MMA), WHICH IS USEFUL FOR THE DIAGNOSIS OF VITAMIN B12 DEFICIENCY.

-Methylcobalamin is synthesized through reduction and methylation of vitamin B.

This reaction represents the link between folate and vitamin B12 coenzymes and
appears to account for the requirement for both vitamins in normal
erythropoiesis.

IMPAIRED DEOXYRIBONUCLEIC ACID (DNA) metabolism causes systemic effects
by impairing production of all rapidly dividing cells of the body.
the cells of the skin, the epithelium of the gastrointestinal tract, and the
hematopoietic tissues. Because these all must be replenished throughout life, any
impairment of cell production is evident in these tissues first.
-Folate is the general term used for any form of the vitamin folic acid.
-Folic acid is the synthetic form in supplements and fortified food.
-function of folate is to transfer carbon units in the form of methyl groups from
donors to receptors.
FOLATE PLAYS AN IMPORTANT ROLE in the metabolism of amino acids and
nucleotides. Deficiency of the vitamin leads to impaired cell replication and other
metabolic alterations.

-The root cause of megaloblastic anemia is impaired DNA synthesis

-Megaloblastic anemia is one example of a macrocytic anemia

the etiology of megaloblastic anemia requires a review of DNA synthesis with

particular attention to the roles of vitamin B12 (cobalamin) and folic acid (folate).

- Vitamin B12 (cobalamin) is an essential nutrient consisting of a tetrapyrrole

(corrin) ring containing cobalt that is attached to 5,6-dimethylbenzimidazolyl
ribonucleotide.

- Vitamin B12 is a coenzyme in two biochemical reactions in humans

-One is isomerization of methylmalonyl coenzyme A (CoA) to succinyl CoA, which

requires vitamin B12 (in the adenosylcobalamin form - as a cofactor and is
catalyzed by the enzyme methylmalonyl CoA mutase.

-In the absence of vitamin B12, the impaired activity of methylmalonyl CoA
mutase leads to a high level of serum methylmalonic acid.
 - Folate deficiency has the more direct effect, ultimately preventing the
methylation of dUMP.
- effect of vitamin B12 deficiency is more indirect, preventing the production of
THF from 5-methyl THF.

-When vitamin B12 is deficient, progressively more and more of the folate
becomes metabolically trapped as 5-methyl THF.
:called the folate trap as 5-methyl THF accumulates and is unable to supply the
folate cycle with THF.

-either folate or vitamin B12 is deficient, homocysteine accumulates because

methionine synthase is unable to convert it to methionine without vitamin B12
-Folate circulates in the blood predominantly as 5-methyl THF.3 5-Methyl THF is as a cofactor.
metabolically inactive until it is demethylated to tetrahydrofolate (THF),
whereupon folate-dependent reactions may take place.

-Folate has an important role in DNA synthesis.

1. a methyl group is transferred from 5-methyl THF to homocysteine

2. converts it to methionine and generates THF
3. reaction is catalyzed by the enzyme methionine synthase and requires vitamin
B12 in the form of methylcobalamin as a cofactor
4. THF is then converted to 5,10-methylenetetrahydrofolate (5,10-methylene
THF)

Vitamin B12 and folate deficiency are not the only causes of megaloblastic
erythrocytes.

-Dysplastic erythroid cells in myelodysplastic syndrome (MDS) can also have

megaloblastoid features (the macrocytic erythrocytes and their progenitors
- When either folate or vitamin B12 is missing, thymidine nucleotide production
characteristically show delayed cytoplasmic and nuclear maturation)
for DNA synthesis is impaired.
-nuclear-cytoplasmic asynchrony and megaloblastic RBCs may be seen in
congenital dyserythropoietic anemia (CDA) types I and III.
-In CDA I, internuclear chromatin bridging of erythroid cells or binucleated forms
are observed.
-CDA III, giant multinucleated erythroblasts are present. Another rare condition in
which RBC precursors have a megaloblastic appearance is acute erythroid
leukemia, previously classified as FAB M6.
(the cells are macrocytic, and the immature appearance of the nuclear chromatin
is similar to the more open appearance of the chromatin in megaloblasts)
- aberrant finding, erythroid leukemia
REVERSE TRANSCRIPTASE INHIBITORS
-used to treat human immunodeficiency virus (HIV) infections, interfere with DNA
production and may also lead to megaloblastic changes.
-When DNA synthesis and subsequent cell division are im paired by lack of folate
or vitamin B12.
MEGALOBLASTIC ANEMIA: SYMPTOMS
- (fatigue, weakness, and shortness of breath.
GLOSSITIS
-loss of epithelium on the tongue results in a smooth surface and soreness
(glossitis).
GASTRITIS
-Loss of epithelium along the gastrointestinal tract causes nausea, or
constipation.
VITAMIN B12 DEFICIENCY
-neurologic symptoms may be pronounced and may even occur in the absence of
anemia: memory loss, numbness and tingling in toes and fingers, loss of balance,
and further impairment of walking by loss of vibratory sense, especially in the
lower limbs.
NEUROPSYCHIATRIC SYMPTOMS
may also be present, including personality changes and psychosis, symptoms
seem to be the result of demyelinization of the spinal cord and peripheral nerves,
but the relationship of this demyelinization to vitamin B12 deficiency is unclear.
-Folate levels appear to influence the effectiveness of treatments for depression.
FOLATE DEFICIENCY DURING PREGNANCY
can result in impaired formation of the fetal nervous system, resulting in neural
tube defects such as spina bifida, even the fetus accumulates folate at the
expense of the mother. Pregnancy requires a considerable increase in folate to
fulfill the requirements related to rapid fetal growth, uterine expansion, placental
maturation, and expanded blood volume.
(Insuring adequate folate levels in women of childbearing age is particularly
important)
IMPAIRED ABSORPTION
- Food folates must be hydrolyzed in the gut before absorption in the small
intestine: only 50% of what is ingested is available for absorption.
RARE AUTOSOMAL RECESSIVE DEFICIENCY OF A FOLATE TRANSPORTER
PROTEIN (PCFT)
-severely decreases intestinal absorption of folate.
most folate is transported in the plasma as 5-methyl THF.

(Folate absorption may also be impaired by intestinal disease, especially sprue
and celiac disease)
- Sprue is characterized by weakness, weight loss, and steatorrhea (fat in the
feces).
CELIAC DISEASE (nontropical sprue) has been traced to intolerance of the gluten
in some grains, (gluten-induced enteropathy) and can be controlled by
eliminating wheat, barley, and rye products from the diet.
BOWEL DISEASE - can also decrease folate absorption.
IMPAIRED USE OF FOLATE
-Numerous drugs impair folate metabolism: Anti-epileptic drug
resulting macrocytosis with frank megaloblastic anemia.
-folate deficiency results in inhibition of cell replication, several anticancer drugs,
including methotrexate, are folate inhibitors.
EXCESSIVE LOSS OF FOLATE
- Physiologic loss of folate occurs through the kidney, Patients undergoing renal
dialysis lose folate in the dialysate, however; thus supplemental folic acid is
routinely provided to these individuals to prevent megaloblastic anemia.
- Folate is synthesized by microorganisms and higher plants.
- Folate is ubiquitous in foods, but a generally poor diet can result in deficiency.
SOURCES OF FOLATE
- include leafy green vegetables, dried beans, liver, beef, fortified breakfast
cereals, and some fruits, especially oranges:
FOLATES ARE HEAT LABILE
-overcooking of foods can diminish their nutritional value.
INCREASED NEED
Increased need for folate occurs during pregnancy and lactation when the mother
must supply her own needs plus those of the fetus or infant. Infants and children
also have increased need for folate during growth.
- The best dietary sources are animal products such as liver, dairy products, fish,
shellfish, and eggs.
- vitamin B12 is not destroyed by cooking
this condition is possible for strict vegetarians (vegans)
INCREASED NEED
Increased need for vitamin B12 occurs during pregnancy, lactation, and growth.
Due to the vigorous cell replication.
IMPAIRED ABSORPTION
Vitamin B12 in food is released from food proteins primarily in the acid
environment of the stomach, aided by pepsin, and is subsequently bound by a
specific salivary protein, haptocorrin, also known as R protein or transcobalamin,
small intestine.
-vitamin B12 is released from haptocorrin by the action of pancreatic proteases.
-CUBILIN-AMNIONLESS COMPLEX
collectively known as cubam, which binds the vitamin B12–intrinsic factor
complex, and megalin, a membrane transport protein.
- the enterocyte, the vitamin B12 is then freed from intrin sic factor and bound to
transcobalamin (previously called transcobalamin II) and released into the
circulation.
VITAMIN B12–TRANSCOBALAMIN COMPLEX, termed holotranscobalamin
(holoTC), is the metabolically active form of vitamin B12.
HOLOTRANSCOBALAMIN binds to specific receptors on the surfaces of many
different types of cells and enters the cells by endocytosis, with subsequent
release of vitamin B12 from the carrier.
the absorption of vitamin B12 can be impaired by (1) failure to separate vitamin
B12 from food proteins in the stomach, (2) failure to separate vitamin B12 from
haptocorrin in the intestine, (3) lack of intrinsic factor, (4) malabsorption, and (5)
competition for available vitamin B12.
FAILURE TO SEPARATE VITAMIN B12 FROM FOOD PROTEINS
condition known as food-cobalamin malabsorption is characterized by
hypochlorhydria and the resulting inability of the body to release vitamin B12
from food or intestinal transport proteins.
Food-cobalamin malabsorption is caused primarily by atrophic gastritis or
atrophy of the stomach lining.
HISTAMINE 2 RECEPTOR BLOCKERS and PROTON PUMP INHIBITORS LOWER
GASTRIC ACIDITY, the long-term use of these drugs for the treatment of ulcers
and gastroesophageal reflux disease, and gastric bypass surgery also induce food-
cobalamin malabsorption.
FAILURE TO SEPARATE VITAMIN B12 FROM HAPTOCORRIN
Lack of gastric acidity or lack of trypsin as a result of chronic pancreatic disease
can prevent vitamin B12 absorption.
-vitamin remains bound to haptocorrin in the intestine
LACK OF INTRINSIC FACTOR
-significant cause of impaired vitamin B12 absorption.
-most commonly due to autoimmune disease.
PERNICIOUS ANEMIA, but can also result from the loss of parietal cells with
Helicobacter pylori infection (partial gastrectomy, or hereditary intrinsic factor
deficiency).
PERNICIOUS ANEMIA
Pernicious anemia is an autoimmune disorder characterized by impaired
absorption of vitamin B12 due to a lack of intrinsic factor.
-Patients with pernicious anemia have an increased risk of developing gastric
tumors.
pernicious anemia, autoimmune lymphocyte-mediated destruction of gastric
parietal cells severely reduces the amount of intrinsic factor secreted in the
stomach.
Pathologic CD4 T cells
inappropriately recognize and initiate an autoimmune response against the
H1/K1–adenosine triphosphatase embedded in the membrane of the parietal
cells.
-Chronic inflammatory infiltration, progressive development of atrophic gastritis
resulting in the loss of the parietal cells with their secretory products, H1 and
intrinsic factor. The loss of H1 production in the stomach constitutes achlorhydria.
LOW GASTRIC ACIDITY
-was previously an important diagnostic criterion for pernicious anemia.
SERUM GASTRIN LEVELS
-can be markedly elevated due to the gastric achlorhydria.
SCHILLING TEST
used to detect the absence of intrinsic factor.
OTHER CAUSES OF LACK OF INTRINSIC FACTOR:
- lack of intrinsic factor may also be related to H. pylori infection. Left untreated,
colonization of the gastric mucosa with H. pylori progresses until the parietal cells
are entirely destroyed: resulting to removal of intrinsic factor–producing parietal
cells, invariably leads to vitamin B12 deficiency.
Impaired absorption of vitamin B12 can also be caused by hereditary intrinsic
factor deficiency:

MALABSORPTION
malabsorption of vitamin B12 can be caused by the same conditions interfering
with folate absorption, such as celiac disease, tropical sprue, and inflammatory
bowel disease.

INHERITED ERRORS OF VITAMIN B12 ABSORPTION AND TRANSPORT

- Imerslund-Gräsbeck syndrome is a rare autosomal recessive condition caused
by mutations in the genes for either cubilin or amnionless: results in decreased
endocytosis of the intrinsic factor–vitamin B12 complex by ileal enterocytes.

Transcobalamin deficiency is another rare autosomal recessive condition leads to

vitamin b12 deficiency.

COMPETITION FOR VITAMIN B12

-Competition for available vitamin B12 in the intestine.
The FISH TAPEWORM DIPHYLLOBOTHRIUM LATUM is able to split vitamin B12
from intrinsic factor.
- Rendering the vitamin unavailable for host absorption.
become overgrown with intestinal bacteria that compete effectively with the host
for available vitamin B12: RESULTING OF - host is unable to absorb sufficient
vitamin B12, and megaloblastic anemia results.