritin, transferrin, and iron binding capacity were measured pre-operatively. All patients had intra-operative liver biopsies and were genotyped for the C282Y and H63D mutations in the HFE gene. Associations between surgical complications and serum iron measures, HFE gene status, and liver iron histology were determined. RESULTS We found that increased serum iron and transferrin saturation were present in patients with any post-operative complication, and that increased serum ferritin was also increased in patients with major complications. Increased serum transferrin saturation was also associated with wound complications in open RYGB, and transferrin saturation and ferritin with prolonged lengths of stay. The presence of 2 or more HFE mutations was associated with overall complications as well as wound complications in open RYGB. No differences were found in complication rates between those with stainable liver iron and those without. CONCLUSION Serum iron status and HFE genotype may be associated with complications following RYGB surgery in the extremely obese.
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Affiliation(s)
- Glenn S Gerhard
- Weis Center for Research, Geisinger Clinic, 100 North Academy Avenue, Danville, PA 17822, USA.
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26
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Meneses FGA, Schnabel B, Silva IDCG, Alberto FL, Toma L, Nader HB, Lopes CC. Identification of the mutations associated with hereditary hyperferritinemia cataract syndrome and hemochromatosis in a Brazilian family. Clin Genet 2011; 79:189-92. [PMID: 21210779 DOI: 10.1111/j.1399-0004.2010.01517.x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
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Mikhailova SV, Babenko VN, Voevoda MI, Romashchenko AG. The ethnospecific distribution of the HFE haplotypes for IVS2(+4)t/c, IVS4(-44)t/c, and IVS5(-47)g/a in populations of Russia and possible effects of these single-nucleotide polymorphisms in splicing. Genet Test Mol Biomarkers 2010; 14:461-9. [PMID: 20642366 DOI: 10.1089/gtmb.2009.0203] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
AIM The aim of this work was a haplotype analysis of the major mutations (C282Y, H63D, S65C) and IVS2(+4)t/c, IVS4(-44)t/c, and IVS5(-47)a/g polymorphisms of the hemochromatosis HFE gene in populations inhabiting the territories of Russia (Russians, Finno-Ugrians, Central Asians, and Arctic Mongoloids). METHOD The hemochromatosis gene (HFE) alleles were detected using the polymerase chain reaction/restriction fragment length polymorphism method. RESULTS Of the eight possible intronic haplotype variants, the TTG, TTA, CTA, and CCA were identified. The HFE alleles with the different haplotype variants were distributed in an ethnospecific manner among the populations. Our finding was that every one of the C282Y, H63D, and S65C mutations was in linkage disequilibrium only with one of the intronic haplotype variants: TTG, CTA, and CCA, respectively. The data from context analysis of DNA regions where the examined single-nucleotide polymorphisms are located suggested their involvement in splicing. CONCLUSIONS Different genotypes of the HFE gene occur at different frequencies among populations of Russia. Carriers of the specific genotype variants may potentially express distinct sets of alternative HFE mRNAs.
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Affiliation(s)
- Svetlana Vladimirovna Mikhailova
- Laboratory of Animal Molecular Genetics, Institute of Cytology and Genetics of the Siberian Division of the Russian Academy of Sciences, Novosibirsk, Russia.
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Møller DV, Pecini R, Gustafsson F, Hassager C, Hedley P, Jespersgaard C, Torp-Pedersen C, Christiansen M, Køber LV. Hereditary hemochromatosis (HFE) genotypes in heart failure: relation to etiology and prognosis. BMC MEDICAL GENETICS 2010; 11:117. [PMID: 20670400 PMCID: PMC2920247 DOI: 10.1186/1471-2350-11-117] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 12/11/2009] [Accepted: 07/29/2010] [Indexed: 01/07/2023]
Abstract
Background It is believed that hereditary hemochromatosis (HH) might play a role in cardiac disease (heart failure (HF) and ischemia). Mutations within several genes are HH-associated, the most common being the HFE gene. In a large cohort of HF patients, we sought to determine the etiological role and the prognostic significance of HFE genotypes. Methods We studied 667 HF patients (72.7% men) with depressed systolic function, enrolled in a multicentre trial with a follow-up period of up to 5 years. All were genotyped for the known HFE variants C282Y, H63D and S65C. Results The genotype and allele frequencies in the HF group were similar to the frequencies determined in the general Danish population. In multivariable analysis mortality was not predicted by C282Y-carrier status (HR 1.2, 95% CI: 0.8-1.7); H63D-carrier status (HR 1.0, 95% CI: 0.7-1.3); nor S65C-carrier status (HR 1.2, 95% CI: 0.7-2.0). We identified 27 (4.1%) homozygous or compound heterozygous carriers of HFE variants. None of these carriers had a clinical presentation suggesting hemochromatosis, but hemoglobin and ferritin levels were higher than in the rest of the cohort. Furthermore, a trend towards reduced mortality was seen in this group in univariate analyses (HR 0.4, 95% CI: 0.2-0.9, p = 0.03), but not in multivariate (HR 0.5, 95% CI: 0.2-1.2). Conclusion HFE genotypes do not seem to be a significant contributor to the etiology of heart failure in Denmark. HFE variants do not affect mortality in HF.
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Affiliation(s)
- Daniel V Møller
- Department of Cardiology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
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Abstract
Iron overload in humans is associated with a variety of genetic and acquired conditions. Of these, HFE hemochromatosis (HFE-HC) is by far the most frequent and most well-defined inherited cause when considering epidemiological aspects and risks for iron-related morbidity and mortality. The majority of patients with HFE-HC are homozygotes for the C282Y polymorphism [1]. Without therapeutic intervention, there is a risk that iron overload will occur, with the potential for tissue damage and disease. While a specific genetic test now allows for the diagnosis of HFE-HC, the uncertainty in defining cases and disease burden, as well as the low phenotypic penetrance of C282Y homozygosity poses a number of clinical problems in the management of patients with HC. This Clinical Practice Guideline will therefore, focus on HFE-HC, while rarer forms of genetic iron overload recently attributed to pathogenic mutations of transferrin receptor 2, (TFR2), hepcidin (HAMP), hemojuvelin (HJV), or to a sub-type of ferroportin (FPN) mutations, on which limited and sparse clinical and epidemiologic data are available, will not be discussed. We have developed recommendations for the screening, diagnosis, and management of HFE-HC.
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Gan EK, Ayonrinde OT, Trinder D, Olynyk JK. Phenotypic expression of hereditary hemochromatosis: what have we learned from the population studies? Curr Gastroenterol Rep 2010; 12:7-12. [PMID: 20425479 DOI: 10.1007/s11894-009-0078-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/29/2023]
Abstract
Profound advances in our knowledge of hereditary hemochromatosis (HH) during the past 150 years have resulted in two distinct "iron ages": the pre-HFE gene era and the post-HFE gene era. During these periods, family studies, HLA association studies, and ultimately HFE gene studies in various populations informed us of the genotypic prevalence as well as the clinical and biochemical penetrance of HH. We learned that HH has a highly variable clinical penetrance in susceptible individuals of Northern European ancestry. Further, we now recognize that the natural history of HH is not as discrete as previously believed, because genetic and environmental modifiers of disease penetrance are increasingly identified as influencing the clinical expression of HH.
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Affiliation(s)
- Eng K Gan
- School of Medicine and Pharmacology, University of Western Australia, Fremantle Hospital, Fremantle, WA, Australia
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Dever J, Kowdley KV. Iron metabolism and diagnosis of iron overload disorders. ACTA ACUST UNITED AC 2009; 4:67-77. [DOI: 10.1517/17530050903440138] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
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Licata A, Nebbia ME, Cabibbo G, Iacono GL, Barbaria F, Brucato V, Alessi N, Porrovecchio S, Di Marco V, Craxì A, Cammà C. Hyperferritinemia is a risk factor for steatosis in chronic liver disease. World J Gastroenterol 2009. [PMID: 19418586 DOI: 10.3748/wjg.15.2132.] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 09/29/2022] Open
Abstract
AIM To investigate the relationship between ferritin and steatosis in patients with chronically abnormal liver function tests (LFTs) and high ferritin level. METHODS One hundred and twenty-four consecutive patients with hyperferritinemia (male > 300 ng/mL, female > 200 ng/mL) were evaluated; clinical, biochemical and serological data, iron status parameters, HFE gene mutations and homeostasis model assessment score were obtained. Steatosis was graded by ultrasound as absent or present. Histology was available in 53 patients only. RESULTS Mean level of ferritin was 881 +/- 77 ng/mL in men and 549 +/- 82 ng/mL in women. The diagnosis was chronic hepatitis C in 53 (42.7%), non-alcoholic fatty liver disease/non-alcoholic steatohepatitis in 57 (45.9%), and cryptogenic liver damage in 14 (11.3%). None was diagnosed as hereditary hemochromatosis (HH). Hepatic siderosis on liver biopsy was present in 17 of 54 (32%) patients; grade 1 in eight and grade 2 in nine. Overall, 92 patients (74.2%) had steatosis. By logistic regression, ferritin and gamma-glutamyltransferase were independent predictors of steatosis. Ferritin levels were significantly related to low platelet count, steatosis and hepatitis C virus infection. CONCLUSION In a non-obese cohort of non-alcoholic patients with chronically abnormal LFTs without HH, high serum ferritin level is a risk factor for steatosis.
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Affiliation(s)
- Anna Licata
- Gastroenterology and Hepatology Unit, Department of Internal Medicine, University of Palermo, 90127 Palermo, Italy.
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Picot J, Bryant J, Cooper K, Clegg A, Roderick P, Rosenberg W, Patch C. Psychosocial aspects of DNA testing for hereditary hemochromatosis in at-risk individuals: a systematic review. Genet Test Mol Biomarkers 2009; 13:7-14. [PMID: 19309267 DOI: 10.1089/gtmb.2008.0064] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
AIM To review the psychosocial benefits and harms of DNA testing for HFE-related hereditary hemochromatosis (HH) in at-risk individuals. BACKGROUND HH is a common genetic disease in people of European descent. DNA-based predisposition testing is used for diagnosis or in the context of family testing, but there are concerns about potential psychosocial consequences. METHODS Fifteen electronic databases (including Medline and Cochrane) were searched from inception to April 2007 to identify any quantitative or qualitative primary research that considered DNA testing of individuals considered at-risk of HH and reported psychosocial outcomes. Inclusion criteria, data extraction, and quality assessment were undertaken by standard methodology. RESULTS Three observational studies met the inclusion criteria of the review; each had methodological limitations. On receipt of test results, anxiety levels fell or were unchanged; general health-related quality-of-life outcomes improved in some aspects, or were unchanged with respect to pretest result values. Outcomes were not reported separately for those referred for diagnosis and those with family history of HH. Results suggest that genetic testing for HH in at-risk individuals is accompanied by few negative psychosocial outcomes. CONCLUSION The evidence on the psychosocial aspects of DNA testing for HH in at-risk individuals is limited. Further research might be required if other factors influencing the natural history of the disease phenotype are identified.
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Affiliation(s)
- Joanna Picot
- Southampton Health Technology Assessments Centre, University of Southampton, Southampton, United Kingdom.
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Potrich C, Lunelli L, Forti S, Vozzi D, Pasquardini L, Vanzetti L, Panciatichi C, Anderle M, Pederzolli C. Effect of materials for micro-electro-mechanical systems on PCR yield. EUROPEAN BIOPHYSICS JOURNAL: EBJ 2009; 39:979-86. [DOI: 10.1007/s00249-009-0466-5] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/02/2009] [Revised: 04/27/2009] [Accepted: 04/29/2009] [Indexed: 11/28/2022]
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Licata A, Nebbia ME, Cabibbo G, Iacono GL, Barbaria F, Brucato V, Alessi N, Porrovecchio S, Di Marco V, Craxì A, Cammà C. Hyperferritinemia is a risk factor for steatosis in chronic liver disease. World J Gastroenterol 2009; 15:2132-8. [PMID: 19418586 PMCID: PMC2678584 DOI: 10.3748/wjg.15.2132] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the relationship between ferritin and steatosis in patients with chronically abnormal liver function tests (LFTs) and high ferritin level.
METHODS: One hundred and twenty-four consecutive patients with hyperferritinemia (male > 300 ng/mL, female > 200 ng/mL) were evaluated; clinical, biochemical and serological data, iron status parameters, HFE gene mutations and homeostasis model assessment score were obtained. Steatosis was graded by ultrasound as absent or present. Histology was available in 53 patients only.
RESULTS: Mean level of ferritin was 881 ± 77 ng/mL in men and 549 ± 82 ng/mL in women. The diagnosis was chronic hepatitis C in 53 (42.7%), non-alcoholic fatty liver disease/non-alcoholic steatohepatitis in 57 (45.9%), and cryptogenic liver damage in 14 (11.3%). None was diagnosed as hereditary hemochromatosis (HH). Hepatic siderosis on liver biopsy was present in 17 of 54 (32%) patients; grade 1 in eight and grade 2 in nine. Overall, 92 patients (74.2%) had steatosis. By logistic regression, ferritin and γ-glutamyltransferase were independent predictors of steatosis. Ferritin levels were significantly related to low platelet count, steatosis and hepatitis C virus infection.
CONCLUSION: In a non-obese cohort of non-alcoholic patients with chronically abnormal LFTs without HH, high serum ferritin level is a risk factor for steatosis.
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Kohane IS. The twin questions of personalized medicine: who are you and whom do you most resemble? Genome Med 2009; 1:4. [PMID: 19348691 PMCID: PMC2651581 DOI: 10.1186/gm4] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Personalized medicine is typically described as the use of molecular or genetic characteristics to customize therapy. This perspective at best provides an incomplete model of the patient and at worst can lead to grossly inappropriate practices. Personalization of medicine requires two characterizations: a well-grounded understanding of who the patient is and an equally robust understanding of the subpopulation that most resembles that patient in the context of the decisions at hand. These characterizations are readily represented probabilistically and can be used to drive decision-making in a rational manner that maximizes the positive outcomes for the patient.
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Affiliation(s)
- Isaac S Kohane
- Harvard Medical School, 10 Shattuck Street, Boston, MA 02115, USA
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Dunn T, Blankenship D, Beal N, Allen R, Schechter E, Moore W, Perveen G, Eichner J. HFE mutations in heart disease. Heart Vessels 2008; 23:348-55. [DOI: 10.1007/s00380-008-1047-8] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/09/2007] [Accepted: 02/05/2008] [Indexed: 11/30/2022]
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Lee PL, Gelbart T, West C, Barton JC. SLC40A1 c.1402G-->a results in aberrant splicing, ferroportin truncation after glycine 330, and an autosomal dominant hemochromatosis phenotype. Acta Haematol 2007; 118:237-41. [PMID: 18160816 DOI: 10.1159/000112830] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2007] [Accepted: 09/05/2007] [Indexed: 11/19/2022]
Abstract
BACKGROUND/AIMS To determine the molecular basis of a mild hemochromatosis phenotype in a man of Scottish-Irish descent. METHODS We sequenced genomic DNA to detect mutations of HFE, SLC40A1, TFR2, HAMP, and HFE2. RNA isolated from blood mononuclear cells was used to make cDNA. RT-PCR was performed to amplify ferroportin from cDNA, and amplified products were visualized by electrophoresis and sequenced. RESULTS The proband was heterozygous for the novel mutation c.1402G-->A (predicted G468S) in exon 7 of the ferroportin gene (SLC40A1). Located in the last nucleotide before the splice junction, this mutation results in aberrant splicing to a cryptic upstream splice site located at nt 990 within the same exon. This causes truncation of ferroportin after glycine 330 and the addition of 4 irrelevant amino acids before terminating. The truncated ferroportin protein, missing its C-terminal 241 amino acids, would lack all structural motifs beyond transmembrane region 7. The patient was also heterozygous for the common HFE H63D polymorphism, but did not have coding region mutations in TFR2, HAMP, or HFE2. CONCLUSIONS We conclude that this patient represents a unique example of hemochromatosis due to a single base-pair mutation of SLC40A1 that results in aberrant splicing and truncation of ferroportin.
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Affiliation(s)
- Pauline L Lee
- Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, Calif, USA
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Hayashi H, Wakusawa S, Yano M, Okada T. Genetic background of Japanese patients with adult-onset storage diseases in the liver. Hepatol Res 2007; 37:777-83. [PMID: 17517077 DOI: 10.1111/j.1872-034x.2007.00114.x] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
In contrast to primary lysosomal diseases in young subjects, adult-onset liver storage disorders may be explained by non-lysosomal genetic defects. The aim of the present review is to summarize the genetic backgrounds of Japanese patients with hemochromatosis of unknown etiology, Wilson disease of primary copper toxicosis, and the black liver of Dubin-Johnson syndrome. Three patients with middle-age onset hemochromatosis were homozygous for mutations of HJV and two patients were homozygous for mutations of TFR2. Minor genes other than HJV and TFR2 might be involved in Japanese patients. Five of the six patients with Wilson disease were compound heterozygous, while the remaining patient was heterozygous for the mutation in ATP7B responsible for copper toxicosis. Involvement of MURR1 was not proved in the heterozygote of ATP7B. Because of ferroxidase deficiency,most patients had secondary lysosomes shared by cuprothioneins and iron complex. Six patients with Dubin-Johnson syndrome were homozygous or compound heterozygous for mutant MRP2. Despite complex metabolic disorders, the syndrome had a single genetic background. Thus, most patients with adult-onset lysosomal proliferation in the liver had genetic defects in non-lysosomal organelles, named the secondary lysosomal diseases. The proliferating lysosomes in these conditions seemed to be heterogeneous in their matrices.
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Affiliation(s)
- Hisao Hayashi
- Department of Medicine, Asanogawa General Hospital, Kanazawa, Japan
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40
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Tafe LJ, Belloni DR, Tsongalis GJ. Detection of the C282Y and H63D Polymorphisms Associated With Hereditary Hemochromatosis Using the ABI 7500 FAST Real Time PCR Platform. ACTA ACUST UNITED AC 2007; 16:112-5. [PMID: 17525682 DOI: 10.1097/pdm.0b013e3180310489] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Classic hereditary hemochromatosis is an autosomal recessive disorder characterized by iron overload and sequence variants in the HFE gene. The HFE gene is located at 6p21.3 and contains 2 common single nucleotide polymorphisms (SNPs) C282Y and H63D, which are routinely tested for in the molecular diagnostics laboratory. In this study, we used DNA samples from 59 patients in which clinicians wanted to confirm or rule-out hereditary hemochromatosis that had been previously tested for the HFE SNPs using a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay and the ABI 7700 real time PCR assay with a MGB Eclipse ASR Probe system. The new assay used TAQman SNP Genotyping Assays, which were performed on the ABI 7500 FAST real time PCR platform. Allelic discrimination was determined during a postamplification plate read. Of the 59 samples genotyped, 7 were homozygous for C282Y, 6 were heterozygous for C282Y, 9 were homozygous for H63D, 10 were heterozygous for H63D, 6 were compound heterozygotes, and 20 were wild type. With the exception of one sample that was indeterminate by the TAQman SNP Genotyping Assay, all others showed 100% concordance between the 3 assays. The one indeterminate sample was heterozygous for C282Y by the PCR-RFLP and ABI 7700 real time PCR assays, but there was an insufficient quantity of DNA to perform the TAQman SNP Genotyping Assay. Our study suggests that the ABI 7500 FAST TAQman SNP Genotyping Assay is comparable with the PCR-RFLP and ABI 7700 real time PCR methods in detecting and characterizing these 2 HFE SNPs. Improved software and thermocycling capabilities have resulted in a very robust TAQman assay with the advantage of a much improved turn-around-time and throughput.
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Affiliation(s)
- Laura J Tafe
- Department of Pathology, Dartmouth Medical School, Dartmouth-Hitchcock Medical Center, Lebanon, NH 03756, USA
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41
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Walsh A, Dixon JL, Ramm GA, Hewett DG, Lincoln DJ, Anderson GJ, Subramaniam VN, Dodemaide J, Cavanaugh JA, Bassett ML, Powell LW. The clinical relevance of compound heterozygosity for the C282Y and H63D substitutions in hemochromatosis. Clin Gastroenterol Hepatol 2006; 4:1403-10. [PMID: 16979952 DOI: 10.1016/j.cgh.2006.07.009] [Citation(s) in RCA: 74] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Two major mutations are defined within the hemochromatosis gene, HFE. Although the effects of the C282Y substitution have been well characterized, the clinical significance of the C282Y/H63D state remains unclear. This study assessed the phenotypic expression in C282Y/H63D subjects as compared with C282Y homozygotes. METHODS Data were obtained from 91 C282Y/H63D probands, 158 C282Y/H63D subjects identified through family screening, and 483 C282Y homozygotes. Subjects underwent clinical evaluation, genotyping, biochemical assessment, and liver biopsy examination where clinically indicated. RESULTS C282Y/H63D probands had significantly less clinical and biochemical expression than C282Y homozygotes. Biochemical expression was higher in C282Y/H63D probands than in C282Y/H63D subjects identified through family screening (P < .001). Of the C282Y/H63D subjects with serum ferritin levels greater than 1000 mug/L, all had known comorbid factors that could have contributed to the increased ferritin level. Of the 51 C282Y/H63D subjects who underwent liver biopsy examination, significantly increased iron stores were present in 9 subjects and hepatic fibrosis was present in 13. Twelve of the 13 had evidence of hepatic steatosis, excess alcohol consumption, or diabetes. The mobilizable iron level was significantly higher in C282Y homozygous males than in compound heterozygous males (P < .001). Genetic screening of C282Y/H63D first-degree relatives detected 5 C282Y homozygotes. CONCLUSIONS C282Y/H63D subjects referred for assessment had a high prevalence of increased iron indices but did not develop progressive clinical disease without comorbid factors such as steatosis, diabetes, or excess alcohol consumption. When fibrosis was seen, 1 or more comorbid factors almost always were present. Thus, phlebotomy therapy is warranted and cascade screening of relatives should be performed because expressing C282Y homozygotes may be detected.
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Affiliation(s)
- Alissa Walsh
- The Department of Gastroenterology & Hepatology, Royal Brisbane & Women's Hospital, Brisbane, Australia
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Hoppe C, Watson RM, Long CM, Lorey F, Robles L, Klitz W, Styles L, Vichinsky E. Prevalence of HFE mutations in California newborns. Pediatr Hematol Oncol 2006; 23:507-16. [PMID: 16849282 DOI: 10.1080/08880010600751918] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Advances in molecular diagnostics have led to an increased interest in expanding population-based screening to include genetic diseases that occur outside the newborn period. Hereditary hemochromatosis may be a candidate for large-scale screening in populations with a high prevalence of the common HFE mutations. To determine race-specific frequencies of the HFE mutations, C282Y and H63D, the authors applied an automated, high-throughput genotyping method to dried blood spot samples from a representative population of California newborns. In this sample of 3989 newborns, C282Y and H63D allele frequencies were highest in white (C282Y: 5.5 +/- 0.5%; H63D: 13.4 +/- 0.76%) and Hispanic (C282Y: 1.8 +/- 0.29%; H63D: 11.9 +/- 0.72%) newborns, and lowest in black (C282Y: 1.3 +/- 0.25%; H63D: 3.0 +/- 0.38%) and Asian (C282Y 0.5 +/- 0.16%; H63D 2.9 +/- 0.37%) newborns. The estimated prevalence of C282Y homozygotes in this multiracial population is 1.4/1000. As additional genetic and environmental risk factors for HHC are identified, neonatal screening may become an acceptable strategy to follow susceptible individuals and prevent clinical disease.
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Affiliation(s)
- Carolyn Hoppe
- Department of Hematology/Oncology, Children's Hospital and Research Center at Oakland, Oakland, California 94609, USA.
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Abstract
A number of genetic disorders can result in the accumulation of excess iron in the body. These causes of hereditary hemochromatosis include defects in genes encoding HFE, transferrin receptor 2, ferroportin, hepcidin, and hemojuvelin. Hepcidin, with its cognate receptor, ferroportin, has emerged as a central regulator of iron homeostasis; all of the known causes of hemochromatosis appear to prevent this system from functioning normally. The most common form of primary hemochromatosis is that caused by C282Y mutation of the HFE gene. This mutation is most prevalent among Northern Europeans. Although the frequency of the homozygous genotype is approximately 5 per 1000, the disease itself is quite rare because the clinical penetrance of the genotype is very low.
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Affiliation(s)
- Ernest Beutler
- Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California 92037, USA.
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44
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Yen AW, Fancher TL, Bowlus CL. Revisiting hereditary hemochromatosis: current concepts and progress. Am J Med 2006; 119:391-9. [PMID: 16651049 DOI: 10.1016/j.amjmed.2005.10.041] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/17/2005] [Revised: 10/22/2005] [Accepted: 10/22/2005] [Indexed: 12/14/2022]
Abstract
Originally regarded as a rare affliction notable for its distinctive evolution to "bronze diabetes," hereditary hemochromatosis is now recognized as the most common genetic disorder in populations of European ancestry. Recent advances in our understanding of iron metabolism, the identification of the gene responsible for hemochromatosis, and large epidemiologic studies have changed the diagnostic approach toward patients with hereditary hemochromatosis and other forms of iron overload. This article reviews the pathophysiology, epidemiology, clinical features, diagnostic testing, and management of hemochromatosis for the primary care provider.
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Affiliation(s)
- Andrew W Yen
- University of California, Davis Medical Center, Department of Internal Medicine, Sacramento, Calif 95817, USA.
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45
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Khusainova RI, Khusnutdinova NN, Khusnutdinova EK. Analysis of the hemochromatosis gene (HFE) mutations, C282Y and H63D, in the populations of Central Asia. RUSS J GENET+ 2006. [DOI: 10.1134/s102279540603015x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
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Gunel-Ozcan A, Alyılmaz-Bekmez S, Guler EN, Guc D. HFE H63D mutation frequency shows an increase in Turkish women with breast cancer. BMC Cancer 2006; 6:37. [PMID: 16503999 PMCID: PMC1402308 DOI: 10.1186/1471-2407-6-37] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2005] [Accepted: 02/19/2006] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND The hereditary hemochromatosis gene HFE plays a pivotal role in iron homeostasis. The association between cancer and HFE hetero- or homozygosity has previously been shown including hepatocellular and nonhepatocellular malignancies. This study was performed to compare frequencies of HFE C282Y and H63D variants in Turkish women with breast cancer and healthy controls. METHODS Archived DNA samples of Hacettepe University Oncology Institute were used in this study. The HFE gene was investigated by PCR-RFLP. RESULTS All subjects studied were free from C282Y mutation. Thirty-nine patients had H63D mutation and were all heterozygous. H63D allele frequency was 22.2% (39/176) in the breast cancer patients, and 14% (28/200) in the healthy volunteers. Statistical analysis of cases with HFE H63D phenotype showed significant difference between breast cancer and healthy volunteers (P = 0.02). CONCLUSION Our results suggest that HFE H63D mutation frequencies were increased in the breast cancer patients in comparison to those in the general population. Also, odds ratios (odds ratio = 2.05) computed in this study suggest that H63D has a positive association with breast cancer.
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Affiliation(s)
- Aysen Gunel-Ozcan
- Kirikkale University School of Medicine, Department of Medical Biology and Genetics, Kirikkale, Turkey
| | - Sibel Alyılmaz-Bekmez
- Kirikkale University School of Medicine, Department of Medical Biology and Genetics, Kirikkale, Turkey
| | - Emine Nilufer Guler
- Hacettepe University, Oncology Institute, Medical Oncology Department, Ankara, Turkey
| | - Dicle Guc
- Hacettepe University, Oncology Institute, Basic Oncology Department, Ankara, Turkey
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Lee PL, Barton JC. Hemochromatosis and severe iron overload associated with compound heterozygosity for TFR2 R455Q and two novel mutations TFR2 R396X and G792R. Acta Haematol 2006; 115:102-5. [PMID: 16424658 DOI: 10.1159/000089474] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2005] [Accepted: 04/25/2005] [Indexed: 01/08/2023]
Abstract
We report three mutations of transferrin receptor 2 (TFR2)--R396X (exon 9; nt 1186C-->T), R455Q (exon 10; nt 1364G-->A) and G792R (exon 18; nt 2374G-->A)--in a man of Scottish descent with hemochromatosis and severe iron overload. He was also heterozygous for the common HFE H63D polymorphism. The patient did not have coding region mutations in HAMP, FPN1, HJV or ALAS2. We conclude that this patient represents another example of hemochromatosis due to mutations of the gene encoding transferrin receptor 2.
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Affiliation(s)
- Pauline L Lee
- Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California, USA
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Abstract
Genetic variation is known to affect food tolerances among human subpopulations and may also influence dietary requirements, giving rise to the new field of nutritional genomics and raising the possibility of individualizing nutritional intake for optimal health and disease prevention on the basis of an individual's genome. However, because gene-diet interactions are complex and poorly understood, the use of genomic knowledge to adjust population-based dietary recommendations is not without risk. Whereas current recommendations target most of the population to prevent nutritional deficiencies, inclusion of genomic criteria may indicate subpopulations that may incur differential benefit or risk from generalized recommendations and fortification policies. Current efforts to identify gene alleles that affect nutrient utilization have been enhanced by the identification of genetic variations that have expanded as a consequence of selection under extreme conditions. Identification of genetic variation that arose as a consequence of diet as a selective pressure helps to identify gene alleles that affect nutrient utilization. Understanding the molecular mechanisms underlying gene-nutrient interactions and their modification by genetic variation is expected to result in dietary recommendations and nutritional interventions that optimize individual health.
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Affiliation(s)
- Patrick J Stover
- Division of Nutritional Sciences, Cornell University, Ithaca NY 14853, USA.
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Potekhina ES, Lavrov AV, Samokhodskaya LM, Efimenko AY, Balatskiy AV, Baev AA, Litvinova MM, Nikitina LA, Shipulin GA, Bochkov NP, Tkachuk VA, Bochkov VN. Unique genetic profile of hereditary hemochromatosis in Russians: high frequency of C282Y mutation in population, but not in patients. Blood Cells Mol Dis 2006; 35:182-8. [PMID: 16055358 DOI: 10.1016/j.bcmd.2005.06.012] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2005] [Revised: 06/30/2005] [Accepted: 06/30/2005] [Indexed: 11/27/2022]
Abstract
Hereditary hemochromatosis (HH) is a common cause of primary iron overload induced by genetic impairment of iron metabolism. More than 80% of HH patients in populations of European origin are homozygotes for a single mutation C282Y, or compound heterozygotes for C282Y and H63D mutations in the HFE gene. However, in the majority of Asian, African, Australasian, and Amerindian populations, frequencies of C282Y are close to zero. Data on the prevalence of HFE mutations in Russian population and in Russian patients with HH are very limited. In this work, we determined frequencies of C282Y and H63D in ethnical Russians living in the Central European region of Russia. Furthermore, we tested whether homozygocity for C282Y is the major cause of HH in Russians. We found that, in the Russian population, the frequency of C282Y mutation in the HFE gene is relatively high and corresponds to mean European levels. However, in contrast to the majority of European populations, homozygocity for C282Y is found only in a small proportion (5%) of patients with biochemical and clinical signs of HH. These data suggest that either the penetrance of C282Y in Russia is lower than in Western countries, or that a more frequent non-HFE dependent mechanism of primary iron overload dominates in Russian population.
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50
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Barton JC, Acton RT, Dawkins FW, Adams PC, Lovato L, Leiendecker-Foster C, McLaren CE, Reboussin DM, Speechley MR, Gordeuk VR, McLaren GD, Sholinsky P, Harris EL. Initial screening transferrin saturation values, serum ferritin concentrations, and HFE genotypes in whites and blacks in the Hemochromatosis and Iron Overload Screening Study. ACTA ACUST UNITED AC 2006; 9:231-41. [PMID: 16225403 DOI: 10.1089/gte.2005.9.231] [Citation(s) in RCA: 54] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
We compared initial screening data of 44,082 white and 27,124 black Hemochromatosis and Iron Overload Screening (HEIRS) Study participants. Each underwent serum transferrin saturation (TfSat) and ferritin (SF) measurements without regard to fasting, and HFE C282Y and H63D genotyping. Elevated measurements were defined as: TfSat more than 50% (men), more than 45% (women); and SF more than 300 ng/ml (men), more than 200 ng/ml (women). Mean TfSat and percentages of participants with elevated TfSat were significantly greater in whites than in blacks. Mean SF and percentages of participants with elevated SF were significantly greater in blacks than in whites. TfSat and SF varied by gender and age in whites and blacks. Prevalences of genotypes that included either C282Y or H63D were significantly greater in whites than in blacks. The prevalence of elevated TfSat and SF plus genotypes C282Y/C282Y, C282Y/H63D, or H63D/H63D was 0.006 in whites and 0.0003 in blacks. Among whites with HFE C282Y homozygosity, 76.8% of men and 46.9% of women had elevated TfSat and SF values. Three black participants had HFE C282Y homozygosity; one had elevated TfSat and SF values. Possible explanations for differences in TfSat and SF in whites and blacks and pertinence to the detection of hemochromatosis, iron overload, and other disorders with similar phenotypes are discussed.
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Affiliation(s)
- James C Barton
- Southern Iron Disorders Center, Birmingham, Alabama 35209, USA.
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