Epidemiology and Disease Pathophysiology: Hereditary Haemochromatosis

1
Epidemiology and Disease Pathophysiology
Hereditary Haemochromatosis

• Pierre Brissot, MD
• Professor of Medicine
• Liver Disease Department
• University Hospital Pontchaillou
• Rennes, France

2
Overview

• Definition/classification
• Epidemiology
• Prevalence
• Penetrance
• Inheritance
• Pathophysiology
• Iron overload
• Hepcidin-ferroportin interaction
• Ferroportin disease vs aceruloplasminaemia
• Defect in hepcidin-ferroportin interaction
• Diagnosis
• Treatment
• Family screening

3
Definition

• Haemochromatosis chronic iron overload of
  genetic origin1
• HFE-haemochromatosis (type 1)
• Homozygous C282Y mutation (affected chromosome
  6)1,2
• Non-HFE haemochromatosis

4
Non-HFE Haemochromatosis

• Juvenile haemochromatosis (HC) (type 2)1
• Haemojuvelin mutations (type 2A) 11,2
• Hepcidin mutations (type 2B) 191,2
• TfR2 HC (type 3)1
• Transferrin receptor 2 mutations 7 1,2
• Ferroportin disease (Type 4)1
• Ferroportin mutations 2 (subtypes A and B)1,2
• Aceruloplasminaemia3
• Ceruloplasmin mutations 31,3
• Other types atransferrinaemia, DMT1
  mutationrelated iron overload, GLRX5
  mutationrelated iron overload1,2

Affected chromosome
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EpidemiologyPrevalence

• HFE-haemochromatosis (type 1)4
• gt90 of cases1
• Generally of Northern European descent4
• Prevalence for C282Y homozygosity
  3/10005/10002,4
• NonHFE-haemochromatosis1
• Rare (ferroportin disease) or exceptional

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EpidemiologyPenetrance1Incomplete for
HFE-HCPhenotypic Variability (5-Scale Grading)
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Life
3
Quality of life
Quality of life
2
Ferritin
Ferritin
Ferritin
1
Tf Sat
Tf Sat
Tf Sat
Tf Sat
0
CLINICAL
PRECLINICAL
Tf Sat (transferrin saturation) gt45 ferritin
gt300 µg/L (male), gt200 µg/L (female). Quality
of life symptoms asthaenia, impotence,
arthropathy life-threatening symptoms
cirrhosis, diabetes, cardiomyopathy.
Reprinted from Brissot P, et al, Hematology, Jan
200636, with permission from the American
Society of Hematology.
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EpidemiologyPenetrance1

• Modifying factors
• Acquired
• Diet
• Menses
• Pregnancies
• Blood loss/blood donation
• Genetic
• Polymorphism or mutations of other genes related
  to iron metabolism

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EpidemiologyInheritance1

• Genetic transmission of HC
• Autosomal recessive
• Exception ferroportin disease
• (Dominant transmission)

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Pathophysiology5
Iron Overload
Hepcidin Deficiency
For Types 1, 2, and 3 HC
HFE (type 1) or non-HFE (type 2 or 3) mutations

• HFE or non-HFE mutations decrease hepcidin
  hepatic synthesis
• Hepcidin deficiency targets the duodenum, site of
  iron absorption
• As a result of 2, duodenalabsorption of iron
  increases
• Hepcidin deficiency targets thespleen
• As a result of 4, splenic iron release into the
  plasma increases
• As a result of 3 and 5, plasma iron concentration
  significantly increases
• Increased plasma iron (especially under its
  nontransferrin-bound iron species) produces
  parenchymal iron deposition (here, only the liver
  target is indicated)

1
1
Liver
2
HEPCIDIN
3
4
4
7
5
2
5
Spleen
6
IRON
7
6
Blood
3
Duodenum
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Pathophysiology6
Physiology of Hepcidin-Ferroportin Interaction6
Cell
5
4
6
Ferroportin
3
1
Hepcidin
Plasma
2
Ferroportin iron export protein
Circulating hepcidin
Decreased iron release due to decreased
ferroportin
Degraded ferroportin
Hepcidin bindsto ferroportin
Internalization, then ferroportin degradation
2
3
4
5
1
6
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Pathophysiology
Quantitative Defect in Hepcidin-Ferroportin
Interaction (Types 1, 2, 3 HC)7
Cell( enterocyte and macrophage)
Fe
3
Fe
4
5
2
Hepcidin
Fe
Fe
1
Fe
Plasma
Internalization, but decreased ferroportin
degradation
Decreased hepcidin binding to ferroportin
Decreased circulating hepcidin
Increased iron release due to increased
ferroportin activity
Increased ferroportin
2
3
4
5
1
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Pathophysiology
Iron Overload
For Ferroportin Disease(type 4 HC) and
Aceruloplasminaemia
Deficiency of Cellular Iron Export
Ferroportin Disease
Aceruloplasminaemia
Transferrin
Fe3
1
2
Cp
2
1
Fe2
3
4
Blood
Blood
.

Iron atom
In both diseases plasma iron concentration is
normal or low
Mutated ferroportin
1
Mutated ceruloplasmin (Cp)
1
Macrophagic iron excess due to deficient iron
export (kupffer cell siderosis shown in 3)
2
Mutation leads to absence of ferroxidase activity
(needed for iron uptake by transferrin)
2
Excessive ferroportin degradation leads to
decreased cellular export of iron
3
Valid for form A. In form B (resistance to
hepcidin) mechanism of iron excess (corresponding
to inactive hepcidin) is similar to type 1, 2, or
3 HC.
This leads to intracellular retention of iron
4
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Pathophysiology
Qualitative Defect in Hepcidin-Ferroportin
Interaction (Type 4B HC) Hepcidin Resistance
Cell( enterocyte and macrophage)
4
3
5
Mutated ferroportin
2
Hepcidin
Fe
Fe
1
Fe
Plasma
Decreased ferroportin degradation
Defect in hepcidin binding to ferroportin
Normal hepcidin
Increased iron release due to increased
ferroportin activity
Increased ferroportin
2
3
4
5
1
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Diagnosis to Establish Iron Overload Clinical
and Biochemical

• Clinical syndromes
• Asthaenia, arthropathy, osteopaenia, skin
  pigmentation, impotence, diabetes, hepatomegaly,
  cardiac symptoms8
• Biochemical parameter
• Hyperferritinaemia gt300 µg/L in men,gt200 µg/L
  in women1
• Confounding factors1
• Alcoholism
• Polymetabolic syndrome
• Inflammation
• Hepatitis

Arthropathy
Skin Pigmentation
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Diagnosis to Establish Iron OverloadMRI9

• Magnetic resonance imaging (MRI)
• Hyposignal (T2 weighted MRI) provides
  hepaticiron concentration
• Benefits of MRI
• Accurate, noninvasive strategy that most often
  eliminates the need for liver biopsy in
  diagnosingiron overload

(www.radio.univ-rennes1.fr)
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Diagnosis to Prove Genetic Origin1

• Family data
• HC diagnosis or symptoms in favor of iron excess
  among family members
• Personal data
• Transferrin saturation level is a key parameter

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Diagnosis to Prove Genetic Origin Elevated TF1

Elevated transferrin (gt60 men, gt50 women)
Caucasian ?
Yes
No
Genetic test
Genetic test
C282Y/C282Y ?
Haemojuvelin (Type 2A HC) Hepcidin (Type 2B
HC) Ferroportin (Type 4B HC) TfR2 (Type 3 HC)
if lt 30 years old
Yes
No
Type 1 HC
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Diagnosis to Prove Genetic Origin Normal or
Low TF1
Normal or low transferrin (lt45)
If anaemia neurologic symptoms
Plasma ceruloplasmin level
0 (or low)
Normal
Aceruloplasminaemia
Genetic test
Ferroportin?
No
Yes
(Type 4A HC)
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TreatmentVenesection Therapy

• Treatment of choice for HC related to hepcidin
  deficiency (types 1, 2, and 3 HC) or inactivity
  (type 4B HC)4
• Revisited guidelines (for type 1 HC)1
• Start grade 2 (ferritin level gt300 µg/L for men,
  gt200 µg/L for women)1
• Induction phase 7 mL/kg body weight (lt550 mL)
  weekly until ferritin 50 µg/L1
• Maintenance phase every 14 months until
  ferritin 50 µg/L (lifetime regimen thereafter)1

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Results/Contraindications for Venesection
Therapy1

• Results in types 1, 2, 3, and 4B
• Good for asthaenia, skin pigmentation, liver
  disease, cardiac function
• Moderate for arthropathy (which may worsen) and
  diabetes
• Poor for cirrhosis (risk of hepatocellular
  carcinoma)
• Ferroportin disease (type 4A HC)
• Poorly tolerated risk of anaemia
• Aceruloplasminaemia
• Contraindicated anaemia

Note Life expectancy is normal if treatment
starts before cirrhosis and insulin-dependent
diabetes
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Treatment Perspectives

• Short-term perspective
• Once daily oral chelator (deferasirox)
• If ongoing study establishes good tolerance1
• Possibly for types 1, 2, 3, and 4A HC
• Probably for type 4B
• Mainly for aceruloplasminaemia
• Longer-term perspective
• Hepcidin supplementation (for types 1, 2, and 3
  HC)

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Family Screening1

• HFE-HC (type 1)
• Whatever the grading of the C282Y/C282Y proband,
  should evaluate first-degree relatives (18 years
  or older) for C282Y mutation serum iron markers
  (transferrin saturation, ferritin)

C282Y 2
C282Y 0 or C282Y 1
Grading
No special follow-up
Venesections if grade 2
C282Y/wild-type
C282Y/C282Y
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Family Screening1

• Types 2 and 3 HC (juvenile HC and TfR2 HC)
• Similar procedure search for identity using the
  proband mutation profile coupled with evaluation
  of individuals biochemical iron status
• Type 4 (A and B) HC (ferroportin disease)
• The screening approach is different because of
  dominant transmission hyperferritinaemia
  (corresponding to ferroportin mutation) would
  exist in 50 of siblings and offspring

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Conclusions

• In haemochromatosis, many new entities have been
  identified in addition to classic (type 1)
  haemochromatosis
• These advances in knowledge of disease
  pathophysiology have improved diagnosis, and
  enhanced screening and approach to treatment of
  haemochromatosis

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References

• Brissot P, de Bels F. Current approaches to the
  management of hemochromatosis. Hematology. Am Soc
  Hematol Educ Program. 200636-41.
• Pietrangelo A. Hereditary hemochromatosisa new
  look at an old disease. N Engl J Med.
  20043502383-2397.
• Kono S, Suzuki H, Takahashi K, et al. Hepatic
  iron overload associated with a decreased serum
  ceruloplasmin level in a novel clinical type of
  aceruloplasminemia. Gastroenterology.
  2006131240-245.
• Camaschella C. Understanding iron homeostasis
  through genetic analysis of hemochromatosis and
  related disorders. Blood. 20051063710-3717.
• Loreal O, Haziza-Pigeon C, Troadec MB, et al.
  Hepcidin in iron metabolism. Curr Protein Pept
  Sci. 20056279-291.
• Nemeth E, Tuttle MS, Powelson J, et al. Hepcidin
  regulates cellular iron efflux by binding to
  ferroportin and inducing its internalization.
  Science. 20043062090-2093.
• Donovan A, Roy CN, Andrews NC. The ins and outs
  of homeostasis. Physiology. 200621115-123.
• Brissot P, Le Lan C, Troadec MB, et al. Diagnosis
  and treatment of HFE-haemochromatosis. In The
  Handbook Disorders of Iron Homeostasis,
  Erythrocytes, Erythropoiesis. European School of
  Haematology (ESH) 2006 pp 454-464.
• Gandon Y, Olivié D, Guyader D, et al.
  Non-invasive assessment of hepatic iron stores by
  MRI. Lancet. 2004363357-362.

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