Transcript Document
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 origin
1 – 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 • Aceruloplasminaemia 3 – Ceruloplasmin mutations [3]* 1,3 • Other types: atransferrinaemia, DMT1 mutation–related iron overload, GLRX5 mutation –related iron overload 1,2 *Affected chromosome
Epidemiology —Prevalence • HFE-haemochromatosis (type 1)
4 – >90% of cases 1 – Generally of Northern European descent 4 Prevalence for C282Y homozygosity = 3/1000 – 5/1000 2,4
• Non–HFE-haemochromatosis
1 – Rare (ferroportin disease) or exceptional
Epidemiology —Penetrance 1
Incomplete for HFE-HC –Phenotypic Variability (5-Scale Grading)
4 2 3
Life Quality of life Quality of life
1
Ferritin Ferritin Ferritin Tf Sat Tf Sat Tf Sat Tf Sat
0 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.
Epidemiology —Penetrance
1
Modifying factors
• Acquired – Diet – Menses – Pregnancies – Blood loss/blood donation • Genetic – Polymorphism or mutations of other genes related to iron metabolism
Epidemiology —Inheritance
1 Genetic transmission of HC • Autosomal recessive • Exception: ferroportin disease (Dominant transmission)
Pathophysiology 5
Iron Overload
For Types 1, 2, and 3 HC Hepcidin Deficiency 1 HFE or non-HFE mutations decrease hepcidin hepatic synthesis 2 Hepcidin deficiency targets the duodenum, site of iron absorption 3 As a result of 2, duodenal absorption of iron increases 4 Hepcidin deficiency targets the spleen 5 As a result of 4, splenic iron release into the plasma increases 6 As a result of 3 and 5, plasma iron concentration significantly increases 7 Increased plasma iron (especially under its non –transferrin-bound iron species) produces parenchymal iron deposition (here, only the liver target is indicated) Liver HEPCIDIN 2 3 7 Duodenum 1 4 IRON Blood 6 5 HFE (type 1) or non-HFE (type 2 or 3) mutations Spleen
Fe
Pathophysiology 6
Physiology of Hepcidin-Ferroportin Interaction 6
Cell 5 4 Fe Fe Ferroportin 6 3 1 Fe 2 Hepcidin Plasma 1 Ferroportin = iron export protein 2 Circulating 3 hepcidin Hepcidin binds to ferroportin 4 Internalization, then ferroportin degradation 5 Degraded ferroportin 6 Decreased iron release due to decreased ferroportin
Pathophysiology
Quantitative Defect in Hepcidin-Ferroportin Interaction (Types 1, 2, 3 HC) 7
Cell (= enterocyte and macrophage) Fe 3 Fe 4 5 2 1 Decreased circulating hepcidin 1 Hepcidin 2 Decreased hepcidin binding to ferroportin 3 Internalization, but decreased ferroportin degradation Fe Fe 4 Increased ferroportin Fe 5 Plasma Increased iron release due to increased ferroportin activity
Pathophysiology
Iron Overload
For Ferroportin Disease (type 4 HC) and Aceruloplasminaemia Deficiency of Cellular Iron Export Ferroportin Disease* Aceruloplasminaemia 2 1 Transferrin 2 Fe 3+ Cp 1 Fe 2+ 3 4 Blood Blood
.
1 2
=
Iron atom Mutated ferroportin In both diseases plasma iron concentration is normal or low 1 Mutated ceruloplasmin (Cp) 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) *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.
3 4 Excessive ferroportin degradation leads to decreased cellular export of iron This leads to intracellular retention of iron
Pathophysiology
Qualitative Defect in Hepcidin-Ferroportin Interaction (Type 4B HC) Hepcidin Resistance
Cell (= enterocyte and macrophage) 4 Fe 3 Fe Mutated ferroportin 2 5 1 Hepcidin 1 Normal hepcidin 2 Defect in hepcidin binding to ferroportin 3 Decreased ferroportin degradation 4 Fe Increased ferroportin Fe 5 Fe Plasma Increased iron release due to increased ferroportin activity
Diagnosis to Establish Iron Overload — Clinical and Biochemical
• Clinical syndromes – Asthaenia, arthropathy, osteopaenia, skin pigmentation, impotence, diabetes, hepatomegaly, cardiac symptoms 8 • Biochemical parameter – Hyperferritinaemia = >300 µg/L in men, >200 µg/L in women 1 • Confounding factors 1 – Alcoholism – Polymetabolic syndrome – Inflammation – Hepatitis
Arthropathy Skin Pigmentation
Diagnosis to Establish Iron Overload —MRI
9 • 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
( www.radio.univ-rennes1.fr
)
Diagnosis to Prove Genetic Origin
1 • Family data – HC diagnosis or symptoms in favor of iron excess among family members • Personal data – Transferrin saturation level is a key parameter
Diagnosis to Prove Genetic Origin — Elevated TF
1
Elevated transferrin (>60% men, >50% women) Caucasian ?
Yes Genetic test C282Y/C282Y ?
Yes Type 1 HC No No Genetic test Haemojuvelin (Type 2A HC)
if < 30 years old
Hepcidin (Type 2B HC) Ferroportin (Type 4B HC) TfR2 (Type 3 HC)
Diagnosis to Prove Genetic Origin — Normal or Low TF
1
Normal or low transferrin (<45%) If anaemia & neurologic symptoms Plasma ceruloplasmin level Normal 0 (or low) Genetic test Ferroportin?
Yes Aceruloplasminaemia No (Type 4A HC)
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/L 1
Maintenance phase
: every 1 –4 months until ferritin ≤50 µg/L (lifetime regimen thereafter) 1
Results/Contraindications for Venesection Therapy
1 • 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)
Note: Life expectancy is normal if treatment starts before cirrhosis and insulin-dependent diabetes
• Ferroportin disease (type 4A HC) – Poorly tolerated: risk of anaemia • Aceruloplasminaemia – Contraindicated: anaemia
Treatment Perspectives
• Short-term perspective – Once daily oral chelator (deferasirox) If ongoing study establishes good tolerance 1 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 Screening
1 • 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 † C282Y/C282Y Venesections if grade ≥ 2
Family Screening
1 • 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
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