More detailed notes on the physiology of haemoglobin and iron homeostasis are available elsewhere on this site.
Iron is stored in a number of locations in the body. The total iron content of an adult male is around 3.5g, broken down as:
Haemoglobin - 2.1g
Ferritin - 700mg
Haemosiderin - 300mg
Myoglobin - 200mg
Enzymes - 150mg
Only about 3mg is in the ‘mobile’ form of transferrin at any one time.
Iron is absorbed in the gut primarily in the duodenum and proximal jejunum. Ironin the ferrous state is much more easily absorbed that the ferric state. It is generally easier to absorb haem iron (from red meat) rather than non-heam iron, which must undergo liberation from it’s food source (often plant form) and reduced. Absorption of non-haem iron can be impaired by a number of other ingested substances e.g. bran, tetracycline antibiotics, although vitamin C actually improves absorption. However, the absorption mechanism has a significant limitation to it’s rate. It usually only absorbs 1mg/day, which is just enough to cover the iron loss of cells that desquamate from the skin and GI tract. In cases of increased loss, this uptake can also increase, but rarely beyond 6mg/day. This is often less than the total iron content of the diet, so the rate limiting step is often GI absorption rather than a lack in dietary intake.
From the gut, iron binds with apotransferrin to form transferrin, the transport molecule of iron (it’s transferring the iron). This bond is relatively weak, so iron can be distributed around the body. This can be to:
The haematopoietic organs for inclusion into Hb
To the storage pool
The storage pool is primarily in the liver, but is also in the bone marrow and spleen, as well as circulating in RBCs. Ferritin is a readily convertible form of iron to provide an easily accessible source when needed. It is essentially a cluster of protein molecules, with the iron included within them. Haemosiderin is more insoluble (significantly so), and primarily just found in the liver and marrow in smaller quantities. When the iron is needed for haemotopoiesis, it is transferred by transferrin to the haematopoietic organs.
Due to the problems with iron uptake, it is heavily recycled by the body. When RBCs undergo destruction at the end of their lifespan, when they undergo phagocytosis the iron component is retained and reused.
Iron also has an important role in many other body systems. As such, it is increasingly being recognised that iron deficiency (absolute or functional) may impact on patients health in ways other than just anaemia.
Key roles include:
Cellular oxygen transport
Electron transfer reactions
If we understand the pathophysiology, we can start to consider the causes. An approach to categorisation could be:
Malignancy - particularly colonic
Other chronic blood loss
Excess blood donation
Infection e.g. hookworm
Small bowel malabsorption conditions e.g. coeliac disease
Drug binding e.g. tetracyclines
Reduced dietary intake
Blood loss is the most common cause, where GI uptake can’t keep up with the iron losses from the chronic blood loss. In particular, occult GI bleeding needs consideration, as IDA may be the first presentation of a pathology that is not otherwise displaying symptoms e.g. bowel cancer. Menstruation can lead to an average loss of 0.5g of iron per day, so can be a common cause in women.
Dietary causes are rare, as iron is fairly widespread. Many vegetables have a significant iron content, so even though the iron load is less than with meat intake, a proper vegetarian diet shouldn’t lead to iron deficiency.
An acute increase in iron requirement may lead to a deficiency. This is common in times of rapid growth, such as early infancy, adolescence or pregnancy.
The overlap of chronic inflammation is also particularly interesting here. It is being increasingly recognised that the key regulator of iron, hepcidin, is induced by inflammatory processes (particulalry through IL-6). As such, chronic inflammation can lead to a state of iron deficiency through impaired enteral iron uptake.
As noted in the overview of anaemia notes (link), there can be a variety of ways anaemia can present, from incidentally through to the effects of impaired oxygen delivery. The presentation of IDA is essentially the same as this. However. additional symptoms may occur due to the iron deficiency itself:
Dysphagia - Plummer-Vinson syndrome of oesophageal web
History The history should aim to gather information on possible causes of IDA. This is particularly because it is commonly related to blood loss which may be from a potentially harmful cause. Areas of the history to cover include:
Past medical history
Family history - thalassaemia
Travel history - hookworm
Bowel habit change
Examination This will be again aimed at detecting an underlying possible pathological cause and will involve an appropriately focused examination e.g. abdominal exam. Specific signs of IDA include:
Koilonychia - spoon shaped nails
Investigation This will typically include routine blood investigation of anaemia:
Full blood count
The typical finding of IDA are:
Hypochromic microcytic anaemia
Low serum ferritin (<15-30mcg/L)
Low transferrin saturation (<20%)
Raised total iron binding capacity
Anisocytosis (variation in RBC size) and poikilocytosis (abnormally shaped RBCs)
Hypochromic microcytic anaemia arise because of the limited production of Hb possible with iron deficiency. Coexisting disease (e.g. B12 deficiency) may affect this though, and many result in a normal MCV. Haemoglobinopathies will also result in this picture. Hb electrophoresis should be considered if a haemoglobinopathy is a relatively likely differential to avoid excessive investigation for occult bleeding.
Serum ferritin levels correlate with total body iron stores and is potentially the most useful diagnostic test. However, it is an acute phase protein so can be elevated in inflammatory conditions. A level under 15mcg/L confirms a diagnosis of IDA (under 30mcg/L is quoted in some literature). Levels above 100mcg/L effectively rule out IDA except on the presence of significant inflammation. In cases of diagnostic difficulty, a trial of iron supplementation is often the least invasive treatment.
Normal transferrin saturation levels are around 33%. Total iron binding capacity is related to transferrin levels.
Further investigation will then be guided on identifying a cause (if one is not readily apparent). This may include:
Oral iron supplementation is generally first line. If there is a possible dietary cause (e.g. specific diets), dietician advice may be useful. Simple advice on iron rich foods include: meats, dark green vegetables, prunes, raisins. Tablets should be taken on an empty stomach, as food can impair absorption.
Iron salts are commonly required e.g. ferrous sulphate 200mg 2-3 times daily There is no clear difference between the different preparations in terms of iron absorption. Side effects include:
Adverse effects are common and can frequently lead to discontinuation, which should be enquired about in cases of ‘treatment failure’. They can be helped by switching preparations, reducing intake and direct treatment of symptoms e.g. laxatives. Alternate day dosing is also advocated as an option to improve tolerance.
Repeat FBC is done at 2-4 weeks to assess response. Once the IDA is corrected, treatment is continued for 3 months to replenish body stores.
Parenteral Iron Therapy This may be indicated in patients who cannot tolerate enteral replacement, or those who don’t respond. Some patients may also have pathology that will impair GI absorption e.g. coeliac disease. Options include:
Ferinject - ferric carboxymaltose - intravenous
Venofer - iron sucrose - IV
Cosmofer - iron (III) hydroxide dextran - deep IM/IV
These can provide a more rapid elevation of body iron stores and Hb than the enteral route, but there is a similar response seen at 12 weeks. However, this may be significant in those patients who are awaiting urgent surgery e.g. cancer surgery, and therefore may be better than oral therapy. The oral route is considered safer and more economical and thus remains first list, but the safety profile of parenteral iron has improved (there have been deaths associated with its use) and the threshold for using this treatment is reducing. Adverse reactions include:
Non allergic immune reaction - (arthralgia, flushing)
Blood transfusion may be required in a small number of patients. This is generally only when the anaemia is so significant (or comorbidity severe enough) that it is leading to cardiovascular compromise.
Iron deficiency anemia has been well recognised as a significant risk factor for major surgery. There is evidence that it imparts an increased chance of numerous adverse effects. A meta analysis from Fowler et al noted these as increased risk of:
Mortality (OR 2.90)
AKI (OR 3.75)
Infection (OR 1.93)
Requiring transfusion (OR 5.04)
It is a challenge to fully unpick whether this is causally related to the effects of the anaemia, adverse effects of allogeneic blood cell transfusion, or the underlying disease.
The possibility of anaemia should be assessed before any surgery with blood loss of >500ml expected.
Major non-urgent surgery should be postponed to allow the diagnosis and treatment anaemia
A Hb treatment target of > 130g/L (in both sexes) should be used to minimise the risk of transfusion
Parenteral iron therapy should be considered as first line treatment for urgent surgery (under 6 weeks) and those unable to tolerate oral iron.
Oral iron therapy should be remain first line in most cases
Hb values of under 130g/l increases the likelihood of needing a blood transfusion and the associated increase in mortality and risk. A value of above this in both sexes should be targeted to reduce the risk of transfusion. This is true for all patients, but the risk is clearly greater with more significant surgery (and the associated increased risk of blood loss).
Low dose oral iron e.g. 40-60mg is generally recommended in patients with time for oral therapy to work. There should be a reassessment of the response 4 weeks prior to surgery, with the understanding that oral therapy may not result in a response from everyone (side effects etc.) In these patients, IV iron is likely to be beneficial.
The condition of iron deficiency without anaemia may also have a negative impact on patient outcomes, for example resulting in a limited ability to recover from blood loss. There is still ongoing research in this domain, but suggestions are that iron supplementation of this group may also be beneficial.
The decision to postpone surgery based on anaemia will be patient specific. In some cases the conditions will be linked e.g. GI cancer, and the surgical treatment will be time critical. In a less urgent situation, the benefits of improving anaemia and iron stores before surgery should be discussed with the patient. However, when the surgery is minor and anticipated blood loss is small (<500ml) it has been advocated to proceed with surgery whilst investigation and treatment of anaemia continues.
Perioperatively a patient blood management approach is advocated to optimise patient care, with a major focus on minimising the needs for blood transfusion. Relevant componenets of this include:
Use of tranexamic acid
Minimising haemodilution from excess IV fluid
Surgical techniques to minimise blood loss e.g. torniquets, minimally invasive surgery
Optimising physiology for haemostasis
Postoperative anaemia is common (blood loss, blood sampling, poor nutrition), and may impact on recovery. Oral absorption of iron is very limited because of the impact of inflammation on iron physiology and so supplementation is of little benefit. Parenteral iron may have a role here in certain scenarios.
Functional Iron Deficiency
This refers to a state of impaired iron utilisation brought about by chronic disease, previously referred to as anaemia of chronic disease. As noted above, inflammation results in an increased hepcidin level and thus an impaired ability for the body to utilise iron for ongoing erythropoiesis. Reduced production or functionality of erythropoietin may also play a role in the pathophysiology here. The diagnosis is usually one of exclusion, but there will likely be evidence of a disease process within the history and/or features of inflammation on investigations.