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) [1]*1,2
Hepcidin mutations (type 2B) [19]*1,2
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 [3]*1,3
Other types: atransferrinaemia, DMT1 mutation–related iron overload, GLRX5 mutation–related iron overload1,2
*Affected chromosome

5. Epidemiology—Prevalence
HFE-haemochromatosis (type 1)4
>90% of cases1
Generally of Northern European descent4
Prevalence for C282Y homozygosity = 3/1000–5/10002,4
Non–HFE-haemochromatosis1
Rare (ferroportin disease) or exceptional

6. Epidemiology—Penetrance1 Incomplete for HFE-HC–Phenotypic Variability (5-Scale Grading)4
Life 3
Quality of life
Quality of life 2
Ferritin
Ferritin
Ferritin 1
Tf Sat
Tf Sat
Tf Sat
Tf Sat
PRECLINICAL
CLINICAL
Tf Sat (transferrin saturation) = >45%; ferritin = >300 µg/L (male), >200 µg/L (female).
Quality of life symptoms = asthaenia, impotence, arthropathy; life-threatening symptoms = cirrhosis, diabetes, cardiomyopathy.
Reprinted from Brissot P, et al, Hematology, Jan 2006:36, with permission from the American Society of Hematology.

7. Epidemiology—Penetrance1
Modifying factors
Acquired
Diet
Menses
Pregnancies
Blood loss/blood donation
Genetic
Polymorphism or mutations of other genes related to iron metabolism

8. Epidemiology—Inheritance1
Genetic transmission of HC
Autosomal recessive
Exception: ferroportin disease
(Dominant transmission)

9. Pathophysiology5 Iron Overload For Types 1, 2, and 3 HC
Hepcidin Deficiency 1
HFE or non-HFE mutations decrease hepcidin hepatic synthesis
Hepcidin deficiency targets the duodenum, site of iron absorption
As a result of 2, duodenal absorption of iron increases
Hepcidin deficiency targets the spleen
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 non–transferrin-bound iron species) produces parenchymal iron deposition (here, only the liver target is indicated)
HFE (type 1) or non-HFE (type 2 or 3) mutations 1
Liver 2 3
HEPCIDIN 4 4 7 5 2 5
Spleen 6
IRON 7 6
Blood 3
Duodenum

10. Physiology of Hepcidin-Ferroportin Interaction6
Pathophysiology6
Physiology of Hepcidin-Ferroportin Interaction6
Cell 5 Fe 4 Fe Fe 6
Ferroportin 3 1
Hepcidin
Plasma Fe 2
Ferroportin = iron export protein
Circulating hepcidin
Hepcidin binds to ferroportin
Internalization, then ferroportin degradation
Degraded ferroportin
Decreased iron release due to decreased ferroportin 1 2 3 4 5 6

11. Cell (= enterocyte and macrophage)
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 1 Fe Fe
Plasma
Decreased circulating hepcidin
Decreased hepcidin binding to ferroportin
Internalization, but decreased ferroportin degradation
Increased ferroportin
Increased iron release due to increased ferroportin activity 1 2 3 4 5

12. In both diseases plasma iron concentration is normal or low
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 1
Mutated ferroportin 1
Mutated ceruloplasmin (Cp)
Macrophagic iron excess due to deficient iron export (kupffer cell siderosis shown in 3) 2 2
Mutation leads to absence of ferroxidase activity (needed for iron uptake by transferrin) 3
Excessive ferroportin degradation leads to decreased cellular export of iron
*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. 4
This leads to intracellular retention of iron

13. Cell (= enterocyte and macrophage)
Pathophysiology
Qualitative Defect in Hepcidin-Ferroportin Interaction (Type 4B HC) Hepcidin Resistance
Cell (= enterocyte and macrophage) 4 Fe 3 Fe
Mutated ferroportin 5 2
Hepcidin Fe 1 Fe Fe
Plasma
Normal hepcidin
Defect in hepcidin binding to ferroportin
Decreased ferroportin degradation
Increased ferroportin
Increased iron release due to increased ferroportin activity 1 2 3 4 5

14. Diagnosis to Establish Iron Overload— Clinical and Biochemical
Clinical syndromes
Asthaenia, arthropathy, osteopaenia, skin pigmentation, impotence, diabetes, hepatomegaly, cardiac symptoms8
Biochemical parameter
Hyperferritinaemia = >300 µg/L in men, >200 µg/L in women1
Confounding factors1
Alcoholism
Polymetabolic syndrome
Inflammation
Hepatitis
Arthropathy
Skin Pigmentation

15. Diagnosis to Establish Iron Overload—MRI9
Magnetic resonance imaging (MRI)
Hyposignal (T2 weighted MRI) provides hepatic iron concentration
Benefits of MRI
Accurate, noninvasive strategy that most often eliminates the need for liver biopsy in diagnosing iron overload (

16. 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

17. (>60% men, >50% women)
Diagnosis to Prove Genetic Origin— Elevated TF1
Elevated transferrin
(>60% men, >50% 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 < 30 years old
Yes No
Type 1 HC

18. Normal or low transferrin (<45%) Plasma ceruloplasmin level
Diagnosis to Prove Genetic Origin—
Normal or Low TF1
Normal or low transferrin (<45%)
If anaemia & neurologic symptoms
Plasma ceruloplasmin level
Normal
0 (or low)
Aceruloplasminaemia
Genetic test
Ferroportin? No
Yes
(Type 4A HC)

19. Treatment—Venesection 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 >300 µg/L for men, >200 µg/L for women)1
Induction phase: 7 mL/kg body weight (<550 mL) weekly until ferritin = 50 µg/L1
Maintenance phase: every 1–4 months until ferritin ≤50 µg/L (lifetime regimen thereafter)1

20. 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

21. 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)

22. Venesections if grade ≥ 2
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 = 0 or C282Y = 1*
C282Y = 2†
Grading
No special follow-up
*C282Y/wild-type
Venesections if grade ≥ 2
†C282Y/C282Y

23. 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 individual’s 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

24. 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

25. References
Brissot P, de Bels F. Current approaches to the management of hemochromatosis. Hematology. Am Soc Hematol Educ Program. 2006:36-41.
Pietrangelo A. Hereditary hemochromatosis—a new look at an old disease. N Engl J Med. 2004;350:
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. 2006;131:
Camaschella C. Understanding iron homeostasis through genetic analysis of hemochromatosis and related disorders. Blood. 2005;106:
Loreal O, Haziza-Pigeon C, Troadec MB, et al. Hepcidin in iron metabolism. Curr Protein Pept Sci. 2005;6:
Nemeth E, Tuttle MS, Powelson J, et al. Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization. Science. 2004;306:
Donovan A, Roy CN, Andrews NC. The ins and outs of homeostasis. Physiology. 2006;21:
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
Gandon Y, Olivié D, Guyader D, et al. Non-invasive assessment of hepatic iron stores by MRI. Lancet. 2004;363:

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