Inherited haemolytic anaemias are due to defects in one or more components of the mature red blood cell:
■ Cell membrane
■ Metabolic machinery of the red blood cell.
Membrane defects Hereditary spherocytosis
This is the most common inherited haemolytic anaemia in northern Euro-peans, and is inherited in an autosomal dominant manner. A defect in the
Fig. 5.2 An approach to investigation of suspected haemolytic anaemia. LDH, lactate dehydrogenase; G6PD, glucose-6-phosphate dehydrogenase; DIC, disseminated intravascular coagulation; NSAID, non-steroidal anti-inflammatory drug; DCT, direct Coombs’ test.
red cell membrane causes an increased permeability to sodium, the red cells become spherical in shape, are more rigid and less deformable than normal red cells, and are destroyed prematurely in the spleen. The commonest cause of hereditary spherocytosis is a deticiency of the red cell structural membrane protein spectrin.
The clinical severity varies from symptom-free carrier to severe haemolysis with anaemia, jaundice and splenomegaly. As in many haemolytic anaemias, the course of the disease may be interrupted by aplastic, haemolytic and megaloblastic crises. Aplastic anaemia usually occurs after infections, par-ticularly with erythro(parvo)virus, whereas megaloblastic anaemia is the result of folate depletion caused by hyperactivity of the bone marrow. Chronic haemolysis may lead to the development of pigment gallstones.
■ Blood count demonstrates reticulocytosis and anaemia, which is usually mild.
■ The blood film shows spherocytes (also seen in autoimmune haemolytic anaemia) and reticulocytes.
The diagnosis is usually straightforward and made on the basis of clinical features, family history, laboratory investigation (as above) and exclusion of other causes of haemolytic anaemia, particularly autoimmune haemolytic anaemia.
Splenectomy should be performed in all but the mildest of cases. This is usually postponed until after childhood to minimize the risk of overwhelming infections (p. 222).
Hereditary elliptocytosis is similar to spherocytosis but the red cells are elliptical in shape. It is milder clinically and usually does not require splenectomy.
Normal adult Hb is made up of haem and two polypeptide globin chains, α and β. The haemoglobinopathies can be classified into two subgroups: abnormal chain production or abnormal chain structure of the polypeptide chains (Table 5.9).
In normal Hb there is balanced (1 : 1) production of α and β chains. The thalassaemias are a group of disorders arising from one or multiple gene defects, resulting in a reduced rate of production of one or more globin chains. The imbalanced globin chain production leads to precipitation of globin chains within red cells or precursors. This results in cell damage, death of red cell precursors in the bone marrow (ineffective erythropoiesis), and haemolysis. The thalassaemias affect people throughout the world. There are two main types:
■ α-Thalassaemia: reduced a chain synthesis
■ β-Thalassaemia: reduced p chain synthesis.
β-Thalassaemia In homozygous β-Thalassaemia there is little or no p chain production, resulting in excess a chains. These combine with whatever s and Y chains are produced, leading to increased Hb A2 and Hb F. There are three main clinical forms of β-Thalassaemia:
■ β-Thalassaemia minor (trait). This is the asymptomatic heterozygous carrier state. Anaemia is mild or absent, with a low MCV and MCH. Iron stores and serum ferritin levels are normal.
■ β-Thalassaemia intermedia. This includes patients with moderate anaemia (Hb 7-10 g/dL) that does not require regular blood transfusions. Splenomegaly, bone deformities, recurrent leg ulcers and gallstones are other features. This may be caused by a combination of homozygous p- and α-Thalassaemias.
■ β-Thalassaemia major (homozygous p-thalassaemiậ. This presents in the first year of life with severe anaemia (Cooley’s anaemia), failure to thrive and recurrent infections. Hypertrophy of the ineffective bone marrow leads to bony abnormalities: the thalassaemic facies, with an enlarged maxilla and prominent frontal and parietal bones. Resumption of haemopoiesis in the spleen and liver (extramedullary haemopoiesis), the chief sites of red cell production in fetal life, leads to hepatosplenomegaly.
In homozygous disease, blood count and film show a hypochromic/microcytic anaemia, raised reticulocyte count and nucleated red cells in the peripheral circulation.
The diagnosis is made by haemoglobin electrophoresis, which shows an increase in Hb F and absent or markedly reduced Hb A.
In homozygous patients, the mainstay of treatment is blood transfusion, aiming to keep the haemoglobin above 10 g/dL, thus suppressing ineffective erythropoiesis, preventing bony abnormalities and allowing normal develop-ment. Iron overload caused by repeated blood transfusions may lead to damage of the endocrine glands, liver, pancreas and heart, with death in the second decade from cardiac failure. Treatment with iron-chelating agents (subcutaneous desferrioxamine, oral deferasirox or deferiprone) decreases iron loading. Ascorbic acid 200 mg daily is also given as it increases the urinary excretion of iron in response to desferrioxamine. BMT has been used in some cases of thalassaemia.
α-Thalassaemia The clinical manifestations of this disorder vary from a mild anaemia with microcytosis to a severe condition incompatible with life. There are four a-globin genes per cell. The manifestations depend on whether one, two, three or all four of the genes are deleted, and thus whether a chain synthesis is partial or completely absent. In the most severe form, where there is complete absence of a-globin (Hb Barts), infants are stillborn (hydrops fetalis).
Antenatal diagnosis of haemoglobin abnormalities
A fetus with severe haemoglobin abnormalities can be identified by DNA analysis of chorionic villus samples taken in the first trimester, or by testing umbilical cord blood in the second trimester. Abortion is offered if the fetus is found to be affected. This examination is appropriate if the mother is found to have a haemoglobin defect during antenatal testing and if, on subsequent screening, her partner is also affected.
Sickle syndromes are a family of haemoglobin disorders in which the sickle p-globin gene is inherited (Table 5.9). The sickle p gene is spread widely throughout Africa (25% carry the gene), India, the Middle East and Mediter-ranean countries. In the homozygous state (sickle cell anaemia) both genes are abnormal (Hb SS), whereas in the heterozygous state (sickle cell trait, Hb AS) only one chromosome carries the abnormal gene. Inheritance of the HbS gene from one parent and HbC from the other parent gives rises to Hb SC disease, which tends to run a milder clinical course than sickle cell disease but with more thromboses.
In the deoxygenated state Hb S molecules are insoluble and polymerize. This results in increased rigidity of the red cells, causing the classic sickle appearance (Fig. 5.3). Sickling can produce:
■ Premature destruction of red cells (haemolysis)
■ Obstruction of the microcirculation (vaso-occlusion), leading to tissue infarction.
Sickling is precipitated by hypoxia, dehydration, infection and cold.
Sickle cell anaemia
As the production of Hb F is normal, the disease is usually not manifest until Hb F decreases to adult levels at about 6 months of age. There is extreme phenotypic variation with some patients having few or no symptoms and others having recurrent crises and a markedly reduced life expectancy.
Vaso-occlusion In early childhood acute pain in the hands and feet (dactylitis) is due to occlusion of the small vessels and avascular necrosis of bone marrow. In adults, bone pain most commonly affects the long bones, ribs, spine and pelvis. The frequency of attacks varies from daily to perhaps once a year.
Anaemia Most patients have a steady-state Hb of 6-8 g/dL with a high reticulocyte count (10-20%). They often do not have symptoms of anaemia because Hb S releases oxygen to the tissues more easily than normal Hb. A rapid fall in the Hb can occur due to:
■ Splenic sequestration. The spleen becomes engorged with red cells, leading to an acute fall in Hb and rapid enlargement of the spleen. Liver sequestration can also occur.
■ Bone marrow aplasia most commonly due to erythrovirus B19 infection, which destroys erythrocyte precursors
■ Further haemolysis due to drugs or acute infection.
Fig. 5.3 Sickle cells (arrowed) and target cells (‘Mexican hat cells’).
Long-term problems Avascular necrosis of bones results in shortened, deformed bones in children. Other complications of vaso-occlusion include splenic atrophy (resulting in susceptibility to infection with pneumococcus, Salmonella species and Haemophilus), retinal ischaemia (which may precipi-tate proliferative sickle retinopathy and visual loss) and cerebral infarction (causing fits and strokes). Transcranial Doppler ultrasound measures mean velocity of blood flow in the large intracranial vessels and is used to screen for patients at high risk of stroke and offer them prophylactic transfusion. Sequestration of red cells within the corpora cavernosa causes priapism (prolonged painful erections) and eventual impotence. Chronic haemolysis is associated with increased formation of pigment gallstones. Other complica-tions of sickle cell disease include chronic kidney disease, leg ulcers, osteo-myelitis, pulmonary hypertension and the acute chest syndrome. The latter is a medical emergency and characterized by fever, cough, dyspnoea and pulmonary infiltrates on the chest X-ray. It is caused by infection, fat embo-lism from necrotic bone marrow or pulmonary infarction due to sequestration of sickle cells.
Sickle cell disease is diagnosed by screening in the neonate (using cord blood or the heel prick test), in the fetus of at-risk couples through prenatal diag-nosis, and in children and adults from high-risk areas before undergoing surgery. In Africa many patients are still diagnosed only when they present with complications.
■ Blood count. Hb (6-8 g/dL) is low with a high reticulocyte count.
■ Blood film shows sickled erythrocytes (Fig. 5.3).
Diagnosis is made with Hb electrophoresis showing 80-95% Hb SS and absent Hb A. In addition, sickling can be induced in vitro with sodium dithionite.
Precipitating factors should be avoided or treated promptly. Transfusions are not routinely given in steady state anaemia. Folic acid is given to all patients with haemolysis. Pneumococcal and influenza vaccination is given routinely and daily penicillin, 500 mg orally.
Most patients with a painful crisis are managed in the community, but hospital admission is necessary when the pain is not controlled by non-opiate analgesia such as paracetamol and non-steroidal anti-inflammatory drugs, or if there are complications (Table 5.10). Many patients carry cards with details of their ideal analgesic regimen. The management of a painful sickle crisis is summarized in Emergency Box 5.2.
Blood transfusions are given only in certain situations including atter transient ischaemic attacks and stroke, acute chest syndrome, splenic
|Table 5.10 Complications requiring inpatient management|
|Pain – uncontrolled by non-opiate analgesia
Swollen painful joints
Acute sickle chest syndrome or pneumonia
Mesenteric sickling and bowel ischaemia
Splenic or hepatic sequestration
Central nervous system deficit
Cholecystitis (pigment stones)
Renal papillary necrosis resulting in colic or severe haematuria
Hyphema (layer of red cells in anterior chamber of eye) or retinal detachment
sequestration crisis, aplastic crises, before elective operation and during pregnancy.
Hydroxycarbamide (hydroxyurea) raises the concentration of fetal Hb and is used in some patients with recurrent painful crises. BMT from an HLa-matched sibling is used in some patients with severe disease.
Sickle cell trait
In the heterozygous state, Hb AS, the blood count and film are normal. There are usually no symptoms unless extreme circumstances leading to hypoxia such as flying in a non-pressurized aircraft.
Metabolic red cell disorders
A number of red cell enzyme deficiencies may produce haemolytic anaemia, the most common of which is glucose-6-phosphate dehydrogenase (G6PD) deficiency.
Glucose-6-phosphate dehydrogenase deficiency
G6PD is a vital enzyme in the hexose monophosphate shunt, which maintains glutathione in the reduced state. Glutathione protects against oxidant injury in the red cell. G6PD deficiency is a common heterogeneous X-linked trait found predominantly in African, Mediterranean and Middle Eastern populations.
G6PD deficiency causes neonatal jaundice, chronic haemolytic anaemia, and acute haemolysis precipitated by the ingestion of fava beans and a number of common drugs such as quinine, sulphonamides, quinolones and nitrofurantoin. Diagnosis is by direct measurement of enzyme levels in the red cell. Treatment is the avoidance of precipitating factors, and transfusion if necessary.
|Emergency Box 5.2|
|Management of an acute painful sickle cell crisis in
• Morphine/diamorphine 0.1 mg/kg i.v./s.c. every 20 minutes until pain controlled, then 0.05–0.1 mg/kg i.v./s.c./p.o. every 2–4 hours.
Consider patient-controlled analgesia (PCA)
• Side-effects of morphine include nausea, respiratory depression and hypotension
• Give adjuvant non-opioid analgesia: paracetamol, ibuprofen, diclofenac
• Prescribe laxatives routinely and other adjuvants as necessary:
• Laxatives: lactulose 10 mL twice daily, senna 2–4 tablets daily
• Anti-pruritics: hydroxyzine 25 mg twice daily
• Antiemetics: cyclizine 50 mg three times daily
• Anxiolytic: haloperidol 1–3 mg oral/i.m. as required
• Oxygen, 60% by face mask if arterial oxygen saturation <95%
• Rehydration, encourage oral fluids 60 mL/kg/24 hours. Give i.v. or nasogastric fluids if insufficient intake orally
• Investigations in all patients: full blood count, reticulocyte count, urea and electrolytes – repeat daily. In others, depending on clinical circumstances: liver biochemistry, blood and urine cultures, chest X-ray, arterial blood gases (if saturations <95%), ultrasound of abdomen
• Monitor pain, sedation, vital signs, respiratory rate and oxygen saturations every 30 minutes until the pain is controlled and stable and then every 2 hours
• Examine daily: the respiratory system for the acute chest syndrome, and the abdomen for increase in liver or spleen size which may indicate a sequestration crisis
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
5. Haematological disease
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
Clinical features, Investigations
INFECTION OF JOINTS AND BONES
AUTOIMMUNE RHEUMATIC DISEASES
SYSTEMIC INFLAMMATORY VASCULITIS
DISEASES OF BONE
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
9. Renal disease
INVESTIGATION OF RENAL DISEASE
URINARY TRACT INFECTION
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
10. Cardiovascular disease
COMMON PRESENTING SYMPTOMS OF HEART DISEASE
INVESTIGATIONS IN CARDIAC DISEASE
ISCHAEMIC HEART DISEASE
VALVULAR HEART DISEASE
PULMONARY HEART DISEASE
ARTERIAL AND VENOUS DISEASE
DRUGS FOR ARRHYTHMIAS
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
14. 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
15. Diabetes mellitus and other disorders of metabolism
16. The special senses
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
HEADACHE, MIGRAINE AND FACIAL PAIN
SPINAL CORD DISEASE
DEGENERATIVE NEURONAL DISEASES
DISEASES OF THE PERIPHERAL NERVES