The Consequences of Iron Toxicity
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Unmanaged Iron Toxicity Causes Cumulative Toxicity and Progressive, Life-Threatening Organ
Damage
Unmanaged chronic iron overload causes progressive damage to the liver, heart, and
endocrine glands, and may eventually lead to premature death.1-9 Furthermore,
nonspecific early symptoms (such as abdominal discomfort and fatigue) may delay
diagnosis until severe damage to heart or liver tissues produces clinically apparent
symptoms.2,10 Therefore at-risk patients (such as those who have received multiple
blood transfusions) should be screened for iron toxicity.
Clinical Sequelae of Iron Toxicity. Transfusional iron overload can lead to life-altering
conditions and premature mortality.1-9 Patients can be asymptomatic as iron is invading
and accumulating in their organs.2,10
The Impact of Iron Toxicity on Survival
The impact of iron toxicity on survival is significant. Severe iron overload is associated
with premature death.11 Among patients with sickle cell disease (SCD), iron overload is
among the most frequent findings at death. Iron overload is associated with the
development of cirrhosis and cardiac disease, which are also leading findings at death in
SCD.8
Iron Overload Was a Leading Finding at Death in Patients with SCD, Who Died at an
Average Age of 36 Years8
*Including endocarditis.
†
Other than endocarditis and cor pulmonale.
Above is a proportional mortality study that looked at the circumstances of death in 141
adults with sickle cell disease, who died over a 25-year period. Iron overload was a
leading finding at death in patients with sickle cell disease, who died at an average age
of 36 years.8
Iron Buildup in the Body
There is no physiologic mechanism for removing excess iron.12 Regardless of disease
state or the number of years between transfusions, once the bodys natural ability to store
iron is exceeded, transfusional excess iron will build up in the body and may lead to
serious health consequences.1,12
When iron is bound to transferrin, ferritin, or other iron transport and storage proteins, it
cannot participate in oxidative reactions, and therefore cannot cause cellular damage.13
In iron overloaded patients, the capacity of these proteins to neutralize the damaging
effects of iron is exceeded. Excess iron binds weakly to various other low-molecularweight proteins in the plasma and cells, and in this form propagates cellular damage by
peroxidation of organelles such as mitochondria and lysosomes.13,14
Download the Iron Overload Brochure and have an important resource on the clinical
consequences of iron toxicity.
Cardiac Complications
Cardiac iron accumulation usually occurs after organs such as the liver and spleen have
become saturated with iron. Cardiac function may not change significantly until iron
levels reach a critical value or duration, after which systolic function rapidly
deteriorates and refractory heart failure occurs.14,15 Once cardiac dysfunction is
detected, the prognosis is poor without intervention, but can be improved if appropriate
therapy is given to address the iron overload.7,16
Iron overload cardiomyopathy is an old disease that has become increasingly
common.14 Currently, it is thought that iron overload cardiomyopathy is caused by the
direct effect of non–transferrin-bound iron (NTBI) on myocytes, rather than by
interstitial iron infiltration.14 NTBI is toxic to cardiac myocytes in extremely low
concentrations.14 Diastolic dysfunction is a result of myocardial damage due to iron
overload.14 Conduction defects are also linked to excess iron deposition in the bundle of
His and the Purkinje system.17,18
The incidence of cardiac disease for those with transfusion-dependent anemias is of
great concern. The most useful noninvasive diagnostic techniques for hemosiderotic
cardiomyopathy are left ventricular ejection fraction (LVEF) studies performed with
radionuclide ventriculography (in adults) or echocardiography (in children). The lower
the myocardial MRI T2* value, the higher the risk of cardiac dysfunction; T2* values
<20 ms are associated with a progressive and significant decline in LVEF.19
It was once thought that liver and cardiac iron levels were directly correlated;20
however, their relationship has proven to be more complex. The mechanisms of iron
uptake and clearance differ in heart and liver tissue, resulting in differing iron transport
kinetics. Iron transport is not well understood.21 Patients may develop cardiac
dysfunction despite low liver iron levels. Some data suggest a critical liver iron
concentration (LIC) above which high myocardial iron levels are present.20 In one
longitudinal study of patients with β-thalassemia receiving chelation therapy, an LIC
>15 mg/g dry weight was shown to be suggestive of increased risk of cardiac disease
and early death.20 Similarly, the maintenance of serum ferritin levels below 2500 mcg/L
has been associated with improved cardiac disease-free survival.7
As a marker of iron toxicity, serum ferritin levels can predict the chances that at-risk
patients will develop cardiac disease.
Persistently High Serum Ferritin Levels Substantially Increased the Risk of Cardiac
Disease in Patients with β-Thalassemia7
This clinical study tracked cardiac disease-free survival in patients with thalassemia
over a period of 15 years, using serum ferritin as an indicator of iron burden.7 Cardiac
disease-free survival was achieved in only 18% of patients with high iron burden over
this time period. However, cardiac disease-free survival in the patient group that
adequately controlled serum ferritin levels was 91% during the 15-year follow-up.
Hepatic Complications
The liver is the major site of iron storage, and as such it is susceptible to damage from
iron overload. At the cellular level, mitochondria swell and their membranes rupture,
resulting in cell death.22
Two main clinical sequelae of excess iron deposition in the liver are fibrosis/cirrhosis
and hepatocellular carcinoma.23 In patients receiving regular transfusions, serious liver
damage can occur within 2 years of the first transfusion,23 and liver cirrhosis can
develop if the excess iron is not removed.
Studies have shown a correlation between the development of liver fibrosis and high
liver iron24 and serum ferritin20 levels. The study evaluating liver iron found that the
fibrosis score was higher in patients with greater baseline liver iron levels, as well as in
those patients who were hepatitis C positive.
Hepatic iron burden can be assessed noninvasively through regular monitoring of serum
ferritin levels. Cirrhosis is more prevalent in those with serum ferritin >1000 mcg/L
than in those below this level.25
Damage to Other Major Organs
Skeletomuscular Damage

Osteoporosis is common among patients with thalassemia26

Other troubling musculoskeletal problems include severe muscle cramps and
disabling myalgia. Muscle biopsy often reveals iron deposits in the myocytes27
Compromised Immune Function



Patients with iron overload appear to have increased susceptibility to infections,
often with unusual microorganisms28-30
This apparent immune compromise may result from the abnormally high
transferrin saturations seen in patients with iron overload
Transferrin has been shown in vitro to have bacteriostatic properties31; high
saturations may compromise this property
Skin Pigmentation



Cutaneous iron deposition induces melanin production, causing a characteristic
bronze pigmentation in fair-skinned people
Exposure to ultraviolet light acts synergistically with this process, and as a result
many people with iron toxicity tan very easily, although these effects are
variable
Fair-skinned people seldom develop hyperpigmentation even with a large iron
burden, while people of moderate baseline pigmentation often develop a striking
almond-colored hue
For more information on the relationship between iron toxicity and damage to organs
and glands, visit irontoxicity.com/hcp/consequences.jsp
1. Porter J. Pathophysiology of iron overload. Hematol Oncol Clin North Am.
2005;19(suppl 1):7-12.
2. Cabantchik ZI, Breuer W, Zanninelli G, Cianciulli P. LPI-labile plasma iron in
iron overload. Best Pract Res Clin Haematol. 2005;18:277-287.
3. Kushner JP, Porter JP, Olivieri NF. Secondary iron overload. Hematology (Am
Soc Hematol Educ Program). 2001:47-61.
4. Gabutti V, Piga A. Results of long-term iron-chelating therapy. Acta Haematol.
1996;95:26-36.
5. Telfer PT, Prestcott E, Holden S, Walker M, Hoffbrand AV, Wonke B. Hepatic
iron concentration combined with long-term monitoring of serum ferritin to
predict complications of iron overload in thalassaemia major. Br J Haematol.
2000;110:971-977.
6. Schafer AI, Cheron RG, Dluhy R, et al. Clinical consequences of acquired
transfusional iron overload in adults. N Engl J Med. 1981;304:319-324.
7. Olivieri NF, Nathan DG, MacMillan JH, et al. Survival in medically-treated
patients with homozygous β-thalassemia. N Engl J Med. 1994;331:574-578.
8. Darbari DS, Kple-Faget P, Kwagyan J, Rana S, Gordeuk VR, Castro O.
Circumstances of death in adult sickle cell disease patients. Am J Hematol.
2006;81:858-863.
9. Leitch HA, Goodman TA, Wong KK, Vickars LM, Galbraith PF, Leger CS.
Improved survival in patients with myelodysplastic syndrome (MDS) receiving
iron chelation therapy [abstract]. Blood (ASH Annual Meeting Abstracts).
2006;108:Abstract 249.
10. Abetz L, Baladi J-F, Jones P, Rofail D. The impact of iron overload and its
treatment on quality of life: results from a literature review. Health Qual Life
Outcomes. 2006;4:73.
11. Karnon J, Zeuner D, Brown J, Ades AE, Wonke B, Modell B. Lifetime
treatment costs of beta-thalassaemia major. Clin Lab Haematol. 1999;21:377385.
12. Andrews NC. Disorders of iron metabolism. N Engl J Med. 1999;341:19861995.
13. Wang WC, Ahmed N, Hanna M. Non-transferrin-bound iron in long-term
transfusion in children with congenital anemias. J Pediatr. 1986;108:552-557.
14. Liu P, Olivieri N. Iron overload cardiomyopathies: new insights into an old
disease. Cardiovasc Drugs Ther. 1994;8:101-110.
15. Jaeger M, Aul C, Sohngen D, et al. Secondary hemochromatosis in
polytransfused patients with myelodysplastic syndromes. Beitr Infusionsther.
1992;30:464-468.
16. Brittenham GM, Griffith PM, Nienhuis AW, et al. Efficacy of deferoxamine in
preventing complications of iron overload in patients with thalassemia major. N
Engl J Med. 1994;331:567-573.
17. Buja LM, Roberts WC. Iron in the heart. Etiology and clinical significance. Am
J Med. 1971;51:209-221.
18. Schwartz KA, Li Z, Schwartz DE, et al. Earliest cardiac toxicity induced by iron
overload selectively inhibits electrical conduction. J Appl Physiol.
2002;93(2):746-751.
19. Anderson LJ, Holden S, Davis B, et al. Cardiovascular T2-star (T2*) magnetic
resonance for the early diagnosis of myocardial iron overload. Eur Heart J.
2001;22:2171-2179.
20. Berdoukas V, Bohane T, Tobias V, et al. Liver iron concentration and fibrosis in
a cohort of transfusion-dependent patients on long-term desferrioxamine
therapy. Hematol J. 2005;5:572-578.
21. Oudit GY, Trivieri MG, Khaper N, Liu PP, Backx PH. Role of L-type Ca2+
channels in iron transport and iron-overload cardiomyopathy. J Mol Med.
2006;84:349-364.
22. Thakerngpol K, Fucharoen S, Boonyaphipat P, et al. Liver injury due to iron
overload in thalassemia: histopathologic and ultrastructural studies. Biometals.
1996;9:177-183.
23. Conte D, Piperno A, Mandelli C, et al. Clinical, biochemical and histological
features of primary haemochromatosis: a report of 67 cases. Liver. 1986;6:310315.
24. Tsukamoto H, Horne W, Kamimura S, et al. Experimental liver cirrhosis
induced by alcohol and iron. J Clin Invest. 1995;96:620-630.
25. Morrison ED, Brandhagen DJ, Phatak PD, et al. Serum ferritin level predicts
advanced hepatic fibrosis among U.S. patients with phenotypic
hemochromatosis. Ann Intern Med. 2003;138:627-633.
26. Christenson RA, Pootrakul P, Burnell JM, et al. Patients with thalassemia
develop osteoporosis, osteomalacia, and hypoparathyroidism, all of which are
corrected by transfusion. Birth Defects Orig Artic Ser. 1987;23(5A):409-416.
27. Vallat JM, Loubet R, Leboutet MJ, et al. Hemosiderin deposition in muscle.
Report of three cases. Acta Neuropathol (Berl). 1978;42:153-156.
28. Abbott M, Galloway A, Cunningham JL. Haemochromatosis presenting with a
double Yersinia infection. J Infect. 1986;13:143-145.
29. Brennan RO, Crain BJ, Proctor AM, et al. Cunninghamella: a newly recognized
cause of rhinocerebral mucormycosis. Am J Clin Pathol. 1983;80:98-102.
30. Bullen JJ, Spalding PB, Ward CG, et al. Hemochromatosis, iron and septicemia
caused by Vibrio vulnificus. Arch Intern Med. 1991;151:1606-1609.
31. Reiter B, Brock JH, Steel ED. Inhibition of Escherichia coli by bovine colostrum
and post-colostral milk. II. The bacteriostatic effect of lactoferrin on a serum
susceptible and serum resistant strain of E. coli. Immunology. 1975;28:83-95.