Clinical Review: Raised ferritin

Contributed by Dr Mike Galloway, consultant haematologist, Sunderland Royal Hospital.

Obese patients with type-2 diabetes or fatty liver are likely to have raised ferritin levels (Photograph: SPL)
Obese patients with type-2 diabetes or fatty liver are likely to have raised ferritin levels (Photograph: SPL)

Section 1: Aetiology
Over the last decade the mechanisms responsible for the regulation of iron metabolism have become increasingly clear.

Recognising mutations in iron regulatory genes that result in clinical diseases has helped the understanding of how iron metabolism is regulated.1

Ferritin is the cellular storage protein for iron. It consists of a heavy and a light chain. Ferritin levels are a reflection of total iron stores.

The value of ferritin when measuring iron stores is somewhat limited by the fact that it is an acute phase protein. Levels will increase in situations where there is acute or chronic inflammation.

Low ferritin levels are useful for assessing patients with suspected iron deficiency and assessing ferritin levels in patients with chronic inflammation can still provide useful information on iron stores.2

In contrast, high ferritin levels may suggest a disorder that has led to an excess accumulation of iron, resulting in iron overload.

The important point to remember when dealing with a patient with a raised ferritin level is that conditions other than iron overload may account for the raised level.

Reason for testing
Before considering the causes of raised ferritin levels it is worth reflecting on why the laboratory tests are needed.

There are numerous reasons why a laboratory test may be requested, these include:

  • drug monitoring
  • monitoring specific conditions
  • monitoring response to treatment
  • asking a specific diagnostic question.

Frequently, laboratory tests are requested without a considered indication.

An abnormal result then poses a diagnostic dilemma for the clinician. The following assessment reflects such a case when ferritin was indiscriminately requested.

Section 2: Patient assessment
The flow chart summarises the assessment of a patient who is found to have an unexpectedly raised ferritin level.

If a previous FBC shows a microcytic picture (with or without anaemia) then the two most likely diagnoses are either a type of thalassaemia or a myelodysplastic syndrome.

Any systemic illness will result in an increase in ferritin, since ferritin is also an acute phase reactant.

Common causes
A common cause of raised ferritin in primary care is excess alcohol intake. Ferritin levels have been shown to correlate with the amount of alcohol consumed in men.3 Ferritin levels in this situation may be elevated even in the presence of normal LFTs.

Another cause of raised ferritin is obesity.4 This is particularly seen in obese patients with type-2 diabetes, hypertriglyceridaemia or fatty liver. The serum iron and transferrin saturation are usually normal suggesting that the raised ferritin is part of a reactive acute phase response.

Iron overload
There are a number of causes of iron overload that should be excluded as part of the assessment of raised ferritin.

Raised ferritin may reflect increased iron overload as a result of inappropriate long-term oral treatment with ferrous sulphate.

It is important to investigate the cause of a microcytic anaemia and then reassess the haemoglobin following treatment with ferrous sulphate.2

Iron overload may be due to one of the forms of hereditary haemochromatosis.5 The commonest form is due to a mutation in the HFE gene.

The diagnosis is established by the findings of a raised serum iron, raised transferrin saturation, raised ferritin and the abnormal mutation detected using the blood test to check for mutations of the HFE gene.

Porphyria cutanea tarda (PCT) is the commonest from of the porphyrias. It presents as a chronic blistering skin rash on exposed areas and is due to photosensitisation related to the deposition of porphyrins in the skin.

The clinical manifestations of PCT may be triggered by a number of factors including iron overload.6

Rarer causes
Rarer causes of a raised ferritin include hyperferritinaemia cataract syndrome, an autosomal dominant inherited syndrome resulting from a mutation of the L-chain of ferritin that results in a change in function of the ferritin molecule.7

Ferritin accumulates in the tissues and can result in early-onset bilateral cataracts. Cataract surgery may be required by age 25 or below.8

There is also a form of genetic haemochromatosis that is characterised by normal or low serum iron levels and normal transferrin saturation with raised ferritin levels.

This form of haemochromatosis (type 4a) is associated with mutations affecting the ferroportin gene (another regulatory gene).5

Finally, the raised ferritin may have no clinical significance. A recently described mutation affecting the L-chain of ferritin can present with ferritin levels in the range of 400-6,000 ug/l without any evidence of iron overload.9

This mutation does not seem to result in any change in function of the ferritin molecule and the patients are therefore asymptomatic.

This is called benign hyperferritinaemia.5

This is a diagnosis that can only be made by excluding other causes of a raised ferritin.

Section 3: Management
Patient management will be determined by identifying the cause of the raised ferritin.

The underlying causes of raised ferritin range from conditions that have no clinical significance, such as benign hyperferritinaemia, through to conditions due to lifestyle, to potentially life-shortening conditions associated with hereditary causes of iron overload.

Appropriate patient management is important to ensure that the correct pathway is followed.

If it is suspected that the raised ferritin is part of a reactive process due to a systemic illness, further patient assessment will be determined by findings from the history or examination.

If iron overload is due to haemochromatosis then the patient should be referred to either a gastroenterologist or a haematologist.

Venesection
Treatment includes weekly venesections to reduce ferritin levels to the lower limit of the normal range.

Depending on the ferritin level this may take six to 12 months to achieve. Some patients cannot tolerate this due to the development of anaemia. Reducing the frequency of venesections to alternate weeks can overcome this problem. Patients with genetic haemochromatosis due to mutations of the ferroportin gene usually cannot tolerate venesections.

Other approaches to removing the stored iron, such as the use of oral iron chelators, may have to be considered.

Patients with PCT require a small number of venesections to achieve iron depletion, which then helps to prevent a rash recurrence.

Iatrogenic iron overload
For patients that have iatrogenic iron overload as a result of long-term inappropriate treatment with oral iron, it may be difficult to decide how to manage this situation. The patient should be discussed with a haematologist. Observation over a number of months may indicate if the ferritin levels will reduce over time as the iron stores are used up.

Section 4: Investigating ferritin
The aim of asking a specific diagnostic question is to obtain information about the probability of the target disorder being present (or absent) before the test is undertaken (ie attempting to define the pretest probability of the disease being present).

The result from the diagnostic test can then be used to derive the post-test probability of that disease then being the most likely diagnosis.10

Before considering requesting a ferritin test, identify what question you are hoping the result will answer. In relation to raised ferritin levels, the most likely question would appear to be: 'Does this patient have evidence of iron overload?'

Some assessment of the pretest probability of iron overload can then be made from information collected from the family history or other laboratory investigations, such as a finding of abnormal liver function.

Pretest probability
It is important to frame an appropriate clinical question before requesting the test. Defining the pretest probability of a disorder before the test is taken will help to interpret the result if it is outside the laboratory reference range.

Many of the laboratory reference ranges will be based on the mean plus or minus two standard deviations, and this will include 95 per cent of the population. This leaves 2.5 per cent of the population at each of its upper and lower limits who by definition are then abnormal.

So the probability that a patient will be called normal after one diagnostic test is 0.95. If the patient has two diagnostic tests, the probability of being called normal is now 0.95 x 0.95=0.90.11

By the nature of this definition of normality the more diagnostic tests that are performed the less the probability there is of that patient being labelled as normal if they are indeed abnormal - emphasising the importance of framing the clinical question before the test is carried out.

Serum hepcidin
It is essential to understand that there are causes of raised ferritin levels other than iron overload.

Failure to identify the correct cause of a raised ferritin level can lead to further unnecessary invasive investigations such as liver biopsy and potentially unnecessary treatments such as venesection.

The FBC may give some important clues as to the cause, such as a myelodysplastic syndrome or a thalassaemia.

Assessment of other peptides that are part of the iron regulatory process may help to further assess this group of patients.

Hepcidin is a peptide involved in iron regulation. As iron stores increase, hepcidin levels fall. However, in chronic inflammation increased levels of hepcidin are produced by the liver.

Hepcidin then inhibits iron release from macrophages in the liver resulting in increased iron in the stores and a reduction in serum iron levels. Hepcidin levels are raised in patients with chronic inflammation and low in most patients with genetic haemochromatosis.5

At present, the technology used to measure serum hepcidin levels is not reliable enough to be used in the routine laboratory. However, in future, assessment of hepcidin levels in patients with raised ferritin levels will be a useful approach in confirming the presence of a chronic inflammatory process that would explain the raised ferritin levels.

Resources

1. Donovan A, Andrews NC. The molecular regulation of iron metabolism. Haematol J 2004; 5: 373-80.

2. Smellie WS, Forth J, Bareford D et al. Best practice in primary care pathology: Review 3. J Clin Pathol 2006; 59: 781-9.

3. Leggett BA, Brown NN, Bryant SJ, Duplock L, Powell LW, Halliday JW. Factors affecting the concentrations of ferritin in healthy Australian population. Clin Chem 1990; 36: 1350-55.

4. Lecube A, Hernandez C, Pelegri D, Simo R. Factors accounting for high ferritin levels in obesity. Int J Obes 2008; 32: 1665-9.

5. Camaschella C, Poggiali E. Towards explaining "unexplained" hyperferritinemia. Haematologica 2009; 94: 307-9.

6. Sampietro M, Fiorelli G, Fargion S. Iron overload in porphyria cutanea tarda. Haematologica 1999; 84: 248-53.

7. Girelli D, Corrocher R, Bisceglia L et al. Hereditary hyperferritinemia-cataract syndrome caused by a 29-base pair deletion in the iron responsive element of ferritin L-subunit gene. Blood 1997; 90: 2084-8.

8. Siddiq, Bauer K, Temple K, Mumford AD. Clinical and laboratory features of seven British kindreds with hereditary hyperferritaemia cataract syndrome. Br J Haematol 2004; 125(S1): 33-46.

9. Kannengiesser C, Jouanolle AM, Hetet G et al. A new missense mutation in the L ferritin coding sequence associated with elevated levels of glycosated ferritin in serum and absence of iron overload. Haematologica 2009; 94: 335-9.

10. Galloway MJ, Reid MM. Is the practice of haematology evidence based? III Evidence based diagnostic testing. J Clin Pathol 1998; 51: 489-91.

11. Sackett, DL, Haynes RB, Guyatt GH, Tugwell P. Clinical epidemiology. A basic science for clinical medicine. Second Edition. Little, Brown and Co. London 1991: 51-68.

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