Erika Poggiali

An update on iron chelation therapy

Iron overload is a common clinical problem, arising from disorders of increased iron absorption such as hereditary haemochromatosis or thalassaemia intermedia syndromes or as a consequence of chronic blood transfusions for various blood disorders. Regular red blood cell (RBC) transfusions are the principal supportive therapy for many rare anaemias involving a decrease in RBC production, an increase in cell destruction, or chronic blood loss1. Anaemias such as beta-thalassaemia and sickle cell disease are examples of chronic diseases that require long-term transfusion therapy to improve life expectancy. Although transfusion requirements may vary according to the diagnosis, chronic blood transfusion therapy inevitably leads to secondary iron overload that can cause significant damage to many organs, such as the liver and heart, and to the endocrine system2,3. Iron overload is associated with the production of free radicals that can damage tissues, resulting in cardiac toxicity, endocrine dysfunction, and liver toxicity. The effects of iron overload are visible after damage has been done, when patients already have liver dysfunction, cirrhosis, cardiomyopathy or diabetes1,4. Iron is an essential element within the body and its quantity is tightly regulated physiologically; however, the body has no mechanism to excrete excess iron and it deposits iron into end organs leading to severe dysfunction. Each unit of RBC transfused contains 180 to 200 mg of iron. Chronic packed RBC transfusion therapy increases liver iron by approximately 1 mg/mL (by dry weight) for every 15 mL/kg delivered5. Labile plasma iron (LPI) is a toxic and chelatable form of iron that is produced continually during conditions of iron overload, and has been linked to the development of co-morbidities6. It is very important to remove excess iron and suppress LPI to avoid the serious clinical sequelae associated with iron overload. In this specific context phlebotomy cannot be used because patients are usually anaemic and other means must be used to mobilise the excess iron. The gold standard is iron chelation therapy.

Inherited disorders of iron metabolism.

Purpose of review To discuss inherited iron disorders, their pathophysiology and clinical implications in the light of the recent advances in our knowledge of iron metabolism and its regulation. Recent findings In previous years the molecular mechanisms of cellular iron uptake and release and the cellular and systemic iron homeostasis have been substantially clarified. New proteins (hepcidin, hemojuvelin, HFE, TFR2 and ferroportin), mutated in hereditary hemochromatosis, have been identified with a crucial role in iron regulation. These advances have modified our understanding of the pathophysiology of hemochromatosis, now considered a disorder either due to hepcidin deficiency or (rarely) due to hepcidin resistance. Novel genetic forms of iron-related microcytic anemia have been identified, due to defects of iron transport/utilization or to TMPRSS6 deficiency and hepcidin hyperproduction, as occurs in iron-refractory iron deficiency anemia (IRIDA). A role for hepcidin has been identified also in acquired conditions, as in iron-loading anemias and in anemia of chronic diseases and inflammation. Summary Advances in basic research have improved the classification and diagnosis of genetic anemias and iron overload and are paving the way towards the development of drugs that target the molecular lesions.

Towards explaining “unexplained hyperferritinemia”

Elevated serum ferritin is found in a large spectrum of conditions both genetic and acquired, associated or not with iron overload. In this perspective article, Drs. Camaschella and Poggiali examine our current knowledge of the molecular basis of inherited hyperferritinemia. See related article on page 335.

Hypercoagulability in β-thalassemia : a status quo

Life expectancy of thalassemia patients has markedly improved over the last few decades, but patients still suffer from many complications of their congenital chronic disease, and several new complications are now being acknowledged, including thrombosis. The high prevalence of thromboembolic events, especially in thalassemia intermedia, has led to the identification of a hypercoagulable state in these patients. This review summarizes current knowledge of the clinical and pathophysiological characteristics of hypercoagulability in thalassemia patients. Strategies to prevent thrombotic events are also discussed.

Rare Types of Genetic Hemochromatosis

Most types of genetic hemochromatosis are due to mutations in the HFE gene, although similar iron overload and organ damage can also result from mutations in genes other than HFE in rare types of hemochromatosis. Non-HFE hemochromatoses have been divided into two subgroups with distinctive features. The first includes juvenile and TFR2-related hemochromatoses that, similar to HFE hemochromatosis, show recessive inheritance, increased transferrin saturation, iron storage in hepatocytes and responsiveness to phlebotomy. Disorders in this subgroup, although differing regarding the severity of iron overload and/or the age at presentation, are all either due to hepcidin deficiency or to the inability to increase hepcidin levels according to iron stores. The second subgroup of hemochromatosis is caused by autosomal dominant mutations in the SLC40A1 gene encoding the iron exporter ferroportin with distinctive features. Iron loading of Kupffer cells and normal transferrin saturation characterize the so-called ‘ferroportin disease’. In contrast, few mutations in SLC40A1 that cause hepcidin resistance lead to a hemochromatosis-like phenotype with dominant inheritance. The precise diagnosis of the genetic type of hemochromatosis is relevant for the follow-up, treatment, and for family counseling.

Gaucher disease: A diagnostic challenge for internists

Gaucher disease (GD), the most common inherited lysosomal storage disorder, is a multiorgan disease due to an autosomal recessive defect of the gene encoding glucocerebrosidase enzyme, responsible for the accumulation of glucosylceramide (glucocerebroside) into reticuloendothelial cells, particularly in the liver, spleen and bone marrow. GD is a clinically heterogeneous disorder and it is conventionally classified in type 1 (non-neuronopathic disease), types 2 and 3 (acute and chronic neuronopathic disease, respectively). Features of clinical presentation and organ involvement as well as age, at presentation are highly variable among affected patients. Splenomegaly and/or thrombocytopenia are the most common presenting features either as incidental findings during routine blood count or physical examination. Other possible clinical manifestations can be hepatomegaly with abnormal liver function tests, bone pain often associated with skeletal complications (pathological fractures, avascular necrosis, osteopenia), pulmonary hypertension and, in neuronopathic forms, neurological manifestations (dysfunction of eye motility, mild mental retardation, behavioural difficulties, choreoathetosis and cramp attacks). For all these reasons GD diagnosis is often a real challenge for internists. In the presence of clinical suspicion of GD, the diagnosis has to be confirmed measuring the betaglucocerebrosidase activity in the peripheral leukocytes and by molecular analysis. Each patient needs an accurate initial multisystemic assessment, staging the damage of all the possible organs involved, and the burden of the disease, followed by regular followup. The correct and early diagnosis permits to treat patients properly, avoiding the complications of the disease.

Hypercoagulability in non-transfusion-dependent thalassemia.

Beta (β)-thalassemia is characterized by a hypercoagulable state and an increased risk of thrombosis, which can result in significant morbidity and mortality. The molecular and cellular mechanisms contributing to hypercoagulability are diverse and include chronic platelet activation, alteration of red blood cell membranes, abnormal expression of adhesion molecules on vascular endothelial cells, and dysregulation of hemostasis. Regular transfusions decrease the risk of thrombosis, whereas splenectomy significantly increases the risk. Splenectomized adults with non-transfusion-dependent thalassemia are also at high risk for ischemic brain damage. Strategies to lower the risk of thrombosis should be considered, including transfusion therapy to raise hemoglobin levels and avoidance or delay of splenectomy.

The role of TMPRSS6 polymorphisms in iron deficiency anemia partially responsive to oral iron treatment

Iron refractory iron deficiency anemia (IRIDA) is a rare hereditary disease caused by mutations in TMPRSS6 gene encoding Matriptase‐2, a negative regulator of hepcidin transcription. Up to now, 53 IRIDA patients from 35 families with different ethnic origins have been reported and 41 TMPRSS6 mutations have been identified. TMPRSS6 polymorphisms are more frequent than mutations, and have been associated with variation in iron and hematologic parameters. Our study evaluated their presence in 113 subjects with iron deficiency anemia (IDA) partially responsive to oral iron therapy and in 50 healthy blood donors. Thalassemic trait was diagnosed in 38 patients. Sequencing analysis of TMPRSS6 gene revealed that the frequency of several polymorphisms was markedly different between IDA subjects and controls. In particular, the V736A TMPRSS6 polymorphism was associated to moderately lower hemoglobin, mean corpuscular volume, and mean corpuscular hemoglobin levels, and in thalassemia carriers with marked anemia and microcytosis. A new variant—H448R– and two uncommon polymorphisms —A719T and V795I— were also identified. These results indicate that TMPRSS6 polymorphisms are more frequent in subjects with persistent IDA than in healthy controls, and in thalassemia carriers V736A variant may account for lower hemoglobin and MCV levels. Further studies in larger court of patients are necessary to identify potential haplotypes and polymorphisms responsible for low response to oral iron treatment and may be useful for planning a correct iron supplementation. Am. J. Hematol. 90:306–309, 2015.

A multicentre observational study for early diagnosis of Gaucher disease in patients with Splenomegaly and/or Thrombocytopenia.

Gaucher disease (GD) is the most common lysosomal disorder resulting from deficient activity of the β‐glucosidase enzyme that causes accumulation of glucosylceramide in the macrophage–monocyte system. Notably, because of non‐specific symptoms and a lack of awareness, patients with GD experience long diagnostic delays. The aim of this study was to apply a diagnostic algorithm to identify GD type 1 among adults subjects referred to Italian haematology outpatient units because of splenomegaly and/or thrombocytopenia and, eventually, to estimate the prevalence of GD in this selected population. One hundred and ninety‐six subjects (61 females, 135 males; mean age 47.8 ± 18.2 years) have been enrolled in the study and tested for β‐glucosidase enzyme activity on dried blood spot (DBS). Seven of 196 patients have been diagnosed with GD, (5 females and 2 males) with mean age 31.8 ± 8.2 years, with a prevalence of 3.6% (with a prevalence of 3.6% (I95% CI 1.4–7.2; 1/28 patients) in this population. These results show that the use of an appropriate diagnostic algorithm and a simple diagnostic method, such as DBS, are important tools to facilitate the diagnosis of a rare disease even for not disease‐expert physicians.

Does TMPRSS6 RS855791 Polymorphism Contribute to Iron Deficiency in Treated Celiac Disease

Does TMPRSS6 RS855791 Polymorphism Contribute to Iron Deficiency in Treated Celiac Disease?