High serum ferritin

Dr Mark Crowther and Dr Henry G Watson give an update on the diagnosis and management of patients with high serum ferritin.

1. Epidemiology and aetiology

Ferritin is a molecule used for the storage of iron. It is water-soluble, meaning that the level in the blood is proportional to the total body ferritin and in most cases total body iron. A low serum ferritin is only seen in an iron-deficient state, however, there are several causes of a raised serum ferritin.

Causes
Raised serum ferritin can be caused by five main mechanisms: damage to ferritin-containing tissues, for example, the bone marrow and liver; inflammation or infection, because ferritin is an acute-phase protein; genetic iron-loading conditions; secondary iron-loading conditions, which are mainly due to blood transfusions but are also seen in African haemosiderosis due to the ingestion of large quantities of iron; and chronic anaemias caused by ineffective haematopoesis, for example, thalassaemias.

Raised ferritin due to tissue damage or as part of the inflammatory process is not a sign of iron overload and does not, on its own, cause a pathological state. It does not require further specific investigation and will not be discussed further.

All genetic iron-loading conditions are very rare in Northern Europeans except for type-1 hereditary haemochromatosis caused by mutations in the HFE gene.

Type-1 hereditary haemochromatosis is an autosomal recessive condition with variable penetrance. The most common mutation associated with pathological iron overload is homozygous C282Y.

Compound heterozygosity for C282Y/C63D is occasionally associated with iron overload. The C282Y mutation is found in between 6.5 and 9.4 per cent of the UK population. Iron overload due to hereditary haemochromatosis has been found in one in 300 people from Northern Europe.

Patients receiving blood transfusion for anaemia other than that caused by iron deficiency or blood loss are at risk of iron overload, and hence may have an increased ferritin level. Iron overload occurs after transfusion of approximately 20 units of blood.

In chronic anaemias the drive to produce red cells causes excess iron absorption. Unless there is additional transfusion it is unlikely that this iron will cause clinical iron overload.

2. Making a diagnosis

As mentioned above, raised serum ferritin due to tissue damage or as part of the acute-phase response does not require treatment and can be differentiated from the iron-loading causes by measuring the fasting transferrin saturation. In tissue damage or part of the acute-phase response it is usually below 50 per cent compared with over 50 per cent in iron loading.

In iron loading the iron is deposited in tissues leading to an inflammatory reaction and tissue damage. Deposits occur in the liver, heart, skin, musculoskeletal and endocrine systems. Clinical features are: cirrhosis with progression to hepatocellular carcinoma; heart failure and arrhythmias; osteoarthritis; slate grey skin pigmentation; and hypothyroidism, hypoadrenalism, diabetes, impotence and hypoparathyroidism.

Hereditary haemochromatosis should be considered in patients with a history (or family history) of one of these conditions where no obvious other cause has been found. Patients receiving blood transfusions should also be monitored for signs of iron overload and a raised ferritin that may require treatment.

Genetic haemochromatosis
Genetic haemochromatosis can usually be diagnosed by genetic testing. In the UK it is normal for laboratories to test for the H282Y and C63D genes. If these are negative it may be necessary to test for rarer genes if clinical suspicion is high. Once hereditary haemochromatosis is diagnosed, the next stage is to determine the extent of associated tissue damage that may require treatment.

It is unlikely that there will be tissue damage with a ferritin level below 1,000(mu)g/l but see the table below for suggested investigations in individuals with significant iron overload. At high levels, ferritin is a poor measure of total body iron and either liver biopsy or advanced radiological techniques are needed, but this is required in only a few cases.

Investigations

  • Liver: Liver function tests and liver biopsy if abnormal liver function or ferritin >1,000[g12]g/L. Monitor for hepatocellular carcinoma with ultrasound if cirrhosis present
  • Heart: ECG then echocardiogram if abnormal ECG or symptoms/signs of heart failure
  • Endocrine: Glucose/HbA1c, TSH, calcium, LH/FSH

3. Managing the condition

In patients who are not transfusion dependent, venesection can be used to reduce total body iron, and for those who are transfusion dependent or who cannot tolerate venesection pharmacological iron chelation is required.

Where venesection is being used, 300-400ml blood is removed, usually in a similar fashion to a blood donation. This can happen every seven days but careful monitoring of the full blood count is required to prevent the development of anaemia.

The aim of the procedure is to render the patient iron-deficient and to achieve a ferritin of less than 50(mu)g/l. Some of the symptoms of tiredness may improve but the main aim is to prevent further tissue damage. Once the ferritin has reached an acceptable level the frequency can be reduced.

In patients receiving transfusions, for example patients with thalassaemia, treatment for high ferritin is usually indicated when the level reaches 1,000(mu)g/l. Two drugs are licensed in the UK for iron chelation: deferoxamine mesilate and deferasirox.

Deferoxamine mesilate is given subcutaneously through a pump. Side-effects include pain at the injection site, ototoxicity and retinopathy (screening required), GI disturbances, asthma, fever, headache, arthralgia and myalgia. For many years this has been the standard treatment for iron chelation but side-effects and issues of administration make adherence and concordance with treatment poor.

Deferasirox is given orally. Side-effects include GI disturbances, headache, proteinuria, pruritus and rash. This is the newest drug and seems well tolerated. It is replacing deferoxamine in many cases but it is expensive.

In summary it is not unusual to find a raised ferritin. Clinical history should allow reactive cases to be identified. Only cases where there is no obvious underlying infection, inflammation or malignancy need to be referred for evaluation of iron loading.

Dr Mark Crowther is a specialist registrar in haematology and Dr Henry G Watson is a consultant haematologist for the Department of Haematology a the Aberdeen Royal Infirmary.

REFERENCES

  • British Committee for Standards in Haematology. www.bcshguidelines.com/pdf/chpt9b.pdf.
  • Hoffbrand A V, Catovsky D, Tuddenham E G D (eds). Postgraduate Haematology. Fifth edition. Chapter 4, pp44-59, Blackwell Publishing, Oxford, 2005.
  • Yen A W, Fancher T L, Bowlus C L. Revisiting hereditary hemochromatosis: current concepts and progress. Am J Med 2006; 119: 391-9.

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