42 Folate, Cobalamin and Megaloblastic Anemias Flashcards
To form a functional compound, folates must be in the reduced ____________________ form
Tetrahydrofolate form (FH4)
Enzyme that catalyzes both FA→FH2 and FH2→FH4
Dihydrofolate reductase
Stable form of folic acid and the form preferred for clinical use
N5-formyl FH4, also called citrovorum factor, leucovorin, or folinic acid
The richest sources of folic acid are
Dark green leafy vegetables
Others:
* fruit sources are oranges, lemons, bananas, strawberries, and melons
* liver, kidney, yeast, mushrooms, and peanuts
Meat, with the exception of_______, is generally not a good source of folate.
Liver
In the normal adult, the recommended daily allowance (RDA) for folate is expressed as
Dietary folate equivalents (DFEs)
One microgram of food folate is the dietary equivalent of_____mcg folic acid added to food
0.6 mcg folic acid
The officially recommended dietary allowance of food folate expressed as DFEs for an adult is ___ mg
0.4 mg
The body is thought to contain approximately _____ of folate.
5 mg
When folate intake is reduced to _____ mcg/day, megaloblastic anemia develops in approximately 4 months.
5 mcg/day
Folate requirements in pregnanancy
600 mcg/day
Folate requirements in lactating women
500 mcg/day
Conditions where folic acid requirements increase
- Hemolytic anemia
- Leukemia and other malignant diseases
- Alcoholism
- During growth
- Pregnancy and during lactation
Among the several 1-carbon transfers mediated by folic acid, the transfer that is the most important clinically is the
Methylation of deoxyuridylate to thymidylate
This reaction is an essential step in the synthesis of DNA
The methylation of deoxyuridylate to thymidylate is catalyzed by the enzyme
Thymidylate synthase
Mono or Poly
Intracellular folates exist primarily as _________________
Polyglutamate conjugates
Inside the cells, the polyglutamate chain is sequentially built up by an ATP-dependent
Folylpoly-γ-glutamyl synthase
Folylmonoglutamate appears in plasma
TRUE OR FALSE
Folylpolyglutamates are superior to monoglutamates as substrates for folate-dependent enzyme reactions.
TRUE
Folylpolyglutamates are superior to monoglutamates as substrates for folate-dependent enzyme reactions.
The principal sites of folate absorption
Duodenum and proximal jejunum
Because only folylmonoglutamate appears in plasma, all folylpolyglutamates must first be hydrolyzed by the enzyme _________ during absorption across the intestine.
Glutamate carboxypeptidase II (folate hydrolase)
Lysosomal carboxypeptidases that are not involved in absorption of folates from the intestine, but which play a role in the release of folate from storage sites in the liver and kidney
γ-glutamyl hydrolases
Folate receptors that despite its missing cytoplasmic extension, is effective in mediating endocytosis
Folate receptor-α
A probenecid-inhibitable organic anion carrier that, among other functions, carries reduced folates and methotrexate in and out of the cytoplasm
Membrane folate transporter
The principal form of the folate in tissues and in blood
N5-methyl form
Breakdown product of folic acid metabolism
p-Aminobenzoylglutamate
Folate-binding proteins of serum and milk can be detected in approximately ___% of normal individuals
15%
Found at increased levels in some pregnant women, women taking oral contraceptives, folate-deficient alcoholics (but not patients with cobalamin deficiency), and patients with uremia, hepatic cirrhosis, and chronic myelogenous leukemia
Folate bound to the milk folate binder in suckling animals is absorbed chiefly in the_______, rather than the jejunum, the principal site of absorption of free folate.
Ileum
- The milk folate binder, a glycoprotein, also promotes folate transport into the liver via the asialoglycoprotein receptor.
- The milk folate binder is speculated to protect an infant’s folate supply by preventing bacteria from sequestering the vitamin away from the intestinal absorptive surface
Primary or secondary
The folate-binding protein in granulocytes has been localized to the _________ granules, from which it is released when the granulocytes are stimulated and may serve a bacteriostatic effect.
Secondary granules
The cobalamin molecule has a porphyrin-like near-planar macrocycle known as_______
Corrin
The usual therapeutic form of cobalamin
Cyanocobalamin
Four cobalamins are important in animal cell metabolism
- Cyanocobalamin (CnCbl; vitamin B12)
- Hydroxocobalamin (OHCbl) or aquocobalamin (HOHCbl)
- Adenosylcobalamin (AdoCbl)
- Methylcobalamin (MeCbl)
The latter 2 cobalamins are alkyl derivatives that are synthesized from OHCbl and serve as coenzymes.
2 cobalamins are alkyl derivatives that are synthesized from OHCbl and serve as coenzymes
Adenosylcobalamin (AdoCbl)
Methylcobalamin (MeCbl)
The major form of cobalamin in human blood plasma
MeCbl
TRUE OR FALSE
Cobalamin is known to be synthesized in plants and its presence in foods of plant origin are believed to have come from microbial contamination or through a symbiotic relationship with bacteria.
FALSE
Cobalamin is not known to be synthesized in plants and its presence in foods of plant origin are believed to have come from microbial contamination or through a symbiotic relationship with bacteria.
Foods that contain cobalamin are of animal origin: meat, liver, seafood, and dairy products
Total body content of cobalamin
2–5 mg
Amount of cobalamin found in liver
1 mg
The kidneys also are rich in cobalamin
TRUE OR FALSE
Relative to the daily requirement, body reserves of cobalamin are much larger than those of folate.
TRUE
Relative to the daily requirement, body reserves of cobalamin are much larger than those of folate.
- Daily rate of obligatory loss of approximately 0.1% of the total-body pool, irrespective of the pool size
- For this reason, a deficiency state does not develop for several years after cessation of cobalamin intake.
The official RDA for cobalamin among adults
2.4 mcg
A mitochondrial enzyme that participates in the disposal of the propionate formed during the breakdown of valine, isoleucine, and odd-carbon fatty acids
Methylmalonyl Coenzyme A Mutase
Participates in cobalamin-dependent synthesis of methionine from homocysteine
Also serves as a mechanism critical for converting N5-methyltetrahydrofolate to tetrahydrofolate required for synthesis of polyglutamates as well as other important 1-carbon adducts of folate
N5-Methyltetrahydrofolate-Homocysteine Methyltransferase
TRUE OR FALSE
Because cobalamin has the capacity to bind cyanide, it may participate in detoxification of cyanide.
TRUE
Because cobalamin has the capacity to bind cyanide, it may participate in detoxification of cyanide.
TRUE OR FALSE
The megaloblastic anemia of cobalamin deficiency also is variably corrected by folic acid supplementation even if no cobalamin is given, although the remission is partial and only temporary.
TRUE
The megaloblastic anemia of cobalamin deficiency also is variably corrected by folic acid supplementation even if no cobalamin is given, although the remission is partial and only temporary.
TRUE OR FALSE
The anemia of folate deficiency is generally helped by cobalamin
FALSE
The anemia of folate deficiency is generally not helped at all by cobalamin
Two explanations have been proposed to account for the folate responsiveness of cobalamin-deficient megaloblastic anemia:
- Methylfolate Trap Hypothesis
- Formate Starvation Hypothesis
Hypothesis based on the fact that the folate-requiring enzyme N5-methyl FH4–homocysteine methyltransferase is also dependent on cobalamin
Hypothesis predicts that in cobalamin deficiency tissue levels of N5-methyl FH4 are abnormally high and those of other forms of folate are abnormally low
Methylfolate Trap Hypothesis
This theory is based on the diminished capacity of cobalamin-deficient lymphoblasts to incorporate formaldehyde into purine and methionine and on experiments showing that N5-formyl FH4 is more effective than FH4 at correcting some of the abnormalities in folate metabolism seen in cobalamin deficiency.
Formate Starvation Hypothesis
Human intrinsic factor is a glycoprotein (Mr approximately 44,000) encoded by a gene on _________________
Chromosome 11
Promotes absorption uptake of cobalamin by ileum
Source: Gastric parietal cells of the cardiac and fundic mucosa
Intrinsic factor
Secretion of intrinsic factor usually parallels that of hydrochloric acid (HCl).
Gastric juice also contains other cobalamin-binding glycoproteins
Belong to the same family of isoproteins as the plasma haptocorrin (HC) binder
Also produced by the salivary gland
R proteins
Cobalamin binds much more tightly to HC than to intrinsic factor at the acid pH of the stomach.
Promotes uptake of cobalamin by cells
Source: Probably all cells
Transcobalamin
Helps dispose of cobalamin analogues; possible antimicrobial function(?)
Source: Exocrine glands, phagocytes
Haptocorrin
(previously known as R proteins or TC I and TC III)
TRUE OR FALSE
Cobalamin binds much more tightly to HC than to intrinsic factor at the acid pH of the stomach
TRUE
Cobalamin binds much more tightly to HC than to intrinsic factor at the acid pH of the stomach
The intrinsic factor receptor, located in the microvillus pits of the ileal mucosa brush border
Cubilin
The ileal cubilin receptor complex consists of 2 proteins:
Cubilin (CUB) and amnionless (AMN)
“CUBAM complex”
In the portal blood, the cobalamin is complexed with a cobalamin-transporting protein known as
Transcobalamin (TC) previously known as transcobalamin II
The protein with which cobalamin given parenterally associates almost immediately
Mediates the transport of cobalamin into the tissues.
Transcobalamin (TC)
Transcobalamin receptor is designated as ____; it belongs to the low-density lipoprotein receptor family and its internalization involves megalin
CD320
Bind cobalamin but lack intrinsic factor activity, that is, they are unable to promote the intestinal absorption of the vitamin
Carries most (70–90%) of the circulating cobalamin
Haptocorrin
(previously known as R proteins or TC I and TC III)
- Found in milk, plasma, saliva, gastric juice, and numerous other body fluid
- Encoded by a gene on chromosome 11
- Clearance from the plasma is very slow (terminal half-life: 9–10 days)
- Binds its ligands more tightly and less restrictive than IF and TC
- Helps clear the system of nonphysiologic cobalamin analogues
Current assays use ______________ as the binder and give more reliable values for serum cobalamin.
Intrinsic factor
Shows some evidence of improved specificity compared with the standard cobalamin assay for identifying true cobalamin deficiency, although the assays appear to be generally comparable with respect to sensitivity.
Holotranscobalamin
Conditions with Increased haptocorrin (transcobalamin I, R protein)
- Myeloproliferative disorders
- Polycythemia vera
- Myelofibrosis
- Benign neutrophilia
- Chronic myelocytic leukemia
- Hepatoma (occasionally)
- Metastatic cancer
Conditions with Increased transcobalamin
- Liver disease
- Inflammatory disorders
- Gaucher disease
Morphologic hallmark of megaloblastic anemias
Presence of megaloblastic cells
Cell with a large horseshoe-shaped nucleus, sometimes irregularly shaped, containing ragged open chromatin
Giant metamyelocyte
The most common causes worldwide of megaloblastic anemia
Folate deficiency and cobalamin deficiency
TRUE OR FALSE
Megaloblastic cells have much more cytoplasm and RNA than do their normal counterparts, but they have a relatively normal amount of DNA, suggesting that cytoplasmic constituents (RNA and protein) are synthesized faster than is DNA.
TRUE
Megaloblastic cells have much more cytoplasm and RNA than do their normal counterparts, but they have a relatively normal amount of DNA, suggesting that cytoplasmic constituents (RNA and protein) are synthesized faster than is DNA.
Megaloblstic Anemia
The anemia is usually macrocytic (mean corpuscular volume [MCV] is ___________ fL or more)
Mean corpuscular volume [MCV] is 100–150 fL or more
Although coexisting iron deficiency, thalassemia trait, or inflammation can prevent macrocytosis.
The earliest observable change in red cell indices in megaloblastic anemia is
Increase in the red cell distribution width
Platelets are often reduced in number and slightly smaller than normal with a wider variation in size (increased platelet distribution width).
Typically, more than _________% of the neutrophils have 5 lobes
more than 5%
TRUE OR FALSE
Neutrophil hypersegmentation was found to be a sensitive test for mild cobalamin deficiency
FALSE
Neutrophil hypersegmentation was not found to be a sensitive test for mild cobalamin deficiency
In folate deficiency, hypersegmented neutrophils are an early sign of megaloblastosis and persist in the blood for many days after treatment
Specific therapy corrects these abnormalities, usually within _____ days, although some abnormalities do not disappear for months.
2 days
Megaloblastic Anemia
Plasma bilirubin, iron, and ferritin levels are (increased or decreased).
Increased
TRUE OR FALSE
In megaloblastic anemia LDH-1 is greater than LDH-2, whereas in other anemias LDH-2 is greater than LDH-1.
TRUE
In megaloblastic anemia LDH-1 is greater than LDH-2, whereas in other anemias LDH-2 is greater than LDH-1.
Megaloblastic anemia is associated with two pathophysiologic abnormalities:
Ineffective erythropoiesis (exaggerated apoptosis of precursor cells) and hemolysis
Folate deficiency is caused by:
- (a) dietary deficiency
- (b) impaired absorption
- (c) increased requirements or losses
Related to ingestion of wheat gluten
Findings include weight loss; glossitis; other signs of a generalized vitamin deficiency; diarrhea; and passage of light-colored, bulky stools with a particularly foul odor caused by steatorrhea.
Nontropical sprue (celiac disease in children)
TRUE OR FALSE
Clinically and pathologically, tropical sprue is like nontropical sprue, except that tropical sprue is more severe in the distal small intestine.
TRUE
Clinically and pathologically, tropical sprue is like nontropical sprue, except that tropical sprue is more severe in the distal small intestine.
Tropical sprue is rapidly corrected by folate therapy, even though folate deficiency is not the primary cause of the disease.
During pregnancy folate requirements increase ________-fold because of transfer of folate to the growing fetus, which draws down maternal folate stores.
5- to 10-fold
The major cause of the megaloblastic anemia of pregnancy
Folate deficiency
Specific features of folate deficiency:
- (a) a history and laboratory studies indicating folate deficiency
- (b) absence of the neurologic signs of cobalamin deficiency
- (c) a full response to physiologic doses of folate
The earliest specific indicator of folate deficiency
Low serum or plasma folate
A better indicator of the tissue folate status
Reflects folate status over the preceding 2–3 months
Red cell folate
Red cell folate cannot be used to distinguish between folate and cobalamin deficiencies.
Because red cell folate also is low in more than 50% of patients with cobalamin-deficient megaloblastic anemia owing to impaired synthesis of polyglutamates and the poor retention of methyl THF monoglutamate within the cells
In folate deficiency, uncomplicated by causes of microcytosis, the MCV is usually higher than ______ fL.
110 fL
TRUE OR FALSE
A full hematologic response to physiologic doses of folate (ie, 200 mcg daily) distinguishes folate deficiency from cobalamin deficiency, in which a response occurs only at pharmacologic doses of folate (typically 5 mg daily or more).
TRUE
A full hematologic response to physiologic doses of folate (ie, 200 mcg daily) distinguishes folate deficiency from cobalamin deficiency, in which a response occurs only at pharmacologic doses of folate (typically 5 mg daily or more).
Higher folate pag cobalamin deficiency. wa epek cobalamin sa folate def
This is not recommended as a diagnostic test because neurologic problems may develop in cobalamin-deficient patients treated with folate alone.
The diagnosis of nontropical sprue rests on
- (a) the demonstration of malabsorption
- (b) a jejunal biopsy showing villus atrophy
- (c) the response to a gluten-free diet
Consumption of _________ can not only cause folate deficiency with resulting megaloblastic anemia but also can cause vitamin B6 deficiency and present as a combined clinicopathologic picture of megaloblastic and sideroblastic anemia.
Goat’s milk
A close association exists between mild folate deficiency and congenital anomalies of the fetus, most notably________________, but also abnormalities involving the heart, urinary tract, limbs, and other sites
Defects in neural tube closure
A portion of the neural tube closure defects are associated with antibodies against folate receptors that may be overcome by higher folate intake
TRUE OR FALSE
A mildly decreased homocysteine level is a major independent risk factor for atherosclerosis and venous thrombosis, possibly because of an effect on the vascular endothelium.
TRUE
A mildly elevated homocysteine level is a major independent risk factor for atherosclerosis and venous thrombosis, possibly because of an effect on the vascular endothelium.
A large study of nurses in the United States indicated that supplementation with more than 400 mcg of folic acid per day reduces the incidence of _____________ cancer by 31%
Colon cancer
Usual dose of folic acid therapy
1-5 mg/day
*1 mg usually is sufficient. *
Treatment for tropical sprue
- Usual doses of folate, plus cobalamin if indicated
- To prevent relapse, treatment should be maintained for at least 2 years.
- Broad-spectrum antibiotics are helpful adjuncts, although antibiotics alone fail to correct the condition.
Dosage of folate among pregnant women
400 mcg of folate per day
In pregnant women at risk for cobalamin deficiency (eg, vegans or patients with malabsorption), the risk of an associated cobalamin deficiency is easily prevented with vitamin B12, ______________ during the pregnancy.
1 mg given parenterally every 3 months
Low-dose methotrexate
Administration of _____________ can prevent or greatly diminish the major side effects without reducing the therapeutic effect of low-dose methotrexate.
The incidence of side effects, including hepatotoxicity, has been correlated with reduced folate levels.
Folic or folinic acid
An autoimmune disease characterized by failure of gastric intrinsic factor production
Gastric manifestations include achlorhydria, acquired intrinsic factor deficiency previously demonstrable through showing malabsorption of cobalamin by the Schilling test, and an increased incidence of certain malignancies.
Pernicious Anemia
Frequent in patients with other autoimmune diseases
In patients with PA, antibodies occur that recognize the _______________
H+/K+- ATPase
Types of antibodies in Pernicious Anemia
- Antibodies to intrinsic factor (“type I,” or “blocking,” antibodies
- Antibodies to intrinsic factor–cobalamin (Cbl) complex (“type II,” or “binding,” antibodies)
The disease is associated with human leukocyte antigen types____________ and with blood group _______
- Human leukocyte antigen types A2, A3, B7, and B12
- Blood group A
In Pernicious Anemia, there is ____fold increase in the incidence of gastric cancer
Twofold
Measurement of ________________ in serum represents the only available method to confirm a diagnosis of PA
Antiintrinsic factor antibodies
Most common type of anemia after gastric surgery
Iron-deficiency anemia
Iron-deficiency anemia is most common, but cobalamin deficiency with megaloblastic anemia can occur.
After total gastrectomy, cobalamin deficiency develops within _______ years
5 or 6 years
TRUE OR FALSE
Postgastrectomy patients with low serum cobalamin levels usually have low serum iron levels, in contrast to the high iron levels otherwise typical of cobalamin deficiency.
TRUE
Postgastrectomy patients with low serum cobalamin levels usually have low serum iron levels, in contrast to the high iron levels otherwise typical of cobalamin deficiency.
A gastrin-producing tumor, usually in the pancreas, stimulates the gastric mucosa to secrete immense amounts of HCl
The major clinical problem is a severe ulcer diathesis.
Zollinger-Ellison Syndrome
The resulting acidification of the duodenal contents prevents transfer of Cbl from HC binder to intrinsic factor and also inactivates pancreatic proteases
A state of cobalamin malabsorption with megaloblastic anemia caused by intestinal stasis from anatomic lesions (strictures, diverticula, anastomoses, surgical blind loops) or impaired motility (scleroderma, amyloid)
Serum cobalamin is low, but intrinsic factor secretion is normal.
Corrected by antibiotic treatment
Caused by colonization of the diseased small intestine by bacteria that take up ingested cobalamin before it can be absorbed from the intestine.
“Blind Loop Syndrome”
Another cause of cobalamin deficiency is infestation with this fish tapeworm
Diphyllobothrium latum
It may take _____ years for an individual consuming a vegan diet to manifest features of cobalamin deficiency.
10–20 years
This is because the enterohepatic pathway for biliary cobalamin absorption remains intact, which conserves body cobalamin stores.
Breastfed infants of vegan mothers also may develop cobalamin deficiency.
The neurologic lesions of cobalamin deficiency result from
Deranged methyl group metabolism
The development of these disorders is prevented by methionine, which is produced in a cobalamin-dependent reaction and is the precursor of the biologic methylating reagent SAM
Specific feature caused by the lack of cobalamin
Neurologic abnormalities
- Cobalamin deficiency may also contribute to the risk of vascular disease through elevation of homocysteine levels.
- These include a possible increase in breast cancer risk in premenopausal women and of osteoporosis.
The earliest signs of cobalamin deficiency, which precede other neurologic findings by months, are
Loss of position sense in the second toe and loss of vibration sense for a 256-Hz but not a 128-Hz tuning fork
Left untreated, the neurologic disorder progresses to spastic ataxia resulting from demyelination of the dorsal and lateral columns of the spinal cord, so-called
Combined system disease
Frank psychosis in cobalamin deficiency has been given the sobriquet
Megaloblastic madness
The neurologic lesions of cobalamin deficiency can be detected by
Magnetic resonance imaging (MRI)
T2-weighted hyperintensity of the white matter
Cases of thrombotic microangiopathy with severe vitamin B12 deficiency resulting from the inborn errors of metabolism have been described and referred to as
cblC or cblG disease
Characterized by mutation in the MTR gene leading to a dysfunctional methionine synthase enzyme
cblG
Prone to vasculopathies, thrombotic and red cell dysfunction
Disease involves a defect in the enzyme responsible for conversion of cobalamin into its metabolically active reduced forms causing accumulation of homocysteine
cblC
Conditions where cobalamin levels are usually normal
- Cobalamin deficiency resulting from exposure to nitrous oxide, TC deficiency, and inborn errors of cobalamin metabolism
- Patients with high HC levels resulting from myeloproliferative diseases
Plasma cobalamin levels may be low in the presence of normal tissue cobalamins in
Vegetarians, in individuals taking megadoses of ascorbic acid, in pregnancy (25%), in the presence of HC deficiency,and in megaloblastic anemia resulting from folate deficiency (30%)
Plasma folate may be high in cobalamin deficiency because of the methyl folate “trap” resulting in retardation in conversion of methyl-THF, which is the predominant form in plasma
The fraction of the cobalamin in plasma that is bound to TC
Fraction that is functionally important and also better reflects the integrity of the cobalamin absorptive status of an individual
Plasma or Serum Holotranscobalamin
A reliable indicator of cobalamin deficiency
Methylmalonic aciduria
- In cobalamin deficiency, urine methylmalonate usually is elevated.
Indicators of tissue cobalamin deficiency
Plasma or serum methylmalonic acid and homocysteine
Levels are high in more than 90% of cobalamin-deficient patients and rise before plasma cobalamin falls to subnormal levels
TRUE OR FALSE
Homocysteine measurement is less sensitive and more specific
FALSE
Methylmalonic acid measurement is both more sensitive and more specific than homocysteine
- Elevated methylmalonic acid will persist for several days, even after cobalamin treatment is instituted
- Unlike homocysteine levels that rise in folate and pyridoxine deficiencies, as well as in hypothyroidism, methylmalonic acid elevation occurs only in cobalamin deficiency.
- Spinal fluid methylmalonic acid levels are markedly elevated in cobalamin deficiency.
Polymorphism results in higher methylmalonic acid concentrations unrelated to B12 status
3-hydroxyisobutyryl- CoA hydrolase (HIBCH)
Previous “gold standard” for assessment of cobalamin absorption
Schilling test
Treatment of cobalamin deficiency consists of
Parenteral CnCbl (vitamin B12) or OHCbl
Normally contain 2–5 mg of cobalamin
Doses exceeding 100 mcg saturate the cobalamin-binding proteins (TC and HC), and the excess is lost in the urine.
Typical treatment schedule for cobalamin deficiency
1000 mcg cobalamin intramuscularly daily for 2 weeks, then weekly until the hematocrit is normal, and then monthly for life
Treatment schedule for cobalamin deficiency with neurologic manifestations
1000 mcg every 2 weeks for 6 months
Transfusion occasionally is required when the hematocrit is less than ____% or the patient is debilitated, infected, or in heart failure.
less than 15%
Response to Treatment and Therapeutic Trial
Within _____ hours, the marrow begins to change from megaloblastic to normoblastic, a process that is complete in ______ days.
12 hours
2–3 days
Other changes include:
* (a) prompt and dramatic improvement in the sense of well-being;
* (b) normalization of leukocyte and platelet counts, although neutrophil hypersegmentation may persist for 10–14 days; and
* (c) rise in serum cobalamin and folate; return to normal of plasma homocysteine and methylmalonate levels
Response to Treatment and Therapeutic Trial
Blood hemoglobin concentration becomes normal within _____ months
1–2 months
If normal values are not achieved by 2 months, another cause of anemia should be sought.
TRUE OR FALSE
Cobalamin deficiency does not respond to a physiologic dose of folate (100–400 mcg/ day), although this dose produces a maximal response in folate deficiency.
TRUE
Cobalamin deficiency does not respond to a physiologic dose of folate (100–400 mcg/ day), although this dose produces a maximal response in folate deficiency.
large dose dapat
Larger doses of folate ________ (mg/day) can produce a reticulocytosis and partially or temporarily correct the anemia in cobalamin deficiency.
5–15 mg/day
To avoid the risk of masking an underlying cobalamin deficiency by inducing a hematologic remission in response to folate, doses in excess of 1 mg folic acid daily should be shunned until an underlying cobalamin deficiency has been ruled out.
TRUE OR FALSE
Cobalamin administration is not necessary after total gastrectomy
FALSE
Cobalamin administration is not necessary after partial gastrectomy
Cobalamin should always be given after total gastrectomy.
Treatment for Blind Loop Syndrome
- Parenteral cobalamin therapy
- 1 week to oral broad-spectrum antibiotics (cephalexin monohydrate [Keflex] 250 mg QID plus metronidazole 250 mg TID for 10 days)
- Surgical correction of an anatomic lesion
Treatment for Fish Tapeworm
50 mg/kg of niclosamide
5–10 mg/kg of praziquantel
Oral cobalamin can be used for:
- Dietary cobalamin deficiency
- Patients (eg, hemophiliacs, the frail elderly) who cannot take intramuscular injections
- Patients with PA
1000–2000 mcg/ day of oral cobalamin supplies most PA patients with their daily cobalamin requirement without the need for injections and their accompanying pain and expense
The most common cause of acute megaloblastic anemia
N2O anesthesia
N2O rapidly destroys MeCbl, leading to a megaloblastic state.
Present with rapidly developing thrombocytopenia and/ or leukopenia and counts that sometimes fall to very low levels, but little change in red cell levels
ACUTE MEGALOBLASTIC ANEMIA
Hypersegmented neutrophils do not appear until _____ days after exposure but then persist for several days.
5 days after exposure
Grossly megaloblastic changes are seen in the marrow after 12–24 hours.
Risk factors for Acute megaloblastic anemia
- Transfused extensively at surgery
- Those on dialysis or total parenteral nutrition
- Those receiving weak folate antagonists such as trimethoprim
A rapid response to therapeutic doses of parenteral folate (5 mg/day) and cobalamin (1 mg) is the rule.
Inhibitors of dihydrofolate reductase
Aminopterin and methotrexate
Cause irreversible inhibition of thymidylate synthase
5-fluorouracil and 5-fluorodeoxyuridine
Inhibit dihydroorotate dehydrogenase
Leflunomide for inflammatory arthritis and teriflunomide for multiple sclerosis
Toxicity caused by dihydrofolate antagonists is treated with
Folinic acid (N5-formyl FH4)
The usual dose of folinic acid is 3–6 mg/day intramuscularly
Folic acid itself is useless in this setting because the blocked reductase cannot convert folic acid and dihydrofolate to the active tetrahydro form.
ARV that causes severe megaloblastic anemia
The blood film shows vacuolated monocytes.
Zidovudine (azidothymidine [AZT])
Megaloblastosis in HIV infection may result from folate or cobalamin deficiency or AZT or trimethoprim toxicity.
It inhibits conversion of ribonucleotides to deoxyribonucleotides.
megaloblastic changes are routinely found in the marrow 1–2 days after initiating therapy
Hydroxyurea
An antifolate approved for use in mesothelioma and for treatment of non–small cell lung cancer
Pemetrexed
A dihydrofolate reductase inhibitor that is designed to act on the microbial rather than the mammalian enzyme
Trimethoprim
Cobalamin malabsorption occurs in 4 childhood conditions associated with a genetic component:
(a) cobalamin malabsorption in the presence of normal intrinsic factor secretion
(b) congenital abnormality of intrinsic factor
(c) TC deficiency
(d) true PA of childhood
An inherited failure of transport of the intrinsic factor–Cbl complex by the ileum, usually accompanied by proteinuria, mostly of albumin
It may be the most common cause of cobalamin deficiency in infancy in some populations.
Imerslund- Gräsbeck disease
Patients are treated with intramuscular cobalamin.
Affected genes in Imerslund- Gräsbeck disease
CUBN
AMN
An autosomal recessive disease in which parietal cells fail to produce functionally normal intrinsic factor
Patients present with irritability and megaloblastic anemia when cobalamin stores (<25 mcg at birth) are exhausted.
Congenital Intrinsic Factor Deficiency
Treatment consists of standard doses of intramuscular cobalamin.
An autosomal recessive disorder causing a flagrant megaloblastic anemia that generally presents in early infancy.
The disease is dangerously deceptive because it results from a very severe deficiency of tissue cobalamin, usually with serum cobalamin levels in the reference range because most of the plasma cobalamin is bound to HC, resulting in a misleading test result if reliance is placed simply on serum cobalamin measurement.
Transcobalamin Deficiency
The diagnosis is made by measuring plasma TC.
Treated with cobalamin doses sufficiently large to force enough vitamin into the cells to allow normal function
Initial therapy can consist of oral CnCbl or OHCbl 500–1000 mcg twice a week, or intramuscular OHCbl 1000 mcg/week.
Congenital deficiency is not associated with clinically manifested cobalamin deficiency
Haptocorrin Deficiency
The absence of morbidity in these patients indicates that HCs are not essential for health.
Condition where AdoCbl production is impaired but MeCbl production is normal
Methylmalonic Aciduria Only (cblA, cblB, and cblH)
MethA-BHA
- Present in infancy with acidosis because they cannot catabolize methylmalonic acid
- Mental retardation is not prominent, and megaloblastic anemia is absent.
N5-methyltetrahydrofolate-homocysteine methyltransferase is defective and lacks the capacity to produce MeCbl
Homocystinuria Only (cblE and cblG)
GE-Cys
cblG: methionine synthase is missing or defective
cblE: failure to reactivate methionine synthase that was inactivated by oxidation of its bound cobalamin
- Presents with vomiting, mental retardation, and megaloblastic anemia
- Marked homocystinuria and hyperhomocysteinemia without methylmalonic aciduria or methylmalonic acidemia
Result from reduction of cobalt from Co2+ to Co1+ is defective
These patients have both hyperhomocysteinemia and methylmalonic acidemia
Methylmalonic Aciduria and Homocystinuria (cblC, cblD, and cblF)
CDF (walang E for both)
cblF: inability to release cobalamin from lysosomes
The most common of the cobalamin inborn errors
cblC
A rare inherited disorder in which patients cannot absorb folate from the gastrointestinal tract or transport it across the choroid plexus and into the cerebrospinal fluid.
The molecular basis for this disorder is caused by abnormalities in the proton-coupled folate transporter.
Hereditary Folate Malabsorption
Treatment with daily folinic acid by injection maintains the spinal fluid level and can lead to normal development.
TRUE OR FALSE
The megaloblastic anemia in Dihydrofolate Reductase Deficiency responds to folinic acid but not to folic acid.
TRUE
The megaloblastic anemia in Dihydrofolate Reductase Deficiency responds to folinic acid but not to folic acid.
In this rare autosomal recessive disorder, there is a severe hyperhomocysteinemia and homocystinuria with low plasma methionine.
Patients have neurologic and vascular complications, but no megaloblastic anemia or methylmalonic aciduria.
Methylene Tetrahydrofolate Reductase Deficiency
The second most common folate disorder
There is a mutation in the gene encoding glutamate formiminotransferase (FTCD), required for the conversion of formiminoglutamate to 5-formiminotetrahydrofolate followed by cyclodeamination of the formimino group forming 5,10-methenyltetrahydrofolate and ammonia
Formiminoglutamic Aciduria
An autosomal recessive disorder of pyrimidine metabolism characterized by megaloblastic anemia, growth impairment, and excretion of orotic acid in the urine.
Hereditary Orotic Aciduria
An X-linked disorder of purine metabolism characterized by hyperuricemia, hyperuricosuria, and a neurologic disease with self-mutilation
It is caused by a hypoxanthine-guanine phosphoribosyltransferase deficiency.
Lesch-Nyhan Syndrome
Children with severe megaloblastic anemia, sensorineural deafness, and non-autoimmune diabetes mellitus, all presenting symptoms in the early childhood or adolescence
The gene for this puzzling disorder has been mapped to the long arm of chromosome 1
Thiamine-Responsive Megaloblastic Anemia (also known as Rogers syndrome)
The anemia and diabetes responds to thiamine (25–100 mg/day)
Types of Congenital Dyserythropoietic Anemia that show megaloblastic red cell precursors
Type I usually and type III occasionally
Regarded as a manifestation of some sideroblastic anemias and myelodysplastic disorders
Dysplastic features are confined to the erythroid series.
Refractory Megaloblastic Anemia
Patients at high risk to develop acute megaloblastic anemia
Patients transfused extensively during surgery
Patients on dialysis
Patients on TPN
