Anaemia is one of the most common presenting complaints to general practice. One of several ways in which anaemias can be classified, is by red cell size. As such, anaemias can be said to be:

• Microcytic (small RBCs)
• Normocytic (RBC size within the normal range)
• Macrocytic (large RBCs) – see macrocytic anaemias

Differentiating the cause of microcytic anaemias is important because the treatments can be different. The most common cause of microcytic anaemia is iron deficiency anaemia – which itself can have many underlying causes – but it is also important to consider anaemia of chronic disease and the haemoglobinopathies – such as thalassaemia – especially in iron deficiency presenting in children.

Microcytic anaemia can be identified on blood film (looking at the red blood cells under the microscope) and noting the small size of the cells (more formally the low mean corpuscular volume or low MCV), as well as the hypochromia (reduced colouring – i.e. the cells appear more pale). See below the normal blood film (top) and microcytic anaemia of iron deficiency (bottom). Note that these images have different levels of magnification – and when measured the cells of microcytosis will always be smaller than those of a normal film.

History

• Diet history – particularly if diet is low in iron
  • In children – also ask about cow’s milk intake (should be <500mls per day)
  • Cow’s milk itself doesn’t cause iron deficiency, but children who drink more than 500mls / day tend to eat less food and thus are at risk of iron deficiency
  • Also – intake of java bean / broad beans – can precipitate haemolysis in G6PD deficiency
• Family history
  • Anaemia
  • Jaundice
  • Splenomegaly
• History of blood loss
  • Menorrhagia in females
  • GI bleeding – ask about stool colour, haemorrhoids
    • Be aware that the bleeding is often occult – consider faecal occult blood test

Examination

• Pallor
• Pale conjunctive
• Tachycardia
• SOB – especially on exertion
• Lethargy
• Poor concentration
• Weakness
• Heart failure
• Failure to thrive (in children)

Investigations

• FBC – Hb <90 g/L is particularly significant
  • Microcytosis (small RBCs)
• Iron studies
  • If normal, but patient has microcytic anaemia, request Hb electrophoresis
  • Elevated HbA2 >3.5% (+/- elevated HbF) suggests beta thalassaemia
  • Alpha thalassaemia requires genetic testing for diagnosis

Red flags

Consider urgent hospital admission for anybody with:

• Hb <70g/L (local policies may vary with a cut-off of 60-80g/L for transfusion)
• Tachycardia
• Murmur
• Signs of heart failure
  • Signs of haemolysis, dark urine, jaundice
• Co-existing thrmobocytopaenia or neutropenia
  • May indicate malignancy

Microcytic anaemia in children

• Occurs in 8% of all children in Australia
• The most common cause of anaemia in children
• The reference range for children is different from adults:
  • 2 months – 90 g/L
  • 2-6 months – 95 g/L
  • 6-24 months – 105 g/L
  • 2-11 years – 115 g/L
  • 12+ – 120g/L (female) and 130g/L (male)
• Differentials in children
  • Iron deficiency
  • Thalassaemia
  • G6PD deficiency

References

• Murtagh’s General Practice. 6th Ed. (2015) John Murtagh, Jill Rosenblatt
• Oxford Handbook of General Practice. 3rd Ed. (2010) Simon, C., Everitt, H., van Drop, F.
• Beers, MH., Porter RS., Jones, TV., Kaplan JL., Berkwits, M. The Merck Manual of Diagnosis and Therapy
• Anaemia – RCH

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Iron deficiency anaemia (IDA) is the most common cause of anaemia world-wide. It occurs when there is insufficient iron to facilitate red blood cell production. It is particularly important in the developing world as a cause of poor development in children.

It typically produces a microcytic anaemia, of which iron-deficiency anaemia is the most common type. Anaemia of chronic disease is the other main cause of microcytic anaemia, and it is also seen in thalassaemia and rarely – lead poisoning.

Anaemia in general is defined as haemoglobin (Hb) less than:

• 130 g/L in men
• 120 g/L in women
• 110 g/L in pregnant women and children
• Note that some centres use the unit g/dL, which result in a number 10x lower:
  • 13 g/dL in men
  • 12 g/dL in women
  • 11 g/dL in pregnant women and children <12

Epidemiology

• Affects 2-5% of the population world-wide
  • More common in menstruating females – up to 20%
• Most common cause of anaemia in pregnancy – which can have detrimental effects to both mother and foetus

Aetiology

Malabsorption

• Dietary deficiency (inadequate intake, veganism / vegetarianism makes iron deficiency more likely but green vegetables re a good source and a proper vegetarian diet should not cause deficiency)
  • More common in children (picky eaters) and the elderly
• Coeliac disease
• Post-gastrectomy
• Pica – ingestion of none-food items – e.g. dirt

Drugs can lead to malabsorption through various mechanisms:

• PPI – reduces absorption due to increased gastric pH
• Tetracyclines and quinolone bind to iron and reduce absorption

Blood loss

If often “occult” (not seen) and originating from the gastrointestinal tract. Any cause of blood loss can lead to iron deficiency anaemia. Some of the more common reasons include:

• NSAIDs (cause GI blood loss)
• Anticoagulants
• Peptic ulcer disease
• Menorrhagia
• Malignancy
  • Colon cancer
  • Gastric cancer
• Frequent blood donation
• Hookworm (in tropical areas)
• Oesophageal varices
• Haemorrhoids

Increased physiological requirements

• Pregnancy
• Infancy

Presentation

Anaemia may often not be an obvious diagnosis. Be wary of this as a cause of symptoms in anyone with an aggravation of angina, heart failure or claudication. Many cases also present with non-specific symptoms of tiredness.

Symptoms can include:

• Tiredness or fatigue
• Headaches
• Muscle aches or weakness (without true neurological weakness)
• SOBOE (shortness of breath on exertion)
• Palpitations
• Angina
• Intermittent claudication
• Hair loss

Signs may be non-specific but can include general signs of anaemia:

• Pallor (paleness) of tongue, nail and conjunctiva (unreliable signs)
• Tachycardia
• Systolic (pulmonary) flow murmur
• Signs of heart failure (if severe)
• Jaundice – seen in haemolytic anaemias

Specific to iron deficiency:

• Angular stomatitis
• Glossitis (inflamed tongue), and taste disturbance
• Brittle nails
• Koilonychia – spoon shaped nails – late sign of severe iron deficiency anaemia
• Hair loss

Investigation

A combination of FBC (full blood count) and iron studies is required to make the diagnosis.

Actual serum iron levels are often not particularly useful – prone is an acute phase reactant and levels increase with acute inflammation, and thus are very variable. Serum ferritin is a much more reliable marker. Transferrin is also physiologically raised in pgrenancy

Once a diagnosis of iron deficiency is made, then further investigation for the underlying cause is necessary:

• Screen for coeliac disease (all patients)
• Consider endoscopy (upper and lower) in men and post-menopausal women, if any concerning features
• Consider H. pylori testing
• In the over 50s consider endoscopy in patents with iron deficiency even without anaemia

Be particularly more concerned for a sinister cause in patients who are unable to maintain normal iron levels despite supplementation.

Differential Diagnoses

• Thalassaemia
• Anaemia of chronic disease
• Sideroblastic anaemia
• Lead poisoning

Management

Usually involved treating the underlying cause.

• Dietary factors – encourage foods high in iron, such as:
  • Legumes
  • Red meat – beef, veal, port, liver, poultry
  • Green vegetables – spinach, lettuce, silver beet
  • Pumpkin and sweet potato
  • Seafood – oysters, sardines, tuna
  • Seeds – sesame and pumpkin
  • Eggs – especially egg yolk
  • Fresh fruit
  • Also encourage foods high in vitamin C – as this aids the absorption of iron
    • Citrus flirts, brussels sprouts, broccoli, cauliflower
  • Limit milk intake to <500mls per day
  • Bread is often fortified with iron in developed countries
• Iron supplements
  • Many brans available
  • Ferrous sulphate and ferrous fumarate are the two active ingredients
    • There is thought to be minimal difference in absorption, although side effects may be variable
  • Usually tablets have a dose of around 200-300mg
  • Take 1-2 tabs daily
  • Advise to take with a glass of orange juice
  • Commonly cause GI side effects
    • Constipation or diarrhoea
    • Dark stools
    • Dyspepsia (heartburn)
    • Nausea
    • Abdominal pain
• Iron infusion
  • Can be used in severe cases, or those who have failed oral supplementation
  • Beware that iron infusion can cause permanent staining of the skin around and proximal to the cannula site (usually if the cannula “tissues”) – which has been a source of litigation against medical practitioners
  • Avoid blood transfusion unless severe symptomatic anaemia
• Consider contraceptive methods that rescue menorrhagia in women suffering from this

Re-check FBC 2-4 weeks after initiating treatment

• Then every 3 months for 1 year
• Then again after another year

If blood results are not improving:

• Check compliance and treat any side effects (e.g. laxatives for constipation), or adjust the dose. Reassure black stools are normal and harmless

When to refer

• Anaemia with heart failure – consider urgent referral to hospital
• Women with menorrhagia where the menorrhagia is unresponsive to treatment – refer to gynaecology
• If uncertainty about the type of anaemia – consider referral to haematology
• Men or post-menopausal women without an obvious cause, or not responding to oral therapy – refer to gastroenterology for urgent endoscopy
  • Men of any age with Hb <110 g/L need urgent referral for endoscopy
• Consider referral to dietician if diet is believed to be an important contributing factor

References

• Iron-deficiency Anaemia – patient.info
• Murtagh’s General Practice. 6th Ed. (2015) John Murtagh, Jill Rosenblatt
• Oxford Handbook of General Practice. 3rd Ed. (2010) Simon, C., Everitt, H., van Drop, F.

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Anaemia is one of the most common presenting complaints to general practice. One of several ways in which anaemias can be classified, is by red cell size. As such, anaemias can be said to be:

• Microcytic (small RBCs)
• Normocytic (RBC size within the normal range)
• Macrocytic (large RBCs)

In general, macrocytic anaemias occurs where there is a disorder of red blood cell synthesis, and microcytic anaemias occurs where there is a disorder of haemoglobin synthesis. 

In this article we will discuss macrocytic anaemias. An anaemia can be said be macrocyclic when the Hb is low and the MCV is high (typically >100).

• In cases where the Hb is normal, but there are large RBCs, we refer to this as macrocytosis
• Macrocytosis still usually warrants a diagnosis to prevent progression to macrocytic anaemia

Macrocytic anaemias can be sub-divided into:

• Megaloblastic – deficiency of vit B12 and / or folate
• Nonmegaloblastic – macrocytic anaemia of other cause (e.g. alcoholism, hypothyroidism, liver disease, myelodisplastic syndromes, drugs)

Megaloblastic anaemia is usually managed by identifying and treating the underlying cause, and the most important part of the diagnostic process is to differentiate megaloblastic from nonmegaloblastic anaemias.

• It is particularly important to identify cases where myelodysplastic syndromes or myeloid neoplasm – such cases typically affect the elderly and also involve leukcoytopenia (low white cells) and / or thrombocytopenia (low platelets)

Macrocytic anaemias are common in elderly patients due to multiple factors, and as such, the incidence is expected to increase with the ageing population in the coming decades.

Epidemiology

• Causes:
  • Medication – 40%
    • Drugs that affect DNA synthesis – e.g. azathioprine, cyclophosphamide, sulfasalazine
    • Trimethoprim
    • Phenytoin, sodium valproate
    • Metformin
    • Antivirals – e.g. valacyclovir
  • Alcoholism – 25%
  • Vit B12 / folate deficiency – 6%
  • Liver disease – 6%
  • Myelodysplasia (MDS – myelodyslpastic syndrome – with a risk of progression to AML) – 6%
• Megaloblastic anaemia
  • Most cases caused by pernicious anaemia
  • Peak age of onset: 60
  • Often FHx
  • Often associated with other autoimmune disorders
  • Rarely, vitamin B12 deficiency may be due to malabsorption – particularly in coeliac disease affecting the terminal ileum

Pathology

Macrocytosis is a common finding on FBC (full blood count) tests.

• It is commonly an artefact of the testing process – particularly if the sample has been left a long time before being processed
• It is also seen in hyperglycaemia

In megaloblastic anaemias, maturation of the nucleus is delayed, which causes larger RBCs.

In liver disease, there is accumulation of cholesterol and / or phospholipids on the cell surface, which leads to larger than normal cells.

Megaloblastic anaemia

Vitamin B12 deficiency is by far the most common cause of megaloblastic anaemia. It is either caused by:

• Insufficient dietary intake
  • Vegetarianism / vegansim
• Malabsorption
  • Pernicious anaemia – accounts for 50% of cases of B12 deficiency
    • Or lack of intrinsic factor after gastric surgery
  • Coeliac disease (particularly of the terminal ileum)
• HIV

Vitamin B12 is contained in animal products. The recommended daily intake is 3-30 ug/day

Folate (folic acid) deficiency is less common.

• Folate found in green leafy vegetables and animal products
• Recommended daily intake is 240 ug per day (400 ug in pregnancy and lactating females)
• Folate deficiency can lead to neural tube defects in the foetus
• Folate is absorbed by passive diffusion in the jejunum
• Causes of folate deficiency include:
  • Poor diet
  • Alcoholism
  • Coeliac disease
  • Inflammatory bowel disease
  • Medication
    • Methotrexate
    • Trimethoprim
    • Phenytoin
    • Drug causes tend to only be apparent if there is a prolonged course and / or a high dose
• Serum folate levels vary widely in association with diet, and as such, measuring RBC folate levels, which fluctuate less widely is considered more reliable.

Pernicious anaemia

• The term pernicious refers to the slow and insidious onset nature of the condition
  • Large amounts of B12 are stored in the liver – typically 5-10 years supply – and thus any deficiency can take many years to manifest itself
• Intrinsic factor is normally secreted by the gastric parietal cells and absorbed in the terminal ileum
• B12 binds to intrinsic factor and is absorbed with it
• B12 is a coenzyme that produces methionine from homocysteine – which converts folic acid into its active form
• So, whenever B12 is deficient, folic acid cannot be utilised
• Prevalence of about 10-50 per 100 000 in European populations, less in Asians.
• Destruction of the parietal cells leads to lack on intrinsic factor production and autoantibodies against intrinsic factor

Presentation

Macrocytosis in itself is often aysmtpoamtic. Presentation of macrocytic anaemia can include:

• Fatigue
• SOB – particularly on exertion
• Angina
• Headache
• Palpitations
• Neurological symptoms
  • Reduced sensation
  • Tingling sensations in the limbs (parasthesia)
  • In severe cases, symptoms can involve ataxia, decreased propriception and vibration sense
• In severe cases there may be signs of cardiac failure
• Textbook physical signs of anaemia:
  • Pallor (nail beds, tongue and conjunctiva)
  • Bounding pulse
  • Systolic (pulmonary) flow murmur

Investigations

It is often discovered when a patient present with vague symptoms of lethargy, tiredness, and  has a FBC performed. Once macrocytosis has been confirmed, consider further investigation, including:

• If a blood film has not already been performed – perform a blood film
  • If reticulocytes are ABSENT, this suggests a non-megaloblastic cause – i.e. alcoholism, hypothyroidism or liver cause
  • If reticulocytes are increased, this indicates rapid turnover of reticulocytes
  • The presence of target cells indicate a non-megaloblastic cause
  • May help identify a myelodysplastic syndrome
• Vit B12 levels
  • Low <200 pg/ml
  • Indeterminate 200 – 300 pg/ml
  • Normal >300 pg/ml
• Folate levels (consider ‘red cell folate’ if available as opposed to ‘serum folate’ as it is more reliable)
  • Normal >4 ng/ml
  • Low <2 ng/ml
• TFTs
• LFTs
  • For liver disease and / or alcoholism
• Coeliac serology (if indicated)

If no obvious cause can be found – consider referral to haematology.

Also note that homocysteine levels are often raised in folate and B12 deficiency, and that a homocysteineuria can exist when B12 deficiency exists. It is not routinely clinically useful to check for these, but these tests are sometimes performed by alternative medicine practitioners and patients may present to you with these results.

Management

Depends on the cause

• Pernicious anaemia / B12 deficiency
  • Vit B12 IM injections every 3 months (may be lifelong if pernicious anaemia, may be short term if another cause can be rectified (e.g. poor nutrition)
• Folate deficiency
  • Folic acid 5mg daily for 4 months (oral)
  • If B12 and folate deficiency occur concurrently you MUST treat the B12 deficiency first, or you can aggravate B12 deficiency and risk causing degeneration of the spinal cord

When to refer to haematology

• Neurological symptoms
• Pregnancy
• Suspected haematological malignancy
• No cause can be identified

When to refer to gastroenterology

• Suspected malabsorption (other than pernicious anaemia) – e.g. coeliac disease or inflammatory bowel disease

References

• Macrocytosis and Macrocytic Anaemia – Patient.info
• Diagnosis and treatment of macrocytic anemias in adults – J Gen Fam Med. 2017 Oct; 18(5): 200–204.
• Murtagh’s General Practice. 6th Ed. (2015) John Murtagh, Jill Rosenblatt
• Oxford Handbook of General Practice. 3rd Ed. (2010) Simon, C., Everitt, H., van Drop, F.

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Anaemia of Chronic Disease (ACD) is common, particularly in the hospital setting. It occurs as a result of:

• Chronic infection
• Chronic inflammation
• Neoplasia
• Chronic kidney disease

The anaemia is typically:

• Normochromic – the concentration of Hb within each individual RBC is normal
• Normocytic – the size of the red bloods cells themselves is within the normal range

As such, the anaemia is defined in terms of the total Hb and haematocrit.

However, it can also be:

• Microcytic – small red blood cells
• Hypochromic – reduced amounts of haemoglobin in each individual red blood cell

In this case may be difficult to distinguish from an iron deficiency anaemia (IDA), and in many cases, an iron deficiency anaemia may co-exist with anaemia of chronic disease.

Sometimes, anaemia of CKD is considered separately to the other causes of anaemia of chronic disease. In this artifice we will try to explain where the differences arise between the causes of anaemia of chronic disease.

Other definitions

Epidemiology

In chronic kidney disease

• About 12% of patients will have an anaemia of chronic disease
• This increases as the eGFR falls
• Patients with CKD and diabetes are a greater risk of anaemia

Pathology

• The administration of EPO to patients with rheumatoid arthritis has shown to be of benefit to these patients.
• Note that transferrin is the protein used to transport iron in the blood. It binds iron very strongly, but reversibly.
• Ferritin is a compound that binds free iron within cells. In anaemia of chronic disease, levels of ferritin are often raised.

Complications

• Anaemia puts strain on the heart, increasing the risk of left ventricular hypertrophy
• Strongly associated with increased mortality

References

• Murtagh’s General Practice. 6th Ed. (2015) John Murtagh, Jill Rosenblatt
• Oxford Handbook of General Practice. 3rd Ed. (2010) Simon, C., Everitt, H., van Drop, F.
• Anaemia in chronic kidney disease – Patient.info

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