OVERVIEW: What every practioner needs to knowAre you sure your patient has iron overload? What are the typical findings for this disease?

Iron overload simply means excess iron in the body. It can occur by various mechanisms. In hereditary hemochromatosis (HH) excessive absorption of iron because of genetic defects leads to iron overload. Hemochromatosis is the disease state caused by iron overload and hemosiderosis refers to an increase in tissue iron levels without organ damage. Iron deposition that is limited to a specific organ or tissue, such as pulmonary and renal hemosiderosis, will not be discussed here.

Multiple blood transfusions, hemolyic anemias, and other conditions associated with excessive iron intake are important causes of iron overload.

The disease is notoriously asymptomatic until very late in the course, often leading to a long delay in diagnosis. The presenting symptoms and signs are often quite nonspecific and include chronic fatigue and usually endocrine-related symptoms such as amenorrhea, decreased libido, hypogonadism, impotence, infertility, hypothyroidism, hypopituitarism, diabetes mellitus, and rarely decreased adrenal function.

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Other manifestations include elevated levels of liver enzymes, cirrhosis, abdominal pain, skin discoloration (bronze coloration), arrhythmias, cardiac failure, osteoarthritis, osteoporosis, joint pain, hair loss, and hepatosplenomegaly. Symptoms related to organ dysfunction (see above) due to iron accumulation are often apparent only after significant irreversible organ damage has occurred. However, once identified, further deterioration can be delayed or halted.

The diagnosis in most cases is made with a high index of suspicion based on elevated elevated levels of transferrin saturation (TS), serum iron (SI), and ferritin in the absence of inflammation and in the presence of family history of HH or related diseases (e.g., hemolytic anemia, multiple blood transfusions).

What other disease/condition shares some of these symptoms?

The clinical manifestations of iron overload are generally due to toxic effects of iron on specific organs (i.e., liver, pancreas, heart, skin). Thus iron overload causes the same symptoms as many diseases that involve those organs, including the various causes of hepatic injuries, cirrhosis, diabetes, cardiac arrhythmias, cardiac failure, and various causes of hypoendocrinopathies, such as hypothroidism, hypogonadism, and hypopituitarism.

What caused this disease to develop at this time?

Predisposing factors: HH is seen frequently in white populations. Anemia is the most common disease in the world, and thus iron is a precious resource. The mutations must have arisen as a mechanism to extract and preserve more iron.

Iron overload associated with hemolytic anemia is mild and develops slowly and may never be significant in a patient’s lifetime. However, these patients are also much more likely to need blood transfusions than is the general population and thus they carry a very high risk of having iron overload once they have received 10 or more blood transfusions.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

The key diagnostic blood tests are elevated TS (>60%) and serum ferritin (>400 ng/mL) in the presence of other factors such as family history of HH, hemolytic anemia, or other conditions associated with iron overload.

Ideally one measures SI and total iron binding capacity (TIBC) after a 12-hour period of fasting TS is calculated by the formula TS = SI/TIBC. High TS (usually >45%) is suggestive of iron overload, whereas higher levels (>60%) are more likely associated with iron overload. Low TS is indicative of iron deficiency. Unbound iron binding capacity is decreased (usually <145) with iron overload. Serum ferritin (normal range, 10-400 ng/mL) ) is increased with inflammation and also with iron overload. Although it is not very sensitive or specific it is an easy test and is used very frequently in many insittutions to roughly monitor iron overload.

Liver biopsy is the gold standard test for quanitfying iron overload. It is invasive and not routinely performed in many institutions. Iron level greater than 3 µg/g indicate iron overload, whereas iron level greater than 6 µg/g is considered diagnostic for significant overload.

Gene testing for C282Y mutation is helpful to predict predisposition to HH because it is the most common mutation in white populations. Gene testing is also available for H63D and S65C mutations. There are numerous other mutations that cannot be tested and others that are unknown and yet cause HH. However, it does not indicate the amount of iron overload in the body.

Would imaging studies be helpful? If so, which ones?

Role of imaging studies in iron overload

Imaging can help identify and quantify iron overload in various organs.

Using magnetic resonance imaging (MRI), different techniques (T2, R2) can be used to quantify iron overlaod in various organs, including liver, heart, thyroid, kidneys, pancreas.

Typically liver MRI is usually performed yearly to identify and follow iron overload in chronically iron-overloaded individuals. Although MRI is costly and time-consuming, it does not entail any radiation and no contrast medium is required.

In patients with severe and long-term iron overload, especially chronically transfused patients with thalassemia, cardiac MRI can accurately predict cardiac iron overload and its associated complications, including arrythmias and cardiac failure, before the occur. This provides the chance for health care personnel and the patient to intervene with more aggressive measures (Table 1) before irreversible cardiac damage ensues.

If you are able to confirm that the patient has iron overload, what treatment should be initiated?

Treatment for iron overload

Prevention of iron overload: Interventions include strategies to lower iron intake such as educating populations to stop the use of iron vessels in “African type” acquired hemosiderosis, encouraging the use of multivitamins
without iron if indicated, and generally avoiding iron supplements.

Decreasing rate of iron overload:

Each red cell unit contains about 200 mg of iron. Use of the “freshest” packed red cell infusions whenever blood transfusions are indicated can maximize the life of transfused red cells in the body and hence minimize transfusions in chronically transfused patients along with the resultant iron overload.

In patients with anemia, keeping a reasonable level of hemoglobin (about 9 g/dL) is helpful to suppress erythropoiesis and iron absorption from the gut, thus cutting iron overload.

Once a patient is identified as being likely to acquire iron overload, adopt a strategy to avoid blood transfusions unless absolutely necesssary.

Removing excess iron from body:

Phlebotomy is an extremely effective and safe method to remove excess iron from body. Each unit of blood removed would effectively remove 200 mg of iron from the body.

Chelation therapy can remove excess iron from the body. Deferasirox is the only oral drug that is approved by the US Food and Drug Administration for the treatment of iron overload. Deferoxamine can also be given parenterally for iron chelation. Another drug, deferiprone, is used in Europe but has not been approved in the United States.

We have instituted general clinical guidelines in our institution for identifying and monitoring iron overload and also instituting, withholding, and restarting chelation therapy (see below).

Patients with sickle cell disease who are chronically transfused to prevent stroke are at high risk for iron overload. If such a patient is noncompliant with chelation therapy, he/she is at extremely high risk for iron overload. In that circumstance, one should discuss with the patient and caretakers the option of stopping chelation and starting phlebotomy with hydroxyurea. The risk of stroke versus complications of iron overload should be dicussed.

Although iron chelators may also chelate other heavy metals in the body, supplementation of other heavy metals (such as zinc) is usually not required. However, checking zinc levels yearly may be indicated.

Guidelines for deferasirox therapy for patients with iron overload

Prerequisites and monitoring

Deferasirox should be started once the serum ferritin level is greater than 1000 ng/mL. This level of ferritin is typically achieved once the patient has had more than 10 transfusions (about a year of monthly transfusions).

An ophthalmic examination for vision and the presence of cataracts is needed before starting deferasirox and yearly during therapy.

An audiogram is necessary before the patient starts deferasirox and yearly (high-frequency hearing loss may appear on therapy).

Check lactate dehydrogenase and serum ferritin levels every 3 months and urinalysis every 6 months.

Monitor comprehensive metabolic panel (CMP), complete blood count (CBC), absolute neutrophil count (ANC), and platelet count before transfusion with differential and reticulocyte count monthly.

Check ferritin level monthly after 6 months of monthly blood transfusions until deferasirox is started (then every 3 months).

Check CBC and CMP every 2 weeks twice—when deferasirox is started and when the dose is changed.

Discontinue deferasirox if the ferritin level is less than 500 ng/mL twice (check ferritin level monthly at this time until it is >1000 ng/mL ×2) and MRI consistent with absent or low iron overload and restart once ferritin >1000 ng/mL.

Caution patient not to take deferasirox with aluminum antacids!

Discontinue deferasirox if the creatinine level increases to greater than 33% over baseline or if the level of alanine aminotransferase is greater than five times baseline. Inform the physician. Monitor CMP closely. Restart deferasirox only after discussion with physician.

Deferasirox dosing

Deferasirox should be taken 1 hour before/after food mixed with juice (preferably orange juice). Drop tablets in juice (3.5 ounces for <1 g and 7 ounces for >1 g) and drink once it is fully dissolved. After completely drinking the glass of juice, again add quarter glass of juice to the empty glass and shake well (to dissolve residual deferasirox) and drink the juice.

Start deferasirox at 20 mg/kg once a day (averaged over 2 days) rounded up to the nearest 250 mg.

Increase deferasirox to 30 mg/kg if ferritin level is greater than 2000 ng/mL twice and/or if there is significant or worsening iron overload.

Consider an increase to 35 mg/kg and then to 40 mg/kg if ferritin concentration is persistently greater than 2000 ng/mL and/or significant or worsening iron overload is seen on a dose of 30 mg/kg.

Watch for toxicity by carefully following CBC with ANC, platelets, and CMP every month after starting deferasirox and every 2 weeks twice after changing deferasirox dose.

For severe and worsening liver/cardiac iron load (per MRI/liver biopsy/ferritin level) consider addition of (or changing to) nightly deferoxamine (if insurance permits), weekend admission (monthly with transfusion) for intravenous deferoxamine infusion, stopping transfusions and starting hydroxurea with phlebotomy (despite risk of stroke) after detailed discussion with patient and family.

Before starting/increasing deferasirox, consider repeating a ferritin deterination with CRP the following month if there is a concern that elevated ferritin concentration may be caused by inflammation (in the case of a sudden increase in ferritin level).

Note: These guidelines do not indicate an exclusive course of treatment or serve as a standard of care. Variations based on a physician’s best medical judgment may be appropriate in individual cases.

What are the adverse effects associated with each treatment option?

Adverse effects and risk/benefits associated with each treatment option

Deferasirox and deferoxamine are both associated with multiple side effects, including hepatotoxicity, nephrotoxicity, color vision abnormalities, cataract formation, and high-frequency hearing loss.

Deficiencies in other heavy metals (such as zinc) resulting from chelation therapy is a theoretic concern. However, clinical manifestations of zinc deficiency are rarely encountered, and routine check of zinc levels or zinc supplementation with deferasirox therapy is not necessary. The toxicities mentioned are usually more prominent when iron overload is minimal. Hence it is recommended that chelation therapy be discontinued once the ferritin level falls to less than 1000 ng/mL.

Likely causes for noncompliance with deferasirox therapy are nausea, vomiting, stomach upsets, and the chalky taste, all of which are common yet less serious side effects.

Noncompliance with deferoxamine therapy is related to the inconvenience of daily subcutaneous infusions that last more than 8 hours 5-7 days of the week, as well as pain and lipodystrophic changes at injection site.

Deferiprone is associated with serious side effects, including agranulocytosis in 1% of patients, neutropenia in 5% of patients, as well as arthropathy, zinc deficiency, and gastrointestinal and hepatic abnormalities.

Regular phlebotomy is very safe. However, possibility of side effects related to a sudden fall in blood volume is always a possibility, especially if the patient is dehydrated. Once iron stores are exhausted by repeated phlebotomy, hemoglobin can fall precipitously, leading to poor concentration, dizziness, and syncopal attacks.

What are the possible outcomes of iron overload?

Prognosis of this disease depends on the organ damage at diagnosis.

When disease such as HH is diagnosed by genetic testing, ferritin and TS can be periodically monitored and intervention can be planned before organ damage occurs. A similar strategy involving close montioring of TS and ferritin levels in cases of hemolytic anemia and transfusion-induced iron overload, is extremely helpful. Patients getting multiple (and regular) blood transfusions usually get iron overload (ferritin level >1000 ng/mL) after about 10 red cell transfusions (10 mL/kg each), hence monitoring of the number of transfusions is also critical.

If iron overload is diagnosed after the patient has become symptomatic, the ferritin levels are usually greater than 1000 ng/mL and it is likely that significant organ damage has already occurred. Vigorous iron chelation, in addition to adopting strategies to prevent further iron overload and close monitoring of organ damage will be helpful in preventing further damage and complications associated with organ damage, such as complications of cirrhosis, diabetes mellitus, cardiac arrhythmias, and cardiac failure (which probably occurs at around 75 mL/kg or more of blood transfusions with inadequate chelation therapy).

What causes iron overload and how frequent is it?

Iron overload is directly related to the presence of a genetic mutation for HH or hemolytic anemia and/or excessive iron intake in the form of oral or parenteral iron/blood transfusions. It is usually symptomatic in adults (older than 50 years of age). However, it can manifest earlier in the presence of a more severe mutation or excessive iron load to the body (orally or parenterally).

Epidemiology: The prevalance of HH, especially its classic form, is very high in white populations. The prevalance rate in Americans is roughly 1/200 for homozygosity, 1/50 for compound heterozygosity, and 1/10 for heterozygosity. Some studies indicate an incidence of almost 30%. It is higher in Scottish, Irish, British, German, Dutch, French, and Spanish populations. In certain populations in sub-Saharan Africa, 10% of persons carry the gene. Interestingly, HH is extremely uncommon in Asians. Juvenile and neonatal forms of HH are extremely rare.

Genetics: Various mutations in different genes involved in iron metabolism leading to HH are present in different populations, signifying evolutionary advantage in those carrying the abnormal gene. Anemia is the most common disease in the world, and thus iron is a precious resource. Iron overload issues in most types of HH occur in or after the fifth decade of life when reproduction and most meaningful functions, such as protection of offspring, have already occurred.

Most white populations have missense mutation C282Y (cysteine replaced by tyrosine) in the gene encoding a protein HFE on chromosome 6p. Another common mutation is H63D. This and most other mutations lead to inappropriately low hepcidin production.

The African form of iron overload syndrome was originally thought to be caused by excessive iron intake due to improperly brewed liquor in iron vessels. However, the missense mutation in ferroportin, Q248H, may also be a contributory genetic factor.

Neonatal hemochromatosis is characterized by neonatal onset of hepatic failure with systemic iron overload in the absence of other causative factors and is nearly uniformly fatal. Iron chelation can transiently improve the condition, but liver tranplantation has been shown to cure the disease, pointing to a hepatic origin of the disease.

Juvenile hemochromatosis is diagnosed when patients are symptomatic from iron overload before 30 years of age. The prognisis is poorer compared with the much more common adult form.

The adult form of HH (also called classic form) is the most common type of HH and symptoms develop usually after 50 years of age or later.

Mutations in various genes causing HH result in increased absorption of iron from the gut, leading to deposition of dangerous levels of hemosiderin that cause oxidative cell injury in various organs, leading to organ dysfunction eventually resulting in death.

How do these pathogens/genes/exposures cause the disease?

The presence of genetic mutations for HH (see above) predisposes to iron overload. However, the presence or absence of a mutation alone does not predict the severity or course of the disease.

Exposure to multiple blood transfusions (>10), an iron-rich diet, or prolonged iron supplementation in patients with HH or in patients who are prone to the development of iron overload, such as those with hemolytic anemia, increases the risk of iron overload developing.

Other clinical manifestations that might help with diagnosis and management

A high element of suspicion in the clinical work-up is critical in the diagnosis of iron overload. Thus, a patient with hemolytic anemia who is receiving multiple transfusions and patients receiving excessive iron supplements should be screened periodically (with TS and ferritin levels) for iron overload and screened immediately if they are symptomatic (e.g., fatigue, malaise, poor glucose tolerance, poor libido).

What complications might you expect from the disease or treatment of the disease?

Very high TS and toxic levels of iron are associated with unsual infectious organisms in pateints with iron overload. These include bacterial infections such as Yersinia enterocolitica, Salmonella typhimurium, Vibrio vulnificus, Listeria monocytogenes, Klebsiella pneumoniae, Aeromonas hydrophila, and Escherichia coli and fungal infections caused by Rhizopus oryzae (mucormycosis) and Cunninghamella bertholletiae.

Iron overload also markedly increases the risk of cirrhosis and liver cancer once ferritin levels rise to greater than 1000 ng/mL, possibly 20-100 times the general population.

Unlike deferiprone, treatment with deferoxamine is likely to increase the susceptibility of the iron-overloaded individual to these organisms. Hence therapy with deferoxamine is usually withheld when infection with the above organisms is suspected or the diagnosis is made.

How can iron overload be prevented?

Genetic testing in the presence of a family history, avoiding excess iron intake, and avoiding blood transfusions (see above) is helpful in postponing/slowing/preventing iron overload.

What is the evidence?

Andrews, NC, Ullrich, CK, Fleming, MD, Orkin, SH, Nathan, DG, Look, AT. “Disorders of iron metabolism and sideroblastic anemias”. Nathan and Oski's hematology of infancy and childhood. 2009. pp. 521-70. (Very high-quality textbook of pediatric hematology.)

Beutler, E, Kaushansky, K, Lichtman, M, Beutler, E. “Disorders of iron metabolism”. Williams Hematology. 2010. (Very high-quality textbook of adult hematology. Since the disease is manifested far more frequently in adults, there is a preponderence of high-quality adult literature.)

Neufeld, EJ. “Update on iron chelators in thalassemia”. Hematology. vol. 2010. 2010. pp. 451-5.

Vichinsky, E. “Oral iron chelators and the treatment of iron overload in pediatric patients with chronic anemia”. Pediatrics. vol. 121. 2008. pp. 1253-6. (Extremely good pediatric perspective.)

Brittenham, GM. “Iron-chelating therapy for transfusional iron overload”. N Engl J Med. vol. 364. 2011. pp. 146-56. (Extremely good pediatric/adult review.)

Hoffman, R, Benz, E, Shattil, S. Hematology: Basic principles and practice. 1995. (Another very high-quality adult textbook.)

Ongoing controversies regarding etiology, diagnosis, treatment?

Ascorbic acid given with deferoxamine may promote iron mobilization from tissues to circulation, thus promoting chelation and removal from body. However, high doses (15-25 mg/kg), reported earlier, was associated with sudden death presumably due to arrhythmias. Lower doses of 2-4 mg/kg are likely to be safe and helpful adjuvants to deferoxamine therapy.

Scanning with a superconducting quantum interference device is a very sophisticated method of accurately quantifying iron overload, but recent studies show that it may underestimate under certain circumstances. It is available in only very few centers around the world.