The various types of anaemia are classified in terms of the red cell size—the mean corpuscular volume (MCV):
microcytic—MCV ≤ 80 fL
macrocytic—MCV >100 fL
normocytic—MCV 80–100 fL
Note: Upper limit of MCV varies from 95–100 fL depending on age and laboratory.
TABLE 22.2 outlines a classification of some of the more common causes of anaemia encountered in general practice. There can be an interchange of disorders between the above groups, for example, the anaemia of chronic disorders (chronic infection, inflammation and malignancy) can occasionally be microcytic as well as normocytic; the anaemia of hypothyroidism can be macrocytic in addition to the more likely normocytic; the anaemia of bone marrow disorder or infiltration can also be occasionally macrocytic.
Table 22.2Selected causes and investigations of anaemia |Favorite Table|Download (.pdf) Table 22.2 Selected causes and investigations of anaemia
|Causes/classification ||Primary diagnostic features ||Secondary investigations |
|Microcytic (MCV <80 fL) || || |
| Iron deficiency ||s.Fe ↓; s.ferr ↓; transferrin ↑ ||Therapeutic trial of iron; GIT evaluation for blood loss |
| Haemoglobinopathy (e.g. thalassaemia) ||s.Fe N or ↑; s.ferr N or ↑ ||Haemoglobin investigation, e.g. electrophoresis |
| Sideroblastic anaemia (hereditary) ||s.Fe N or ↑; s.ferr N or ↑ ||Bone marrow examination |
|Occasionally microcytic || || |
| Anaemia of chronic disease (sometimes microcytic) ||s.Fe ↓; s.ferr N or ↑; transferrin ↓ ||Specific for underlying disorder |
|Macrocytic (MCV >100 fL) || || |
|(a) With megaloblastic changes || || |
| Vitamin B12 deficiency ||s.B12 ↓; rc.Fol N or ↑ ||IF antibody assay; Schilling test |
| Folate deficiency ||s.B12 N; rc.Fol ↓ ||Usually none |
| Cytotoxic drugs ||Appropriate setting; s.B12 N; rc.Fol N ||None |
|(b) Without megaloblastic changes || || |
| Liver disease/alcoholism ||Appropriate setting; uniform macrocytosis; s.B12 N; rc.Fol N ||Liver function tests |
| Myelodysplastic disorders (including sideroblastic anaemia) ||Specific peripheral blood findings; s.B12 N; rc.Fol N ||Bone marrow examination |
|Normocytic (MCV 80–100 fL) || || |
|Acute blood loss/occult ||Isolated anaemia; Retic ↑ ||Dictated by clinical findings |
|Anaemia of chronic disease1 ||Appropriate setting; Retic ↓ ||s.Fe ↓ and s.ferr N or ↑ |
|Haemolysis ||Specific red cell changes; Retic ↑ ||s.Bil and s.LDH ↑; s.hapt ↓ specific tests for cause |
|Chronic kidney disease ||Isolated anaemia; Retic ↓ ||Kidney function |
|Endocrine disorders (e.g. hypothyroidism) ||Appropriate setting; isolated anaemia; Retic ↓ ||Specific endocrine investigation |
MICROCYTIC ANAEMIA—MCV ≤ 80 FL
The main causes of microcytic anaemia are iron deficiency and haemoglobulinopathy, particularly thalassaemia. Consider lead poisoning.
Iron deficiency is the most common cause of anaemia worldwide. It is the biggest cause of microcytic anaemia, with the main differential diagnosis of microcytic anaemia being a haemoglobinopathy such as thalassaemia.
An understanding of the interpretation of iron studies is important in management.
Serum ferritin level low (NR: F 15–200 mcg/L: M 30–300 mcg/L)
Serum iron level low
Increased transferrin level
MCV ↓, MCH ↓, MCHC ↓
Reduced transferrin saturation
Response to iron therapy
Non-haematological effects of chronic iron deficiency
Gastrointestinal bleeding (e.g. carcinoma, haemorrhoids, peptic ulcer, hiatus hernia, GORD, NSAID therapy)
Frequent blood donations
Hookworm (common in tropics)
Increased physiological requirements
Special diets (e.g. fad, vegetarianism)
Pica—eating unnatural food, e.g. dirt, ashes
Investigations are based on the history and physical examination, including the rectal examination. If GIT bleeding is suspected the faecal occult blood test is not considered very valuable but appropriate investigations include gastroscopy and colonoscopy, small bowel biopsy and small bowel enema.
Haematological investigations: typical findings
Microcytic, hypochromic red cells
Anisocytosis (variation in size), poikilocytosis (shape)—pencil-shaped rods
Low serum iron level
Raised iron-binding capacity
Serum ferritin level low (the most useful index)
Soluble transferrin receptor factor—this factor is increased in iron deficiency, but not in chronic disease. It is very helpful therefore in differentiating iron deficiency from other forms. It is an indirect marker of what is happening in the bone marrow.4
The state of the iron stores is assessed by considering the serum iron, the serum ferritin and the serum transferrin levels in combination. Typically, in iron deficiency, the serum iron and ferritin levels are low and the transferrin high, but the serum iron level is also low in all infections—severe, mild and even subclinical—as well as in inflammatory states, malignancy and other chronic conditions. Serum ferritin estimations are spuriously raised in liver disease of all types, chronic inflammatory conditions and malignancy; transferrin is normally raised in pregnancy. Since each of these estimations can be altered in conditions other than iron deficiency, all three quantities have to be considered together to establish the iron status (see TABLE 22.3).2
Table 22.3The interpretation of iron studies2 |Favorite Table|Download (.pdf) Table 22.3 The interpretation of iron studies2
|Condition ||Serum Fe ||TIBC ||% Transferrin saturation ||Ferritin |
|Iron deficiency ||↓ ||N or ↑ ||↓ ||↓ ↓ |
|β-thalassaemia ||N or ↑ ||N ||N or ↑ ||N or ↑ |
|Anaemia of chronic disease ||↓ ||N or ↓ ||↓ ||N or ↑ |
|Sideroblastic anaemia ||N or ↑ ||N ||N or ↑ ||↑ |
|Haemochromatosis ||↑ ||↓ ||↑ ↑ ||↑ ↑ |
|N = normal || || || || |
Correct the identified cause.
Diet—iron-rich foods, vitamin C-rich foods (see TABLE 22.4). Iron is present in meat and legumes as Fe+++ and therefore requires gastric acid for conversion to Fe++.
– oral iron (ferrous sulphate 1–2 tablets daily between meals for 6 months), e.g. Ferro-Gradumet with orange juice or ascorbic acid until Hb is normal
– parenteral iron preferably by IV infusion is probably best reserved for special circumstances such as a failed trial of oral iron for symptomatic iron deficiency anaemia (there is a risk of an allergic reaction and postinfusion skin staining around the cannula site). Infusion is best with ferric carboxymaltose in 0.9% (N) saline.6 Avoid blood transfusions if possible.
Table 22.4Optimal adult diet for iron deficiency |Favorite Table|Download (.pdf) Table 22.4 Optimal adult diet for iron deficiency
|Adults should limit milk intake to 500 mL a day while on iron tablets. |
|Avoid excess caffeine, fad diets and excess processed bread. |
|Eat ample iron-rich foods (especially protein). |
|Protein foods |
|Meats—beef (especially), veal, pork, liver, poultry |
|Fish and shellfish (e.g. oysters, sardines, tuna) |
|Seeds (e.g. sesame, pumpkin) |
|Eggs, especially egg yolk |
|Dried fruit (e.g. prunes, figs, raisins, currants, peaches) |
|Juices (e.g. prune, blackberry) |
|Most fresh fruit |
|Greens (e.g. spinach, silver beet, lettuce) |
|Dried peas and beans (e.g. kidney beans) |
|Pumpkin, sweet potatoes |
|Iron-fortified breads and dry cereals |
|Oatmeal cereal |
|For better iron absorption, add foods rich in vitamin C (e.g. citrus fruits, cantaloupe, Brussels sprouts, broccoli, cauliflower) |
Anaemia responds after about 2 weeks and is usually corrected after 2 months (if underlying cause addressed).1
Oral iron is continued for 3 to 6 months to replenish stores.
Monitor progress with regular serum ferritin levels.
A serum ferritin level >50 mcg/L generally indicates adequate stores.
continuing blood loss
malabsorption (e.g. severe coeliac disease)
incorrect diagnosis (e.g. thalassaemia minor, chronic disease)
bone marrow infiltration
This inherited condition is seen mainly (although not exclusively) in people from the Mediterranean basin, the Middle East, north and central India and South-East Asia, including south China. The heterozygous form is usually asymptomatic; patients show little if any anaemia and require no treatment. The condition is relatively common in people from these areas. The homozygous form is a very severe congenital anaemia needing lifelong transfusional support but is comparatively rare, even among the populations prone to thalassaemia (refer to CHAPTER 18).2
The key to the diagnosis of heterozygous thalassaemia minor is significant microcytosis quite out of proportion to the normal Hb or slight anaemia, and confirmed by finding a raised HbA2 on Hb electrophoresis. DNA screening analysis is now available. The importance of recognising the condition lies in distinguishing it from iron-deficiency anaemia, for iron does not help people with thalassaemia and is theoretically contraindicated. Even more importantly, it lies in recognising the risk that, if both parents have thalassaemia minor, they run a one in four chance of having a baby with thalassaemia major in every pregnancy, with devastating consequences for both the affected child and the whole family.
Treatment of thalassaemia major is transfusion to a high normal Hb with packed cells plus desferrioxamine.
This Hb variant is common throughout South-East Asia.4 It has virtually no clinical effects in either the homozygous or heterozygous forms, but these people have microcytosis, which must be distinguished from iron deficiency; moreover, if the HbE gene is combined with the thalassaemia gene, the child may have a lifelong anaemia almost as severe as thalassaemia major. Both genes are well established in the South-East Asian populations in Australia as well as in their own countries.
MACROCYTIC ANAEMIA—MCV >100 FL
Alcohol and liver disease
Each individually, or in combination, leads to macrocytosis with or without anaemia. The importance of this finding lies in its often being the first indication of alcohol abuse, which can so frequently go unnoticed unless there is a firm index of suspicion. Chronic liver disease due to other causes may also be late in producing specific clinical symptoms.
Cytotoxic drugs, anticonvulsants in particular, and various others (see TABLE 22.5) may cause macrocytosis. This is of little clinical significance and does not need correction unless associated with anaemia or other cytopaenia.
Table 22.5Drugs causing macrocytosis2,5 |Favorite Table|Download (.pdf) Table 22.5 Drugs causing macrocytosis2,5
|Alcohol || |
|Cytotoxics/immunosuppressants ||Azathioprine |
| ||Methotrexate, 5-fluorouracil |
|Antibiotics ||Cotrimoxazole, Pyrimethamine (incl. Fansidar and Maloprim) |
| ||Zidovudine |
|Anticonvulsants ||Phenytoin |
| ||Primidone |
| ||Phenobarbitone |
These conditions have been recognised under a variety of names, such as ‘refractory anaemia’ and ‘preleukaemia’, for a long time, but only relatively recently have they been grouped together. They are quite common in the elderly but may be seen in any age group (refer TABLE 22.2).
These conditions frequently present as a macrocytic anaemia with normal serum vitamin B12 and red cell folate, and are unresponsive to these or any other haematinics. They are usually associated with progressive intractable neutropaenia or thrombocytopenia or both, and progress slowly but relentlessly to be eventually fatal, terminating with infection, haemorrhage or, less often, acute leukaemia.
Vitamin B12 deficiency (pernicious anaemia)
Although well recognised, this is a much less common cause of macrocytosis than the foregoing conditions. It is usually caused by lack of intrinsic factor due to autoimmune atrophic changes and by gastrectomy. Anaemia does not develop for about 3 years after total gastrectomy. Vitamin B12 deficiency may also be seen together with other deficiencies in some cases of malabsorption and Crohn disease.
Vitamin B12 (cobalamin) is found in the normal diet but only in foods of animal origin and consequently very strict vegetarians may eventually develop deficiency. Causes of food vitamin B12 deficiency are:4
The clinical features are anaemia (macrocytic), weight loss and neurological symptoms, especially a polyneuropathy. It can precipitate subacute combined degeneration of the cord. The serum vitamin B12 is below the normal level (normal range 150–700 pmol/L).
Intrinsic factor antibody level is diagnostic.
Treatment (replacement therapy)1
Vitamin B12 (1000 mcg, i.e. 1 mg) IM injection; body stores (3–5 mg) are replenished after 10–15 injections given every 2 to 3 days
Maintenance with 1000 mcg injections every third month
Can use crystalline oral B12
Co-therapy with oral folate 5 mg/day (initially) is indicated.9,10
Transfusion is best avoided. May need additional iron.
Diagnostic test: serum folate (normal range 7–45 nmol/L) and red cell folate—best test (normal >630 nmol/L).7
The main cause is poor intake associated with old age, poverty and malnutrition, usually associated with alcoholism. It may be seen in malabsorption and regular medication with anti-epileptic drugs such as phenytoin.9 It is rarely, but very importantly, associated with pregnancy, when the demands of the developing fetus together with the needs of the mother outstrip the dietary intake—the so-called ‘pernicious anaemia of pregnancy’ which, if not recognised and treated immediately, can still be a fatal condition. Unlike vitamin B12, folic acid is not stored in the body to any significant degree and requirements have to be satisfied by the daily dietary intake, which invariably meets the requirement of 5–10 mcg/day. Folic acid is present in most fruit and vegetables, especially citrus fruits, nuts and green leafy vegetables (see CHAPTER 10).
Treatment (replacement therapy)
Oral folate 5 mg/day to replenish body stores (5–10 mg). This takes about 4 weeks but continue for 4 months. Vitamin B12 is usually given unless levels normal.
NORMOCYTIC ANAEMIA2 (ANAEMIAS WITHOUT CHANGE IN THE MCV)
This is the most common cause of normocytic anaemia and is usually due to haematemesis and/or melaena.
Intercellular iron transport within the marrow is suppressed in inflammation so that, despite normal iron stores, the developing red cells are deprived of iron and erythropoiesis is depressed. If the inflammation is short-lived, the fall in Hb is not noticeable but, if it continues, an anaemia may develop that responds only when the inflammation subsides.
Anaemia may develop for the same reasons that apply to chronic inflammation.
This is often associated with anaemia due to failure of erythropoietin secretion and is unresponsive to treatment, other than by alleviating the insufficiency or until erythropoietin is administered.
Suspect haemolytic anaemia if there is a reticulocytosis, mild macrocytosis, reduced haptoglobin, increased bilirubin and urobilinogen. Haemolytic anaemias are relatively infrequent. The more common of the congenital ones are hereditary spherocytosis, sickle cell anaemia and deficiencies of the red cell enzymes, pyruvate kinase and G-6-PD, although most cases of G-6-PD deficiency haemolyse only when the patient takes oxidant drugs such as sulphonamides or eats broad beans—‘favism’.
Acquired haemolytic anaemias include those of the newborn due to maternal haemolytic blood group antibodies passing back through the placenta to the fetus, and adult anaemias due to drug toxicity or to acquired auto-antibodies. About half of the latter are idiopathic and half associated with non-Hodgkin lymphomas, and the anaemia may be the presenting sign of lymphoma. Some of these antibodies are active only at cool temperatures—cold agglutinin disease; others act at body temperature and are the more potent cause of autoimmune haemolytic anaemia.
Keep in mind the rare acquired genetic disorder of paroxysmal nocturnal haemoglobinuria if dark morning urine is observed in the presence of anaemia. Flow cytometry is required for diagnosis.
This may be due to foreign tissue, such as carcinomatous metastases or fibrous tissue as in myelofibrosis; it may also be due to overgrowth by one or other normal elements of the bone marrow, as in chronic myeloid leukaemia, chronic lymphocytic leukaemia and lymphoma, as well as by acute leukaemic tissue. A leuco-erythroblastic picture, in which immature red and white cells appear in the peripheral blood, is often seen when the marrow is replaced by foreign tissue.