Hereditary Hemochromatosis

Hereditary Hemochromatosis

Lecture Presenter
Roger Orth, MD -428×607

Roger Orth, M.D.

Dr. Orth was born in Chicago, Illinois, and received his Bachelor of Science Degree at Illinois Institute of Technology. His Medical Degree is from Tulane University School of Medicine and he completed his internship and residency at the Univ…Full Profile

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Is Hemochromatosis a medical curiosity?

Most common mendelian disorder
USA affects .3-.8%
1:200 people
1.5 Million people
Genetic Discordance
Genotypic prevalence: 1:100 to 1:250
Phenotypic prevalence: 1:300
Highly underdiagnosed
Like other specific protein disease can be lethal
But is curable and preventable

Clinical Hemochromatosis Symptoms

Weakness lethargy
Loss of libido
RUQ pain-capsular distension


Hepatosplenomegaly, ascites, edema, jaundice
bronze skin-melanin/gray skin-iron deposition
2nd, 3rd Metacarpophalangeal joint arthropathy
Subchondral cysts, osteopenia, joint swelling
Clinical diabetes
Unusual infections Vibrio vulnificus
Pasteurella pseudotuberculosis

Clinical Pathophysiology

Iron Homeostasis

Intestinal iron absorption is excessive in relation to body iron status.
Normal iron absorbed 1 to 2 mg per day balanced with skin and GI loss
HH 3 to 4 mg per day absorbed – 1gram per year
Saturation of intracellular and extracellular storage
Iron free to participate in toxic reactions
Redox-reactive creates hydroxyl radicals leads to oxidative damage membrane structures, proteins and DNA
Organ deposition:
Liver cirrhosis, hepatocellularcarcinoma
Cardiomyopathy, arrythmias
Pancreas, diabetes
Pituitary-gonadal, hypogonadism

Genetic Basis of Disease

Rarest diseases to commonest – our genome is involved

Think Molecular

DNA variability – known as DNA polymorphism
Different versions – called variants

Specific Protein Diseases

Cystic fibrosis, Duchenne MD., hemochromatosis

Multifactorial Diseases

Genes interacting with the environment
Diabetes, Asthma, ASCVD, Cancer
Environment – diet, carcinogens

23 Chromosones

80,000 genes – Non coding DNA

Types of DNA Polymorphism

Single nucleotide polymorphism (SNP)
Gene product changes lead to disease
Repeat sequence polymorphism
Only 5% DNA is coding
Repeat sequence DNA – function maybe
important multifactorial diseases
Certainly helps in locating coding genes

Genetic Basis of Disease

Linkage analysis for identifying genetic disorders
Classic Mendelian traits: now 100 such diseases
Mendelian crossover recombination
analysis can
estimate linkage – Distance between genes on
a chromosone.
Hemochromatosis: Good Example
Chromosone 6: closely linked to HLA-
Histocompatability complex (HCC)
Proximity linkage narrowed search to a manageable DNA span:
Gene probes identify candidate gene, search for mutations in HH patients, identify the disease related gene and PCR clones the gene.
Amplification techniques allow study of the gene.

Amplification of final DNA sequences

In Vitro model:

DNA chip technology:
Plate with attached short sequences of an array of DNA Also used in gene diagnostic testing ie: genotyping
Yeast Artificial Chromosones (YAC)
Large pieces of DNA inserted into specialized DNA molecule an replicate in yeast, just like a normal chromosone
YACs have successfully been used to clone DNA fragments covering 95% of human genone
In Vivo model:
“Knockout Mouse”:
Transgenic mice created with defined mutations or deletions in specific genes.
Mice created for numerous diseases including:
Huntington’s Chorea
Cystic Fibrosis
Mice can be created for any other gene including H+, K ATPase.
Hemochromatosis Gene HFE
Major histocompatability complex
(MHC) protein
Encodes for special protein important in iron uptake
Transmembrane Protein
Extracellular component presents:
1) immumoglobulin like domain binds B2 microglobulin
2) peptide-binding domain binds diferric transferrin
Intracellular component
presents short cytoplasmic tail anchoring HFE protein
80 to 90% HH have same HFE gene flaw
Substitution of A for G as 845 nucleotide – causing substitution of Tyr for Cys as 282nd amino acid, termed C282Y
Looses disulfide bond, can’t bind B2 microglobuline
“Knockout” or loss of function mutation
Iron Metabolism
Serum Iron – transferrin bound
Diferric FE+++
Lumen Absorption ferrous FE++
Transferring Receptor (TFR) modulates uptake
Iron sensitive
Post transcription control
HFE probable regulates iron metabolism by
binding to a transferrin receptor. HFE slows
transport of iron from HFE-transparent receptor complex into cytoplasm.
Mutant form precedes with negative
regulation and cells become iron overloaded
Iron Regulator Proteins (IRP)
Bind postranscription mRNA at iron
responsive elements (IRE)
IRE at 3’mRNA leads to slow degredation of
mRNA ie: more transferrin receptor produced
Divalent metal transporter 1, DMT-1 appears to be
the transluminal transporter. Controls all divalent
cations, such as Fe, Zn, Co, Mn, Cu, Ni, Cd, Pb.
DMT – 1 also has
regulating elements of IRP and IRE type resulting in post transcription regulation of mRNA.
Future Prospects
Hemochromatosis general population
Porphyria cutanea tarda (PCT)
Hepatitis C, especially with PCT
Study environmental cofactors
Hepatitis C
Other divalent cations
Drug effects
Therapeutic options
Remove iron supplements – archaic
Dietary counseling
Iron food content
Use of black tea
Use of vitamin C
Avoidance of lemon and milk
Liver Transplants do poorly
Gene splicing, People “knockout”, People “knock in”.
Genomics – drugs that affect the genome or regulator proteins. Designer Drugs
First case description
Coined hemochromatosis described
“Blood Disorder”, skin pigment, cirrhosis
1935 Sheldon
Reviewed 311 cases. Described as inborn error of metabolism manifestations were iron deposition.
1951 First liver biopsy, phelobotomy therapy
1960’s Controversy
suggested HH was a
disorder secondary to alcoholism
1976 HH linked to HLA
(major histo
complex) on chromosome 6 confirmed genetic origin
1986 HH frequency
described white
1:220 to 1:400
1996 Novel gene
described – HFe – in HH
178 patients, 32 centers
C282Y – homozygous 83%
H63D – many others
Disease may require C282Y
1998 HFE knockout mice
1999 PNAS – mechanism
of HFE action
Diseases for which the causative gene has been identified using likage analysis.
Duchenne muscular
dystrophy 1986
Cystic fibrosis 1989
Fragile-X syndrome 1991
Myotonic dystrophy 1992
Huntington’s disease 1993
breast/ovarian cancer 1994
Ataxia telangiectasia 1995
Hemochromatosis (HH) 1996
Familial Mediterranean Fever 1997

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