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Chapter Two: Vitamins, Minerals, and Trace Elements The Beginning Chapter Sections: I. II. III. Vitamins Minerals Trace Elements Vitamins, minerals, and trace elements play the biggest role in enzymes. What is the role of enzymes? To help you create energy (through all the pathways). If the vitami...

Chapter Two: Vitamins, Minerals, and Trace Elements The Beginning Chapter Sections: I. II. III. Vitamins Minerals Trace Elements Vitamins, minerals, and trace elements play the biggest role in enzymes. What is the role of enzymes? To help you create energy (through all the pathways). If the vitamin, mineral or trace element is missing, it will lead to a low energy state. Vitamins Vitamin A • Cofactor for parathyroid hormone function o Stimulates osteoclastic activity (calcium increases, phosphorus decreases) o Whenever PTH is involved, serum calcium and phosphorus will go in opposite directions o Calcium and the hormone always go in the same direction (except in pseudo) o If the calcium and phosphorus go in the same direction, the problem is a vitamin D issue • Used for cerebrospinal fluid (CSF) production • Used for epithelial cell maturation (anywhere) o Especially hair, skin, and eyes o Most unique function is night vision • A mild antioxidant Clinical Correlation Vitamin A is used for the maturity of cells: 1. 2. 3. 4. Measles (regenerate epithelium of lung) Cancer (T15/17) Infections that destroy cells Burn patients 19 Vitamins, Minerals, and Trace Elements The Beginning Antioxidants • • • • • • Eat up free radicals (made of oxygen, high energy molecules) Free radicals pierce the cell membrane, then the nuclear membrane and then through the DNA Cells then have only 2 choices: die or mutate If they mutate, they will cause cancer Therefore, free radicals cause cells to die or mutate Ex: cancer after radiation therapy due to free radical production Figure 2.1 Free Radicals Penetrating the Membrane 20 Vitamins, Minerals, and Trace Elements The Beginning PP Clue What is the most common cause of free radical formation? • • Infections, of which viruses are the most common Neutrophils are the cells that make free radicals, via the enzyme NADPH oxidase Vitamin A excess • Hyperparathyroidism o Calcium will go up, phosphorus will go down o Moans, groans, bones, and stones  Moans and groans are from pancreatitis, the most common severe abdominal pain  When calcium deposits into the pancreas (saponification), it will irritate the fat that is right behind the pancreas; this in turn will irritate the pancreas, causing pancreatitis o When calcium flows into the cell (concentration gradient), it is called metastatic calcification, which can also cause pancreatitis o Bones are going to hurt because the PTH is destroying the bones o Stones can be caused by the excess calcium, causing gallstones, kidney stones or calcification all throughout the body (metastatic calcification) Figure 2.2 Sodium-Calcium Gradient • Pseudotumor cerebri o Most common cause is obesity; #2 is vitamin A toxicity 21 Vitamins, Minerals, and Trace Elements The Beginning o Vitamins A, D, E, and K get stuck in the adipose tissue. One day, it lets go of it and it floods the serum. o Sign: papilledema (evidence of high intracranial pressure) o Symptom: headache o Evaluation: CT scan (shows enlarged ventricles) o Treatment: d/c vitamin A; serial LPs (see box) o Main complication: blindness o This is the only cause of increased intracranial pressure (ICP) where you do not have to worry about herniation Figure 2.3 CT Dilated Brain Ventricles Management: Headache with Papilledema- (Vitamin A Excess) If you suspect high intracranial pressure: Step 1: Rule out the worst it could be • • Mass (i.e., cancer) How? CT scan (Non-contrast first, in case it is a bleed. This way, the contrast will not leak out all over the brain and cause more damage.) Step 2: What is the next worse thing it could be? • • Infection (i.e. Meningitis) How? Lumbar puncture If dilated ventricles (+), next step will be treatment of Pseudotumor Cerebri • • • • Discontinue vitamin A Acute: serial lumbar punctures Remove ≤ 30 cc/24 hrs. until the papilledema is gone Chronic: Weight loss, carbonic anhydrase inhibitors (acetazolamide) in the meantime or mannitol, which decreases ICP acutely 22 Vitamins, Minerals, and Trace Elements The Beginning Figure 2.4 Papilledema Clinical Correlation Why remove less than 30 ccs of CSF/24 hrs.? CSF is continuous with plasma? Avoid osmotic shifts which may lead to damage of the pons. Vitamin B1: Thiamine • • • Necessary for four important enzymes: 1. Pyruvate dehydrogenase 2. Alpha-ketoglutarate dehydrogenase 3. Branched chain amino acid dehydrogenase 4. Transketolase All use thiamine pyrophosphate (TPP) The heart needs all 3 dehydrogenases; brain uses transketolase Thiamine deficiency • Wernicke’s encephalopathy (signs of increased ICP) o Wernicke’s is in the posterior Temporal Lobe; responsible for receiving Spoken or written language 23 Vitamins, Minerals, and Trace Elements The Beginning Figure 2.5 MRI of Temporal Lobe • • Wernicke’s Aphasia o Receptive aphasia Wernicke-Korsakoff Syndrome o Mamillary bodies now also involved o Confabulation (start making things up) o Unable to move short term memory into long term memory Figure 2.6 MRI Mamillary Bodies • Beriberi (heart has given out; massive dilation) o Dry beriberi (until you have heart failure) o Wet beriberi (when there is fluid in the lungs, massive ventricular dilatation) 24 Vitamins, Minerals, and Trace Elements The Beginning Test-Taking Strategy: The next step in management is a loaded question for Boards 2 (it is a multi-level question). First you must figure out what it is the patient has. Then you must figure out the pathophysiology of what they have. Then, ask yourself, what is the worst it could be, i.e. What is going to kill the patient first? Rule this out first! Figure 2.7 Angular Cheilosis Vitamin B2: Riboflavin • • Used in cofactors (like FAD) Best source is milk Riboflavin deficiency • • Sunlight breaks riboflavin down Angular cheilosis Vitamin B3: Niacin • • Necessary for cofactors (NAD, NADH, NADP, NADPH) Needed by o Pyruvate dehydrogenase o Alpha-ketoglutarate dehydrogenase o Branched chain amino acid dehydrogenase Niacin Deficiency • • Pellagra: 4 D’s o Diarrhea, dermatitis, dementia, and death Hartnup’s Disease o Presents just like pellagra o Defective renal transport of tryptophan, causing tryptophan to leak into urine o Tryptophan is needed to make niacin 25 Vitamins, Minerals, and Trace Elements The Beginning Make the Connection Carcinoid syndrome • • • Another disease that uses up tryptophan. Tryptophan is needed to make serotonin or niacin Serotonin gets excreted out rapidly, using up a lot of tryptophan. Clinical Correlation Niacin • • Blocks VLDL production in the liver, therefore treating hypertriglyceridemia (probucol also) Increases HDL better than any other drug on the market (45%) BUT has side effects: 1. Flushing and itching due to release of prostaglandins, which stimulate mast cells to degranulate and release histamine, causing itching and flushing from vasodilation Prevention: aspirin or any NSAID Treatment: antihistamines 2. Blocks insulin receptors, leading to insulin resistance 3. Competes with uric acid, causing gout Figure 2.8 Patient with Gout 26 Vitamins, Minerals, and Trace Elements The Beginning Management: Gout Acute gout • • • Most effective treatment: colchicine o Blocks microtubules, therefore blocking all rapidly dividing cells (because microtubules are needed for mitosis) o Causes bone marrow suppression and renal failure Current treatment: indomethacin o Reversibly inhibits COX 1 and 2 In case of renal failure, locally inject with an IV steroid (because colchicine and indomethacin are renally excreted) Chronic/Recurrent gout • • • Allopurinol—blocks xanthine oxidase Rasburicase— a recombinant of urate oxidase (or uricase) that metabolizes uric acid Probenecid—increases excretion of uric acid by blocking the reabsorption of uric acid Vitamin B4: Lipoic Acid • • Needed by o Pyruvate dehydrogenase o Alpha-ketoglutarate dehydrogenase o Branched chain amino acid dehydrogenase No deficiency state Vitamin B5: Pantothenic Acid • • Needed by o Pyruvate dehydrogenase o Alpha ketoglutarate dehydrogenase o Branched chain amino acid dehydrogenase o Coenzyme A No deficiency states Vitamin B6: Pyridoxine • • Needed to make heme Needed by all transaminases 27 Vitamins, Minerals, and Trace Elements The Beginning • • INH pulls pyridoxine out of the body Forms the cofactor pyridoxal phosphate Pyridoxine deficiency • Neuropathy Management: Chronic Neuropathy/Pain • • • Drug of choice is amitriptyline (TCA) o Blocks reuptake of catecholamine (so levels increase) If heart disease, drug of choice is gabapentin If shooting/stabbing neuropathy/pain, drug of choice is carbamazepine (ex: syphilis) Vitamin B9: Folate • Lasts for 24 hours • The first vitamin to run out whenever you have rapidly dividing cells • Used to make tetrahydrofolate (THF) from which you make nucleotides (Thymidine) PP Clue When are cells most rapidly dividing? 1. 2. 3. 4. Pregnancy 0-2 years of age 4-7 years of age Puberty Folate deficiency • • Megaloblastic anemia Hyper segmented neutrophils o Cytoplasm divided; nucleus did not divide but tried to, forming many segments 28 Vitamins, Minerals, and Trace Elements The Beginning Figure 2.9 Megaloblastic Cells • • Figure 2.10 Hyper segmented Neutrophils Neural tube defects in fetuses Most common cause: overcooked vegetables Clinical Correlation The order in which groups over cook their food: 1. 2. 3. 4. Black Hispanics White Asians Who has the highest life expectancy: 1. 2. 3. 4. Asians Whites Hispanics Blacks Vitamin B12: Cyanocobalamin • Lasts for 6-9 months in the liver (acts like a fat-soluble vitamin, even though it is water- soluble) • Needed by two enzymes: o Homocysteine methyltransferase  Like with B9, it is needed to make THF o Methyl malonyl-CoA mutase • Needed to recycle odd-numbered carbon fatty acids o Ex: cholesterol is a 27-C FA used to make myelin • Used to make tetrahydrofolate 29 Vitamins, Minerals, and Trace Elements The Beginning • B12 is also used in treatment of cyanide poisoning Vitamin B12 Deficiency • • • • Deficiency occurs after 3 to 4 years Megaloblastic anemia Hyper segmented neutrophils Neuropathy, especially involving the dorsal column pathways and corticospinal tracts • MCC in the US: pernicious anemia (type A gastritis) Vitamin C • • • Used for hydroxylation Hydroxylates proline and lysine in collagen and elastin Main antioxidant in the GI system Vitamin C deficiency • • Scurvy Bleeding from hair follicles and gums Figure 2.11 Scurvy Clinical Correlation Viruses cause free radicals which destroy cells. The body needs to replace those cells, utilizing a lot of energy, which leads to weakness and shortness of breath: Low Energy State. Therefore, we take Vitamin C to fight colds and the flu. 30 Clinical Correlation Vitamin C protects iron from being oxidized in the GI tract. So, therefore, we advise patients to drink orange juice when taking iron. Vitamins, Minerals, and Trace Elements The Beginning Vitamin D • • • • • Necessary for bone and teeth formation Stimulates osteoblastic activity and osteoclastic activity Stimulates calcium and phosphorus absorption from GI tract, resorption from the bone, reabsorption from the kidney. It suppresses PTH. Both calcium and phosphorus go in the same direction Mineralizes bones and teeth PP Clue Vitamin D deficiency • • • • • What infection causes anterior bowing of the legs? #1 vitamin deficiency in the US Due to obesity Rickets: in children o Lateral bowing of the legs Osteomalacia (soft bones): in adults Vitamin D resistant rickets o Defective renal reabsorption of phosphorus o As phosphorus leaks out, it pulls calcium out with it o X-lied dominant (dads give it to all daughters) o Labs: low calcium, low phosphorus o Diagnosis: if you administer dose of vitamin D, calcium and phosphorus remain low Syphilis Figure 2.12 Patient with Rickets 31 Vitamins, Minerals, and Trace Elements The Beginning Vitamin E • • The main antioxidant in your blood Absorbs free radicals Diseases involving oxidation • • • • Cancer Alzheimer’s disease Coronary artery disease Hemolytic anemia (esp. G6PD) Vitamin E is used to treat all these disorders. Antioxidants 1. Vitamin E: in blood 2. Vitamin C: in GI tract 3. Milder forms: a. Vitamin A b. Beta-Carotene c. Trace elements Biotin • Necessary for carboxylation Biotin deficiency • Many carboxylases would lose their function Vitamin K • • Vitamin K needed for gamma-carboxylation Adds a third (gamma) carboxyl group to the vitamin K dependent clotting factors o Clotting factors II, VII, IX, X, (1972), Protein C & Protein S o Protein C has shortest half-life (6 hours), followed by factor VII (2 days) Vitamin K Gamma (γ)-carboxylation • Vitamin K- dependent clotting factors already have 2 carboxyl groups (COOH): alpha (α) and beta (β); gamma will be the third, added on by a vitamin Kdependent enzyme. 32 Vitamins, Minerals, and Trace Elements The Beginning • • • They have 10 glutamic acids on their carboxyl terminal (the one to the right); these glutamic acids already have 20 carboxyl groups. So, 2 X 10 = 20 negative charges. When you add the 3rd group, this will produce 30 negative charges. These negative charges will be attracted to calcium released by platelets, attracting the Vitamin-K dependent factors (II, VII, IX, X; Protein C and Protein S). Figure 2.13 Clotting Cycle Warfarin • • • • • • • • Given orally Always give heparin first when treating venous clots Crosses the placenta Teratogenic Follow PT (prothrombin time) o For extrinsic pathway where Factor VII (+ tissue factor) is located INR 2 to 3x normal o 2-3 times less likely to form a clot (it will take 2-3 times as long to form a clot) If PT too high, give them vitamin K IM; if bleeding all over the floor, give them prothrombin complex or FFP because it has all the clotting factors in it Give Warfarin for: o First time venous clot with known cause, give for 3 months o Second time venous clot with known cause, give for 12 months 33 Vitamins, Minerals, and Trace Elements The Beginning o Third time venous clot (or anytime you do not know the cause), give for lifetime Factor V Leiden Mutation • MCC of in in genetic spontaneous venous clot formation o Patient must stay on warfarin lifelong. Management: Warfarin Management: Heparin Before Warfarin • Protein C (the first thrombolytic) will disappear first. • Why? Protein C has a t1/2 of 6 hours; it takes 30 hours for Heparin to reach steady state (5 t1/2 x 6 hrs.). In 30 hours, Protein C will be completely gone, but starting at 6 hours, 50% of the Protein C will be knocked out. • This causes the patient to be more likely to form a clot 6 hrs. after administration of Warfarin. • This process will occur even more rapidly if they have a congenital Protein C deficiency (causes skin necrosis). • This is the reason why we need some other drug to start protecting them starting at 6 hrs. (Heparin). • Heparin starts working at 6 hrs. (its t1/2 is 6hrs) • Heparin will activate antithrombin III so that we have protection against clots. • Factor VII, the first of the clotting factors, has the shortest t1/2 of 2 days. • It will take 10 days to reach steady state (5 t1/2 x 2days). • This is how I know why you will have to stay in the hospital on heparin for 2 days until your warfarin has blocked factor VII. Heparin • • • Acts as a cofactor for antithrombin III Blocks thrombin, as well as clotting factors IX, X, XI, XII (intrinsic pathway) o Follow by measuring PTT o 2.5-3.5 if cardiolipin antibody syndrome or metallic heart valve o If antithrombin 3 is deficient (due to protein loss), when you administer heparin, PTT will not change o To reverse the action: protamine sulfate o If patient acutely bleeding: give FFP to reverse immediately Side Effects/Issues 34 Vitamins, Minerals, and Trace Elements The Beginning • • • o Bleeding o Hyperlipidemia by activating hormone-sensitive lipase (like glucagon)  Milky white plasma o Heparin-induced thrombosis (HIT 1)-from platelet clumping, occurs on day 1 or 2 o Heparin-induced thrombosis (HIT-2)-occurs after day 3  Thrombocytopenia precedes the clotting  Heparin acts as a hapten on the platelet, causing antibodies to form. They then attack the platelets that are floating around the blood vessels. This causes inflammation— vasculitis.  This causes clots to form on the now sticky endothelium  Switch to Lepirudin or Argatroban (block thrombin directly) or fondaparinux (factor Xa inhibitor) Low-molecular weight heparin (LMWH) o Used to decrease risk of side effects o “-parin” is the parent compound o Any name that does not start with “he” is low molecular weight (enoxaparin, denoxaparin, lenoxaparin) o Pros: fewer side effects; less bleeding; cost less; no need to follow PTT or PT Safe for pregnancy o For entire pregnancy o Safe because it is charged, so it does not cross the placenta Contraindicated o Recent head injury o Recent CPR o Uncontrolled hypertension o Bleeding ulcer o Use a Greenfield filter/IVC filter instead Gut flora makes 1. 2. 3. 4. 5. 90% of vitamin K Biotin Folate Pantothenic Acid They help absorb vitamin B12 35 Vitamins, Minerals, and Trace Elements The Beginning When do you not have enough gut flora? • • Newborns o Why we give Vitamin K to all newborns (IM) o Hemorrhagic disease of the newborn occurs @ 2 days old  Why? Factor VII t1/2 is 2 days Broad-spectrum antibiotics PP Clue What 4 cephalosporins inhibit vitamin K? 1. 2. 3. 4. Cefamandole Cefotetan Moxalactam Cefoperazone Minerals • • • • • Calcium Magnesium Zinc Copper Iron Calcium • • • • • • • Intracellular calcium needed for all muscle contraction Smooth muscle uses extracellular calcium for second messenger systems Atrium and thalamus are the only membranes that use calcium to depolarize Cardiac ventricle depends on extracellular calcium to trigger off its intracellular calcium release o “Calcium-induced calcium release” Used for axonal transport Presynaptic influx of calcium necessary for release of all neurotransmitters Needed for normal bone and teeth development Clinical Correlation Babies in utero need calcium for the release of neurotransmitters. If not, may be born with mental retardation 36 Vitamins, Minerals, and Trace Elements The Beginning Magnesium • • • • A cofactor for all kinases, which make and use negatively charged ATP (so kinases need something with a positive charge to hold onto negative charges) A cofactor for PTH Interacts with potassium somewhere in the early distal convoluted tubules of the kidneys Cotransport protein for both potassium and magnesium Zinc • • • Needed by hair, skin, sperm, and taste buds Zinc deficiency: dysgeusia May turn hair color red Copper • • Needed by lysine oxidase in the formation of collagen Also needed by complex IV of the electron transport system Figure 2.14 Electron Transport Chain Copper excess • Wilson’s disease o Autosomal recessive o Ceruloplasmin deficiency (protein that carries copper) o Copper deposition in lenticular nucleus (basal ganglia), cornea (KayserFleischer rings) and in the liver (causing cirrhosis) 37 Vitamins, Minerals, and Trace Elements The Beginning o Tx: penicillamine (binds anything that is 2+ - iron, calcium, zinc, magnesium); causes drug-induced lupus; may not use if patient has anaphylaxis to penicillin Management: Movement Disorder in a Middle-Aged Person HUNTINGTON’S DISEASE (90%) • • • • • • Autosomal dominant Trinucleotide repeats Involves caudate nucleus Has anticipation Treat with antipsychotics (dopamine blockers) MCC of death: suicide WILSON’S DISEASE • • • • Autosomal recessive Ceruloplasmin def Copper deposition in lenticular nucleus, liver, and iris Treat: penicillamine Figure 2.15 Patient with Wilson’s Disease 38 Vitamins, Minerals, and Trace Elements The Beginning Figure 2.16 Autosomal Recessive Inheritance Figure 2.17 Autosomal Dominant Inheritance REMEMBER Trinucleotide Repeats: 5 diseases that COULD have trinucleotide repeats 1. 2. 3. 4. 5. Huntington’s disease Fragile X Friedreich’s Ataxia Prader Willi syndrome Myotonic dystrophy Copper deficiency • Menke’s Kinky Hair syndrome o Orange colored hair because the copper gets stuck in her hair o Hair feels like copper wire Figure 2.18 Menke’s Kinky Hair Syndrome 39 Vitamins, Minerals, and Trace Elements The Beginning Iron • • • Needed for formation of heme and hemoglobin Ferrous iron (Fe2+) binds oxygen; ferric iron (Fe3+) has been oxidized Needed by complex III and IV of electron transport system Trace Elements • • • • • • Chromium Selenium Molybdenum Manganese Tin Fluoride Chromium • • Enhances insulin action, therefore delays progression of diabetes Deficiency: causes diabetes Selenium • • • Needed primarily by the heart Excess: breath smells like garlic (arsenic as well) Deficiency: dilated cardiomyopathy Molybdenum and Manganese • • Needed by many enzymes in glycolysis Xanthine oxidase: needs both elements o Enzyme needed to make uric acid • Needed for hair growth Tin Fluoride • • Needed for teeth and bone growth Excess: blocks enolase of glycolysis, causing low energy state 40