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What is ferritin?
Iron is an essential bioelement for life; however, free ionic iron is toxic and must be correctly stored inside the cell.
Ferritin is the main protein that stores safely the iron inside the cell. This protein is expressed in all the organism
cells.
Tissue ferritin (ferritin that is inside the tissues) is composed by 24 subunits of two types of ferritins named: L chain
(light, 19 kDa, chromosome 19) and H chains (heavy, 21 kDa, chromosome 11). The proportion of each subunit varies
according to the need for storage and homeostasis of the cell. These subunits form a spherical cavity which stores the
free iron (Fe2+) and saves it therein in the form of Fe3+, through the action of the H-ferritin ferroxidase activity.
Thus, ferritin consists of a soluble protein (apoferritin) and an inner layer composed of ferric hydrophosphate.
Plasma or serum ferritin, is secreted by all ferritin-producer cells and unlike tissue ferritin it is partially glycosylated
and nearly completely iron-free. Serum ferritin is currently regarded as the main test for deficiency states or body
iron overload, since its value is proportional to iron stores, indicating the amount of iron available in the body. Each
microgram of plasma ferritin per litre (µg;/L) is equivalent to between 8-10 milligrams of iron deposit. Normally, a
low level of ferritin indicates a low level of iron (Iron Deficiency Anaemia). However, a high level of ferritin may
indicate various pathologies, including inflammation or infection, since this protein is an acute phase reactant that
increases its concentration in that context.
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Hemochromatosis: A disease of excessive accumulation of iron in the organism that can be genetic (Hereditary
Hemochromatosis type 1, Hereditary Hemochromatosis type 2A, Hereditary Hemochromatosis type 2B,
Hereditary Hemochromatosis type 3, Hereditary Hemochromatosis type 4) or acquired (Secondary
Hemochromatosis). Excess iron inside the organs seriously affects their function and leads to the development
of various clinical symptoms such as liver cirrhosis, heart disease, arthritis, impotence, diabetes,
hypogonadism, dark skin pigmentation, and others.
In Hereditary Hemochromatosis type 1, 2A, 2B, 3 and 4B hyperferritinemia is present together with elevated
transferrin saturation (> 45%). In Hereditary Hemochromatosis type 4A hyperferritinemia is present together
with normal transferrin saturation (< 45%).
See treatment and recommendations
Hemosiderosis: Excess of hemosiderin (micellar aggregates of ferritin) in tissues, which is not a priori harmful,
but can evolve to Hemochromatosis. It occurs when there is a systemic iron overload due to:
Transfusional hemosiderosis: caused by frequent red blood cell transfusions in patients with conditions
that requires them (thalassemia, sickle cell anaemia, aplastic anaemia, myelodysplastic syndrome). Red
blood cells or erythrocytes are a very important source of exogenous iron. (See also multiple blood
transfusions).
Pulmonary hemosiderosis (Idiopathic pulmonary hemosiderosis and other diseases associated with
pulmonary hemorrhage)
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I. First phase with nausea, vomiting, abdominal pain and diarrhea that may be bloody
II. Second phase of apparent recovery during which iron accumulates in mitochondria and in various organs
III. Third phase with gastrointestinal bleeding, hepatotoxicity, metabolic acidosis, hyperglycemia,
coagulopathy, cardiovascular collapse, etc.
IV. Fourth phase of wound healing or pyloric stenosis can cause liver cirrhosis
See treatment and recommendations
Inflammation: Complex biological response of vascular tissues to harmful stimuli such as injury or pathogens,
damaged cells, or toxics. Inflammation is classified as acute (initial response of the organism to harmful stimuli)
or chronic (prolonged inflammation). Ferritin is an acute phase response protein whose concentration is
increased in inflammatory diseases (acute or chronic) and infections, therefore, in such circumstances it no
longer reflects the magnitude of iron stores. The simultaneous measurement of protein acute phase response as
C-reactive protein (CRP) or α1-acid glycoprotein (GPA) may facilitate the interpretation of serum ferritin
concentrations.
See recommendations
Many diseases curse with inflammation including autoimmune diseases such as rheumatoid arthritis, systemic
lupus erythematosus, Still’s disease, Macrophage activation syndrome.
Some diseases such as Still's disease, macrophage activation syndrome (MAS) and drug-induced hypersensitivity
syndrome occurs with extreme hyperferritinemia (serum ferritin levels > 10,000 µg/L).
Still’s disease is an immune-mediated systemic disease with inflammatory arthritis and other symptoms.
Extreme hyperferritinemia of >10,000 ug/L is found in Still’s disease where plasma ferritin is a marker of
disease activity. Still's disease that occurs in children is called systemic juvenile idiopathic arthritis (SJIA).
Extreme hyperferritinemia of >10,000 ug/L can also be due to the Macrophage activation syndrome (MAS). MAS
is a life-threatening genetic or acquired complication of rheumatic disease that, for unknown reasons, occurs
much more frequently in individuals with systemic juvenile idiopathic arthritis (SJIA) and in those with adult-
onset Still's disease. MAS is thought to be caused by the activation and uncontrolled proliferation of T
lymphocytes and well-differentiated macrophages, leading to widespread hemophagocytosis (phagocytosis by
histiocytes of erythrocytes, leukocytes, platelets, and their precursors in bone marrow and other tissues) and
cytokine overproduction. MAS is associated with abnormally raised liver enzymes, hepatosplenomegaly,
pancytopenia, hypertriglyceridaemia, coagulopathy and hypofibrinogenaemia, persistent fever and neurologic
symptoms (eg, irritability, disorientation, lethargy, headache, seizures, coma).
Drug-induced hypersensitivity syndrome is a severe drug reaction characterized by fever and multiorgan
failure, which occurs about a month after drug initiation (eg. anticonvulsant drugs). It is an immune-mediated
process associated with activation of macrophages and T-lymphocytes, overproduction of cytokines and extreme
hyperferritinemia.
Chronic kidney disease (CKD): It is a progressive, irreversible loss of kidney function, including the production of
erythropoietin required for erythropoiesis and the consequent development of anaemia (renal anaemia). In this
disease the kidneys lose their ability to remove waste, concentrate urine and maintain blood electrolytes. The
most common causes of CKD are diabetes mellitus, hypertension, and glomerulonephritis. Hyperferritinemia is
commonly found in patients with chronic kidney disease regardless of their hemoglobin level, and is often
considered to be related to chronic inflammatory status or neoplasias. However, patients with CKD under
different forms of renal replacement therapy are also at a risk of developing secondary iron overload because
for correction of renal anaemia they receive multiple red blood cell transfusions and routinely iron
supplementations (oral or intravenous).
See treatment and recommendations
Neoplasia: Uncontrolled process of proliferation of cells in a tissue or organ that results in the formation of a
neoplasm that can be benign, potentially malignant or clearly malignant. In the process of formation of a
tumor, inflammation plays a major role. Ferritin is an acute phase response protein whose concentration is
elevated in cancer-associated inflammatory processes, so that in such circumstances it does no longer reflects
the magnitude of the iron stores.
See recommendations
Multiple red blood cells transfusions: Red blood cells or erythrocytes are a major source of iron, each
transfusion (aprox. 500 ml of blood) contains about 250 mg of iron. Therefore, a high number of red cell
transfusions lead to hepatic iron overload and high levels of serum ferritin. Multiple blood transfusions are
needed to treat some hereditary anaemias such as thalassemia, sideroblastic anaemia and congenital
dyserythropoietic anaemias and some acquired conditions such as myelodysplastic syndrome.
See recommendations
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Hemolytic anaemia: Hemolytic anaemia is a type of anaemia that occurs when the bone marrow is unable to
replace prematurely destroyed red blood cells because of attacks by the immune system (autoimmune
hemolytic anaemia, for example in paroxysmal nocturnal hemoglobinuria or PNH), genetic defects (thalassemia,
glucose-6-phosphate dehydrogenase, sickle cell anaemia), infections or exposure to certain drugs or toxins. In
these diseases there is a secondary iron overload and increased serum ferritin levels due to the release of
haemoglobin and the blood transfusions or iron supplements required to treat them.
See recommendations
Iron loading anaemias: Congenital sideroblastic anaemia (CSA), congenital dyserythropoietic anaemias (CDA),
atransferrinemias, aceruloplasminemia and DMT1 deficiency are rare anaemias that present at the same time
iron overload in parenchymal tissues (eg. liver). The iron overload in these diseases occurs regardless of the
transfusion or iron treatments and it is exacerbated by them.
See treatment and recommendations
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Liver biopsy procedure to obtain a small sample of liver tissue for direct examination under a microscope.
Advantages: Histology can be studied
Disadvantages: Invasive method, uncomfortable and not free of risk. A false estimation iron concentration
can be given when the distribution of iron in the liver is heterogeneous, especially in cases of
heterogeneous liver cirrhosis.
Magnetic resonance imaging (MRI): non-invasive technique that uses the phenomenon of MRI to obtain
information on the structure and composition of the scanned body.
Advantages: Non-invasive method that allows a fully evaluate of the whole body.
Disadvantages: High cost. The availability of the necessary instrumentation is not always possible.
Quantification of iron and values in liver biopsy and MRI:
Patients with hemosiderosis
No significant iron overload: Values below 3 mg/g
Mild iron overload: between 3 and 7 mg/g
Moderate iron overload: between 7 and 14 mg/g
Hgh iron overload: Higher values of 14 mg/g
Patients with genetic hemochromatosis: As HH is a progressive accumulation disease, normally it is also
calculated the hepatic iron index. This index is the result of dividing the hepatic iron concentration in
mol/g by the patient's age in years.
The patient has hemochromatosis when HII values are greater than 1.9
The patient does not have hemochromatosis when HII values are less than 1.1
Intermediate values are indicative of moderate iron overload.
In those patients with significant iron overload demonstrated by biopsy or MRI further studies in specialized
laboratories are required.
If the rate of transferrin saturation (TS) is greater than 45% the following genetic studies are recommended:
If the rate of transferrin saturation (ST) is less than 45% following genetic studies are recommended:
Genetic studies in specialized laboratories can confirm the disease diagnostic in iron loading anaemias and
hereditary hemolitic anaemias. Genetic studies:
Congenital sideroblastic anaemia with microcytosis. Genes ALAS2, SLC25A38, ABCB7, GLRX5.
Congenital dyserythropoietic anaemias. Genes CDAN1, SEC23B, KLF1.
Aceruloplasminemia. CP gene. Protein ceruloplasmin.
Atransferrinemia. TF gene. Protein transferrin.
DMT1-deficiency anaemia. SLC11A2 gene.
Thalassemia and sickle cell anaemia. Globin genes.
Deficiency in Glucose 6-phosphate dehydrogenase. G6PD gene.
For other hereditary anaemias: see ENERCA.
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