Epidemiology and Disease Pathophysiology: Hereditary

Haemochromatosis

Pierre Brissot, MD

Professor of Medicine

Liver Disease Department

University Hospital Pontchaillou

Rennes, France

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

Definition

• Haemochromatosis = chronic iron overload of genetic origin1

– HFE-haemochromatosis (type 1) Homozygous C282Y mutation (affected

chromosome [6])1,2

– Non-HFE haemochromatosis

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

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

Epidemiology—Penetrance1

Incomplete for HFE-HC–Phenotypic Variability (5-Scale Grading)

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.

Tf Sat

Ferritin

Tf Sat0

1

2

PRECLINICAL

3

4

Ferritin

Quality of life

Tf Sat

Life

Ferritin

Quality of life

Tf Sat

CLINICAL

Reprinted from Brissot P, et al, Hematology, Jan 2006:36, with permission from the American Society of Hematology.

Epidemiology—Penetrance1

Modifying factors • Acquired

– Diet

– Menses

– Pregnancies

– Blood loss/blood donation

• Genetic

– Polymorphism or mutations of other genes related to iron metabolism

Epidemiology—Inheritance1

Genetic transmission of HC

• Autosomal recessive

• Exception: ferroportin disease (Dominant

transmission)

HEPCIDIN

Blood

IRON

Liver

1

Spleen

Duodenum

Iron Overload

For Types 1, 2, and 3 HC Hepcidin Deficiency

Pathophysiology5

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 non–transferrin-bound iron species) produces parenchymal iron deposition (here, only the liver target is indicated)

2

3

4

5

6

1

2

3

4

5

6

7

7

HFE (type 1) or non-HFE (type 2 or 3) mutations

Fe

Fe

FeFe

Ferroportin

Hepcidin

Cell

Plasma

1

2

3

4

5

Pathophysiology6

6

Physiology of Hepcidin-Ferroportin Interaction6

Ferroportin =iron export protein

Circulating hepcidin

Decreased iron release due to decreased ferroportin

Degraded ferroportin

1 2 3 Hepcidin bindsto ferroportin

4 Internalization, then ferroportin degradation

5 6

Internalization, but decreased ferroportin degradation

Decreased hepcidin binding to ferroportin

Fe

FeFeFe

Hepcidin

Cell(= enterocyte

and macrophage)

Plasma1

2

3

4 5

1 2Decreased circulating hepcidin

3 4 5 Increased iron release due to increased ferroportin activity

Quantitative Defect in Hepcidin-Ferroportin Interaction (Types 1, 2, 3 HC)7

Fe

Increased ferroportin

Pathophysiology

Blood

= Iron atom

PathophysiologyIron Overload

For Ferroportin Disease(type 4 HC) and Aceruloplasminaemia Deficiency of Cellular Iron Export

Ferroportin Disease* Aceruloplasminaemia

Mutated ferroportin

Macrophagic iron excess due to deficient iron export (kupffer cell siderosis shown in 3)

Fe2+

Fe3+

Cp

.

Transferrin

Mutated ceruloplasmin (Cp)

Mutation leads to absence of ferroxidase activity (needed for iron uptake by transferrin)

Excessive ferroportin degradation leads to decreased cellular export of iron

Blood

*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

1

2

1

2

1

1

2

2

3

43

4

In both diseases plasma iron concentration is normal or low

Decreased ferroportin degradation

Defect in hepcidin binding to ferroportin

Fe

FeFe

Hepcidin

Plasma1

2

3

4

5

1 2Normal hepcidin

3 4 5 Increased iron release due to increased ferroportin activity

Fe

Increased ferroportin

Mutated ferroporti

n

Qualitative Defect in Hepcidin-Ferroportin Interaction (Type 4B HC) Hepcidin ResistancePathophysiology

Cell(= enterocyte

and macrophage)

Fe

Arthropathy

Skin Pigmentation

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

(www.radio.univ-rennes1.fr)

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 diagnosingiron overload

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

Caucasian ?

Elevated transferrin

(>60% men, >50% women)

Yes

C282Y/C282Y ?

Type 1 HC

No

Yes No

Genetic test Genetic test

if < 30 years old

Haemojuvelin(Type 2A HC)

Hepcidin(Type 2B HC)

Ferroportin(Type 4B HC)

TfR2 (Type 3 HC)

Diagnosis to Prove Genetic Origin— Elevated TF1

Diagnosis to Prove Genetic Origin— Normal or Low TF1

Normal or low transferrin (<45%)

Plasma ceruloplasmin level

Aceruloplasminaemia

If anaemia & neurologic symptoms

0 (or low) Normal

Genetic testFerroportin?

(Type 4A HC)

Yes

No

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

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

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)

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*

No special follow-up

*C282Y/wild-type

C282Y = 2†

Grading

Venesections if grade ≥ 2†C282Y/C282Y

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

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

References 1. Brissot P, de Bels F. Current approaches to the management of hemochromatosis.

Hematology. Am Soc Hematol Educ Program. 2006:36-41.2. Pietrangelo A. Hereditary hemochromatosis—a new look at an old disease. N Engl J

Med. 2004;350:2383-2397.3. 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;131:240-245.

4. Camaschella C. Understanding iron homeostasis through genetic analysis of hemochromatosis and related disorders. Blood. 2005;106:3710-3717.

5. Loreal O, Haziza-Pigeon C, Troadec MB, et al. Hepcidin in iron metabolism. Curr Protein Pept Sci. 2005;6:279-291.

6. Nemeth E, Tuttle MS, Powelson J, et al. Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization. Science. 2004;306:2090-2093.

7. Donovan A, Roy CN, Andrews NC. The ins and outs of homeostasis. Physiology. 2006;21:115-123.

8. 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.

9. Gandon Y, Olivié D, Guyader D, et al. Non-invasive assessment of hepatic iron stores by MRI. Lancet. 2004;363:357-362.

Thank you for participatingin this webcast

Please remember to take the posttest