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Iron Toxicity and Clinical Sequelae. John B. Porter, MA, MD, FRCP Professor Department of Haematology University College London London, United Kingdom. Learning Objectives.

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Iron toxicity and clinical sequelae
Iron Toxicity and Clinical Sequelae

John B. Porter, MA, MD, FRCP

ProfessorDepartment of HaematologyUniversity College LondonLondon, United Kingdom


Learning objectives
Learning Objectives

  • Analyze the mechanisms contributing to the development of iron overload and the clinical consequences of iron overload on the liver, heart, and endocrine system.

  • Utilizing an understanding of the factors contributing to the development of iron overload, identify patients at risk in the practice setting.


Topics
Topics

  • Causes of iron overload

  • Mechanisms of iron-overload–mediated toxicity

    • Molecular level

    • Non–transferrin-bound iron—extracellular

    • Labile iron pool—intracellular

    • Free radical formation

      • Microscopic level

      • Macroscopic level

  • Clinical impact consequences of iron overload


Conditions associated with iron overload
Conditions Associated with Iron Overload

Transfusional Nontransfusional Age of onset Complications

Thalassaemia major1 Type 2 haemochromatosis (rare)2 Childhood

Blackfan Diamond Anaemia1 2a hemojuvelin2(Risks from HH)

Fanconi’s Anaemia1 2b hepcidin2

Early stroke with HbSS1

Severe haemolytic anaemias1

Aplastic anaemia1,2 Type 1 haemochromatosis1 Typically adult

Other transfusion in HbSS1 Thalassaemia intermedia1

Myelodysplasia (MDS)3

Repeated myeloablative chemotherapy1

Slide courtesy of Dr. J. Porter.

  • Porter JB. Br J Haematol. 2001;115:239. 2. Brittenham G. In Hoffman R, et al, ed. Hematology: Basic Principles and Practice, 4th ed. Philadelphia, PA: Churchill Livingstone, 2004. 3. Taher A, et al. Semin Hematol. 2007;44:S2.


Acquired nontransfusional forms of iron overload
Acquired, Nontransfusional Forms of Iron Overload

  • Chronic liver disease

    • Hepatitis C

    • Alcoholic liver disease

    • Nonalcoholic steatohepatitis

  • Porphyria cutanea tarda

  • Portacaval shunting

  • Inappropriately high dietary intake

    • Latrogenic (eg, treatment of microcytosis)

    • African (Bantu) siderosis*

*Dietary and hereditary components.

Bacon BR. In Goldman L, ed. Cecil’s Textbook of Medicine, 23rd ed. Philadelphia, PA: Saunders-Elsevier, 2008.


Rare abnormalities of iron distribution
Rare Abnormalities of Iron Distribution

Condition Cause Iron Distribution Effects

Aceruloplasminaemia Plasma reductase Retina Retinopathy

AR1,2 Basal ganglia Extrapyramidal

Pancreas Diabetes

Hallervorden-Spatz Pantotenate kinase Basal ganglia Extrapyramidal

AR3 cysteine accumulation

Neuroferritinopathy Ferritin light chain Basal ganglia Extrapyramidal

AD4 Forebrain Parkinsonian

Cerebellum

Freidrich’s Ataxia5,6 Frataxin Mitochondrial Ataxia

AR oxidative stress Sensory neurons Spinal cord Dorsal root ganglia Myocardium Cardiomyopathy

AR = autosomal recessive; AD = autosomal dominant.

1. Mariani R, et al. Gut. 2004;53:756-8. 2. Hellman NE, et al. Gut. 2000;47:858-60. 3. Hayflick SJ. Curr Opin Pediatr. 2003;15:572-7. 4. Crompton DE, et al. Blood Cells Mol Dis. 2002;29:522-31. 5. Koepen A, et al. Acta Neuropahtol. 2007;114:163-73. 6. Michael, et al. Cerebellum. 2007;5:257-67.


How does transfusional iron loading develop
How Does Transfusional Iron Loading Develop?


Simplified iron turnover and storage
Simplified Iron Turnover and Storage

Erythron

2g

20–30 mg/day

Other

parenchyma

0.3 g

Hepatocytes

1 g

20–30 mg/day

Red

Transferrin

Macrophages

0.6 g

2–3 mg/day

20–30 mg/day

1–2 mg/day

Gut

Porter J. Hematol/Oncol Clinics. 2005;19(suppl 1):7.


Rate of iron loading from transfusion
Rate of Iron Loading from Transfusion

  • Simple estimation1

    • 1 unit contains 200 mg of iron

    • Adult may receive 4–10 g/y from transfusion

  • More-precise method2

    • Volume of blood transfused x mean haematocrit of processed blood obtained from the transfusion centre x 1.08

  • For exchange transfusion need to know

    • Volume and haematocrit transfused

    • Volume and haematocrit removed

  • Taher A, et al. Semin Hematol. 2007;44:S2.

  • Porter JB. Br J Haematol. 2001;115:239.


Transfusional iron overload
Transfusional Iron Overload

Transfusion

Erythron

Parenchyma

20–40 mg/day

(0.3–0.7 mg/kg/day)

Parenchyma

Hepatocytes

NTBI

Red

Hepatocytes

Macrophages

Transferrin

Gut

NTBI = non–transferrin-bound iron.

Adapted from Porter JB. Hematol/Oncol Clinics. 2005;19(suppl 1):7-12.


Liver iron and risk from iron overload
Liver Iron and Risk from Iron Overload

50

250

Thalassaemia major

40

200

30

HH homozygote

150

Hepatic Iron (µmol/g wet weight)

HepaticIron (mg/g, dry weight)

20

Threshold for cardiac disease and early death

100

Increased risk of complications

10

50

HH heterozygote

Normal

0

0

0

10

20

30

40

50

Age (years)

HH = hereditary haemochromatosis.

Olivieri N, Brittenham G. Blood. 1997;89:739.



Effect of hepcidin on iron turnover
Effect of Hepcidin on Iron Turnover Develop?

Erythron

20–30 mg/day

Hepatocytes

20–30 mg/day

IL6

Iron

Hypoxia

Macrophages

-

Transferrin

+

2–3 mg/day

20–30 mg/day

Prohepcidin

1–2 mg/day

Gut

Hepcidin

Adapted from Porter JB. Hematol/Oncol Clinics. 2005;19(suppl 1):7.


Factors affecting hepcidin expression

TfR2 Develop?1

HJV2

Oral iron1

Iron stores1,2

LPS2

IL-62

HFE1

Factors Affecting Hepcidin Expression?

Hepcidin

-

+

  • Erythropoiesis1

  • Anaemia1

  • Hypoxia1

  • NTBI?

Tf = transferrin; TfR = transferrin receptor; HJV = hemojuvelin; LPS = lipopolysaccharide; IL = interleukin; NTBI = non–transferrin-bound iron.

1. Leong W, Lönnerdal B. J Nutr. 2004;134:1.

2. Lee P, et al. Proc Natl Acad Sci U S A. 2004;101:9263.


Classification of haemochromatosis
Classification of Haemochromatosis Develop?

With permission from Worwood M. Blood Rev. 2005;19:69.



Redox cycling of iron
Redox Cycling of Iron Develop?

Fe2+

Fe3+

- e-

+ e-

Slide courtesy of Dr. J. Porter.


Hydroxyl radical ho generation
Hydroxyl Radical (HO Develop?.) Generation

Haber Weiss Reaction

O2.- + H2O2 -----> O2 + OH- + HO.

Catalysed by Iron in two steps; (Fenton reaction)

Fe3++ O2.- -----> Fe2++ O2

Fe2++ H2O2 -----> Fe3++OH- + HO.

Porter J. Hematol/Oncol Clinics 2005;19(suppl 1):7.


Lipid peroxidation by ho
Lipid Peroxidation by HO Develop?.

.

H2O

Hydrogen abstraction ( H.)

Molecular rearrangement

.

+ O2

Oxygen uptake

Peroxyl radical

propagates peroxidation byabstracting H. from another fatty acid

O

O

.

Lipid hydroperoxide

Decomposition

eg, to MDA

O

O

H

Porter J. Hematol/Oncol Clinics 2005;19(suppl 1):7.With permission from Gutteridge JM, Halliwell B. Baillieries Clin Haematol. 1989;2:195.


Consequences of iron mediated toxicity
Consequences of Iron-Mediated Toxicity Develop?

Increased free iron

Hydroxyl radical generation

Lipid peroxidation

Organelle damage

TGF-b1

Lysosomal fragilityEnzyme leakage

Collagensynthesis

Cell death

Fibrosis

Gutteridge JMC, Halliwell B. BailleresClin Haematol. 1989;2:195-256. Bacon BR, et al, J Clin Invest. 1983;71:429-439.Myers BM, et al. J Clin Invest. 1991;88:1207-1215. Tsakamota H, et al. J Clin Invest. 1995;96:620-630.Houglum K, et al. Hepatology.1997;26:605-610.


Nature of ntbi
Nature of NTBI Develop?

  • Nature of NTBI

    • Citrate iron

      • Polymeric Slowly chelated

      • Oligomeric

      • Dimeric

      • Monomeric Rapidly chelated

  • Protein-bound iron

    • Binds weakly to albumin

    • As citrate oligomers bound to albumin

  • Other

NTBI = non–transferrin-bound iron.

Evans R et al. J Biol Inorg Chem. 2007;13:57.


Uptake of ntbi receptors
Uptake of NTBI Develop?Receptors

  • Divalent metal transporter (DMT1)1

    • Enterocytes

    • Erythron (negatively regulated by iron loading)

    • ? Other

  • L-type calcium-dependent channels2

    • Myocardium (positively induced by iron loading)

    • Anterior pituitary (positively induced by iron loading)

  • T-type calcium channels3

    • Hepatocytes (positively induced by iron loading)

1.Bacon BR. In Goldman L, ed. Cecil’s Textbook of Medicine, 23rd ed. Philadelphia, PA: Saunders-Elsevier, 2008. 2. Oudit GY, et al. Circulation. 2004;109:1877. 3. Rafique et al. Blood. 2006;108:1542a.


Antioxidant capacity in iron overload

0 Develop?

20

40

60

80

Antioxidant Capacity in Iron Overload

  • 48 thalassaemia major (age 11–22 years)

  • Vitamin E and NTBI negatively correlate (r = -0.81)

  • No correlation with serum ferritin

Lycopene

Ubiquinol

Vitamin E

Ubiquinone

Vitamin A

B-carotene

Vitamin C

% Decrease of Control

Slide courtesy of Dr. J. Porter.

De Luca C, et al. Free Radic Res. 1999;30:453.


Intracellular iron mediated toxicity from labile intracellular iron

Ferritin Develop?

Non-transferrin

iron

LVDCC

Labile

iron pool(LIP)

Lysosomal

degradation

Free-radical generation

Iron

proteins

Organelle damage

Intracellular Iron-Mediated Toxicityfrom Labile Intracellular Iron

Transferrin

iron

LVDCC = L-type voltage-dependent calcium channel.

Porter JB. AmJ Hematol. 2007;82:1136.



Transfusional iron overload1
Transfusional Iron Overload Develop?

Transfusion

Erythron

Parenchyma

20–40 mg/day

(0.3–0.7 mg/kg/day)

Parenchyma

Hepatocytes

NTBI

Hepatocytes

Macrophages

Transferrin

Gut

NTBI = non–transferrin-bound iron.

Adapted from Porter JB. Hematol/Oncol Clinics 2005;19(suppl 1):7.


Iron distribution in transfusional overload
Iron Distribution in Develop?Transfusional Overload

  • Transfusional overload distribution differs from absorption distribution at early stages1

  • Why great variability in iron distribution in different tissues?

    • Liver, endocrine glands, anterior pituitary1

    • Very little in brain, skeletal muscle1

    • Liver iron correlates with units transfused2

1. Porter JB. Hematol/Oncol Clinics 2005;19(suppl 1):7.

2. Taher A, et al. Semin Hematol. 2007;44:S2.


Distribution of body iron at postmortem in tm in prechelation era
Distribution of Body Iron at Postmortem in TM in Prechelation Era

Skeletal muscle

Testes

Kidney

Heart

Adrenal

Salivary gland

Thyroid

Pancreas

Liver

Parathyroid

Minimum

Maximum

0

2

4

6

8

F

e

%

d

.

w

.

Tm = thalassaemia major; d.w. = dry weight.

Adapted from Modell B, Mathews R. Birth Defects Orig Artic Ser. 1976;12:13.



Causes of death in thalassaemia
Causes of Death in Thalassaemia Prechelation Era

Age (years)

0–4 5–9 10–14 15–19 >20 Total

Heart disease 0 6 39 35 16 96

Infection 2 6 9 3 0 20

Liver disease 0 0 2 7 1 10

Malignancy 2 2 1 1 2 8

Endocrine disease 0 0 2 1 1 4

Accident 0 0 2 2 0 4

Thromboembolism 0 0 2 1 1 4

Anaemia 2 0 0 0 0 2

Other 0 1 1 0 1 3

Unknown 0 1 3 3 18

Total 6 16 61 53 23 159

n = 1078

Zurlo MG, et al. Lancet. 1989;2:27.


Blood transfusion and cardiac iron deposits at postmortem in the prechelation era

131 transfused adult patients Prechelation Era

101 leukaemias

30 other anaemias

100

80

60

40

20

0

26–50

51–75

76–100

101–200

201–300

0–25

Blood Transfusion and Cardiac Iron Deposits at Postmortem in the Prechelation Era

Patients with Cardiac Iron (%)

Units of Blood Transfused

Slide courtesy of Dr. J. Porter.

Buja LM, Roberts WC. Am J Med. 1971;51:209.


Blood transfusion predicts heart iron in unchelated patients
Blood Transfusion Predicts Heart Iron Prechelation Erain Unchelated Patients

20

18

16

14

12

Estimated Heart Iron (µmol/g)

10

8

Upper

Normal

Limit

6

4

2

0

25

50

75

100

125

150

Blood Units Transfused

Slide courtesy of Dr. J. Porter.

Jensen PD, et al. Blood. 2003;101:4632.


Is the heart equally at risk of iron loading in all forms of transfusional iron
Is the Heart Equally at Risk of Iron Loading in All Forms of Transfusional Iron?

UCLH patients with cardiac MRI

Sickle (n = 37)

Myelodysplasia (n = 7)

Diamond Blackfan (n = 7)

PK deficiency (n = 9)

Congenital sideroblastic (n = 4)

Thalassaemia intermedia (n = 23)

Thalassaemia major (n = 108)

0

20

40

60

80

Patients (%, n) with T2* < 20 ms

Glanvillle J, et al. Presented at ASH 2006. Blood. 2006;108:abstract 1553.


Ntbi in sickle cell or thalassaemia major matched for liver iron concentration
NTBI in Sickle Cell or Thalassaemia Major Transfusional Iron? Matched for Liver Iron Concentration

Patients Treated at UCLH

8

P = 0.0001

7

6

5

4

NTBI (µM)

3.38 ± 2.4

3

2

1

0.17 ± 1.8

0

-1

-2

HbSS

Thalassaemia major

LIC = 4.34

LIC = 4.22

Slide courtesy of Dr. J. Porter.

Shah F. Presentation at ASH Dec 2002. Blood 2002;100:668a.



Labile toxic iron pools
Labile Toxic Iron Pools? Transfusional Iron?

  • NTBI in plasma?

    • Correlates with antioxidant depletion

    • Promotion of lipid peroxidation in vitro

    • BUT which species?

  • Labile iron pools (LIP) in cells?

    • In vitro: clear evidence linking free iron to lipid peroxidation and organelle damage

  • Clinical evidence?

    • Improvement in cardiac performance with intravenous desferrioxamine precedes changes in cardiac iron

    • BUT direct link of NTBI or LIP to clinical damage not established

Porter J. Hematol/Oncol Clinics. 2005;(suppl 1):S7.


Absolute tissue levels
Absolute Tissue Levels? Transfusional Iron?

  • Evidence (serum ferritin) >2500 µg/L & cardiac disease-free survival1

  • Liver iron association with cardiac death2

    • Of 15/53 thalassaemia major patients with cardiac disease, all had liver iron >15 mg/g dry weight3

  • Association or causation?

  • But

    • Iron in different tissues at postmortem does not correlate with damage to those organs3

    • Link of cardiac iron to damage & death not known3

    • Olivieri NF, et al. N Engl J Med. 1994;331:574.

    • Brittenham GM, et al. N Engl J Med. 1994;331:567.

    • Porter JB. Hematol/Oncol Clinics. 2005;19(suppl 1):S7.


    Intracellular iron levels and toxicity
    Intracellular Iron Levels and Toxicity Transfusional Iron?

    • Concepts

      • “Safe iron”

        • No toxicity in heterozygotes of hereditary haemochromatosis where liver levels < 7mg/g dry weight.1

      • “Dangerous iron”

        • High risk of cardiac death if liver >15 mg/g dry weight.1

    • Limitations

      • Uneven distribution within and between tissues2

      • Relationship between heart iron and mortality unknown2

    1. Porter JB. Br J Haematol. 2001;115:239.

    2. Porter J. Hematol/Oncol Clinics. 2005;19(suppl 1):7.


    Functional consequences of transfusional iron overload
    Functional Consequences Transfusional Iron?of Transfusional Iron Overload

    • Liver1

    • Heart1

    • Endocrine system1

    • Cancer

    • Other potential sequelae

      • Arthropathy2

      • Hyperpigmentation2

    1. Porter JB. Hematol/Oncol Clinics. 2005;19(suppl 1):S7.

    2. Brittenham G. In Hoffman R, et al, ed. Hematology: Basic Principles and Practice, 4th ed. Philadelphia, PA: Churchill Livingstone, 2004.


    Organ systems affected by iron overload
    Organ Systems Affected by Iron Overload Transfusional Iron?

    Organ

    Consequences

    Pituitary

    Hypogonadotrophic hypogonadism1

    Hypothyroidism1

    Thyroid

    Hypoparathyoidism1

    Parathyroid

    Heart

    Cardiomyopathy1

    Liver

    Cirrhosis, carcinoma1

    Pancreas

    Diabetes1

    Pigmentation2

    Skin

    Gonads

    Hypogonadotrophic hypogonadism1

    Joints

    Arthropathy2

    1. Taher A, et al. Semin Hematol. 2007;44:S2.

    2. Brittenham G. In Hoffman R, et al, ed. Hematology: Basic Principles and Practice, 4th ed. Philadelphia, PA: Churchill Livingstone, 2004.


    Conclusions
    Conclusions Transfusional Iron?

    • Conditions associated with iron overload include transfusional iron overload as well as hereditary and acquired nontransfusional iron overload

    • Because the body has no mechanism for excretion of excess iron, iron can accumulate

    • Iron accumulation results in

      • Increased free iron

      • Hydroxyl radical generation

      • Lipid peroxidation

    • This results in cell death and fibrosis, with impact on a variety of organ systems and functional consequences

      • Heart

      • Liver

      • Endocrine system


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