Anaemia folates

Deficiency of Bi2 or folic acid, or both, causes a macrocytic, normochromic anaemia. Maria s red cells are larger than normal, so it is probable that she has this form of anaemia. Folate deficiency is more common that B12 deficiency because there is usually a good store of Bi2 in the liver. When Bi2... 

In historical terms, folates are among the most recently identified of the vitamins. Wills was the first to describe a form of anaemia associated with pregnancy and malnutrition which could be cured by yeast or liver extract (Wills, 1933 Wills et al, 1937). The active constituent of these dietary... 

There are many causes of the clinical condition referred to as anaemia. One particular type, whose cause can be traced to a genuine metabolic defect is megaloblastic anaemia and is due to a deficiency of the vitamins B12 (cobalamin) and/or folate. These vitamins are required for normal cell division in all tissues, but the rapid production of red cells makes them more susceptible to deficiency. In megaloblastic anaemia the blood haemoglobin concentration falls the synthesis of haem is not impaired. Examination of the blood reveals the appearance of larger then normal cells called macrocytes and megaloblasts are found in the bone marrow. 

It is the role of jV5-methyl THF which is key to understanding the involvement of cobalamin in megaloblastic anaemia. The metabolic requirement for N-methyl THF is to maintain a supply of the amino acid methionine, the precursor of S-adenosyl methionine (SAM), which is required for a number of methylation reactions. The transfer of the methyl group from jV5-methyl THF to homocysteine is cobalamin-dependent, so in B12 deficiency states, the production of SAM is reduced. Furthermore, the reaction which brings about the formation of Ns-methyl THF from N5,N10-methylene THF is irreversible and controlled by feedback inhibition by SAM. Thus, if B12 is unavailable, SAM concentration falls and Ah -methyl THF accumulates and THF cannot be re-formed. The accumulation of AT-methyl THF is sometimes referred to as the methyl trap because a functional deficiency of folate is created. 

Vitamin Bn deficiency Deficiency, although rare, results in two serious problems megaloblastic anaemia (which is identical to that caused by folate deficiency) and a specific neuropathy called Bi2-associated neuropathy or cobalamin-deficiency-associated neuropathy (previously called, subacute combined degeneration of the cord). A normal healthy adult can survive more than a decade without dietary vitamin B12 without any signs of deficiency since it is synthesised by microorganisms in the colon and then absorbed. However, pernicious anaemia develops fairly rapidly in patients who have a defective vitamin B12 absorption system due to a lack of intrinsic factor. It results in death in 3 days. Minot and Murphy discovered that giving patients liver, which contains the intrinsic factor, and which is lightly cooked to avoid denaturation, cured the anaemia. For this discovery they were awarded the Nobel Prize in Medicine in 1934. 

Macrocytic and hyperchromic cells Folate deficiency Pernicious anaemia Myelodysplasia... 

Prescribing perspective is vital so that, if there is any doubt as to whether the macrocytic anaemia is due to shortage of folate acid or vitamin B12, then 1000 mg of the latter must be given by intramuscular injection prior to starting the oral replacement. This will protect the patient from inadvertent precipitation of irreversible damage to the spinal cord known as subacute combined degeneration. 

Pathophysiologically, there is a macrocytic anaemia with megaloblastic haematopoiesis that occurs in the face of normal folate and vitamin B12 and is refractory to therapeutic trials of these two nutrients. Patients are characterized as having a preleukaemic syndrome, which is currently regarded by many as a neoplastic process arising in the haematopoietic stem cells that is analogous to early acute myeloblas-tic leukaemia. 

Megaloblastic anaemia and gastrointestinal disturbances such as diarrhoea, distension and flatulence. Severe folate deficiency causes infertility or even sterility. 

The well-known dose-related side effects include gingival hyperplasia (due to altered collagen metabolism), cerebellar-vestibular effects (nystagmus, vertigo, ataxia), behavioural changes (confusion, drowsiness, hallucinations), increased seizure frequency, gastrointestinal disturbances (nausea, anorexia), osteomalacia (due to reduced calcium absorption and increased vitamin D metabolism) and megaloblastic anaemia (due to reduced folate absorption). 

H16. Herbert, V., Zalusky, R., and Davidson, C. S., Correlation of folate deficiency with alcoholism and associated macrocytosis, anaemia, and liver disease. Ann. Intern. Med. 58, 977-988 (1963). 

Q8 Is Maria s anaemia likely to be caused by a dietary deficiency How may anaemia be caused by a deficiency of folate and B12 ... 

Q9 Are folate and B12 equally effective forms of therapy for anaemia ... 

Macrocytic anaemia is defined as one in which the red blood cells are larger than normal. Megaloblastic anaemia is the most common cause of macrocytic anaemia, caused by a deficiency of either vitamin B12 or fohc acid (or both). Deficiency in folate and/or vitamin B12 may result from either inadequate intake or malabsorption. Pernicious anaemia is caused by a lack of intrinsic factor, which is required to absorb vitamin B12 from food (see below). 

Macrocytic anaemia can also be caused by removal of the functional portion of the stomach, such as during gastric bypass surgery, leading to reduced vitamin B12 and folate absorption. 

Other effects include Dupu5dren s contracture and pseudolymphoma. Some degree of macrocyto-sis is common but anaemia probably occurs only when dietary folate is inadequate. This responds to folate supplement (the requirement for folate is increased, as it is a cofactor in some hydroxylation reactions that are accelerated by enzyme induction by phenytoin). Osteomalacia due to increased metabolism of vitamin D occurs after years of therapy. 

Deficiency of folic acid leads to a megaloblastic anaemia because it is necessary for the production of purines and pyrimidines, which are essential precursors of deoxyribonucleic acid (DNA). The megaloblastic marrow of cobalamin deficiency is due to interference with folic acid utilisation and the morphological changes of cobalamin deficiency can be reversed by folic acid. It is vital to realise that folic acid does not provide adequate treatment for pernicious anaemia. Nor does vitamin 3 2 provide adequate treatment for the megaloblastic anaemia of folic acid deficiency, although a partial response may occur because vitamin plays a role in folate metabolism. 

Drugs. Antiepilepsy drugs, particularly phenytoin, primidone and phenobarbital, occasionally cause a macrocytic anaemia that responds to folic acid. This may be due to enzyme induction by the antiepileptics increasing the need for folic acid to perform hydroxylation reactions (see Epilepsy) but 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 conversion of folates to the active tetrahydrofolic acid, causing macrocytic anaemia. Methotrexate, another folate antagonist, may cause a megaloblastic anaemia especially when used long-term for leukaemia, rheumatoid arthritis or psoriasis. 

Imprecisely diagnosed megaloblastic anaemia is the principal contraindication. Tumour cell proliferation in some cancers may be folate dependent and folic acid should be used in malignant disease only where there is confirmed folate deficiency anaemia. 

Vitamin Bij (cyanocobalamin extrinsic factor) is required in folate metabolism for DNA synthesis, and a deficiency leads to pernicious anaemia. It is used to supplement the diet after certain operations that remove the site of production of intrinsic factor, such as total gastrectomy. Deficiency causes megaloblastic haemopoiesis in which there is a marked disorder of formation of erythroblasts, and can be rectified by giving hydroxocobalamin. 

Omer, A., and Mowat, A. G., Nature of anaemia in rheumatoid arthritis. IX. Folate metabolism in patients with rheumatoid arthritis. Ann. Rheum. Dis. 27, 414-424 (1968). 

VI. Vives Mane, J., Vives-Carrows, J. L., and Rozman, C., Congenital folate-dependent megaloblastic anaemia of unknown aetiology. Lancet 1, 262-263 (1977). 

Folale Megaloblastic anaemia Serum folate. RBC folale. full blood count... 

Oral therapy with iron salts is widely used to treat iron deficiency anaemia. It can take up to 6 months to replete the body stores. Compliance is a problem since side effects such a.s nausea, diarrhoea and other intestinal complaints may be encountered. These are all lessened if the iron. salts arc taken with food. A combination of iron and folate is widely prescribed during pregnancy. 

Recurrence or metastatic spread of the breast cancer would need to be excluded in this woman by imaging her liver and skeleton. Alkaline phosphatase isoenzyme studies should be performed. However, if the increase is due to an increased bone activity, this does not necessarily represent metastatic spread of the tumour. In view of the history and symptoms, osteomalacia due to malnutrition or malabsorption may be the reason. If the patient has malabsorption or malnutrition she may have a macrocytic anaemia due to folate or deficiency and may be deficient in other micronutrients such as zinc and other vitamins. Malabsorption is often difficult to detect clinically and she should undergo tests of malabsorption such as faecal fat measurement. 

Folic acid deficiency leading to a megaloblastic anaemia, which requires oral folic acid (bottom right), may occur in pregnancy (folate requirement is increased) and in malabsorption syndromes (e.g. sieai-orriioea and sprue). 

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