Iron Disorders Genescreen

Iron Disorders Genescreen

The role of iron metabolism in health and disease

The importance of iron metabolism now extends beyond the traditional areas of erythropoiesis and nutrition, representing a key factor in pathology, cardiology, oncology, neurological and infectious diseases. Molecular genetic research has revealed that the phenotypic expression of specific mutations in genes involved in iron metabolism may vary significantly. Hereditary iron overload was shown to be of multigenic nature, caused by a genetically determined inability to prevent the excessive influx of iron into the circulatory pool and characterized by progressive parenchymal iron overload with potential for multi-organ damage and disease.

Iron deficiency, iron overload and the anaemia of inflammation are the commonest disorders of iron metabolism:

Nutritional iron deficiency
results from a diet that contains insufficient bioavailable iron to meet requirements. In developing countries, traditional foods usually contain large quantities of iron absorption inhibitors, particularly phytates and polyphenols. Conditions that cause blood loss, particularly hookworm infections, have an important contributory role leading to a high prevalence of iron deficiency in many developing countries.

Primary iron overload
is far less prevalent than iron deficiency. Primary systemic iron overload (haemochromatosis) is almost always the result of an inherited abnormality of the regulation of iron transport that affects hepcidin or its receptor ferroportin.

The anaemia of inflammation
(anaemia of chronic disease) is the result of increased hepcidin expression induced by inflammatory cytokines which is generally considered to be a host response that evolved to make iron less available to pathogens. It is characterized by decreased release from iron stores, low plasma iron and transferrin concentrations, restriction of the available iron supply for red blood cell production and mild or moderate anaemia.

Nutritional anaemia is also characterized by other nutritional deficiencies. Both copper and zinc are essential nutrients and deficiencies of both result in anaemia. Resistance to infections depends on a healthy immune function and copper and zinc are both necessary for normal function of the immune system. It has been found that zinc supplementation may reduce the incidence of malaria. Copper deficit should be included in the differential diagnosis of anaemia unresponsive to iron supplementation.

Although most anaemia in developing countries is due to iron deficiency, a proportion may be due to deficiency of vitamins of B complex, principally folate and vitamin B12. The anaemia is macrocytic but with presence of abnormal red cell precursors in the bone marrow called megaloblasts. Because of the well proven case of increased risk for spina bifida, neural tube defects and other birth defects, folic acid supplementation before, during and after pregnancy is now accepted as being critical regardless of the nutritional status of the woman.

Vitamin B12 enters the human food chain exclusively through animal sources. Its synthesis is completely absent in plants of all kinds, only being present in such foods by way of bacterial contamination or fermentation. For this reason vegetarians and more particularly vegans, are at high risk of insufficient dietary intake.

Everybody should take notice of the potential danger of inherited iron overload as it starts with the same symptoms as iron deficiency, namely chronic fatigue. When feeling tired, many people assume iron deficiency and take iron supplements. The degree of iron overload, if any, depends on interaction between genetic (low penetrance) and environmental factors. Individuals with a genetic predisposition for haemochromatosis respond differently to iron intake due to gene-diet interaction, a concept termed nutrigenetics.

The Iron Disorders GeneScreen concept discussed at the GeneTalk Workshop on the 27th of May 2009 includes genetic testing for hereditary haemochromatosis .

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Until recently, the HFE gene was considered the only major cause of inherited iron overload, which could lead to organ failure if left untreated. Failure to identify mutations in a relatively large number of patients referred by clinicians for genetic testing contributed to the identification of several other genes involved in iron overload. It also highlighted the importance of a step-wise approach in the diagnosis and treatment of iron overload disorders.

Key Reference:
Brissot et al. Current approach to hemochromatosis. Blood Reviews 2008; 22: 195-210.

From single- to multi-gene testing

The application of genetic testing is limited in monogenic diseases such as familial hypercholesterolaemia (FH) and hereditary haemochromatosis (HH), considered to be the most common autosomal dominant and recessive diseases in Caucasians, respectively. The genotype insufficiently predicts clinical outcome in the presence of other modifier genes and relevant environmental influences.

Therefore, a pathology supported genetic testing approach was developed for dyslipidaemic patients, where the diagnosis of FH is considered to be one of several potential contributing factors to cardiovascular disease (CVD) risk and an important target for aggressive treatment. Similarly, in patients with high ferritin levels, a step-wise process has been proposed to confirm or exclude a diagnosis of HH as part of overall clinical risk management.

Pathology supported genetic testing in patients at risk of haemochromatosis and associated medical conditions involves the following steps:

  1. Consider iron overload based on presenting clinical features and iron status, taking into account the main confounding factors such as alcoholism, inflammatory conditions, acute or chronic hepatitis and polymetabolic syndrome.
  2. Evaluate hepatic vs splenic iron load in order to direct the diagnosis to the most likely cause of iron excess.
  3. Rule out acquired iron overload due to external factors such as prolonged iron supplementation (e.g. in the setting of competitive sports) or repeated transfusions in patients with haematological diseases, represented by chronic anaemias such as thalassaemia major and sickle cell disease.
  4. Identify the genetic origin of iron overload by considering both family and personal information (e.g. plasma ceruloplasmin level when transferrin saturation is normal or low).
  5. Treat patients with iron overload according to genetic subtype: venesection is the treatment of choice in patients with haemochromatosis related to hepcidin deficiency, but is poorly tolerated or contraindicated in patients with iron overload due to ferroportin failure.
  6. Monitor treatment response by assessment of relevant biochemical parameters and health outcomes.