By Dr : Ramy Ahmed Samy Blood consists of ■ red cells ■ white cells ■ platelets ■ plasma, in...
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- By Dr : Ramy Ahmed Samy
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- Blood consists of red cells white cells platelets plasma, in
which the above elements are suspended
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- Plasma is the liquid component of blood, which contains soluble
fibrinogen. Serum is what remains after the formation of the fibrin
clot.
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- The haemopoietic system includes : the bone marrow, liver,
spleen, lymph nodes and thymus. The turnover of cells is
enormous
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- Haemopoietic growth factors are glycoproteins which regulate
the differentiation and proliferation of haemopoietic progenitor
cells and the function of mature blood cells. They act on receptors
expressed on haemopoietic cells at various stages of development to
maintain the haemopoietic progenitor cells and to stimulate
increased production of one or more cell lines in response to
stresses such as blood loss and infection.
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- the MCV is elevated (>100 fL), the nucleus and cytoplasm
mature at different rates, giving rise to cells with large,
immature appearing nuclei and a normal cytoplasm. This is referred
to as nuclear-cytoplasmic asynchrony.
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- There are numerous causes of megaloblastic anemia, but by far
the most common are folate deficiency, cobalamin (vitamin B12)
deficiency, and certain drugs.
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- For normal adults, the daily requirement of folate is 50 g.
Foods rich in folate include green vegetables and fruits. The
average daily American diet contains 400 to 600 g of folate.
Because some of the dietary folate may not be readily absorbed, the
recommended daily allowance of folate is 0.4 mg. The total folate
content in the average adult is approximately 5 mg. Therefore, when
folate intake is deficient, megaloblastic anemia develops over a
period of many months (>4 months). Folate requirements are
increased when cell turnover or cell synthetic rates rise eg,
hemolytic anemias, alcoholism, pregnancy, and lactation (6-fold
increase). Folate is absorbed mostly in the proximal jejunum,
therefore, clinical conditions that induce injury at this site may
impair folate absorption (sprue).
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- Cobalamin is a required cofactor for the enzymes involved in
producing bioactive folate. Therefore,it is believed that cobalamin
deficiency leads to megaloblastic anemia by engendering a
deficiency of usable folate (the methylfolate trap
hypothesis).
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- The dietary sources of cobalamin include meat, liver, seafood,
and dairy products. Individuals not consuming these products must
receive a cobalamin supplement to prevent deficiency. The average
Western diet contains up to 30 g of cobalamin per day, but only
between 1 to 5 g is absorbed. The average adults total body
cobalamin content is 2 to 5 mg. Because the average daily losses of
cobalamin amount to less than 0.1% of the body pool, it may take
years to develop cobalamin deficiency even with complete
abstinence. The recommended daily allowance of cobalamin for adults
is 5 g.
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- The absorption of cobalamin requires intrinsic factor, a
glycoprotein synthesized and secreted by the parietal cells of the
stomach. Additionally, gastric secretions contain R proteins, which
bind cobalamin. Cobalamin in the diet is released via digestive
enzymes in the stomach. Once free, the cobalamin is bound by R
proteins in the stomach, and the cobalamin-R complexes are then
degraded by pancreatic enzymes in the duodenum. The free cobalamin
is then bound by intrinsic factor, and the intrinsic
factor-cobalamin complex interacts with the intrinsic factor
receptor, cubilin, and is subsequently absorbed. The terminal ileum
has the highest density of cubilin.
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- The symptoms of megaloblastic anemia parallel those of anemia
in general: weakness, fatigue, dyspnea, and light-headedness.
Pallor and jaundice combine to produce the classic lemon-yellow
skin of megaloblastic anemia. Additionally, patients may develop a
beefy,red smooth tongue, weight loss, thrombocytopenia, and
neutropenia. Classically, the neutrophils have hypersegmented
nuclei (>5 lobes).
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- In addition to the general features listed above, cobalamin
deficiency can produce a neurologic syndrome that may precede the
development of megaloblastic anemia. Importantly, the neurological
manifestations require immediate treatment to prevent irreversible
deficits. The initial symptoms are usually characterized by
paresthesias of the fingers and feet along with a decrease in
proprioception and vibratory sense. If left untreated, the syndrome
can progress to spastic ataxia. The syndrome is caused by
demyelination of the dorsal and lateral columns of the spinal cord.
Dementia mimicking Alzheimer disease may also develop.
Megaloblastic madness describes patients with cobalamin deficiency
who develop psychosis.
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- Serum B12 levels are almost always low. In borderline cases,
serum methylmalonic acid and homocysteine levels can be measured;
both are elevated in B12 deficiency. Once the diagnosis is
established, the underlying cause must be determined. Antiintrinsic
factor and antiparietal cell antibodies should be quantitated to
establish the diagnosis of pernicious anemia. Upper endoscopy may
reveal an intestinal cause (malabsorption). The three-part Shilling
test is largely of historical significance and is rarely used
today.
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- Treatment consists of vitamin B12 1000 g intramuscularly daily
for 7 days, then weekly for 1 month, then monthly for life unless
the underlying etiology is correctable. B12 administration produces
a reticulocytosis within 5 to 7 days, followed by resolution of
hematologic abnormalities in 2 to 3 months. The neurologic symptoms
may not resolve, particularly if they have been present for a
significant period of time.
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- Unlike cobalamin, there are no neurological abnormalities
associated with folate deficiency. However, administration of
folate to a cobalamin-deficient patient can correct the anemia but
will have no effect on the neurologic features. Therefore, it is
imperative to distinguish B12 deficiency from folate
deficiency.
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- Both serum and RBC folate levels should be measured. The serum
folate reflects recent folate intake (preceding few days) and,
therefore can be falsely normal after a single folate-rich meal.
The RBC folate levels, which reflect folate turnover during the
preceding 2 to 3 months, are a better indicator of tissue
stores.
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- Folate deficiency is treated with oral folate 1 mg/day. To
prevent a relapse, treatment should be continued for at least 2
years.
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- Pernicious anaemia (PA) is an autoimmune disorder in which
there is atrophic gastritis with loss of parietal cells in the
gastric mucosa with consequent failure of intrinsic factor
production and vitamin B12 malabsorption.
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- This disease is common in the elderly, with 1 in 8000 ofA the
population aged over 60 years being affected in the UK. It can be
seen in all races, but occurs more frequently in fair-haired and
blue-eyed individuals, and those who have the blood group A. It is
more common in females than males.
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- There is an association with other autoimmune diseases,
particularly thyroid disease, Addison's disease and vitiligo.
Approximately one-half of all patients with PA have thyroid
antibodies. There is a higher incidence of gastric carcinoma with
PA than in the general population; the incidence in PA is
1-3%.
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- Parietal cell antibodies are present in the serum in 90% of
patients with PA- and also in many older patients with gastric
atrophy. Conversely, intrinsic factor antibodies, although found in
only 50% of patients with PA, are specific for this diagnosis. Two
types of intrinsic factor antibodies are found: a blocking
antibody, which inhibits binding of intrinsic factor to B12, and a
precipitating antibody, which inhibits the binding of the
B12-intrinsic factor complex to its receptor site in the
ileum.
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- B12 deficiency may rarely occur in children from a congenital
deficiency or abnormality of intrinsic factor, or as a result of
early onset of the adult autoimmune type.
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- Autoimmune gastritis affecting the fundus is present with
plasma cell and lymphoid infiltration. The parietal and chief cells
are replaced by mucin-secreting cells. There is achlorhydria and
absent secretion of intrinsic factor. The histological abnormality
can be improved by corticosteroid therapy, which supports an
autoimmune basis for the disease.
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- The onset of PA is insidious, with progressively increasing
symptoms of anaemia. Patients are sometimes said to have a
lemon-yellow colour owing to a combination of pallor and mild
jaundice caused by excess breakdown of haemoglobin. A red sore
tongue (glossitis) and angular stomatitis are sometimes
present.
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- Bone marrow shows the typical features of megaloblastic
erythropoiesis (Fig. 8.10), although it is frequently not performed
in cases of straightforward macrocytic anaemia and a low serum
vitamin B12. Serum bilirubin may be raised as a result of
ineffective erythropoiesis. Normally a minor fraction of serum
bilirubin results from premature breakdown of newly formed red
cells in the bone marrow. In many megaloblastic anaemias, where the
destruction of developing red cells is much increased, the serum
bilirubin can be increased. Serum vitamin B12 is usually well below
160 ng/L, which is the lower end of the normal range. Serum vitamin
B12 can be assayed using radioisotope dilution or immunological
assays. Serum folate level is normal or high, and the red cell
folate is normal or reduced owing to inhibition of normal folate
synthesis.
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- Schilling test. Radioactive B12 is given orally followed by an
i.m. injection of non-radioactive B12 to saturate B12 binding
proteins and to flush out 58Co-B12. The urine is collected for 24
hours and > 10% of the oral dose would be excreted in a normal
person. If this is abnormal, the test is repeated with the addition
of oral intrinsic factor capsules. If the excretion is now normal,
the diagnosis is pernicious anaemia or gastrectomy. If the
excretion is still abnormal, the lesion must be in the terminal
ileum or there may be bacterial overgrowth. The latter could be
confirmed by repeating the test after a course of antibiotics.
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- Gastrointestinal investigations In PA there is achlorhydria.
Intubation studies can be performed to confirm this but are rarely
carried out in routine practice. Endoscopy or barium meal
examination of the stomach is performed only if gastric symptoms
are present.
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