Fat Soluble Vitamins, Minerals & Electrolytes - Skildum Flashcards
1
Q
What cofactors are required by the pyruvate dehydrogenase complex?
A
- TPP (Thiamine)
- NAD+
- CoASH
- Lipoate
- FAD
2
Q
What are the four fat soluble vitamins that we need to know?
A
- Vitamin A
- Vitamin D
- Vitamin E
- Vitamin K
3
Q
What are all the activation transfer cofactors that we need to know?
A
- Ascorbic acid (Vitamin C)
- Thiamine
- Pyridoxine
- Biotin
- Pantothenic acid
- Lipoate
- Cobalamin
- Folate
- Tetrahydrobiopterin (Ring hydroxylations; PKU)
4
Q
What is the RDA?
A
- Recommended Daily Allowance.
- The average daily dietary nutrient intake level sufficient to meet the nutritional requirements of nearly all (97-98%) healthy persons in a particular life stage and gender group.
5
Q
What is the EAR?
A
- Estimated Average Requirement.
- The average daily nutrient intake level estimated to meet the requirements of half of the healthy members of a particular life stage and gender group.
6
Q
What is the UL?
A
- Tolerable Upper Limit.
- Risk of ‘overdose’ is ~0.1% (risk of adverse effects)
7
Q
What are the structural elements of Vitamin A?
A
- b-ionone ring
- branched polyunsaturated acyl chain alcohol
The biologically active form of Vitamin A is all-trans-retinol.
8
Q
In the body, the alcohol of trans-retinol (Vitamin A) can be converted to what?
A
aldehyde carboxylic acid ester with fatty acid (e.g. palmitate)
9
Q
What are the main dietary forms of Vitamin A?
A
- retinyl-acyl esters and carotenes
- They all can be converted to all-trans-retinol.
- Found in: Red, yellow, orange fruits and vegetables.
10
Q
What nutrient digestion parallels the digestion of Vitamin A?
A
- Fats/lipids
- bile salts help package free carotenoids into micelles that can be transported into the intestinal cells
11
Q
What form of digested Vitamin A is soluble enought to be transported in the blood by being associated with albumin?
A
Retinoic acid
12
Q
What part of the liver serves as a reservoir for Vitamin A storage?
A
Stellate cells
13
Q
What role do hepatocytes play in the digestion/absorption/storage of Vitamin A in the body?
A
- Hepatocytes mediate retinol homeostasis in the body.
- Retinyl esters go in…
- Sources: Dietary → Chylomicrons
- Stored: Stellate cells
- Retinyl esters go out to. . .
- Stellate cells (storage) VLDL (to tissues)
- Retinyl esters go in…
14
Q
Why is Vitamin A important in the body?
A
- Retinol is important for vision, and vitamin A deficiency can manifest as night blindness.
- Vitamin A toxicity can result in blurred vision.
15
Q
What specific role does Vitamin A/Retinol play in vision?
A
- cis-retinal bound to the protein opsin = photoreceptor rhodopsin
- Light causes conversion to trans-retinal.
- Rhodopsin bound to trans-retinal activates a heterotrimeric G protein, closure of a Na+ channel, hyperpolarization of the rod cell => signaling to the neuron.
16
Q
What specific role does Vitamin A/Retinol play in transcription factor activation?
A
- Retinoic acid acts as a ligand for the retinoic acid receptors (RAR)
- retinoic X receptors (RXR) and some peroxisome proliferator activated receptor (PPARb and PPARd).
- RAR, RXR, and PPAR act as ligand activated transcription factors.
- Differentiation of goblet cells.
- Prevention of keratinization of goblet cells
- Apoptosis of cancer cells.
- Maturation of dendritic cells.
- Recruitment of antibody secreting cells to small intestine.
17
Q
How does Vitamin A help in immune system function in the GI System?
A
Dietary Vitamin A => stores of retinyl esters => Retinoic Acid => Maturation of dendritic cells => Recruitment of antibody secreting cells (ASC) to small intestine
18
Q
What happens if the Carotene by-products of Vitamin A digestion are not cut by monooxygenases to form molecules of retinal?
A
Without being cut, carotenes act as antioxidants.
Their double bonds can neutralize singlet oxygen and free radicals.
19
Q
What are the consequences of Vitamin A deficiency?
A
- anorexia
- retarded growth
- increased susceptibility to infections
- alopecia
- keratinization of epithelial cells eyes:
- night blindness
- xeropthalmia (dry eye due to keratinization)
- Bitot’s spots
20
Q
How do you diagnose Vitamin A deficiency?
A
- The Relative Dose Response (RDR) Measure plasma retinol concentration.
- Give an oral bolus of retinyl-palmitate.
- Measure plasma retinol concentration again after 5 hours.
- The higher the RDR, the more the body is relying on short term dietary Vitamin A, rather than liver and adipose stores.
- RDRs > 20% indicate the liver is not maintaining serum Vitamin A.
21
Q
What happens in Hypervitaminosis A?
A
- The tolerable upper limit (TUL) for Vitamin A is 3,000 mg RAE / day.
- Doses in vast excess of this can cause:
- nausea
- vomiting
- blurred vision
- headache
- desquamation of skin
- alopecia
- ataxia
- liver damage (from excess stellate cell growth and proliferation)
- conjunctivitis
- eye pain
22
Q
What are the structural elements of Vitamin E?
A
- tocopherols
- with saturated 16 carbon acyl chains
- tocotrienols
- with polyunsaturated 16 carbon acyl chains
23
Q
What are the dietary sources of Vitamin E?
A
- Abundant in plant oils
- e.g. palm oil, sunflower oil, canola oil, wheat germ
24
Q
Vitamin E digestion and absorption parallels digestion and absorption of what other nutrient?
A
Fat/lipids
25
What is the general outline of Vitamin E digestion?
* tocopherols, tocotrienol-acyl esters + pancreatic lipase =\> tocopherols, tocotrienols
* uptake by intestinal epithelial cell
* tocopherols, tocotrienols =\> packaged into chylomicrons
* chylomicrons distribute to tissues
* chylomicron remnants return to liver =\> taken up by VLDL (only RRR stereoisomers of vitamin E)
* VLDL distributes remnants to tissues
26
What are the main functions (4) of Vitamin E?
* Vitamin E functions in lipid bilayers in intracellular and plasma membranes.
* The phenolic hydroxyl can distribute and stabilize singlet oxygen and free radicals as part of cellular oxidative stress defense =\> ANTIOXIDANT
* Regenerate Vitamin C:
* Vitamin E, when oxidized, can be regenerated by ascorbate (vitamin C).
* Vitamin E inhibits Vitamin K absorption and metabolism.
27
What are the consequences of Vitamin E deficiency?
* Deficiency is rare except in people with absorption problems
* e.g. premature infants, Crohns, short bowel syndrome.
* Also can occur with inherited lipoprotein disorders.
* Symptoms:
* myopathy
* hemolytic anemia
* peripheral neuropathy
* ataxia
* loss of vibratory sense
28
Tell me about Vitamin E toxicity?
* Not very toxic.
* TUL is 1,000 mg per day (high)
29
What are the dietary sources of Vitamin K?
* \*Phylloquinone is the main form of Vitamin K in the diet.
* It is abundant in leafy green vegetables.
* \*Menaquinones have variable numbers of isoprenoid subunits on the acyl chain.
* They are produced by fermentation. (In gut, in cheese.)
* (Menadione is a synthetic Vitamin K used in animal feed.)
30
What is the main function of Vitamin K?
Carboxylation + Coagulation
31
Vitamin K digestion and absorption parallels digestion and absorption of what nutrient?
Fat/lipids
32
Where is Vitamin K stored in the body?
* Vitamin K is stored in cellular membranes
* especially the lung, kidney, bone marrow, and adrenal glands.
33
What is the general outline of Vitamin K digestion?
* phylloquinone, menaquinone =\> taken up by intestinal epithelial cells
* packaged into chylomicrons =\> distributed to tissues
* remnants go back to liver =\> packaged into VLDL
* VLDL distributes remnants to tissues
34
How does Vitamin K act to promote coagulation?
* In target cells, Vitamin K acts as a cofactor for g-glutamyl carboxylase.
* This enzyme carboxylates glutamic acid side chains on blood clotting proteins.
35
What clotting factors are dependent on Vitamin K dependent carboxylation?
* Factor IX (Christmas factor)
* Factor VIIa
* Factor X (Stuart factor)
* Prothrombin
36
What are the consequences of Vitamin K deficiency?
* Rare; most people get adequate Vitamin K.
* Can occur in infants (milk is low in Vitamin K), people with absorption disorders.
* Severe deficiency manifests as coagulation disorder:
* increased prothrombin time
* increased bleeding
37
Tell me about Vitamin K toxicity?
* Not described
* no TUL for Vitamin K
* Menadione causes liver toxicity at high doses
38
What are the sources of Vitamin D?
* Vitamin D is found primarily in food of animal origin such as:
* liver, eggs, fatty fish.
* It is also present in shitake mushrooms, and is fortified in many dairy products.
* Vitamin D can be synthesized de novo from cholesterol.
* To make the active Vitamin D3, metabolism of skin, liver, and kidney is required.
39
What is the most important function of Vitamin D?
* Vitamin D’s most important function is to regulate calcium homeostasis, but it may play other beneficial roles.
* cancer prevention
40
How is dietary form of Vitamin D digested?
* The dietary form of Vitamin D, cholecalciferol, is absorbed through passive diffusion with fat into intestinal epithelial cells.
* It is transported to tissue in chylomicrons, and taken up by the liver in chylomicron remnants.
41
What is the main form circulating in the blood and the form measured to assess Vitamin D status?
25-hydroxycholecalciferol (25-OH D3)
42
What is the key enzyme regulating Vitamin D digestion?
1-alpha-hydroxylase
43
What important hormone regulates 1-alpha-hydroxylase and the digestion of Vitamin D?
* 1-alpha-hydroxylase expression is regulated by parathyroid hormone in the kidney
* this helps maintain calcium homeostasis
* The hydroxylation to make the biologically active 1,25-dihydrocholecalciferol (1,25-OH D3) occurs in the kidney in response to parathyroid hormone (PTH).
* PTH is produced by the parathyroid in response to low calcium concentrations.
44
What does the Vitamin D receptor in the gut act as?
* The vitamin D receptor (VDR) acts as a **ligand activated transcription factor**.
* regulates transcription of Calcium transport proteins: calbindin, TRPV6, PMCA1b
* Activated VDR increases expression of:
* the calcium channel TRPV6 at the brush border
* calbindin in the cytoplasm
* calcium ATPase pumps at the basolateral membrane
45
What are the consequences of Vitamin D deficiency?
* Rickets
* characterized by seizures, growth retardation, failure of bone mineralization (osteomalacia).
* Vitamin D deficiency can be dietary, genetic, or secondary to an absorption problem such as Crohns.
46
What are the effects of Vitamin D toxicity?
* Vitamin D is the most likely vitamin to have toxic effects.
* The TUL is 4,000 IU for age 9+
* Toxic effects begin when serum 25-OHD3 \> 500 ng/mL
* calcification of soft tissues (kidneys, heart, lungs, blood vessels)
* hyperphosphatemia
* hypertension
47
What are the redox cofactors that are water soluble vitamins?
* Niacin
* Riboflavin
* Ascorbic acid (Vitamin C)
48
What are the water soluble vitmans that we need to know?
* Redox cofactors:
* Niacin
* Riboflavin
* Ascorbic acid (Vitamin C)
* Activation transfer cofactors:
* Ascorbic acid (Vitamin C)
* Thiamine
* Pyridoxine
* Biotin
* Pantothenic acid
* Lipoate
* Cobalamin
* Folate
* Tetrahydrobiopterin (Ring hydroxylations; PKU)
49
What is the most toxic vitamin?
Vitamin D
50
How does Vitamin D prevent colorectal cancer?
* The Vitamin D receptor physically interacts with b-catenin
* preventing its transactivation of genes that promote cellular proliferation.
51
What are the 5 major minerals in order of abundance in the body?
1. Calcium
2. Phosphorous
3. Potassium
4. Sodium, Chloride
5. Magnesium
52
What are the four trace elements that the body requires \< 100 mg/day?
* Iron
* Zinc
* Copper
* Manganese
53
What are the functions of the minerals in the body?
* Osmotic balance
* Maintaining charge / concentration gradients across membranes
* Enzyme cofactors
* Structure
* Taste
54
What is the most abundant metal ion in the body?
CALCIUM
A 70 kg man has ~1.4 kg of calcium, mostly in bone.
55
What are the dietary sources of Calcium?
Dairy, seafood, turnip, broccoli, kale, dietary supplements
56
What are the major function of calcium?
* Bone mineralization
* Blood clotting
* Muscle contraction
* Metabolism regulator
57
How does calcium absorption happen in the body?
* Saturable carrier mediated transport: TRPV6 transports Ca2+ across the brush border membrane
* Calbindin chaperones Ca2+ within the cell Ca2+ /ATPase transports Ca2+ across the basolateral membrane
* Pericellular transport around tight junctions:
* Claudin
58
What increases calcium absorption?
* Vitamin D sugars;
* sugar
* alcohols
* protein
59
What decreases calcium absorption?
* Fiber
* Phytic, oxalic acids
* Other divalent cations
* e.g. Mg2+ and Zn2+
* Unabsorbed fatty acids
60
What is the composition of calcium in the blood?
* [Ca2+] = 8.5 – 10 mg/dL
* ~40% of Ca2+ is bound to protein
* e.g. albumin
* ~50% is free ionized Ca2+
* ~10% is complexed with sulfate, phosphate, citrate, etc
61
What is the composition of calicum in the cells?
* The cytosolic concentration of Ca2+ is very low (100 nmol).
* The extracellular concentration of Ca2+ is 10,000x higher (2.3 mmol).
* Ca2+ is stored in intracellular compartments
* e.g. mitchondria, ER
62
How is calcium exported from the cells?
* Ca2+/3Na+ exchanger is a low affinity, high capacity transporter
* Ca2+/2H+ exchanger is a high affinity, low capacity transporter
63
What is calcium's main function inside the cell?
* Secondary messenger!
* Intracellular signaling by calcium is mediated by calmodulin, a protein whose association with other proteins is regulated by calcium binding.
64
What protein activated by Calmodulin-Calcium Complex blocks calcium uptake into the cell?
Calcineurin
65
What are the downstream effects of increased intracellular calcium?
* glycogen synthase is inactivated (via calcium/calmodulin kinase activated by Calmodulin-Calcium Complex )
* glycogen phosphorylase is activated (via phosphorylase kinase activated by Calmodulin-Calcium Complex )
66
What three additional dietary interactions does calcium effect?
* Calcium blocks phosphorous uptake
* High doses of Ca2+ used to treat hyperphosphatemia secondary to kidney failure.
* Calcium transiently blocks iron uptake
* Calcium can trap fatty acids and bile salts in ‘soaps’ that are not digestable.
* Bile salts are not recycycled
* Cholesterol is diverted to bile acid synthesis decreased chenodeoxycholate in bile LDL decreases
67
How is calcium excreted?
* Excretion: Urinary 100-240 mg/day
* Resorption in the proximal tubule is controlled by calcitriol.
* Caffeine increases urinary excretion of calcium.
* Sodium and calcium share common resorption mechanism in the proximal tubule.
* Very high sodium inhibits calcium reuptake and increases excretion.
* Feces 45 – 100 mg/day
* Sweat 60 mg/day
68
Who is at risk for calcium deficiency?
* People with fat malabsorption disorders
* Immobilized patients
* (bone calcium stores depleted)
69
What are the consequences of calcium deficiency?
* Calcium deficiency causes:
* Rickets
* Tetany (intermittant muscle contractions)
* Osteoporosis
* Calcium deficiency is associated with:
* Colorectal cancer
* Hypertension
* Type II diabetes
70
What happens in calcium toxicity?
* TUL = 2,500 mg/day
* Acute toxicity:
* constipation
* bloating
* Chronic toxicity:
* hypercalcemia can cause calcification of soft tissue
* may lead to hypercalciuria and kidney stones
* cardiovascular disease (?)
71
How do you assess magnesium in a patient?
* Normal serum [Mg2+] ~ 1.7 mg/dL
* Assessment: Serum is a minor store of magnesium, so concentrations are not reliable.
* Erythrocyte magensium is not turned over as rapidly, and can be a better measure.
* **Renal Mg2+ excretion** before and after a loading dose is the best measure of magnesium status.
72
What are the consequences of magnesium deficiency?
* Dietary deficiency is not described, but can be experimentally induced.
* Symptoms include:
* nausea, vomiting, headache, anorexia; progresses to seizures, ataxia, fibrilation.
* Chronic magnesium deficiency is associated with hypertension and type II diabetes.
* Gitelman syndrome is an autosomal recessive mutation of SLC12A3, a thiazide sensitive Na/Cl transporter characterized by hypomagnesemia, hypokalemia, hypocalciuria.
73
What causes magnesium toxicity? What are the symptoms?
* TUL = 350 mg/day
* Toxicity associated with use of epsom salts (MgSO4).
* Symptoms are:
* diarrhea, dehydration, flushing, slurred speech, muscle weakness, loss of deep tendon reflex.
* At concentrations higher than 15 mg/dL, can cause cardiac arrest.
74
Where does magnesium reside in the body?
* Magnesium in the body: 25 grams
* 50-60% in bone
* 40-50% in soft tissues
* 1% in extracellular fluid
75
What are the dietary sources of magnesium?
* Magnesium rich foods include:
* nuts
* legumes
* whole grains
* chlorophyll
* chocolate
* ‘hard’ water
76
Where does chloride reside in the body?
* Chloride accounts for ~105 grams in a 70 kg man.
* 88% in extracellular fluid
* 12% intracellular
77
How is chloride absorbed/secreted in the body?
* Chloride is absorbed paracellularly, or through a Na+/Cl- electroneutral transporter.
* Chloride is the only anion secreted by gastrointestinal cells.
78
What are the functions of chloride?
* Chloride / bicarbonate exchanger:
* Chloride enters red blood cells in exchange for bicarbonate when cells deliver oxygen to tissues
* when bicarbonate goes out, chloride goes in to balance charge
* Hypochlorous acid (~ bleach) is secreted by neutrophils during phagocytosis to neutralize pathogens.
* Gastric hydrochloric acid secretion by parietal cells.
79
How is magnesium absorbed in the gut?
* Saturable transport across brush border: TRPM6
* Basolateral transport:
* 2Na+/Mg2+ antiporter
* 2K+/3Na+/ATPase
* Non-saturable paracellular diffusion.
80
What are the functions of magnesium?
* Bone:
* 70% of bone magnesium is associated with phosphorous and calcium in crystal lattice.
* 30% of bone magnesium is in amorphous form on the surface; this is available for exchange with serum to maintain magnesium homeostasis.
* Intracellularly:
* \>90% of magenesium is associated with ATP.
* Magnesium is essential for kinases and polymerases that use nucleotide triphosphates.
* Activation of vitamin D requires magnesium.
* 25-hydroxylase requires magnesium to convert Cholecalciferol =\> 25-Hydroxycholcalciferol
81
What are the dietary sources of potassium?
* In the diet: Fruit, leafy green vegetables, milk
* In a 70 kg man, there are ~245 grams of potassium.
82
How is potassium absorbed in the gut?
* Absorption:
* Paracellular diffusion
* K+/H+ ATPase
* Basolateral: K+ channel
83
What are the functions of potassium?
* Potassium functions as the major intracellular cation.
* generates and maintains electrical potential across cell membranes
* muscle contractility (smooth, skeletal, cardiac)
* Na+/K+ ATPases consume energy to accumulate potassium within cells
* Channels then allow potassium to flow out of the cell, resulting in a loss of positive charge
84
How is potassium regulated in the body?
* **Vasopressin** and **aldosterone** increase urinary potassium excretion.
* Opposite of sodium.
85
What are the consequences of potassium deficiency?
* Normal [K+] ~ 3.5 – 5.0 mEq/L
* Deficiency: \< 3.5 mEq/L is Hypokalemia
* Caused by fluid loss, thiazide or loop diuretics, or refeeding syndrome.
* Symptoms:
* Cardiac arrythmias, muscular weakness, hypercalciuria, glucose intolerance, mental disorientation
* Moderate deficiency associated with:
* elevated blood pressure
* decreased bone density (increased urinary Ca++ excretion)
86
What happens in potassium toxicity?
Hyperkalemia can be caused by renal failure and can cause cardiac arrythmia / arrest.
87
Where does phosphorus reside in the body?
* A 70 kg man has 560 – 850 grams of phosphorous.
* 85% in bone
* 1% in fluids
* 14% in soft tissue
* esp. muscle
88
What are the dietary sources of phosphorus?
* Phosphorous is widely distributed in the diet:
* Meat
* poultry
* fish
* eggs
* dairy
* cola (phosporic acid)
89
How is phosphorus absorbed in the gut?
* Saturable carrier mediated active transport is used when phosphate intake is low.
* It is activated by calcitriol.
* Diffusion occurs in the proximal duodenum (slightly acidic and phosphate is in the H2PO4- form).
90
Phosphorous absorption is inhibited by what?
* Magnesium (Mg3(PO4)2 is un-absorbable.)
* Aluminum
* Calcium
\*\*\*All abundant in TUMS! Can use to treat phosphorus toxicity.
91
What are the functions of phosphorus?
* Bone mineralization:
* amorphous: Ca3(PO4)2, CaHPO4-2H2O, Ca3(PO4)2-3H2O
* crystalline: hydroxyapatite: Ca10(PO4)6(OH)2
* calcitonin =\> phosphorous deposition in bone
* calcitriol =\> phosphorous desorption from bone
* Molecules with high energy bonds:
* Nucleotides
* Nucleic acids: DNA, RNA
* Proteins: Serine, Threonine, Tyrosine
* Phospholipids
* Vitamins =\> cofactors
* e.g. thiamin =\> thiamine pyrophosphate (TPP)
* pryidoxine =\> pyridoxal phosphate (PLP)
* Acid base balance: Na2HPO4 + H+ =\> NaH2PO4 + Na+
* Phosphorous is an important buffer in the kidney.
* Availability of oxygen: 2,3-bisphosphoglycerate
92
How is phosphorus regulated in the body?
* Regulation of phosphorous is at the level of renal clearance.
* Excretion of phosphorous is promoted by:
* elevated dietary phosphorous
* parathyroid hormone (PTH)
* acidosis
* phosphotonins (e.g. FGF-23; secreted by osteoblasts and osteocytes)
* Excretion of phosphorous if inhibited by:
* low dietary phosphorous
* calcitriol
* alkalosis
* estrogen
* thyroid hormone
* growth hormone
93
Even though phosphorus deficiency is rare, what situations may cause a deficiency in phosphorus?
* Extreme use of antacids containing magnesium, calcium, aluminum
* Malnourishment Refeeding syndrome Inherited disorders:
* Dents disease: X-linked, mutation in renal chloride channel
* X-linked hyphosphatemic Rickets: Mutation in PHEX gene causes elevated FGF-23
* Autosomal dominant hypophosphatemic Rickets: Mutation in the gene encoding FGF-23, prevents its degradation.
94
What are the symptoms of phosphorus deficiency?
* anorexia
* reduced cardiac output
* decreased diaphragmatic contractility
* myopathy
* death
95
What dietary components does magnesium interact with?
* Vitamin D Mg2+ may mimic Ca2+ and compete for resorption in the kidney.
* Mg2+ inhibits phosphorous absorption by forming Mg3(PO4)2 precipitate.
