HH DNA related topics, HFE testing, results, carriers, etc.  
Click on the titles to get to the abstracts/articles, etc..

***Located at the bottom of the page are links to articles on HH withOUT the known HFE mutations as well as genetic discrimination issues.

Click here for a list of labs that offer DNA testing by PCR for adults/children for hereditary hemochromatosis. 
[U.S. & Canada only are listed here]

• A battery-powered notebook thermal cycler for rapid multiplex real-time PCR analysis
  Anal Chem 2001 Jan A compact, real-time PCR instrument was developed for rapid, multiplex analysis of nucleic acids in an inexpensive, portable format

• A genotypic study of 217 unrelated probands diagnosed as "genetic hemochromatosis" on "classical" phenotypic criteria. J Hepatol. 1999 Apr The HFE gene is a crucial candidate gene for hemochromatosis. The aims of this study were to assess the HFE genotypic profile in a large series of unrelated probands diagnosed as having phenotypic hemochromatosis, to characterize the sub-group of patients who were not homozygous for the major C282Y mutation, and to report the iron status of the detected HFE-identical siblings.

• A  high prevalence of HLA-H 845A mutations in hemochromatosis patients and the normal population in eastern England. Blood Cells Mol Dis 1997 Aug; We found a gene frequency in 200 normal subjects for teh 845A (C282Y) allele of 0.085, corresponding to a carrier frequency of 17% which is among the highest reported anywhere in the world.  This population will be an excellent model for studies on the penetrance of the 845A homozygous genotype and population screening.

• A middle aged man with diabetes mellitus and a liver mass.  Steven Eliason, M.D., Elizabeth M. Brunt, M.D., Bruce R. Bacon, M.D., Leonard E. Grosso, M.D., Ph.D.  SLUCARE PathLab Case of the Month  

• A mutation in SLC11A3 is associated with autosomal dominant hemochromatosis
  Nat Genet 2001 Jul;28(3):213-4

• Analysis of the HFE gene in a large Spanish kindred with hereditary hemochromatosis Med Clin (Barc). 2001 Jan 27  [Article in Spanish] Analysis of the HFE gene in the members of a large Spanish kindred, living in the same geographical area, shows that only those homozygous for the C282Y mutation develop hemochromatosis.

• A new syndrome of liver iron overload with normal transferrin saturation. Lancet. 1997 Jan 11 We have found a new non-HLA-linked iron-overload syndrome which suggests a link between iron excess and metabolic disorders. The current diagnostic criteria for genetic haemochromatosis should be reviewed.

• An improved real time PCR method for simultaneous detection of C282Y and H63D mutations in the HFE gene associated with hereditary hemochromatosis Mutat Res 2001 Jan

• Annals of Internal Medicine SUPPLEMENT DIAGNOSIS AND MANAGEMENT 
  Diagnosis of Hemochromatosis, Annals of Internal Medicine, 1 December 1998. 129:925-931.Lawrie W. Powell, MD; D. Keith George, MD; Sharon M. McDonnell, MD; and Kris V. Kowdley, MD

• An unusual melting curve profile in LightCycler multiplex genotyping of the hemochromatosis H63D/C282Y gene mutations Clin Biochem 2001 Sep

• A population based study of the clinical expression of the clinical expression of the Hemochromatosis gene NEJM Sept 1999  Our findings have implications for population screening for hereditary hemochromatosis. [a pdf file]

• A previously undescribed nonsense mutation of the HFE gene. Clin Genet 2002 Jan 61:40-42. Beutler E, Griffin M, Gelbart T, and West C  The Scripps Research Institute, Department of Molecular and Experimental Medicine, Division of Hematology, La Jolla, CA, USA; Maine General Medical Center, Waterville ME, USA.  A patient with clinically manifest hereditary hemochromatosis was found to be heterozygous for the c.845 A-->G (C282Y) mutation.  As simple heterozygotes for this mutation do not develop the hemochromatosis phenotype, the coding region of the patient's HFE gene was sequenced and a previously undescribed nonsense mutation was identified at c.211 C-->T (R74X).

• A prospective study of coronary heart disease and the hemochromatosis gene (HFE) C282Y mutation: the Atherosclerosis Risk in Communities (ARIC) study.  Atherosclerosis 2001 Feb 15 Our prospective findings suggest that individuals carrying the HFE C282Y mutation may be at increased risk of CHD.

• A rapid PCR-SSP assay for the hemochromatosis-associated Tyr250Stop mutation in the TFR2 gene,
  Genet Test 2001 Summer

• Are hereditary hemochromatosis mutations involved in Alzheimer disease?  
  The possibility that HFE mutations are important new genetic risk factors for AD should be pursued further. Am J Med Genet 2000 Jul

• Are the hemochromatosis (HFE) gene mutation and hepatitis C virus (HCV) infection risk factors for porphyria cutanea tarda? Orv Hetil 2000 Sep 10 HCV infection and HFE C282Y mutations may probably be independent predisposing factors for development of PCT in Hungarian patients.

• Arthropathy in hereditary hemochromatosis  Curr Opin Rheumatol 2001 Jan; Arthropathy is one of the leading clinical manifestations of hereditary hemochromatosis (HH). Although cirrhosis of the liver is crucial for mortality in patients with HH, arthropathy has the greatest impact on the quality of life

• A simple genetic test identifies 90% of UK patients with haemochromatosis. 
  The UK Haemochromatosis Consortium Gut 1997 Dec;41(6):841-4

• Association of mutations in the hemochromatosis gene with shorter life expectancy.
  Arch Intern Med. 2001 Nov 12  In a high-carrier frequency population like Denmark, mutations in HFE show an age-related reduction in the frequency of heterozygotes for C282Y, which suggests that carrier status is associated with shorter life expectancy.

• Asymptomatic hemochromatosis subjects: genotypic and phenotypic profiles 
  Blood, 1 December 2000, Vol. 96, No. 12, pp. 3707-3711;  Ronald L. Sham, Richard F. Raubertas, Caroline Braggins, Joseph Cappuccio, Margaret Gallagher, and Pradyumna D. Phatak;  From the Department of Medicine, Rochester General Hospital, the Mary M. Gooley Hemophilia Center Inc, and The University of Rochester School of Medicine and Dentistry, Rochester, NY; and The Centers for Disease Control and Prevention, Atlanta GA.  Our study demonstrates that TS screening will identify many individuals with only modest degrees of iron loading who may not meet traditional phenotypic diagnostic criteria but who have genotypes associated with iron loading. Those with lower degrees of iron overload are less likely to be C282Y homozygotes. 

• Autosomal-dominant hemochromatosis is associated with a mutation in the ferroportin (SLC11A3) gene.   J Clin Invest, August 2001  We propose that partial loss of ferroportin function leads to an imbalance in iron distribution and a consequent increase in tissue iron accumulation. [full article]

• Barton Book excerpt: The role of the C282Y mutation in hemochromatosis pg. 46-47 
  Excerpt from this Chapter regarding their findings.

• Biochemical and Genetic Markers of Iron Status and the Risk of Coronary Artery Disease: An Angiography-based Study.   Clin Chem 2002 Apr;48(4):622-8   Bozzini C, Girelli D, Tinazzi E, Olivieri O, Stranieri C, Bassi A, Trabetti E, Faccini G, Pignatti PF, Corrocher R.    Department of Clinical and Experimental Medicine, Department of Mother and Child, Biology and Genetics, and. the Institute of Clinical Chemistry, University of Verona, 37134 Verona, Italy.    CONCLUSIONS: Our results do not support a role for biochemical or genetic markers of iron stores as predictors of the risk of CAD or its thrombotic complications.

• Biochemical expression of heterozygous hereditary hemochromatosis.
   Eur J Intern Med 2000 Dec 20 C282Y heterozygotes seem to be an intermediate group between compound heterozygotes and the normal population

• Bio-Rad Laboratories Hereditary Hemochromatosis Reagents

• C282Y and H63D mutation frequencies in a population from central Spain.  
  Dis Markers 2001

• C282Y and H63D mutations of HFE gene in patients with advanced alcoholic liver disease. 
  Rev Esp Enferm Dig 2001 Mar  Our results suggest that H63D mutation of the HFE gene, but not the C282Y mutation, is associated to the risk of developing advanced liver alcoholic disease.

• C282Y and H63D mutations of the haemochromatosis gene in patients with iron overload
  Rev Esp Enferm Dig 2001 [a pdf file]

• C282Y and H63D mutation of the hemochromatosis gene in German porphyria cutanea tarda patients.
  Virchows Arch. 2001 Jul CONCLUSIONS: The high frequency of homo- and heterozygosity for the C282Y and H63D alleles strongly suggests that these mutations are important predisposing factors for PCT in German patients.
  
• Classification and diagnosis of iron overload   Haematologica 1998 May The recent description of new conditions associated with iron overload and the identification of the genetic defect of hereditary hemochromatosis prompted us to review this subject and to redefine the diagnostic criteria of iron overload disorders.

• Clinical and genetic aspects of hereditary hemochromatosis
  Pathologe 2001 May. As laboratory parameters for measuring HH lack specificity, and HH remains asymptomatic for a long time, methods for genetic screening are highly valuable.

• Clinical and genetic heterogeneity in hereditary haemochromatosis: association between lymphocyte counts and expression of iron overload.  These results suggest that a lower peripheral blood lymphocyte count is associated with a greater degree of iron loading in HFE haemochromatosis but not in African iron overload, and they support the notion that the lymphocyte count may serve as a marker of a non-HFE gene that influences the clinical expression of HFE haemochromatosis. Eur J Haematol 2001 Aug

• Clinical aspects of hemochromatosis. Transfus Sci. 2000 Dec Brissot P, Guyader D, Loreal O, Laine F, Guillygomarc'h A, Moirand R, Deugnier Y. The diagnosis can, from now on, be ascertained on the sole association of a plasma transferrin saturation (TS) over 45% and homozygosity for the C282Y mutation. Liver biopsy is only required to search for cirrhosis whenever there is hepatomegaly and/or serum ferritin >1000 ng/ml and/or elevated serum AST.

• Clinical Consequences of New Insights in the Pathophysiology of Disorders of Iron and Heme Metabolism Hematology 2000  The American Society of Hematology The screening strategy could be based on the assessment of serum transferrin saturation in adults aged 18 or more. Genetic testing testing for C282Y would be confined to individuals with transferrin saturation > 45%. This strategy would then avoid the ethical, logistical, and financial problems raised by systematic genetic testing as well as the societal impact of discovering a genetic mutation in asymptomatic persons without a disease. It is, in fact, essential that major changes occur in the attitudes towards unexpressed or slightly expressed HFE homozygosity, especially by insurers and health care administrators, to avoid any adverse genetic discrimination.

• Clinical management of iron overload. Gastroenterol Clin North Am. 1998 Sep HHC is a common inherited disorder, characterized by iron accumulation in the liver, heart, pancreas, and other organs. The clinical consequences of systemic iron loading are diverse and not always improved with iron reduction therapy.

• Clinical Studies of Haemochromatosis  Queensland Institute of Medical  Research, Hepatocellular Cancer Laboratory, Professor Lawrie Powell   Knowledge of haemochromatosis, its prevention, the type and severity of symptoms it causes, the availability and nature of treatment, ability of sufferers to participate in normal activities, and longevity are relevant issues for community education. Members of an informed public can mobilise support for the early diagnosis of haemochromatosis, encourage people to be tested for the disorder and influence the debate about screening.
   
• Co-inheritance of mutations in the uroporphyrinogen decarboxylase and hemochromatosis genes accelerates the onset of porphyria cutanea tarda Homozygosity for the C282Y hemochromatosis mutation was associated with an earlier onset of skin lesions in both familial and sporadic porphyria cutanea tarda. J Invest Dermatol 2000 Nov

• Compound heterozygosity for haemochromatosis gene mutations and hepatic iron overload in allogeneic bone marrow transplant recipients.  Pathology 2001 Feb; Iron overload has been proposed as a cause of liver dysfunction after BMT Factors which could be relevant to iron overload include the number of red cell transfusions and mutations within the haemochromatosis gene (HFE).

• Contribution of different HFE genotypes to iron overload disease: a pooled analysis. Genet Med 2000 Oct,  C282Y homozygosity confers the highest risk for iron overload but the H63D mutation is also associated with increased risk.

• Controversy in primary care BMJ 2000;320:1314-1317 ( 13 May )    Should asymptomatic haemochromatosis be treated?  Treatment can be onerous for patient and doctor  Commentary: False certainty of clinical guidance  Commentary: Early treatment is essential
 
• Co-selection of the H63D mutation and the HLA-A29 allele: a new paradigm of linkage disequilibrium? Immunogenetics 2002 Mar 53:1002-8 Cardoso CS, Alves H, Mascarenhas M, Goncalves R, Oliveira P, Rodrigues P, Cruz E, de Sousa M, and Porto G The results reveal significant linkage disequilibrium between the H63D mutation and all HLA-A29-containing haplotypes, favoring the hypothesis of a co-selection of H63D and the HLA-A29 allele itself. An insight into the biological significance of this association is given by the finding of significantly higher CD8(+) T-lymphocyte counts in subjects simultaneously carrying the H63D mutation and the HLA-A29 allele.

• Detection of an unusual combination of mutations in the HFE gene for hemochromatosis. Genet Test 2000 In the present paper, we describe an individual, found as part of a screening study, being homozygous for the C282Y mutation and at the same time heterozygous for the H63D mutation in the HFE gene

• Diagnostic Testing Fails the Test   The pitfalls of patents are illustrated by the case of  Hemochromatosis. Article which discusses the cost issues of genetic testing & patents. Feb. 2002  www.nature.com  [a pdf file]

• Diagnosis and management of hemochromatosis
  by Dr. Anthony Tavill, Director of the Maurice and Sadie Friedman Center For Digestive Diseases and Liver Disorders, Mathile and Morton J. Stone Professor of Digestive Diseases and Liver Disorders at the Mt. Sinai Medical Center, Professor of Medicine and Nutrition at Case Wetern Reserve University. [Excellent & thorough article of diagnosis & treatment.  This is a pdf file] 

• Diagnosis and treatment of genetic hemochromatosis Rev Prat. 2000 May 1 [Article in French]
  Moirand R, Guillygomarc'h A, Brissot P, Deugnier Y. The disease can be lethal due to liver disease, carcinoma or heart disease, but life expectancy goes to normal if patients are treated before the occurrence of cirrhosis. Treatment relies on regular venesections. Familial screening is essential.

• Differential HFE allele expression in hemochromatosis heterozygotes
  Gastroenterology 2000 Oct We demonstrate the existence of differential allelic expression of the HFE alleles, suggesting that the (187C > G; H63D) mutation plays a role in the disease expression in H63D heterozygotes, in particular when associated with environmental or host factors.

• Disease-Related Conditions in Relatives of Patients with Hemochromatosis
  Zaneta J. Bulaj, M.D., Richard S. Ajioka, Ph.D., John D. Phillips, Ph.D., Bernard A. LaSalle, B.S., Lynn B. Jorde, Ph.D., Linda M. Griffen, B.A., Corwin Q. Edwards, M.D., and James P. Kushner, M.D.  Volume 343:1529-1535  November 23, 2000  Number 21  In conclusion, our data emphasize the importance of screening relatives of persons with hemochromatosis.

• DNA testing for haemochromatosis: diagnostic, predictive and screening implications.
  Pathology 2000 Nov The range of DNA testing available includes: (1) diagnostic, (2) predictive (also called presymptomatic testing) and (3) screening.

• Effect of hemochromatosis genotype and lifestyle factors on iron and red cell indices in a community population Clin Chem 2001 Feb; There was a significant increase in ferritin concentrations in both genders with increasing frequency of red meat consumption above a baseline of 1-2 times per week and alcohol intakes >10 g/day.

• Effects of HFE C282Y and H63D Polymorphisms and Polygenic Background on Iron Stores in a Large Community Sample of Twins Am. J. Hum. Genet., 66:1246-1258, 2000 These studies and the present study show that HFE polymorphisms affect iron stores even among heterozygotes but that ferritin is less affected than is transferrin saturation.

• End-stage liver disease without hemochromatosis associated with elevated hepatic iron index. 
  J Hepatol. 1998 Aug;29 Cotler SJ, Bronner MP, Press RD, Carlson TH, Perkins JD, Emond MJ, Kowdley KV.  Department of Medicine, University of Washington, Seattle, USA. (i) Serum transferrin saturation and hepatic iron index lack specificity for hereditary hemochromatosis in end-stage liver disease. (ii) Genotyping for Cys 282 Tyr may provide the best method to identify hereditary hemochromatosis in the setting of end-stage liver disease.

• Exploring Genetics Big Breakthroughs
  St. Louis University   Dr. William Sly makes discoveries that change medicine

• Evaluation and interpretation of iron in the liver  Semin Diagn Pathol 1998 Nov  Because homozygosity for the C282Y mutation is diagnostic of the condition regardless of the liver iron concentration-to-age ratio, indication for liver biopsy in C282Y homozygotes is restricted to the assessment of prognostic lesions, such as fibrosis and iron-free-foci.

• Familial porphyria cutanea tarda: characterization of seven novel uroporphyrinogen decarboxylase mutations and frequency of common hemochromatosis alleles.  Am J Hum Genet. 1998 Nov Screening of nine f-PCT probands revealed that 44% were heterozygous or homozygous for the common hemochromatosis mutations, which suggests that iron overload may predispose to clinical expression.

• Frequency analysis and allele map in favor of the celtic origin of the c282y mutation of hemochromatosis.
  Blood Cells Mol Dis 2001 Mar-Apr

• Frequency and biochemical expression of C282Y/H63D hemochromatosis (HFE) gene mutations in the healthy adult population in Italy J Hepatol 2001 Apr No homozygotes for the C282Y mutation were found. Heterozygosity for the C282Y mutation was 3.1%, while heterozygosity and homozygosity for the H63D mutation were 21.5% and 2.5%, respectively.

• Genes that modify the hemochromatosis phenotype in mice
  J Clin Invest, May 2000, Volume 105, Number 9, 1209-1216

• Genetic Alliance Inc. 
  The Genetic Alliance is an international coalition representing more than 300 consumer and health professional organizations with millions of members--all working together to promote healthy lives for everyone impacted by genetics.

• Genetic Discrimination Bills,  Genetic Discrimination Legislation State-by-State, AMA

• Genetic epidemiology and HLA survey of primary hemochromatosis among Chinese Miao ethnic  Zhonghua Nei Ke Za Zhi 2001 Oct  HLA haplotype shows obvious deviation from random distribution, which indicates that there exists linkage between HH pathogenic gene and HLA. The results of genetic analysis in this disease group suggest that hemochromatosis is an autosomal dominant inheritance but not autosomal recessive inheritance disease.

• Genetic Haemochromatosis:   A guideline on Diagnosis & Therapy compiled on behalf of the Clinical Task Force of the  British Committee for Standards in Haemotology  2/2000 [a pdf file]

• Genetic Health-What Is Hemochromatosis?
   By Amanda Ewart Toland, PhD  Reviewed by Chris Friedrich, MD, PhD Last updated September 1, 2000

• Genetic hemochromatosis and the HFE gene: from molecular genetics to clinical diagnosis   
  Z Gastroenterol 2000 Jun   More than 90% of patients with genetic hemochromatosis carry a characteristic mutation in the HFE-gene (C282Y) Heterozygosity for the C282Y mutation appears to alter the course of other liver diseases like porphyria cutanea tarda and nonalcoholic steatohepatitis.

• Genetic hemochromatosis is a rare disease entity among French Basques: a center-based study from the General Hospital of Basque Country  Abstract Volume 80 Issue 8 (2001)

• Genetic hemochromatosis, a Celtic disease: is it now time for population screening?
  Genet Test 2001 Summer

• Genetic liver disease in adults. Early recognition of the three most common causes.  Morrison ED, Kowdley KV.  Genetic testing is probably most helpful in HHC because of the high frequency of the homozygous C282Y mutation among patients of northern European descent and the relatively high penetrance of the mutation with regard to clinical expression
   
• Genotypic/phenotypic correlations in genetic hemochromatosis: evolution of diagnostic criteria.
  Gastroenterology. 1998 Feb The sensitivity of the phenotypic tests in decreasing order was as follows: serum ferritin, hepatic iron index, transferrin saturation, and iron removed by venesection. Although the genetic test is useful in the diagnostic algorithm, this study has shown both iron-loaded patients without the mutation and homozygous patients without iron overload.

• Global prevalence of putative haemochromatosis mutations  
  Journal of Medical Genetics, 1997

• Haemochromatosis and HFE gene. Acta Gastroenterol Belg. 1999 Oct-Dec The practical management of haemochromatosis has been greatly modified, since liver biopsy is no more necessary for diagnosis in C282Y homozygotes, and is only needed for exclusion of cirrhosis. Family screening has also greatly benefited from genotyping.

• Haemochromatosis gene mutations in idiopathic dilated cardiomyopathy
  Heart 2000 Nov The frequency of the H63D mutation is significantly increased in patients with idiopathic dilated cardiomyopathy. As H63D has a relatively minor effect on iron status, the mechanism of this association may be unrelated to iron metabolism.

• Haemochromatosis: iron still matters. Intern Med J 2001 May-Jun Our ability to detect those predisposed to haemochromatosis is greatly enhanced by testing for HFE mutations. Although the precise definition of iron overload is debated, a diagnosis of haemochromatosis cannot be made without demonstrating increased body iron stores.

• Haemochromatosis: novel gene discovery and the molecular pathophysiology of iron metabolism. Hum Mol Genet 2000 Oct   The discovery of genes that determine heritable defects of iron absorption and regulation in animals and humans thus holds promise for a complete mechanistic understanding of the molecular pathophysiology of iron metabolism.

• Haplotype Analysis of the HFE Gene:  Implications for the Origins of Hemochromatosis Related Mutations  Blood Cells, Molecules and Diseases 1999 [a pdf file]

• Haptoglobin phenotype 2-2 overrepresentation in Cys282Tyr hemochromatotic patients. 
  J Hepatol 2001 Dec We hypothesized that the genetic haptoglobin (Hp) polymorphism, because of its effect on iron metabolism, could be a modifying factor that influences the clinical presentation of hereditary hemochromatosis.

• Hemochromatosis can now be appropriately defined as the presence of two hemochromatosis alleles with or without organ injury, and with or without the presence of iron overload. [I have not been able to retrieve the url to the website from where this came, so if anyone locates it, please let me know!]

• Hemochromatosis  Powell LW, Yapp TR  Clin Liver Dis 2000 Feb:  It is now apparent that iron, even in the modest tissue concentrations, can act as a co-factor in potentiating cell injury in other liver diseases.

• Hemochromatosis: A Common, Rarely Diagnosed Disease
  By Vincent J. Felitti, MD, FACP  Commentary by David Baer, MD, FACP.  Hemochromatosis is the most common, life-threatening genetic disorder in North America, yet most physicians have never personally diagnosed a case: all see an unrecognized case in their offices every two weeks.

• Hemochromatosis, A simple genetic trait,
  Dr. Richard D. Press, Oregon Health Sciences University With the discovery of the causative gene, the disorder stands revealed as America's single most common mendelian disease. Unlike other genetic diseases, it is already curable. Indeed, genetic screening makes it potentially preventable.

• Hemochromatosis: association of severity of iron overload with genetic markers.
  Blood Cells Mol Dis. 1996 Barton JC, Harmon L, Rivers C, Acton RT Our results support the hypothesis that the severity of iron overload in hemochromatosis is determined predominantly by genetic factors, and provide evidence that two or more mutations for hemochromatosis exist.

• Hemochromatosis at the intersection of classical medicine and molecular biology 
  C R Acad Sci III 2001 Sep Brissot P

• Hemochromatosis Clue 
  JAMA Vol. 286 No. 6, August 8, 2001 a new mutation in a gene called SLC11A3

• Hemochromatosis:  Conemaugh Health System   Hemochromatosis is a condition that develops when too much iron builds up in the body. Excess iron is stored in the organs, such as the kidneys, liver, and heart, and in the joint tissues.

• Hemochromatosis, Cooley Dickinson Hospital   Editor: George R Bowers MD CDH Oncology  January 2000 Volume 4: No. 1.   Hemochromatosis is a common, genetically transmitted disease. The diagnosis of hemochromatosis is sometimes difficult and frequently missed. This issue will review the pathogenesis, diagnosis and treatment of this fascinating disease. Ms. Kathy Fleming will review the management of a most troubling complication of therapy---lymphedema. 

• Hemochromatosis: diagnosis and management. Bacon BR.Gastroenterology 2001 Feb  HFE mutation analysis has strengthened our ability to diagnose HH accurately and is useful in family studies. HFE mutations may play a contributory role in some patients with PCT, NASH, or chronic HCV.

• Hemochromatosis gene HFE Cys282Tyr polymorphism is associated with two-fold increased risk at acute myocardial infarction in men.  Tuomainen T-P, Kontula K, Nyyssonen K, Lakka TA, Salonen JT. Circulation 1998;98 These data suggest that HFE gene Cys282Tyr substitution is an independent risk factor for AMI. This finding supports the assumption that increased body iron contributes to the development of AMI.

• Hemochromatosis genes and other factors contributing to the pathogenesis of porphyria cutanea tarda. Blood. 2000 Mar 1 Mutations at the HFE locus, HCV infection, excess alcohol intake, and exposure to estrogens all proved to be risk factors for the development of PCT. HFE mutations and HCV infection imparted the greatest relative risk, and the presence of multiple risk factors was more frequent than the presence of single risk factors.

• Hemochromatosis: genetics helps to define a multifactorial disease 
  Clin Genet, 54(1):1-9 1998 Jul University of Washington, Seattle 98105 wburke@u.washington.edu  Early detection is desirable, because periodic phlebotomy provides effective treatment for iron overload and may prevent complications of the disorder.

• Hemochromatosis:  Genetics, Pathophysiology, Diagnosis and Treatment, "Introduction to Hemochromatosis"  Part I,  by Barton & Edwards.  Except from their book, [a pdf file] This is a large & excellent book covering all areas of hemochromatosis.  Published in 2000, $215.00

• Hemochromatosis gene variants in three different ethnic populations: effects of admixture for screening programs Hum Biol 2001 Feb  Genetic testing for hemochromatosis may have important implications for diagnosis and screening of the disease.

• Hemochromatosis gene variants in patients with cardiomyopathy 
  Am J Cardiol 2001 Aug 15, HFE gene was associated with ischemic cardiomyopathy

• Hemochromatosis: HEPATOLOGY WATCH  
  Timely Information for Practicing Physicians.  Info. on their site includes the following topics:

  Elevated Hepatic Iron Index and End-stage Liver Disease
  Hemochromatosis Gene Mutations in Chronic HCV Patients
  Heterogeneity of Hemochromatosis in Italy
  HFE Gene Expression
  HFE Gene Mutations in Chronic Viral Hepatitis Patients
  HFE Genotyping
  Phenotypic Expression of HFE Mutations
  Population screening
  Screening for Hemochromatosis

• Hemochromatosis (HFE) gene sequence analysis of formalin-fixed, paraffin-embedded liver biopsy specimens. Mol Diagn 2001 Dec 6CONCLUSION: When HH is clinically and/or histologically suspected, HFE gene sequencing of formalin-fixed, paraffin-embedded liver biopsy specimens is a rapid and cost-effective approach to genotypic diagnosis of HH.
   
• HEMOCHROMATOSIS; HFE Mercier et al. (1997) urged strongly that the symbol HFE be used for the hemochromatosis gene rather than 'HLA-H' as used by Feder et al. (1996)

• Hemochromatosis in Ireland and HFE. Blood Cells Mol Dis. 1998  The allele frequency of 14% for the C282Y mutation in our control population is the highest reported and supports the hypothesis of a Celtic origin for the hereditary hemochromatosis gene.[pdf file]

• Hemochromatosis:  Life Extension Foundation website.  Disease, Prevention & Treatment 3rd editon.  Dietary & Vitamin recommendations listed here including calcium for blocking of iron absorption.

• Hemochromatosis mutations C282Y and H63D in 'cis' phase Clin Genet 2001 Jul

• Hemochromatosis Mutation Detection, Cys282Tyr and His63Asp  
  Guide to Clinical Laboratory Testing &  Interpretation of genetic testing. 

• Hemochromatosis Special  American Liver Foundation newsletter,  ALF Progress, Vol. 21 No. 1, Summer 1999 The ALF newsletter created three scenarios based on the real life ethical, economic and medical quandaries posed by hemochromatosis, and asked three experts from divergent fields to respond with their opinions. The experts are: Bruce R. Bacon, MD [Director, Div. of Gastroenterology & Hepatology, Saint Louis University School of Medicine, St. Louis, M0]; medical ethicist Mark A. Rothstein, Esq. [Director, University of Houston Law Center, Health Law & Policy Institute, Houston, TX] and hemachromatosis patient Gayle Hoffman.

• HEMOCHROMATOSIS, TYPE 2; HFE2 JUVENILE; JH OMIM entry

• HEMOCHROMATOSIS, TYPE 3;
  HFE3 is caused by mutations in the transferrin receptor-2 gene (TFR2) OMIM entry
          TRANSFERRIN RECEPTOR 2; TFR2 explanation

• HEMOCHROMATOSIS, TYPE 4; HFE4 is caused by mutation in the SLC11A3 gene OMIM entry

• Hepatitis C, Iron, and Hemochromatosis Gene Mutations  A Meaningful Relationship or Simple Cohabitation? Dale C. Snover, MD From the Departments of Pathology, Fairview Southdale Hospital, Edina, MN, and the University of Minnesota Medical School, Minneapolis, MN.  It would seem prudent to routinely perform iron stains for all patients with hepatitis C (a practice currently done in many laboratories on all liver biopsy specimens to rule out hemochromatosis) and to report iron by location of deposition (portal tract, hepatocyte, Kupffer cell) and by intensity.

• Hereditary Hemochromatosis and Cancer risk:  More fuel to the fire?  Gastroenterology Vol. 121, No. 5, November 2001  Pg. 1253 [a pdf file]  These data suggest an involvement of iron in carcinogenesis even in heterozygotes for HFE mutations. 

• Hereditary Haemochromatosis and Iron Metabolism, Carlson J, Olsson S, eJIFCC vol 13 no 2, THE JOURNAL OF THE INTERNATIONAL FEDERATION OF CLINICAL CHEMISTRY

• Hereditary Hemochromatosis--A Risk Factor for Cardiovascular Disease The HH mutation is a human genetic model of disturbed iron metabolism, which facilitates research to the mechanism of HH and iron involved in cardiovascular disease. We expect that in the near future, the mechanism of disturbed iron metabolism leading to cardiovascular disease in human will be better understood.

• Hereditary Hemochromatosis 
  CME Activity, Release Date: 2/28/2000 Expiration Date: 2/28/2002 From the February 2000 Issue of Physician Assistant  Objectives: After reading the article, the reader should be able to:
  1. describe the pathophysiology of hereditary hemochromatosis;
  2. recognize the clinical symptoms and signs of hereditary hemochromatosis;
  3. outline screening and evaluation testing; and
  4. provide accurate diagnosis, management, and treatment.

• Hereditary hemochromatosis: diagnosis and treatment in primary care Tenn Med 1999 Nov With early detection and treatment this can be a manageable chronic disease. If undetected, it is potentially fatal.

• Hereditary Hemochromatosis FamilyPractice.com  Robert B. Hash, MD, Department of Family Medicine, Mercer University School of Medicine, Macon, Ga. [J Am Board Fam Pract Dec. 2000] Considering the prevalence of the disease, it is important for physicians to consider it in the differential diagnosis when patients complain of the common signs and symptoms. For most patients hereditary hemochromatosis can be successfully treated in the physician's office. Early diagnosis and treatment, before signs of iron toxicity, if possible, can result in improved quality and quantity of life for many patients.

• Hereditary hemochromatosis: impact of molecular and iron-based testing on the diagnosis, treatment, and prevention of a common, chronic disease.  Arch Pathol Lab Med. 1999 Nov Press RD. Department of Pathology, Oregon Health Sciences University, Portland 97201, USA. pressr@ohsu.edu This direct HFE mutation test can now be used not only to confirm the diagnosis of HH in those with symptomatic disease, but also, perhaps more importantly, to detect those with presymptomatic iron overload in whom future disease manifestations may be prevented (with phlebotomy therapy).

• Hereditary hemochromatosis in adults without pathogenic mutations in the hemochromatosis gene  
  Hereditary hemochromatosis can occur in adults who do not have pathogenic mutations in the hemochromatosis gene.N Engl J Med 1999 Sep 2;341(10):725-32

• Hereditary hemochromatosis. J Fam Pract. 1997 Mar Hereditary hemochromatosis is a genetic disorder of iron metabolism that has an excellent prognosis if diagnosed early.

• Hereditary hemochromatosis: Preventing chronic effects of this underdiagnosed disorder
  Sharon M. McDonnell, MD, MPH; David Witte, MD, PhD VOL 102 / NO 6 / DECEMBER 1997 / POSTGRADUATE MEDICINE.  In this article, Drs McDonnell and Witte discuss the diagnosis and management of this underrecognized problem as well as the various issues involved in screening. An illustrative case of hemochromatosis is also included.

• Hereditary hemochromatosis Rev Med Interne 2000 Nov  At present, any patient admitted with an isolated case of asthenia, or with arthralgia or hypertransaminasemia should be examined via transferrin-saturation testing: if the transferrin saturation coefficient is > 45%, then the presence of the C282Y mutation should be investigated to confirm the diagnosis of hemochromatosis. A liver biopsy is no longer necessary to establish the diagnosis.

• Hereditary Hemochromatosis Since Discovery of the HFE Gene  Clinical Chemistry 2001 [a pdf file] Includes an algorithm for screening and diagnosis of hemochromatosis. This review provides a comprehensive discussion of known mutations in the HFE gene and their phenotypic expression.

• Heterogeneity of hemochromatosis in Italy  The frequency of C282Y homozygotes was 64%, with a decreasing gradient from north to south. C282Y homozygotes showed more severe iron overload than the other HFE genotypes. Gastroenterology 1998 May.

• Heterozygosity for hereditary hemochromatosis is associated with more fibrosis in chronic hepatitis C. Hepatology. 1998 Jun  Thus, despite relatively minor increases in iron stores, individuals who are heterozygous for hemochromatosis appear to develop more fibrosis in chronic hepatitis C. Venesection may be useful therapy in this subgroup.

• Heterozygosity for a hereditary hemochromatosis gene is associated with cardiovascular death in women Abstract.  For full text article in pdf format, click here. Circulation, 100(12):1268-73 1999 Sep 21

• Heterozygosity for the C282Y mutation in the hemochromatosis gene is associated with increased serum iron, transferrin saturation, and hemoglobin in young women: a protective role against iron deficiency? Clinical Chemistry. 1998;44:2429-2432

• Heterozygosity for the H63D mutation in the hereditary hemochromatosis (HFE) gene may lead into severe iron overload in beta-thalassemia minor: observations in a thalassemic kindred.  Rev Invest Clin 2001 Mar-Apr  Heterozygosity for beta-thalassemia (minor) by itself does not lead into iron overload; however, when it is inherited together with a homozygous state for either the H63D or the C282Y mutations of the hereditary hemochromatosis gene (HFE gene), iron overload may ensue.

• Heterozygosity for the hemochromatosis gene in liver diseases--prevalence and effects on liver histology. Liver 2000  Dec The C282Y mutation alone only leads to a mild increase in iron accumulation in the majority of the patients, with the exception of H63D/C282Y compound heterozygotes.

• HFE gene and hereditary hemochromatosis: a HuGE review. Human Genome Epidemiology 
  Am J Epidemiol 2001 Aug 1

• HFE gene knockout produces mouse model of hereditary hemochromatosis Proc Natl Acad Sci U S A. 1998 Mar.  Xiao Yan Zhou, Shunji Tomatsu, Robert E. Fleming, Seppo Parkkila, Abdul Waheed, Jinxing Jiang, Ying Fei, Elizabeth M. Brunt, David A. Ruddy, Cynthia E. Prass, Randall C. Schatzman, Rosemary O'Neill, Robert S. Britton, Bruce R. Bacon, and William S. Sly  The knockout mouse model of HH will facilitate investigation into the pathogenesis of increased iron accumulation in HH and provide opportunities to evaluate therapeutic strategies for prevention or correction of iron overload.

• HFE gene mutation (C282Y) and phenotypic expression among a hospitalised population in a high prevalence area of haemochromatosis Gut 2000 Oct The prevalence of C282Y homozygosity in a hospitalised population was 0.74%

• HFE gene mutations in patients with rheumatoid arthritis
   J Rheumatol 2000 Sep H63D mutation appears to play a role in pathogenesis of RA.

• HFE genotype in patients with hemochromatosis and other liver diseases.  Ann Intern Med. 1999 Jun 15 Bacon BR, Olynyk JK, Brunt EM, Britton RS, Wolff RK.   All 66 patients homozygous for the C282Y mutation of HFE had an elevated hepatic iron concentration, but approximately 15% of these patients did not meet a previous diagnostic criterion for hemochromatosis (hepatic iron index > 1.9 mmol/kg per year). Determination of HFE genotype is clinically useful in patients with liver disease and suspected iron overload and may lead to identification of otherwise unsuspected C282Y homozygotes.

• HFE Mutations Analysis in 711 probands:  Evidence for S65C Implication in Mild Form of Hemochromatosis

•  HFE mutations and transferrin receptor polymorphism analysis in porphyria cutanea tarda: a prospective study of 36 cases from southern France.  Br J Dermatol. 2001 Mar CONCLUSIONS: This study confirms the high frequency of HFE mutations in patients with PCT and supports the hypothesis that HFE gene abnormalities might play a significant part in the PCT pathomechanism, probably through iron overload;

• HFE mutations do not account for transfusional iron overload in patients with acute myeloid leukemia.  Transfusion. 2001 Jun HFE mutations do not account for the harmful iron overload that develops in AML patients who receive large quantities of RBC concentrates after intensive chemotherapy.

• HFE mutations in insulin resistance-associated hepatic iron overload.J Hepatol. 2000 Sep;33;33(3):515-6. No abstract available.
   

• HFE mutations, iron deficiency and overload in 10,500 blood donors. 
  Br J Haematol 2001 Aug People with genetic haemochromatosis (GH) accumulate iron from excessive dietary absorption. In populations of northern European origin, over 90% of patients are homozygous for the C282Y mutation of the HFE gene.

• HFE-PROTEIN IN HEREDITARY HEMOCHROMATOSIS
  Hereditary hemochromatosis is the most common known autosomal recessive disorder in Caucasians

• High frequency of the H63D mutation of the hemochromatosis gene (HFE) in malignant gliomas. Neurology 2001 Oct 9  No abstract available but if anyone gets access to the article, I would like to see it!

• High incidence of the Cys 282 Tyr mutation in the HFE gene in the Irish population--implications for haemochromatosis Tissue Antigens 1998 Nov

• High prevalence of the His63Asp HFE mutation in Italian patients with porphyria cutanea tarda.  Hepatology. 1998 Jan Our data do not confirm an association of PCT with the Cys282Tyr HFE mutation, strongly associated with hemochromatosis in Northern European countries. A second mutation of HFE, His63Asp, however, had a significantly increased frequency as it was present in half of the patients.

• Histological evaluation of iron in liver biopsies: relationship to HFE mutations.  Am J Gastroenterol. 2000 Jul Brunt EM, Olynyk JK, Britton RS, Janney CG, Di Bisceglie AM, Bacon BR.  The use of histological evaluation for iron deposition is simple, assists in expanding information communicated from histopathologic observations, and may be clinically useful in determining the necessity of further evaluation of HFE genotype in subjects with histological evidence of hepatic iron overload.

• Human cytomegalovirus protein US2 interferes with the expression of human HFE, a nonclassical class I major histocompatibility complex molecule that regulates iron homeostasis: 
  J Virol 2001 Nov Whether this interference with the regulation of iron metabolism by a viral protein is a means of potentiating viral replication remains to be determined.

• Human Genetic Diseases E. Beutler, D. Balicki, L. Forman, T. Gelbart, C. Halloran, E. Boas, P. Lee, C. West  Division of Hematology  About 82% of U.S. patients with hereditary hemochromatosis are homozygous for the 845A mutation of the gene HFE. HFE, the product of this gene, is a class 1 MHC protein, and its role in regulating iron absorption is unknown. We are attempting to answer a number of important but difficult questions about HFE.

• Idiopathic hemochromatosis with the mutation of Ala176Val heterozygous for HFE gene: 
  Intern Med 2001 Jun  Most patients with hereditary hemochromatosis are homozygous for C282Y in the HFE gene in populations of Celtic origin, but the genetic cause of this disease is unknown in Japan because of its rarity.

• Illustrations to Hemochromatosis, Radiology CT scan pictures

• Importance of 5569G/A polymorphism in intron 4 of HFE gene in the diagnosis of hereditary hemochromatosis  Med Clin (Barc) 2001 Dec 1

• Increased frequency of the haemochromatosis Cys282Tyr mutation in sporadic porphyria cutanea tarda. Lancet. 1997 Feb 1 Inheritance of one or more haemochromatosis genes is an important susceptibility factor for sporadic porphyria cutanea tarda.

• Increased hepatic iron concentration in nonalcoholic steatohepatitis is associated with increased fibrosis.  Gastroenterology 1998 Feb The Cys282Tyr mutation is responsible for most of the mild iron overload found in NASH and thus has a significant association with hepatic damage in these patients. Heterozygosity for the hemochromatosis gene mutation therefore cannot always be considered benign.

• Interaction between haemochromatosis and transferrin receptor genes in hepatocellular carcinoma
  Oncology 2000 Nov In hepatocellular carcinoma (HCC) iron has been implicated as a risk factor primarily in patients with hereditary haemochromatosis (HH) and cirrhosis

• Intestinal expression of genes involved in iron absorption in humans.  Am J Physiol Gastrointest Liver Physiol 2002 Apr;282(4):G598-607    Rolfs A, Bonkovsky HL, Kohlroser JG, McNeal K, Sharma A, Berger UV, Hediger MA.     Membrane Biology Program and Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, 02115, Massachusetts.   The lack of appropriate downregulation of apical and basolateral iron transporters in duodenum likely leads to excessive iron absorption in persons with HHC.

• Investigating Anaemia and Iron Storage Disease
  Discussion of the different types of anemia, as well as the effects of iron overload.  

• 'Iron' Gene Mutation Increases Heart Attack Risk  
  Full Health Nutrition Canada ArterialHealth e-News^© December 1999 [located about halfway down the page] Carriers almost universally don't know that they are at increased risk... They have almost no increase in iron stores, but that small increase is significant and that small increase is probably what caused the increased incidence of heart disease deaths.

• Iron in the era of molecular biology Pathol Biol (Paris). 1999 Nov Identification of the HFE gene and its C282Y and H63D mutations has improved the classification of iron overload disorders

• Iron is Hot:  An Update on the Pathophysiology of Hemochromatosis: Blood Journal Sept. 15, 1998  Genetic iron overload disorders are prevalent yet poorly understood. [A pdf file.]

• Iron-overload and genotypic expression of HFE mutations H63D/C282Y and transferrin receptor Hin6I and BanI polymorphism in german patients with hereditary haemochromatosis 
  Eur J Immunogenet 2000 Jun  These data indicate that the iron intake is higher among C282Y homozygous patients compared with C282Y heterozygous or C282Y/H63D compound heterozygous individuals and supports the functional role of the HFE protein in iron metabolism whereas the TfR gene variants seem to have no influence on iron uptake.

• Iron and the Genetics of Cardiovascular Disease Jerome L. Sullivan, MD, PhD Circulation 1999 AHA

• IRON AND HFE MUTATIONS IN HCV.  Hemochromatosis gene mutations in chronic hepatitis C virus (HCV) patients.   The authors conclude that HFE gene mutations contribute to hepatic iron overload in chronic HCV patients. (Kazemi-Shirazi L, et al. Gastroenterology 1999; 116: 127-134)

• Iron overload cardiomyopathies: new insights into an old disease Cardiovasc Drugs Ther 1994 Feb Iron overload cardiomyopathy is an old disease that has evolved from a rare undiagnosable and untreatable condition to a now much more common, diagnosable, and potentially treatable condition.

• Iron Overload (Hemosiderosis; Hemochromatosis) The Merck Manual of Diagnosis and Therapy Section 11. Hematology And Oncology Chapter 128. Hemochromatosis is often diagnosed late in the course of disease after significant tissue injury is present because the clinical symptoms are insidious and the extent of organ involvement varies; thus, the full clinical picture evolves slowly

• Iron overload in Porphyria cutanea tarda Haematologica 1999 HFE mutations related to PCT? [a pdf file]

• Iron overload without the C282Y mutation in patients with epilepsy.  J Neurol Neurosurg Psychiatry. 2001 Apr; To test the hypothesis that iron overload predisposes to epilepsy, transferrin saturation in 130 patients with epilepsy and sex and age matched 128 control subjects without epilepsy were studied.

• Iron transport in a lymphoid cell line with the hemochromatosis C282Y mutation.
  Blood. 2001 May 1 Our results indicate that in this B-lymphoid cell line, the HFE C282Y mutation affects both Tf-dependent and -independent iron uptake and enhances cell sensitivity to oxidative stress. The role of HFE in iron uptake by B cells may extend beyond its known interaction with the TfR.

• Low penetrant hemochromatosis phenotype in eight families: no evidence of modifiers in the mhc region.
  Blood Cells Mol Dis. 2001 Mar-Apr  We investigated eight families including C282Y homozygous relatives showing no clinical signs of the disease, in addition to the hemochromatosis patients.

• Kimball Genetics
  Hemochromatosis DNA- PCR analysis for both the Cys282Tyr and the His63Asp mutations

• Making a Difference in Genetic Disease  Endeavor  VOLUME ONE NUMBER TWO Ernest Buetler M.D.  It will be the largest such screening study ever undertaken. The NIH and the CDC have provided funding of more than $4,000,000 for these clinical studies and the basic studies of iron metabolism that will be performed in the Beutler laboratory. 

• Melanie Bennett's HFE webpage

• Metastatic carcinomatous cirrhosis and hepatic hemosiderosis in a patient heterozygous for the H63D genotype.  Arch Pathol Lab Med 2001 Aug . The possibility of cirrhosis-associated hemosiderosis secondary to an iron metabolism abnormality associated with the H63D mutation of the HFE gene is proposed.

• Michigan State University DNA Diagnostic Program Direct mutation analysis: DNA amplification (PCR) and RFLP analysis to test for 3 mutations in the HFE gene; C282Y, H63D, and S65C.

• Molecular Aspects of Iron Absorption and HFE Expression Gastroenterology 2001 Dec

• Molecular genetics of hemochromatosis Ann Endocrinol (Paris) 1999 Sep Hemochromatosis is a recessive disorder of iron metabolism characterized by progressive iron loading of parenchymal organs, which accounts for clinical complications such as cirrhosis, diabetes mellitus, cardiopathy, endocrine dysfunctions and arthropathy.

• Multicentric origin of hemochromatosis gene (HFE) mutations Am J Hum Genet 1999 Apr Genetic hemochromatosis (GH) is believed to be a disease restricted to those of European ancestry

• Mutation analysis of the HFE gene in german hemochromatosis patients and controls using automated SSCP-based capillary electrophoresis and a new PCR-ELISA technique
   Scand J Gastroenterol 2001 Nov

• Mutation screening for prenatal and presymptomatic diagnosis: cystic fibrosis and haemochromatosis 
   Eur J Pediatr 2000 Dec; Mutation analysis is widely recommended for presymptomatic diagnosis of cystic fibrosis and hereditary haemochromatosis because of the presumed benefit.

• Mutations in the hfe gene and their interaction with exogenous risk factors in hepatocellular carcinoma:  Blood Cells Mol Dis 2001 Mar-Apr; These data indicate that the prevalence of the main mutation associated with hereditary hemochromatosis is significantly higher in cirrhotic Italian patients with hepatocellular carcinoma compared to a normal population and suggest that heterozygotes for HFE mutations exposed to hepatitis virus infections or who had been alcohol abusers could have an increased risk of developing cirrhosis and later liver cancer than people without the mutations exposed to the same risk factors.

• Non-alcoholic steatohepatitis and iron: increased prevalence of mutations of the HFE gene in non-alcoholic steatohepatitis.  J Hepatol. 1999 Sep  : The prevalences of the HFE gene mutations associated with hereditary hemochromatosis are increased among North American subjects with NASH.

• Nonexpressing homozygotes for C282Y hemochromatosis: minority or majority of cases?
  Mol Genet Metab. 2000 Sep-Oct In this review, the available data on nonexpressing C282Y homozygotes is collected including information on pathogenesis, environmental interactions, and implications for population screening using genetic testing

• Noninvasive Prediction of Fibrosis in C282Y Homozygous Hemochromatosis 
  GASTROENTEROLOGY 1998;115:929-936  In C282Y homozygous patients, the diagnosis of severe fibrosis relies on liver biopsy, but absence of severe fibrosis can be accurately predicted in most patients on the basis of simple clinical and biochemical variables.

• Overview on Iron Overload and Hemochromatosis CDC website, National Center for Chronic Disease Prevention and Health Promotion.  Early detection of hemochromatosis is essential because the disease’s potentially serious complications can be prevented by early therapy.

• Patents increasing costs of blood test, researchers say  At issue are patents on the most common genetic mutations linked to hereditary hemachromatosis or iron overload, a surprisingly common and easily treatable disorder that can cause fatal damage to the heart and liver. Newspaper article from The Mercury News in San Jose, Calif. quotes David Snyder of AHS.

• Patients with type 2 diabetes have a high frequency of the C282Y mutation of the hemochromatosis gene The C282Y gene mutation is a potential genetic marker for type 2 diabetes. It, or a closely linked gene, may be associated with greater than 20% of cases of type 2 diabetes.

• Phenotypic expression of HFE mutations: a French study of 1110 unrelated iron-overloaded patients and relatives. Gastroenterology. 1999 Feb   Iron overload in patients with the non-C282Y +/+ genotype is mild to moderate, strikingly lower than in C282Y homozygotes, and is not influenced by HFE genotype, except, to a small extent, for compound heterozygotes. The role of H63D mutation therefore seems to be marginal.

• Piecing together our future: The new map of the human genome will change our lives forever
  Sunday, June 25, 2000 By Byron Spice, Science Editor, Post-Gazette Reading the book of life. A four part series: How genetics will transform medicine.  Story includes Keith Stewart & Dr. Block

• Polymorphisms in the HFE gene. Hum Hered. 1999 Jan The aim of this study was to search for new mutations in the HFE gene in 16 such patients. Direct sequencing of exons and 3 introns did not reveal any new mutation but identified a few polymorphisms

• Porphyria cutanea tarda, hepatitis C, and HFE gene mutations in North America.
  Hepatology. 1998 Jun All PCT patients should be tested for HCV infection and for HFE gene mutations.

• Porphyria cutanea tarda in Brazilian patients: association with hemochromatosis C282Y mutation and hepatitis C virus infection. Am J Gastroenterol. 2000 Dec PCT patients exhibited evidence of iron overload, a high frequency of HCV, and an association with C282Y mutation. These data further support the notion that both acquired and inherited factors contribute to the occurrence of PCT, and indicate that screening for C282Y may be justified in PCT patients.

• Prevalence and clinical significance of HFE gene mutations in patients with iron overload 
  Am J Gastroenterol 2000 Oct In all, 85% of our patients with iron overload were C282Y homozygotes, although a few had no HFE gene mutations. Pooled data and analysis of chromosomes considered to be at risk for H63D indicate that H63D is associated with iron overload.

• Prevalence of the C282Y mutation for haemochromatosis on the Island of Majorca.
  Clin Genet. 2000 Aug  In the group of hereditary haemochromatosis probands, 13 out of 14 were homozygous for the C282Y mutation. In the distribution of the C282Y mutation, a north-west to south-east cline was detected, supporting the Celtic origin of this mutation.

• Prevalence of C282Y and H63D mutations in the hemochromatosis (HFE) gene in the United States. 
  JAMA 2001 May 2 Estimates of prevalence of HFE mutations are within the expected range for non-Hispanic whites and blacks but the estimated prevalence of the C282Y mutation among Mexican-Americans is less than expected.

• Prevalence of the Cys282Tyr and His63Asp mutation in Flemish patients with hereditary hemochromatosis  Acta Gastroenterol Belg 2000 Jul-Sep  Of the 49 patients, 46 patients were homozygous for the Cys282Tyr mutation (94%), 2 were heterozygous (4%) and 1 carried two normal alleles (2%). Of the 3 patients not homozygous for the Cys282Tyr mutation, 3 were heterozygous for the His63Asp mutation (2 patients were 'compound heterozygotes').

• Psychosocial impact of C282Y mutation testing for hemochromatosis  
  Genet Test 2001 Summer

• Pumping iron: the strange partnership of the hemochromatosis protein, a class I MHC homolog, with the transferrin receptor Traffic 2001 Mar

• Recent advances in disorders of iron metabolism: mutations, mechanisms and modifiers
  Hum Mol Genet 2001 Oct 1 The spectrum of known disorders of iron metabolism has expanded dramatically over the past few years

• Recent haemochromatosis genetics references

• Recognition and management of hereditary hemochromatosis.   Am Fam Physician 2002 Mar 1 65:853-60 Brandhagen DJ, Fairbanks VF, and Baldus W Mayo Medical School, Rochester, Minnesota, USA. The HFE gene test is useful in confirming the diagnosis of hereditary hemochromatosis, screening adult family members of patients with HFE mutations and resolving ambiguities concerning iron overload.

• Recovery of pancreatic beta-cell function in hemochromatosis: combined treatment with recombinant human erythropoietin and phlebotomy.  Am J Med Sci. 1997 Dec This case suggests that pancreatic beta-cell recovers in diabetes caused by hemochromatosis by reducing iron overload during a short period.

• Reference centiles for serum ferritin and percentage of transferrin saturation, with application to mutations of the HFE gene Clin Chem 2001 Oct

• Relating Genomic Research to Patient Care JAMA 11/2000 Educating health care professionals about the complexities of the genetics of adult disease (in addition to congenital illness) is an important goal, and one disease model that is useful for this purpose involves hemochromatosis.

• Renal Transplantation and Evolution of Hemochromatosis:  A Clinical Case Report
  Despite being one of the world's most frequent autosomal recessive diseases, there are very few cases in the literature concerning hereditary hemochromatosis and renal transplantation. [a pdf file]

• Review article: the screening, diagnosis and optimal management of haemochromatosis.
  Aliment Pharmacol Ther. 1997 Aug   George DK, Powell LW.  Joint Liver Program, Queensland Institute of Medical Research, Brisbane, Australia.  Haemochromatosis is common, occurring in approximately 1 in 300 people in Caucasian populations, and untreated can cause serious morbidity and early death.

• Risk of disease in siblings of patients with hereditary hemochromatosis Digestion 2001

• Role of C282Y mutation in haemochromatosis gene in development of type 2 diabetes in healthy men: prospective cohort study. British Medical Journal BMJ 2000;(24 June) As the incidence of diabetes in northern Europe is among the highest in the world and rising, screening for C282Y mutation by DNA analysis, monitoring of iron status, and iron depleting treatment could potentially constitute new important measures in the primary prevention of diabetes.

• Role of the hemochromatosis gene in prophyria cutanea tarda. Prospective study of 56 cases
  Ann Dermatol Venereol. 2001 May  [Article in French] Compound heterozygous and to a lesser degree H63D homozygous status explained the highest iron overload in our patients. This favors clinical expression of porphyria cutanea tarda. This iron overload due to HFE mutations is a new triggering factor of porphyria cutanea tarda independent of classical triggering factors: mutation of the erythrocytic uroporpyrinogen decarbocylase gene, alcohol abuse, hepatitis C, and drugs.

• Screening for genetic haemochromatosis in blood samples with raised alanine aminotransferase  
  Gut 2000;46:707-710 ( May )

• Screening for hemochromatosis: high prevalence and low morbidity in an unselected population of 65,238 persons Scand J Gastroenterol 2001 Oct

• Screening for Hereditary Hemochromatosis in Siblings and Children of Affected Patients
  A Cost-Effectiveness Analysis Hashem B. El-Serag, MD, MPH; John M. Inadomi, MD; and Kris V. Kowdley, MD Annals of Internal Medicine, 15 February 2000 Volume 132 Number 4. HFE gene testing for the C282Y mutation is a cost-effective method of screening relatives of patients with hereditary hemochromatosis.

• Should all patients with diabetes mellitus be screened for hemochromatosis?   Department of Family Medicine University of California, Los Angeles 924 Westwood Blvd, Suite 650 Los Angeles, CA 90095-1628  West J Med 2002;176:110-114  Enhanced case finding becomes the first stage in a public health response when evidence has emerged for an effective early treatment of a disorder. It means the detection of HHC at the time of early symptoms, and it allows patients to benefit from early phlebotomy.  The implementation of this approach would include adding fasting serum transferrin saturation to the usual workup of patients with newly diagnosed diabetes mellitus, arthritis, and impotence.  The CDC recommends such iron-overload testing in anyone with possible symptoms of hemochromatosis, which includes patients with newly diagnosed diabetes mellitus.

• Should we genetically test everyone for haemochromatosis?
   J Med Ethics. 1999 Apr  This paper will identify and discuss key issues regarding DNA-based population screening for haemochromatosis, and argue that population-based genetic screening for haemochromatosis should be supported when a number of contentious issues are addressed.

• Significance and prevalence of the C282Y gene mutation of primary hemochromatosis in the pathogenesis of pophyria cutanea tarda   Frequency of C282Y gene mutation in our patients with porphyria cutanea tarda appears similar to that in other Middle European countries. Cas Lek Cesk 2000 Nov 22

• Significance of "minor" genetic mutations in hereditary hemochromatosis: 2 case reports
  Ann Ital Med Int. 2000 Jul-Sep These two cases concord with the present scientific orientation, i.e.: 1) homozygosity for the major mutation is associated with the phenotypical (clinical) picture of hemochromatosis, but compound heterozygosity also determines significant iron metabolism abnormalities; 2) homozygosity for the minor mutation does not appear to determine important phenotypical abnormalities.

• Solid-phase amplification for detection of C282y and H63D hemochromatosis (HFE) gene mutations.
  Clin Chem. 2001 Aug There is a need for simple, rapid, and inexpensive methods for the detection of single-nucleotide polymorphisms. Our aim was to develop a single-tube ELISA-like PCR assay and evaluate it by detecting the common C282Y and H63D mutations found in the hemochromatosis gene (HFE) by use of clinical samples

• T-cell receptor repertoire in hereditary hemochromatosis: a study of 32 hemochromatosis patients and 274 healthy subjects.  Hum Immunol. 2001 May These findings suggest that Hfe has an effect in the shaping of T-cell populations either directly, as indicated by the lymphopenia seen in the two chains in C282Y heterozygous without iron overload, or indirectly by contributing to iron overload pathology.

• The challenge of integrating genetic medicine into primary care.  
  BMJ. 2001 Apr 28 Population screening for hereditary haemochromatosis has been promoted because of the relatively high prevalence of mutations in the HFE gene that cause the disease and because there is effective treatment through regular phlebotomy.

• The clinical expression of hemochromatosis in Oslo, Norway. Excessive oral iron intake may lead to secondary hemochromatosis even in HFE C282Y mutation negative subjects.   Scand J Gastroenterol 2000 Dec The prevalence of hereditary hemochromatosis in Norway is one of the highest reported in the world.

• The diagnosis of hemochromatosis in the era of the gene Ann Endocrinol (Paris). 1999 Sep [article in French] The discovery of the hemochromatosis gene has deeply changed and simplified the diagnosis of the disease. In a given individual, establishing the diagnosis relies, from now on, on a simple blood sample showing the couple: elevated transferrin saturation and homozygous C282Y mutation (= C282Y +/+). Liver biopsy should only be performed when iron overload is massive in order to detect cirrhosis (or bridging fibrosis), i.e. in a prognostic view.

• The effect of HFE genotypes on measurements of iron overload in patients attending a health appraisal clinic Ann Intern Med 2000 Sep 5

• The effect of HFE mutations on serum ferritin and transferrin saturation in the Jersey population
   Br J Haematol 1998 May

• The haemochromatosis gene: a co-factor for chronic liver diseases?
  J Gastroenterol Hepatol. 1999 Aug George DK, Powell LW, Losowsky MS  Iron loading of mild to moderate degree due to heterozygosity or homozygosity for the haemochromatosis genetic mutations acts as a significant hepatotoxin aggravating hepatic damage from other causes of liver disease.

• The haemochromatosis gene: a global perspective and implications for the Asia-Pacific region.
  J Gastroenterol Hepatol. 1999 Sep; Epidemiological studies have shown that this gene is more widespread than its phenotypic expression would suggest and that the heterozygous state may be implicated in the expression of other diseases of the liver such as porphyria cutanea tarda, hepatitis C virus infection and non-alcoholic steatohepatitis.

• The Hemochromatosis 845 A and 187 CG Mutations: Prevalence in Non-Caucasian Populations
  Am. J. Hum. Genet., 62:1403-1407, 1998. Although hemochromatosis is common in Caucasians, affecting 1/300 individuals of northern European origin, it has not been recognized in other populations. The present study used PCR and restriction-enzyme digestion to analyze the frequency of the 845 GA and 187 CG mutations in HLA-typed samples from non-Caucasian populations, comprising Australian Aboriginal, Chinese, and Pacific Islanders.

• The HFE CYS282Tyr polymorphism is associated with cardiovascular mortality.
  Roest M, Schouw Yvd, B. de Valk BD, Marx JJM, Tempelman M, de Groot P, Sixma J, Banga JD.  Presented at the July 1998 meeting of the European Iron Club. Conclusions: Heterozygosity for HH is associated with increased risk of cerebrovascular and total cardiovascular mortality, in particular in combination with hypertension and smoking. Long term exposure to minimal iron overload may enhance atherosclerosis.

• The Roles of Iron in Health and Disease 
  [87pages, pdf file] Molecular Aspects of Medicine 22 [2001] 

• The S65C mutation in Spain. Implications for iron overload screening 
  Hereditary hemochromatosis is related to mutations of the HFE gene. The role of the S65C mutation of this gene was evaluated in a Spanish population, consisting of 100 controls and 41 patients who had resulted positive to screening for iron overload. Only one patient was heterozygous for the S65C mutation, so the S65C mutation is infrequent in our area. Nevertheless, it is advisable to search for this mutation in cases with iron overload and heterozygosity for the C282Y or H63D mutations of the HFE gene. 

• THE S65C MUTATION OF HFE MAY CONTRIBUTE TO IRON OVERLOAD IN C282Y HETEROZYGOTES

• The significance of the 187G (H63D) mutation in hemochromatosis 
  Am J Hum Genet 1997 Sep.  No abstract available.

• The significance of haemochromatosis gene mutations in the general population: implications for screening.  Gut. 1998 Dec HFE mutations are present in 38.4% of the population, affect serum iron indexes, and are important determinants of iron status. The population frequency of genetically defined haemochromatosis (C282Y homozygosity) is approximately one in 200 and is higher than the prevalence of clinically apparent haemochromatosis

• Update on hereditary hemochromatosis and the HFE gene.
  Brandhagen DJ, Fairbanks VF, Batts KP, Thibodeau SN. Division of Gastroenterology and Hepatology and Internal Medicine, Mayo Clinic Rochester, Minn 55905, USA. Mayo Clin Proc 1999 Sep

• Use of HFE Mutation Analysis for Hereditary Hemochromatosis:  The Need for Physician Education in the Translation of Basic Science to Clinical Practice Manish Kohli, MB, ChB, Steven A. Schichman, MD, PhD, Louis Fink, MD, Clive S. Zent, MB, BCh, Department of Internal Medicine, Division of Hematology/Oncology and the Department of Pathology, John L. McClellan Memorial Veteran's Hospital and University of Arkansas for Medical Sciences, Little Rock.  Southern Medical Journal

• Vibrio vulnificus septicemia in a patient with the hemochromatosis HFE C282Y mutation
  Arch Pathol Lab Med 2001 Aug We report a case of fatal V vulnificus sepsis in a 56-year-old man who died within 1 to 3 days after consuming raw seafood.

• What's new in hemochromatosis.  Curr Opin Hematol 2001 Mar  The high correlation of HFE to HHC has caused it to be considered as a candidate gene for population-based genetic testing for diagnosis and detection of predisposition to HHC. 

• Will Your Genes Prevent You From Getting Health Insurance? St. Louis University News Release  October 13, 2000 "People may be reluctant to take advantage of genetic tests that could save their lives," Dr. Bacon said. "In hemochromatosis, for example, symptoms usually do not appear until between 40 and 60 years of age. By then, the patient may have already sustained serious liver damage. Early detection is essential. No one should be afraid to seek information to make educated choices regarding their health."

• Yersinia enterocolitica infection with multiple liver abscesses uncovering a primary hemochromatosis.
  Scand J Gastroenterol 2001 Feb  In conclusion, severe septic forms of yersiniosis are mainly found in patients with iron overload, due to a handicapped iron metabolism of the Yersinia bacteria. Mortality is high despite treatment.
  
  

  ---

  HH and/or iron overload withOUT the known HFE mutations

   

• Autosomal-dominant hemochromatosis is associated with a mutation in the ferroportin (SLC11A3) gene.   J Clin Invest, August 2001  We propose that partial loss of ferroportin function leads to an imbalance in iron distribution and a consequent increase in tissue iron accumulation. [full article]

• Hereditary Hemochromatosis in Adults without Pathogenic Mutations in the Hemochromatosis Gene
  NEJM September 2, 1999 Hereditary hemochromatosis can occur in adults who do not have pathogenic mutations in the hemochromatosis gene. 

• Iron overload without the C282Y mutation in patients with epilepsy.  J Neurol Neurosurg Psychiatry. 2001 Apr; To test the hypothesis that iron overload predisposes to epilepsy, transferrin saturation in 130 patients with epilepsy and sex and age matched 128 control subjects without epilepsy were studied.

• Prevalence and clinical significance of HFE gene mutations in patients with iron overload 
  Am J Gastroenterol 2000 Oct In all, 85% of our patients with iron overload were C282Y homozygotes, although a few had no HFE gene mutations. Pooled data and analysis of chromosomes considered to be at risk for H63D indicate that H63D is associated with iron overload.

• Renal Transplantation and Evolution of Hemochromatosis:  A Clinical Case Report
  Despite being one of the world's most frequent autosomal recessive diseases, there are very few cases in the literature concerning hereditary hemochromatosis and renal transplantation. [a pdf file]

• Screening for hereditary haemochromatosis should be implemented now.  
  BMJ 2000;320:183 ( 15 January ) We believe that to benefit all those at risk there is an ethical imperative to implement screening for the major mutation causing haemochromatosis now, rather than wait years for confirmation of what is currently known that at least half of those with the predisposing genotype will develop some form of the disease.

Links related to genetic discrimination issues:

• Hemochromatosis Special  American Liver Foundation newsletter,  ALF Progress, Vol. 21 No. 1, Summer 1999 The ALF newsletter created three scenarios based on the real life ethical, economic and medical quandaries posed by hemochromatosis, and asked three experts from divergent fields to respond with their opinions. The experts are: Bruce R. Bacon, MD [Director, Div. of Gastroenterology & Hepatology, Saint Louis University School of Medicine, St. Louis, M0]; medical ethicist Mark A. Rothstein, Esq. [Director, University of Houston Law Center, Health Law & Policy Institute, Houston, TX] and hemachromatosis patient Gayle Hoffman.

• Insurance Issues and Genetic Disorders

Click on this link to read about HH. Discussion of a liver biopsy is also here: 

Back to the "Munnsters" main Hemochromatosis page