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WILLIAM'S HEMATOLOGY > 42 Folate, Cobalamin and Megaloblastic Anemias > Flashcards

42 Folate, Cobalamin and Megaloblastic Anemias Flashcards

1
Q

To form a functional compound, folates must be in the reduced ____________________ form

A

Tetrahydrofolate form (FH4)

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2
Q

Enzyme that catalyzes both FA→FH2 and FH2→FH4

A

Dihydrofolate reductase

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3
Q

Stable form of folic acid and the form preferred for clinical use

A

N5-formyl FH4, also called citrovorum factor, leucovorin, or folinic acid

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4
Q

The richest sources of folic acid are

A

Dark green leafy vegetables

Others:
* fruit sources are oranges, lemons, bananas, strawberries, and melons
* liver, kidney, yeast, mushrooms, and peanuts

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5
Q

Meat, with the exception of_______, is generally not a good source of folate.

A

Liver

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6
Q

In the normal adult, the recommended daily allowance (RDA) for folate is expressed as

A

Dietary folate equivalents (DFEs)

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7
Q

One microgram of food folate is the dietary equivalent of_____mcg folic acid added to food

A

0.6 mcg folic acid

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8
Q

The officially recommended dietary allowance of food folate expressed as DFEs for an adult is ___ mg

A

0.4 mg

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9
Q

The body is thought to contain approximately _____ of folate.

A

5 mg

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10
Q

When folate intake is reduced to _____ mcg/day, megaloblastic anemia develops in approximately 4 months.

A

5 mcg/day

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11
Q

Folate requirements in pregnanancy

A

600 mcg/day

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12
Q

Folate requirements in lactating women

A

500 mcg/day

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13
Q

Conditions where folic acid requirements increase

A
  • Hemolytic anemia
  • Leukemia and other malignant diseases
  • Alcoholism
  • During growth
  • Pregnancy and during lactation
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14
Q

Among the several 1-carbon transfers mediated by folic acid, the transfer that is the most important clinically is the

A

Methylation of deoxyuridylate to thymidylate

This reaction is an essential step in the synthesis of DNA

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15
Q

The methylation of deoxyuridylate to thymidylate is catalyzed by the enzyme

A

Thymidylate synthase

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16
Q

Mono or Poly

Intracellular folates exist primarily as _________________

A

Polyglutamate conjugates

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17
Q

Inside the cells, the polyglutamate chain is sequentially built up by an ATP-dependent

A

Folylpoly-γ-glutamyl synthase

Folylmonoglutamate appears in plasma

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18
Q

TRUE OR FALSE

Folylpolyglutamates are superior to monoglutamates as substrates for folate-dependent enzyme reactions.

A

TRUE

Folylpolyglutamates are superior to monoglutamates as substrates for folate-dependent enzyme reactions.

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19
Q

The principal sites of folate absorption

A

Duodenum and proximal jejunum

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20
Q

Because only folylmonoglutamate appears in plasma, all folylpolyglutamates must first be hydrolyzed by the enzyme _________ during absorption across the intestine.

A

Glutamate carboxypeptidase II (folate hydrolase)

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21
Q

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

A

γ-glutamyl hydrolases

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22
Q

Folate receptors that despite its missing cytoplasmic extension, is effective in mediating endocytosis

A

Folate receptor-α

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23
Q

A probenecid-inhibitable organic anion carrier that, among other functions, carries reduced folates and methotrexate in and out of the cytoplasm

A

Membrane folate transporter

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24
Q

The principal form of the folate in tissues and in blood

A

N5-methyl form

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25
Q

Breakdown product of folic acid metabolism

A

p-Aminobenzoylglutamate

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26
Q

Folate-binding proteins of serum and milk can be detected in approximately ___% of normal individuals

A

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

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27
Q

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.

A

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
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28
Q

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.

A

Secondary granules

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29
Q

The cobalamin molecule has a porphyrin-like near-planar macrocycle known as_______

A

Corrin

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30
Q

The usual therapeutic form of cobalamin

A

Cyanocobalamin

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31
Q

Four cobalamins are important in animal cell metabolism

A
  • 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.

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32
Q

2 cobalamins are alkyl derivatives that are synthesized from OHCbl and serve as coenzymes

A

Adenosylcobalamin (AdoCbl)
Methylcobalamin (MeCbl)

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33
Q

The major form of cobalamin in human blood plasma

A

MeCbl

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34
Q

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.

A

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

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35
Q

Total body content of cobalamin

A

2–5 mg

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36
Q

Amount of cobalamin found in liver

A

1 mg

The kidneys also are rich in cobalamin

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37
Q

TRUE OR FALSE

Relative to the daily requirement, body reserves of cobalamin are much larger than those of folate.

A

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.
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38
Q

The official RDA for cobalamin among adults

A

2.4 mcg

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39
Q

A mitochondrial enzyme that participates in the disposal of the propionate formed during the breakdown of valine, isoleucine, and odd-carbon fatty acids

A

Methylmalonyl Coenzyme A Mutase

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40
Q

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

A

N5-Methyltetrahydrofolate-Homocysteine Methyltransferase

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41
Q

TRUE OR FALSE

Because cobalamin has the capacity to bind cyanide, it may participate in detoxification of cyanide.

A

TRUE

Because cobalamin has the capacity to bind cyanide, it may participate in detoxification of cyanide.

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42
Q

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.

A

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.

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43
Q

TRUE OR FALSE

The anemia of folate deficiency is generally helped by cobalamin

A

FALSE

The anemia of folate deficiency is generally not helped at all by cobalamin

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44
Q

Two explanations have been proposed to account for the folate responsiveness of cobalamin-deficient megaloblastic anemia:

A
  • Methylfolate Trap Hypothesis
  • Formate Starvation Hypothesis
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45
Q

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

A

Methylfolate Trap Hypothesis

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46
Q

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.

A

Formate Starvation Hypothesis

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47
Q

Human intrinsic factor is a glycoprotein (Mr approximately 44,000) encoded by a gene on _________________

A

Chromosome 11

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48
Q

Promotes absorption uptake of cobalamin by ileum

Source: Gastric parietal cells of the cardiac and fundic mucosa

A

Intrinsic factor

Secretion of intrinsic factor usually parallels that of hydrochloric acid (HCl).

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49
Q

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

A

R proteins

Cobalamin binds much more tightly to HC than to intrinsic factor at the acid pH of the stomach.

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50
Q

Promotes uptake of cobalamin by cells

Source: Probably all cells

A

Transcobalamin

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51
Q

Helps dispose of cobalamin analogues; possible antimicrobial function(?)

Source: Exocrine glands, phagocytes

A

Haptocorrin

(previously known as R proteins or TC I and TC III)

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52
Q

TRUE OR FALSE

Cobalamin binds much more tightly to HC than to intrinsic factor at the acid pH of the stomach

A

TRUE

Cobalamin binds much more tightly to HC than to intrinsic factor at the acid pH of the stomach

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53
Q

The intrinsic factor receptor, located in the microvillus pits of the ileal mucosa brush border

A

Cubilin

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54
Q

The ileal cubilin receptor complex consists of 2 proteins:

A

Cubilin (CUB) and amnionless (AMN)

“CUBAM complex”

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55
Q

In the portal blood, the cobalamin is complexed with a cobalamin-transporting protein known as

A

Transcobalamin (TC) previously known as transcobalamin II

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56
Q

The protein with which cobalamin given parenterally associates almost immediately

Mediates the transport of cobalamin into the tissues.

A

Transcobalamin (TC)

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57
Q

Transcobalamin receptor is designated as ____; it belongs to the low-density lipoprotein receptor family and its internalization involves megalin

A

CD320

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58
Q

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

A

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
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59
Q

Current assays use ______________ as the binder and give more reliable values for serum cobalamin.

A

Intrinsic factor

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60
Q

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.

A

Holotranscobalamin

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61
Q

Conditions with Increased haptocorrin (transcobalamin I, R protein)

A
  • Myeloproliferative disorders
  • Polycythemia vera
  • Myelofibrosis
  • Benign neutrophilia
  • Chronic myelocytic leukemia
  • Hepatoma (occasionally)
  • Metastatic cancer
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62
Q

Conditions with Increased transcobalamin

A
  • Liver disease
  • Inflammatory disorders
  • Gaucher disease
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63
Q

Morphologic hallmark of megaloblastic anemias

A

Presence of megaloblastic cells

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64
Q

Cell with a large horseshoe-shaped nucleus, sometimes irregularly shaped, containing ragged open chromatin

A

Giant metamyelocyte

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65
Q

The most common causes worldwide of megaloblastic anemia

A

Folate deficiency and cobalamin deficiency

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66
Q

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.

A

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.

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67
Q

Megaloblstic Anemia

The anemia is usually macrocytic (mean corpuscular volume [MCV] is ___________ fL or more)

A

Mean corpuscular volume [MCV] is 100–150 fL or more

Although coexisting iron deficiency, thalassemia trait, or inflammation can prevent macrocytosis.

68
Q

The earliest observable change in red cell indices in megaloblastic anemia is

A

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).

69
Q

Typically, more than _________% of the neutrophils have 5 lobes

A

more than 5%

70
Q

TRUE OR FALSE

Neutrophil hypersegmentation was found to be a sensitive test for mild cobalamin deficiency

A

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

71
Q

Specific therapy corrects these abnormalities, usually within _____ days, although some abnormalities do not disappear for months.

A

2 days

72
Q

Megaloblastic Anemia

Plasma bilirubin, iron, and ferritin levels are (increased or decreased).

A

Increased

73
Q

TRUE OR FALSE

In megaloblastic anemia LDH-1 is greater than LDH-2, whereas in other anemias LDH-2 is greater than LDH-1.

A

TRUE

In megaloblastic anemia LDH-1 is greater than LDH-2, whereas in other anemias LDH-2 is greater than LDH-1.

74
Q

Megaloblastic anemia is associated with two pathophysiologic abnormalities:

A

Ineffective erythropoiesis (exaggerated apoptosis of precursor cells) and hemolysis

75
Q

Folate deficiency is caused by:

A
  • (a) dietary deficiency
  • (b) impaired absorption
  • (c) increased requirements or losses
76
Q

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.

A

Nontropical sprue (celiac disease in children)

77
Q

TRUE OR FALSE

Clinically and pathologically, tropical sprue is like nontropical sprue, except that tropical sprue is more severe in the distal small intestine.

A

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.

78
Q

During pregnancy folate requirements increase ________-fold because of transfer of folate to the growing fetus, which draws down maternal folate stores.

A

5- to 10-fold

79
Q

The major cause of the megaloblastic anemia of pregnancy

A

Folate deficiency

80
Q

Specific features of folate deficiency:

A
  • (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
81
Q

The earliest specific indicator of folate deficiency

A

Low serum or plasma folate

82
Q

A better indicator of the tissue folate status

Reflects folate status over the preceding 2–3 months

A

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

83
Q

In folate deficiency, uncomplicated by causes of microcytosis, the MCV is usually higher than ______ fL.

A

110 fL

84
Q

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).

A

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.

85
Q

The diagnosis of nontropical sprue rests on

A
  • (a) the demonstration of malabsorption
  • (b) a jejunal biopsy showing villus atrophy
  • (c) the response to a gluten-free diet
86
Q

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.

A

Goat’s milk

87
Q

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

A

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

88
Q

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.

A

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.

89
Q

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%

A

Colon cancer

90
Q

Usual dose of folic acid therapy

A

1-5 mg/day

*1 mg usually is sufficient. *

91
Q

Treatment for tropical sprue

A
  • 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.
92
Q

Dosage of folate among pregnant women

A

400 mcg of folate per day

93
Q

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.

A

1 mg given parenterally every 3 months

94
Q

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.

A

Folic or folinic acid

95
Q

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.

A

Pernicious Anemia

Frequent in patients with other autoimmune diseases

96
Q

In patients with PA, antibodies occur that recognize the _______________

A

H+/K+- ATPase

97
Q

Types of antibodies in Pernicious Anemia

A
  • Antibodies to intrinsic factor (“type I,” or “blocking,” antibodies
  • Antibodies to intrinsic factor–cobalamin (Cbl) complex (“type II,” or “binding,” antibodies)
98
Q

The disease is associated with human leukocyte antigen types____________ and with blood group _______

A
  • Human leukocyte antigen types A2, A3, B7, and B12
  • Blood group A
99
Q

In Pernicious Anemia, there is ____fold increase in the incidence of gastric cancer

A

Twofold

100
Q

Measurement of ________________ in serum represents the only available method to confirm a diagnosis of PA

A

Antiintrinsic factor antibodies

101
Q

Most common type of anemia after gastric surgery

A

Iron-deficiency anemia

Iron-deficiency anemia is most common, but cobalamin deficiency with megaloblastic anemia can occur.

102
Q

After total gastrectomy, cobalamin deficiency develops within _______ years

A

5 or 6 years

103
Q

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.

A

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.

104
Q

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.

A

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

105
Q

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.

A

“Blind Loop Syndrome”

106
Q

Another cause of cobalamin deficiency is infestation with this fish tapeworm

A

Diphyllobothrium latum

107
Q

It may take _____ years for an individual consuming a vegan diet to manifest features of cobalamin deficiency.

A

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.

108
Q

The neurologic lesions of cobalamin deficiency result from

A

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

109
Q

Specific feature caused by the lack of cobalamin

A

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.
110
Q

The earliest signs of cobalamin deficiency, which precede other neurologic findings by months, are

A

Loss of position sense in the second toe and loss of vibration sense for a 256-Hz but not a 128-Hz tuning fork

111
Q

Left untreated, the neurologic disorder progresses to spastic ataxia resulting from demyelination of the dorsal and lateral columns of the spinal cord, so-called

A

Combined system disease

112
Q

Frank psychosis in cobalamin deficiency has been given the sobriquet

A

Megaloblastic madness

113
Q

The neurologic lesions of cobalamin deficiency can be detected by

A

Magnetic resonance imaging (MRI)

T2-weighted hyperintensity of the white matter

114
Q

Cases of thrombotic microangiopathy with severe vitamin B12 deficiency resulting from the inborn errors of metabolism have been described and referred to as

A

cblC or cblG disease

115
Q

Characterized by mutation in the MTR gene leading to a dysfunctional methionine synthase enzyme

A

cblG

Prone to vasculopathies, thrombotic and red cell dysfunction

116
Q

Disease involves a defect in the enzyme responsible for conversion of cobalamin into its metabolically active reduced forms causing accumulation of homocysteine

A

cblC

117
Q

Conditions where cobalamin levels are usually normal

A
  • 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
118
Q

Plasma cobalamin levels may be low in the presence of normal tissue cobalamins in

A

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

119
Q

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

A

Plasma or Serum Holotranscobalamin

120
Q

A reliable indicator of cobalamin deficiency

A

Methylmalonic aciduria

  • In cobalamin deficiency, urine methylmalonate usually is elevated.
121
Q

Indicators of tissue cobalamin deficiency

A

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

122
Q

TRUE OR FALSE

Homocysteine measurement is less sensitive and more specific

A

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.
123
Q

Polymorphism results in higher methylmalonic acid concentrations unrelated to B12 status

A

3-hydroxyisobutyryl- CoA hydrolase (HIBCH)

124
Q

Previous “gold standard” for assessment of cobalamin absorption

A

Schilling test

125
Q

Treatment of cobalamin deficiency consists of

A

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.

126
Q

Typical treatment schedule for cobalamin deficiency

A

1000 mcg cobalamin intramuscularly daily for 2 weeks, then weekly until the hematocrit is normal, and then monthly for life

127
Q

Treatment schedule for cobalamin deficiency with neurologic manifestations

A

1000 mcg every 2 weeks for 6 months

128
Q

Transfusion occasionally is required when the hematocrit is less than ____% or the patient is debilitated, infected, or in heart failure.

A

less than 15%

129
Q

Response to Treatment and Therapeutic Trial

Within _____ hours, the marrow begins to change from megaloblastic to normoblastic, a process that is complete in ______ days.

A

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

130
Q

Response to Treatment and Therapeutic Trial

Blood hemoglobin concentration becomes normal within _____ months

A

1–2 months

If normal values are not achieved by 2 months, another cause of anemia should be sought.

131
Q

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.

A

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

132
Q

Larger doses of folate ________ (mg/day) can produce a reticulocytosis and partially or temporarily correct the anemia in cobalamin deficiency.

A

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.

133
Q

TRUE OR FALSE

Cobalamin administration is not necessary after total gastrectomy

A

FALSE

Cobalamin administration is not necessary after partial gastrectomy

Cobalamin should always be given after total gastrectomy.

134
Q

Treatment for Blind Loop Syndrome

A
  • 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
135
Q

Treatment for Fish Tapeworm

A

50 mg/kg of niclosamide

5–10 mg/kg of praziquantel

136
Q

Oral cobalamin can be used for:

A
  • 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

137
Q

The most common cause of acute megaloblastic anemia

A

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

138
Q

ACUTE MEGALOBLASTIC ANEMIA

Hypersegmented neutrophils do not appear until _____ days after exposure but then persist for several days.

A

5 days after exposure

Grossly megaloblastic changes are seen in the marrow after 12–24 hours.

139
Q

Risk factors for Acute megaloblastic anemia

A
  • 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.

140
Q

Inhibitors of dihydrofolate reductase

A

Aminopterin and methotrexate

141
Q

Cause irreversible inhibition of thymidylate synthase

A

5-fluorouracil and 5-fluorodeoxyuridine

142
Q

Inhibit dihydroorotate dehydrogenase

A

Leflunomide for inflammatory arthritis and teriflunomide for multiple sclerosis

143
Q

Toxicity caused by dihydrofolate antagonists is treated with

A

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.

144
Q

ARV that causes severe megaloblastic anemia

The blood film shows vacuolated monocytes.

A

Zidovudine (azidothymidine [AZT])

Megaloblastosis in HIV infection may result from folate or cobalamin deficiency or AZT or trimethoprim toxicity.

145
Q

It inhibits conversion of ribonucleotides to deoxyribonucleotides.

megaloblastic changes are routinely found in the marrow 1–2 days after initiating therapy

A

Hydroxyurea

146
Q

An antifolate approved for use in mesothelioma and for treatment of non–small cell lung cancer

A

Pemetrexed

147
Q

A dihydrofolate reductase inhibitor that is designed to act on the microbial rather than the mammalian enzyme

A

Trimethoprim

148
Q

Cobalamin malabsorption occurs in 4 childhood conditions associated with a genetic component:

A

(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

149
Q

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.

A

Imerslund- Gräsbeck disease

Patients are treated with intramuscular cobalamin.

150
Q

Affected genes in Imerslund- Gräsbeck disease

A

CUBN

AMN

151
Q

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.

A

Congenital Intrinsic Factor Deficiency

Treatment consists of standard doses of intramuscular cobalamin.

152
Q

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.

A

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.

153
Q

Congenital deficiency is not associated with clinically manifested cobalamin deficiency

A

Haptocorrin Deficiency

The absence of morbidity in these patients indicates that HCs are not essential for health.

154
Q

Condition where AdoCbl production is impaired but MeCbl production is normal

A

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.
155
Q

N5-methyltetrahydrofolate-homocysteine methyltransferase is defective and lacks the capacity to produce MeCbl

A

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
156
Q

Result from reduction of cobalt from Co2+ to Co1+ is defective

These patients have both hyperhomocysteinemia and methylmalonic acidemia

A

Methylmalonic Aciduria and Homocystinuria (cblC, cblD, and cblF)

CDF (walang E for both)

cblF: inability to release cobalamin from lysosomes

157
Q

The most common of the cobalamin inborn errors

A

cblC

158
Q

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.

A

Hereditary Folate Malabsorption

Treatment with daily folinic acid by injection maintains the spinal fluid level and can lead to normal development.

159
Q

TRUE OR FALSE

The megaloblastic anemia in Dihydrofolate Reductase Deficiency responds to folinic acid but not to folic acid.

A

TRUE

The megaloblastic anemia in Dihydrofolate Reductase Deficiency responds to folinic acid but not to folic acid.

160
Q

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.

A

Methylene Tetrahydrofolate Reductase Deficiency

161
Q

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

A

Formiminoglutamic Aciduria

162
Q

An autosomal recessive disorder of pyrimidine metabolism characterized by megaloblastic anemia, growth impairment, and excretion of orotic acid in the urine.

A

Hereditary Orotic Aciduria

163
Q

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.

A

Lesch-Nyhan Syndrome

164
Q

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

A

Thiamine-Responsive Megaloblastic Anemia (also known as Rogers syndrome)

The anemia and diabetes responds to thiamine (25–100 mg/day)

165
Q

Types of Congenital Dyserythropoietic Anemia that show megaloblastic red cell precursors

A

Type I usually and type III occasionally

166
Q

Regarded as a manifestation of some sideroblastic anemias and myelodysplastic disorders

Dysplastic features are confined to the erythroid series.

A

Refractory Megaloblastic Anemia

167
Q

Patients at high risk to develop acute megaloblastic anemia

A

Patients transfused extensively during surgery
Patients on dialysis
Patients on TPN

WILLIAM'S HEMATOLOGY (109 decks)

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