Indications for successful iron overload treatment and monitoring hereditary haemochromatosis
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Indications for Successful Iron Overload Treatment and Monitoring: Hereditary Haemochromatosis. Pierre Brissot, MD Professor of Medicine Liver Disease Department University Hospital Pontchaillou Rennes, France. Outline. Iron overload treatment of HFE-haemochromatosis Type 1 or C282Y/C282Y HC

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Indications for successful iron overload treatment and monitoring hereditary haemochromatosis l.jpg

Indications for Successful Iron Overload Treatment and Monitoring:Hereditary Haemochromatosis

Pierre Brissot, MDProfessor of Medicine

Liver Disease DepartmentUniversity Hospital PontchaillouRennes, France


Outline l.jpg
Outline Monitoring:

Iron overload treatment of

  • HFE-haemochromatosis

    • Type 1 or C282Y/C282Y HC

  • Non–HFE-haemochromatosis

    • Type 2 HC (juvenile HC)

    • Type 3 HC (TfR2 HC)

    • Type 4 HC (ferroportin disease)

    • Hereditary aceruloplasminaemia

HC = haemochromatosis; TfR2 = transferrin receptor 2.


Hfe haemochromatosis l.jpg

Principle Monitoring:

Practical management

Results

Limitations

HFE-Haemochromatosis

Phlebotomy = Therapy of Choice

Courtesy of P. Garo, Phanie Agency


Hfe haemochromatosis principle of phlebotomy l.jpg

Fe Monitoring:

Fe

Fe

Fe

Fe

Fe

RBC

RBC

RBC

Phlebotomy

HFE-HaemochromatosisPrinciple of Phlebotomy

Hepatocyte

Bone marrow

3

2

BLOOD

1

Courtesy of P. Brissot


Hfe haemochromatosis practical management of phlebotomies l.jpg
HFE-Haemochromatosis Monitoring:Practical Management of Phlebotomies

  • Overall schedule1

    • Start: grade 2 HC (ferritin level >300 µg/L for men,>200 µg/L for women)

    • Induction phase: 7 mL/kg body weight (<550 mL), weekly,until ferritin ≤50 µg/L (haemoglobin remaining ≥11 g/dL)

    • Maintenance phase: every 1–4 months to maintainferritin ≤50 µg/L (lifetime regimen)

  • Technical details

    • Nonfasting subject

    • In a half-recumbent position

    • Drinking an equivalent volume to that removed

    • Monitor blood pressure before and after the venesection

1. Brissot P, de Bets F.Hematology. Am Soc Hematol Educ Program. 2006:36.


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HFE-Haemochromatosis Monitoring:Results of Phlebotomies

  • Good results on

    • General health

    • Hyperpigmentation

    • Hypertransaminasaemia and hepatic fibrosis (if moderate)

    • Cardiac symptoms

  • Mixed results on

    • Joint symptoms (may persist or even worsen)

    • Diabetes (remains insulin-dependent)

Brissot P, de Bets F. Hematology. Am Soc Hematol Educ Program. 2006:36.


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HFE-Haemochromatosis Monitoring:Results of Phlebotomies

Two important notions

  • If cirrhosis was present prior to phlebotomies, the risk for hepatocellular carcinoma remains (requiring plasma alpha-feto-protein dosage and liver ultrasound every 6 months)1

  • If cirrhosis or insulin-dependent diabetes was not present prior to phlebotomies, life expectancy returns to normal2

1. Brissot P, de Bels F. HematologyAm Soc Hematol Educ Program. 2006:36. 2. Dooley JS. Pract Res Clin Haematol. 2002;15:277.


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HFE-Haemochromatosis Monitoring:Limitations of Phlebotomies—Conceptual

Phlebotomies

  • By inducing marked iron release from hepatocytes(at the induction phase)

    and

  • By increasing intestinal absorption of iron (through enhancing hepcidin deficiency)

    May contribute to increase in plasma transferrin saturation (TfSat) and favour (whenever TfSat is ≥75%1) the appearance of labile plasma iron (LPI), which is the potentially toxic form of circulating iron

1. Le Lan C, et al. Blood. 2005;105:4527.


Hfe haemochromatosis limitations of phlebotomies practical l.jpg
HFE-Haemochromatosis Monitoring:Limitations of Phlebotomies—Practical

From the clinical viewpoint

  • Venous punctures may be (or become) difficult1

  • Arthropathy may worsen2

  • General lassitude in the long run

  • Efficacy may be insufficiently rapid in massive iron excess, especially with cardiomyopathy

Adams PC. Lancet. 2007;370:1855.

Dooley JS. Pract Res Clin Haematol. 2002;15:277.


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HFE-Haemochromatosis Monitoring:Limitations of Phlebotomies—Practical

From the societal viewpoint:

  • Time-consuming procedure (especially during professional activity)

  • Unsatisfactory health center network for venesections

  • Poorly defined procedure when performed at home (blood elimination process…)


Hfe haemochromatosis iron chelation a changing view l.jpg
HFE-Haemochromatosis Monitoring:Iron Chelation—A Changing View

Until recently: a very limited place

  • Desferrioxamine

    • Subcutaneous infusion (2 g/day; 12 hours/day;5 days/week; usually for several months)

    • Only

      • When phlebotomies are contraindicated or not feasible, or

      • In case of massive iron excess (with cardiac disease), and then combined with bloodletting

    • Efficient for iron depletion

    • But uncomfortable procedure and possibleside-effects (audiometry and eye exams annually)


Hfe haemochromatosis iron chelation a changing view12 l.jpg
HFE-Haemochromatosis Monitoring:Iron Chelation—A Changing View

  • Until recently—a very limited place

    • Deferiprone

      • Oral chelator

      • Not advisable due to its very rare butunpredictable risk of agranulocytosis

  • Now—a promising perspective…


Hfe haemochromatosis oral chelation by deferasirox an interesting perspective l.jpg

• Principle Monitoring:

• Indications

• Limitations

HFE-Haemochromatosis Oral Chelation by Deferasirox—An Interesting Perspective


Hfe haemochromatosis principle of oral chelation deferasirox l.jpg
HFE-Haemochromatosis Monitoring:Principle of Oral Chelation—Deferasirox

  • Efficacy can be expected in type 1 haemochromatosis,due to

    • Its preferential hepatocytic target (as indicated by its very high degree of biliary elimination)1

    • Its capacity for removing labile plasma iron (LPI)

      1. Adams PC. Lancet. 2007;370:1855.

11


Hfe haemochromatosis indications of oral chelation deferasirox l.jpg
HFE-Haemochromatosis Monitoring:Indications of Oral Chelation—Deferasirox

Could be used

  • Alone, as replacement for phlebotomies, in case of

    • Moderate or important iron excess

    • Technical impossibility for venesection1

    • Contraindication for venesection (eg, anaemia)1,2

  • In association with phlebotomies, in case of massive iron overload, especially with severe visceral (especially cardiac) damage

1. Adams PC. Lancet. 2007;370:1855. 2. Beutler E. Blood Cells Mol Dis. 2007;39:140.


Hfe haemochromatosis limitations of oral chelation l.jpg
HFE-Haemochromatosis Monitoring:Limitations of Oral Chelation

Deferasirox will be used, provided it does not lead to significant side-effects

This is the goal of an ongoing international safety trial

11


In non hfe haemochromatosis l.jpg
In Non–HFE-Haemochromatosis Monitoring:

The respective place of phlebotomies and oral chelation depends greatly on the underlying pathophysiological mechanisms accounting for iron overload

11


Non hfe haemochromatosis l.jpg
Non–HFE-Haemochromatosis Monitoring:

For type 2 HC (juvenile HC by haemojuvelin or hepcidin mutations), type 3 HC (TfR2 HC) or type 4-B HC (ferroportin disease with hepcidin resistance)

  • The therapeutic management for iron overload is very close to that of type 1 HC

  • In juvenile HC, massively damaging iron excess favors combining phlebotomy and oral chelation in order to accelerate iron removal


Non hfe haemochromatosis19 l.jpg
Non–HFE-Haemochromatosis Monitoring:

For type 4-A HC (usual form of ferroportin disease), and hereditary aceruloplasminaemia, both characterized by an impairment of cellular iron release into the blood (= iron recycling defect)

  • Phlebotomies may be poorly tolerated (risk of anaemia)1in type 4-A HC, so that oral chelation may be, if well tolerated, a good indication

  • Phlebotomies are contraindicated in hereditary aceruloplasminaemia, due to pre-existing anaemia.

  • Parenteral desferrioxamine can be efficient,2 but oral chelation appears clearly an excellent indication

  • 1. Montosi GJ, et al. J Clin Invest. 2001;108:619. 2. Loreal OJ, et al. J Hepatol. 2002;36:851.



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Long-Term Treatment Perspectives Monitoring:

For all forms of HC related to hepcidin deficiency (ie,Types 1, 2, and 3 haemochromatosis):

The therapeutic approach will be either exogenous hepcidin supplementation or endogenous stimulation of hepcidin production


Long term treatment perspectives22 l.jpg
Long-Term Treatment Perspectives Monitoring:

  • For all forms of HC related to hepcidin deficiency, (ie, Types 1, 2, and 3 haemochromatosis), it is anticipated that:

    • The major indication of hepcidin upgrading will be during the maintenance phase, as it is expected that the use of hepcidin prior to restoration of normal iron stores by phlebotomies/iron chelation may hamper depletion of excess iron

    • Therefore, it might not be advisable for hepcidin supplementation to be done concurrently with phlebotomies/iron chelation


Conclusions l.jpg
Conclusions Monitoring:

  • Phlebotomy remains the treatment of choice for HFE-haemochromatosis

  • Oral chelation by deferasirox may offer an alternative to phlebotomy or as an addition to phlebotomy in cases of massive iron overload and/or severe visceral damage

  • Respective roles of phlebotomy and iron chelation depend on the pathophysiologic mechanisms responsible for iron overload


Conclusions24 l.jpg
Conclusions Monitoring:

  • Management of iron overload for types 2 and 3 HC is similar to that of type 1

  • Oral chelation may be preferable in managing iron overload in type 4A HC and hereditary aceruloplasminaemia


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