Vitamin D = VERY imp on the boards; MC source of vit D is from sunlight

a. Cholesterol is the

1. Main component of our cell membranes

2. Starting point for making bile salts and bile acids

3. First compound that starts the synthesis of steroid hormones in the adrenal cortex

4. And the 7-dehydrocholesterol in the skin is photoconverted to vitamin D.

Therefore we need cholesterol! (makes bile salts, hormones, cell membranes, and vit D).

b. Source: Sun is the most imp source of vit D. take baby out to expose to sunlight (no vit D or vit K in breast milk, therefore must be supplemented – expose to sun for vit D).

c. Synthesis of Vitamin D: Reabsorbed in the jejunum. Undergoes 2 hydroxylation steps; first is in the liver, where it is 25 hydroxylated and the 2^nd is in the kidney and its 1 alpha hydroxylase. What hormone puts 1-alpha hydroxylase in the proximal tubule?

PTH. PTH is responsible for synthesis of 1-a-hydroxylase and is synthesized in the proximal tubule. (ACE is from the endothelial cells of the pulmonary capillary, EPO is from the endothelial cells of the peritubular capillary). 1-a-hydroxylase is the 2^nd hydroxylation step, and now it is active (the first was in the kidney).

d. Vit D function: reabsorb Ca and phosphorus from the jejunum. It HAS to reabsorb both of these, b/c its main job is mineralizing bone and cartilage. Have to have appropriate solubility product to be able to do that; Ca and phosphorus are necessary to mineralize cartilage and bone (like the osteoid making bone). Therefore, it makes sense to reabsorb Ca and phosphorus b/c it needs to make sure that both of them are present in adequate amounts to have an adequate solubility product to mineralize bone.

e. Parathyroid Hormone (PTH) – Functions: (1)is somewhat related to Vitamin D metabolism, it helps last step for hydroxylation of vit D syn. (2) PTH will lead to reabsorption of Ca in the early distal tubule (this is also where Na is reabsorbed, and thiazides block this channel). At that location, there is a Ca channel; PTH helps reabsorption of the Ca in this location. Ca has to ‘take turns’ with Na, usually more Na,  reabsorbed; therefore Ca has to sneak through channel, with help of PTH. Therefore, with thiazides, Na is blocked, leaving the Ca channel completely open, and the

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thiazides will lead to hypercalcemia. Therefore, use in Ca stone formers – most of stone formers have hypercalciurea; these pts have too much Ca in their urine; when they are on thiazides, the drug takes Ca OUT of the urine, so they do not form stones.

(3) PTH will decrease reabsorption of phosphorus in the prox tubule, and (4) decrease the reaccumulation of bicarb, too.

f. Vitamin D and PTH and how they work together:

Vit D’s main function is mineralizing bone, and osteoblasts (bone builders) are involved with this process, therefore the receptor for Vit D is located on the osteoblast. When vit D hooks into the receptor, it causes the release of alkaline phosphatase. So, when you are growing bone or rehealing of a fracture, you expect to see an increase in alkaline phosphatase, which makes the appropriate solubility product to mineralized cartilage and bone. Knowing that PTH breaks down bone (maintains Ca levels in the blood stream) you would think that its receptor would be on the osteoclast (cell normally breaks bone down). However, only one hormone has a receptor on ostoeclasts and that is calcitonin. When calcitonin hooks into the osteoclast receptor, it inhibits the osteoclast, and therefore is used to treat hypercalcemia. Calcitonin also used in treating osteoporosis. The receptor for PTH is on the osteoblast, but not sharing the same one as vit D. When PTH hooks on the osteoblast, it releases IL-1. Another name for IL-1 is osteoclast activating factor (other functions of IL-1 are also involved in fever, stimulates Ab synthesis, and B cell stimulation). So, IL-1 (released from the osteoblast) activates osteoclasts via IL-1 release from osteoblast, and osteoclast is signaled to break down bone to maintain Ca levels in our bloodstream. Sex hormones keep IL-1 in check; in women, estrogen levels keep a check on IL-1 (do not want too much osteoclast activation); in men, it is testosterone that keeps IL-1 in check (puts inhibitory effect on IL-1 release from the osteoblast after PTH hooks in). Therefore, in women, can see why they get osteoporosis – lack of estrogen = IL-1 not in check and breaking more bone down than making (this is the mechanism of postmenopausal osteoporosis).

PTH is more involved in maintaining Ca levels in our blood, while Vit D is more involved in mineralizing our bones and cartilage.

g. Vitamin D deficiency: Many reasons: lack of sun, poor diet, liver dz, renal dz.

Example: Pt on phenytoin and pt has hypocalcemia, why? Phenytoin, alcohol, barb’s,  rifampin all induce the cyt p450 system located in the SER. Therefore, get SER hyperplasia; therefore, you metabolize drugs and other things made in the liver,

including 25-hydroxyvitamin D.  Therefore, anything that rev’s up the p450 enzymes will  cause a decrease in vit D, and any other drugs being taken.

Example: woman on birth control pills and taking phenytoin, and she got pregnant, why? The phenytoin rev’ed up the p450 system, which increased the metabolism of  estrogen and progesterone in the birth control pills, therefore not enough levels to prevent pregnancy.

Example: what is the enzyme in the SER that increases when the p450 is rev’d up? 

Gamma glutamyl transferase (GGT) – enzyme of SER! (look at in alcoholics)

Example: MCC chronic renal dz in USA: diabetes mellitus – tubular damage, so no 1-a-hydroxylase, therefore inactive vit D. Therefore, pts with chronic renal failure are put on 1-25-vit D.

Example: if someone gets OTC vit D, what steps does it go through to become metabolically active? 25 hydroxylated in liver, and 1-a-hydroxylated in your kidney (it is NOT 1, 25 vit D – this is a prescription drug, and extremely dangerous). Many people

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have the misconception that the vitamin D is already working. This is not the case; pt must have a functioning liver and kidney.

With vit D def in kids = rickets; vit D def in adults = osteomalacia (soft bones).

If you can’t mineralize bone, you cannot mineralize cartilage, and they will both be soft, therefore pathologic fractures are common.

Kids have different a few things that are different in rickets – ie craniotopies, soft skulls (can actually press in and it will recoil). They can also get ricketic rosaries, b/c the osteoid is located in the costochondral junc, and b/c they are vit D def, there is a lot of normal osteoid waiting to be mineralized, but not an appropriate Calcium/phosphorus solubility product; will have excess osteoid with little bumps, which is called ricketic rosary.  Not seen in adults’ b/c they are getting fused.

So, 2 things you see in kids and not adults: 1) craniotopies 2) ricketic rosaries; rhe rest is the same, with pathologic fractures being the main problem.

8. Child with rickets:

h. Toxicity/Hypervitaminosis of vit D: hypercalcemia, therefore risk of having too many stones in the urine, and stones is a MCC complication.

Type 1 rickets – missing the 1-a-hydroxylase Type 2 rickets – missing the receptor for vit D 3. Vitamin E

a. Main function: maintain cell membranes and prevent lipid peroxidation of the cell membranes; in other words, it protects the cell membranes from being broken down by phospholipase A (lipid peroxidation, which is free radical damage on the cell

membrane, and is prevented with vit E). Other function: neutralized oxidized LDL, which is far more atherogenic than LDL by itself. When LDL is oxidized, it is way more injurious to the cell then when it is not oxidized. Vit E will neutralize oxidized LDL, therefore is a cardioprotectant (vit E and C both neutralize oxidized LDL). In summary:

vit E func = 1) protects cell mem from free radical damage. 2) Oxidizes free LDL (this is the LDL that macrophages phagocytose to produce foam cells, and leads to

atherosclerotic plaques).

b. Deficiency of vitamin E: Is seen but is very uncommon, and if seen if would be in kids with cystic fibrosis; from birth, kids have resp probs and pancreas problems. (look at in robbins, too). A kid that has cystic fibrosis will have malabsorption problems; therefore what four vitamins should you give him? Cystic fibrosis pt has a malabsorption of fat;

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therefore they will have malabsorption of fat soluble vitamins – A, D, E, and K. Vit E def in USA is usually seen in cystic fibrosis patients.

c. Clinical presentations: One of the features of vit E def is hemolytic anemia (vit E normally maintains the integrity of the membrane); this pt is now susceptible to free radical damage, damaged mem of RBC leads to hemolysis of RBC and hemolytic anemia. Another feature of vit E are things related to myelin: posterior column dz, spinal cerebellar probs. Therefore, with vit E def, have neurological problems and hemolytic anemia.

d. Vitamin E toxicity: anything more than 1100 units (average capsule is 400 units, therefore, if take 3 pills, already toxic). Vitamin E toxicity will inhibit synthesis of Vit K dependent Coagulation factors (2, 7, 9, 10, protein C, protein S); in other words, you are antiCoagulated. Example: pt with MI – take antioxidants, and aspirin; with anterior MI, they antiCoagulate the pt, and pt goes home on three months of warfarin.

Normal INR ratio, and takes lots and lots of vit E and other vitamins. Take a lot of vit E and will help warfarin, leading to over antiCoagulated state, (remember that warfarin blocks gamma carboxylation of vitamin K dep factors). Vit E will prevent the

SYNTHESIS of these factors. Therefore, vit E toxicity is synergistic in activity with warfarin. Example: pt on warfarin, came home from MI, INR ratio is huge; why? Taking vit E.

4. Vitamin K

a. Sources: Can come from what we eat, but most is synthesized by our colonic bacteria (our anaerobes in our gut) – this is why we give vit K injections to our baby when they are born; they only have 3 days worth of vit K from mom, but after that, they won’t have any b/c its not in breast milk; therefore, a very low level of vit K between  days 3-5; also, they don’t have bacteria to make the vit K.  Therefore, can get  hemorrhagic dz of the newborn (this is why we give vit k when they are born); after 5 days, the bacteria colonize, and vit is made by the baby.

b. Metabolism: Bacteria make vit K in an inactive form – K2. K2 (inactive form must be converted by epoxide reductase to K1 (K1 is the active form of vitamin K). K1 will gamma carboxylates the vit K dependent factors (2, 7, 9, 10, protein C and S). Gamma carboxylates requires the same understanding as Vitamin C, in vit C If you don’t 

hydroxylate pro and lys then the crosslinks are weaker (anchor pt). Gamma

carboxylation of vit K dep factors actually activates them to become functional. Vit K dep factors all have something in common: (1)have to be activated by vit K1 and (2) they are the only Coagulation factors that are bound to a clot by Calcium (Ca); so they have to be bound by Ca in order to work and form a clot; if you can’t bind, then you are  antiCoagulated. That is what gamma carboxylation: glutamic acid residues are gamma carboxylated on the vit K dep factors (which is done with K1), and allows Ca to bind the factors; therefore, it keeps them together and you are able to form a clot; therefore, if they are not gammacarboxylated, they are useless b/c Ca can’t grab them to form  a  clot (so, gammacarboxylation is the anchor pt, so Ca can bind to form a clot, similar to hydroxylation of proline and lysine in collagen synthesis).

Warfarin blocks epoxide reductase, so all the vit K pt has is K2 and no gammacarboxylation will occur. Therefore, the patient is anticoagulated.

c. Vitamin K deficiency: MCC vit K def (in hospital) = broad spectrum Ab’s. 2^nd MCC = poor diet, being a newborn, malabsorption. Def vit K = hemorrhagic diathesis (bleeding into skin or brain). Know why newborn has vit K def: Example: kid with rat poison –rat poison is warfarin; when rats eat it, they get antiCoagulated and die. Treat with intramuscular Vitamin K. Example: kid lived with grandparents and developed

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hemorrhagic diathesis: why? B/c the elderly were on warfarin, and kid ate the warfarin, and led to toxic levels.

9. Patient with periorbital hemorrhage from vitamin K

In document Goljan Lectures Notes Part 1 (Page 50-54)