The principal physiological function of haemoglobin (Hb) is to carry and deliver oxygen to the tissues from the lungs. Hb is a tetramer consisting of two pairs of globin polypeptide chains: one pair of alpha chains and one pair of non-alpha chains. A haem group, consisting of a single molecule of proto-porphyrin IX bound to a single ferrous ion (Fe2+) is linked covalently at a specific site to each globin chain. Oxygenation and deoxygenation of haemo-globin occur at the haem iron.
Anaemia is present when there is a decrease in the level of Hb in the blood below the reference range for the age and sex of the individual. Reduction of Hb is usually accompanied by a fall in red cell count (RCC) and packed cell volume (PCV, haematocrit), although an increase in plasma volume (as with massive splenomegaly) may cause anaemia with a normal RCC and PCV (‘dilutional anaemia'). The normal values for these indices are given in Table 5.1, all of which are measured using automated cell counters as part of a routine full blood count (FBC).
Symptoms depend on the severity and speed of onset of anaemia. A very slowly falling level of Hb allows for haemodynamic compensation and enhancement of the oxygen-carrying capacity of the blood, and thus patients with anaemia may be asymptomatic. In general, elderly people tolerate anaemia less well than young people. The symptoms are non-specific and include fatigue, faintness and breathlessness. Angina pectoris and intermit-tent claudication may occur in those with coexistent atheromatous arterial disease. On examination the skin and mucous membranes are pale; there
Table 5.1 Normal values for adult peripheral blood
PCV (haematocrit, L/L)
0.5-2.5% (50-100 X 109/L)
ESR, erythrocyte sedimentation rate; Hb, haemoglobin; MCH, mean corpuscular
Table 5.2 Classification of the anaemias based on the mean corpuscular volume (MCV)
Small cells (microcytes) Low MCV (< 80 fL)
Normal-sized cells Normal MCV
Large cells (macrocytes)
High MCV (> 96 fL)
Acute blood loss
Anaemia of chronic disease
Anaemia of chronic disease
Vitamin B12 deficiency
Combined deficiency, e.g. ron and tblate
↑ Reticulocytes, e.g. haemorrhage, haemolysis
Drug therapy e.g. azathioprine
may be a tachycardia and a systolic flow murmur. Cardiac failure may occur in elderly people or those with compromised cardiac function.
Classification of anaemia (Table 5.2)
The causes of anaemia are classified according to the measurement of red blood cell size. Automatic cell counters provide a value for the mean of the red blood cell volume based on counting millions of cells (the mean corpus-cular volume, MCV). This classification is useful because the type of anaemia then indicates the underlying causes and necessary investigations. Irrespec-tive of the cause, most patients with chronic anaemia do not require blood transfusion and the appropriate management, unless severely anaemic, is treatment of the underlying cause.
Microcytosis usually reflects a decreased Hb content within the red blood cell and is then often associated with a reduction in the mean corpuscular haemo-globin (MCH) and mean corpuscular haemoglobin concentration (MCHC), producing a hypochromic appearance on the blood film. The causes of microcytic anaemia are listed in Table 5.2: a- or β-Thalassaemia minor (p. 208) is associated with a microcytosis usually in the absence of anaemia.
Iron is necessary for the formation of haem and iron deficiency is the most common cause of anaemia world-wide. The average daily diet in the UK contains 15-20 mg of iron although normally only 10% of this is absorbed, mainly in the duodenum. Body iron content is regulated by alteration in intestinal iron absorption. Factors that promote intestinal absorption include gastric acid, iron deficiency and increased erythropoietic activity. Elimination of iron is fixed at 1 mg/day and occurs through loss in sloughed skin and mucosal cells through sweat, urine and faeces. In women there is an addi-tional loss during menses, and pre-menopausal women may often border on iron deficiency. There are 1wo forms of dietary iron:
■ Non-haem iron forms the main part of dietary iron and is derived from fortified cereals and vegetables. It is dissolved in the low pH of the stomach and reduced from the ferric to the ferrous form by a brush border ferriredudase before transportation across the mucosal cells.
■ Haem iron is derived from haemoglobin and myoglobin in red or organ meats. Haem iron is better absorbed than non-haem iron.
Iron is transported in the plasma bound to the protein transferrin, which is synthesized in the liver and normally about one-third saturated with iron (Fig.
5.1). Most of the body's iron content is incorporated into haemoglobin in developing erythroid precursors and mature red cells. Most of the remaining
Fig. 5.1 Serum iron and total iron-binding capacity (transferrin) in normal subjects, iron deficiency anaemia and anaemia of chronic disease.
body iron is stored as ferritin and haemosiderin in hepatocytes, skeletal muscle and reticuloendothelial macrophages.
Causes of iron deficiency
■ Causes of iron deficiency are:
■ Blood loss
■ Increased demands such as growth and pregnancy
■ Decreased absorption, e.g. small bowel disease or post-gastrectomy
■ Poor intake; this is rare in developed countries.
Most iron deficiency is due to blood loss, usually from the uterus or gastro-intestinal tract. On a world-wide basis hookworm is a common cause of intestinal blood loss and iron deficiency. In women of childbearing age, menstrual blood loss, pregnancy and breast-feeding contribute to iron deficiency.
Symptoms and signs are the result of anaemia (p. 194) and of decreased epithelial cell iron, which causes brittle hair and nails, atrophic glossitis and angular stomatitis.
■ Blood count and film. The red cells are microcytic (MCV <80 fL) and hypochromic (mean corpuscular haemoglobin <27 pg). There is aniso-cytosis (variation in size) and poikilocytosis (variation in shape).
■ Serum ferritin reflects iron stores and is low. However, ferritin is an acute-phase reactant and in the presence of inflammatory or malignant disease levels may be within the normal range in the presence of iron deficiency.
■ Serum iron is low and the total iron-binding capacity (TIBC) is high, resulting in a transferrin saturation (serum iron divided by TIBC) <19% (Fig. 5.1).
■ Serum soluble transferrin receptor number increases in iron deficiency.
■ Bone marrow examination is only necessary in complicated cases, and shows erythroid hyperplasia and absence of iron.
Iron deficiency is almost always the result of chronic, often occult, gastro-intestinal blood loss in men and in post-menopausal women, and further investigation of the gastrointestinal tract is required to determine the cause of the blood loss (see p. 91). Iron deficiency anaemia in pre-menopausal women is usually the result of menstrual blood loss. In this group the only investigation necessary is serology for coeliac disease, and endoscopic inves-tigation only if there are intestinal symptoms or a family history of colorectal cancer (two first-degree relatives or one <45 years of age).
This is from other causes of a microcytic/hypochromic anaemia (see Table 5.2).
■ Find and treat the underlying cause.
■ Oral iron, e.g. ferrous sulphate or ferrous gluconate (p. 240). A response to iron treatment is characterized by an increase in the reticulocyte count followed by an increase in Hb at a rate of about 1 g/dL every week until the Hb concentration is normal.
■ Parenteral iron (deep intramuscular or intravenous infusion) is rarely necessary and used only when patients are intolerant or there is a poor response to oral iron, e.g. severe malabsorption.
Anaemia of chronic disease
This occurs in patients with chronic inflammatory diseases such as Crohn's disease and rheumatoid arthritis, chronic infections such as tuberculosis, malignancy and chronic kidney disease. There is a normochromic, normo-cytic or microcytic anaemia. Characteristic laboratory findings include low serum iron levels, low serum iron-binding capacity (Fig. 5.1) and increased or normal serum ferritin. The exact mechanisms responsible for these effects are not clear and include decreased release of iron from bone marrow to developing erythroblasts, inadequate erythropoietin response to the anaemia and high levels of hepcidin expression. Hepcidin is synthesized in the liver and binds to the export transport protein, ferroportin, in the basolateral surface of the iron absorbing cells in the duodenum, thereby causing its internalization and degradation. Treatment of anaemia of chronic disease is that of the underlying cause and sometimes recombinant erythropoietin (p. 394).
Sideroblastic anaemia is a rare disorder of haem synthesis characterized by a refractory anaemia with hypochromic cells in the peripheral blood and ring sideroblasts in the bone marrow. Ring sideroblasts are erythroblasts with iron deposited in mitochondria and reflect impaired utilization of iron delivered to the developing erythroblast. It may be inherited or acquired (secondary to myelodysplasia, alcohol excess, lead toxicity, isoniazid). Treatment is to withdraw the causative agents and some cases respond to pyridoxine (vitamin B6).
Macrocytosis is a rise in mean cell volume of the red cells above the normal range. Macrocytic anaemia can be divided into megaloblastic and non-megaloblastic types, depending on the bone marrow findings. In prac-tice, macrocytosis is usually investigated without performing a bone marrow examination. The initial investigation is measurement of serum B12 and red cell folate.
Megaloblastic anaemia is characterized by the presence in the bone marrow of developing red blood cells with delayed nuclear maturation relative to that of the cytoplasm (megaloblasts). The underlying mechanism is defective DNA synthesis, which may also affect the white cells (causing hypersegmented neutrophil nuclei with six lobes, and sometimes leucopenia) and platelets (causing thrombocytopenia). The most common cause of megaloblastic anaemia is deficiency of vitamin B12 or folate, both of which are necessary for the synthesis of DNA (Table 5.2).
Vitamin B12 deficiency
Animal products (meat and dairy products) provide the only dietary source of vitamin B12 for humans. The daily requirement is 1 μg, which is easily sup-plied by a balanced Western diet (containing 5-30 μg daily). Vitamin B12 is liberated from protein complexes in food by gastric acid and pepsin and binds to a vitamin B12-binding protein (‘R' binder) derived from saliva. Free B12 is then released by pancreatic enzymes and becomes bound to intrinsic factor, which, along with H+ ions, is secreted from gastric parietal cells. This complex is delivered to the terminal ileum, where vitamin B12 is absorbed and trans-ported to the tissues by the carrier protein transcobalamin II. Vitamin B12 is stored in the liver, where there is sufficient supply for 2 or more years. About 1% of an oral dose of B12 is absorbed ‘passively' without the need for intrinsic factor, mainly through the duodenum and ileum. The causes of vitamin B12 deficiency are listed in Table 5.3.
Pernicious anaemia is an autoimmune condition in which there is atrophic gastritis (plasma and lymphoid cell infiltration in the fundus) with loss of parietal cells and hence failure of intrinsic factor production and vitamin B12 malabsorption. There is also achlorhydria. It is the most common cause of vitamin B12 deficiency in adults in Western countries.
This disease is common in elderly people and many cases are undiagnosed. It is more common in women and in people with fair hair and blue eyes. There is an association with other autoimmune diseases, particularly thyroid disease, Addison's disease and vitiligo.
|Table 5.3 Vitamin B12 deficiency - causes Low dietary intake|
|Low dietary intake
Congenital deficiency of intrinsic factor
Ileal disease or resection, e.g. Crohn’s disease
Fish tapeworm (Diphyllobothrium latum)
Congenital transcobalamin II deficiency (rare)
Nitrous oxide (inactivates B12)
The onset of pernicious anaemia is insidious, with progressively increasing symptoms of anaemia. There may be glossitis (a red sore tongue), angular stomatitis and mild jaundice caused by excess breakdown of haemoglobin. Neurological features can occur with very low levels of serum B12 and include a polyneuropathy caused by symmetrical damage to the peripheral nerves and posterior and lateral columns of the spinal cord (subacute combined degeneration of the cord). The latter presents with progressive weakness, ataxia and eventually paraplegia if untreated. Dementia and visual distur-bances due to optic atrophy may also occur. There is a higher incidence of gastric carcinoma with pernicious anaemia than in the general population.
Investigation of B12 deíiciency
■ Blood count and film. There is a macrocytic anaemia (MCV often >110 fL) with hypersegmented neutrophil nuclei and, in severe cases, leucopenia and thrombocytopenia.
■ Serum vitamin B12 is low, frequently <50 ng/L (normal >160 ng/L).
■ Red cell folate may be reduced because vitamin B12 is necessary to convert serum folate to the active intracellular form.
■ Serum autoantibodies. Parietal cell antibodies (not specific) are present in 90% and intrinsic factor antibodies (specific to the diagnosis) in 50% of patients with pernicious anaemia.
■ Serum bilirubin may be raised as a result of excess breakdown of haemoglobin, owing to ineffective erythropoiesis in the bone marrow.
■ In most cases, the cause is apparent from the history and autoantibody screen. A small bowel barium follow-through (to look at the terminal ileum) and distal duodenal biopsies (to look for coeliac disease) may be necessary in some patients.
■ Bone marrow examination shows a hypercellular bone marrow with megaloblastic changes. This is not necessary in straightforward cases.
Vitamin B12 deficiency must be differentiated from other causes of megalo-blastic anaemia, principally folate deficiency, but this is usually clear from the blood levels of these two vitamins. Pernicious anaemia should be dis-tinguished from other causes of vitamin B12 deficiency (Table 5.3).
Treatment is with intramuscular hydroxocobalamin (vitamin B12, p. 241) or oral B12 2 mg per day.
Folate is found in green vegetables and offal such as liver and kidney. It is absorbed in the upper small intestine. The daily requirement for folate is 100-200 μg and a normal mixed diet contains 200-300 μg. Body stores are sufficient for about 4 months, but folate deficiency may develop much more rapidly in patients who have a poor intake and excess utilization of folate, for example patients in intensive care. The main cause of folate deficiency is poor intake, which may occur alone or in combination with excessive utilization or malabsorption (Table 5.4).
Symptoms and signs are the result of anaemia.
Table 5.4 Causes of folate deficiency
Old age, poverty, alcohol excess (also impaired utilization), anorexia
Coeliac disease, Crohn’s disease, tropical sprue
Physiological: pregnancy, lactation, prematurity
Pathological: chronic haemolytic anaemia, malignant and inílammatory diseases, renal dialysis
Phenytoin, trimethoprim, sulfasalazine, methotrexate
Red cell folate is low (normal range 160-640 μg/mL) and is a more accurate guide to tissue folate than serum folate, which is also usually low (normal range 4.0-18 μg/L). If the history does not suggest dietary deficiency as the cause, further investigations such as endoscopic small bowel biopsy should be performed to look for small bowel disease.
The underlying cause must be treated and folate deficiency corrected by giving oral folic acid 5 mg daily for 4 months; higher daily doses may be necessary with malabsorption. In megaloblastic anaemia of undetermined cause, folic acid alone must not be given, as this will aggravate the neuro-pathy of vitamin B12 deficiency. Prophylactic folic acid is given to patients with chronic haemolysis (5 mg weekly) and pregnant women.
Prevention of neural tube defects with folic acid To prevent first occurrence of neural tube defects, women who are planning a pregnancy should be advised to take folate supplements (at least 400 μg/day) before conception and during pregnancy. Larger doses (5 mg daily) are recom-mended for mothers who already have an infant with a neural tube defect.
A raised MCV with macrocytosis on the peripheral blood film can occur with a normoblastic rather than a megaloblastic bone marrow (Table 5.5). The
|Table 5.5 Causes of macrocytosis other than megaloblastic anaemia Physiological|
most common cause of macrocytosis in the UK is alcohol excess. The exact mechanism for the large red cells in each of these conditions is uncertain, but in some it is thought to be due to altered or excessive lipid deposition on red cell membranes.
Anaemia caused by marrow failure (aplastic anaemia)
Aplastic anaemia is defined as pancytopenia (deficiency of all cell elements of the blood) with hypocellularity (aplasia) of the bone marrow. It is an uncom-mon but serious condition which may be inherited but is more commonly acquired. There is a reduction in the number of pluripotential stem cells together with a fault in those remaining or an immune reaction against them so that they are unable to repopulate the bone marrow. Failure of only one cell line may also occur, resulting in isolated deficiencies, e.g. red cell aplasia.
Aplastic anaemia can be induced by a variety of disorders (Table 5.6). Many drugs have been associated with the development of aplastic anaemia, and this occurs as a predictable dose-related effect (e.g. chemotherapeutic agents) or as an idiosyncratic reaction (e.g. chloramphenicol, phenytoin, non-steroidal anti-inflammatory agents).
Symptoms are the result of the deficiency of red blood cells, white blood cells and platelets, and include anaemia, increased susceptibility to infection and bleeding. Physical findings include bruising, bleeding gums and epistaxis. Mouth infections are common.
|Table 5.6 Causes of aplastic anaemia|
Congenital, e.g. Fanconi’s anaemia Idiopathic acquired (67% of cases) Cytotoxic drugs and radiation Idiosyncratic drug reaction, e.g. phenytoin Chemicals: benzene, insecticides Infections, e.g. HIV, hepatitis, tuberculosis Paroxysmal nocturnal haemoglobinuria Miscellaneous, e.g. pregnancy
|HIV, human immunodeficiency virus.|
■ Blood count shows pancytopenia with low or absent reticulocytes.
■ Bone marrow examination shows a hypocellular marrow with increased fat spaces.
This is from other causes of pancytopenia (Table 5.7). A bone marrow tre-phine biopsy is essential for assessment of the bone marrow cellularity.
Treatment includes withdrawal of the offending agent, supportive care and some form of definitive therapy (see below). Blood and platelet transfusions are used cautiously in patients who are candidates for bone marrow trans-plantation (BMT) to avoid sensitization. Patients with severe neutropenia (absolute neutrophil count <500 cells/^L) are at risk of serious infections with bacteria, fungi (e.g. Candida and aspergillosis) and viruses (herpesvirus). Fever in a neutropenic patient is a medical emergency (Emergency Box 5.1).
The course of aplastic anaemia is very variable, ranging from a rapid spontaneous remission to a persistent, increasingly severe pancytopenia, which may lead to death through haemorrhage or infection. Features that indicate a poor prognosis are neutrophil count <0.5 X 109/L, platelet count <20 X 109/L and a reticulocyte count of <40 X 109/L.
In those patients who do not undergo spontaneous recovery the options for treatment are as follows:
■ BMT from a human leucocyte antigen (HLA)-identical sibling donor is the treatment of choice for patients under 40 years of age.
■ Immunosuppressive therapy with antilymphocyte globulin and ciclosporin is used for patients over the age of 40 years in whom BMT is not indicated because of the high risk of graft-versus-host disease.
|Table 5.7 Causes of pancytopenia|
|Aplastic anaemia (see Table 5.6)
Bone marrow infiltration or replacement: lymphoma, acute leukaemia,
myeloma, secondary carcinoma, myelofibrosis
Systemic lupus erythematosus
Paroxysmal nocturnal haemoglobinuria
1. Ethics and communication
2. Infectious diseases
3. Gastroenterology and nutrition
4. Liver, biliary tract and pancreatic disease
Liver, biliary tract and pancreatic disease
LIVER BIOCHEMISTRY AND LIVER FUNCTION TESTS
SYMPTOMS AND SIGNS OF LIVER DISEASE
NON - ALCOHOLIC FATTY LIVER DISEASE (NAFLD)
COMPLICATIONS AND EFFECTS OF CIRRHOSIS
TYPES OF CHRONIC LIVER DISEASE AND CIRRHOSIS
PRIMARY SCLEROSING CHOLANGITIS
BUDD - CHIARI SYNDROME
LIVER DISEASE IN PREGNANCY
CARCINOMA OF THE PANCREAS
NEUROENDOCRINE TUMOURS OF THE PANCREAS
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Assessment and treatment of suspected neutropenic sepsis
INHERITED HAEMOLYTIC ANAEMIAS
ACQUIRED HAEMOLYTIC ANAEMIA
THE WHITE CELL
HAEMOSTASIS AND THROMBOSIS
6. Malignant disease
COMMON INVESTIGATIONS IN MUSCULOSKELETAL DISEASE
COMMON REGIONAL MUSCULOSKELETAL PROBLEMS
THE SERONEGATIVE SPONDYLOARTHROPATHIES
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INFECTION OF JOINTS AND BONES
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INVESTIGATION OF RENAL DISEASE
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VALVULAR HEART DISEASE
PULMONARY HEART DISEASE
ARTERIAL AND VENOUS DISEASE
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DRUGS FOR HEART FAILURE
DRUGS AFFECTING THE RENIN - ANGIOTENSIN SYSTEM
NITRATES, CALCIUM - CHANNEL BLOCKERS AND POTASSIUM - CHANNEL ACTIVATORS
11. Respiratory disease
12. Intensive care medicine
13. Drug therapy, poisoning, and alcohol misuse
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THE THYROID AXIS
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FEMALE REPRODUCTION AND SEX
THE GLUCOCORTICOID AXIS
THE THIRST AXIS
DISORDERS OF CALCIUM METABOLISM
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ENDOCRINOLOGY OF BLOOD PRESSURE CONTROL
DISORDERS OF TEMPERATURE REGULATION
15. Diabetes mellitus and other disorders of metabolism
16. The special senses
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COORDINATION OF MOVEMENT
THE CRANIAL NERVES
COMMON INVESTIGATIONS IN NEUROLOGICAL DISEASE
UNCONSCIOUSNESS AND COMA
STROKE AND CEREBROVASCULAR DISEASE
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SPINAL CORD DISEASE
DEGENERATIVE NEURONAL DISEASES
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