Home « Consequences
Consequences of Chronic Iron Overload
Chronic iron overload causes progressive damage to the liver, heart, and endocrine glands, and may eventually lead to premature death. Furthermore, non-specific early symptoms (such as abdominal discomfort and fatigue) may delay diagnosis until severe damage to heart or liver tissues produces clinically apparent symptoms. Therefore at-risk patients (such as those who have received multiple blood transfusions or who have a family history of iron metabolic disorders) should be screened for iron overload.
How iron deposition affects key tissues
The consequences of iron deposition appear to vary in different body tissues. In the heart or liver, hemosiderotic injury can eventually be fatal. In the skin, advanced hemosiderosis produces a characteristic — but benign — bronze pigmentation.
Click on the tabs below to learn about the potential effects of iron deposition in specific organs and glands.
Email
Print
Monitor Serum Ferritin
In both primary
and secondary iron overload, serum
ferritin >1000 mcg/L
is associated with worsened prognosis.
Click on the diagram below to learn about the potential effects of iron deposition in specific organs and glands.
Pituitary
Thyroidal
Cardiac
Hepatic
Pancreatic
Gonadal
Impact of iron overload on survival
Whether primary or secondary, severe iron overload is associated with premature death (1).
Among patients with sickle cell disease, iron overload is among the most frequent findings at death, and is associated with the development of cirrhosis and cardiac disease — other leading findings at death in SCD (2).
Iron overload and early mortality in patients with sickle cell diseaseIron overload and early mortality in patients with sickle cell disease
Proportional mortality study evaluating the findings at death in 141 adults with SCD. Average age at death was 36 years.
*Including endocarditis
†Other than endocarditis and cor pulmonale.
Adapted with permission from Darbari, et al (2).
How iron overload damages tissues
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 (3). 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-molecular-weight proteins in the plasma and cells, and in this form propagates cellular damage by peroxidation of organelles such as mitochondria, lysosomes, and sarcoplastic membranes.
- In the plasma, high transferrin saturation results in circulating non-transferrin-bound iron (NTBI). In patients with heavy iron overloading, NTBI is detectible in the plasma (4).
- When cellular iron storage proteins are saturated, NTBI comprises an intracellular labile iron pool (LIP) that causes most cellular damage (3). Reticuloendothelial macrophages produce large quantities of storage proteins, and can thus neutralize large quantities of NTBI. Parenchymal tissues have a limited capacity to safely store iron; once this capacity is exceeded, NTBI causes cellular damage (3).
Cardiac complications
The most common form of cardiac hemosiderotic injury is congestive cardiomyopathy. Other cardiac pathologies linked to excess iron include pericarditis, angina, and conduction defects.
Learn more about cardiac complications
Hepatic complications
The main clinical sequelae of excess iron deposition in the liver are fibrosis/cirrhosis and hepatocellular carcinoma. In patients receiving regular transfusions, collagen formation and portal fibrosis can occur within 2 years of the first transfusion (5), while liver cirrhosis can develop within the first decade of life if the excess iron is not removed.
Learn more about hepatic complications
Skeletomuscular damage
Arthropathy of large joints such as the hips is common in hereditary hemochromatosis (6) — presumably because such damage develops gradually over decades of iron deposition in articular cartilage. Osteoporosis is common among patients with thalassemia (7).
Other troubling musculoskeletal problems include severe muscle cramps and disabling myalgia. Muscle biopsy often reveals iron deposits in the myocytes (8).
Compromise of immune function
Patients with iron overload appear to have increased susceptibility to infections, often with unusual microorganisms (9-11). 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 properties (12); 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 overload 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.
In This Section
Cardiac consequences
Learn more about the most common types of cardiac injury, mechanisms of cardiac iron uptake, assessment of cardiac iron burden, and the association of LIC and serum ferritin with cardiac iron overload.
Hepatic consequences
Learn more about the assessment of hepatic iron burden, the association of liver iron and serum ferritin levels with fibrosis, and factors that may exacerbate liver damage.
References
- (1) Karnon J, Zeuner D, Brown J, Ades AE, Wonke B, Modell B. Lifetime treatment costs of beta-thalassaemia major. Clin Lab Haematol. 1999. Dec;21(6):377-85.
- (2) 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;81:858-63
- (3) Wang WC, Ahmed N, Hanna M, Non-transferrin-bound iron in long-term transfusion in children with congenital anemias. J Pediatr. 1986;108(4):552-7.
- (4) Hershko C, Peto TE, Non-transferrin plasma iron. Br J Haematol. 1987;66(2):149-51.
- (5) Conte D, Piperno A, Mandelli C, et al, Clinical, biochemical and histological features of primary haemochromatosis: a report of 67 cases. Liver. 1986;6(5):310-5.
- (6) Axford JS, Bomford A, Revell P, et al, Hip arthropathy in genetic hemochromatosis. Radiographic and histologic features. Arthritis Rheum. 1991;34(3):357-61.
- (7) 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):409-16.
- (8) Vallat JM, Loubet R, Leboutet MJ, et al, Hemosiderin deposition in muscle. Report of three cases. Acta Neuropathol (Berl). 1978;42(2):153-6.
- (9) Abbott M, Galloway A, Cunningham JL, Haemochromatosis presenting with a double Yersinia infection. J Infect. 1986;13(2):143-5.
- (10) Brennan RO, Crain BJ, Proctor AM, et al, Cunninghamella: a newly recognized cause of rhinocerebral mucormycosis. Am J Clin Pathol. 1983;80(1):98-102.
- (11) Bullen JJ, Spalding PB, Ward CG, et al, Hemochromatosis, iron and septicemia caused by Vibrio vulnificus. Arch Intern Med. 1991;151(8):1606-9.
- (12) 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(1):83-95.