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
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
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 B
12. 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.
12 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
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
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
Key Reference: Brissot et al. Current approach to
hemochromatosis. Blood Reviews 2008; 22: 195-210.
Form 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:
- 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.
- Evaluate hepatic vs splenic iron load in order to direct the diagnosis to the most likely cause of iron excess.
- 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.
- 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).
- 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.
- Monitor treatment response by assessment of relevant biochemical parameters and health outcomes.