Vitamin B12 Flashcards
(74 cards)
1
Q
Thomas Addison
A
English Physician. Describes a group of patients with a “remarkable form of anemia”.
2
Q
Biermer
A
Named Pernicious anemia (fatal anemia)
3
Q
Whipple
A
Describes treating experimental anemia in dogs by feeding raw liver.
4
Q
Minot and Murphy
A
Successfully treat pernicious anemia in humans by feeding cooked liver (120 to 240 g/d)
5
Q
1934 Noble Prize in Physiology or Medicine
A
Whipple, Minot and Murphy. “for their discoveries concerning liver therapy in cases of anemia”
6
Q
Vitamin B12
A
the generic descriptor for corrinoid compounds exhibiting the biological activity for B12.
7
Q
Cyanocobalamin
A
-CN
8
Q
Hydroxocobalamin
A
-OH
9
Q
Aquocobalamin
A
-H2O
10
Q
Nitritocobalamin
A
-NO2
11
Q
5’-deoxyadenosylcobalamin
A
5’-deoxyadenosyl
12
Q
Methylcobalamin
A
-CH3
13
Q
Food sources
A
- Synthesized solely by bacteria
- Only dietary sources are animal products, which have derived their B12 from bacteria
14
Q
Why animal tissues?
A
- Animal tissues accumulate B12 (liver)
- Ruminant animals obtain B12 from gut bacteria
15
Q
What does not contain B12?
A
- Plants do not synthesize B12
- Fruits, vegetables, and grains contain no B12 (unless contaminated by bacteria).
16
Q
Most amount of B12
A
- Beef liver
- clams
- oysters
17
Q
Vegan friendly sources of VitB12
A
Silk, cereal, tofu
18
Q
Naturally occurring B12 in food
A
- Bound to protein
- Must be released for absorption
- Gastric acid is essential
19
Q
Synthetic B12 in fortified foods
A
Not bound to protein
20
Q
Vitamin B12-binding/ transport proteins
A
R-Protein
Intrinsic Factor
Transcobalamin II
21
Q
R-Protein
A
- Also called haptocorrin or transcobalamin I)
- Glycoproteins secreted by salivary glands
- Binds to B12 and protects it from stomach acid
22
Q
Intrinsic Factor
A
- Glycoproteins secreted by gastric parietal cells
- Binds to B12 in intestine and transport it to IF receptor
23
Q
Transcobalamin II
A
Main transport protein for B12 in plasma
24
Q
Vitamin B12: Active Absorption
A
Stomach, Duodenum, Ileum
25
Stomach
Food B12 is released from proteins by pepsin and HCl
26
Duodenum
- B12-R is acted upon by pancreatic protease, releasing free B12
- Free B12 binds to intrinsic factor, forming B12-IF complex
27
Ileum
- B12-IF binds to B12-IF receptor (cubilin) on intestinal cell
- B12-IF-cubilin complex is internalized by endocytosis
- B12 is released from IF-cubilin
- Free B12 binds to transcobalamin II in portal bloodstream.
28
Passive Absorption
- Simple diffusion
- Occurs throughout the small intestine
- Inefficient (~1% absorbed)
- Used in therapy (>500 ug/day)
- Usually given per os
- Can be given intranasally
29
Atrophic Gastritis
- Chronic inflammation of gastric mucosa with loss of parietal cell function
- Autoimmune disorder in which antibodies destroy parietal cells
- Results in loss of intrinsic factor
- MOST COMMON CAUSE OF PERNICIOUS ANEMIA
30
Dr. William B Caste
Found the IF. Ate raw beef. Added HCl, let simmer for 6 hours put back into a container and given to patient. RBC count increases
31
Vitamin B12 Transport
TCI, TCII, TCIII
| -B12 in plasma is bound to transcobalamin (TC) proteins
32
TCI
- ~80%
- Also known as haptocorrin (see absorption)
- Circulating storage form
33
TCII
- (10-25%)
- MAIN TRANSPORT PROTEIN
- delivers B12 to all cells
34
TCIII
Function unknown
35
B12 Storage
- 2-4 mg store in body, mainly (~50%) in liver
| - 70% stored as adenosylcobalamin
36
B12 Excretion
- Bile (~1.5 ug/day)
- about 70% reabsorbed
- Patients with pernicious anemia do not reabsorb b/c they lack intrinsic factor
37
Vitamin B12 Function
2 Types of Reactions
- methyl group transfer reactions
- mutases
- exchange a hydrogen and some other groups between 2 adjacent carbons atoms
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Methionine Synthase (MS)
- Uses methylcobalamin as an intermediate methyl carrier at one active site of MS enzyme
- Transfers methyl group from cobalamin to homocysteine at another site
39
Methylmalonyl CoA Mutase (MCM)
- Located in mitochondria
- Enzyme that catalyzes the isomerization of methylmalonyl-CoA to succinyl-CoA
- Uses adenosylcobalamin in active site
40
Adenosylcobalamin
The Co-CH2 bond is relatively weak and can therefore be easily broken, forming a free radical that can abstact a hydrogen (from methylmalonyl)
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Vitamin B12 Function
Two Primary enzymatic pathways
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B12 Function #1
Remethylation of homocysteine
- methylcobalamin
- occurs in cytoplasm
43
B12 Function #2
L-methylmalonyl CoA --> Succinyl CoA
- Adenosylcobalamin
- Occurs in Mitochondria
44
Methyl Trap Hypothesis
In a vitamin B12 deficiency
- Methyl group is "trapped" in the N-5 methyl form
- MTHFR reaction is irreversible
45
When B12 is low. What is high?
- Homocysteine
| - 5-CH3THF
46
When B12 is low... What else is?
EVERYTHING
47
Megaloblastic Anemia
- DNA synthesis is needed for early erythroblasts to divide and mature.
- In folate/b12 deficiency DNA synthesis is impaired; early erythroblasts cannot divide and escape into bloodstream
- Early erythroblasts cannot divide and escape into bloodstream
- Early erythroblasts are large (megalo) and do not contain much hemoglobin
- clinically known as megaloblastic anemia
48
B12 Deficiency and MMA
B12 is required for conversion of methylmalonyl CoA to succiny CoA
- In B12 deficiency, methylmalonyl-CoA accumulates and is hydrolyzed to CoA and Methylmalonic acid (MMA)
- MMA is associated with neurodegeneration
49
Masking of B12 deficiency by folic acid
- B12 deficiency is often identified by megaloblastic anemia
- folic acid can correct megaloblastic anemia due to B12 defiency-- but cannot correct the other effects of B12 deficiency (neurologic effects)
- Thus, folic acid can "mask" or hide B12 defiency
50
How does folic acid mask B12 deficiency?
Folic acid treatment reverses anemia because B12 deficiency causes "secondary folate deficiency" because it reduces THF and thus 5,10methyleneTHF for DNA
51
If anemia due to B12 deficiency:
- degeneration of the spinal cord
- difficult to diagnose early stages
- worsens without B12 therapy
- cells view folate/ b12 deficiency the same way
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Vitamin B12 Deficiency
Status Assessment
Causes
Clinical Significance
53
B12 Status Indicators
- Diet and supplement history & medical history
- Serum vitamin B12
- Homocysteine increases: NOT specific but functional
- METHYL MALONIC ACID INCREASES: SPECIFIC INDICATOR, FUNCTIONAL
- Holotranscobalamin (
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Serum deficiencies
-
55
Monitoring Vit. B-12 in the U.S.
uses plasma methylmalonic acid & serum Vit. B12
56
Vit B12 deficiency causes
```
-malabsorption
Pernicious anemia
Food Bound
-Nitrous oxide
-Dietary Inadequacy
```
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Pernicious Anemia
- usually caused by lack of functional IF in stomach
- autoimmune destruction of the gastic parietal cells
- prevalence 2-3% of the populations >65 years
- rarely occurs in younger individuals
- gastrectomy
- surgical removal of stomach
58
Treatment for pernicious anemia
- IM b12 injections (100-1000ug cyanocobalamin)
- injections at monthly intervals
- Oral b12 supplement (> or + to 1000ug)
- daily dosing recommended
59
Gastric Atrophy
- Loss of stomach acid for extraction of B12 from food
- Can absorb crystalline normally (have intrinsic factor)
- May affect >30% of elderly
- H. pylori is a cause of gastric atrophy
60
Elderly B12 status in the US
- Elderly have lower serum vitamin B12 than younger individuals
- related to food-bound malabsorption
- elevated serum methylmalonic acid concentrations common in elderly
- population-based data
61
Nitrous oxide
- laughing gas, anesthesia
- oxidizes cobalt in B12
- results in B12 deficiency and spinal cord degeneration as seen in classical B12 deficiency
- seen in dentists, dental assistants, individuals who use nitrous oxide as recreational drug
62
Lacto-ovo vegetarians
excludes all meat except dairy and eggs
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Lacto-vegetarians
excludes all meat except dairy
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Vegans
Exludes all meat and products
65
Deficiency and vegetarianism
- Reported in all who do not take supplements or eat B12-fortified foods
- the more restricted the diet, the more likely a deficiency may occur
66
Infants on Macrobiotic diets
Research study
-41 infants (10-20mo) fed a macrobiotic diet
-50 controls (omnivorous)
Mothers of macrobiotic infants consumed macrobiotic diet for ~3 years
-Breast fed infants from birth with complementary macrobiotic foods
67
Macrobiotic B12 deficient diet
Diet consists of:
- grain cereals
- mainly rice
- veggies
- pulses
- mainly soy
- sea vegetables
- small amount of fruit
68
Infants whose mothers ate macrobiotic vegetarian diets
- High in methylmalonic acid, homocysteine.
| - Low in cobalamin
69
Clinical significance
- Impaired neurological function
- megaloblastic anemia
- neural tube defect increased risk
70
Neurological Abnormalities
- Neurological degeneration of peripheral nerves
- impaired touch and pain sensation
- Ataxia - unsteady gait
- Degeneration of spinal nerves
71
Other neurological abnormalities
- -Physical reflexes and stamina
- mental attributes including memory loss
- behavioral changes
- altered mood and reaction to stress
72
Demylination of nervous system: proposed mechanisms
- Decreased synthesis of S-adenosylmethionine
- methylation reactions
- neurotransmitters
- membrane phospholipids in myelin
- Disrupted odd chain fatty acid metabolism related to the accumulation of methylmalonic acid and its precursos (proprionic acid)
73
EAR
2 ug/day
74
RDA
2.4 ug/day
