Exam 4 Topics to Know

Exam 4 Topics to Know Dr. L comments 7/14 Not in bad shape for my first review, I’ll review and provide feedback on this again on Monday. Dr. L comments 7/17 Improved from Friday, but there are still topics that can be better addressed. Understand the difference between folic acid and folate Folate is a B vitamin that exists in either its reduced form (folate) or oxidized form (folic acid). When folate is used in this section, we are referring to the reduced form, not the vitamin itself. Another key distinction between the 2 terms is that folic acid refers to the synthetic form, while folate refers to the natural form. Folic acid is only found in certain foods because they have been fortified with it, not because they produce it. Another key difference between folate and folic acid is the number of glutamates in their tails. Folic acid always exists as a monoglutamate, meaning it only contains 1 glutamate. On the other hand, about 90% of the folate found in foods are polyglutamates, meaning there is more than 1 glutamate in their tail. Folic acid is more stable than folate, which can be destroyed by heat, oxidation, and light. Understand the purpose of dietary folate equivalents (DFEs) The DRI committee created dietary folate equivalents (DFEs) to account for the differences in bioavailability between folic acid and folate. (Folic acid from food is 85% bioavailable, compared to 50% for folate) Know the cofactor form of folate The cofactor form of folate is tetrahydrofolate (THF). In order for THF to be formed, a methyl group is transferred to cobalamin (vitamin B12 ) from 5-methyl THF(THF plus a methyl group) forming methyl- cobalamin. THF is required for the synthesis of DNA bases (purines and pyrimidines). Understand why the US fortifies foods with folic acid The neural tube closes 24-28 days after conception, and with 50% of pregnancies estimated to be unplanned, many women are not aware they are pregnant during this period. It is recommended that women of childbearing age consume 400 ug of folic acid daily. However, to expect all women to do this through supplements would likely be most difficult for those at most risk (women of low socioeconomic status, young mothers) because they might not be able to afford or not know to take the supplement. Thus, in 1998 the FDA mandated that all refined cereals and grains be fortified with 140 ug folic acid /100 grams of product. The link below is to the announcement that in 2016 the FDA approved the fortification of corn masa flour. This may be beneficial for Hispanic/Latinx populations that might not consume much fortified

refined cereals or grains. Understand what megaloblastic anemia is and why folate and vitamin B 12 deficiencies lead to this condition Macrocytic anemia is characterized by large red blood cells and can be megaloblastic or non-megaloblastic. Megaloblastic anemia is characterized by large, nucleated (most red blood cells do not have a nucleus), immature red blood cells. This occurs because folate (as THF) is needed for DNA synthesis; without it red blood cells are not able to divide properly. As a result, fewer and poorer functioning red blood cells are produced that cannot carry oxygen as efficiently as normal red blood cells. B12 (Cobalamin) is a cofactor for methionine synthase and is needed to convert 5 methyl THF to THF. Know the scientific name of vitamin B 12 Cobalamin Know why vitamin B 12 deficiency is an issue for vegans and why most reliable sources of B 12 are animal- based foods Vitamin B12 is unique among vitamins in that it I s found almost exclusively in animal products. Neither plants nor animals can synthesize vitamin B12. Instead, vitamin in animal products is produced by microorganisms within the animal that the products came from. Animals consume the microorganisms in soil or microorganisms in the GI tract of ruminant animals produce vitamin B12 that can then be absorbed. For vegans, supplements, nutritional yeast, and fortified products like fortified soy milk can help them meet their vitamin needs Understand pernicious anemia, atrophic gastritis, intrinsic factor, and vitamin B 12 deficiency The most common cause of vitamin deficiency is pernicious anemia, a condition of inadequate intrinsic factor production that causes poor vitamin absorption. This condition is common in people over the age of 50 because they have the condition atrophic gastritis. Atrophic gastritis is a chronic inflammatory condition that leads to the loss of glands in the stomach. The loss of glands leads to decreased intrinsic factor production. It is estimated that ~6% of those age 60 and over are vitamin B12 deficient, with 20% having marginal status. In the duodenum, pancreatic proteases break down haptocorrin, and again vitamin b12 is freed. Intrinsic factor then binds vitamin (intrinsic factor + ); intrinsic factor + continues into the ileum to prepare for absorption. In the ileum, intrinsic factor + B12 is believed to be endocytosed by intrinsic factor binding to cubulin (aka intrinsic factor receptor), forming an endosome inside the enterocyte. Intrinsic factor is broken down in the enterocyte, freeing vitamins B12. The free vitamin is then bound to transcobalamin II (TC II + B12 ); TC II + B12 moves into circulation. Understand how folate/folic acid can mask a vitamin B 12 deficiency and why it could be problematic Folate and vitamin B12 lead to the same megaloblastic (macrocytic) anemia. If high levels of folate or folic acid (most of the concern is with folic acid since it is fortified in foods and commonly taken in supplements) is given during vitamin B12 deficiency, it can correct this anemia. This is referred to as masking because it does not rectify the deficiency, but it "cures" this symptom. Folate/folic acid can do this by providing so much folate that there is enough THF for red blood cell division to occur even without having the cobalamin

Skin pigmentation-Another factor that plays an important role in vitamin synthesis is skin pigmentation. Skin color is the result of increased production of the pigment melanin. Age also plays a factor in vitamin synthesis. Aging results in decreased 7-dehydrocholesterol concentrations in the skin, resulting in an approximately 75% reduction in the vitamin synthesis capability by age 70. Clothing- Clothing is another factor that influences vitamin synthesis. More clothing means that less sun reaches your skin, and thus less vitamin synthesis. Understand the debate surrounding “sensible sun exposure” Researchers recommend sun exposure on the face, arms, and hands for 10-15 minutes 2-3 times per week between 10 AM. However, dermatologists do not like "sensible sun exposure" because this is also the peak time for harmful sun exposure. Dermatologists say that "sensible sun exposure" appeals to those who are looking for a reason to support tanning and are at highest risk (primarily young, fair-skinned females) of sun damage. They argue that vitamin D can be provided through supplementation. Understand why milk fortification with vitamin D might be a problematic policy for groups such as African-Americans Many people are lactose intolerant. Coincidentally, many of these people have darker pigmented skin, meaning that they have an increased risk of vitamin D deficiency/insufficiency because they require greater sun exposure to synthesize adequate amounts of vitamin. Have an integrated understanding of how the body responds to low blood calcium levels, including PTH and 1,25(OH) 2 D, vitamin D receptor and calbindin The parathyroid senses low blood calcium concentrations and releases PTH. These steps are designed to maintain consistent blood calcium concentrations, but also affect phosphate (phosphorus) concentrations. PTH has 3 effects: 1. Increases bone resorption 2. Decreases calcium and increases phosphorus urinary excretion 3. Increases 1,25(OH )2D activation in the kidney. The first effect of PTH is increased bone resorption. Hydroxyapatite must be broken down to release both calcium and phosphate. The second effect of PTH is decreased calcium excretion in urine. This is a result of increased calcium reabsorption by the kidney before it is excreted in urine. Kidney phosphate reabsorption is decreased, meaning the net effect is less calcium, but more phosphate in urinary excretion. The 3rd effect of PTH is that it increases 1,25(OH)2D activation in the kidney, by increasing 1alpha- hydroxylase levels. The 1,25(OH)2D then increases calcium and phosphorus absorption in the small intestine to help raise blood calcium levels. Increased 1,25(OH)2D synthesis in the kidney causes increased binding to the vitamin D receptor, which increases calbindin synthesis. Increased calbindin ultimately increases calcium uptake and absorption. Know what hormone is released, and where from, if blood calcium levels get too high

High blood calcium concentrations are sensed by the thyroid, which releases calcitonin. Understand the difference between insufficiency, suboptimal and deficiency Intake levels above deficient, but less than optimal, are referred to as low suboptimal. Suboptimal means the levels are not optimal. Thus, low suboptimal and high suboptimal sandwich optimal. The high suboptimal level is between optimal and where the nutrient becomes toxic. Insufficiency means that the level of intake, or body status, is suboptimal (neither deficient nor optimal). Suboptimal/insufficient means intake, or status, is higher than deficient, but lower than optimal. This is an important distinction to understand particularly for vitamin D, because there have been some saying that people are vitamin D deficient when their circulating 25(OH)D concentrations are lower than optimal. This is different from a classical deficiency definition, where there is a condition associated with too low level of intake or body status. What is really being described is that circulating 25(OH)D concentrations might be suboptimal. Deficiency- Shortage of a required substance (usually a nutrient in nutrition) needed by the body. Understand calbindin’s function in enterocytes Calbindin is the calcium binding protein that facilitates uptake and transport across the enterocyte. Know the inhibitors of calcium absorption and why calcium content of a food alone can be misleading There are a couple of calcium-binding compounds that inhibit its absorption (normally by binding to it). Therefore, even though some foods are good sources of calcium, the calcium is not very bioavailable. Oxalate, found in high levels in spinach, rhubarb, sweet potatoes, and dried beans, is the most potent inhibitor of calcium absorption. Recall that calcium oxalate is one of the compounds that makes up kidney stones. Based on this understanding, it should not be a surprise that formation of this compound inhibits calcium absorption. Another inhibitor of calcium absorption is phytate. Phytate is found in whole grains and legumes. Understand the differences between osteomalacia, osteopenia, and osteoporosis and normal bone Osteomalacia - Bone mass is normal, but the matrix to mineral ratio is increased, meaning there is less mineral in bone. Osteopenia - Bone mass is decreased, but the matrix to mineral ratio is not altered from normal bone. This condition is intermediate between normal and osteoporosis. Osteoporosis - Bone mass is further decreased from osteopenia, but the matrix to mineral ratio is not altered from normal bone. Understand what peak bone mass and bone mineral density are and why it is important to build peak bone mass To prevent osteoporosis it is important to build peak bone mass (the maximum amount that a person will

Another form of vitamin K, menaquinone (K2), is synthesized by bacteria in the colon (and potentially elsewhere). Its structure contains a tail with varying lengths of repeating units. Example of how the structure is named: it was menaquinone-8, there would be 7 (8-1) repeating units of the structure inside the brackets. Menaquinone comprises ~10% of absorbed vitamin K every day and can also be found in small amounts in animal products. The synthetic form of vitamin K is menadione (K3). A tail, similar to the one found in menaquinone, has to be added to menadione for it to be biologically active. Have an integrated understanding of what Gla proteins are, why vitamin K is needed for their production, what enzyme forms Gla, and how they are important in blood clotting The enzyme , gamma-glutamyl carboxylase , uses a vitamin K cofactor to convert glutamic acid to gamma- carboxyglutamic acid (Gla ). Gla proteins are those that contain gamma-carboxyglutamic acid (s). This formation of gamma-carboxyglutamic acid allows the 2 positive charges of calcium to bind between the 2 negative charges on the carboxylic acid groups (COO-) in the Gla . The binding of calcium activates these proteins . Activated Gla proteins are important in blood clotting. Within the blood clotting cascade, there are a number of potential Gla proteins. If these proteins within the blood clotting cascade are not activated Gla proteins, the cascade does not proceed as normal, leading to impaired blood clotting. Understand how warfarin and dicumarol act as anticoagulants Warfarin (Coumadin ) and dicumarol are a couple of blood thinning drugs that inhibit this regeneration of vitamin K. This reduces the amount of activated Gla proteins in the blood clotting cascade , thus reducing the clotting response. After being used as a cofactor to produce a Gla protein, vitamin K becomes vitamin K epoxide. Vitamin K epoxide needs to be converted back to vitamin K to serve as a cofactor again. Know why newborns receive vitamin K injections Vitamin K deficiency is rare , but can occur in newborn infants. They are at higher risk , because there is poor transfer of vitamin K across the placental barrier (from mother to fetus in utero), their gastrointestinal tracts do not contain vitamin K producing bacteria, and breast milk is generally low in vitamin K (most infant formula is fortified). As a result, it is recommended (and widely practiced) that all infants receive a vitamin K injection within 6 hours of birth. Know the different retinoids and how they are converted to each other There are 3 forms of vitamin A (retinol, retinal, and retinoic acid) that collectively are known as retinoids . Retinol is the alcohol (OH) form, retinal is the aldehyde (COH) form, and retinoic acid is the carboxylic acid (COOH) form, as shown in the figure below (areas of difference are indicated by red).

Among these different retinoids , retinol and retinal are fairly interchangeable. Either form is readily converted to the other. However, only retinal is used to form retinoic acid, and this is a one-way reaction. Thus, once retinoic acid is formed it can't be converted back to retinal. Know the dietary sources of vitamin A and where they come from The 2 primary dietary sources of vitamin A are Retinyl/retinol esters (Animal Products) and Provitamin A Carotenoids (Plants). Understand the difference between provitamin A carotenoids, nonprovitamin A carotenoids, and preformed vitamin A Preformed vitamin A means that the compound is a retinoid . Preformed vitamin A is only found in animal products (carrots are not a good source of preformed vitamin A ). Provitamin A is a compound that can be converted to vitamin A in the body, but currently is not in vitamin A form. Carotenoids can be classified as provitamin A or non-provitamin A. Provitamin A carotenoids are those that can be cleaved to form retinal, while the non-provitamin A carotenoids cannot. Understand what RAEs are and why they are needed To help account for the fact that retinol can be made from carotenoids , the DRI committee made retinol activity equivalents (RAE ) that take into account the bioavailability and bioconversion of provitamin A carotenoids . Conversions: 1ug RAE =1 ug retinol =2 ug supplemental beta-carotene = 12 ug of dietary beta carotene

A in those who are deficient. However, debate about the use of GMOs to accomplish this has prevented its use. Know what Accutane is and why it is important for pregnant women not to consume too high levels of it or vitamin A Accutane is the brand name for isotretinoin (13-cis retinoic acid). It is used to treat acne. This can cause toxic levels of Vitamin A to develop which is a known teratogen that can cause birth defects. Know what happens when you consume high amounts of beta-carotene versus vitamin A itself Vitamin A toxicity can cause blurred vision, liver abnormalities, skin disorders, and joint pain. While Vitamin A can be very toxic if consumed in high amounts, beta-carotene does not cause vitamin A toxicity because the enzyme that cleaves beta-carotene into vitamin A is regulated by vitamin A levels. Instead, a non-toxic condition known as carotenodermia can happen when there is an accumulation of carotenoids in the fat below the skin, making it appear orange. Know the different forms of iron Forms of Iron can be divided into non-heme or heme iron depending on if it is bound to heme. Know the 2 forms of non-heme iron and the difference between the absorption of the 2 forms Within non-heme iron, iron can exist as ferric (Fe3+, oxidized) or ferrous (Fe2+, reduced). If the oxidized form of non-heme iron is present, duodenal cytochrome b (Dcytb) catalyzes the reduction of Fe3+ back to Fe2+ so that it can be taken up into the enterocyte. Which form of non-heme iron is more readily absorbed? Ferrous (Fe2+, Reduced) Have an integrated understanding of iron uptake, absorption, transport through circulation, and storage Non-heme iron is transported into the enterocytes via a transporter and heme iron is transported into the enterocyte by a different transporter where they are both metabolized to Fe2+. Fe2+ may be used by enzymes or other proteins, stored as Ferritin (storage form of iron) any other storage? or sent into circulation as Ferroportin (circulating form of iron). Transport, storage? Not correct or complete yet. Know some enhancers and inhibitors of non-heme iron absorption Enhancers of non-heme iron absorption include vitamin C and meat protein factor. Inhibitors include iron chelators like phytates, polyphenols, and oxalates Know how we regulate Fe status and decrease absorption if levels get too high and understand how this regulation is different than most micronutrients “The only way to regulate iron status is through absorption via the transporter ferroportin in the enterocytes, which is controlled by the hormone hepcidin. When the liver senses iron concentrations

becoming too high, it signals the release of hepcidin which travels to enterocytes where it causes the degradation of ferroportin, decreasing iron absorption.” Understand the functions of Fe in the body “Iron functions in hemoglobin and myoglobin where it allows them to bind to oxygen and maintain tissue- oxygen levels. Iron also plays a role in many enzymes as a cofactor such as the antioxidant enzyme, catalase or the proline and lysyl hydroxylases in collagen cross-linking.” Understand what hematocrit is and the limitations of this assessment along with hemoglobin measurement for iron status “The hematocrit is a measure of the proportion of red blood cells (erythrocytes) as compared to all other components of blood.” It is used as a proxy for iron content as hematocrit indirectly measures hemoglobin concentration, which contains iron. However, hematocrit is one of the last indicators of depressed iron as its levels are maintained using stores of iron until those stores are completely exhausted, as are circulating and functional stores. Hematocrit is not altered until someone has become iron-deficient. If these measures are normal, what can you say about status of stores? Stores not addressed. Understand what occurs in iron deficiency and people who are especially at risk or require more Fe including why they are at greater risk “In iron deficiency, stores are completely exhausted and the circulating and functional iron levels are also depleted. In iron anemia, the circulating and functional iron levels are further depleted from iron- deficiency.” “Iron deficiency often results in a microcytic (small cell), hypochromic (low color) anemia, that is a result of decreased hemoglobin production. With decreased hemoglobin, the red blood cells cannot carry as much oxygen. Decreased oxygen leads to slower metabolism. Thus, a person with this anemia feels fatigued, weak, apathetic, and can experience headaches. Other side effects include decreased immune function and delayed cognitive development in children.” At risk: ● Women of childbearing age (due to menstruation) ● Pregnant women (due to levels of iron required to support growing baby/increased blood volume) ● vegetarians/vegans (due to the lack of the more bioavailable heme iron from animals that is not obtained through diet) ● Infants and young children (due to iron required for rapid growth that occurs in infants and young children)