Anaemia
From Pharmpedia
Anaemia is defined as a condition with an insufficient oxygen carrying capacity of the patients blood. For both sexes and all age groups a blood haemoglobin concentration below 130 g per l (8 mM) implies reduced working capacity and thus a consequential clinical condition. Reference levels for age and sex are also available, but they differ from laboratory to laboratory.
Mean corpuscular volume (MCV) expresses the mean volume of each red cell. MCV is calculated from the packed cell volume (PCV) by
division with the red cell count. An example with normal values provides the following: 0.45 (l/l)/5*1012 (red cells/l). Thus MCV
is equal to 90*10-15 l per red cell. One femtolitre (1 fl) equals 10-15 l. The normal range is 80-96 fl. The MCV index is used to
classify anaemia’s into microcytic (MCV<80 fl), normocytic (MCV 80-96 fl) and macrocytic forms (MCV >96 fl), but the
classification is not causal.
Mean corpuscular haemoglobin concentration (MCHC) provides the mean concentration in each red cell. MCHC is calculated from the
haemoglobin concentration by division with the packed cell volume (PCV). An example with normal values provides the following:
150 (g/l)/ 0.45 (l/l). Thus, normal MCHC is 333 g per l of red cells. Since the concentration of haemoglobin in a normal red cell
is maximal, the maximal value (380 g/l) is the highest occurring. Normochromic anaemia’s have MCHC values in the range 320-380
mostly within 320-350 g/l. Anaemia with MCHC below 320 g/l is called hypochromic, and they are often also microcytic such as in
iron deficiency anaemia. Anaemias are classified into two groups based on their cause. The first group is deficiency anaemias
with insufficient haemoglobin production due to dietary/ absorptive defects or to bone marrow hypoplasia from cell destruction by
chemicals or radiation (Box 8-3).
Deficiency anaemias are caused by defect haem synthesis (iron deficiency, anaemia of chronic disease, sideroblastic anaemia) or by defect globin synthesis (thalassaemia). The second group is waste anaemias with waste of red cells (Box 8-3). The waste of red cells is caused by bleeding (haemorrhage) or by haemolysis.
A1. Iron deficiency anaemia is caused by chronic bleeding, growth, endurance exercise, pregnancy and nursing, poor intake, malabsorption). Iron deficiency is characterised by low serum-iron, high total iron binding capacity (TIBC), and a transferrin saturation below 19%.
A2. Anaemia of chronic disease (defect synthesis of haem):
1.Chronic bacterial, viral, fungal, protozoal, and helminthic infections (see Ch. 33). 2.Chronic inflammatory diseases (eg, rheumatoid arthritis, polymyalgia etc, see Ch. 32). 3.Malignant disorders. This anaemia is characterised by low serum-iron as well as low total iron binding capacity.
A3. Sideroblastic anaemia (defect synthesis of haem) with ring sideroblasts, is genetic or acquired. The genetic type is X-linked
and transmitted by the mother. The acquired types are caused by alcohol, drugs, lead, other disorders or the cause is unknown
(primary type). Sideroblastic anaemia is characterised normal total iron binding capacity, raised serum-iron and raised
serum-ferritin.
A4. Macrocytic anaemia with megaloblasts in the bone marrow is due to folate deficiency or to vitamin B12 deficiency. Folate
deficiency anaemia is recognised when the folate concentration in red cells low. This deficiency is due to poor intake,
malabsorption, antifolate drugs and excess utilization. Since the folate stores of the body are low the anaemia develops rapidly
(over months) compared to years for pernicious anaemia. Folate polyglutamates are synthesized in human cells. These compounds are
biologically active, as coenzymes in amino acid metabolism and in the DNA synthesis. The synthesis of the biologically active
form of folate is dependent of vitamin B12. Lack of folate inhibits the purine-pyrimidine-DNA-synthesis, and without new DNA cell
division is seriously reduced. The typical patient appears with glossitis and a megaloblastic anaemia is found. The amount of
folate in red cells is below 160 mg ml-1. The normal range is 160-640mg ml-1.
Pernicious anaemia is the most common cause of vitamin B12 (cobalamin) deficiency. Pernicious anaemia is characterised by a low serum-[vitamin B12] (below 160 ng l-1). Megaloblastic anaemia with lack of gastric HCl confirms the diagnosis. Pernicious anaemia is caused by atrophy of the gastric mucosa, resulting in insufficient synthesis of intrinsic factor. The stomach cannot secrete intrinsic factor, hydrochloric acid and pepsin.
Pernicious anaemia occurs in three forms: 1) most patients have an autoimmune disorder, with plasma antibodies against their own parietal cells; 2) rarely, new-born babies suffer from congenital intrinsic factor deficiency with normal pepsin and acid secretion; and 3) finally as vitamin B12 malabsorption, because of a defect in the intrinsic factor-B12 receptors in the terminal ileum.
Vitamin B12 malabsorption in adults is caused by one of two intrinsic factor antibodies. One antibody blocks the binding of intrinsic factor to B12, so the protease-resistant complex is never formed. The other intrinsic factor antibody blocks the binding of the intrinsic factor- B12 complex to the intrinsic factor-B12 receptors of the terminal ileum. The result is vitamin B12 malabsorption.
Parietal cell antibodies are present in the plasma of 90% of all patients with pernicious anaemia. The parietal cells of the gastric glands fail to secrete HCl and intrinsic factor. Intrinsic factor is a glycoprotein, which combines with vitamin B12 of the food. This combination normally makes vitamin B12 available for absorption in the ileum. The site of red cell production is the red bone marrow, which is normally one of the most proliferative tissues.
The lack of vitamin B12 in the liver and the red bone marrow inhibits the methyl-malonyl Co-A mutase and also spoils the purine-pyrimidine-DNA-synthesis. The inhibition of these and other processes leads to the neurological and the haematological disorders in pernicious anaemia.
The neurological features are progressive polyneuropathy with degeneration of the posterior and lateral column of the spinal cord and peripheral nerves (eg, optic atrophy, symmetrical paraesthesia, weakness, dementia and ataxia).
Haematological disorders. Lack of vitamin B12 in the bone marrow turns the normal erythroblasts into abnormal megaloblasts. The erythrocyte production is inhibited, and the cells synthesise much more RNA than normal and much less DNA. Besides, the formation of leucocytes and platelets suffer causing leucopenia and thrombocytopenia. Instead of normal erythrocytes, the megaloblasts deliver megalocytes to the circulation. Megalocytes are fragile and only have an average life of 40 days, as compared to 120 days for adult erythrocytes.
Cobalamine is the chemical name of vitamin B12. Pernicious anaemia is treated with intramuscular injections of hydroxycobalamin storage, followed by 1 mg every 3 months as long as the patient lives.
A5. Macrocytic anaemia without megaloblasts in the bone marrow is a physiological anaemia in pregnancy and in new-born babies. This anaemia is also found in patients with alcohol abuse, hepatic disorders, hypothyroidism, and aplastic anaemia. The concentration of vitamin B12 and folate in the plasma is normal. The relative number of reticulocytes and the MCV is increased. – In some cases there is fat accumulation in the red cell membrane, but the pathogenesis of these conditions is not clarified.
A6. Aplastic anaemia refers to a condition of bone marrow failure with only few pluripotent stem cells in the bone marrow. This is due to immune suppression of stem cells by T suppressor cells, or to direct destruction of the stem cells caused by chemicals, drugs, infection or radiation. Pancytopenia, absence of reticulocytes and an aplastic bone marrow is characteristic.
A7. Thalassaemia (see Chapter 33).
B1. Acute bleeding (loss of red cells). Normochromic normocytic anaemia occurs following an acute bleeding with plasma dilution, before the iron stores are depleted. - Lack of vitamin K can change the development of even a simple tooth bleeding to a serious condition.
B2. Haemolytic anaemias (increased destruction of red cells): They are inherited or acquired. Inherited are hereditary
spherocytosis or ellipsocytosis, thalassaemia (defect synthesis of globin -see Chapter 33), Sickle syndromes, etc. Acquired
haemolytic anaemias are caused by immune destruction of red cells, membrane defects (paroxysmal nocturnal haemoglobinuria,
mechanical destruction of cell membranes, haemolysis caused by renal, endocrine or liver disease. Haemolytic anaemia is
characterised by osmotic fragility, reticulocytosis, increased serum-bilirubin, and erythroid hyperplasia of the bone marrow.
General for anaemia
In most cases of anaemia the fall in transport capacity develops slowly, whereby there is time for physiological adaptations to minimise symptoms and signs. A rise in 2,3-DPG improves the release of oxygen to the cells. Unspecific symptoms such as fatigue, headaches and faintness have varying origin and are not always recognised as a disease. Dyspnoea, palpitations, cardiac cramps, and intermittent claudication are also difficult to interpret. The signs of anaemia are tachycardia, systolic murmur over the heart, and cardiac failure. Drumstick fingers with spoon-shaped nails are seen in chronic anaemia with hypoxia such as in chronic iron deficiency. Jaundice suggests the possibility of haemolytic anaemia.
The falling red cell count reduces the oxygen delivery but also leads to falling viscosity of the blood. The reduced viscosity can reduce the total peripheral vascular resistance (TPVR) to less than half of the resting value, which is an appropriate event, since it easens the cardiac work and improves the bloodflow. A slight fall in systemic arterial pressure reduces the stimulus of the arterial baroreceptors, and causes a rise in heart rate and cardiac output. The low oxygen capacity of haemoglobin is compensated by an increased coronary bloodflow at rest. The myocardial anoxia results in cardiac failure (Fig. 10-10) with oedema, large liver, and stasis of the neck veins. Severe anaemia increases respiration, metabolic rate, and temperature due to the large cardiopulmonary work.
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