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Nutrition 6 & 7 - Water Soluble Vitamins
Vitamin C (Ascorbic Acid)
- an essential nutrient in humans
- 1. it's an electron donor (antioxidant) in a number of reactions
- 2. it contributes to protein & neurotransmitter metabolism
- 3. facilitates absorption of non-heme iron in the small intestine
- active form: L-ascorbic acid
- most stable form: dehydroascorbic acid (DHAA)
- excreted as: diketogulonic acid (irreversible)
Vitamin C’s Specific Roles
- Collagen synthesis: hydroxylation of proline (for triple helix) & lysine (for hydroxylysine cross-links)
- Carnitine synthesis: made from lysine & methionine w/ vitamin C as cofactor (among other things)
- Neurotransmitter metabolism: C is used in tyrosine catabolism & hydroxylation of dopamine --> norepineph.
- Antioxidant function: in PMN, monocytes, macrophages, lung and eye, & in the regeneration of reduced vitamin E
What type of enzyme (and co-factor) is required for hydroxylation of proline and lysine during collagen formation?
Hydroxylases; ascorbic acid (Vitamin C is the co-factor)
What conditions can destroy ascorbic acid?
- it's easily destroyed by oxidation, heat, exposure to air, an alkaline medium, & by contact with copper & iron, which oxidize it to dehydroascorbic acid (DHAA)
- this explains in part why the Vitamin C content of foods is subject to degradation with storage & cooking
- it's labile & content will diminishes with storage, long shelf time, & cooking
Which has more Vitamin C, frozen, fresh, or canned vegetables?
FROZEN vegetables usually have more Vitamin C that their canned or fresh counterparts because it's preserved in the frozen state
Where can ascorbic acid be found?
- it's widely found in any plant that is fresh & rapidly growing (eg. fruits, some vegetables, while dormant foods such as nuts, seeds and grains are poor sources)
- synthesized by some non-primates and most plants from glucose & fructose
What may help preserve vitamin C content in food?
- 1. organic acids
- 2. antioxidants
Where is Vitamin C absorbed?
- in the small intestine by specific transporters
- plasma concentrations are tightly controlled, mediated by absorption but more so by RENAL handling: ascorbic acid is filtered by the glomerulus & reabsorbed in the proximal convoluted tubule
How much Vitamin C is reabsorbed in the proximal convoluted tubule after different doses & variable concentrations?
- low doses, normal concentrations: nearly 100% is reabsorbed
- high doses: less than 50% is reabsorbed
What is a risk of Vitamin C catabolism in humans?
- in humans ascorbic acid is catabolized to oxalic acid
- there is a risk for oxalate kidney stones in susceptible persons who consume a large amount of vitamin C (aka it may potentiate oxalate nephrolithiasis)
What does a deficiency of vitamin C lead to?
- weakness and lassitude
- skin and soft tissue (impaired wound healing, petechial hemorrhage, perifollicular hyperkeratosis, ecchymosis)
- oral issues: swollen gums that bleed easily & are friable, tooth loss
- coiled hair
- joint issues: bleeding into joints, arthralgias
- cardiopulmonary issues: shortness of breath, pericardial bleeding
- bone: impaired growth & bowing, subperiosteal hemorrhage, impaired healing
- CNS issues (depression, confusion, hysteria, hypochondriasis)
- internal bleeding
What is the RDA for Vitamin C based on?
- intake adequate to maintain normal neutrophil concentrations & urinary excretion
- women: 75 mg/day
- men: 90 mg/day
What is the RDA for smokers?
- 35 mg/day higher than for nonsmokers
- this is because smoking leads to oxidative stress and smokers generally have reduced circulating concentrations of ascorbic acid
How does cigarette smoking lead to oxidative stress?
- cigarette smoke oxidizes a methionine residue on alpha1-antitrypsin involved in binding elastase
- methionine --> methionine sulfoxide
- Oxidation of this residue PREVENTS inhibition of elastase, results in over-degradation of lung elastin fibers --> lung scarring & emphysema
- b/c Vitamin C can act as an antioxidant (probably due to it's OH group) reducing harmful free radicals, it can help mitigate the effects of smoking
What is the UL of Vitamin C?
- 2 g/day
- it's based on the gastrointestinal side effects of diarrhea and bloating
- also excess intake can lead to increased urinary excretion of oxalate & uric acid (hyperoxaluria), both of which may potentiate kidney stones in predisposed individuals
- + enhanced iron absorption
Thiamine (Vitamin B1)
- a cofactor for enzymes such as transketolases & dehydrogenases & is essential in energy utilization and synthesis
- in nerves, thiamine participates in synthesis of acetylcholine, glutamate, + GABA, & is released from nerves with nerve stimulation
- it's found in whole grains, some vegetables, legumes, & pork, but less so in beef, lamb, poultry, or dairy
functions in the pentose phosphate pathway to produce NADPH for biosynthesis
- such as pyruvate dehydrogenase, which converts pyruvate to acetyl CoA
- a thiamine deficiency causes E1 to not function properly, meaning pyruvate can only be converted to lactate
What degrades thiamine?
- 1. the processing of grains: which is why it's added to enriched grains and cereals
- 2. thiaminases: found in fish, shellfish, ferns, & some microorganisms
- 3. antithiamine compounds
- compounds that degrade thiamine in raw food or in the digestive system (after consumption of foods that have thiamine)
- found in fish, shellfish, ferns, & microrganisms
- are thermoLABILE, aka destroyed by cooking (heat)
- cleaves thiamine to form oxidized inactive comounds
- *is thermoSTABLE
- found in coffee, teas, betel nuts, & other foods w/ polyphenol-like compounds
Are thiaminases & antithiamine compounds usually significant risk factors for deficiency with varied balanced diets in healthy persons?
Where is Thiamine absorbed?
- absorption occurs most in the jejunum & ileum
- once inside intestinal cells, thiamine is trapped there by phosphorylation
- it's secreted into the portal circulation through SLC19 transporters or by basolateral export to circulate free form or as thiamine monophosphate
- thiamine phosphates are sequestered in RBCs & other tissues
Approximately 50% of body thiamine is found in which tissue?
- there is also some stored in the liver
Where have thiamine transporters (of the SLC19 family) been found?
- in several tissues, including intestines and kidney
- mutations for these carriers cause thiamine deficiency (DISEASE) due to impaired transport
What is the total body pool of thiamine?
- 30 mg
- roughly equal to 30 days of intake at the RDA
- the rapid turnover of thiamine requires near CONTINUOUS intake to prevent deficiency
- there is renal excretion of thiamine and metabolites
What is the most common condition that thiamine deficiency is seen in?
- alcohol abuse
- ethanol prevents basolateral absorption of thiamine from the small intestine endothelium, which manifests as thiamine deficiency
- it also impairs it's phosphorylation to the active cofactor diphosphate form (TPP, thiamine pyrophosphate)
- there are reduced liver stores of it due to liver fibrosis/cirrhosis
What are some risk factors for thiamine deficiency?
- Poor dietary intake
- Persistent vomiting (especially after bariatric surgery, hyperemesis gravidarum)
- Gastrointestinal disease
- Refeeding syndrome
- A limited diet that contains large amounts of foods w/ thiaminases or antithiamines (raw fish, coffee)
thiamine deficiency results in:
- cellular energy failure
- manifests as fatigue, central + peripheral nervous system defects, & cardiovascular issues
- lactate accumulation
- fewer TCA intermediates
- less high energy phosphate synthesis
- less NT synthesis
- Peripheral neuropathy, distal > proximal
- Involves motor and sensory nerves
- Diminished reflexes
- Calf tenderness
- Tachycardia & low peripheral resistance
- Cardiomegaly & high output congestive heart failure
- Peripheral neuropathy
- characterized by cardiac & CNS manifestations
- it can occur in mothers who are thiamine deficient but asymptomatic, which may lead to delays in the diagnosis in the infant
- can arise from deficiency of vitamin B1 (thiamine) - acute/early
- C confusion
- O ophthalmoplegia
- A ataxia (difficulty with motor control)
- T thiamine Tx
- can arise from deficiency of vitamin B1 (thiamine) - chronic/late
- R retrograde amnesia
- A anterograde amnesia
- C confabulation (tall tales)
- K Korsakoff's psychosis
How was the RDA for thiamine determined?
- by depletion/repletion studies & erythrocyte transketolase activity
- is such an assay, thiamine is added to red blood cells and the increased activity of transketolase is measured
- a deficiency is associated with greater degrees of transketolase activity stimulation by addition of thiamine
What is the UL for thiamine?
THERE IS NON3! CAN NEVER HAVE TOO MUCH!
Niacin (Vitamin B3)
- also known as nicotinic acid/nicotinamide/niacinamide
- forms the coenzymes NAD (nicotinamide adenine dinucleotide) & NADPH (nicotinamide adenine dinucleotide phosphate)
What else can NAD can be synthesized from?
- however, niacin/NAD deficiency can still occur when tryptophan is sufficiently present in the diet to synthesize NAD
What are good sources of niacin?
meats, fish, yeast, some nuts, whole grains, & wheat germ
Why is niacin biounavailable in some foods like corn?
- it may be bound to carbohydrates
- unless it's treated with alkali (eg. limewater as used for corn tortillas), this form of niacin is NOT bioavailable
- limewater is the common name for an saturated solution of calcium hydroxide
For what condition is a large niacin dose (greater than that present from food intake) prescribed?
- niacin (not nicotinamide though) binds to & stimulates a G-protein-coupled receptor, which initiates a cascade that inhibits fat breakdown in adipose tissue -> LESS VLDL & LDL in blood
How does Niacin primarily exist in the plasma?
- as nicotinamide
- approximately 1/3 of plasma nicotinamide is bound to plasma proteins
How does Niacin primarily exist in tissues?
- as coenzymes NAD & NADPH
- excess hepatic NAD may be stored in small amounts unbound to proteins
NAD & NADP
coenzymes involved in energy utilization and synthetic reactions in processes such as glycolysis, the TCA cycle, beta-oxidation of fatty acids, ethanol oxidation, ADP-ribosylation, DNA excision repair, cell replication, cell differentiation, & apoptosis
major role of NADH
- to donate its electrons to the electron transport chain allowing the generation of ATP
- NADPH is a reducing agent in multiple biosynthetic reactions
What populations are at risk for niacin deficiency?
- those of lower socioeconomic class who primarily consume corn, which contains niacin but it remains complexed to carbohydrate & is unavailable unless treated with alkali
- people who have diets characterized by 3 Ms:
- 1. Maize (if untreated w/ alkali)
- 2. Meat (if poor quality + high fat)
- 3. Molasses
Why do diets that primarily consist of sorghum lead to niacin deficiency?
because sorghum diets have a high leucine content, which interferes with conversion of tryptophan to NAD
- defective tryptophan transporter; leads to abnormal secretion of AAs (including tryptophan and those like it which use the same transporter) in the urine
- it's characterized by dermatitis, diarrhea, & dementia (3 Ds) similar to pellagra b/c tryptophan is a precursor of niacin --> nicotinamide --> NAD+ coenzyme, but Hartnup's is less severe & more intermittent
- it's effects are seen mostly in brain & skin
- the array of symptoms that occur secondary to carcinoid TUMORS, including flushing, diarrhea, heart failure, or bronchoconstriction
- can CAUSE niacin deficiency in that the tumor overuses tryptophan to endogenously synthesize serotonin & kallikrein (+ inflammation stuff)
- caused by niacin deficiency, characterized by the four Ds:
- 1. Dermatitis: in sun-exposed areas of the skin; skin of pellagrins is lower in urocanic acid (degradation product of histidine), which contributes to UV light absorption
- 2. Diarrhea: due to mucosal atrophy + inflammation in GI tract
- 3. Dementia: + mood disorders, altered mental status, neuropathy, or muscle weakness
- 4. Death
What are the dietary guidelines for niacin?
- males: 16 mg NE/day
- females: 14 mg NE/day
- niacin intake is expressed in niacin equivalents (NE), meaning intake can be of niacin or of tryptophan (60 mg tryptophan are needed to synthesize 1 mg of niacin)
What is the UL for niacin?
- 35 mg/day, which is based on flushing
- high doses of nicotinic acid or nicotinamide can result in:
- GI symptoms (heartburn, nausea, vomiting), Hepatotoxicity, Hyperuricemia, Gout (niacin competes with uric acid for excretion), Decreased insulin sensitivity, & Glucose intolerance
Folate (Vitamin B9)
- important for nucleotide & methionine (AA) synthesis, as well as methylation
- made up of a pterin ring connected to glutamic acid residue via a para-amino benzoic acid bridge (lol)
Folate v. Folic Acid
- folates are found in food
- folic acid is the synthetic form of folate found in fortified food supplements (stable oxidized form of folate with one glutamic acid)
In what foods can folate be found?
- it's widely distributed in food, especially food fortified w/ folate
- good examples = spinach, liver, lima & kidney beans, brussel sprouts, broccoli, & yeast
Why is folate/folic acid mainly important?
it prevents neural tube defects, spina bifida and anencephaly
How is folate absorbed?
- in the SI mucosa
- folate is made available after food has been digested, it's been released from some matrix, & converted to a form we can use
- it is stored in liver, resulting in small daily losses when bile is secreted
- however the liver store can last a person for ~2-3 months
- b/c folate is H2O soluble we don't store too much & resupply should be frequent
What is the total body pool of folate?
- 10-20 mg: 4-15 mg stored in liver
- daily folate losses are 200 mcg, 1-2% of stores
- periods of increased folate demand (pregnancy & lactation) may result in more rapid utilization of folate stores
How are folate levels assessed?
- by the concentration in plasma or in RBCs
- plasma folate reflects recent intake
- RBC folate remains relatively stable over the lifespan of the cell, thus decreased RBC folate suggests a more chronic deficiency
- RBCs eventually become macrocytic due to folate deficiency
- anemia due to ineffective hematopoesis occurs later in deficiency
- can also check liver stores
Which is better, the bioavailability of folate or folic acid?
- FOLIC ACID is better absorbed; over 85% is absorbed from a given dosage
- compared to 60% of folate in a food containing it
- bioavailability of folate from food is good, but not as good as for the synthetic acid
- (naturally-occurring folates in food: ~60%
- absorption of folic acid in supplements: approaches 100%
- absorption of folic acid in fortified foods: > 85%)
What is the relationship between folate (B9) & cobalamin (B12)?
- in the reaction catalyzed by methionine synthase, both B12 & methyl THF act as 'coenzymes'
- the B12 is the molecule that actually holds & transfers a methyl group (methylcobalamin) onto homocysteine, forming methionine
- if there is a deficiency of either B12 or folate, this reaction can't happen & homocysteine may accumulate
What are high levels of homocysteine associated with?
- heart disease
- (homocystinurea - but that's usually because of a defective enzyme)
The Folate Trap
- in addition to just not having enough folate, a deficiency in Vitamin B12 (cobalamin) causes a folate deficiency, because without it the CH3 group in methyl tetrahydrofolate cannot be transferred
- folate is sequestered in its non-physiologic form
- sequestering of CH3 in methyl THF results in the same side effects as a folate deficiency
What effect does folate have on cancer?
- a duel effect
- inadequate folate intake predisposes people to colorectal or breast cancer
- overly high levels of folate can precipitate/cause (colorectal) cancer, as it accelerates the growth of cancer or precancerous cells
Who is at risk for folate deficiency?
- 1. someone with a poor diet
- 2. alcoholics (ethanol inhibits absorption of folate, similar to thiamine)
- 3. those who suffer from generalized malabsorption (eg. caused by illness)
- 4. certain medications (eg. anticonvulsants)
How does folate DEFICIENCY manifest (i.e. symptoms)?
- the first cells/tissue to be affected = those that rapidly divide, aka the GI tract & bone marrow
- in the bone marrow megaloblastic anemia may be seen
- diarrhea & malabsorption are seen as a result of the GI tract being affected
- anemia caused by inhibition of DNA synthesis during RBC production
- When DNA synthesis is impaired, the cell cycle cannot progress from the G2 growth stage to the mitosis (M) stage
- this leads to continuing cell growth without division, which presents as macrocytosis, large cells w/ a ton of cytoplasm but a slow growing nucleus
- hypersegmented neutrophils & mishaped RBCs are characteristic of this disease
Vitamin B12 (Cobalamin)
- functions as a cofactor for 2 enzymes, methionine synthase in the the cytosol (homocysteine -> methionine) & methylmalonyl CoA in the mitochondria (methylmalonyl CoA -> succinyl CoA
- a water soluble family of vitamins
What are the active forms of Vitamin B12?
- methyl cobalamin
What are sources of Vitamin B12?
- meat, poulty, fish, dairy, eggs
- fortified foods
- yeast & some fermented foods
- *vegans tend to be deficient
How is Vitamin B12 absorbed?
- in food B12 is protein bound - must be separated in order for absorption to occur; this is done via 2 mechanisms in the stomach
- 1. gastric acid
- 2. protease enzymes (eg. pepsin)
- *if either is missing, defective, or perhaps affected by medication, B12 absorption is compromised
What initially binds Vit. B12 in the stomach once it's liberated from the protein it's originally bound to in food?
- R-binders, a glycoprotein found in gastric juices & saliva
- vitamin B12 released from protein is bound to R binders in the stomach
- Intrinsic factor (IF) is released by parietal cells in the stomach but does not bind vitamin B12 there
- once in the small intestine, pancreatic secretions release vitamin B12 from the R binder
- NOW IF binds to vitamin B12
- in the ileum, the B12-IF complex is recognized and enters the enterocyte by pinocytosis via a highly specialized receptor
- in the ileal enterocyte, vitamin B12 is bound to the transport protein transcobalamin II (TC II) and released into the portal circulation
Who is at risk for Vitamin B12 deficiency?
- older adults (who have atrophic gastritis)
- people who suffer from malabsorption
- people who've undergone GI surgery
- people w/ Pernicious Anemia
- chronic inflammation of the stomach mucosa, leading to loss of gastric glandular cells & loss of stomach acid
- as a result, the stomach's secretion of essential substances like HCl, pepsin, & intrinsic factor is impaired
- this causes digestive problems, vitamin B12 deficiency, megaloblastic anemia (folate), or malabsorbtion of iron --> iron deficiency anaemia
- caused by a loss of gastric parietal cells, which secrete intrinsic factor
- no IF, no subsequent absorption of vitamin B12 in the ileum
What are the symptoms of Vit. B12 deficiency?
- Hematologic (Megaloblastic Anemia)
- Neurologic (system degeneration, peripheral or optic neuropathy)
- Neuropsychiatric (personality changes, impaired memory, depression)
Subacute Combined Degeneration of Spinal Cord
- vitamin B12 deficiency results in neuronal death in the posterior and lateral columns of the spinal cord
- starts as diminished position and vibratory sense in the feet, w/ gradual progression to ataxia, spasticity, & incontinence
The woman who presents with a burning, oddly flat tongue has:
- glossitis: a smooth but swollen tongue that may be sore
- might come along with some sort of anemia which can be CAUSED by malabsorption of B12, folate, or iron
- *other symptoms = fatigue & malaise
How can one check for a Vit B12 deficiency?
- 1. CBC (checking a complete blood count will show anemia)
- 2. serum Vit. B12
- 3. methylmalonic acid (accumulates w/out B12 as a cofactor)
- 4. homocysteine (not as conclusive b/c levels can also be affected by folate, Vit. B6 [PLP])
What form of Vitamin B12 is recommended for persons 51 years and older?
- that most of the RDA for vitamin B12 be consumed in the crystalline form, reflecting the increasing prevalence of atrophic gastritis & difficulty with B12 digestion
- there is no apparent toxicity of vitamin B12 --> there is NO UL
Major Diseases Associated w/ Each Vitamin Deficiency
- Vitamin C (ascorbic acid): Scurvy
- Thiamine (B1): Beriberi, Wernicke-Korsakoff
- Niacin (B3): Pellagra, Hartnup's (less severe)
- Folate (B9): Megaloblastic anemia, defects w/ rapid growing tissue
- Cobalamin (B12): anemias, psychotic issues