Interpreting Iron Studies
September 17th, 2020
Overview
Iron is an important mineral that is involved in red blood cell metabolism and oxygen transport. Iron studies are used to identify iron deficiency or overload states, and are a common test performed as part of the anaemia screen.
Iron Physiology
Measures of Iron Status
| Iron Deficiency | Anaemia of Chronic Disease | Acute Phase Reaction | Iron Overload | |
| Serum Iron | ↓ | ↓ | ↓ | ↑ |
| Transferrin / TIBC | ↑ | ↓ | ↓ | N / ↓ |
| Transferrin Saturation | ↓ | ↓ | ↓ | ↑ |
| Ferritin | ↓ | Normal | ↑ | ↑ |
| Soluble Transferrin Receptor | ↑ | Normal | Normal | ↓ |
Serum Iron
- Total serum iron is a measure of the ferric (Fe3+) ions bound to serum transferrin. There is significant variation of iron levels with due to multiple factors, and therefore the serum iron is a poor marker of iron status.
Ferritin
- Ferritin is an intracellular iron storage protein whose levels are indicative of the body's total iron stores.
A reduced ferritin level is the most specific indicator of iron deficiency, as there are no other major causes of hypoferritinaemia. Note that inflammation or liver disease can falsely elevate serum ferritin, masking a concomitant iron deficiency.
A Elevated serum ferritin is classically a marker of iron overload, though ferritin is also an acute phase reactant and can be non-specifically elevated with alcohol intake, liver disease or chronic inflammation.
Transferrin & TIBG
- Transferrin is an transport protein that binds to iron in plasma. This is proportional to the total iron binding capacity (TIBG: the total amount of iron that can be bound to serum transferrin). An elevated transferrin level or TIBG is a marker of iron deficiency; a reduced transferrin / TIBG may occur in the context of an acute phase reaction, chronic disease or iron overload.
Transferrin Saturation
- The transferrin saturation (TSat) is the percentage of transferrin that is bound to iron. This is a more accurate measure of total body iron than the serum iron concentration.
An elevated transferrin saturation is an indicator of iron overload, such as due to haemochromatosis, multiple transfusions and iron-loading anaemias.
A reduced transferrin saturation is a marker of iron deficiency, though can also occur with chronic disease. This is a useful way of differentiating iron deficiency from anaemia of chronic disease: ferritin is unlikely to be reduced in chronic disease though is almost always reduced in iron deficiency.
Soluble Transferrin Receptor
- The soluble transferrin receptor is rarely performed in clinical practice. Its main utility is in differentiating iron deficiency from anaemia of chronic disease, which can be difficult to distinguish based on standard iron studies. In iron deficiency, the soluble transferrin receptor level will be increased. Haemolysis will also caused a raised level.
Bone Marrow Iron Stores
- The gold standard for assessing the body's iron status is by performing an iron stain on a bone marrow aspirate specimen. This is almost never used for this purpose, however if a bone marrow aspirate is performed for another reason then this is a useful tool for assessing total body iron.
Iron Deficiency
Iron deficiency may occur due to poor intake, poor absorption or loss of iron. The most common complication of iron deficiency is anaemia, which presents as a microcytic, hypochromic anaemia.
Causes
- Blood loss is the most concerning cause of iron deficiency, most commonly due to menstrual or gastrointestinal loss. Poor iron intake is a common cause of deficiency, and less commonly deficiency can be caused by malabsorption. Iron deficiency may occur in late pregnancy, though the most common obstetric cause of anaemia is haemodilution.
Manifestations
- Patients may present with symptoms of anaemia, such as fatigue and lethargy. A particular symptom that occurs in iron deficiency is pica, which is a craving of non-foods such as chalk and dirt. Patients may also report a history of bleeding: heavy menstrual periods, GI blood or recent trauma.
Examination findings include conjunctival pallor, pallor of the nail beds and hand creases, as well as tachycardia. A sign specific to iron deficiency is koilonychia, or spoon-shaped nails.
Diagnosis
- Iron deficiency manifests on a full blood count and blood film as a microcytic, hypochromic anaemia. This may be associated with elliptocytes, target cells and often an increased platelet count.
Iron studies reveal a reduced ferritin level and reduced transferrin saturation. If a soluble transferrin receptor is ordered, this is usually increased.
Iron Overload
This refers to an excess of total body iron stores. This may be due to haemochromatosis, or one of several secondary causes of iron overload.
Causes
- Hereditary haemochromatosis is the classic cause of iron overload, with the potential for iron deposition in major organs including the skin, liver, pancreas and heart. The main gene defect causing haemochromatosis is mutation of the C282Y HFE gene (type I haemochromatosis). Other genes defects that cause haemochromatosis are haemojuvelin (IIa), hepcidin (IIb), transferrin receptor 2 (III) and ferroportin 1 (IV).
Frequent blood transfusion can result in iron overload, as one unit of packed red blood cells contains approximately 250mg of iron. Overload can also be caused by excessive iron administration; this is mainly through parenteral means as oral intake is unlikely to be sufficient to cause significantly elevated stores.
Iron loading anaemias such as sideroblastic anaemia, thalassaemia and congenital dyserythropoietic anaemia tend to cause significant anaemia with clinical iron overload, even in the absence of frequent blood transfusions.
Manifestations
Iron overload is generally severe before it begins to manifest: this may occur in the following ways:- Skin involvement - bronze discolouration of skin
- Cardiac involvement - palpitations, exertional dyspnoea, orthopnoea, paroxysmal nocturnal dyspnoea, peripheral oedema
- Hepatic involvement - jaundice, ascites, haematemesis, malaena, confusion
- Endocrine involvement - diabetes mellitus, evidence of hypopituitarism or hypogonadism
- Joint involvement - arthralgias, secondary osteoarthritis
Diagnosis
- Elevated ferritin is a key marker of iron overload. Ferritin is also an acute phase reactant, and as such an isolated elevation of ferritin is not necessarily an indicator of iron overload. Ferritin levels >200 ug/L in premenopausal women or >300 ug/L in men and postmenopausal women are concerning for true iron overload.
Elevated transferrin saturations >50% in women or >60% in men are indicative of iron overload.
Next Page
----------------------------------------------------------------------------------------------------------------------------------------------------------------------------
Want more info like this?
MedSchool
- Your electronic clinical medicine handbook
- Guides to help pass your exams
- Tools every medical student needs
- Quick diagrams to have the answers, fast
- Quizzes to test your knowledge
References
Andres E, Serraj K, Zhu J, Vermorken AJ. The pathophysiology of elevated vitamin B12 in clinical practice. QJM: An International Journal of Medicine. 2013 Jun 1;106(6):505-15.Baik HW, Russell RM. Vitamin B12 deficiency in the elderly. Annu Rev Nutr. 1999;19:357-377.Benz Jr EJ. Iron Loading Anaemia. eLS.Brugnara C. Iron Deficiency and Erythropoiesis: New Diagnostic Approaches. Clinical Chemistry. 2003; 49(10): 1573-1578.Cook JD, Flowers CH, Skikne BS. The quantitative assessment of body iron. Blood. 2003; 101: 3359-3363.Goot K, Hazeldine S, Bentley P, Olynyk J, Crawford D. Elevated serum ferritin: What should GPs know?. Australian family physician. 2012;41(12):945-9.Kelly AU, McSorley ST, Patel P, Talwar D. Interpreting iron studies. BMJ: British Medical Journal. 2017 Jun 15;357.Lieu PT, Heiskala M, Peterson PA, Yang Y. The roles of iron in health and disease. Molecular aspects of medicine. 2001 Feb 1;22(1-2):1-87.Lopez A, Cacoub P, Macdougall IC, Peyrin-Biroulet L. Iron deficiency anaemia. The Lancet. 2016 Feb 27;387(10021):907-16.
Metz J. Appropriate use of tests for folate and vitamin B12 deficiency. Australian Prescriber. 1999 Feb 1;22(1):16-8.
Muñoz M, Villar I, GarcÃa-Erce JA. An update on iron physiology. World journal of gastroenterology: WJG. 2009 Oct 7;15(37):4617.
Neumann WL, Coss E, Rugge M, Genta RM. Autoimmune atrophic gastritis--pathogenesis, pathology and management. Nat Rev Gastroenterol Hepatol. 2013;10(9):529-541.Rossi E. Hepcidin-the iron regulatory hormone. Clinical Biochemist Reviews. 2005 Aug;26(3):47.Snow CF. Laboratory diagnosis of vitamin B12 and folate deficiency: a guide for the primary care physician. Archives of internal medicine. 1999 Jun 28;159(12):1289-98.Stabler SP. Vitamin B12 deficiency. New England Journal of Medicine. 2013 Jan 10;368(2):149-60.Stanger O. Physiology of folic acid in health and disease. Current drug metabolism. 2002 Apr 1;3(2):211-23.Van Vranken M. Evaluation of microcytosis. American family physician. 2010 Nov 1;82(9).VanWagner LB, Green RM. Elevated serum ferritin. Jama. 2014 Aug 20;312(7):743-4.Waldvogel-Abramowski S, Waeber G, Gassner C, Buser A, Frey BM, Favrat B, Tissot JD. Physiology of iron metabolism. Transfusion Medicine and Hemotherapy. 2014;41(3):213-21.