Page 44 - Color Atlas Of Pathophysiology (S Silbernagl Et Al, Thieme 2000)

Megaloblastic Anemia Due to Abnormalities in DNA Synthesis
Some acquired forms of anemia are due to ab- ! Increased requirement (pregnancy);
normalities in the absorption or metabolism of ! Malabsorption, for example, in diseases of
folate or cobalamine (vit. B 12 ) (→ A). The result the small intestine, or inhibition of the folate
is that DNA synthesis is inhibited and the cell carrier caused by methotrexate (→ A1);
cycle is slowed down during erythropoiesis. ! Cobalamine deficiency (→ A4);
However, hemoglobin synthesis in the cyto- ! Inhibition of thymidylate synthase by the
plasm continues unchanged so that the eryth- fluorouracil metabolite fluordeoxyuridylate;
roblasts increase in size (megaloblasts) and ! Inhibition of dihydrofolate reductase by ami-
over-large, oval erythrocytes pass into the nopterin or methotrexate, whose affinity for
blood (megalocytes: MCV > 100 fL). The forma- the enzyme is 100 times that of the natural
tion of granulocytes and megakaryocytes is substrate 7,8-dihydrofolate (→ A3).
also disturbed. In addition to the delay in pro- As inhibition of folate metabolism also re-
liferation, the anemia is aggravated by the pre- tards tumor growth, the drugs fluorouracil,
mature destruction of megaloblasts in bone methotrexate, and aminopterin are used as cy-
marrow (increased inefficient erythropoiesis; tostatic chemotherapeutics. Their side effect on
→ p. 38) as well as by the shortened life-span erythropoiesis is usually undesirable and
of the megalocytes that have passed into the therefore often limits their dosage.
blood (premature hemolysis). ! Cobalamine (vitamin B 12 ) must be taken up
Blood lene-tetrahydrofolate is necessary for the by humans in their food (daily requirement:
Folate. The folate metabolite N , N -methy-
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10
3–5 µg). About a thousand times this amount
3 synthesis of deoxythymidylate (→ A3), the is stored in the liver. Bound to different pro-
only source of thymine, which is in turn neces- teins, it is transported inside the organism
sary for DNA synthesis. Thus, a folate deficien- from food to the site of its action where, in the
cy inhibits DNA synthesis. This particularly af- form of methylcobalamine, it serves as coen-
fects the rate of formation of rapidly proliferat- zyme in demethylating N -methyltetrahydro-
5
ing cells, for example, during erythropoiesis folate (→ A2). Among possible causes of cobal-
and tumor formation. The folate requirement amine deficiency are (→ A4):
for two to four months is stored in the liver. Fo- ! Too little uptake with food (e.g., a strict veg-
late is largely present in food in the form of etarian diet);
pteroylpolyglutamate, from which excess glu- ! Intrinsic factor (IF) deficiency (in atrophic
tamate residues must be split off before it can gastritis etc.; see p.142): IF is essential for the
be absorbed in the form of pteroylmonogluta- binding and absorption of cobalamine. It is
5
mate in the upper small intestine (→ A1). N - freed from its binding to salivary proteins in
methyltetrahydrofolate, the substrate for tet- the lumen of the small intestine;
rahydrofolate formation (→ A2), is then ! Competition for cobalamine and splitting of
formed in the intestinal mucosa. Methyl-co- IF from bacteria (blind-loop syndrome;
balamine is essential for this step (see below). → p.148), or broad fish tapeworms in the in-
N ,N -methyltetrahydrofolate is formed from testinal lumen;
10
5
tetrahydrofolate, the former together with ! Absence (congenital, after resection) or in-
deoxyuridylate being metabolized through flammation of the terminal ileum, i.e., at the
the action of thymidylate synthase to deoxy- site of absorption of cobalamine (→ p.152f.);
thymidylate and 7,8-dihydrofolate. Finally, the ! Defective transcobalamine II (TCII), which is
used up tetrahydrofolate is regenerated from responsible for cobalamine transport in plas-
7,8-dihydrofolate (→ A3). ma and for its uptake into cells.
The following disorders of folate absorption Because of the great store of cobalamine in
or metabolism impair DNA synthesis, and thus the liver, the symptoms of cobalamine defi-
erythropoiesis: ciency (pernicious anemia, neurological ab-
! Too little folate uptake with food (< 50 µg/d; normalities) occur only after years of blocked
34 overcooking food destroys folate); supply.
Silbernagl/Lang, Color Atlas of Pathophysiology © 2000 Thieme
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