Management of iron overload in hemoglobinopathies: what is the appropriate target iron level?

Abstract

Patients with thalassemia become iron overloaded from increased absorption of iron, ineffective erythropoiesis, and chronic transfusion. Before effective iron chelation became available, thalassemia major patients died of iron-related cardiac failure in the second decade of life. Initial treatment goals for chelation therapy were aimed at levels of ferritin and liver iron concentrations associated with prevention of adverse cardiac outcomes and avoidance of chelator toxicity. Cardiac deaths were greatly reduced and survival was much longer. Epidemiological data from the general population draw clear associations between increased transferrin saturation (and, by inference, labile iron) and early death, diabetes, and malignant transformation. The rate of cancers now seems to be significantly higher in thalassemia than in the general population. Reduction in iron can reverse many of these complications and reduce the risk of malignancy. As toxicity can result from prolonged exposure to even low levels of excess iron, and survival in thalassemia patients is now many decades, it would seem prudent to refocus attention on prevention of long-term complications of iron overload and to maintain labile iron and total body iron levels within a normal range, if expertise and resources are available to avoid complications of overtreatment.

Clinical management of hemochromatosis: current perspectives

“…Acquired iron overload should be excluded, which is usually easy by considering the following clinical background: chronic anemia necessitating numerous blood transfusions (mainly hemoglobinopathies such as thalassemia 1 and sickle cell disease 2 ) and excessive parenteral iron supplementation. 3 Arguments favoring genetic origin should be collected.…”

Iron storage in liver, bone marrow and splenic Gaucheroma reflects residual disease in type 1 Gaucher disease patients on treatment

“…Whether multiple transfusions played a role in the GD population is uncertain, as the transfusion history was not different between GD patients with abnormal iron storage and those without. Longstanding exposure to even low levels of excess iron can induce toxic effects (Zacharski et al, 2008;Coates et al, 2016). Iron-loaded Kupffer cells in the liver have been associated with the development of fibrosis (Stal et al, 1995;Ramm & Ruddell, 2010) and increased iron stores in the liver are a risk for development of hepatocellular carcinoma (HCC) via several direct and indirect pathways (Kowdley, 2004;Maakaron et al, 2013;Borgna-Pignatti et al, 2014;Adar et al, 2016).…”

How we manage iron overload in sickle cell patients

“…Regardless, as survival in SCD is increasing (Gardner, et al 2016), the lifetime exposure to iron will increase and we can expect iron-related complications to become more frequent in these patients, as is the case in thalassaemia (reviewed in (Coates, et al 2016)).…”

“…In our opinion, regardless of the underlying disease process, the major goal of treatment should be to maintain these reactive forms of iron in the normal range throughout life. If this can be achieved, most of the complications of iron overload can be reduced or even eliminated (Coates, et al 2016, Farmaki, et al 2010, Kolnagou, et al 2010, Kolnagou and Kontoghiorghes 2010a, Kolnagou and Kontoghiorghes 2010b, Kontoghiorghes 2010). However, achieving this goal without risking unacceptable treatment toxicity may not be possible, and some experts do not agree with trying to keep iron at near normal levels.…”

“…If the transferrin saturation is greater than 50%, NTBI/LPI levels are likely to be high, and if it is >70%, NTBI/LPI levels are significantly elevated (Porter, et al 2016, Sahlstedt, et al 2001). Transferrin saturation has been used to screen for iron overload in epidemiology studies and can predict long-term complications of iron overload in large populations [reviewed in (Coates, et al 2016, Puliyel, et al 2015)]. However, transferrin saturation can change literally within minutes to hours, and should be assessed while the patient is fasting.…”