Molecular medicine and hemochromatosis: At the crossroads

doi:10.1016/S0016-5085(99)70244-1

Gastroenterology

Volume 116, Issue 1, January 1999, Pages 193-207

https://doi.org/10.1016/S0016-5085(99)70244-1 Get rights and content

Abstract

Summary of a conference sponsored by the Division of Digestive Diseases and Nutrition and the Division of Kidney, Urology and Hematology of the National Institute of Diabetes, Digestive and Kidney Diseases, Bethesda, Maryland

GASTROENTEROLOGY 1999;116:193-207

Section snippets

Hemochromatosis and iron metabolism

Tracey A. Rouault, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland; Matthias A. Hediger, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts; and Nancy C. Andrews, Howard Hughes Medical Institute at Children's Hospital, Boston, Massachusetts.

In humans, iron circulates in serum tightly bound to transferrin.¹⁷ Each transferrin molecule can bind 2 molecules of ferric iron, and normally about 30% of the binding

The HFE gene

John N. Feder, Progenitor Inc., Menlo Park, California; Pamela J. Bjorkman, California Institute of Technology, Pasadena, California; and William S. Sly, Saint Louis University School of Medicine, St. Louis, Missouri.

The identification of HFE was the result of molecular genetics and positional cloning performed in a defined cohort of patients with hemochromatosis.⁵ The HFE gene encodes a novel MHC class 1–like protein whose relationship to iron metabolism was not immediately clear. Two missense

Epidemiology of hereditary hemochromatosis

Lawrie W. Powell, Clinical Sciences Unit, Queensland Institute of Medical Research, Brisbane, Queensland, Australia; Kathryn J. Robson, Institute of Molecular Medicine, John Radcliffe Hospital, Oxford, England; James P. Kushner, University of Utah School of Medicine, Salt Lake City, Utah; Sharon M. McDonnell, Centers for Disease Control and Prevention, Atlanta, Georgia; and Pradyumna D. Phatak, Rochester General Hospital, Rochester, New York.

Hereditary hemochromatosis occurs worldwide but is

Genotype and phenotype in hemochromatosis

Paul C. Adams, University of Western Ontario, London, Ontario, Canada; Clara Camaschella, University of Torino, Orbassano, Torino, Italy; Ernest Beutler, Scripps Research Institute, La Jolla, California; and Victor R. Gordeuk, George Washington University Medical Center, Washington, D.C.

The genetic defect in hereditary hemochromatosis is present at birth, but the clinical symptoms and signs of the disease rarely appear before adulthood.52, 53, 54, 55 Years of increased absorption of dietary

Clinical issues in hemochromatosis and liver disease

Kris V. Kowdley, University of Washington, Seattle, Washington; Herbert L. Bonkovsky, University of Massachusetts Medical Center, Worcester, Massachusetts; and James C. Barton, Southern Iron Disorders Center, Birmingham, Alabama.

If not diagnosed and treated, hereditary hemochromatosis can lead to cirrhosis and end-stage liver disease, conditions that are not reversed by phlebotomy. Some of these patients will qualify for liver transplantation. The success of liver transplantation for

Management controversies in hemochromatosis

Yves M. Deugnier, Hopital Pontchaillou, INSERM Unité 49, Rennes, France; Anthony S. Tavill, Mount Sinai Medical Center, Cleveland, Ohio; and Norman D. Grace, Tufts University School of Medicine, Boston, Massachusetts.

Management objectives in hemochromatosis focus on the early diagnosis to prevent organ damage in the form of cirrhosis, congestive heart failure, impotence, or diabetes mellitus.53, 54, 55, 94, 95 Once the diagnosis is made, the mainstay of management is iron depletion by

Acknowledgements

The authors thank the many speakers and moderators for the symposium “Molecular Medicine and Hemochromatosis: At the Crossroads,” in particular, Drs. Tracey Rouault, Caroline Philpott, Nancy Andrews, and Pamela Bjorkman for their review and suggestions.

References (101)

E Beutler et al.
Mutation analysis in hereditary hemochromatosis
Blood Cells Mol Dis
(1996)
JC Barton et al.
Genetic and clinical description of hemochromatosis probands and heterozygotes: evidence that multiple genes linked to the major histocompatibility complex are responsible for hemochromatosis
Blood Cells Mol Dis
(1997)
PC Adams et al.
Clinical and family studies in genetic hemochromatosis: microsatellite and HFE studies in five atypical families
Hepatology
(1997)
T Rouault et al.
Regulation of iron metabolism in eukaryotes
Curr Top Cell Regul
(1997)
KJ Addess et al.
Structure and dynamics of the iron responsive element RNA: implications for binding of the RNA by iron regulatory binding proteins
J Mol Biol
(1997)
HY Kim et al.
Translational repressor activity is equivalent and is quantitatively predicted by in vitro RNA binding for two iron-responsive element binding proteins, IRP1 and IRP2
J Biol Chem
(1995)
JN Feder et al.
The hemochromatosis founder mutation in HLA-H disrupts β2 microglobulin interaction and cell surface expression
J Biol Chem
(1997)
JA Lebron et al.
Crystal structure of the hemochromatosis protein HFE and characterization of its interaction with transferrin receptor
Cell
(1998)
A Piperno et al.
Heterogeneity of hemochromatosis in Italy
Gastroenterology
(1998)
VR Gordeuk et al.
Distribution of transferrin saturations in the African-American population
Blood
(1998)

RK Wurapa et al.

Primary iron overload in African Americans

Am J Med

(1996)

ML Bassett et al.

Analysis of the cost of population screening for haemochromatosis using biochemical and genetic markers

J Hepatol

(1997)

DM Baer et al.

Hemochromatosis screening in asymptomatic ambulatory men 30 years of age and older

Am J Med

(1995)

CE McLaren et al.

Distribution of transferrin saturation in an Australian population: relevance to the early diagnosis of hemochromatosis

Gastroenterology

(1998)

V Balan et al.

Screening for hemochromatosis: a cost-effectiveness study based on 12,258 patients

Gastroenterology

(1994)

PC Adams et al.

Screening blood donors for hereditary hemochromatosis: decision analysis based on a 30-year database

Gastroenterology

(1995)

PC Adams et al.

Population screening for hemochromatosis with the unbound iron-binding capacity (UIBC)

Gastroenterology

(1998)

C Niederau et al.

Long-term survival in patients with hereditary hemochromatosis

Gastroenterology

(1996)

PC Adams et al.

The relationship between iron overload, clinical symptoms, and age in 410 patients with genetic hemochromatosis

Hepatology

(1997)

DHG Crawford et al.

Expression of HLA-linked hemochromatosis in subjects homozygous or heterozygous for the C282Y mutation

Gastroenterology

(1998)

PC Adams et al.

Genotypic/phenotypic correlations in genetic hemochromatosis: evolution of diagnostic criteria

Gastroenterology

(1998)

RL Sham et al.

Correlation between genotype and phenotype in hereditary hemochromatosis: analysis of 61 cases

Blood Cells Mol Dis

(1997)

J Ludwig et al.

Hemosiderosis in cirrhosis: a study of 447 native livers

Gastroenterology

(1997)

AM Di Bisceglie et al.

Measurements of iron status in patients with chronic hepatitis

Gastroenterology

(1992)

PC Adams et al.

Evaluation of the hepatic iron index as a diagnostic criterion in genetic hemochromatosis

J Lab Clin Med

(1997)

GD LeSage et al.

Hemochromatosis: genetic or alcohol-induced?

Gastroenterology

(1983)

BR Bacon et al.

Nonalcoholic steatohepatitis: an expanded clinical entity

Gastroenterology

(1994)

DK George et al.

Increased hepatic iron concentration in non-alcoholic steatohepatitis is associated with increased fibrosis

Gastroenterology

(1998)

JK Olynyk et al.

Hepatic iron concentration as a predictor of response to interferon alfa therapy in chronic hepatitis C

Gastroenterology

(1995)

AM Di Bisceglie et al.

Effect of dietary iron loading in chimpanzees with chronic hepatitis C virus infection

Gastroenterology

(1998)

DH Van Thiel et al.

Response to interferon α therapy is influenced by the iron content of the liver

J Hepatol

(1994)

S Barrett et al.

The C282Y mutation is not a significant cofactor for more severe liver disease in a cohort of Irish hepatitis C patients

Gastroenterology

(1998)

AG Roberts et al.

Increased frequency of the haemochromatosis Cys282-Tyr mutation in sporadic porphyria cutanea tarda

Lancet

(1997)

KA Stuart et al.

The C282Y mutation in the haemochromatosis gene (HFE) and hepatitis C virus infection are independent cofactors for porphyria cutanea tarda in Australian patients

J Hepatol

(1998)

BR. Bacon

Diagnosis and management of hemochromatosis

Gastroenterology

(1997)

PC Adams et al.

Long-term survival analysis in hereditary hemochromatosis

Gastroenterology

(1991)

D Guyader et al.

Noninvasive prediction of fibrosis in C282Y homozygous hemochromatosis

Gastroenterology

(1998)

A. Trousseau

Glycosurie, diabète, sucré

FD. Von Recklinghausen

Über Hämochromatose

Tagebl Versamml Natur Ärzte Heidelberg

(1889)

JH. Sheldon

Haemochromatosis

(1935)

M Simon et al.

Idiopathic hemochromatosis. Demonstration of recessive transmission and early detection by family HLA typing

N Engl J Med

(1977)

JN Feder et al.

A novel MHC class I–like gene is mutated in patients with hereditary haemochromatosis

Nat Genet

(1996)

JG Bodmer et al.

Putting a hold on ‘HLA-H.’

Nat Genet

(1997)

EC Jazwinska et al.

Haemochromatosis and HLA-H

Nat Genet

(1996)

The UK Haemochromatosis Consortium

A simple genetic test identifies 90% of UK patients with haemochromatosis

Gut

(1997)

EMP Cardoso et al.

HFE mutations in patients with hereditary haemochromatosis in Sweden

J Intern Med

(1998)

A-M Jouanolle et al.

Haemochromatosis and HLA-H

Nat Genet

(1996)

N Borot et al.

Mutations in the MHC class I–like candidate gene for hemochromatosis in French patients

Immunogenetics

(1997)

M Carella et al.

Mutation analysis of the HLA-H gene in Italian hemochromatosis patients

Am J Hum Genet

(1997)

XY Zhou et al.

HFE gene knockout produces mouse model of hereditary hemochromatosis

Proc Natl Acad Sci USA

(1998)

Cited by (273)

Hereditary hyperferritinemia-cataract syndrome in three Czech families: molecular genetic testing and clinical implications
2020, Journal of AAPOS
Hereditary hyperferritinemia-cataract syndrome (HHCS) is an autosomal dominant disorder manifesting with high serum ferritin levels and the formation of early-onset cataracts, with numerous small opacities, predominantly in the lens cortex. HHCS is caused by mutations in the iron-responsive element of the FTL gene. The aim of this study was to establish a molecular diagnosis in three Czech probands with suspected HHCS.
A complex ocular and systemic evaluation, including ferritin and iron measurements, was performed. The 5′ untranslated region of FTL was directly sequenced in all available family members, followed by paternity testing in one family.
Three different FLT pathogenic variants (c.-161C>T, c.-167C>T, and c.-168G>C) present in the heterozygous state were detected in each of the 3 probands. Two segregated with the disease phenotype within the families, but c.-167C>T occurred de novo (confirmed by paternity testing). Prior to establishing molecular diagnosis, two probands were misdiagnosed with hemochromatosis. One individual, aged 43 years, underwent phlebotomy; another, aged 8.5 years, was treated with the iron chelator deferasirox, leading to life-threatening acute hyperammonemia, without severe liver injury.
Lack of family history does not exclude HHCS, because the pathogenic variant can arise de novo. Noncoding regions are often omitted from diagnostic gene panels, thus evading detection. Careful clinical evaluations and targeted genetic screening are important for avoiding potentially harmful treatments.
Site-specific intestinal DMT1 silencing to mitigate iron absorption using pH-sensitive multi-compartmental nanoparticulate oral delivery system
2019, Nanomedicine: Nanotechnology, Biology, and Medicine
Iron is a nutrient metal, but excess iron promotes tissue damage. Since iron chelation therapies exhibit multiple off-target toxicities, there is a substantial demand for more specific approaches to decrease iron burden in iron overload. While the divalent metal transporter 1 (DMT1) plays a well-established role in the absorption of dietary iron, up-regulation of intestinal DMT1 is associated with iron overload in both humans and rodents. Hence, we developed a novel pH-sensitive multi-compartmental particulate (MCP) oral delivery system that encapsulates DMT1 siRNA and validated its efficacy in mice. Using the gelatin NPs coated with Eudragit® L100-55, we demonstrated that DMT1 siRNA-loaded MCPs down-regulated DMT1 mRNA levels in the duodenum, which was consistent with decreased intestinal absorption of orally-administered ⁵⁹Fe. Together, the Eudragit® L100-55-based oral siRNA delivery system could provide an effective strategy to specifically down-regulate duodenal DMT1 and mitigate iron absorption.
Iron-processing genotypes, nutrient intakes, and cadmium levels in the Normative Aging Study: Evidence of sensitive subpopulations in cadmium risk assessment
2018, Environment International
Because iron and cadmium share common transport mechanisms, iron-processing protein variants such as HFE C282Y, HFE H63D, and Transferrin P570S may influence cadmium metabolism. Our aim was to evaluate associations between common HFE and Transferrin polymorphisms and toenail cadmium levels among older men.
In a longitudinal cohort of men age 51–97, the Normative Aging Study (NAS), we evaluated toenail cadmium concentrations and missense single nucleotide polymorphisms (SNPs) in the HFE and Transferrin genes. We fit age-adjusted models to estimate associations between genotypes and toenail cadmium concentrations. We then considered potential interactions with smoking status, hemoglobin, and nutritional intakes known to modulate cadmium absorption. For the significant interactions, we also evaluated genotype specific effect estimates.
HFE and Transferrin genotypes were not associated with toenail cadmium concentrations in the main effect analyses, but there were significant interactions between HFE H63D and hemoglobin (p_interaction = 0.021), as well as HFE H63D and vitamin C intake (p_interaction = 0.048). Genotype specific effect estimates suggested: 1) an inverse relationship between hemoglobin and cadmium levels among HFE H63D homozygotes, and 2) an inverse relationship between vitamin C intake and cadmium levels that strengthens with the number of HFE H63D variant alleles a subject carries.
These findings suggest that sensitive subpopulations defined by diet, hemoglobin level, and genotype may absorb more cadmium from their environment and thus should be considered in cadmium risk analyses. These findings are particularly relevant given the high prevalence of the H63D variant worldwide.
HFE genotype affects exosome phenotype in cancer
2017, Biochimica et Biophysica Acta - General Subjects
Neuroblastoma is the third most common childhood cancer, and timely diagnosis and sensitive therapeutic monitoring remain major challenges. Tumor progression and recurrence is common with little understanding of mechanisms. A major recent focus in cancer biology is the impact of exosomes on metastatic behavior and the tumor microenvironment. Exosomes have been demonstrated to contribute to the oncogenic effect on the surrounding tumor environment and also mediate resistance to therapy. The effect of genotype on exosomal phenotype has not yet been explored. We interrogated exosomes from human neuroblastoma cells that express wild-type or mutant forms of the HFE gene. HFE, one of the most common autosomal recessive polymorphisms in the Caucasian population, originally associated with hemochromatosis, has also been associated with increased tumor burden, therapeutic resistance boost, and negative impact on patient survival. Herein, we demonstrate that changes in genotype cause major differences in the molecular and functional properties of exosomes; specifically, HFE mutant derived exosomes have increased expression of proteins relating to invasion, angiogenesis, and cancer therapeutic resistance. HFE mutant derived exosomes were also shown to transfer this cargo to recipient cells and cause an increased oncogenic functionality in those recipient cells.
Haemochromatosis
2016, The Lancet
Haemochromatosis is now known to be an iron-storage disease with genetic heterogeneity but with a final common metabolic pathway resulting in inappropriately low production of the hormone hepcidin. This leads to increase in intestinal absorption and deposition of excessive amounts of iron in parenchymal cells which in turn results in eventual tissue damage and organ failure. A clinical enigma has been the variable clinical expression with some patients presenting with hepatic cirrhosis at a young age and others almost asymptomatic for life. Research is unravelling this puzzle by identifying environmental factors—especially alcohol consumption—and associated modifying genes that modulate phenotypic expression. A high index of suspicion is required for early diagnosis but this can lead to presymptomatic therapy and a normal life expectancy. Venesection (phlebotomy) therapy remains the mainstay of therapy, but alternative therapies are the subject of current research.
Frequency of HFE gene variants in Polish HIV infected and HIV/HCV co-infected patients
2015, HIV and AIDS Review
The HFE gene mutations play a significant role in the development of hereditary hemochromatosis, which is a disorder of iron metabolism characterised by tissue iron overload. It is also one of the most common genetic diseases among Caucasians.
In the current study, the frequencies of common single nucleotide polymorphisms in HFE gene [845G→A (C282Y) and 187C→G (H63D)] were estimated in a group of 409 HIV-infected individuals of Caucasian origin from Poland, from which 243 were also HCV-coinfected. TaqMan Real-Time SNP genotyping was performed to screen for the variants. HFE haplotypes and linkage disequilibrium was analysed by the CubeX online tool.
Frequencies of compound HFE genotypes in the studied population were as follows: 845(GG)–187(CC) – 63.8% (n = 261), 845(GG)–187(CG) – 25.7% (n = 105), 845(GG)–187(GG) – 3.4% (n = 14), 845(GA)–187(CC) – 5.6% (n = 23), 845(GA)–187(CG) – 1.2% (n = 5) and 845(AA)–187(CC) – 0.2% (n = 1). The allele frequencies in HIV-monoinfected were: 845(G) – 95.9%, 845(A) – 4.1%, 187(C) – 81.7%, 187(G) – 18.3% and in HIV/HCV-coinfected: 845(G) – 97.0%, 845(A) – 3.8%, 187(C) – 85.2%, 187(G) – 14.8%.
Presence of mutations in the HFE gene in the Polish HIV/HCV infected population is similar to those reported for other Caucasian populations. This applies both to the C282Y and H63D variants, although in the second case, recessive allele G appeared numerically more commonly than among other populations tested.

View all citing articles on Scopus

^☆: Address requests for reprints to: Jay H. Hoofnagle, Building 31, Room 9A23, National Institutes of Health, Bethesda, Maryland 20892-6600. e-mail: [email protected]; fax: (301) 496-2830.

View full text

Meeting ReportsMolecular medicine and hemochromatosis: At the crossroads☆

Abstract

Section snippets

Hemochromatosis and iron metabolism

The HFE gene

Epidemiology of hereditary hemochromatosis

Genotype and phenotype in hemochromatosis

Clinical issues in hemochromatosis and liver disease

Management controversies in hemochromatosis

Acknowledgements

Blood Cells Mol Dis

Blood Cells Mol Dis

Hepatology

Curr Top Cell Regul

J Mol Biol

J Biol Chem

J Biol Chem

Cell

Gastroenterology

Blood

Am J Med

J Hepatol

Am J Med

Gastroenterology

Gastroenterology

Gastroenterology

Gastroenterology

Gastroenterology

Hepatology

Gastroenterology

Gastroenterology

Blood Cells Mol Dis

Gastroenterology

Gastroenterology

J Lab Clin Med

Gastroenterology

Gastroenterology

Gastroenterology

Gastroenterology

Gastroenterology

J Hepatol

Gastroenterology

Lancet

J Hepatol

Gastroenterology

Gastroenterology

Gastroenterology

Glycosurie, diabète, sucré

Über Hämochromatose

Tagebl Versamml Natur Ärzte Heidelberg

Haemochromatosis

Idiopathic hemochromatosis. Demonstration of recessive transmission and early detection by family HLA typing

N Engl J Med

A novel MHC class I–like gene is mutated in patients with hereditary haemochromatosis

Nat Genet

Putting a hold on ‘HLA-H.’

Nat Genet

Haemochromatosis and HLA-H

Nat Genet

A simple genetic test identifies 90% of UK patients with haemochromatosis

Gut

HFE mutations in patients with hereditary haemochromatosis in Sweden

J Intern Med

Haemochromatosis and HLA-H

Nat Genet

Mutations in the MHC class I–like candidate gene for hemochromatosis in French patients

Immunogenetics

Mutation analysis of the HLA-H gene in Italian hemochromatosis patients

Am J Hum Genet

HFE gene knockout produces mouse model of hereditary hemochromatosis

Proc Natl Acad Sci USA

Meeting Reports
Molecular medicine and hemochromatosis: At the crossroads☆