Haemochromatosis: Pathophysiology and the red blood cell1

Abstract

Haemochromatosis remains the most prevalent genetic disorder of Caucasian populations in Australia and the United States, occurring in ∼1 of 200 individuals and having a carrier frequency of 10-14%. Hereditary haemochromatosis is an autosomal recessive condition, that is phenotypically characterised by a gradual accumulation of iron, above and beyond that required for biological function. Once the binding capacity of iron carriers reaches saturation, the highly reactive free iron generates radicals that may lead to widespread cellular dysfunction. Thus, the compounding effects of systemic iron overload and the associated oxidative stress in untreated haemochromatosis patients results in tissue damage precipitating severe complications, including: liver cirrhosis, hepatocellular cancer, cardiomyopathy, and diabetes. The primary treatment indicated for individuals with haemochromatosis is venesection therapy (i.e., regular bloodletting of ∼450 mL). Given the frequency of venesection required to decrease and normalise the elevated iron levels, this population may serve as a valuable source of blood products which are in short supply. While the complications associated with elevated iron deposits are frequently reported, the influence of haemochromatosis on the rheological properties of blood and red blood cells (RBC) - major determinants of microvascular blood flow and tissue perfusion - are poorly understood. Limited studies investigating haemorheology in patients with haemochromatosis have reported altered physical properties of blood, which may partly explain the comorbidities associated with the disorder. The current review will explore the aetiology, pathology, and clinical implications of haemochromatosis disease and the associated oxidative stress, with particular emphasis on RBC.

Iron Metabolism in Cardiovascular Disease: Physiology, Mechanisms, and Therapeutic Targets

“…75 The excess iron can deposit into various organs leading to multiorgan dysfunction with a particular predilection for the liver, heart, and endocrine glands. 76…”

Interactive Effects between Chronic Lead Exposure and the Homeostatic Iron Regulator Transport HFE Polymorphism on the Human Red Blood Cell Mean Corpuscular Volume (MCV)

“…The HFE (hemochromatosis) gene, reported about two decades ago [13,14,15]—which was found in patients with hereditary hemochromatosis (HH)—is an autosomal recessive genetic disease producing an increase in the absorption of ingested iron. Affected subjects may develop iron overload, which leads to diabetes, heart disease, and liver disease, but afflicted individuals generally did not present symptoms until mid- to late-adulthood.…”

Mechanical sensitivity of red blood cells improves in individuals with hemochromatosis following venesection therapy

“…17 The mechanism for this impaired RBC deformability in HH is currently suggested to occur secondary to an increased blood iron concentration that precipitates free radical generation, leading to oxidative damage of the RBC membrane and increased rigidity of the cell. 18 Given that high-volume transfusion further exposes RBCs to high levels of shear stress, it is plausible that blood products derived from HH donors (with an already impaired cellular deformability) would exhibit a compounding effect of both oxidation and mechanical stress. Nevertheless, given that blood iron is well managed via venesection in HH, it is proposed that the level of impaired cell mechanics induced by iron-mediated oxidative stress may be ameliorated with successive therapies.…”

“…This is particularly important in the context of HH, given that even in the absence of prior shear exposure, RBCs from these donors exhibit significantly impaired cellular deformability, when compared to age‐matched controls 17 . The mechanism for this impaired RBC deformability in HH is currently suggested to occur secondary to an increased blood iron concentration that precipitates free radical generation, leading to oxidative damage of the RBC membrane and increased rigidity of the cell 18 …”