ANAEMIA - Clinical features, Differential diagnosis, Prophylaxis

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).

Clinical features

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

Male

Female

Hb (g/dL)

13.5-17.5

11.5-16

PCV (haematocrit, L/L)

0.4-0.54

0.37-0.47

RCC (1012/L)
4.5-6.0
3.9-5.0
MCV (fL)
80-96
MCH (pg)
27-32
MCHC (g/dL)
32-36
RDW (%)
11-15
WCC (109/L)
4.0-11.0
Platelets (109/L)
150-400
ESR (mm/h)
< 20

Reticulocytes

0.5-2.5% (50-100 X 109/L)

ESR, erythrocyte sedimentation rate; Hb, haemoglobin; MCH, mean corpuscular
haemoglobin; MCHC, mean corpuscular haemoglobin concentration; MCV, mean
corpuscular volume of red cells; PCVm packed cell volume; RCC, red cell count; RDW,
red blood cell distribution width (an increase indicates greater variation in red cell size
with both large and small red cells); WCC, white cell count.

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)

Iron deíiciency

Acute blood loss

Megaloblastic

Anaemia of chronic disease

Anaemia of chronic disease

Vitamin B12 deficiency

Thalassaemia

Combined deficiency, e.g. ron and tblate

Folate deficiency

Sideroblastic anaemia

Marrow inflltration/flbrosis

Normoblastic

Endocrine disease

Alcohol

Haemolytic anaemias

↑ Reticulocytes, e.g. haemorrhage, haemolysis

Liver disease

Hypothyroidism

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.

Microcytic anaemia

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 deficiency

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

Iron deficiency

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.

Clinical features

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.

Investigations

■ 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).

Differential diagnosis

This is from other causes of a microcytic/hypochromic anaemia (see Table 5.2).

Management

■ 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

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).

Macrocytic anaemia

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

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

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.

Epidemiology

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
Vegans
Impaired absorption
Stomach
Pernicious anaemia
Gastrectomy
Congenital deficiency of intrinsic factor
Small bowel
Ileal disease or resection, e.g. Crohn’s disease
Coeliac disease
Tropical sprue
Bacterial overgrowth
Fish tapeworm (Diphyllobothrium latum)
Abnormal utilization
Congenital transcobalamin II deficiency (rare)
Nitrous oxide (inactivates B12)

Clinical features

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.

Differential diagnosis

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).

Management

Treatment is with intramuscular hydroxocobalamin (vitamin B12, p. 241) or oral B12 2 mg per day.

Folate deficiency

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).

Clinical features

Symptoms and signs are the result of anaemia.

Table 5.4 Causes of folate deficiency

Poor intake

Old age, poverty, alcohol excess (also impaired utilization), anorexia

Malabsorption

Coeliac disease, Crohn’s disease, tropical sprue

Excess utilization

Physiological: pregnancy, lactation, prematurity

Pathological: chronic haemolytic anaemia, malignant and inílammatory diseases, renal dialysis

Drugs

Phenytoin, trimethoprim, sulfasalazine, methotrexate

Investigations

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.

Management

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.

Differential diagnosis

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
Physiological
Pregnancy
Newborn
Pathological
Alcohol excess
Liver disease
Reticulocytosis
Hypothyroidism
Haematological disorders:
Myelodysplastic syndrome
Sideroblastic anaemia
Aplastic anaemia
Drugs:
Hydroxycarbamide (hydroxyurea)
Azathioprine
Cold agglutinins

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.

Aetiology

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).

Clinical features

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.

Investigations

■ Blood count shows pancytopenia with low or absent reticulocytes.

■ Bone marrow examination shows a hypocellular marrow with increased fat spaces.

Differential diagnosis

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.

Management

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)
Drugs
Megaloblastic anaemia
Bone marrow infiltration or replacement: lymphoma, acute leukaemia,
myeloma, secondary carcinoma, myelofibrosis
Hypersplenism
Systemic lupus erythematosus
Disseminated tuberculosis
Paroxysmal nocturnal haemoglobinuria
Overwhelming sepsis

Ebook Essentials of Kumar and Clark's Clinical Medicine, 5e

1. Ethics and communication

Ethics and communication

2. Infectious diseases

Infectious diseases

3. Gastroenterology and nutrition

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
JAUNDICE
HEPATITIS
NON - ALCOHOLIC FATTY LIVER DISEASE (NAFLD)
CIRRHOSIS
COMPLICATIONS AND EFFECTS OF CIRRHOSIS
LIVER TRANSPLANTATION
TYPES OF CHRONIC LIVER DISEASE AND CIRRHOSIS
PRIMARY SCLEROSING CHOLANGITIS
BUDD - CHIARI SYNDROME
LIVER ABSCESS
LIVER DISEASE IN PREGNANCY
LIVER TUMOURS
GALLSTONES
THE PANCREAS
CARCINOMA OF THE PANCREAS
NEUROENDOCRINE TUMOURS OF THE PANCREAS

5. Haematological disease

Haematological disease
ANAEMIA
Assessment and treatment of suspected neutropenic sepsis
HAEMOLYTIC ANAEMIA
INHERITED HAEMOLYTIC ANAEMIAS
ACQUIRED HAEMOLYTIC ANAEMIA
MYELOPROLIFERATIVE DISORDERS
THE SPLEEN
BLOOD TRANSFUSION
THE WHITE CELL
HAEMOSTASIS AND THROMBOSIS
THROMBOSIS
THERAPEUTICS

6. Malignant disease

Malignant disease
MYELOABLATIVE THERAPY AND HAEMOPOIETIC STEM CELL TRANSPLANTATION
THE LYMPHOMAS
THE PARAPROTEINAEMIAS
PALLIATIVE MEDICINE AND SYMPTOM CONTROL

7. Rheumatology

Rheumatology
COMMON INVESTIGATIONS IN MUSCULOSKELETAL DISEASE
COMMON REGIONAL MUSCULOSKELETAL PROBLEMS
BACK PAIN
OSTEOARTHRITIS
INFLAMMATORY ARTHRITIS
THE SERONEGATIVE SPONDYLOARTHROPATHIES
Clinical features, Investigations
INFECTION OF JOINTS AND BONES
AUTOIMMUNE RHEUMATIC DISEASES
SYSTEMIC INFLAMMATORY VASCULITIS
DISEASES OF BONE
THERAPEUTICS

8. Water, electrolytes and acid–base balance

WATER AND ELECTROLYTE REQUIREMENTS
BODY FLUID COMPARTMENTS
REGULATION OF BODY FLUID HOMEOSTASIS
PLASMA OSMOLALITY AND DISORDERS OF SODIUM REGULATION
DISORDERS OF POTASSIUM REGULATION
DISORDERS OF MAGNESIUM REGULATION
DISORDERS OF ACID - BASE BALANCE
THERAPEUTICS

9. Renal disease

Renal disease
INVESTIGATION OF RENAL DISEASE
GLOMERULAR DISEASES
NEPHROTIC SYNDROME
URINARY TRACT INFECTION
TUBULOINTERSTITIAL NEPHRITIS
HYPERTENSION AND THE KIDNEY
RENAL CALCULI AND NEPHROCALCINOSIS
URINARY TRACT OBSTRUCTION
ACUTE RENAL FAILURE/ACUTE KIDNEY INJURY
CHRONIC KIDNEY DISEASE
RENAL REPLACEMENT THERAPY
CYSTIC RENAL DISEASE
TUMOURS OF THE KIDNEY AND GENITOURINARY TRACT
DISEASES OF THE PROSTATE GLAND
TESTICULAR TUMOUR
URINARY INCONTINENCE

10. Cardiovascular disease

COMMON PRESENTING SYMPTOMS OF HEART DISEASE
INVESTIGATIONS IN CARDIAC DISEASE
CARDIAC ARRHYTHMIAS
HEART FAILURE
ISCHAEMIC HEART DISEASE
RHEUMATIC FEVER
VALVULAR HEART DISEASE
PULMONARY HEART DISEASE
MYOCARDIAL DISEASE
CARDIOMYOPATHY
PERICARDIAL DISEASE
SYSTEMIC HYPERTENSION
ARTERIAL AND VENOUS DISEASE
ELECTRICAL CARDIOVERSION
DRUGS FOR ARRHYTHMIAS
DRUGS FOR HEART FAILURE
DRUGS AFFECTING THE RENIN - ANGIOTENSIN SYSTEM
NITRATES, CALCIUM - CHANNEL BLOCKERS AND POTASSIUM - CHANNEL ACTIVATORS

11. Respiratory disease


Respiratory disease
TUBERCULOSISnd
DIFFUSE DISEASES OF THE LUNG PARENCHYMA
OCCUPATIONAL LUNG DISEASE
CARCINOMA OF THE LUNG
DISEASES OF THE CHEST WALL AND PLEURA
DISORDERS OF THE DIAPHRAGM

12. Intensive care medicine

Intensive care medicine

13. Drug therapy, poisoning, and alcohol misuse

Drug therapy, poisoning, and alcohol misuse

14. Endocrine disease

Endocrine disease
PITUITARY HYPERSECRETION SYNDROMES
THE THYROID AXIS
MALE REPRODUCTION AND SEX
FEMALE REPRODUCTION AND SEX
THE GLUCOCORTICOID AXIS
THE THIRST AXIS
DISORDERS OF CALCIUM METABOLISM
DISORDERS OF PHOSPHATE CONCENTRATION
ENDOCRINOLOGY OF BLOOD PRESSURE CONTROL
DISORDERS OF TEMPERATURE REGULATION
THERAPEUTICS

15. Diabetes mellitus and other disorders of metabolism

DIABETES MELLITUS
DIABETIC METABOLIC EMERGENCIES
COMPLICATIONS OF DIABETES
SPECIAL SITUATIONS
HYPOGLYCAEMIA IN THE NON - DIABETIC
DISORDERS OF LIPID METABOLISM
THE PORPHYRIAS

16. The special senses

THE EAR
THE NOSE AND NASAL CAVITY
THE THROAT
THE EYE

17. Neurology

COMMON NEUROLOGICAL SYMPTOMS
COORDINATION OF MOVEMENT
THE CRANIAL NERVES
COMMON INVESTIGATIONS IN NEUROLOGICAL DISEASE
UNCONSCIOUSNESS AND COMA
STROKE AND CEREBROVASCULAR DISEASE
EPILEPSY AND LOSS OF CONSCIOUSNESS
NERVOUS SYSTEM INFECTION AND INFLAMMATION
HYDROCEPHALUS
HEADACHE, MIGRAINE AND FACIAL PAIN
SPINAL CORD DISEASE
DEGENERATIVE NEURONAL DISEASES
DISEASES OF THE PERIPHERAL NERVES
MUSCLE DISEASES
MYOTONIAS
DELIRIUM
THERAPEUTICS

18. Dermatology

Dermatology

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