Case 1: In Betathalassemia, Low Liver Iron Does Not Necessarily Indicate That Cardiac Iron is Not Present

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Liver iron has long been thought to be a reliable indicator of total body iron burden, including the likelihood of cardiac iron. In patients with beta-thalassemia, however, that is not always the case.

Initial Presentation

Aalia M., 12-year-old girl of South Asian descent, presented with her mother at a thalassemia treatment center for a blood transfusion to manage her beta-thalassemia; previously, she had been transfused every 3 weeks at another institution, where she adhered to chelation therapy with deferoxamine and had no obvious organ damage secondary to iron overload. Aalia's ferritin levels were mildly high—in the 800 mcg/L to 1000 mcg/L range—and a previous liver biopsy showed her to have a hepatic iron content of 3.2 mg Fe/g dry weight, which is low.

Diagnosis and Treatment

Shortly after her transfer to the thalassemia treatment center, Aalia was switched to deferasirox at her and her mother's request so that she could take an oral medication rather than undergo 10-hour subcutaneous nightly infusions, as was necessary with deferoxamine. Aalia was started on a daily dose of 20 mg/kg of deferasirox to minimize adverse events, which are dose-dependent, and slowly titrated up to 30 mg/kg/day over several months. (With patients who have beta-thalassemia, medication doses are generally increased to trend serum ferritin levels downward toward 500 mcg/L, as long as monthly laboratory tests show no elevation of liver enzymes or creatinine and the patient is experiencing no serious adverse events.) Aalia was also scheduled for an MRI of her heart and liver to assess her iron overload. While her levels of liver iron were still low (3.1 mg Fe/g dry weight), she also had a low T2* (15 ms), indicating iron in the heart, a serious and potentially fatal condition; her ejection fraction was normal (63%).

Aalia was continued on deferasirox 30 mg/kg/day and her ferritin levels were tracked each month. However, her ferritin remained in the 800 mcg/L to 1000 mcg/L range, about where it was on her initial presentation at the center; as a result, her dosage of deferasirox was increased to 35 mg/kg/day in an attempt to bring her ferritin down.

Aalia's ferritin finally began to trend downward on the 35 mg/kg/day dose; MRIs, repeated at 6-month intervals, confirmed this trend. Aalia experienced some gastrointestinal upset (ie, nausea and cramping) on the higher dosage, but switching from morning to evening dosing ameliorated these side effects. Adherence and proper administration were reviewed at each monthly visit with Aalia and her mother.

Follow-Up

After 1 year of aggressive, high-dose chelation with deferasirox, Aalia's T2* returned to normal; her liver iron level of 1.5 mg Fe/g dry weight was near normal. She was monitored closely for any renal or liver toxicities secondary to chelation therapy during this period, including monthly laboratory analyses and regular screenings by the ophthalmology and audiology departments. Her serum ferritin levels are currently stable—in the 500 mcg/L to 600 mcg/L range—and her deferasirox dosage is adjusted as necessary to keep her levels within this range as she grows and gains weight.

Discussion

Cardiac failure secondary to cardiac iron remains the major killer of thalassemia patients. Liver iron, usually an excellent direct measure of total body iron, does not always reflect the level of cardiac iron in these patients. MRI is the gold standard for measuring liver and cardiac iron and is standard equipment in thalassemia centers in the United States.

Evidence of cardiac iron calls for aggressive treatment; if detected early, it can be reversed before dysfunction occurs. Deviations from the treatment regimen, as well as any side effects, should be reported. Monitoring for potential adverse events is necessary to ensure proper, regular administration of deferasirox.

Adverse events and toxicity of chelators tend to increase as total body weight declines; treatment is therefore a balancing act. Serum ferritin levels in patients with beta-thalassemia traditionally have been kept slightly higher than normal serum ferritin levels. However, the emphasis now is increasingly on tighter control.

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