IRON OVERLOAD IN THALASSAEMIA

INTERMEDIA: REASSESSMENT OF IRON CHELATION STRATEGIES

Ali Taher,1 Chaim Hershko2 and Maria Domenica Cappellini

Thalassaemia intermedia (TI) is a syndrome marked by its diverse underlying genetic basis, associated with anaemia and a range of specific complications including extramedullary haematopoiesis, leg ulcers, gallstones, a hypercoagulable state and pulmonary hypertension (PHT)

The clinical manifestations of TI in beta- and beta-thalassaemia/haemoglobin E patients result from three key factors:

- ineffective erythropoiesis - chronic anaemia - iron overload

These life-threatening complications are observed with increasing frequency in untreated TI patients and suggest that earlier intervention aimed at preventing chronic anaemia may benefit TI patients by avoiding the late and irreversible anaemia-related complications

UNDERSTANDING IRON ACCUMULATION INTHALASSAEMIA INTERMEDIA Iron is an essential element for the

functioning of a great number of proteins participating in vital reactions controlling energy production, mitochondrial respiration and DNA synthesis

effective mechanisms have been developed to ensure unimpeded iron supply, facilitating iron transport and accumulation.

The master regulator of iron balance in humans is hepcidin

a Increased production of hepcidin in response to excessive iron or inflammation prevents the absorption of intestinal iron and blocks the recycling of catabolic iron from the reticuloendothelial (RE) system.

In iron deficiency, hepcidin production is inhibited resulting in increased intestinal iron absorption and increased release of RE iron.

In hereditary haemochromatosis, mutations interfering with hepcidin regulation result in an inability to inhibit iron absorption leading to abnormal iron accumulation throughout life.

patients with TI accumulate iron primarily due to increased intestinal iron absorption

In TM and TI, basic iron regulatory mechanisms remain intact. However, the chronic anaemia and ineffective erythropoiesis associated with the thalassaemia syndromes result in abnormal iron regulation.

This dysregulation is caused by two newly described inhibitors of hepcidin production:

- growth differentiation factor 15 (GDF15), secreted by erythroid precursors that are greatly expanded in thalassaemia

- and hypoxiainducible transcription factors (HIFs) that control iron homeostasis by downregulating hepcidin production in response to chronic anaemia/hypoxia.

This results in depletion of macrophage iron, and may explain the relatively low levels of serum ferritin encountered in TI and underestimation of the severity of tissue siderosis.

The situation in TI is similar to that seen in patients with hereditary haemochromatosis syndromes, which is characterised by impaired hepcidin production.

in transfused TM patients, iron is preferentially distributed to the RE system, stimulating ferritin synthesis and its release to the circulation, resulting in high serum ferritin levels

THE IMPACT OF BLOOD TRANSFUSION THERAPY normal conditions: intestinal iron

absorption is 1 mg/d, under maximal stimulation : may reach 3 or 4 mg/d, amounting to an annual

iron accumulation of approximately 1000 mg.

transfused blood contains 200 mg of iron per unit and receiving 2 - 4 units of blood per month, may result in an annual accumulation of 5000- 10 000 mg of iron.

In addition, blood transfusions modify hepcidin production by altering all three factors responsible for the clinical manifestations of thalassaemia

(i) by correcting anaemia, transfusion therapy will suppress ineffective erythropoiesis and the associated increase in GDF15

(ii) by correcting anaemia, blood transfusions will prevent the hypoxia responsible for increased HIF production and

hypoxia-associated suppression of hepcidin

(iii) increased body iron and transferrin saturation will stimulate hepcidin production

The result will be a relative increase in hepcidin production in polytransfused TM patients countering the hepcidin-inhibitory effects of anaemia and ineffective erythropoiesis.

earlier initiation of regular transfusion therapy in patients with TI may improve quality of life, particularly in patients with more severe forms of TI

COMPLICATIONS OF TI THAT MAY BE RELATED TO IRON LOADING accumulation of iron in patients with TI

is an ongoing process that requires regular assessment and management. And is age related, reflecting increased iron accumulation over time, even in the absence of transfusion therapy

Magnetic resonance imaging (MRI) of untransfused or

minimally transfused TI patients has shown that iron accumulation occurs primarily in the liver, which predisposes to the development of fibrosis and cirrhosis, while iron overload in cardiac tissue is generally absent

while heart failure as a result of iron overload is the most common cause of death in patients with TM, cardiac problems due to myocardial siderosis are less apparent in patients with TI

a study of patients with TI has shown that 5.4% had congestive heart failure, 34.5% had chronic pericardial changes, more than 50% had valvular problems and 59.1% had signs of PHT, an important cause of secondary right heart failure

Indeed, PHT is present in 23–60% of TI patients but rarely evident in well-treated TM patients PHT is not only a consequence of the chronic hypoxic damage that progresses with age, but is also gnificantly correlated with iron overload

NORMAL IRON EQUILIBRIUM

IRON BALANCE IN THALASSAEMIA INTERMEDIA

IRON BALANCE IN THALASSAEMIA MAJOR

ASSESSING IRON LEVELS IN PATIENTS WITHTHALASSAEMIA INTERMEDIA principal methods of determining body

iron levels are measurement of serum ferritin and assessment of liver iron concentration (LIC) from biopsy material.

Non-invasive approaches to determine LIC are increasingly used as an alternative to biopsy, and R2· (MRI) is a validated and standardised method that is now widely available

Biomagnetic liver susceptometry, or SQUID (superconducting quantum interference device), is an elegant non-invasive method for measuring LIC but is available only at a limited number of centres worldwide

Non-transferrin bound iron (NTBI) or its labile plasma iron (LPI) component, is the product of severe iron overload and is a marker of increased risk of siderotic myocardial disease in TM.

A significant correlation between serum ferritin and LIC has been established in regularly transfused patients with TM

IRON CHELATION THERAPY There are currently no clear guidelines

for the management of iron overload in patients with TI.

use of one of the orally effective iron chelators would be optimal for TI.

it may be expected that achieving a negative iron balance in thalassaemia intermedia will be relatively simple.

Data on the use of the deferoxamine (DFO) in patients with TI are limited, and our knowledge and understanding of the efficacy

and application of DFO relies mainly on the extensive experience gained from studies of the TM population.

Observations during the study indicated that patients may have positive iron balance from the age of 5 years, even in the absence of transfusions, and the authors recommended that iron chelation therapy be initiated in patients over this age

Data reporting the use of the first oral iron chelator, deferiprone, in patients with TI are also limited.

In the clinical trial, deferiprone was studied in nine intermittently transfused TI patients, demonstrating significant reductions in mean serum ferritin, hepatic iron, red-cell membrane iron and serum nontransferrin-bound iron level

Adverse events in this study were mild and included gastrointestinal symptoms in six patients and arthralgia in one, none requiring withdrawal of treatment.

deferiprone requires three-times-daily dosing to provide adequate chelator coverage, but studies have shown that levels of LPI increase between doses

Deferasirox (Exjade, Novartis Pharma AG, Basel, Switzerland) is the most recent addition to the iron chelator options.

once-daily oral dosing, it can provide 24-h chelation coverage

RECOMMENDATIONS FOR IRON CHELATION THERAPY IN PATIENTS WITH THALASSAEMIA INTERMEDIA

the recommended and preferred method of disease specific guidance for the management of patients with TI is direct assessment of LIC by biopsy, or preferably by noninvasive imaging methods .

Chelation therapy should be initiated when LIC exceeds 7 mg Fe/g dry weight .

Where LIC measurement is not possible, threshold serum ferritin values of 400 - 500 lg/l (which have been shown to correlate with LIC levels of approximately 7 mg/g;

repeated serum ferritin measurements is appropriate for intra-individual monitoring of chelation efficiency on a regular basis.

an association between iron loading evident form longitudinal elevations in serum ferritin level and worsening of hepatic fibrosis in nonchelated patients with thalassemia intermedia has been recently confirmed

reports documenting the occurrence of hepatocellular carcinoma in hepatitis negative

patients with thalassemia intermedia and iron overload continue to emerge

Each 1mg Fe/g dw increase in LIC was significantly associated with an increased risk of thrombosis, pulmonary hypertension, hypothyroidism, hypogonadism, and osteoporosis.

LIC values of at least 6–7mg Fe/g dw discriminated patients who developed morbidity from those who did not

Serum ferritin level of more than 800 ng/ml was the threshold after which all patients became at risk of developing morbidity

An association between iron overload and renal tubular dysfunction as evident from proteinuria has also been recently reported in thalassemia intermedia patients

a high prevalence of silent brain infarction, large cerebral vessel disease, and decreased neuronal function primarily in the temporal and parietal lobes in splenectomized adults with thalassemia intermedia.

A significant association between the occurrence of large-vessel cerebrovascular disease and high NTBI levels

decreased neuronal function was observed more frequently in patients with LIC more than 15mg Fe/g dw .

relationship between iron overload and hepatic or endocrine disease in thalassemia intermedia patients

The presence of NTBI in the sera of thalassemia intermedia patients can cause oxidative vessel injury and endothelial activation

iron overload could lead to hepatic disease and subsequent alterations in coagulation factor levels, thus worsening the hypercoagulable state implicated in thalassemia intermedia

reduction of iron overload affects erythropoietic capacity and leads to improvements in hemoglobin level and red cell survival

IRON OVERLOAD ASSESSMENT INTHALASSEMIA INTERMEDIA PATIENTS Direct assessment of LIC by biopsy or

MRI is recommended (gold standard).

assessment of LIC need not start before patients reach 10 years of age, especially given that the prevalence of iron-related morbidities in patients less than 10 years is low

Measurements can be done at 1 or even 2-year intervals

MANAGEMENT OF IRON OVERLOAD INTHALASSEMIA INTERMEDIA PATIENTS Oral chelator deferasirox ,significant

reduction of LIC compared with placebo following 12 months of therapy in patients aged at least 10 years with a baseline LIC at least 5mg Fe/g dw. LIC decreased by a mean of 2.330.70 and 4.180.69mg Fe/g dw in patients receiving starting doses of 5 and 10 mg/kg per day, respectively.

most common drug-related adverse events being nausea (6.6%), rash (4.8%), and diarrhea (3.6%)

initiation: serum ferritin of 800 ng/ml corresponds to a LIC of 5mg Fe/g dw; suspension: serum ferritin of 300 ng/ml corresponds to a LIC of 3mg Fe/g dw)