Megaloblastic anaemia This results from a deficiency of vitamin B12 or folic acid, or from disturbances in folic acid metabolism. vitamin B12 a co-factor for, the generation of the essential amino acid methionine from homocysteine.
Deficiency of either vitamin B12 or folate will therefore produce high plasma levels of homocysteine and impaired DNA synthesis.
The megaloblastic changes are most evident in the early nucleated red cell precursors, and haemolysis within the marrow results in a raised bilirubin and lactate dehydrogenase (LDH), but without the reticulocytosis characteristic of other forms of haemolysis
Iron stores are usually raised. The mature red cells are large and oval, and sometimes contain nuclear remnants. The mature neutrophils show hypersegmentation of their nuclei, with cells having six or more nuclear lobes. If severe, a pancytopenia may be present in the peripheral blood.
Vitamin B12 deficiency, but not folate deficiency, is associated with neurological disease in up to 40% of cases, although advanced neurological disease due to B12 deficiency is now uncommon in the developed world.
The main pathological finding is focal demyelination affecting the spinal cord, peripheral nerves, optic nerves and cerebrum. The most common manifestations are sensory, with peripheral paraesthesiae and ataxia of gait.
Vitamin B12Vitamin B12 absorptionThe average daily diet contains 5–30 μg of vitamin B12, mainly in meat, fish, eggs and milk – well in excess of the 1 μg daily requirement. In the stomach, gastric enzymes release vitamin B12 from food and at gastric pH it binds to a carrier protein termed R protein.
Gastric parietal cells produce intrinsic factor, a vitamin B12- binding protein which optimally binds vitamin B12 at pH 8. As gastric emptying occurs, pancreatic secretion raises the pH and vitamin B12 released from the diet switches from the R protein to intrinsic factor. Bile also contains vitamin B12 which is available for reabsorption in the intestine.
The vitamin B12–intrinsic factor complex binds to specific receptors in the terminal ileum, and vitamin B12 is actively transported by the enterocytes to plasma, where it binds to transcobalamin II, a transport protein produced by the liver, which carries it to the tissues for utilisation.
The liver stores enough vitamin B12 for 3 years and this, together with the enterohepatic circulation, means that vitamin B12 deficiency takes years to become manifest, even if all dietary intake is stopped or severe B12 malabsorption supervenes.
Blood levels of vitamin B12 provide a reasonable indication of tissue stores and are usually diagnostic of deficiency.
Causes of vitamin B12 deficiency Dietary deficiency This only occurs in strict vegans but the onset of clinical features can occur at any age between 10 and 80 years.
Gastric pathology Release of vitamin B12 from the food requires normal gastric acid and enzyme secretion, and this is impaired by hypochlorhydria in elderly patients or following gastric surgery.
Pernicious anaemia This is an organ-specific autoimmune disorder in which the gastric mucosa is atrophic, with loss of parietal cells causing intrinsic factor deficiency.
It is more common in individuals with other autoimmune disease (Hashimoto’s thyroiditis, Graves’ disease, vitiligo, hypoparathyroidism or Addison’s disease or a family history of these or pernicious anaemia
The finding of anti-intrinsic factor antibodies in the context of B12 deficiency is diagnostic of pernicious anaemia without further investigations.
Small bowel pathology
Folate Folate absorption Folates are produced by plants and bacteria; hence dietary leafy vegetables (spinach, broccoli, lettuce), fruits (bananas, melons) and animal protein (liver, kidney) are a rich source. Total body stores of folate are small and deficiency can occur in a matter of weeks.Folate deficiency The edentulous elderly or psychiatric patient is particularly susceptible to dietary deficiency and this is exacerbated in the presence of gut disease or malignancy.
Pregnancy-induced folate deficiency is the most common cause of megaloblastosis worldwide and is more likely in the context of twin pregnancies, multiparity and hyperemesis gravidarum.
Serum folate is very sensitive to dietary intake; a single folate-rich meal can normalise it in a patient with true folate deficiency, whereas anorexia, alcohol and anticonvulsant therapy can reduce it in the absence of megaloblastosis.
For this reason, red cell folate levels are a more accurate indicator of folate stores and tissue folate deficiency
The use of folic acid alone in the presence of vitamin B12 deficiency may result in worsening of neurological deficits
Vitamin B12 deficiencyVitamin B12 deficiency is treated with hydroxycobalamin 1000 μg IM for 6 doses 2 or 3 days apart, followed by maintenance therapy of 1000 μg every 3 months for life. The reticulocyte count will peak by the 5th–10th day after starting replacement therapy.
The haemoglobin will rise by 10 g/L every week until normalised. The response of the marrow is associated with a fall in plasma potassium levels and rapid depletion of iron stores.
If an initial response is not maintained and the blood film is dimorphic (i.e. shows a mixture of microcytic and macrocytic cells), the patient may need additional iron therapy.
A sensory neuropathy may take 6–12 months to correct; long-standing neurological damage may not improve
Folate deficiency Oral folic acid 5 mg daily for 3 weeks will treat acute deficiency and 5 mg once weekly is adequate maintenance therapy.
Prophylactic folic acid in pregnancy prevents megaloblastosis in women at risk, and reduces the risk of fetal neural tube defects
The anaemia is not related to bleeding, haemolysis or marrow infiltration, is mild, with haemoglobin in the range of 85–115 g/L,
and is usually associated with a normal MCV (normocytic, normochromic),though this may be reduced in long-standing inflammation.
The serum iron is low but iron stores are normal or increased, as indicated by the ferritin or stainable marrow iron
Pathogenesis It has recently become clear that the key regulatory protein that accounts for the findings characteristic of ACD is hepcidin, which is produced by the liver . Hepcidin production is induced by proinflammatory cytokines, and thereby inhibiting the export of iron from these cells into the blood.
The iron remains trapped inside the cells in the form of ferritin,levels of which are therefore normal or high in the face of significant anaemia. Inhibition or blockade of hepcidin is a potential target for treatment of this form of anaemia.
Diagnosis and management It is often difficult to distinguish ACD associated with alow MCV from iron deficiency. Examination of the marrow may ultimately be required to assess iron stores directly.
A trial of oral iron can be given in difficult situations. A positive response occurs in true iron deficiency but not in ACD. Measures which reduce the severity of the underlying disorder generally help to improve the ACD
حاز عالمان على جائزة نوبل للطب عن اكتشافهما طريقة جديدة لمكافحة السرطان باستخدام النظام المناعي للجسم.وقد تمكن أطباء من علاج حالات متقدمة من سرطان الجلد باستخدام الطريقة التي اكتشفها كل من بروفيسور جيمس أليسون من الولايات المتحدة وبروفيسور تاسوكو هونجو من اليابان.وقالت الأكاديمية السويدية التي تمنح الجائزة إن طريقة العلاج الجديدة التي تعتمد على نظام المناعة أحدثت ثورة في طرق علاج السرطان.
Primary idiopathic acquired aplastic anaemia is failure of the pluripotent stem cells, producing hypoplasia of the bone marrow with a pancytopenia in the blood.
The diagnosis rests on exclusion of other causes of secondary aplastic anaemia and rare congenital causes, such as Fanconi’s anaemia
Clinical features and investigations Patients present with symptoms of bone marrow failure, usually anaemia or bleeding, and less commonly, infections. An CBP demonstrates pancytopenia, low reticulocytes and often macrocytosis. Bone marrow aspiration and trephine reveal hypocellularity.
Management All patients will require blood product support and aggressive management of infection. The prognosis of severe aplastic anaemia managed with supportive therapy only is poor and more than 50% of patients die,usually in the first year.
The curative treatment for patients under 30 years of age with severe idiopathic aplastic anaemia is allogeneic HSCT if there is an available donor
Those with a compatible sibling donor should proceed to transplantation as soon as possible; they have a 75–90% chance of long-term cure.
In older patients, immunosuppressive therapy with ciclosporin and antithymocyte globulin gives 5-year survival rates of 75%.
Secondary aplastic anaemia In some instances, the cytopenia is more selective and affects only one cell line, most often the neutrophils. Frequently, this is an incidental finding, with no ill health. It probably has an immune basis but this is difficult to prove. The clinical features and methods of diagnosis are the Same