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Algorithms and recommendations for diagnosis and management of hyperferritinemia

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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.

What means high levels of serum ferritin?

High values ​​of ferritin usually indicate high levels of iron, but this is not always the case. High levels of ferritin or hyperferritinemia is associated with diseases or conditions such as:

• 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)
  • Chronic hemolyic anaemias (See Hemolytic anaemias).
  See treatment and recommendations
• Porphyria cutanea tarda (PCT): A condition in which the enzyme activity of hepatic URO decarboxylase is decreased. The UROD is an enzyme required in the synthesis of heme. There are genetic forms of PCT (with UROD gen mutations) and sporadic cases, which are the most common (about 80% of cases). Alcohol, estrogens, iron overload (including iron overload due to hemochromatosis) and hepatitis viruses are triggers for this disease. The PCT can have a toxic origin by exposure to chlorinated cyclic hydrocarbons. Photosensitivity and skin lesions with late onset are often seen in PCT as well as persistence of elevated transaminases.
  See treatment and recommendations
• Hereditary hyperferritinemia cataract syndrome (HHCS): Rare genetic disease (ORPHA163, OMIM #600886) characterized by a persistent increase in plasma concentrations of ferritin in the absence of iron overload and the presence of early onset cataracts (although usually absent at birth). This syndrome is an autosomal dominant inherited disease which is caused by mutations in the translation regulatory element called IRE (Iron-Responsive Element) of the gene encoding the ferritin-L subunit. It is unknown the precise prevalence of this disease; however it is estimated to be at least 1 in 200,000 individuals.
  See treatment and recommendations
• Benign hereditary hyperferritinemia: It is a genetic rare disease with autosomal dominant inheritance due to mutations in the coding region of the L-ferritin subunit.
  See treatment and recommendations
• Aceruloplasminemia: It is a rare and recessive genetic disease due to mutations in the gene encoding the ceruloplasmin protein that possesses ferroxidase activity and oxidizes Fe²⁺ a Fe³⁺ (ORPHA48818, OMIM #604290). The aceruloplasminemia presents with iron overload in various organs including the liver and brain. The clinical manifestations of this disease are diabetes mellitus, moderate microcytic anaemia, and late-onset neurological abnormalities including retinal degeneration, ataxia, dementia and involuntary movements. Laboratory manifestations include low or absent serum ceruloplasmin, low levels of copper and iron in serum and high levels of serum ferritin without a rise in transferrin saturation.
  See treatment and recommendations
• Metabolic syndrome: This syndrome is due to genetic factors and/or poor eating habits and little exercise. Metabolic syndrome increases 2-5 times the risk of cardiovascular disease or diabetes mellitus. This syndrome is defined by the presence of three or more of the following criteria:
  • Increased waist circumference (taking into account the type of population and specific conditions, see table of normal waist circumference). The measurement should be made at the midpoint between the lowest rib and the iliac crest (the navel).
  • High serum triglycerides > 150 mg/dL (> 1.7 mmol/L). Alternatively, patients on specific treatment, fibrates or nicotinic acid.
  • Decreased HDL cholesterol < 40 mg/dL (<1.0 mmol/L) in men and <50 mg/dL (<1.3 mmol/L) in women. Alternatively specific treatment.
  • High blood pressure: systolic ≥ 130 mmHg and/or diastolic ≥ 85 mmHg. Alternatively specific treatment history.
  • Elevated fasting glucose ≥ 100 mg/dL. Alternatively, treatment of diabetes.
  See table of normal waist circumference.
  See treatment and recommendations
• Alcoholic hepatitis: Inflammation of the liver due to excessive intake of alcohol. Alcohol damages the liver resulting in an increase in liver enzymes detected in blood (ALT, AST and GGT) and increased serum ferritin levels since the liver is the main organ of iron storage. It is suspected in a patient with high alcohol consumption when this person shows the characteristic clinical symptoms (fever, hepatomegaly, jaundice and anorexia) and typical laboratory findings (ALT/AST>2, high GGT, MCV>100, high IgA, high serum ferritin with normal transferrin saturation).
  See treatment and recommendations
• Viral hepatitis: Liver inflammation due to viral infection mainly by hepatotropic viruses named hepatitis A, B, C, D or E. Other viruses can also cause liver inflammation. Viral infection results in liver damage and in an increase in liver enzymes detected in blood (ALT, AST and GGT) as well as in an increase of serum ferritin levels since the liver is the main organ of iron storage. Hepatitis virus serologies, sensitive molecular methods and liver function tests are laboratory tests to diagnose this condition.
  See treatment and recommendations
• Other hepatic diseases: Other diseases that damage the liver can lead to high levels of ferritin blood because the liver is the main organ that holds the iron in ferritin.
• Iron poisoning: Iron poisoning can occur from the massive ingestion of drug preparations containing iron, such as vitamins and oral iron supplements. In severe iron poisoning it can be observed four phases:
  1. First phase with nausea, vomiting, abdominal pain and diarrhea that may be bloody
  2. Second phase of apparent recovery during which iron accumulates in mitochondria and in various organs
  3. Third phase with gastrointestinal bleeding, hepatotoxicity, metabolic acidosis, hyperglycemia, coagulopathy, cardiovascular collapse, etc.
  4. 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
• 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

What means VERY high levels of serum ferritin (>1000 µg/L)?

There are several evidences that indicate that a serum ferritin level greater than 1000 µg/L is highly associated with a severe impairment of the parenchyma, especially the liver parenchyma. These patients should be tested for liver iron concentration using a direct method. Types of medical tests that can be done are:

• 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:

• Hereditary Hemochromatosis type 1. HFE gene. HFE protein.
• Hereditary Hemochromatosis type 2A. HFE2 gene. Hemojuvelin protein.
• Hereditary Hemochromatosis type 2B. HAMP gene. Protein hepcidin.
• Hereditary hemochromatosis type 3. TFR2 gene. Transferrin receptor protein 2
• Hereditary Hemochromatosis type 4B. SLC40A1 gene. Protein ferroportin.
• Atransferrinemia. TF gene. Transferrin protein

If the rate of transferrin saturation (ST) is less than 45% following genetic studies are recommended:

• Hereditary Hemochromatosis type 4A. SLC40A1 gene. Protein ferroportin.
• Aceruloplasminemia. CP Gen. Protein ceruloplasmin.

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.

What kinds of tests are needed to do with people with high serum ferritin levels?

• Anamnesis
  • Family history
  • Presence of cataracts at an early age (<35 years)
  • Alcohol intake
  • History of transfusional iron treatments
  • History of known cancers
  • History of liver diseases
• Physical Examination
  • Abdominal exploration for searching of hepatomegaly
  • Examination for searching of adenopathies
  • Calculation of body mass index calculate BMI
  • Blood pressure
  • Measure waistlines (see table)
• Analytical tests
  • Hemogram or complete blood count (CBC)
  • Transferrin saturation
  • Glucose
  • Cholesterol, HDL cholesterol include
  • Triglycerides
  • Transaminases and GGT
  • C-reactive protein
  • Hepatitis serologies
  • If the ferritin level is greater than 1000 µg/L, assess level of ceruloplasmin and transferrin
  • If the ferritin level is greater than 1000 µg/L, consider perform relevant genetic tests