Anaemia is a condition in which impaired oxygen delivery to body tissues due to reduced haemoglobin affects more than 1.62 billion people globally. It is defined as haemoglobin level two standard deviations below the normal for age and sex. Normal haemoglobin level is 115-165 g/L in women and 130-180 g/L in men due to their larger body size. It can be classified according to average size of red blood cells, referred to as mean corpuscular volume (MCV):
This article will cover the general clinical features of anaemia and causes of microcytic, normocytic and macrocytic anaemia.
Typical symptoms of anaemia include pallor, fatigue, breathlessness, dizziness, palpitations and cold hands and feet. Other important issues to cover in the history include dietary history, possible blood loss, malabsorption, family history of haematological disorders, episode of black tarry stools and symptoms of chronic diseases such as cardiac, renal and hepatic.
In the context of suspected anaemia, a comprehensive examination of the major systems must be performed. Possible clinical findings in anaemia include pallor, rapid or irregular heartbeat on cardiac auscultation, enlarged liver or spleen on palpation, pelvic or rectal exam to assess for blood loss.
Microcytic anaemia is defined as anaemia with an MCV of less than 80. The lack of haemoglobin leads to extra division of red blood cells (RBCs), resulting in smaller and paler (hypochromic) RBCs. The most common cause of microcytic anaemia is iron-deficiency anaemia.
In iron-deficiency anaemia, there is a lack of iron, a vital component of haemoglobin. It usually presents with mild symptoms such as fatigue and palpitations; in some cases, it can lead to strange cravings for ice, dirt or starch. Iron deficiency is usually caused by chronic blood loss, but can also be due to dietary deficiency, malabsorption or increased requirements during childhood or pregnancy. Any patient over 40 with iron deficiency anaemia should undergo an upper and lower gastrointestinal endoscopy.
Investigation findings in iron deficiency anaemia include:
Sideroblastic anaemia is characterised by defective protoporphyrin synthesis. This can be due to congenital or acquired causes:
In sideroblastic anaemia, the iron component of haemoglobin is normal. The lack of protoporphyrin prevents the formation of haem, resulting in iron building up in mitochondria, creating the pathognomonic ringed sideroblasts.
Anaemias can be divided into two main types based on the size of the red blood cells (RBCs). Normocytic anaemias have a normal Mean Corpuscular Volume (MCV) of 80-100, and microcytic anaemias have an MCV of less than 80.
The most common cause of microcytic anaemia is iron deficiency. This can be further divided into complete deficiency (where iron stores are depleted and iron cannot be released) or functional deficiency (where iron is present but is not being released). Iron deficiency is most commonly caused by blood loss, followed by dietary deficiency and malabsorption.12 Other microcytic anaemias include sideroblastic anaemia and thalassaemia.
Thalassaemias occur due to inherited mutations affecting the globin gene. They can be further classified into the specific gene that is affected (alpha or beta), as well as the severity of the condition (major, minor or trait). People with the thalassaemia trait may be asymptomatic or have very mild symptoms, while thalassaemia major can be severe enough to require regular transfusions.14 The most frequent occurrences of thalassaemias are in the Mediterranean, Africa, Western and Southeast Asia, as well as India and Burma.10 This condition seems to be protective against Plasmodium falciparum malaria, which is why the population distribution is so similar for the two conditions. Thalassaemias result in classic clinical features such as chipmunk facies and a crew cut appearance on X-ray.
Investigation findings in thalassaemias include:15
Table 1. An overview of microcytic anaemias.
Iron deficiency anaemia
Low (all of the stored iron is used up because serum iron is depleted)
Anaemia of chronic disease
High (due to built-up stores from hepcidin)
High (iron builds up in cells and then is released into serum once the cell bursts)
High (iron overloaded state)
Normocytic anaemias are identified by having a normal MCV of between 80-100. Since the size of the RBCs isn’t altered, the decreased haemoglobin must be due to another cause, either haemolysis (intravascular or extravascular) or underproduction of normal-sized RBCs. The reticulocyte count enables differentiation between the two causes. A high reticulocyte count would indicate that the bone marrow was functioning normally and therefore the anaemia is not likely to be due to underproduction.16 Unlike microcytic anaemias, normocytic anaemias are usually normochromic.
Anaemia of chronic disease is caused by underlying chronic diseases such as malignancy, chronic infections, or autoimmune conditions, which trigger the liver to produce acute phase reactants such as hepcidin. This hepcidin "hides" the iron in ferritin and reduces its availability in the serum, which initially presents as normocytic anaemia but may progress to microcytic anaemia.
Investigation findings in anaemia of chronic disease include:
Hereditary spherocytosis is an inherited defect of RBC cytoskeleton membrane proteins such as ankyrin and spectrin. This abnormal configuration of RBCs prevents their easy manoeuvrability through the splenic infrastructure, leading to them getting stuck and destroyed (haemolysed) by the spleen.
Investigation findings in hereditary spherocytosis include:
Sickle cell anaemia is caused by an autosomal recessive mutation in the beta-globin chain of haemoglobin, causing valine to replace glutamic acid and deforming the RBCs into a sickle shape. This can result in intravascular and/or extravascular haemolysis, with the spleen having a role in the latter.
Investigation findings in sickle cell anaemia include:
Haemolytic anaemias are a group of conditions in which red blood cells are prematurely destroyed. There are several causes of haemolytic anaemia, each of which has different investigation findings.
Paroxysmal nocturnal haemoglobinuria occurs due to an acquired defect in glycosylphosphatidylinositol (GPI). This leaves cells more susceptible to the complement system. Shallow breathing during sleep can lead to CO2 retention, causing a mild respiratory acidosis which activates the complement system and leads to RBC lysis.
Typical findings include a normal reticulocyte count and an increased serum uric acid due to lysed RBCs.
Glucose-6-phosphate dehydrogenase (G6PD) is required to create nicotinamide adenine dinucleotide phosphate (NADPH) which helps create reduced glutathione and protects the cell from oxidative injury. If G6PD is lacking, intravascular haemolysis may occur due to oxidative stress.
Typical findings include an increased reticulocyte count and increased serum uric acid due to lysed RBCs.
IgG-mediated haemolysis is usually extravascular while IgM-mediated haemolysis is intravascular.
Typical findings include an increased reticulocyte count due to bone marrow compensation for intravascular/extravascular haemolysis, as well as increased serum uric acid due to lysed RBCs.
In this type of haemolytic anaemia, RBCs are destroyed due to structural issues with the vasculature, such as microthrombi, prosthetic heart valves and aortic stenosis. This causes schistocytes, which are visibly distinct when observed in a blood film (Figure 4).
Normocytic anaemias are characterized by a normal mean corpuscular volume (MCV). They are further classified into intravascular and extravascular haemolysis. Table 2 provides an overview of normocytic anaemias and their associated clinical features.
Intravascular haemolysis is characterized by the lysis of red blood cells within the vascular compartment. It is seen in conditions such as Paroxysmal Nocturnal Haemoglobinuria and Glucose-6-Phosphate Dehydrogenase (G6PD) deficiency.
Extravascular haemolysis results from the destruction of red blood cells in the reticuloendothelial system. This is seen in conditions such as Hereditary Spherocytosis and Immune Haemolytic Anaemia.
In normocytic anaemias, a reticulocyte count is increased due to the increased demand for red blood cells.
In normocytic anaemias, uric acid levels are also increased due to the haemolysis of red blood cells.
This subset of anaemias is identified by an increased MCV of over 100. They are further divided into megaloblastic and non-megaloblastic subsets.
Megaloblastic anaemias result from an impaired DNA synthesis leading to an increased MCV.
Non-megaloblastic anaemias do not affect DNA synthesis, but still lead to an increased MCV.
Measuring serum homocysteine and methylmalonic acid levels can be useful when trying to differentiate the causes between megaloblastic and non-megaloblastic anaemias.
Folate deficiency can have multiple causes, including poor diet, an increased demand for folate (for example during pregnancy, haemolytic anaemia or cancer), or the use of folate antagonists.
Anaemia is defined as a haemoglobin level two standard deviations below the normal for age and sex. In women, a normal haemoglobin level is 115-165 g/L, while it is slightly increased in men at 130-180 g/L, due to larger body size. Anaemia is classified by the average size of RBCs: microcytic (smaller than normal), normocytic (normal size) and macrocytic (larger than normal). Clinical features of anaemia include breathlessness, fatigue, pallor, palpitations, dizziness and cold extremities.
Microcytic anaemias have an MCV of less than 80 and include iron deficiency anaemia, sideroblastic anaemia and thalassaemia.
Normocytic anaemias have an MCV of between 80-100 and include anaemia of chronic disease, hereditary spherocytosis, sickle cell anaemia, paroxysmal nocturnal haemoglobinuria, G6PD deficiency, immune haemolytic anaemia, microangiopathic haemolytic anaemia and underproduction of RBCs.
Macrocytic anaemia is classified by an increased MCV that is not due to folate or vitamin B12 deficiency. Causes include alcoholism, hypothyroidism, reticulocytosis and drugs such as fluorouracil.
Investigation findings in folate deficiency include increased MCV (>100), increased serum homocysteine and normal serum methylmalonic acid.
Vitamin B12 deficiency is the less common megaloblastic anaemia as the liver has large hepatic stores of vitamin B12 that take a while to become depleted. Vitamin B12 absorption requires the cofactor known as intrinsic factor, manufactured by gastric parietal cells. In pernicious anaemia, the parietal cells are destroyed through an autoimmune process, impairing the absorption of vitamin B12. Pernicious anaemia is the most common cause of this deficiency but pancreatic insufficiency, damage to the terminal ileum or dietary insufficiency (e.g. vegan diet) are other potential causes. Neurological symptoms occur in B12 deficiency, due to elevated levels of methylmalonic acid. Investigation findings in vitamin B12 deficiency include increased MCV (>100), increased serum homocysteine and increased serum methylmalonic acid.
Investigation findings in non-megaloblastic macrocytic anaemia include increased MCV (>100), normal serum homocysteine and normal serum methylmalonic acid.
Macrocytic anaemias have a mean corpuscular volume (MCV) of greater than 100. These include folate deficiency (megaloblastic anaemia), vitamin B12 deficiency (megaloblastic anaemia) and non-megaloblastic anaemia. Iron studies (such as serum iron, % saturation, ferritin and total iron binding capacity) can help differentiate microcytic anaemia. The reticulocyte count is also helpful in determining if the normocytic anaemia is caused by increased destruction of red blood cells or decreased production.
Serum methylmalonic acid and homocysteine levels are useful to distinguish between different types of macrocytic anaemia.
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