Overview

Definition of normocytic anaemia

Anaemia, or a decrease in circulating red blood cells, is characterised by a fall in the proportion of haemoglobin in the blood or a decrease in the volume of packed red cells found in a specified volume of blood (haematocrit). If a person has anaemia, the haemoglobin concentration reduces to less than 13.0g/dl in men and less than 12.0g/dl in women prior to the menopause.¹ Depending on the cause of the anaemia, the red blood cells (erythrocytes) may increase in size (macrocytic anaemia), decrease in size (microcytic anaemia), or be of normal size (normocytic anaemia).² Most normocytic anaemias arise due to chronic infections, systemic disease and/or inflammation, however, a few are caused by primary disorders of the bone marrow which produces new red blood cells.³

A diagnostic approach to anaemia

Whilst the list of potential causes of anaemia is vast, a logical approach to diagnosis helps to identify possible causes. As all circulating haemoglobin is carried in the red blood cells, a decrease in haemoglobin means one of several scenarios: 

1. The bone marrow is not producing enough red blood cells 
2. Red blood cells are being lost due to bleeding 
3. Red blood cells are being destroyed by a disease process (haemolysis) 
4. Excessive transfusion of intravenous fluids has diluted the concentration of red blood cells in the bloodstream³ 
5. The size of the red blood cells is important as specific causes are associated with microcytic, macrocytic and normocytic anaemia

Finally, the reticulocyte count gives information about the amount of new red blood cells being produced by the body in response to anaemia. Reticulocytes are young immature red blood cells, normally making up 2% of the circulating volume of red cells. A normocytic anaemia may be characterised as a hyperproliferative state (where the reticulocyte count is greater than 2%), hypoproliferative state (where the reticulocyte count is less than 2%) and a normal reticulocyte count.³ A hyperproliferative anaemia occurs when red cells are being lost or destroyed in haemolysis or chronic bleeding whereas a hypoproliferative anaemia indicates not enough red blood cells are being produced, usually indicating a problem in the bone marrow or a chronic systemic disease or infection suppressing blood cell production. (There’s nothing like normal proliferate anaemia). Applying these basic principles allows for a systematic approach to diagnosis.³

Causes of normocytic anaemia

In order to evaluate normocytic anaemia, it is useful to be aware of the potential causes of normocytic anaemia. These can be divided into those in which there is blood cell loss or destruction (high reticulocyte count) and those in which there is reduced red cell production (low or normal reticulocyte count).

Causes of normocytic anaemia characterised by increased blood loss or destruction of red blood cells

• Acute haemorrhage (usually there is an obvious source of bleeding but this may be hidden in bleeding from the gastrointestinal tract or bleeding from hip or pelvic fractures or internal organs after trauma)
• Hypersplenism (enlarged spleen found in liver cirrhosis, myeloproliferative disorders and some infections)
• Congenital haemolytic anaemias
• Acquired haemolytic anaemias 
• Auto-immune haemolytic anaemias 
• Paroxysmal nocturnal haemoglobinuria^3,4

Causes of normocytic anaemia characterised by reduced red blood cell production

Primary causes^3,4

• Bone marrow hypoplasia
• Myelopathies 
• Myeloproliferative neoplasm eg. leukaemia
• Pure red cell aplasia

Secondary causes (the most common)^3,4

• Acute and Chronic kidney disease
• Liver disease
• Endocrine failure eg hypothyroidism, hypoaldosteronism
• Anaemia of chronic disease
• Sideroblastic anaemia

Causes of normocytic anaemia caused by overexpansion of plasma volume

• Intravenous fluid replacement
• Pregnancy

Diagnostic evaluation of normocytic anaemia

History

Most patients with mild anaemia may not exhibit any symptoms. However, if the anaemia shows symptoms, patients may complain of the following:^3,5

• Fatigue
• Dizziness
• Shortness of breath
• Reduction in exercise tolerance
• Malaise
• Headache
• Palpitations
• Difficulties with concentration

Specific inquiry should be made about the following:^3,5

• The patient’s diet
• Abdominal pains, a previous history of gastrointestinal bleeding or peptic ulcer
• The use of medications which cause gastrointestinal bleeding such as aspirin or NSAIDs such as ibuprofen or naproxen
• Autoimmune conditions like. Rheumatoid arthritis or systemic lupus erythematosus
• History of cancer including blood cancers such as leukaemia
• Recent weight loss
• Menstrual history in women (heaviness, frequency and duration of periods)
• Signs of blood loss such as melaena (black tarry stools), vomiting blood (haematemesis), passing blood in urine (haematuria)
• History of congenital disorders eg. sickle cell disease
• Current medications
• History of chronic disease eg chronic renal failure

Obvious clues as to the cause of the anaemia may be noticed from the history, especially if the patient has a known chronic disease or a hereditary syndrome.

Physical examination

Relevant findings in the physical examination are as follows:^3,5

• Generalised pallor especially of lips, mucous membranes and the conjunctivae
• Jaundice (present frequently in haemolytic anaemia)
• A drop between standing and lying blood pressure readings (postural drop) - present if a large amount of blood volume is lost
• Enlargement of liver and spleen (enlarged spleen is seen in various causes of haemolytic anaemia and in some leukaemias, myelofibrosis and lymphoma)
• Abnormal bruising or bleeding (leukaemia)

Blood tests / further investigations

Investigation of normocytic anaemia begins with ordering a full blood count (FBC - and CBC in the USA), corrected reticulocyte index (CRI) and a peripheral blood smear. The FBC gives information about the haemoglobin level, haematocrit and the mean cell volume (MCV), as well as providing information about white blood cell components and platelets, both of which may be altered in leukaemia and other myeloproliferative disorders. An FBC also detects the red blood cell distribution width (i.e. the degree of variation in red cell size). 

A red cell distribution width of 76-96 femtometers is considered homogenous - this is important as this distribution will be homogenous in anaemia of chronic disease which is a common cause of normocytic anaemia. A lot of information can be obtained from microscopic examination of a peripheral blood film. This can show abnormal cells in leukaemia, schistocytes, the presence of spherocytes or sickle cell, wide variations in the red cell volume and the presence of nucleated red blood cells found in bleeding and haemolytic anaemia.^5,6

If the haemoglobin is greater than 9.0 and the red cell distribution is homogenous i e. 76-96 femtometers and the patient has a known chronic disease, it is reasonable to make the assumption that the anaemia is due to anaemia of chronic disease without proceeding with further investigation, however in many cases, further investigations are required.⁵ These investigations are discussed below.

Tests for haemolysis

Serum lactate dehydrogenase, haptoglobin and bilirubin are usually elevated in haemolytic anaemia. Reticulocyte count in haemolytic anaemia will be raised.

Coomb’s test (direct antiglobulin test)

In cases where a haemolytic anaemia is determined (raised reticulocyte count, abnormalities on blood film and raised lactate dehydrogenase or bilirubin) a direct antiglobulin test or Coomb’s test can detect antibodies to red blood cells. This will be positive in warm and cold reactive anaemias (the latter occurs most commonly following mycoplasma and EBV infections) or in drug induced autoimmune haemolytic anaemia. Other haemolytic anaemias are diagnosed on the basis of the blood film and clinical picture.⁵

Iron panel

Iron panel consists of serum iron level, ferritin, total iron binding capacity and transferrin saturation. This gives information about iron stores. As most of the body’s iron is found in red blood cells, a low serum iron is usually the result of bleeding or anaemia of chronic disease. Although iron deficiency anaemia is microcytic not normocytic and early iron deficiency anaemia may present as normocytic. If iron is found to be low, a search should be made for occult bleeding (unseen bleeding from the GI tract) which involves performing a faecal occult blood test and may require gastrointestinal endoscopy to exclude a GI tumour. If Iron is normal but reticulocyte count is decreased or normal, then it is necessary to proceed to bone marrow biopsy.^5,6

Tests for kidney and liver disease

In cases of reduced red cell production, this may be due to acute or chronic kidney disease or chronic liver disease. Urea and electrolytes measure renal function whilst liver function tests (LFTs) measure liver function, however normal LFTs do not exclude chronic liver disease. EPO (Erythropoietin) is a hormone which causes red cell production in the bone marrow. Levels are reduced in chronic kidney disease and measuring EPO may be indicated particularly in the late stages of chronic kidney disease as EPO supplementation can be given to combat anaemia.⁷ 

Tests of immune/inflammatory function

Immune markers such as erythrocyte sedimentation rate, C-reactive protein and antinuclear antibody may be useful in cases where an autoimmune cause is suspected.³

Endocrine tests

Tests of thyroid function, pituitary function and adrenal function (cortisol) as well as aldosterone levels may be indicated in cases where reticulocyte counts are low (indicating reduced red blood cell production).⁵

Bone marrow biopsy

The gold standard test for unexplained anaemia where there is normal or reduced red blood cell production is bone marrow biopsy, however, other serum tests outlined above should be performed first due to the invasiveness of the procedure it is not warranted if blood tests can confirm the diagnosis. A bone marrow biopsy can help diagnose leukaemia, myeloma, myeloproliferative disorders, red cell aplasia and dyserythropoietic anaemia. Serum and urine electrophoresis and serum and urine free light chain tests can also be conducted for multiple myeloma. Additionally bone marrow biopsy should be automatically considered when the initial blood results show a reticulocyte count of <0,1, or if white cells or platelets are low or leukoerythroblastic cells (cells seen in leukaemia) are seen on the blood film.^3,8

Summary

There are many causes of normocytic anaemia. Normocytic anaemia can also be divided into categories where there is blood loss or destruction of red blood cells and causes involving reduced production of new red cells. The reticulocyte count provides information regarding the production of new blood cells and can be used to subdivide normocytic anaemia into these two groups. Further tests can be employed to make the diagnosis, including liver and renal tests, blood film examination, antibody tests, Coomb’s test, endocrine tests and tests of immune function. In cases where there is reduced red cell production and a secondary cause cannot be identified, a primary cause such as leukaemia, myeloma or myelofibrosis may be suspected and a bone marrow biopsy needs to be performed. However, many patients with known chronic disease will be suffering from anaemia of chronic disease (present in kidney and liver disease and rheumatoid arthritis) and in others no identifiable cause may be found.