CLINICAL PHARMACOLOGY 2003 (PART 30)

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Rational use of haematinic drugs is essential to the correction of anaemia in its various forms. The emergence of haemopoietic growth factors as drugs that stimulate erythroid or myeloid cell lines has opened the way to successful management of other forms of haematological disease. Iron: therapy, acute overdose Vitamin B12 (cobalamins) Folic acid Haemopoietic growth factors Sickle cell anaemia Polycythaemia rubra vera Aplastic anaemia 'colouring matter' of the blood and the 'defective nature of the colouring matter' in anaemia were recognised. In fact iron is essential not only to oxygen transport by red cells but as a catalyst for...

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29 Cellular disorders and anaemias 'colouring matter' of the blood and the 'defective SYNOPSIS nature of the colouring matter' in anaemia were recognised. In fact iron is essential not only to Rational use of haematinic drugs is essential to oxygen transport by red cells but as a catalyst for the correction of anaemia in its various forms. oxidative metabolism in all cells. The emergence of haemopoietic growth factors as drugs that stimulate erythroid or myeloid cell lines has opened the way to successful management of other forms of • Total body iron is 3-5 g (40-50 mg/kg) (male > female). haematological disease. • Haemoglobin contains about two-thirds of total body iron. Iron: therapy, acute overdose • Stores comprise about one-third (ferritin, a water- Vitamin B12 (cobalamins) soluble protein-iron complex, and haemosiderin, an Folic acid insoluble aggregate) in liver, marrow, spleen and Haemopoietic growth factors muscle. Sickle cell anaemia • 5-10% is present in tissues throughout the body in Polycythaemia rubra vera myoglobin, a variety of heme enzymes (e.g. Aplastic anaemia cytochromes) and non-haem enzymes (e.g. metalloflavoproteins) • Average Western diet contains 10-15 mg iron/day. Leukaemias and lymphomas: see Chapter 30 • Normal human absorbs 5-10% dietary iron, i.e. 0.5-1.0 mg/d, which is adequate for an adult male or postmenopausal female but the menstruating or pregnant woman requires 1-3 mg/d. Iron • Iron deficient or pregnant woman absorbs about 30% of dietary iron. Iron, which was the metal symbolising strength in • Iron is lost from the body mainly in desquamated skin magical systems, used to be given to people and gut cells and the daily loss in men is under suffering from weakness, and no doubt many were I mg/day, in normal menstruating females 1.5 mg/day benefited, some psychologically (placebo reactors) and in pregnancy averages 2 mg/day. and others because the weakness was due to iron • Menstrual loss is about 30 mg/period; menstruating deficiency anaemia. The rational use of iron could women may therefore be in negative iron balance. not begin until both the presence of iron in the 587
29 CELLULAR DISORDERS AND ANAEMIAS IRON KINETICS precursors where it is used to form haem. The major pathway of internal iron exchange is a Iron absorption takes place predominantly in the unidirectional flow from plasma transferrin to the duodenum where the acid environment enhances erythron (defined as all red cell elements at any solubility, but also throughout the gut, allowing stage of maturity), to the macrophage and back to sustained-release preparations to be used. Most plasma transferrin. Over 80% of the iron passing iron in food is present as ferric hydroxide, ferric- through the transferrin compartment each day is protein complexes or haem-protein complexes. flowing to and from the erythron. Immature red Ferrous (Fe++) iron is more readily absorbed than cells acquire iron from transferrin through a specific ferric (Fe+++). Thus the simultaneous ingestion of a transferrin receptor located on the cell membrane. reducing agent, such as ascorbic acid, increases the Within cells the iron regulatory proteins IRP-1 and amount of the ferrous form; ascorbic acid 50 mg IRP-2 control iron availability by translational increases iron absorption from a meal by 2-3 times. control of the synthesis of transferrin receptor Food reduces iron absorption due to inhibition by (increasing uptake) and of ferritin (increasing phytates, tannates and phosphates. storage). There is a small amount of ferritin in the blood in Iron balance is determined by the difference between balance with the iron stores. Iron is stored as ferritin iron absorption and iron loss. Humans lack a (which sequesters iron in a nontoxic but readily mechanism to excrete excess iron and physiological mobilised form) and its aggregate, haemosiderin, in control of iron balance is achieved by regulation of the cells of the liver, bone marrow and spleen. A absorption. There is a reciprocal relationship between measure of the state of iron stores is provided by stores and absorption so that, as stores decline the amount of ferritin in the serum (normally absorption increases and vice versa. 20-300 mmol/1) and by the relationship of serum The mucosal cells of the proximal small bowel iron concentration (normally 10-30 mmol/1; reduced regulate iron absorption. Dietary and administered in iron deficiency) to the binding capacity of trans- iron is actively transported into the gut mucosal ferrin (normally 45-70 mmol/1; increased in iron cell, probably involving a protein DMT1 though the deficiency). Ferritin is an acute-phase reactant and precise details have not been established. Two other may be an inaccurate measure of iron stores in proteins, hephaestin and ferroportin 1, appear to be inflammatory states, e.g. rheumatoid arthritis. involved in intracellular transport and release into Recently developed techniques to measure the the plasma respectively. Regulation of absorption may plasma level of soluble transferrin receptor (which involve one or more of: (1) control of mucosal is increased in iron deficiency but not by infection uptake; (2) retention of iron in storage form in the or inflammation) may help differentiate the anaemia mucosal cell and (3) transfer from the mucosal cell of iron deficiency from that of chronic disease. to the plasma. Increased erythropoietic activity also stimulates increased absorption. Iron that is not Prolonged heavy excess of iron intake overwhelms needed by the body may be bound to a protein the mechanism described and results in haemo- (apoferritin) as ferritin and lost into the gut lumen siderosis, as there is no physiological mechanism to when the mucosal cell is shed (2-3 days). Iron is increase iron excretion in the face of increased eliminated at a near constant rate in the faeces of absorption. Iron-deficient subjects absorb up to 20 healthy people. times as much administered iron as those with Iron that is required by the body forms a labile normal stores. Abnormalities of the small intestine pool within the cell; if this pool is excessive it may may interfere with either the absorption of iron, as stimulate production of more apoferritin in the in coeliac disease and other malabsorption syn- mucosal cells to bind and lose more iron as ferritin dromes, or possibly with the conversion of iron into when the cell is shed. Labile pool iron in the Fe+++ a soluble and reduced form, e.g. following loss of form enters the plasma bound to a transport acid secretion after a partial gastrectomy. globulin, transferrin, which delivers it to the sites The formation of insoluble iron salts (such as of physiological need, principally erythrocyte phosphate and phytate) in the alkaline environ- 588
I RON 29 merit of most of the small intestine explains why Contraindications. It is illogical to give iron in the much of the iron taken by mouth is not absorbed, anaemia of chronic infection where utilisation of even in severe iron deficiency. iron stores is impaired; but such patients may also have true iron deficiency. This may be difficult to Interactions. Iron chelates in the gut with tetra- diagnose without direct visualisation of stores in a cyclines, penicillamine, methyldopa, levodopa, bone marrow aspirate. Iron should not be given in carbidopa, ciprofloxacin, norfloxacin and ofloxacin; haemolytic anaemias unless there is also haemo- it also forms stable complexes with thyroxine, globinuria, for the iron from the lysed cells remains captopril and biphosphonates. These interactions in the body. Moreover the increased erythropoiesis can be clinically important. Ingestion should be associated with chronic haemolytic states stimulates separated by 3 hours. increased iron absorption and adding to the iron Ascorbic acid increases absorption (see above) but load may cause haemosiderosis. its use (200 mg/day) is not clinically important in routine therapy; desferrioxamine binds iron and Iron therapy is needed in: reduces absorption (see Poisoning, below); tea • Iron deficiency due to dietary lack or to chronic (tannins) and bran reduce absorption. blood loss. • Pregnancy. The extra iron required by mother and fetus totals 1000 mg, chiefly in the latter half IRON THERAPY of pregnancy. The fetus takes iron from the Iron therapy is indicated only for the prevention or mother even if she is iron deficient. Dietary iron cure of iron deficiency. In general terms, making is seldom adequate and iron and folic acid 25 mg of iron per day available to the bone marrow (50-100 mg elemental iron plus folic acid will allow an iron deficiency anaemia to respond 200-500 micrograms/day) should be given to with a rise of 1% of haemoglobin (0.15 g Hb/100 ml) pregnant women from the fourth month. per day; a reticulocyte response occurs between 4 Opinions differ on whether all women should and 12 days. An increase in the haemoglobin of at receive prophylaxis or only those who can be least 2 g/dl after 3 weeks of therapy is a reasonable identified as needing it. There are numerous criterion of an adequate response. Oral prep- formulations. Parents should be particularly arations are the treatment of choice for almost all warned not to let children get at the tablets. patients due to their effectiveness, safety and low • Abnormalities of the gastrointestinal tract in cost. Parenteral preparations should be restricted to which the proportion of dietary iron absorbed the few patients unable to absorb or tolerate oral may be reduced, i.e. in malabsorption preparations. Red cell transfusion is necessary only syndromes such as coeliac disease. in patients with severe symptomatic anaemia or • Premature babies, since they are born with low where chronic blood loss exceeds the possible rate iron stores, and in babies weaned late. There is of oral or parenteral replacement. very little iron in human milk and even less in cow's milk. Oral iron therapy. The goal of iron therapy is to • Early treatment of severe pernicious anaemia repair the haemoglobin deficit and replenish storage with hydroxocobalamin, as the iron stores iron. When oral therapy is used it is reasonable to occasionally become exhausted by the surge in assume that about 30% of the iron will be absorbed red cell formation. and to give 180 mg of elemental iron daily for 1-3 months according to the degree of anaemia. Iron Oral iron preparations. There is an enormous stores are less easily replenished by oral therapy variety of official and proprietary iron preparations. than by injection, and oral therapy (at lower dose) For each milligram of elemental iron taken by should be continued for 3-6 months after the mouth, ferrous sulphate is as effective as more haemoglobin concentration has returned to normal expensive preparations. It is particularly important or until the serum ferritin exceeds 50 microgram/1 to avoid initial overdosage with iron as the resulting (or as long as blood loss continues). symptoms may cause the patient to abandon 589
29 CELLULAR DISORDERS AND ANAEMIAS therapy. A small dose may be given at first and Sulphate Oral Solution, Paediatric: 5 ml contains increased after a few days. The objective is to give 12 mg of elemental iron: but they stain the teeth. 100-200 mg of elemental iron per day in an adult Polysaccharide-iron complex (Niferex): 5 ml con- (3 mg/kg in a child). Iron given on a full stomach tains 100 mg of elemental iron. There are numerous causes less gastrointestinal upset but less is other iron preparations which can give satisfactory absorbed than if given between meals; however, results. use with food is commonly preferred to improve Sustained-release and chelated forms of iron (see compliance. Commonly used preparations, given in above) have the advantage that poisoning is less divided doses, include: serious if a mother's supply is consumed by young Ferrous Sulphate Tabs, 200-600 mg/d (providing children, a real hazard. 67-195 mg/d of elemental iron) Iron therapy blackens the faeces but does not Ferrous Gluconate Tabs, 300-1200 mg daily (pro- generally interfere with modern tests for occult viding 35-140 mg/d of elemental iron) blood (commonly needed in investigation of Ferrous Furmarate Tabs, 200-600 mg daily (providing anaemia), though it may give a false positive with 130-195 mg/d of elemental iron) some older occult blood tests, e.g. guaiac test. Ferrous sucdnate and ferrous glycine sulphate are alternatives. Failure of oral iron therapy is most commonly due to poor patient compliance, persistent bleeding Choice of oral iron preparation. Oral iron is used and, as with all drug therapy, wrong diagnosis. both for therapy and for prophylaxis (pregnancy) of anaemia in people who are often feeling little if any Adverse effects. Most patients tolerate oral iron ill-health. Because of this, the occurrence of gastro- therapy but 10-20% have symptoms that may be intestinal upset is particularly important as it may attributed to iron, generally gastrointestinal upset. cause the patient to give up taking iron. The These effects of oral iron include nausea, abdominal evidence as to which preparation provides best iron pain, and either constipation or diarrhoea. Upper absorption with least adverse effects is conflicting. GI effects appear to be dose-related and are best Gastrointestinal upset is minimal if the daily dose managed by ingestion of the tablet with or after does not exceed 180 mg elemental iron and if iron is food and/or reduction in the amount of iron con- given with food. tent in each dose. This will prolong the necessary period of treatment. Diarrhoea or constipation can A suggested course. Start a patient on ferrous usually be treated symptomatically without a change sulphate taken on a full stomach once, then twice, in regimen. then thrice a day. If gut intolerance occurs, stop the iron and reintroduce it with one week for each step. Parenteral iron therapy If this seems to cause gastrointestinal upset, try ferrous gluconate, succinate or fumarate. If simple This may be required if: preparations (above) are unsuccessful, and this is • Iron cannot be absorbed from the intestine unlikely, then the pharmaceutically sophisticated • The patient cannot be relied on to take it or and expensive sustained-release preparations may be experiences intolerable gut symptoms. tried. They release iron slowly and only after passing the pylorus, from resins, chelates (sodium iron Speed of haemopoietic response is not quicker than edetate) or plastic matrices, e.g. Slow-Fe, Ferrograd, that with full doses of oral iron reliably taken and Feospan, so that iron is released in the lower rather normally absorbed, for both provide as much iron than the upper small intestine. Patients who cannot as an active marrow can use, but a course of injected tolerate standard forms even when taken with food iron is stored and utilised over months. The ionised may get as much iron with fewer unpleasant symp- salts of iron given orally are unsuitable as paren- toms if they use a sustained-release formulation. teral preparations as they are powerful protein Liquid formulations are available for adults who precipitants and un-ionised iron complexes are prefer them and for small children, e.g. Ferrous used. 590
RON 29 Intramuscular iron. Iron sorbitol inj. (50 mg of iron and folic acid, the lack of the latter may not be iron/ml) is an iron-sorbitol-citric-acid complex of obvious because haematopoiesis is impaired by MW < 5000 that is rapidly absorbed into the blood insufficiency of iron. If iron is supplied increased from the site of i.m. injection. Iron sorbitol is bound erythropoiesis reveals the folic acid deficiency. This to plasma globulin, transferrin, and is stored in the is most likely to happen in pregnancy due to high marrow and liver. It is not substantially taken up in fetal requirements for both haematinics and so folic the reticuloendothelial system. Excess unbound acid is commonly given to all pregnant patients iron is excreted in the urine (about 30% of the dose) with anaemia (see below); it also occurs in which may turn black transiently at the time of malabsorption syndromes where both may be peak iron excretion or only on standing for some malabsorbed. hours. Intravenous iron. Iron dextran inj. (ferric Acute overdose: poisoning hydroxide complexed with dextrans; 50 mg/ml) High doses of iron salts by mouth can cause severe and iron sucrose inj. (ferric hydroxide complexed gastrointestinal irritation and even necrosis of the with sucrose; 20 mg/ml) are administered by slow mucous membrane. Autopsy shows severe damage i.v. injection or infusion (not recommended for to brain and liver. Iron poisoning is particularly children). dangerous in children. Sustained-release forms are Oral iron therapy should not be given 24 h safer in homes where heedless parents live with before i.m. injections begin and for 5 days after the small children. Ferrous sulphate is the most toxic. last i.v. injection; not only is continuation unnecess- Typically acute oral iron poisoning has the ary, but it may promote adverse reactions by following phases: saturating the plasma protein (transferrin) binding capacity so that the injected iron gives a higher 1. 0.5-1 h after ingestion there is abdominal pain, unbound plasma iron concentration than is safe. grey/black vomit, diarrhoea, leucocytosis and hyperglycaemia. Severe cases are indicated by Doses. The approximate total requirement is acidosis and cardiovascular collapse which may ascertained from manufacturers' dosage schedules proceed to coma and death. which relate body weight to the haemoglobin 2. There follows a period of improvement lasting deficit. Iron sorbitol is normally given daily or on 6-12 h, which may be sustained or which may alternate days where tolerance is low. It is given by deteriorate to the next stage. deep i.m. injection, which can be painful. It stains 3. Jaundice, hypoglycaemia, bleeding, the skin (for up to 2 years) but this can be encephalopathy, metabolic acidosis and minimised by inserting the needle through the skin convulsions are followed by cardiovascular and then moving the skin and subcutaneous tissue collapse, coma and sometimes death 48-60 h laterally before entering the muscle so that the after ingestion. needle track becomes angulated when the needle is 4. 1-2 months later, upper gastrointestinal withdrawn (the Z-technique). obstruction may result from scarring and stricture. Adverse effects. General reactions include headache, Treatment of acute iron poisoning is urgent and dizziness, nausea, vomiting, disorientation, pressure immediate efforts must be made to chelate iron in sensations in the chest, myalgia, hypotension, a the blood and in the stomach and intestine. Raw metallic taste, urticaria and hypersensitivity. Intra- egg and milk help to bind iron until a chelating venous iron may rarely cause anaphylactoid reactions agent is available. and facilities for cardiopulmonary resuscitation The first step should be to give desferrioxamine should be available. 1-2 g i.m.; the dose is the same in adults and children. Only after this should gastric aspiration or Folic acid deficiency may be unmasked by effective emesis be performed. If lavage is used, the water iron therapy. Where there is a deficiency of both should contain desferrioxamine 2 g/1. After empty- 591
29 CELLULAR DISORDERS AND ANAEMIAS ing the stomach, desferrioxamine 10 g in 50-100 ml Chronic iron overload water should be left in the stomach to chelate any remaining iron in the intestinal lumen; it is not Humans are uniquely unable to excrete excess iron so that, if there is uncontrolled iron intake, it pro- absorbed. gressively accumulates. Grossly excessive parenteral Subsequently, desferrioxamine should be admin- istered by i.v. infusion not exceeding 15 mg/kg/h iron therapy or a hundred or more blood trans- fusions (as in treatment of thalassaemia2) can lead to (maximum 80 mg/kg/24 h) or further i.m. injec- haemosiderosis. Oral iron therapy over many years tions (2 g in sterile water 10 ml) should be given has also been reported to cause haemosiderosis. 12-hourly. Poisoning is severe if the plasma iron concentration exceeds the total iron binding capacity Treatment of chronic iron overload, e.g. haemochro- (upper limit 75 mmol/1) or the plasma becomes pink due to the large formation of ferrioxamine (see matosis, patients who are transfusion-dependent due to chronic haemolytic anaemias, thalassaemia below). If severe poisoning is suspected i.v. rather and refractory anaemias with transfusional iron than i.m. administration of desferrioxamine is indi- overload (siderosis). The goal of therapy is the cated without waiting for the result of the plasma concentration. reduction and maintenance of body iron stores at normal or near-normal levels to avoid the tissue damage associated with iron overload. Desferrioxamine (deferoxamine) (Desferal) (t1/2 6 h) Iron may be removed by repeated venesection in is an iron-chelating agent (see Chelating agents, haemochromatosis where there is no anaemia. A p. 154). During a systematic investigation of actino- single vensection of 450 ml of blood, in the absence mycete metabolites, iron-containing substances of anaemia, removes 200-250 mg of iron and can be (sideramines) were discovered. One of these sub- repeated weekly in individuals with haemo- stances was ferrioxamine. The iron in this can be chromatosis until the ferritin reaches the normal removed chemically, leaving desferrioxamine. range. After complete removal of the iron load, When desferrioxamine comes into contact with maintenance therapy in the form of venesection ferric iron, its straight-chain molecule twines around every 3-4 months is required. A small number of it and forms a nontoxic complex of great stability patients with haemosiderosis and cardiac failure (ferrioxamine), which is excreted in the urine giving may require chelator therapy. it a red/orange colour, and in the bile. It is not Patients with transfusion siderosis require a absorbed from the gut and must be injected for long-term programme of chelation therapy. In patients systemic effect. In acute poisoning, as opposed to who are transfusion-dependent from infancy chronic overload, desferrioxamine 5 g chelates (thalassaemia major, congenital refractory anaemia) the iron contained in about 10 tablets of ferrous chelation therapy is commenced after 10-20 trans- sulphate or gluconate. It has a negligible affinity for fusions at about 3 years of age. In older patients other metals in the presence of iron excess. with acquired transfusion-dependent anaemias Desferrioxamine has been shown to be effective chelation is commenced after 20 transfusions or in the therapy of acute iron poisoning and in the when the serum ferritin is 2-3 times the upper limit treatment and perhaps in the diagnosis of diseases of normal. associated with chronic iron accumulation. A Chelation can be effectively carried out only by topical formulation is available for ocular siderosis. slow parenteral administration of desferrioxamine s.c. or i.v. through an indwelling catheter with a small portable syringe pump e.g. over 9-12 h Serious adverse effects are uncommon but include rashes and anaphylactic reactions; with chronic use 1 cataract, retinal damage and deafness can occur. Tenenbein M et al 1992 Lancet 339: 699. 2 Hypotension occurs if desferrioxamine is infused A 26-year-old subject with beta-thalassaemia major had been transfused 404 units of blood over his lifetime. His iron too rapidly and there is danger of (potentially fatal) stores were so high (estimated at above 100 g) that he adult respiratory distress syndrome if infusion triggered a metal detector at an airport security checkpoint proceeds beyond 24 h.1 (Jim R T S 1979 Lancet 2: 1028). 592
VITAM I N B 29 nocturnally on 5 nights per week. Simultaneous lation of tetrahydrofolate and thus for DNA oral administration of ascorbic acid is to be synthesis. Animals cannot synthesise cobalamin avoided; it increases the availability of free iron for and so are directly or indirectly dependent upon chelation but carries the risk of mobilising iron from microorganisms for it. Cobalamin is produced in relatively safe reticuloendothelial storage sites to a nature only by cobalamin-producing microorganisms, potentially toxic pool in parenchymal cells. This and herbivores obtain their supply from plants regimen can put a transfusion-dependent patient contaminated with bacteria and faeces. Carnivores into the desired negative iron balance. Compliance obtain their supply by ingesting the muscular and is often a problem and is typically difficult during parenchymal tissues of these animals. Animal teenage years in those with lifelong transfusion- protein is the major dietary source of cobalamin in dependence. The expense of chelation therapy over man. Although bacteria in the human colon a long period is currently enormous and raises synthesise cobalamin, it is formed too distally for serious ethical problems in economically poor absorption by the ileal transport system. Rabbits in countries where most patients with thalassaemia the wild would suffer from B12 deficiency if they did and haemoglobinopathies live. not eat their own faeces. A safe, effective, inexpensive, orally-absorbed In the presence of intrinsic factor about 70% of iron chelating agent would improve compliance and ingested cobalamin is absorbed, in its absence < 2% the quality of life of affected patients. Deferiprone, is absorbed. Some cyanocobalamin may be absorbed which is the best of many agents examined, is less by passive diffusion, i.e. independently of intrinsic effective than desferrioxamine, carries a risk of factor, though less reliably and only with large agranulocytosis and may itself cause tissue fibrosis. doses. It remains under clinical trial but may be too toxic Dietary deficiency is virtually confined to people for general use. too impoverished to buy meat, and to Vegans, a sect of particularly uncompromising vegetarians. Deficiency of vitamin B12 in the body leads to: Vitamin B 12 • Megaloblastic anaemia • Degeneration of the brain, spinal cord (subacute PERNICIOUS ANAEMIA combined degeneration) and peripheral nerves; symptoms may be psychiatric and physical In 1925, it was demonstrated that two factors were • Abnormalities of epithelial tissue, particularly of required to cure pernicious anaemia: one in the the alimentary tract, e.g. sore tongue and food (extrinsic factor) and one in gastric juice malabsorption. (intrinsic factor). • Extrinsic factor, cyanocobalamin (vitamin B12), ABSORPTION AND TRANSPORT was isolated in 1948. • Intrinsic factor (a glycoprotein secreted by the The daily requirement of cobalamin is about parietal cells of the fundus and cardia) acts solely 3.0 micrograms. Absorption takes place mainly in as a vehicle for carrying the important extrinsic the terminal ileum, and it is carried in plasma factor into the body via receptors in the ileum. bound to proteins. Some 90% of recently absorbed or administered cobalamin is carried on transco- balamin II an important transport protein which is COBALAMINS rapidly cleared from the circulation (t1/2 6-9 min- Cobalamins comprise a family of compounds utes). Hereditary deficiency of transcobalamin II which share a complex structure. Vitamin B]2 is causes severe cobalamin deficiency. About 80% of known as cyanocobalamin because when originally all circulating cobalamin is bound to transco- isolated, an in-vitro artefact had placed a cyan balamin I (t1/2 9-12 days) which is possibly a plasma group in the cobalt P position. Vitamin B12 is an storage form (hereditary deficiency of which is of active cellular coenzyme essential for demethy- no consequence). Cobalamin in its reduced form 593
29 CELLULAR DISORDERS AND ANAEMIAS cob(I)alamin functions as a coenzyme for methionine Tobacco amblyopia has been attributed to cyanide synthase in a reaction that generates tetrahydrofolate, intoxication from strong tobacco which interferes and is critical for DNA and RNA synthessis. with the coenzyme function of vitamin B12; hydrox- Cobalamin is not significantly metabolised and ocobalamin (not cyanocobalamin) may be given. passes into the bile (there is enterohepatic circula- tion which can be interrupted by intestinal disease DIAGNOSIS OF B|2 DEFICIENCY and hastens the onset of clinical deficiency), and is excreted via the kidney. Body stores amount to The serum concentration of vitamin B12 is low about 5 mg (mainly in the liver) and are sufficient (normal 170-925 nanogram/1). In severe deficiency for 2-4 years if absorption ceases. there is pancytopenia, the blood film shows anisopoikilocytosis with oval macrocytes and hyper- segmented neutrophils; the marrow is megalo- INDICATIONS FORVITAMIN B 12 blastic. In many patients with pernicious anaemia Indications for administration are the prevention antibodies to intrinsic factor can be identified in the and cure of conditions due to its deficiency. serum. Hydroxocobalamin is preferred for clinical use. Absorption of radioactive vitamin B12 (Schilling test) helps to distinguish between gastric and intestinal causes. Pernicious (Addisonian) anaemia. The atrophic First: the patient is given a small dose of radio- gastric mucosa is unable to produce intrinsic factor active vitamin B12 orally, with a simultaneous large (and acid) due to an autoimmune reaction to gastric dose of nonradioactive vitamin B12 intramuscularly. parietal cells and intrinsic factor itself, there is The large injected dose saturates binding sites so failure to absorb vitamin B12 in the terminal ileum that any of the oral radioactive dose that is so that deficiency results. Despite its name (given absorbed cannot bind and will be eliminated in the when no treatment was known and it was believed urine where it can easily be measured (normally to be a neoplastic disorder due to the appearance of > 10% of the administered dose appears in urine the megaloblastic bone marrow), the prognosis of a collected for 24 h, if renal function is normal). In patient with uncomplicated pernicious anaemia, pernicious anaemia and in malabsorption, gut properly treated with hydroxocobalamin, is little absorption and therefore subsequent appearance of different from that of the rest of the population. The radioactivity in the plasma (measured 8-12 h later) neurological complications, particuarly spasticity, and urine are negligible. develop only after prolonged severe deficiency but Second: the test is repeated with intrinsic factor may be permanent; they are rarely seen today. Total added to the oral dose. The radioactive vitamin B12 removal of the stomach or atrophy of the mucous is now absorbed in pernicious anaemia (but not in membrane in a postgastrectomy remnant may, after intestinal malabsorption) and is detected in plasma several years, lead to a similar anaemia. and urine. Both stages of the test are needed to maximise reliability of diagnosis of pernicious Malabsorption syndromes. In stagnant loop syn- anaemia. drome (bacterial overgrowth which competes for the available cobalamin and can be remedied by a CONTRAINDICATIONSTOVITAMIN B|2 broad-spectrum antimicrobial), ileal resection, Crohn's disease and chronic tropical sprue affecting Inconclusively diagnosed anaemia is an important the terminal ileum, vitamin B12 deficiency is com- contraindication. Therapy of pernicious anaemia mon although megaloblastic anaemia occurs only must be both adequate and lifelong, so that accurate relatively late. The fish tape worm Diphyllobothrum diagnosis is essential. Even a single dose of vitamin latum which can infest humans who eat raw or B12 interferes with the haematological picture for partially cooked freshwater fish roe can grow up to weeks (megaloblastic haematopoiesis reverts to 10 meters in the gut and competes for ingested normal within 12 hours), although the Schilling test cobalamin. remains diagnostic. 594
FOLIC ACID (PTEROYLG LUTAM 1C ACID) 29 PREPARATIONS AND USE urinary loss with high plasma concentrations). The reversal of neurological damage is slow (and rarely Hydroxocobalamin is bound to plasma protein to a marked) and the degree of functional recovery is greater extent than is cyanocobalamin, with the inversely related to the extent and duration of result that there is less free to be excreted in the symptoms. urine after an injection and rather lower doses at Haemoglobin estimations are necessary at least longer intervals are adequate. Thus hydroxoco- every 6 months to check adequacy of therapy and balamin is preferred to cyanocobalamin, though the for early detection of iron deficiency anaemia latter can give satisfactory results as the doses due to achlorhydria (common in patients with administered are much greater than are required pernicious anaemia > 60 years) or carcinoma of the physiologically. Cyanocobalamin remains available. stomach, which occurs in about 5% of patients with The initial dose in cobalamin deficiency anaemias, pernicious anaemia. including uncomplicated pernicious anaemia, is When injections are refused or are impracticable hydroxocobalamin 1 mg i.m. every 2-3 days for (rare allergy, bleeding disorder), administration as 5 doses to induce remission and to replenish stores. snuff or aerosol has been effective, but these routes Maintenance may be 1 mg every 3 months; higher are less reliable. Large daily oral doses (1000 micro- doses will not find binding sites and will be grams) are probably preferable; depleted stores eliminated in the urine. Higher doses are justified must be replaced by parenteral cobalamin before during renal or peritoneal dialysis where hydroxy- switching to the oral preparation; the patient must cobalamin clearance is increased, and resultant be compliant; monitoring of the blood must be raised plasma methylmalonic acid and homo- more frequent and adequate serum vitamin B12 cysteine represent an independent risk factor for levels must be demonstrated. vascular events in these patients (see later). Routine low dose supplements of hydroxyco- Adverse effects virtually do not occur, but use of balamin, folate and pyridoxine fail to control vitamin B12 as a 'tonic' is an abuse of a powerful hyperhomocysteinaemia in 75% of dialysis patients remedy for it may obscure the diagnosis of pernicious but supraphysiological doses are effective: hyd- anaemia, which is a matter of great importance in a roxycobalamin 1 mg/d, folic acid 15 mg/d and disease requiring lifelong therapy and prone to pyridoxine 100 mg/d. serious neurological complications. The latter danger After initiation of therapy, patients feel better in is of particular significance when a megaloblastic 2 days, reticulocytes peak at 5-7 days and the anaemia due to pernicious anaemia is incorrectly haemoglobin, red cell count and haematocrit rise by diagnosed as due to folate deficiency; here folic the end of the first week. These indices normalise acid, if used alone (see below) may accelerate pro- within 2 months irrespective of the starting level. gression of subacute combined degeneration of the Failure to respond implies a wrong or incomplete nervous system. diagnosis (coexistent deficiency of another hae- matinic). The initial stimulation of haemoglobin synthesis often depletes the iron and folate stores and supplements of these may be needed. Hypokalaemia may occur at the height of the Folk acid erythrocyte response in severe cases. It is attributed to uptake of potassium by the rapidly increasing (pteroylglutamic acid) erythron (erythrocyte mass). Oral potassium should be given prior to initiating therapy in a Folic acid3 was so named because it was discovered patient with low or borderline potassiuim levels. as a bacterial growth factor present in spinach Once alternative or additional causes of the leaves. It is one of the B group of vitamins and was anaemia have been excluded, inadequate response soon shown to be the same substance as that should be treated by increased frequency of injec- 3 tions as well as increased amount (because of Latin: folium, a leaf. 595
29 CELLULAR DISORDERS AND ANAEMIAS present in yeast and liver which cured a nutritional Dietary deficiency. Folate deficiency is extremely macrocytic anaemia in Indian women. common in the setting of general malnutrition in developing countries and is a particular problem in childhood. In Western countries folate deficiency FUNCTIONS occurs in alcoholics, some slimming diets, the Folic acid is itself inactive; it is converted into the elderly, the infirm and psychiatric patients. biologically active coenzyme, tetrahydrofolic acid, which is important in the biosynthesis of amino Pregnancy. Folic acid requirement is increased to acids and DNA and therefore in cell division. The 300-400 microgram a day. This cannot be met from formyl derivative of tetrahydrofolic acid is folinic the diet by one-third of women in Western societies acid and this is used to bypass the block when the and the problem is greater in less economically body fails to effect the conversion of folic acid (see developed countries where nutritional deficiency Folic acid antagonists, p. 606). Ascorbic acid pro- may be aggravated by high red cell turnover due to tects the active tetrahydrofolic acid from oxidation; haemoglobinopathies and endemic malaria. For this the anaemia of scurvy, although usually normo- reason folic acid is added to iron for prophylaxis of blastic, may be megaloblastic due to deficiency of anaemia in pregnancy. The dose needed is about tetrahydrofolic acid. 300 micrograms of folic acid a day, which is insufficient to alter the blood picture of pernicious Deficiency of folic acid leads to a megaloblastic anaemia and so there is no risk of masking that anaemia because it is necessary for the production disease (pernicious anaemia is also very rare in of purines and pyrimidines, which are essential women of reproductive age and is probably incom- precursors of deoxyribonucleic acid (DNA). The patible with a successful pregnancy). A large megaloblastic marrow of cobalamin deficiency is number of preparations of iron with folic acid is due to interference with folic acid utilisation and available (see also Iron therapy, p. 591). They are the morphological changes of cobalamin deficiency suitable only for prevention. Larger doses may be can be reversed by folic acid. It is vital to realise that used in therapy of anaemia during pregnancy (see folic acid does not provide adequate treatment for below); it will remit spontaneously some weeks pernicious anaemia. Nor does vitamin B12 provide after delivery. Vigorous iron therapy in pregnancy adequate treatment for the megaloblastic anaemia may unmask a folate deficiency. During lactation of folic acid deficiency, although a partial response requirements remain increased. may occur because vitamin B12 plays a role in folate metabolism. Prevention of fetal neural tube defect (spina bifida). Folic acid supplementation taken before conception and during the early weeks of preg- OCCURRENCE AND REQUIREMENTS nancy has been shown in an 8-year trial to prevent Folic acid is widely distributed, especially in green the condition in pregnancies subsequent to an vegetables, yeast and liver. Daily requirement of affected birth.4 Women hoping to conceive and who folic acid in an adult is some 50-100 micrograms have had an affected child are advised to take folic and a diet containing 400 micrograms of poly- acid 5 mg/day. To prevent a first occurrence glutamates will provide this. In childhood the 400 micrograms/day should be taken both before requirement is 50 micrograms per day about 5 x conception, or as soon as possible after diagnosis.5 more on a weight-for-weight basis. Body stores last In both cases folate supplement should be taken for about 4 months. the first 12 weeks of pregnancy. INDICATIONS 4 MRC Vitamin Study research group 1991 Lancet 338:131. Folic acid is used to prevent or cure deficiency of 5 A supplement of folic acid 5 mg/day is proposed for fuller folate which are due either to a decreased supply or risk reduction. Wald N J, Law M R, Morris J K et al 2001 to an increased requirement. Quantifying the effect of folic acid. Lancet 358: 2069-2073. 596
HAEMOPOIETIC GROWTH FACTORS 29 Premature infants. Supplementation is needed the cause of deficiency cannot be removed; because these infants miss the build-up of folate 15 mg/day may be needed in malabsorption states stores that normally occurs in the last few weeks of though usually 5 mg is adequate. There is no pregnancy. advantage in giving folinic acid instead of folic acid, except in the treatment of the toxic effects of Malabsorption syndromes. Particularly in gluten- folic acid antagonists such as methotrexate (folinic sensitive enteropathy and tropical sprue, poor acid 'rescue', see p. 608). absorption of folic acid from the small intestine often leads to a megaloblastic anaemia. • For prophylaxis, with iron, in pregnancy, see page 589 Drugs. Antiepilepsy drugs, particularly phenytoin, • For prophylaxis in haemolytic diseases and in primidone and phenobarbital, occasionally cause a renal dialysis: 5 mg per day or per week macrocytic anaemia that responds to folic acid. This depending on need. may be due to enzyme induction by the anti- epileptics increasing the need for folic acid to Adverse reactions are rare: allergy occurs, and perform hydroxylation reactions (see Epilepsy) but status epilepticus may be precipitated. other factors such as reduced absorption may be involved. Administration of folic acid causes a recurrence of seizures in some patients. Some anti- malarials, e.g. pyrimethamine, may interfere with Haemopoietic growth conversion of folates to the active tetrahydrofolic factors acid, causing macrocytic anaemia. Methotrexate, another folate antagonist, may cause a megalo- Cloning of growth factor genes and recombinant blastic anaemia especially when used long-term for DNA technology allow the large-scale production leukaemia, rheumatoid arthritis or psoriasis. of cytokines for clinical use. Growth factors are now available to stimulate both erythroid and myeloid Miscellaneous causes of excess utilisation or loss. cell lines. These factors are potentially useful when- In chronic haemolytic states, where erythropoiesis ever there is cytopenia, whether due to disease or to is accelerated, and in myelofibrosis, where haemo- cytotoxic chemotherapy. poiesis is inefficient, folate requirement is increased. Extensive shedding of skin cells in exfoliative dermatitis, inflammatory states, e.g. rheumatoid ERYTHROPOIETIN arthritis, and malignant disease (lymphoma), can Erythropoietin is a glycoprotein hormone encoded similarly lead to folate deficiency. Folate loss during by a gene on the long arm of chromosome 7 (7q) chronic haemodialysis may be sufficient to require and 90% is produced in the kidney (the remainder replacement. in the liver and other sites) in response to hypoxia. The anaemia of chronic renal failure is largely due CONTRAINDICATIONS to failure of the diseased kidneys to make enough erythropoietin. The principal action of the hormone Imprecisely diagnosed megaloblastic anaemia is is to stimulate the proliferation, survival and differ- the principal contraindication. Tumour cell prolifer- entiation of erythrocyte precursors. The manu- ation in some cancers may be folate dependent and facture of erythropoietin for clinical use became folic acid should be used in malignant disease only possible when the human gene was successfully where there is confirmed folate deficiency anaemia. inserted into cultured hamster ovary cells. Epoetin (recombinant derived human erythro- PREPARATIONS AND DOSAGE poietin) must be given s.c. (which may be more Synthetic folic acid is taken orally; for therapy 5 mg effective) or i.v.; the t1/2 is 4 h and appears not to be daily is usually given for 4 months, or indefinitely if affected by dialysis. Maximum reticulocyte response 597
29 CELLULAR DISORDERS AND ANAEMIAS occurs in 4 days. Self-administration at home three Granulocyte colony-stimulating factors: G-CSF, an times a week is practicable; the dose is adjusted by 18 kDa protein encoded by a gene on the long arm response. Iron reserves must be adequate for of chromosome 17 (17q), stimulates the prolifer- optimum erythropoiesis, i.e. serum ferritin should ation of granulocyte progenitors and activates exceed 100 micrograms/1. Epoetin is available as neutrophil function. two preparations, epoetin alpha and epoetin beta, which are interchangeable. Filgrastim is recombinant human granulocyte Epoetin is effective in the anaemia of chronic colony-stimulating factor. A single dose will cause renal failure to an extent that it significantly the neutrophil count to rise 4-5-fold within hours enhances the patients' quality of life. Patients and the increased count persists up to 72 h. The drug become independent of blood transfusion, with is rapidly cleared after i.v. injection (t1/2 2h) and great benefit to blood transfusion services as well as administration by i.v. infusion or s.c. is necessary to to themselves. prolong plasma concentration. High concentrations Recombinant erythropoietin has also been used are found in plasma, bone marrow and kidneys. It in anaemia of rheumatoid arthritis, prematurity, is degraded to its component amino acids. following cancer chemotherapy, myelodysplasia G-CSF is widely used to mobilise bone marrow and zidovudine-treated AIDS, and to improve the stem cells into the peripheral blood to support both quality of presurgical autologous blood collection. autologous and allogeneic peripheral blood Athletes in track events and cycling seeking advan- progenitor transplantation. The use of peripheral tage through increased haemoglobin concentra- blood progenitors as opposed to bone marrow tions have misused it. progenitors is associated with earlier neutrophil and platelet recovery, fewer red cell transfusions and earlier discharge from hospital. Adverse effects. A dose-dependent increase in Another major use of G-CSF is for patients with arterial blood pressure follows the rise in red cell neutropenia as a result of cytotoxic chemotherapy, mass and encephalopathy may occur in some to shorten the duration of neutropenia and reduce previously hypertensive patients. Arteriovenous morbidity due to infection. It is also used for the shunts of dialysis patients, especially those that are same purpose after autologous and allogeneic bone compromised, may thrombose as a result of marrow transplantation, in aplastic anaemia, AIDS, increased blood viscosity. and congenital, cyclical and idiopathic neutropenia. Iron deficiency may occur, as increased haemato- In combination with epoetin, G-CSF can be effective poiesis outstrips available iron stores, and this can in the management of some patients with myelo- be a cause of inadequate response to the hormone; dysplastic syndromes. G-CSF not only improves parenteral iron therapy may be needed. Transient the neutrophil count, but dramatically improves the influenza-like symptoms may accompany the first proportion of patients with a raised haemoglobin i.v. injections. in response to epoetin possibly by reduction of erythroid apoptosis (the cause of ineffective erythropoiesis). COLONY-STIMULATING FACTORS Adverse effect. Medullary bone pain occurs with A number of cytokines (see p. 280) stimulate the high i.v. doses. Musculoskeletal pain, dysuria, growth, differentiation and functional activity of splenomegaly, allergic reactions and abnormality of myeloid progenitor cells. As the name implies the liver enzymes also occur. function of these polypeptides was defined by in- vitro colony assays of bone marrow progenitors. Lenograstim is similar. They have effects on all myeloid cells including the multipotential stem cells (but probably not the Granulocyte-monocyte colony-stimulating factor: more immature pluripotential cells), intermediate GM-CSF, a glycoprotein of 14-35 kDa encoded by a progenitors and circulating mature cells. Those in gene on the long arm of chromosome 5 (5q), has clinical use are described below. a broader spectrum of activity than G-CSF, 598
POLYCYTHAEM IA RUBRAVERA 29 stimulating both monocyte and granulocyte pro- red cells changing from flexible biconcave discs to duction with functional effects on the mature cells unyielding sickle shapes that obstruct blood flow. of both cell lines. This gives rise to the clinical features of haemolysis with shortened red cell survival, anaemia and Molgramostim (recombinant human granulocyte- painful bone crises. Haemoglobin F (HbF) interferes monocyte colony-stimulating factor) has a t1/2 of with the polymerisation process and is protective 3 h and administration by i.v. infusion or s.c. is against the disease. needed to maintain plasma concentration. Mol- Hydroxyurea (hydroxycarbamide) is the first widely gramostim has also been used to mobilise peripheral available and affordable agent that provides real blood progenitors and to reduce cytotoxic-induced benefit. It acts by perturbing the maturation of neutropenia, and in bone marrow transplantation erythrocytes and promoting HbF production. The and aplastic anaemia. It is now less widely used mode of action may be more complex; reduction in than G-CSF. Molgramostim has also been used for leukocyte counts may reduce vaso-occlusive events; neutropenia caused by ganciclovir and for AIDS- reduced red cell and endothelial adhesiveness may related cytomegalovirus retinitis. It appears to be be a direct effect. Beneficial effects have been seen in synergistic with amphotericin in the treatment of adults, children and infants. Long-term hydroxyurea invasive pulmonary aspergillosis possibly by (hydroxycarbamide) (at close to myelotoxic doses) activation of macrophages to enhance killing of raises HbF to 15-20% and reduces the frequency of phagocytosed fungi. hospitalisation, pain, acute chest syndrome and blood Adverse effects. Molgramostim causes medullary transfusion. Neurological complications e.g. stroke, bone pain, skin rashes, lethargy and myalgia in 10- may not be reduced. Some 10-20% of patients will 20% of patients. It may also cause fever, the inter- fail to respond due to the condition of the bone pretation of which presents a clinical dilemma in marrow, or genetic effects (see also p. 607, 613). neutropenic patients who are subject to sepsis. Pleural and pericardial effusions occur after high doses. Adverse effects. The long-term risk of leukaemo- genesis cannot yet be assessed. There appears to be Thrombopoietin (TPO), a 36 kDa protein encoded no adverse effects on growth or development. by a gene on the long arm of chromosome 3 (3q) stimulates the growth and differentiation of mega- karyocyte progenitors, mature megakaryocytes and primes platlets to respond to stimuli. Recombinant Polycythaemia rubra vera human TPO has been examined in a small number of clinical trials and found to produce a dose- The clinical course of polycythaemia rubra vera dependent increase in bone marrow megakaryo- (PRV) is marked by a high risk of thrombotic com- cytes and the peripheral blood platelet count. If it plications and a variable incidence of transform- proves nontoxic (concerns include the potential for ation to myelofibrosis or acute myeloblastic platelet activation leading to thrombosis, and the leukaemia. The object of treatment is to minimise risk of myelofibrosis), it may have a role in the treat- the risk of thrombosis and to prevent transform- ment of chemotherapy-induced thrombocytopenia. ation. The following are used. Phlebotomy. The object is to reduce the haematocrit to less than 0.45 by venesection (300-500 ml) every Hydroxyurea 2 days. Thereafter the attempt is made to maintain (hydroxycarbamide) in normal status by occasional venesection. Iron deficiency may occur and need treatment although sickle cell anaemia this may result in a need for more frequent venesection. In sickle cell disease, haemoglobin S (HbS) when Additional myelosuppressive therapy is required deoxygenated forms polymers which result in the in most patients. This is indicated if frequent vene- 599
29 CELLULAR DISORDERS AND ANAEMIAS section is required to maintain a normal haematocrit H2-histamine receptor blockers alone or together. or if the platelet count continues high (added risk of Hyperuricaemia, due to cell destruction, is pre- thrombosis). vented by allopurinol; and iron and folate deficiency by replacement doses (due to the rapid response of Radiophosphorus (32P, sodium radiophosphate) is the myeloproliferative erythron). Aspirin remains given i.v. Phosphorus is concentrated in bone and controversial. Low-dose aspirin (for antiplatelet in cells that are dividing rapidly, so that the action) may be used if the platelet count remains erythrocyte precursors in the bone marrow receive high or thrombosis occurs despite the above treat- most of the [3-irradiation. The effects are similar to ment but is best avoided in patients with a history those of whole-body irradiation, and in PRV, 32P is a of haemorrhage. treatment option for those > 65 years (accumulation in the gonads precludes its use in younger patients). The maximum effect on the blood count is delayed 1-2 months after a single dose that usually provides control for 1-2 years. It reduces vascular events and Aplastic anaemia delays progression to myelofibrosis. Excessive depression of the bone marrow including leuco- Marrow failure (aplastic anaemia) may be primary, cytes and platelets is the main adverse effect, but is of which 75% are idiopathic acquired, and 25% seldom serious. Acute myeloid leukaemia occurs secondary to a variety of agents, including chemicals more frequently in patients treated with 32P espe- (e.g. benzene), drugs and infections. Treatment is cially when used in combination with hydroxyurea. chosen according to the severity of the cytopenia, the age of the patient, the availability of a suitable Alkylating agents. Busulfan is a radio-mimetic bone marrow donor and, less commonly, the cause cytotoxic agent that is effective in PRV, reducing (if known). Good supportive treatment is important. vascular events and delaying myelofibrosis. Its The major therapeutic choice is between allogeneic mutagenic potential should restrict its use to older bone marrow transplantation and immune- patients. Chlorambucil and combination chemo- suppression, e.g. with antilymphocytic globulin therapy should be avoided because of excessive and ciclosporin; and perhaps haemopoietic growth leukaemogenic risk. factors (see above). Survival rates after allogeneic transplantation are in the region of 75-80% for data Hydroxyurea (hydroxycarbamide). This anti- collected from transplant centres by the Inter- metabolite is thought to carry a lower risk of national Bone Marrow Transplant Registry, though leukaemogenesis than either of the above agents chronic graft-versus-host disease causes continued but anxieties remain. It effectively reduces the morbidity. incidence of thrombosis and is regarded as more acceptable therapy for younger patients. Immunosuppression is used in patients who are Anagrelide is an oral agent which inhibits platelet not candidates for bone marrow transplantation aggregation but at lower doses it lowers platelet due to age or to the lack of a donor (up to 70%). counts in man due to a marked effect on mega- Horse antithymocyte globulin (ATG) or rabbit anti- karyocyte maturation. It is nonmutagenic and lymphocyte globulin (ALG) induce haematological effectively controls thrombocytosis in PRV and responses (transfusion-independence and freedom essential thrombocythaemia (ET). Adverse effects from infection) in 40-50%. The addition of ciclosporin are cardiovascular: headache, forceful heartbeats, to ATG or ALG improves response rates to 70-80% fluid retention and arrhythmias. and survival rates in responders to 90%. Adverse Interferon alfa is another probably non-leuk- effects of ATG and ALG include anaphylaxis, aemogenic alternative for younger patients. exacerbation of cytopenias and serum sickness. Ciclosporin is nephrotoxic. In refractory patients G- Other features. Pruritus is troublesome and CSF and erythropoetin can improve blood counts, difficult to relieve; it may be helped by Ha- and as can androgens in some patients. 600
APLASTIC ANAEMIA 29 GUIDETO FURTHER READING Steinberg M H 1999 Management of sickle cell disease. New England Journal of Medicine 340:1021-1030 Andrews N C 1999 Disorders of iron metabolism. Stock W, Hoffman R 2000 White blood cells: non- New England Journal of Medicine 341:1986-1995 malignant disorders. Lancet 355:1351-1357 Botto L D, Moore C A, Khoury M J et al 1999 Neural Tefferi A 2000 Myelofibrosis with myeloid metaplasia. tube defects. New England Journal of Medicine New England Journal of Medicine 342:1255-1265 341:1509-1519 Toh B-H, van Driel I R, Gleeson P A1997 Pernicious Castle W B 1966 Treatment of pernicious anaemia: anaemia. New England Journal of Medicine 337: historical aspects. Clinical Pharmacology and 1441-1448 Therapeutics 7: 347 Weatherall D }, Provan A B 2000 Red cells I: inherited Ferner R E et al 1989 Drugs in donated blood. Lancet anaemias. Lancet 355:1169-1175 2: 93-94 Weatherall D }, Provan A B 2000 Red cells II: Oliveri N F 1999 The B-thalassemias. New England acquired anaemias and polycythaemica. Lancet Journal of Medicine 341: 99-109 355:1260-1268 Roy C N, Enns C A 2000 Iron homeostasis: new tales Young N S, Maciejewski J 1997 The pathophysiology from the crypt. Blood 96: 4020-027 of acquired aplastic anaemia. New England Journal Spivak J L 2000 The blood in systemic disorders. of Medicine 336:1365-1372 Lancet 355:1707-1712 601