Iron toxicity and clinical sequelae
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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

TransfusionalNontransfusionalAge of onsetComplications

Thalassaemia major1Type 2 haemochromatosis (rare)2Childhood

Blackfan Diamond Anaemia12a hemojuvelin2(Risks from HH)

Fanconi’s Anaemia12b hepcidin2

Early stroke with HbSS1

Severe haemolytic anaemias1

Aplastic anaemia1,2Type 1 haemochromatosis1Typically 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

ConditionCauseIron DistributionEffects

AceruloplasminaemiaPlasma reductaseRetinaRetinopathy

AR1,2Basal gangliaExtrapyramidal

PancreasDiabetes

Hallervorden-Spatz Pantotenate kinaseBasal gangliaExtrapyramidal

AR3cysteine accumulation

NeuroferritinopathyFerritin light chainBasal gangliaExtrapyramidal

AD4ForebrainParkinsonian

Cerebellum

Freidrich’s Ataxia5,6FrataxinMitochondrialAtaxia

AR oxidative stressSensory neuronsSpinal cordDorsal root gangliaMyocardiumCardiomyopathy

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.


How do inherited nontransfusional forms of iron loading develop

How Do Inherited Nontransfusional Forms of Iron Loading Develop?


Effect of hepcidin on iron turnover

Effect of Hepcidin on Iron Turnover

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

TfR21

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

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


Why is iron overload toxic

Why Is Iron Overload Toxic?


Redox cycling of iron

Redox Cycling of Iron

Fe2+

Fe3+

- e-

+ e-

Slide courtesy of Dr. J. Porter.


Hydroxyl radical ho generation

Hydroxyl Radical (HO.) 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.

.

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

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

  • Nature of NTBI

    • Citrate iron

      • PolymericSlowly chelated

      • Oligomeric

      • Dimeric

      • MonomericRapidly 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 NTBIReceptors

  • 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

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

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.


Where is iron toxic

Where Is Iron Toxic ?


Transfusional iron overload1

Transfusional Iron Overload

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 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.


Liver and iron content postmortem in thalassaemia major

Liver and Iron Content Postmortem in Thalassaemia Major

Heart

Liver


Causes of death in thalassaemia

Causes of Death in Thalassaemia

Age (years)

0–45–910–1415–19>20Total

Heart disease063935 1696

Infection2693 020

Liver disease0027 110

Malignancy2211 28

Endocrine disease0021 14

Accident0022 04

Thromboembolism0021 14

Anaemia2000 02

Other0110 13

Unknown0133 18

Total6166153 23159

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

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 in 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 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.


Which forms of iron are most toxic

Which Forms of Iron Are Most Toxic?


Labile toxic iron pools

Labile Toxic Iron Pools?

  • 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?

  • 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

    • 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 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

    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

    • 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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