Transfusional iron overload:- Iron overload is the most clinical complication associated with transfusion therapy other transfusion-dependent complications includes;
Patients maintained on a regular transfusion regimen progressively also develop clinical manifestation of iron overload such as; hypogonadism (35-55%) of the patients, hypothyroidism (9-10%) liver fibrosis and heart dysfunction (33%) (Cunninghan et al., 2004 Borgna-Pignatti, 2004).
ASSESSMENT AND TREATMENT OF IRON OVERLOAD
Iron status should be accurately assessed in order to evaluate its clinical relevance, the need for treatment and the timing and monitoring of chelation therapy. The iron status of multi-transfused patients can be assessed by several methods;
- Serum ferritin; has in general been found to correlate with body iron stores (Brittenham et al, 1993). However, as a single value it is not always reliable because being an acute-phase reaction protein, it is influenced by other factors such as inflammatory disorders, liver disease, and malignancy. Despite this, serial measurement of serum ferritin remains a reliable and easiest method to evaluate iron overload and efficacy of chelation therapy.
- Determination of liver iron concentration: Assessment of liver iron concentration in a liver biopsy specimen shows a high correlation with total body iron accumulation and is considered the gold standard for the evaluation of iron overload (Angelucci et al, 2010). However, liver biopsy is an invasive technique with the possibility (though low) of complication. Moreover hepatic fibrosis, which commonly occurs in individual with liver iron over load, HCV infection and heterogeneous iron distribution can lead to possible false negative result (Villeneuve et al., 1996)
- Nuclear magnetic resonance imaging:- In recent years, nuclear magnetic resonance imaging (MRI) techniques for assessing iron loading in the liver and heart have been introduced(Anderson et al., 2001),Wood et al., 2004, Tanner et al., 2006)
- Magnetic bisusceptometry (SQUID):- This is another option for a reliable measurement of hepatic iron concentration (Fischer et al., 2013) however it is presently available only in a limited number of centers worldwide.
BETA-THALASSAEMIA: TREATMENT OF IRON OVERLOAD
As the body has no effective means for removing iron, the only way to remove excess iron is to use iron binders (Chelators), which allow iron excretion through the urine and/or stool. As a general rule, patients should start iron chelation treatment once they have had 10-20 transfusion or when ferritin levels rise above 1000ng/ml as stated by thalassaemia international federation (second edition 2008).
Drugs used for treatment of iron overload include:
1. Desferroxamine (DFO): This is an exadentate iron chelator that is not orally absorbed and thus needs parental administration, usually as a subcutaneous 8-12 hour nightly infusion, 5-7mights a week. Average dosage is 20-40mg/kg body weight for children and 30-50mg/kg body weight for adults (Borgna-Pignath and Galanello, 2004).
In the course of using Desferroxamine (DFO) implantated delivery system are associated with risk of thrombosis, infection and local reactions such as pain, swelling, indurations, erythema, burning, pruritus, wheals and rash occasionally accompanied by fever, chills, and malaise.
Other complications, mainly associated with high doses of DFO in young patients and low ferritin value are;
- Sensorineural hypoacusia, particularly at high frequencies
- Ocular toxicity (night blindness, blurred vision, decreased visual acuity, impairment of colour vision, cataract and other disturbances of the eye).
- Retarded growth and skeletal changes with a disproportionately short trunk and dysplasia of the long bones.
- Infections by Yersinia Enterocolitica and other pathogens (Klebsiella pneumoniae).
It is therefore important to monitor patients receiving DFO regularly with audiometric and ophthalmologic tests and with regular evaluation of growth and bone changes.
Use of DFO decreases morbidity and mortality among those who are able to comply with regular prolonged infusion (Gabutti and Piga., 1996). However, because of the side effects and the inconvenients parenteral administration, a consistent proportion of patients are non-complaint, limiting the usefulness of this chelator (Cuningham et al., 2004).
2. Deferiprone (DFP):- This is an orally active iron chelator which emerged from an extensive search for new treatment of iron overload. Comparative studies have shown that this chelator at doses of 75-100mg/kg/day may be as effective as DFO in removing body iron.(Galanello, 2003).
Retrospective and prospective studies have shown that DFP monotherapy is significantly more effective than deferoxamine in decreasing myocardial siderosis in thalassaemia major (Anderson et al, 2002; Piga et al, 2003; Pemall et al 2006).Agranulocytosis is the most serious side effect of deferiprone.
However the combination of the two drugs can be used to achieve levels of iron excretion that cannot be achieved by either drug alone without increasing toxicity (Wonke et al, 1998; Balveer et al, 2001; Alymara et al, 2004)
3. Other iron chelators includes; deferasirox (DFX) and (S)-31- (OH)-desazadesferithiocinpolyether, (magnesium salt)
BETA-THALASSAEMIA:THERAPIES UNDER INVESTIGATION
New chelation strategies are under investigation
- Combination of two-oral chelators; recent metabolic iron balance study in six affected individuals wherein the relative effectiveness of deferasirox (30mg/kg/day) and deferroxamine (40mg/kg/day) was compared, alone and in combination had demonstrated a negative iron balance in 5/6 using in combination of drugs just three days a week (Grady et al., 2013). Moreover, preliminary studies using in combination the two oral chelators deferasirox and deferiprone appear to be encouraging (Berdoukas et al., 2010; Farmaki et al., 2011; Voskaridou et al., 2011)
- FBS0701: This is a novel, orally available member of the desazadesferrithiocin class of siderophore- related tridentate chelator is currently in clinical development (Neufeld et al, 2012).
- Minihepcidins:- A recent study in a mouse model of severe haemochromatosis has demonstrated that the use of minihepcidins, small drug-like hepcidin agonists could be beneficial in iron overload disorder used either alone for prevention or possibly as adjunctive therapy with phelebotomy or chelation (Ramos et al., 2012).
- Induction of fetal hemoglobin synthesis:- This can reduce the severity of β-thalassaemia by improving the imbalance between alpha and non-alpha globin chains. Several pharmacologic compounds including 5-azacytidine, decytabine, and butyrate derivative hence had encouraging results in clinical trials (Pace and Zein, 2006). These agents induce HbF by different mechanisms that are not yet well defined. Their potential in the management of β-thalassaemia syndromes is under investigation (Perrine, 2008; Boosalis et al., 2011).
- Hydroxyurea: Hydroxyurea is used in patients with thalassaemia intermedia to reduce extramedullary masses, to increase hemoglobin levels and, in some cases to improve leg ulcers (Levin & Koren 2011). Hydroxyurea prevents hemolysis and hypercoagulability by modifying the defective hemoglobin synthesis and reducing thrombocytosis. A retrospective study found no pulmonary hypertension in 50 individuals with thalassaemia intermedia treated with hydroxyurea for seven years (karimi et al 2009; Taher et al 2010). A good response, correlated with particular polymorphisms in the beta globin cluster (i.e C>T at -158 G gamma), has been reported in individuals with transfusion dependence (Bradai et al., 2003; Yavarian et al., 2004). However, controlled and randomized studies are warranted to establish the role of hydroxyurea in the management of thalassaemia syndromes.
- Correction of the molecular defect via gene therapy: - The possibility of correction of the molecular defect in haematopoietic stem cells by transfer of a normal gene via a suitable vector or by homologous recombination is being actively investigated. The most promising results in the mouse model have been obtained with lentiviral vectors (Persons, 2009).
A clinical trial for β-thalassaemia has begun in France, and one individual with transfusion dependent HbE/beta-thalassaemia has demonstrated a therapeutic effect after transplantation with autologous CD34+ cells, genetically modified with beta-globin lentiviral vector (Kaiser, 2009). The level of genetically modified cells increased from 2% in the first few months to 11% at 33 month post-transplant. The affected individuals was last transfused on June 6, 2008, and four years after transplantation (despite being slightly anaemia and undergoing repeated phlebotomies for the decrease of iron overload) does not required blood, transfusions.
However, the integrated vector causes transcriptional activation of HMGA2 (a potential oncogene in various types of cancers) in erythroid cells. Even if this integration seems hitherto benign, the ethical evaluation of risk/benefit ratios of gene therapy in thalassaemia is difficult at present (Cavazzana-Calvo et al., 2010)
Prevention and control of Beta-thalassaemia syndromes.
To prevent the birth of new cases with thalassaemia disease, there is need to include carrier screening, genetic counseling and prenatal diagnosis for the couples at risk. This approach may be by population screening or screening at prenatal clinics. Prevention of further thalasaemic offspring in the case of couples at risk can be planned by prenatal diagnosis and selective abortion. Accurate diagnosis and understanding of gene-gene interaction are important for genetic counseling and for the success of the prevention and control of thalassaemia. This approach is cost-effective and is proving remarkably successful in reducing the frequency of thalassaemia in many countries(Kuliev, 1988, CaO and Rosatelli, 1988, Loukopoulos et al, 1988, Angastinioris, 1990).
Any thalasemia individual should avoid the following:
- Alcohol consumption, which in individual with liver disease has a synergistic effect with iron-induced liver damage.
- Iron-containing preparations to avoid increase in iron overload