42 Folate, Cobalamin and Megaloblastic Anemias Flashcards
(167 cards)
1
Q
To form a functional compound, folates must be in the reduced ____________________ form
A
Tetrahydrofolate form (FH4)
2
Q
Enzyme that catalyzes both FA→FH2 and FH2→FH4
A
Dihydrofolate reductase
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
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
5
Q
Meat, with the exception of_______, is generally not a good source of folate.
A
Liver
6
Q
In the normal adult, the recommended daily allowance (RDA) for folate is expressed as
A
Dietary folate equivalents (DFEs)
7
Q
One microgram of food folate is the dietary equivalent of_____mcg folic acid added to food
A
0.6 mcg folic acid
8
Q
The officially recommended dietary allowance of food folate expressed as DFEs for an adult is ___ mg
A
0.4 mg
9
Q
The body is thought to contain approximately _____ of folate.
A
5 mg
10
Q
When folate intake is reduced to _____ mcg/day, megaloblastic anemia develops in approximately 4 months.
A
5 mcg/day
11
Q
Folate requirements in pregnanancy
A
600 mcg/day
12
Q
Folate requirements in lactating women
A
500 mcg/day
13
Q
Conditions where folic acid requirements increase
A
- Hemolytic anemia
- Leukemia and other malignant diseases
- Alcoholism
- During growth
- Pregnancy and during lactation
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
15
Q
The methylation of deoxyuridylate to thymidylate is catalyzed by the enzyme
A
Thymidylate synthase
16
Q
Mono or Poly
Intracellular folates exist primarily as _________________
A
Polyglutamate conjugates
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
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.
19
Q
The principal sites of folate absorption
A
Duodenum and proximal jejunum
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)
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
22
Q
Folate receptors that despite its missing cytoplasmic extension, is effective in mediating endocytosis
A
Folate receptor-α
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
24
Q
The principal form of the folate in tissues and in blood
A
N5-methyl form
25
Breakdown product of folic acid metabolism
p-Aminobenzoylglutamate
26
**Folate-binding proteins of serum and milk** can be detected in approximately ___% of normal individuals
15%
## Footnote
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
27
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
## Footnote
* 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
28
# 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
29
The cobalamin molecule has a **porphyrin-like near-planar macrocycle** known as_______
Corrin
30
The usual therapeutic form of cobalamin
Cyanocobalamin
31
Four cobalamins are important in animal cell metabolism
* Cyanocobalamin (CnCbl; **vitamin B12**)
* Hydroxocobalamin (OHCbl) or **aquocobalamin** (HOHCbl)
* Adenosylcobalamin (AdoCbl)
* Methylcobalamin (MeCbl)
## Footnote
The latter 2 cobalamins are alkyl derivatives that are synthesized from OHCbl and serve as coenzymes.
32
2 cobalamins are alkyl derivatives that are synthesized **from OHCbl** and serve as **coenzymes**
Adenosylcobalamin (AdoCbl)
Methylcobalamin (MeCbl)
33
The major form of cobalamin in human blood plasma
MeCbl
34
# 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.
## Footnote
Foods that contain cobalamin are of **animal origin: meat, liver, seafood, and dairy products**
35
Total body content of cobalamin
2–5 mg
36
Amount of cobalamin found in liver
1 mg
## Footnote
The kidneys also are rich in cobalamin
37
# 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**.
## Footnote
* 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.
38
The official RDA for cobalamin among adults
2.4 mcg
39
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
40
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
41
# 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**.
42
# 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.
43
# 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**
44
Two explanations have been proposed to account for the **folate responsiveness** of cobalamin-deficient megaloblastic anemia:
* Methylfolate Trap Hypothesis
* Formate Starvation Hypothesis
45
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
46
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
47
Human **intrinsic factor** is a glycoprotein (Mr approximately 44,000) encoded by a gene on _________________
Chromosome 11
48
Promotes absorption uptake of cobalamin by **ileum**
Source: **Gastric parietal cells** of the cardiac and fundic mucosa
Intrinsic factor
## Footnote
Secretion of intrinsic factor usually parallels that of hydrochloric acid (HCl).
49
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
## Footnote
*Cobalamin binds much more tightly to HC than to intrinsic factor at the **acid pH of the stomach**.*
50
Promotes uptake of cobalamin by cells
Source: Probably all cells
Transcobalamin
51
Helps dispose of cobalamin analogues; possible antimicrobial function(?)
Source: Exocrine glands, phagocytes
Haptocorrin
(previously known as R proteins or TC I and TC III)
52
# 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
53
The **intrinsic factor receptor**, located in the microvillus pits of the ileal mucosa brush border
Cubilin
54
The ileal cubilin receptor complex consists of 2 proteins:
Cubilin (CUB) and amnionless (AMN)
“CUBAM complex”
55
In the portal blood, the cobalamin is complexed with a cobalamin-transporting protein known as
**Transcobalamin (TC)** previously known as transcobalamin II
56
The protein with which cobalamin given parenterally associates almost immediately
Mediates the transport of cobalamin into the tissues.
Transcobalamin (TC)
57
**Transcobalamin receptor** is designated as ____; it belongs to the low-density lipoprotein receptor family and its internalization involves **megalin**
CD320
58
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**)
## Footnote
* 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
59
Current assays use ______________ as the binder and give more reliable values for serum cobalamin.
Intrinsic factor
60
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
61
Conditions with **Increased haptocorrin (transcobalamin I, R protein)**
* Myeloproliferative disorders
* Polycythemia vera
* Myelofibrosis
* Benign neutrophilia
* Chronic myelocytic leukemia
* Hepatoma (occasionally)
* Metastatic cancer
62
Conditions with **Increased transcobalamin**
* Liver disease
* Inflammatory disorders
* Gaucher disease
63
Morphologic hallmark of megaloblastic anemias
Presence of megaloblastic cells
64
Cell with a large **horseshoe-shaped nucleus**, sometimes irregularly shaped, containing ragged open chromatin
Giant metamyelocyte
65
The most common causes worldwide of megaloblastic anemia
Folate deficiency and cobalamin deficiency
66
# 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.
67
# 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
## Footnote
Although coexisting iron deficiency, thalassemia trait, or inflammation can prevent macrocytosis.
68
The **earliest** observable change in red cell indices in megaloblastic anemia is
Increase in the red cell distribution width
## Footnote
Platelets are often reduced in number and slightly smaller than normal with a wider variation in size (increased platelet distribution width).
69
Typically, more than _________% of the neutrophils have 5 lobes
more than 5%
70
# 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
## Footnote
In folate deficiency, hypersegmented neutrophils are an **early sign of megaloblastosis** and persist in the blood for many days after treatment
71
Specific therapy corrects these abnormalities, usually within _____ days, although some abnormalities do not disappear for months.
2 days
72
# Megaloblastic Anemia
Plasma bilirubin, iron, and ferritin levels are (increased or decreased).
Increased
73
# 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.
74
Megaloblastic anemia is associated with two pathophysiologic abnormalities:
**Ineffective erythropoiesis** (exaggerated apoptosis of precursor cells) and **hemolysis**
75
Folate deficiency is caused by:
* (a) dietary deficiency
* (b) impaired absorption
* (c) increased requirements or losses
76
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)
77
# 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**.
## Footnote
Tropical sprue is **rapidly corrected by folate therapy**, even though folate deficiency is not the primary cause of the disease.
78
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
79
The major cause of the megaloblastic anemia of pregnancy
Folate deficiency
80
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
81
The earliest specific indicator of folate deficiency
Low serum or plasma folate
82
**A better indicator of the tissue folate status**
Reflects folate status over the preceding 2–3 months
Red cell folate
## Footnote
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
In folate deficiency, uncomplicated by causes of microcytosis, the MCV is usually higher than ______ fL.
110 fL
84
# 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
## Footnote
This is not recommended as a diagnostic test because neurologic problems may develop in cobalamin-deficient patients treated with folate alone.
85
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
86
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
87
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**
## Footnote
A portion of the neural tube closure defects are associated with **antibodies against folate receptors** that may be overcome by higher folate intake
88
# 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.
89
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
90
Usual dose of folic acid therapy
1-5 mg/day
## Footnote
*1 mg usually is sufficient. *
91
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.
92
Dosage of folate among pregnant women
400 mcg of folate per day
93
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
94
# Low-dose methotrexate
Administration of _____________ can prevent or greatly diminish the major side effects without reducing the therapeutic effect of **low-dose methotrexate**.
## Footnote
The incidence of side effects, including hepatotoxicity, has been correlated with reduced folate levels.
Folic or folinic acid
95
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
## Footnote
Frequent in patients with other autoimmune diseases
96
In patients with PA, antibodies occur that recognize the _______________
H+/K+- ATPase
97
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)
98
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
99
In Pernicious Anemia, there is ____fold increase in the incidence of **gastric cancer**
Twofold
100
Measurement of ________________ in serum represents the only available method to confirm a diagnosis of PA
Antiintrinsic factor antibodies
101
Most common type of anemia after gastric surgery
Iron-deficiency anemia
## Footnote
Iron-deficiency anemia is most common, but cobalamin deficiency with megaloblastic anemia can occur.
102
After **total gastrectomy**, cobalamin deficiency develops within _______ years
5 or 6 years
103
# 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.
104
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
## Footnote
The resulting acidification of the duodenal contents prevents transfer of Cbl from HC binder to intrinsic factor and also inactivates pancreatic proteases
105
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
## Footnote
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”
106
Another cause of cobalamin deficiency is infestation with this **fish tapeworm**
Diphyllobothrium latum
107
It may take _____ years for an individual consuming a **vegan** diet to manifest features of cobalamin deficiency.
10–20 years
## Footnote
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
The neurologic lesions of cobalamin deficiency result from
Deranged methyl group metabolism
## Footnote
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
Specific feature caused by the lack of cobalamin
Neurologic abnormalities
## Footnote
* 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
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
111
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
112
Frank psychosis in cobalamin deficiency has been given the sobriquet
Megaloblastic madness
113
The neurologic lesions of cobalamin deficiency can be detected by
Magnetic resonance imaging (MRI)
## Footnote
T2-weighted hyperintensity of the white matter
114
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
115
Characterized by mutation in the **MTR** gene leading to a dysfunctional **methionine synthase enzyme**
cblG
## Footnote
Prone to vasculopathies, thrombotic and red cell dysfunction
116
Disease involves a defect in the enzyme responsible for conversion of cobalamin into its metabolically active reduced forms causing accumulation of homocysteine
cblC
## Footnote
117
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
118
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%)
## Footnote
*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
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
120
A reliable indicator of cobalamin deficiency
Methylmalonic aciduria
## Footnote
* In cobalamin deficiency, urine methylmalonate usually is elevated.
121
Indicators of **tissue cobalamin deficiency**
Plasma or serum methylmalonic acid and homocysteine
## Footnote
Levels are high in more than 90% of cobalamin-deficient patients and rise before plasma cobalamin falls to subnormal levels
122
# TRUE OR FALSE
Homocysteine measurement is less sensitive and more specific
FALSE
**Methylmalonic acid** measurement is both more sensitive and more specific than homocysteine
## Footnote
* 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
Polymorphism results in *higher methylmalonic acid concentrations unrelated to B12 status*
3-hydroxyisobutyryl- CoA hydrolase (HIBCH)
124
Previous “gold standard” for assessment of cobalamin absorption
Schilling test
125
Treatment of cobalamin deficiency consists of
Parenteral CnCbl (vitamin B12) or OHCbl
Normally contain **2–5 mg** of cobalamin
## Footnote
Doses exceeding **100 mcg** *saturate the cobalamin-binding proteins (TC and HC)*, and the excess is lost in the urine.
126
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
127
Treatment schedule for cobalamin deficiency with **neurologic** manifestations
1000 mcg every 2 weeks for 6 months
128
Transfusion occasionally is required when the hematocrit is less than ____% or the patient is **debilitated, infected, or in heart failure.**
less than 15%
129
# 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
## Footnote
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
# Response to Treatment and Therapeutic Trial
Blood hemoglobin concentration becomes normal within _____ months
1–2 months
## Footnote
If normal values are not achieved by 2 months, another cause of anemia should be sought.
131
# 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
132
Larger doses of folate ________ (mg/day) can produce a reticulocytosis and **partially or temporarily correct** the anemia in cobalamin deficiency.
5–15 mg/day
## Footnote
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
# TRUE OR FALSE
Cobalamin administration is not necessary after total gastrectomy
FALSE
Cobalamin administration is **not necessary after partial gastrectomy**
## Footnote
**Cobalamin should always be given after total gastrectomy.**
134
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
135
Treatment for Fish Tapeworm
50 mg/kg of **niclosamide**
5–10 mg/kg of **praziquantel**
136
Oral cobalamin can be used for:
* Dietary cobalamin deficiency
* Patients (eg, hemophiliacs, the frail elderly) who cannot take intramuscular injections
* Patients with PA
## Footnote
**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
The most common cause of **acute megaloblastic anemia**
N2O anesthesia
## Footnote
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
# ACUTE MEGALOBLASTIC ANEMIA
**Hypersegmented neutrophils** do not appear until _____ days after exposure but then persist for several days.
5 days after exposure
## Footnote
Grossly megaloblastic changes are seen in the marrow after 12–24 hours.
139
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
## Footnote
***A rapid response to therapeutic doses of parenteral folate (5 mg/day) and cobalamin (1 mg) is the rule.***
140
Inhibitors of **dihydrofolate reductase**
Aminopterin and methotrexate
141
Cause **irreversible inhibition of thymidylate synthase**
5-fluorouracil and 5-fluorodeoxyuridine
142
Inhibit **dihydroorotate dehydrogenase**
**Leflunomide** for inflammatory arthritis and **teriflunomide** for multiple sclerosis
143
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**
## Footnote
Folic acid itself is useless in this setting because the blocked reductase cannot convert folic acid and dihydrofolate to the active tetrahydro form.
144
ARV that causes severe megaloblastic anemia
The blood film shows **vacuolated monocytes**.
Zidovudine (azidothymidine [AZT])
## Footnote
Megaloblastosis in HIV infection may result from **folate or cobalamin deficiency** or **AZT or trimethoprim toxicity**.
145
It inhibits conversion of ribonucleotides to deoxyribonucleotides.
megaloblastic changes are routinely found in the marrow 1–2 days after initiating therapy
Hydroxyurea
146
An antifolate approved for use in **mesothelioma** and for treatment of **non–small cell lung cancer**
Pemetrexed
147
A **dihydrofolate reductase inhibitor** that is designed to act on the microbial rather than the mammalian enzyme
Trimethoprim
148
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
149
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
## Footnote
Patients are treated with **intramuscular cobalamin.**
150
Affected genes in Imerslund- Gräsbeck disease
CUBN
AMN
151
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
## Footnote
Treatment consists of standard doses of intramuscular cobalamin.
152
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
## Footnote
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
Congenital deficiency is **not associated with clinically manifested cobalamin deficiency**
Haptocorrin Deficiency
## Footnote
The absence of morbidity in these patients indicates that **HCs are not essential for health.**
154
Condition where **AdoCbl production is impaired** but MeCbl production is normal
Methylmalonic Aciduria Only (cblA, cblB, and cblH)
| MethA-BHA
## Footnote
* Present in infancy with **acidosis** because they cannot catabolize methylmalonic acid
* Mental retardation is not prominent, and megaloblastic anemia is absent.
155
**N5-methyltetrahydrofolate-homocysteine methyltransferase** is defective and lacks the capacity to produce **MeCbl**
Homocystinuria Only (cblE and cblG)
| GE-Cys
## Footnote
**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
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)
## Footnote
**cblF**: inability to release cobalamin from lysosomes
157
The most common of the cobalamin inborn errors
cblC
158
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
## Footnote
Treatment with daily folinic acid by injection maintains the spinal fluid level and can lead to normal development.
159
# 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.
160
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
161
**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
162
An autosomal recessive disorder of pyrimidine metabolism characterized by **megaloblastic anemia**, **growth impairment**, and excretion of **orotic acid in the urine**.
Hereditary Orotic Aciduria
163
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
164
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)
## Footnote
The anemia and diabetes responds to thiamine **(25–100 mg/day)**
165
Types of **Congenital Dyserythropoietic Anemia** that show megaloblastic red cell precursors
Type I usually and type III occasionally
166
Regarded as a manifestation of some **sideroblastic anemias and myelodysplastic disorders**
Dysplastic features are confined to the erythroid series.
Refractory Megaloblastic Anemia
167
Patients at high risk to develop acute megaloblastic anemia
Patients transfused extensively during surgery
Patients on dialysis
Patients on TPN
