Megaloblastic anemia

26-10-2015

This results from a deficiency of vitamin B12 or folic acid, or from disturbances in folic acid metabolism. Folate is an important substrate of, and vitamiB12 a co-factor for, the generation of the essential amino acid methionine from homocysteine.

This reaction produces tetrahydrofolate, which is converted to thymidine monophosphate for incorporation into DNA. Deficiency of either vitamin B12 or folate will therefore produce high plasma levels of homocysteine and impaired DNA synthesis.


The end result is cells with arrested nuclear maturation but normal cytoplasmic development: so-called nucleo-cytoplasmic asynchrony. All proliferating cells will exhibit megaloblastosis; hence changes are evident in the buccal mucosa, tongue, small intestine, cervix, vagina and uterus. The high proliferation rate of bone marrow results in striking changes in the haematopoietic system in megaloblastic anaemia.

Cells become arrested in development and die within the marrow; this ineffective erythropoiesis results in an expanded hypercellular marrow. The megaloblastic changes are most evident in the early nucleated red cell precursors, and intramedullary haemolysis results in a raised bilirubin and lactate dehydrogenase (LDH) but no reticulocytosis


Iron stores are usually raised. The mature red cells are large and oval, and sometimes contain nuclear remnants. Nuclear changes are seen in the immature granulocyte precursors and a characteristic appearance is that of 'giant' metamyelocytes with a large 'sausage-shaped' nucleus.

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. The main pathological finding is focal demyelination affecting the: spinal cord peripheral nerves optic nerves cerebrum. The most common manifestations are sensory, with peripheral paraesthesiae and ataxia of gait.


CLINICAL FEATURES OF MEGALOBLASTIC ANAEMIA: :Symptoms Malaise (90%) Breathlessness (50%) Paraesthesiae (80%) Sore mouth (20%) Weight loss Altered skin pigmentation Grey hair Impotence Poor memory Depression Personality change Hallucinations Visual disturbance Signs: Smooth tongue Angular cheilosis Vitiligo Skin pigmentation Heart failure Pyrexia

: DIAGNOSTIC FEATURES OF MEGALOBLASTIC ANAEMIA

Result
Investigation
Often reduced, may be very low
Haemoglobin
Usually raised, commonly > 120 fl
MCV
Low for degree of anaemia
Erythrocyte count
Oval macrocytosis, poikilocytosis, red cell fragmentation, neutrophil hypersegmentation
Blood film
Low for degree of anaemia
Reticulocyte count
Low or normal
Leucocyte count
Low or normal
Platelet count
Increased cellularity, megaloblastic changes in erythroid series, giant metamyelocytes, dysplastic megakaryocytes, increased iron in stores, pathological non-ring sideroblasts
Bone marrow
Elevated
Serum ferritin
Elevated, often markedly
Plasma LDH



The increase in cell size can easily be calibrated using the nucleus of a small lymphocyte. A normal red blood cell is usually the same size as the nucleus of a small lymphocyte. Note that most red cells in this picture are larger than the nucleus of a small lymphocyte.

VITAMIN B12 NEUROLOGICAL FINDINGS IN B12 DEFICIENCY Peripheral nerves Glove and stocking paraesthesiae Spinal cord Subacute combined degeneration Posterior columns-diminished vibration and proprioception Corticospinal tracts-upper motor neuron signs Cerebrum Dementia Optic atrophy Autonomic neuropathy

B12 deficiency:The 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

Vitamin B12 absorption: In the stomach, gastric enzymes release vitamin B12 from food and at gastric pH it binds to a carrier protein termed R protein. The 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.


Blood levels of vitamin B12 provide a reasonable indication of tissue stores and are usually diagnostic of deficiency. Levels of cobalamins fall in normal pregnancy. Each laboratory must validate its own normal range but levels below 150 ng/L are common and in the last trimester 5-10% of women have levels below 100 ng/L.

The total amount of vitamin B12 stored in body is about 2–5 mg in adults. Around 50% of this is stored in the liver. Approximately 0.1% of this is lost per day by secretions into the gut, as not all these secretions are reabsorbed.. Causes of vitamin B12 deficiency: 1-Dietary deficiency: strict vegans onset of clinical features can occure at any age between 10 -80 years.


2-Gastric factors: 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.

Total gastrectomy invariably results in vitamin B12 deficiency within 5 years, often combined with iron deficiency; these patients need life-long 3-monthly vitamin B12 injections. After partial gastrectomy vitamin B12 deficiency only develops in 10-20% of patients by 5 years; an annual injection of vitamin B12 should prevent deficiency in this group.


3-Pernicious anaemia: This is an autoimmune disorder in which the gastric mucosa is atrophic with loss of parietal cells causing intrinsic factor deficiency. In the absence of intrinsic factor less than 1% of dietary vitamin B12 is absorbed


incidence of 25/100 000 population over the age of 40 years in developed countries, but an average age of onset of 60 years. 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


Anti-parietal cell antibodies are present in over 90% of cases but are also present in 20% of normal females over the age of 60 years. A negative result makes pernicious anaemia less likely but a positive result is not diagnostic Antibodies to intrinsic factor are found in the serum of 60% of patients with pernicious anaemia and, if present, in the context of vitamin B12 deficiency are diagnostic without Furthrt investigations.


Patients with low B12 levels and negative anti-intrinsic factor antibodies should have a Schilling test performed to determine whether there is B12 malabsorption, and if so, where it is occurring

4- Small bowel factors: a. One-third of all patients with pancreatic insufficiency fail to transfer dietary vitamin B12from R protein to intrinsic factor. This usually results in slightly low vitamin B12 values b. Motility disorders or hypogammaglobulinaemia can result in bacterial overgrowth and the resulting competition for free vitamin B12can result in deficiency. This will be corrected to some extent by a course of antibiotics c. fish tapeworm d. Inflammatory disease of the terminal ileum, such as Crohn's disease, may impair the interaction of the vitamin B12- intrinsic factor complex with its receptor, as will surgery on this part of the bowel. Both may result in vitamin B12 malabsorption.


Management:1. Specific therapy:Related to underlying disorder as antibiotics for intestinal over growth with bacteria.2. Replacement therapy:hydroxycobalamin 1000 μg i.m. in five 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 therapy and may be as high as 50% - The haemoglobin will rise by 10 g/l every week - 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, 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 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. An average Western diet contains more than the minimum daily intake of 50 μg but excess cooking for longer than 15 minutes destroys folates. Folate absorption


Most dietary folate is present as polyglutamates; these are converted to monoglutamate in the upper small bowel and actively transported into plasma. Plasma folate is loosely bound to plasma proteins such as albumin and there is an enterohepatic circulation. Total body stores of folate are small and deficiency can occur in a matter of weeks

CAUSES OF FOLATE DEFICIENCY

Diet
Poor intake of vegetables
Malabsorption
e.g. Coeliac disease
Increased demand
Pregnancy Cell proliferation, e.g. haemolysis
Drugs*
Certain anticonvulsants (e.g. phenytoin) Contraceptive pill Certain cytotoxic drugs (e.g. methotrexate)

Investigations of folic acid deiciency: 1- diagnostic findings -low serum folate level(fasting blood sample) -red cell folate level low 2-corroporative findings -macrocytic dysplastic blood picture. -megaloblastic marrow


Treatment of 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 will prevent megaloblastosis in women at risk.

Folic acid supplementation may reduce the risk of neural tube defects, and in some countries all pregnant women receive routine folic acid supplementation. Prophylactic supplementation is also given in chronic haematological disease associated with reduced red cell lifespan (e.g. autoimmune haemolytic anaemia or haemoglobinopathies).

There is also evidence that supraphysiological supplementation (400 μg/day) can reduce the risk of coronary and cerebrovascular disease by reducing plasma homocysteine levels. This has led the US Food and Drug Administration to introduce fortification of bread, flour and rice with folic acid .



Rarely if sever angina or heart failure if present, transfusion can be used in megaloblastic anaemia. The cardiovascular system is adapted to the chronic anaemia present in megaloblastosis, and the volume load imposed by transfusion may result in decompensation and severe cardiac failure. In such circumstances, exchange transfusion or slow administration of 1 unit each day with diuretic cover