Biochemistry, Nutrients

Article Author:
Alyssa Morris
Article Editor:
Shamim Mohiuddin
Updated:
5/18/2020 10:56:07 AM
PubMed Link:
Biochemistry, Nutrients

Introduction

Nutrients are chemical substances required by the body to sustain basic functions and are optimally obtained by eating a balanced diet. There are six major classes of nutrients essential for human health: carbohydrates, lipids, proteins, vitamins, minerals, and water. Carbohydrates, lipids, and proteins are considered macronutrients and serve as a source of energy. Water is required in large amounts but does not yield energy. Vitamins and minerals are considered micronutrients and play essential roles in metabolism. Vitamins are organic micronutrients classified as either water-soluble or fat-soluble. The essential water-soluble vitamins include vitamins B1, B2, B3, B5, B6, B7, B9, B12, and C. The essential fat-soluble vitamins include vitamins A, E, D, and K. Minerals are inorganic micronutrients. Minerals can classify as macrominerals or microminerals. Macrominerals are required in amounts greater than 100 mg per day and include calcium, phosphorous, magnesium, sodium, potassium, and chloride. Sodium, potassium, and chloride are also electrolytes. Microminerals are those required in amounts less than 100 mg per day and include iron, copper, zinc, selenium, and iodine. This article will review the following biochemical aspects of the essential nutrients: fundamentals, cellular, molecular, function, testing, and clinical significance.[1][2]

Fundamentals

Carbohydrates

Carbohydrates are essential macronutrients that are the primary source of energy for humans; 1 gram of carbohydrate contains 4 kcal of energy.[3] Carbohydrates also play roles in gut health and immune function. Carbohydrates are present in plant-based foods like grains, fruits, vegetables, and milk. Carbohydrates are ingested in the form of simple carbohydrates, like monosaccharides and disaccharides, or complex carbohydrates, like oligosaccharides and polysaccharides. Monosaccharides are the basic building blocks of all carbohydrates and include glucose, fructose, and galactose. Glucose is the primary form to which carbohydrates become metabolized in humans. Disaccharides contain two sugar units and include lactose, sucrose, and maltose. Lactose is a carbohydrate found in milk, and sucrose is basic table sugar. Oligosaccharides consist of 3 to 10 sugar units and include raffinose and stachyose, which are in legumes. Polysaccharides include greater than ten sugar units and consist of starches, glycogen, and fibers, like pectin and cellulose. Starches like amylose are in grains, starchy vegetables, and legumes and consist of glucose monomers. Glycogen is the storage form of glucose in animals and is present in liver and muscle, but there is little to none in the diet. Fibers are plant polysaccharides like pectin and cellulose that are found in whole-grains, fruits, vegetables, and legumes but are not digestible by humans. However, they play a major role in gut health and function and can be digested by microbiota in the large intestine.[4] For healthy children and adults, carbohydrates should make up approximately 45 to 65% of energy intake based on the minimum required glucose for brain function. The recommended fiber intake is greater than 38 g for men and 25 g for women, which is the intake that research has observed to lower the risk of coronary artery disease. Some carbohydrates are more nutritious than others. Optimal carbohydrate intake consists of fiber-rich, nutrient-dense whole grains, fruits, vegetables, and legumes and minimizing added sugar.[5]

Proteins 

Proteins are essential macronutrients that contribute to structural and mechanical function, regulate processes in the cells and body, and provide energy if necessary. Proteins are composed of amino acids and in food sources like meats, dairy foods, legumes, vegetables, and grains.[6] 1 gram of protein contains 4 kcal of energy.[5] The recommended protein intake is 0.8 to 1 gram per kilogram of body weight per day.[7] For healthy children ages 1 to 3, ages 4 to 18, and adults, approximately 5 to 20%, 10 to 30%, and 10 to 35% of daily energy intake should come from protein, respectively, based on the adequate amount for nitrogen equilibrium.[5]

Lipids

Lipids are essential macronutrients that are the main source of stored energy in the body, contribute to cellular structure and function, regulate temperature, and provide protection to body organs. Lipids are found in fats, oils, meats, dairy, and plants and consumed mostly in the form of triglycerides.[8] One gram of fat contains 9 kcal of energy.[3] For healthy children ages 1 to 3, ages 4 to 18, and adults, approximately 30 to 40%, 25 to 15%, and 20 to 35% of daily energy intake should come from fat, respectively. Approximately 5 to 10% and 0.6 to 1.2% of the daily fat energy intake should consist of n-6 polyunsaturated fatty acids (linoleic acid) and n-3 polyunsaturated fatty acids (α-linolenic acid), respectively.[5]

Vitamin B1 (Thiamin)

Thiamin, or vitamin B1, is an essential water-soluble vitamin that acts as a coenzyme in carbohydrate and branched-chain amino acid metabolism. Thiamin is in food sources such as enriched and whole grains, legumes, and pork. The RDA (Recommended Dietary Allowance) of thiamin for adults is 1.1 mg/day for women and 1.2 mg/day for men.[9] 

Vitamin B2 (Riboflavin)

Riboflavin, or vitamin B2, is an essential water-soluble vitamin that acts as a coenzyme in redox reactions. Riboflavin is present in food sources such as enriched and whole grains, milk and dairy products, leafy vegetables, and beef. The RDA of riboflavin for adults is 1.1 mg/day for women and 1.3 mg/day for men.[9] 

Vitamin B3 (Niacin)

Niacin, or vitamin B3, is an essential water-soluble vitamin that acts as a coenzyme to dehydrogenase enzymes in the transfer of the hydride ion and an essential component of the electron carriers NAD and NADP. Niacin is present in enriched and whole grains and high protein foods like meat, milk, and eggs. The RDA of niacin for adults is 14 mg/day of NEs (niacin equivalents) for women and 16 mg/day of NEs for men.[9] 

Vitamin B5 (Pantothenic Acid)

Pantothenic acid, or vitamin B5, is an essential water-soluble vitamin that acts as a key component of coenzyme A and phosphopantetheine, which are crucial to fatty acid metabolism. Pantothenic acid is widespread in foods. The AI (adequate intake) of pantothenic acid for adults is 5 mg/day.[9] 

Vitamin B6 (Pyridoxine) 

Vitamin B6, or pyridoxine, is an essential water-soluble vitamin that acts as a coenzyme for amino acid, glycogen, and sphingoid base metabolism. Vitamin B6 is widespread among food groups. The RDA for vitamin B6 for adults is 1.3 mg/day.[9] 

Vitamin B7 (Biotin)

Biotin, or vitamin B7, is an essential water-soluble vitamin that acts as a coenzyme in carboxylation reactions that are dependent on bicarbonate. Biotin is found widespread in foods, especially egg yolks, soybeans, and whole grains. The AI of biotin for adults is 30 mcg/day.[9] 

Vitamin B9 (Folate) 

Folate, or vitamin B9, is an essential water-soluble vitamin that acts as a coenzyme in single-carbon transfers in nucleic acid and amino acid metabolism. Folate is in enriched and fortified grains, green leafy vegetables, and legumes. The RDA of folate for adults is 400 mcg/day of DFEs. The recommendation is that women of childbearing age consume an additional 400 mcg/day of folic acid from supplements or fortified foods to decrease the risk of neural tube defects.[9] 

Vitamin B12 (Cobalamin)

Vitamin B12, or cobalamin, is an essential water-soluble vitamin that acts as coenzymes for the crucial methyl transfer reaction in the conversion of homocysteine to methionine and the isomerization reaction that occurs in the conversion of L-methylmalonyl-CoA to succinyl-CoA. Vitamin B12 is only present in animal products because it is a product of bacteria synthesis. Many foods are also fortified with synthetic vitamin B12. The RDA of vitamin B12 for adults is 2.4 mcg/day. It is recommended for older adults to meet their RDA with fortified foods or supplements because many are unable to absorb naturally occurring vitamin B12.[9] 

Vitamin C (Ascorbic Acid)

Vitamin C, or ascorbic acid, is an essential water-soluble vitamin that acts as a reducing agent in enzymatic reactions and nonenzymatically as a soluble antioxidant. Vitamin C is found primarily in fruits and vegetables, except for animal organs like the liver and kidneys. The RDA of vitamin C for adult women and men is 75 mg/day and 90 mg/day, respectively. Smokers require an additional 35 mg/day of vitamin C.[10]

Vitamin A (Retinol)

Vitamin A, or retinol, is an essential fat-soluble vitamin that plays numerous roles in vision, cellular differentiation, gene expression, growth, the immune system, bone development, and reproduction. Vitamin A is found primarily in animal products. Fruits and vegetables are a source of provitamin A carotenoids that can be converted to retinol in the body at a lesser amount. The RDA for vitamin A for adults is 900 mcg/day for males and 700 mcg/day for females.[11]

Vitamin D (Cholecalciferol)

Vitamin D, or cholecalciferol, is an essential fat-soluble vitamin that plays essential roles in calcium metabolism, cell growth and development, and bone health. Vitamin D can be found in fish oils, and in small amounts in plants in its less biologically active form. Interestingly, vitamin D synthesis occurs in the skin with exposure to UV light making dietary sources unnecessary in certain cases. The RDA for vitamin D for adults is 10 to 15 mcg/day.[11]

Vitamin E (Tocopherol)

Vitamin E, or tocopherol, is a fat-soluble vitamin that is an antioxidant and may play roles in cell signaling, platelet aggregation, and vasodilation. Vitamin E, in the form of α-tocopherol, is found in certain vegetable oils, including sunflower, safflower, canola, and olive oil, whole grains, nuts, and green leafy vegetables. The RDA for vitamin E for adults is 15 mg/day.[11]  

Vitamin K (Phylloquinone; Menaquinone)

Vitamin K is an essential fat-soluble vitamin that is the coenzyme in the carboxylation of glutamic acid to form γ-carboxyglutamic acid reaction, which is essential to the proteins involved in blood coagulation. Vitamin K is present in green leafy vegetables, canola oil, and soybean oil. The RDA of vitamin K for adults is 120 mcg/day for men and 90 mcg/day for women.[11]

Calcium

Calcium is an essential macromineral that is responsible for numerous structural components such as bones and teeth and physiological mechanisms in the body. Calcium exists in dietary sources such as dairy, cereals, legumes, and vegetables. The RDA for calcium for adults is 1,000 mg/day.[12][13] 

Magnesium

Magnesium is an essential macromineral that is responsible for numerous functions in the body, including signaling pathways, energy storage, and transfer, glucose metabolism, lipid metabolism, neuromuscular function, and bone development. Magnesium is present in food sources such as fruits, vegetables, whole grains, legumes, nuts, dairy, meat, and fortified foods like cereal. The adult RDA for magnesium is 400 mg/day.[14][15]

Phosphorus

Phosphorus is an essential macromineral that is a structural component of bones and teeth, DNA, RNA, and plasma membrane of cells. It is also critical metabolically to produce and store energy. Phosphorus is pervasive throughout food sources, with the greatest contributors being milk, dairy, meat, and poultry. Phosphorus is also an additive in processed foods as a preservative. The RDA for phosphorus for adults is 700 mg/day.[16] 

Sodium

Sodium is an essential macromineral and electrolyte that plays critical roles in cellular membrane transport, water balance, nerve innervation, and muscle contraction as the most abundant extracellular cation. Sodium is available in dietary sources such as salt, processed foods, meat, milk, eggs, and vegetables. The AI for sodium for adults is 1,500 mg/day; however, the average sodium intake in industrialized nations is 2 or 3 fold in comparison at 3,000 to 4,500 mg/day.[17][18][17]  

Potassium

Potassium is an essential macromineral and electrolyte that plays critical roles in muscle contraction, nerve innervation, blood pH balance, and water balance as the most abundant intracellular cation. Potassium is obtainable in dietary sources such as fruits and vegetables. The AI for potassium is for adults is 4,700 mg/day.[17][19][17]

Chloride

Chloride is an essential macromineral and electrolyte that plays critical roles in digestion, muscular activity, water balance, and acid-base balance as the most abundant extracellular anion in the body. Dietary chloride is almost always present in dietary sources associated with sodium in the form of NaCl, or table salt. Chloride is in processed foods, meat, milk, eggs, and vegetables. The AI for chloride for adults is 1,500 mg/day.[17][20][17]

Iron

Iron is an essential trace mineral that has a critical role in oxygen transport and energy metabolism. Dietary iron is from sources such as meat, fortified grains, and green leafy vegetables. Animal foods contain a more bioavailable form of iron called heme iron, while plant foods and fortified grains contain a less bioavailable form called non-heme iron. The RDA for iron for adults is 8 to 18 mg/day.[21][22] 

Zinc

Zinc is an essential trace mineral that functions structurally in proteins and catalytically as a component of over 300 different enzymes. Zinc appears in a variety of foods, especially shellfish and red meat. The RDA for zinc for adults is 10 mg/day.[23] 

Copper

Copper is an essential trace mineral that acts as a component of numerous proteins, including many important enzymes. Copper is in a variety of food sources but the highest concentrations in organ meats, nuts, seeds, chocolate, and shellfish. The RDA for copper for adults is 1 mg/day.[24][25]

Iodine

Iodine is an essential trace mineral necessary for thyroid hormone synthesis. Iodine is present in meats and plant foods based on the soil content of the region of food production. Otherwise, iodized salt is the main food source of iodine in regions with low soil iodine content. The adult RDA for iodine is 150 mcg/day.[26] 

Selenium

Selenium is an essential trace mineral that is an essential component of selenoproteins that play biological roles in antioxidant defense and anabolic processes in the human body. Selenium occurs in grains and vegetables, but the amounts vary based on the selenium content in the soil that the grains and vegetables were grown in. Brazil nuts are known for having high concentrations of selenium. The RDA for selenium for adults is 55 mcg/day.[27] 

Cellular

Carbohydrates

Carbohydrate digestion takes place in the mouth and small intestine with salivary amylase, pancreatic amylase, and brush border enzymes. Human carbohydrate digesting enzymes catalyze hydrolysis reactions that break the bonds between monomers. However, given fibers have beta bonds, they are indigestible by human enzymes, so some end up getting digested by bacterial enzymes in the large intestine and the remainder is excreted in the feces. In the mouth, salivary amylase begins to break down the polysaccharide starch into the disaccharide maltose, which moth contain monomers of glucose. Carbohydrate digestion bypasses the stomach and continues in the small intestine via pancreatic amylase and brush border enzymes on the microvilli. Pancreatic amylase continues to break down starches into maltose. The brush border enzymes include maltase, sucrase, and lactase. Maltase hydrolyzes maltose into two glucose monomers. Sucrase hydrolyzes sucrose into glucose and fructose. Lactase hydrolyzes lactose into glucose and galactose.[28]

Monosaccharides pass through intestinal epithelial cells via facilitated diffusion and active transport to enter the bloodstream. Fructose is absorbed via facilitated diffusion by GLUT5 and released via facilitated diffusion by GLUT2. Glucose and galactose are absorbed along with sodium via active transport by the symporter sodium-glucose transporter 1 and are released via facilitated diffusion by GLUT2. The monomers enter the portal vein and travel to the liver. When fructose and galactose enter the liver, they must first be converted to glucose in order to be metabolized for energy. These can be converted into intermediates of the glycolysis pathway, glucose-6-phosphate or fructose-6-phosphate, to directly enter the glycolysis pathway or the substrate of glycogenesis, glucose-1-phosphate, to be stored as glycogen.[29] 

Glucose metabolism requires the following B vitamins to act as coenzymes: thiamine (B1), riboflavin (B2), and niacin (B3). Glucose metabolism begins in the cytoplasm of cells with the anaerobic process of glycolysis when one 6-carbon glucose molecule is partially oxidized into two 3-carbon pyruvate molecules. During the process, there is a net yield of two ATP and two NADH, where they will carry the electrons to the electron transport chain, eventually producing ATP. NADH is derived from niacin. ATP is the main source of cellular energy due to its high energy bonds between phosphate groups, which is released when broken via hydrolysis.[29] 

In the absence of oxygen, which can happen during strenuous exercise or in cells without mitochondria, lactate dehydrogenase catalyzes the conversion of pyruvate to lactate, which can then go back to the liver to be converted back to pyruvate and undergo gluconeogenesis to create glucose. Then, the glucose can go back to the muscle cells and go through glycolysis again releasing two ATP molecules. This is called the Cori cycle and shows how lactate, the waste product of skeletal muscles, can be converted to glucose in hepatocytes, and then be used for energy back in the skeletal muscles.[29]

In the presence of oxygen, pyruvate will travel to the mitochondrial matrix, where pyruvate dehydrogenase will catalyze the oxidation and decarboxylation of two 3-carbon molecules of pyruvate from glycolysis into two 2-carbon molecules of acetyl-CoA. Pyruvate dehydrogenase uses thiamine pyrophosphate, or TPP, as a coenzyme. In addition, two carbon dioxide molecules and two NADH molecules are produced, and the NADH molecules will carry electrons to the electron transport chain to ultimately produce ATP. Pyruvate decarboxylation is the link between glycolysis and the citric acid cycle.[29]

The citric acid cycle, also known as the TCA cycle and the Krebs cycle, occurs in the mitochondrial matrix where the 2-carbon acetyl-CoA will join 4-carbon oxalate to produce 6-carbon citrate which gets degraded to produce the energetic molecules GTP, NADH, and FADH2. The cycle will continue so long as there is an input of acetyl-CoA because citrate eventually gets converted back to oxalate. Two pyruvates from glycolysis will release 2 GTP, 6 NADH, and 2 FADH molecules. FADH is derived from riboflavin. NADH and FADH2 will travel to the electron transport chain where ATP will be synthesized via oxidative phosphorylation.[29]

Oxidative phosphorylation begins at the electron transport chain along the inner membrane of the mitochondrion. Four protein complexes I-IV are embedded along the membrane and function to pump protons from the mitochondrial matrix to the intermembrane space in order to create an electrochemical gradient through a chain of redox reactions. Protein complex I receive electrons from NADH in order to pump hydrogen across the inner membrane. FADH2 drops electrons off at protein complex II, and protons get pumped across at protein complex III. One molecule of NADH generates three molecules of ATP while one molecule of FADH2 only generates two molecules of ATP.  When enough protons fill-up the intermembrane space, an electrochemical gradient occurs. At protein complex IV, oxygen acts as the final electron acceptor forming water. Through chemiosmosis, protons will flow from the intermembrane space through the hydrophilic tunnel of ATP synthase back to the matrix. The proton motive force generates energy that allows ATP synthase to condense ADP + Pi into high energy ATP. Overall, this process generates 34 ATP molecules per molecule of glucose and is by far, the most efficient way to produce energy.[29]

Proteins 

Protein digestion begins in the stomach where they are broken down by protease enzyme pepsin. First, gastric parietal cells will release hydrochloric acid, which will denature proteins and convert inactive pepsinogen to active pepsin. Pepsin digests proteins by hydrolyzing peptide bonds between amino acids to form large polypeptides or oligopeptides. Protein digestion continues in the small intestine. In response to the acidic chyme from the stomach, the hormones cholecystokinin and secretin are synthesized in the duodenum. These hormones trigger pancreatic cells to secrete bicarbonate and proenzymes into the intestine. The proenzymes trypsinogen, procarboxypeptidase, and chymotrypsinogen are converted into their active enzyme forms trypsin, carboxypeptidase, and chymotrypsin in a cascade of enzymatic reactions. Trypsin, carboxypeptidase, and chymotrypsin digest polypeptides into tripeptides, dipeptides, and free amino acids that can be absorbed in the small intestine.[28] 

Peptide and amino acid absorption occur across epithelial cells in the small intestine via transporters. Some amino acids can travel across the epithelium paracellularly, while others require amino acid transporters that vary based on the specific amino acid and mechanism in which they transport. Tripeptides and dipeptides are transported into the epithelial cell via PEPT1 coupled with the electrochemical gradient produced by Na+/H+ exchanger on the brush border membrane. Intracellular peptides finish breaking down tripeptides and dipeptides into free amino acids. Free amino acids will exit the basolateral membrane of the epithelial cell and enter the bloodstream at the portal vein to the liver.[28]    

Amino acids can be metabolized via transamination for amino acid interconversion or deamination for the oxidation of the carbon skeleton for energy or excretion. For amino acid interconversion, pyridoxine (B6), cobalamin (B12), and folate (B9) are required. For amino acid oxidation, pyridoxine (B6), cobalamin (B12), and biotin (B7) are required. Amino acids can undergo transamination to enter the TCA cycle in glucose metabolism. Certain amino acids like alanine can be transaminated by an aminotransferase enzyme with the coenzyme PLP, which is derived from pyridoxine, to form pyruvate. Other amino acids can be transaminated by an aminotransferase enzyme with PLP to form α-ketoglutarate, which is an intermediate in the TCA cycle. Some amino acids can be transaminated by an aminotransferase enzyme with PLP to form oxaloacetate, which is an intermediate in the TCA cycle. Other amino acids can be oxidized with enzymes that require biotin and vitamin B12 as coenzymes or from succinyl-CoA, which is an intermediate in the TCA cycle. When the carbon skeletons of amino acids become degraded for energy, they are deaminated and the nitrogen group is excreted in the form of urea.[28][30][28] 

Lipids

Limited digestion of lipids occurs in the mouth and stomach with the enzymes lingual lipase and gastric lipase respectively. However, most ingested lipids arrive at the duodenum of the small intestine undigested. The presence of lipids in the duodenum stimulates the release of enzymes from the pancreas and bile from the gallbladder. Bile emulsifies that lipids preparing them for digestion by pancreatic lipase. Pancreatic lipase hydrolyzes triglycerides to monoglycerides and free fatty acids. Lipids are absorbed via simple diffusion. Short-chain fatty acids and glycerol move directly into the portal circulation and bind to albumin. Long-chain fatty acids, mono/diglycerides, cholesterol, and phospholipids combine with bile to form micelles allowing them to be soluble in the hydrophilic environment and then leave the micelle and enter the intestinal mucosa cell. In the intestinal cell, long-chain fatty acids are re-esterified to form triglycerides. Triglycerides combine with cholesterol, phospholipids, and other proteins to form chylomicrons. The chylomicrons will leave the intestinal cell and enter the lymph system where they will eventually enter the bloodstream through the thoracic duct.[28]

Lipoproteins carry lipids throughout the bloodstream, and the enzyme lipoprotein lipase frees up fatty acids to be taken up by cells. In the bloodstream, the chylomicrons can deliver the dietary fatty acids to body cells where they will form triglycerides and the remaining lipids to the liver to travel to other cells or be excreted. In the liver, triglycerides, cholesterol, phospholipids, and proteins will combine to form VLDL which will leave the liver to deliver lipids mainly in the form of triglycerides to cells in the bloodstream. As VLDL delivers triglycerides to cells, it begins to shrink and become LDL. LDL continues to carry lipids to cells, but the lipids are mainly in the form of cholesterol. LDL binds to LDL receptors of cells for cholesterol to be taken up. The remaining lipids will leave cells in the form of HDL where they will carry lipids back to the liver for either reuse or excretion. In the cells, lipids can be metabolized for energy by entering at different points of the glucose metabolism pathway. Triglycerides are broken down into glycerol and free fatty acids. Glycerol can be converted to pyruvate and catabolized for energy. Free fatty acids can be oxidized to acetyl-CoA to enter the citric acid cycle.[29][31]

Vitamin B1 (Thiamin)

Thiamin absorption occurs mainly in the jejunum of the small intestine. Higher concentrations are absorbed via passive diffusion while lower concentrations are absorbed via an active, carrier-mediated system that involves phosphorylation. In the blood, thiamin is transported in the erythrocytes and plasma. A small percentage of thiamin is absorbed, while the remainder is excreted in the urine.[9]

Vitamin B2 (Riboflavin)

Thiamin is mainly consumed as FMN and FAD bound to a food protein. In the stomach, the acidic environment releases the coenzymes FMN and FAD from the protein. Most absorption of riboflavin occurs in the small intestine via an active or facilitated transport system. FMN and FAD must first be hydrolyzed to riboflavin by nonspecific pyrophosphatases to be absorbed. Riboflavin is transported in the plasma mainly bound to albumin and is excreted in the urine.[9]

Vitamin B3 (Niacin)

At low concentrations, niacin is absorbed in the small intestine via sodium-ion dependent facilitated diffusion. At high concentrations, niacin is absorbed in the small intestine via passive diffusion. Niacin can be transported freely in the blood in the forms of nicotinic acid or nicotinamide. Cells and tissues can take up niacin via passive diffusion or with the use of transporters. Niacin is excreted in urine as 1-methylnicotinamide or NAM.[9]

Vitamin B5 (Pantothenic Acid)

Pantothenic acid is absorbed via active transport at low concentrations and passive transport at high concentrations in the small intestine. Pantothenate kinase catalyzes the synthesis of CoA from pantothenate. CoA plays an important role in the citric acid cycle in the forms of acetyl-CoA and succinyl-CoA. CoA can be hydrolyzed to pantothenate for excretion. Pantothenic acid is excreted in the urine.[9]

Vitamin B6 (Pyridoxine) 

The main dietary form of vitamin B6 is pyridoxal phosphate, or PLP. For PLP to be absorbed in the small intestine, it must first undergo phosphatase-mediated hydrolysis to enter the small intestine in its nonphosphorylated form. Pyridoxal, or PL, crosses the enterocyte via passive diffusion to enter the bloodstream to the liver. In the liver, PL is converted back to PLP by the enzyme PL kinase. PLP is the main circulating form of vitamin B6 and is transported in the blood bound to albumin. The majority of PLP in the body is found in the muscle. Vitamin B6 is excreted in the urine in the form of 4-pyridoxic acid.[9]

Vitamin B7 (Biotin)

Biotin can be ingested as free biotin or protein-bound biotin. In the small intestine, an enzyme called biotinidase releases biotin from its covalent bond to the protein allowing it to be absorbed. Biotin is absorbed in the small intestine through a sodium-dependent transporter. Biotin is transported through the bloodstream to the liver mostly unbound as free biotin. Biotin and biotin metabolites are excreted in the urine.[9]

Vitamin B9 (Folate) 

Food folates are polyglutamate derivatives and must be hydrolyzed to the monoglutamate forms before absorption. The monoglutamate form of folate is absorbed in the small intestine via active transport. Pharmacological doses of folic acid from supplements or fortified foods are absorbed via passive transport. Folate is transported in the bloodstream to the liver in the form of 5-methyl-tetrahydrofolate. Folate is mostly bound to albumin in the bloodstream. Most ingested folate is used or stored. Any dietary folate not absorbed is excreted in feces.[9]

Vitamin B12 (Cobalamin) 

Small amounts of vitamin B12 are absorbed through a coordinated process of the GI tract given naturally occurring B12 is bound to a protein that must be released for absorption. First, in the stomach, the presence of acid and pepsin causes the dissociation of food-bound vitamin B12 from its proteins. Then R-proteins or haptocorrins, secreted by the salivary glands bind to vitamin B12 to protect it from stomach acid. In the small intestine, pancreatic proteases degrade R-proteins in order to allow B-12 to bind to intrinsic factor, which is secreted by gastric parietal cells. Intrinsic factor attaches B12 to specific ileal mucosa receptors allowing the complex to be internalized by endocytosis into the enterocyte and released into the bloodstream where it is bound to transcobalamin I, II, or III. 50% of transcobalamin II bound B12 is taken up by the liver where it is stored while the remainder is transported to other tissues. B12 is excreted in bile, but most of it ends up reabsorbed.[9]

Vitamin C (Ascorbic Acid)

The absorption, tissue distribution, and excretion of vitamin C are tightly regulated by tissue-specific active transporters SVCT-1 and SCVT-2. Ascorbic acid is absorbed into the enterocyte by SVCT-1 and enters the bloodstream via SVCT-2. Other tissues take up ascorbic acid via SVCT-1 and/or SCVT-2. Vitamin C is excreted in the urine at intakes greater than 400 mg/day. Vitamin C is most concentrated in the brain, eyes, and adrenal gland.[10]

Vitamin A (Retinol)

Vitamin A is ingested both in the form of retinol and provitamin A carotenoids. In the small intestine, retinol, and provitamin A carotenoids enter the mucosal cell after combining with bile to form a micelle. Within the intestinal mucosal cells, retinol binds to cellular retinol-binding protein (CRBP) II to form a retinol-CRBP II complex. Then, lecithin retinol aminotransferase esterifies CRBP II retinol with a fatty acid to form CRBP-retinyl palmitate. The retinol esters will be incorporated with other lipids and apoproteins to form a chylomicron. The chylomicron will leave the intestinal cell and enter the lymph system and eventually enter the blood. Β-carotene, a provitamin A carotenoid, is converted to retinoic acid inside the intestinal cells and is able to directly enter the bloodstream where it attaches to albumin to be transported to the liver.[32][33] 

Vitamin D (Cholecalciferol)

Vitamin D is obtained mainly through UV-B-induced production in the skin. A minor amount of vitamin D is obtained through dietary intake. In the skin, vitamin D3, or cholecalciferol, is synthesized when 7-dehydrocholesterol is exposed to UV-B light from the sun. Vitamin D3 is transferred to the liver to be further metabolized. Through dietary intake, vitamin D3 is absorbed in the small intestine via incorporation into a micelle to enter the intestinal cells and incorporation into chylomicrons to leave the intestinal cells to enter the lymph system and eventually enter circulation at the thoracic duct. In the liver, vitamin D3 enters a hepatocyte and is hydroxylated into 25-OH vitamin D3, which is catalyzed by the enzyme 25-hydroxylase. Then, 25-OH vitamin D3 bind to vitamin D-binding protein, or DBP, to leave the hepatocytes and be transported to the kidney for an addition hydroxylation reaction. In the kidney, 25-OH vitamin D3 is hydroxylated to 1,25-(OH)2 vitamin D3, which is catalyzed by the enzyme 1-hydroxylase. 1,25-(OH)2 vitamin D3 is also known as calcitriol, which is considered the active form of vitamin D. 1,25-(OH)2 vitamin D3 bound to DBP is released to the bone, immune cells, and liver cells.[34][35] 

Vitamin E (Tocopherol)

Through dietary intake, vitamin E is absorbed in the small intestine via incorporation into a micelle to enter the intestinal cells and incorporation into a chylomicron to leave the intestinal cells and enter the lymph system and eventually enter circulation at the thoracic duct. Vitamin E is transported in remnant chylomicrons to the liver where it is taken up by a hepatocyte. In the hepatocyte, α-tocopherol transfer protein incorporates α-tocopherols into very low-density lipoproteins, or VLDLs, to transport to peripheral tissues. In circulation lipoprotein lipase (LPL) catalyzes the conversion of VLDL to LDL to HDL. The cellular uptake of α-tocopherol takes place with the uptake of lipoproteins via receptor-mediated endocytosis. Most α-tocopherol is stored in adipose tissue. The remaining tocopherols and tocotrienols are excreted with bile in feces.[36] 

Vitamin K (Phylloquinone; Menaquinone)

Through dietary intake, vitamin K1 and K2 are absorbed in the small intestine via incorporation into a micelle to enter the intestinal cells and incorporation into a chylomicron to leave the intestinal cells and enter the lymph system and eventually enter circulation at the thoracic duct. Vitamin K1 and K2 are transported in remnant chylomicrons to the liver where it is taken up by a hepatocyte. In the hepatocyte, vitamin K1 and K2 are incorporated into very low-density lipoproteins, or VLDLs, to transport to peripheral tissues. In circulation lipoprotein lipase (LPL) catalyzes the conversion of VLDL to LDL to HDL. The cellular uptake of vitamin K1 and K2 takes place with the uptake of lipoproteins via receptor-mediated endocytosis. Vitamin K is stored predominantly in the liver in the form of menaquinone and is excreted in the urine and feces.[37]

Calcium

The intestine, kidney, bone, and parathyroid gland work together to tightly regulate calcium balance in the body. The majority of calcium is absorbed in the small intestine via paracellular diffusion. The remainder of calcium is absorbed transcellularly through the calcium channel TRPV6 when luminal calcium levels are low. Calcium is transported in the bloodstream in three forms: 48% ionized as free Ca2+, 46% bound to the protein albumin, and 7% complexed with citrate, phosphate, or sulfate. In low blood calcium concentration conditions, the parathyroid gland is stimulated to release parathyroid hormone (PTH). PTH then stimulates the kidneys to increase calcium reabsorption in the proximal convoluted tubule. PTH also stimulates the kidneys to convert 25-OH D3 into 1,25(OH)2 D3, or calcitriol. The increase calcitriol and PTH in the blood travel to the bone and stimulate the resorption of calcium and phosphorus from the bone. Calcitriol also stimulates the small intestine to increase calcium absorption. As a result, blood calcium is increased. In high blood calcium conditions, the thyroid gland releases the hormone calcitonin, which prevents calcium mobilization from the bone, thus reducing blood calcium levels. 99% of the calcium in the body is found in the bones and teeth, while the remainder is found in soft tissues and plasma both intracellularly and extracellularly. Most calcium is reabsorbed in the kidney, but the remainder is excreted in urine and feces.[12][14] 

Magnesium

Magnesium is absorbed in the small intestine through paracellular diffusion and transcellular active transport via TRPM6 and TRMP7. At normal magnesium intakes, 30% of intestinal magnesium absorption occurs via transcellular transport. When magnesium intakes are lower, more magnesium is absorbed via transcellular transport. When magnesium intakes are higher, more magnesium is absorbed through paracellular diffusion. Magnesium is transported in the blood as free Mg2+(60%), protein-bound (30%), and complexed to citrate, phosphate, or sulfate (10%). Magnesium homeostasis is controlled by the kidneys. About 70% of serum magnesium is available for glomerular filtration and 96% of the filtered magnesium is reabsorbed in the kidneys through several mechanisms in the proximal tubule, ascending limb, and distal tubule.The remaining magnesium is excreted in the urine. 99% of magnesium in the body is stored intracellularly in bone, muscle, and soft tissues, while 1% of magnesium in the body is found in extracellular fluid.[12][14][15][14] 

Phosphorus

The phosphorus is absorbed in the small intestine into the enterocyte via two processes: active transport by the apical Na+ phosphate transporter NaPi-IIb and paracellular diffusion. Phosphorous leaves the enterocyte to enter the bloodstream via facilitated diffusion. The kidney plays a role in phosphorus homeostasis through reabsorption of inorganic phosphate from the glomerular filtrate in the proximal convoluted tubule. Approximately 75-85% of phosphorus is reabsorbed per day and the remainder is excreted in the urine. Phosphorus homeostasis can also be regulated secondary to that of calcium with resorption from the bone due to high PTH and calcitriol levels. Throughout the body, phosphorus is distributed 85% in the skeleton, 0.4% in the teeth, 14% in the soft tissue, 0.3% in the blood, and 0.3% in the extravascular fluid.[12][14][38][14] 

Sodium

Sodium is absorbed in the small intestine across the brush border membrane of the enterocyte via sodium-glucose cotransporter 1 (SGLT1). SGLT 1 is an active transporter that absorbs 2 sodium ions and 1 glucose across the brush border membrane of the enterocyte. Sodium is then transported out of the enterocyte into the bloodstream across the basolateral membrane via the sodium-potassium pump, or ATPase. The sodium-potassium pump uses ATP to transport 3 sodium ions out of the enterocyte and 2 potassium ions into the enterocyte. Sodium and water balance are closely linked and maintained by the kidneys. Half of the sodium in the body is found in extracellular fluid, while around 10% is found in intracellular fluid. The remaining 40% of sodium is found in the skeleton. Small losses of sodium can occur through urine, feces, and sweat.[39][18]   

Potassium

Most of the dietary potassium is absorbed in the small intestine via passive transport. Potassium homeostasis is maintained by the kidney. About 90% of the potassium that is consumed is excreted in urine with the remaining small amount excreted in stool and sweat. Most of the potassium content in the body is found in the intracellular space of the skeletal muscle.[40][41] 

Chloride

Chloride absorption occurs in the lumen of the small intestine via three distinct mechanisms: paracellularly through passive transport, the coupling of Na+/H+ and Cl−/HCO3− exchangers, and HCO3−-dependent Cl− absorption. Chloride is principally found in extracellular fluid. Chloride concentration is regulated by the kidneys. Around 99% of chloride is reabsorbed in the proximal tubule of the kidneys both paracellularly and transcellularly via the Cl−/HCO3− exchanger. The remainder of chloride can be excreted in urine, feces, or sweat.[12] 

Iron

Iron consumed from food can be present in two forms: heme and nonheme iron. 90% of dietary iron consists of nonheme iron, which is far less bioavailable than heme iron. Iron is absorbed in the small intestine in the duodenum. Given nonheme iron is often present in the form of ferric iron, it must be reduced to the ferrous form prior to enterocyte uptake with the ferric reductase enzyme DCYTB. The apical surface of the enterocyte contains divalent metal transporter 1 (DMT1) which transports ferrous iron into the enterocyte. On the basolateral membrane of the enterocyte, ferroportin releases ferrous iron to hephaestin, which oxidizes ferrous iron to ferric iron so it can bind to the transporting protein transferrin in portal circulation. Ferroportin is the main regulatory point of entry for iron in the body. Iron is stored in the liver bound to ferritin, where it can be sequestered to bone marrow for erythropoiesis, or red blood cell formation. Macrophages in the reticuloendothelial system of the liver, spleen, and bone marrow can ingest old red blood cells to recycle iron to be stored in the liver. There is no specific excretory system for iron. Iron loss can only occur secondary to exfoliation of epithelial cells in the skin and gastrointestinal tract in addition to red blood cell loss from the gastrointestinal tract.[22][42][43][44]  

Zinc

Zinc is absorbed in the small intestine via carrier-mediated transport with ZIP4 taking zinc up into the intestinal cell and ZNT1 releasing it into the bloodstream. Zinc is bound to albumin in circulation. Zinc transporters are pervasive throughout tissues in the body and play a role in maintaining zinc homeostasis. Zinc is excreted in feces.[23] 

Copper

Copper absortion mainly occurs in the small intestine. Copper is taken up by enterocytes with copper transporter 1 (CTR1), which is a copper importer located at the apical membrane of intestinal cells and most tissues. Copper is exported from the enterocytes into the blood by the exporter ATP7A. In portal circulation, most of the copper is bound to the transporter protein ceruloplasmin. Copper is taken up by the liver when copper-bound ceruloplasmin binds to ceruloplasmin receptors. In the hepatocytes, protein metallochaperones serve to assign and transport copper to specific pathways throughout the body. Copper is exported from the hepatocyte via the exporter ATP7B. Excess copper is secreted in the bile which gets excreted in the feces.[45][24]  

Iodine

Iodine can be ingested in many chemical forms. Iodide is rapidly and almost completely absorbed in the stomach and small intestine. Iodate, which is used in iodized salt, is reduced in the gut and then absorbed as iodide. In circulation, iodine is taken up mainly by the thyroid gland and kidney. Iodine uptake by the thyroid is dependent upon iodine intake, whereas uptake by the kidney remains fairly constant. Iodine is excreted in the urine. Most of the body’s iodine is stored in the thyroid to be used in thyroid hormone synthesis.[46] 

Selenium

The mechanism of selenium absorption is not well known. Selenium absorption occurs in the small intestine via mechanisms dependant upon the form of selenium. The absorption of inorganic selenate occurs through active transport with a sodium pump. The absorption of inorganic selenite occurs via passive diffusion. Organic selenomethionine and selenocysteine are absorbed via an active transport mechanism similar to that of neutral amino acids like methionine. From the enterocyte, selenium is absorbed into the portal bloodstream and is transported to the liver in multiple forms. Selenite is taken up by erythrocytes and reduced by glutathione reductase to selenide, which is transported in the plasma bound to albumin. Selenium can also be transported in the form of selenoprotein P. Sometimes selenium may bind to LDL and VLDL. Selenium is stored in tissues in the form of selenomethionine with variable densities in the liver, muscle, kidney, plasma, and other organs. Selenium excretion via urine in the form of methylselenol.[27]    

Molecular

Carbohydrates

Carbohydrates are organic molecules made up of carbon, hydrogen, and oxygen. Carbohydrates are classified based on their chemistry: individual monomer characteristics, degree of polymerization, and type of linkages (α or β). Given this classification, carbohydrates subdivide into three main groups: sugars (degree of polymerization = 1 to 2), oligosaccharides (degree of polymerization = 3 to 10), and polysaccharides (degree of polymerization more than 10). Sugars include monosaccharides and disaccharides. The most common monosaccharides are glucose, fructose, and galactose. The most common disaccharides are sucrose, lactose, and maltose. Examples of oligosaccharides include maltodextrins, raffinose, and polydextrose. Polysaccharides include starches and non-starch polysaccharides. Starches include digestible amylose due to its alpha-linked monosaccharides. Non-starch polysaccharides include non-digestible cellulose due to its β-linked monosaccharides.[4]

Proteins 

Proteins are polymers of amino acids. Amino acids are organic molecules composed of carbon, hydrogen, oxygen, and nitrogen. The general structure of an amino acid consists of a central carbon surrounded by hydrogen, an amino group, a carboxylic acid group, and a side chain “R.” Each amino acid has a unique side chain. Nine essential amino acids must come from dietary sources: histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan, and valine. The body can make eleven non-essential amino acids from precursors: alanine, arginine, asparagine, aspartate, cysteine, glutamate, glutamine, glycine, proline, serine, and tyrosine. There are four structure levels in a protein: primary, secondary, tertiary, and quaternary. The primary structure of a protein is a chain of amino acids connected by peptide bonds; this determines the subsequent structures and biological functions of the protein. The secondary structure of a protein consists of hydrogen bonding within amino acid chains that create either an α-helix or β-sheet conformation. The tertiary structure of a protein derives from attractions between α-helices and β-sheets of a polypeptide resulting in a three-dimensional arrangement of a protein. The quaternary structure of an amino acid consists of a spatial arrangement of multiple polypeptides in a protein.[47]     

Lipids

Lipids are organic molecules that share a common property of being hydrophobic. Dietary lipids are often in the forms of triglycerides, phospholipids, cholesterol, and fatty acids. Fatty acids are classified as saturated or containing no carbon-carbon double bonds, or unsaturated, or containing at least one carbon-carbon double bond. Saturated fatty acids have higher melting points than unsaturated fatty acids, making them solid at room temperature, unlike liquid unsaturated fatty acids. Triglycerides are composed of one 3-carbon glycerol backbone and three fatty acids. Phospholipids contain a phosphate head connected to a glycerol molecule, connected to two fatty acids. Cholesterol is a sterol that is composed of a hydrocarbon ring structure.[48]

Vitamin B1 (Thiamin)

Thiamin consists of pyrimidine and thiazole rings that are linked by a methylene bridge. Thiamin exists in a variety of phosphorylated forms. Its main form is thiamin pyrophosphate or TPP.[9]

Vitamin B2 (Riboflavin)

The basic chemical structure of riboflavin consists of a flavin group formed by the tricyclic heterocyclic isoalloxazine and a ribitol sugar group. The main coenzyme forms of riboflavin are flavin mononucleotide, or FMN, and flavin adenine dinucleotide, or FAD.[9]

Vitamin B3 (Niacin)

Niacin refers to nicotinamide, nicotinic acid, and other derivatives. The basic chemical structure of nicotinic acid consists of a pyridine ring with a substituted carboxylic acid group. The chemical structure of nicotinamide consists of a pyridine ring with a substituted amide group. The main coenzyme forms of niacin are nicotinamide adenine dinucleotide, or NAD, and nicotinamide adenine dinucleotide phosphate, or NADP.[9]

Vitamin B5 (Pantothenic Acid)

Pantothenic acid is a water-soluble vitamin synthesized from the condensation reaction of pantoic acid and β-alanine in only plants and bacteria. Pantothenic acid serves to transfer and carry acyl groups.[49] 

Vitamin B6 (Pyridoxine) 

Vitamin B6 is a generic term for six related compounds: pyridoxal (PL), pyridoxamine (PM, pyridoxine (PN), and their respective 5’-phosphatase forms (PLP, PMP, and PNP). The major forms of vitamin B6 in animal tissues are PLP and PMP.[9]

Vitamin B7 (Biotin)

Biotin’s chemical structure consists of a heterobicyclic ring of reido and thiophene with a valeric acid side chain.[50]

Vitamin B9 (Folate)

Folate is the generic term for the different forms of vitamin B9 that function in single-carbon transfers. The most oxidized and stable form of folate called folic acid is in vitamin supplements. It consists of a p-aminobenzoic acid molecule bound to a pteridine ring on one side and a glutamic acid molecule on the other side. Naturally occurring folates found in food called food folate are pteroylpolyglutamates, which contain between one and six additional glutamate molecules connected by a peptide linkage to glutamate’s γ-carboxyl.[9]

Vitamin B12 (Cobalamin)

Cobalamin, or vitamin B12, is a generic term for a group of cobalt-containing compounds with a corrin ring attached to 5,6-dimethylbenzimidazole, a sugar ribose, and a phosphate. The two cobalamins that are active in human metabolism as coenzymes are methylcobalamin and 5-deoxyadenosylcobalamin.[9]

Vitamin C (Ascorbic Acid)

Vitamin C, or ascorbic acid, chemically is a simple carbohydrate with an ene-diol structure that makes it an essential water-soluble electron donor. The main form of vitamin C found in foods is its reduced form - ascorbic acid. Ascorbate is the main circulating form of vitamin C in the body.[10]

Vitamin A (Retinol)

Vitamin A is a generic descriptor for compounds that exhibit the biological activity of retinol and provitamin A carotenoids. Retinol is an unsaturated 20-carbon cyclic alcohol. Provitamin A carotenoids exhibit a 40-carbon basal structure with cyclic end groups and a conjugated system of double bonds.[51][52] 

Vitamin D (Cholecalciferol)

Vitamin D3, or cholecalciferol, had a chemical structure that contains three steroid rings and an eight carbon side chain. The structure derives from cholesterol.[35]

Vitamin E (Tocopherol)

The term vitamin E encompasses eight lipophilic compounds that include four tocopherols and four tocotrienols, each of which has a designation as α-, β-, γ-, and δ-. Each of these compounds contains a chromanol ring and a lipophilic tail. Tocotrienols differ from tocopherols with their unsaturated side chains. α-tocopherol is the only form of vitamin E that is known to reverse deficiency symptoms.[53] 

Vitamin K (Phylloquinone; Menaquinone)

Vitamin K occurs naturally in two main forms: K1, or phylloquinone, and K2, or menaquinone, which has many different forms. Also, vitamin K occurs in the synthetic form of vitamin K3, or menadione, which contains only the 2-methyl-1, a 4-naphthoquinone nucleus that is common to all forms of vitamin K. The natural forms differ by the number of isoprenoid units in their isoprenoid side chains.[37]  

Calcium

Calcium is an alkaline earth metal cation found in the form of Ca2+. Calcium is a critical divalent cation in intracellular and extracellular fluid.[19]

Magnesium

Magnesium is an alkaline earth metal cation found in the form of Mg2+. Magnesium is the second most abundant intracellular cation in the body.[19] 

Phosphorus

Phosphorous is a multivalent nonmetal that occurs in both inorganic and organic forms throughout the body. The organic forms of phosphorus include phospholipids and various phosphate esters. The inorganic forms of phosphorus include phosphate ions, protein-bound phosphate, and calcium, sodium, or magnesium bound phosphate. Most phosphorus exists in the form of inorganic free phosphate ion (PO42- or PO43-).[38]

Sodium

Sodium is an alkali metal cation found in the form of Na+. Sodium is the major extracellular cation in the body.[18][19]

Potassium

Potassium is an alkali metal cation found in the form of K+. Potassium is the major intracellular cation in the body.[19]

Chloride

Chloride is a nonmetal anion found in the form of Cl-. Chloride is the body’s principal anion making up 70% of the body’s total anion content and serves as the most important extracellular anion of the body.[54] 

Iron

Iron is a transition metal element. Iron exists in two main oxidation states: Fe2+ and Fe3+. The more bioavailable form of iron is its reduced form ferrous iron, or Fe2+, due to its solubility. The less bioavailable form of iron is its oxidized form ferric iron, or Fe3+, due to its lack of solubility. Heme iron is contained in the protoporphyrin ring of hemoglobin, myoglobin, and cytochromes and is highly bioavailable. Nonheme iron can be found in molecules like iron-sulfur enzymes and ferritin and is less bioavailable.[55][43][22] 

Zinc

Zinc is a metal that exists in the form of Zn2+. With the 2+ charge, zinc is a strong electron acceptor in biological systems.[23]

Copper

Copper is a transition metal that exists in the forms of Cu+ and Cu2+. Cu+ is the cuprous reduced form of copper. Cu2+ is the cupric oxidized form of copper. Copper is absorbed into cells in its reduced form but is ingested and travels through the bloodstream in its oxidized form.[45][24] 

Iodine

Iodine is a nonmetal element identified by its distinct violet vapor. Iodine is consumed and absorbed in its reduced form of iodide (I-). Iodine is also consumable in its oxidized form of iodate (IO3-), as well as when it is organically bound to thyroxine (T4) and triiodothyronine (T3).[46] 

Selenium

Selenium is present in nature in both organic and inorganic forms. The main organic forms of selenium are selenomethionine and selenocysteine. The inorganic forms of selenium are selenite (SeO32-), selenide (Se2−), selenate (SeO42-), and the selenium element (Se).[27] 

Function

Macronutrients - Carbohydrates, ProteinsLipids

Macronutrients mainly function to supply energy. Carbohydrates function as the main source of cellular energy from the human diet and are particularly essential to supply energy to the glucose-dependent brain and nervous system. Fiber plays a role in lowering cholesterol by binding to bile and promoting gut health. Proteins function less favorably as a source of energy because they play crucial roles in regulating body processes and contributing majorly to cell and body structure. Proteins particularly function as hormones, enzymes, transporters, and antibodies. Lipids function as a source of stored energy, contribute to cell function and structure and protects body organs. Water acts as a solvent for chemical reactions, a medium for nutrient transport, and a thermoregulator.[5]

Vitamin B1 (Thiamin)

The coenzyme form of thiamin, or TPP, is involved in the following types of metabolic reactions: decarboxylation of α-keto acids and transketolation. These occur in carbohydrate and branched-chain amino acids metabolism.[9]

Vitamin B2 (Riboflavin)

Riboflavin functions as a component of the metabolically essential coenzymes FMN and FAD. FMN and FAD can serve as intermediates in electron transfer in redox reactions. As coenzymes, FAD and FMN are often bound to enzymes that are oxidases and dehydrogenases.[9]

Vitamin B3 (Niacin)

Niacin functions as a component of the metabolically essential coenzymes NAD and NADP. These coenzymes act as hydride ion acceptors or donors in biological redox reactions. They also serve as coenzymes for dehydrogenases.[9]

Vitamin B5 (Pantothenic Acid)

Pantothenic acid functions as a supporter of the synthesis and maintenance of coenzyme A, a cofactor and acyl group carrier for other enzymes, and an acyl protein carrier in the fatty acid synthase complex.[9]

Vitamin B6 (Pyridoxine)

Vitamin B6, in the form of PLP, is a coenzyme for over 100 enzymes involved in amino acid metabolism. PLP is a coenzyme for aminotransferases, decarboxylases, racemases, and dehydratases. PLP is a coenzyme in the first step of heme biosynthesis and the transsulfuration of homocysteine to cysteine.[9]

Vitamin B7 (Biotin)

Biotin functions in metabolism as a coenzyme for transferring single-carbon units in the form of carbon dioxide for the following carboxylases: pyruvate carboxylase, propionyl-CoA carboxylase, acetyl-CoA carboxylase, and β-methylcrotonyl-CoA carboxylase. These enzymes play roles in gluconeogenesis, citric acid cycle, fatty acid synthesis, and leucine degradation, respectively.[9]

Vitamin B9 (Folate) 

Folate functions in nucleic and amino acid metabolism as a coenzyme in single-carbon transfers. Folate functions as a coenzyme in nucleic acid metabolism in the processes of DNA synthesis in purine and pyrimidine nucleotide biosynthesis.  Folate functions as a coenzyme in amino acid metabolism in amino acid interconversions, including the conversion of homocysteine to methionine, which serves as the major source of methionine for the formation of the major methylating agent S-adenosyl-methionine.[9]

Vitamin B12 (Cobalamin) 

Cobalamin functions as a coenzyme in for two enzymes in human metabolism: methionine synthase and L-methylmalonyl-CoA mutase. Vitamin B12, in the form of methylcobalamin, is required as a coenzyme to methionine synthase for the methyl transfer reaction from methyltetrahydrofolate to homocysteine resulting in the formation of methionine and tetrahydrofolate. Vitamin B12, in the form of adenosylcobalamin, is required as a coenzyme to  L-methylmalonyl-CoA mutase in the isomerization reaction that results in the conversion of L-methylmalonyl-CoA to succinyl-CoA.[9]

Vitamin C (Ascorbic Acid)

Vitamin C, in the form of ascorbate, has both enzymatic and nonenzymatic functions in the body. Ascorbate functions as a coenzyme as a reducing agent in the synthesis reactions of collagen, carnitine, neurotransmitters, and tyrosine. Ascorbate functions nonenzymatically as a powerful water-soluble antioxidant with the ability to reduce free radicals and reactive oxygen species. Ascorbate notably reduces glutathione radicals produced by the electron transport chain.[10] 

Vitamin A (Retinol)

Vitamin A functions metabolically in vision, cellular differentiation, gene expression, growth, immune system, and reproduction. Vitamin A, in the form of 11-cis-retinal, is the chromophore group of rhodopsin found in the rod cells of the retina and is essential for night vision. Vitamin A, in the form of retinoic acid, is required for the differentiation of certain cells like keratinocytes to epidermal cells and squamous epithelial keratinizing cells to mucous-secreting cells. Vitamin A can regulate gene expression by acting as transcription factors when bound to RAR and RXR. Vitamin A protects against xerophthalmia by maintaining normal growth of the conjunctival membranes of the eye. Vitamin A plays roles in processes involved in innate and adaptive immunity, including cell differentiation and hematopoiesis. Vitamin A plays a vital role in spermatogenesis in reproduction.[56][57][58][59][60] 

Vitamin D (Cholecalciferol)

Vitamin D, in its active form 1,25-(OH)2 vitamin D3, can function as a hormone by binding to receptors on target tissues to activate a signal transduction pathway and a regulator of gene expression by binding to a nuclear receptor to affect transcription. One of the most important functions of 1,25-(OH)2 vitamin D3 is to work with parathyroid hormone to maintain blood calcium homeostasis. 1,25-(OH)2 vitamin D3 functions to increase the absorption of calcium in the small intestine and reabsorption of calcium in the kidneys in response to low blood calcium. It also works with parathyroid hormone to stimulate the resorption of calcium from the bone to increase blood calcium levels. 1,25-(OH)2 vitamin D3 can also bind to various nuclear vitamin D receptors, or VDRs, in the bones, intestines, kidneys, and skin to stimulate the transcription of genes. This process is key to osteoclast maturation.[35]  

Vitamin E (Tocopherol)

Vitamin E is best known to function as a chain-breaking antioxidant that neutralizes the lipid peroxyl radicals during lipid peroxidation to prevent cyclic propagation of lipid peroxidation. This process is key in protecting the polyunsaturated fatty acids within the phospholipids of plasma membranes and plasma lipoproteins.[53]  

Vitamin K (Phylloquinone; Menaquinone)

Vitamin K mainly functions in the synthesis of several blood coagulation factors. It also plays a role in bone mineralization. Vitamin K performs these functions by enabling the carboxylation of glutamic acid residues in proteins to form γ-glutamic carboxyl (Gla) residues. Gla residues enable proteins to bind with calcium and interact with other proteins, which is necessary for blood coagulation and bone mineralization.[37] 

Calcium

99% of the calcium in the body is in bone and teeth as a structural component. The remaining calcium in the body is found in intracellular and extracellular spaces and plays key roles in innervation, muscle contraction, blood coagulation, hormone secretion, and intracellular adhesion.[14] 

Magnesium

Magnesium is an important intracellular cation for numerous functions throughout the body. Magnesium plays a key role in metabolic reactions such as energy storage, glucose metabolism, and nucleic acid and protein synthesis. Magnesium also functions in oxidative reactions, immune function, and bone development. Magnesium plays a role in stabilizing excitable membranes by maintaining electrolyte balance and homeostasis of calcium, sodium, and potassium. Magnesium acts as a calcium channel antagonist and plays a role in vasodilation.[15] 

Phosphorus

Phosphorus has various structural and metabolic functions throughout the body. Structurally, phosphorus functions to form the structure of bone and teeth along with calcium, the phosphate backbone of DNA and RNA, and the phospholipid bilayer of cell membranes. Metabolically, phosphorus functions to create and store energy in phosphate bonds of ATP, regulate acid/base balance in the blood as a buffer, regulate gene transcription, regulate enzyme activity, and enable signal transduction of numerous regulatory pathways.[16] 

Sodium

As an extracellular cation, sodium functions to regulate blood volume, blood pressure, osmotic equilibrium, and pH. Sodium and potassium ions function together to create an action potential maintained by ion pumps that allow for neurotransmission, muscle contraction, and heart function. Sodium also plays a critical role in the transport of nutrients across the plasma membrane.[19][18] 

Potassium

Potassium is critical for normal cellular function. Sodium and potassium ions function together to create an action potential maintained by Na+-K+ ATPase that allows for neurotransmission, muscle contraction, and heart function. Potassium also works alongside sodium to maintain intracellular and extracellular osmotic pressure.[19][41] 

Chloride

As the most important extracellular anion in the body, chloride functions to maintain fluid balance, acid-base balance, electrolyte balance, electrical neutrality, and muscle function throughout the body. Chloride works with sodium to maintain fluid balance. Chloride also works with bicarbonate to maintain acid-base balance.[54][20] 

Iron

Iron’s functions are essential for oxygen transport and cell proliferation. Iron functions as the core of heme proteins like myoglobin, hemoglobin, and cytochromes. Myoglobin and hemoglobin are essential for oxygen storage and transport, while cytochromes are essential for the electron transport chain reactions in energy metabolism. Iron is also critical in its nonheme form in iron-sulfur enzymes like succinate dehydrogenase and NADH dehydrogenase in oxidative metabolism.[43][22] 

Zinc

Zinc functions structurally as a component of proteins and catalytically as a component of >300 enzymes in the body. Zinc’s functions are pervasive throughout the body and crucial to growth, immunity, cognitive function, and bone health.[23] 

Copper

Copper functions as a critical cofactor to a group of cellular transporters called cuproenzymes. Copper is essential for the proper function of human organs and metabolic processes such as hemoglobin synthesis, neurotransmitter synthesis, iron oxidation, cellular respiration, antioxidant peptide amidation, pigment formation, and connective tissue formation.[45][24] 

Iodine

The primary function of iodine is its role in the synthesis of thyroid hormones thyroxine (T4) and triiodothyronine (T3). At the apical surface of the thyrocyte, iodide is oxidized by the enzymes thyroperoxidase (TPO) and hydrogen peroxide to attach it to tyrosyl residues on thyroglobulin to produce the precursors of thyroid hormones: monoiodotyrosine (MIT) and diiodotyrosine (DIT). TPO then catalyzes the formation of a diether bridge between the phenyl groups of iodotyrosine to create thyroid hormones. The linkage of two DITs produces T4, while the linkage of MIT and DIT produce T3. T3 and T4  are almost structurally identical, but T3 has one less iodine than T4. Thyroid hormones function to regulate fetal cell growth, postnatal growth, and basal metabolic rate.[46] 

Selenium

Selenium functions as an essential component of selenoproteins that play major roles in dense against oxidation, thyroid hormone formation, DNA synthesis, reproduction, and fertility. The functions of most selenoproteins are unknown, but the known functions involve participation in antioxidant and anabolic processes. A family of antioxidant enzymes named glutathione peroxidases is dependent upon selenium to function to neutralize hydrogen peroxide and organic hyperoxides in both intracellular and extracellular compartments. Deiodinases are a group of three selenoenzymes that are responsible for the conversion of T4 to T3 in thyroid hormone activation. Selenoprotein-P is the most abundant selenoprotein found in plasma and plays a major role in the transport and homeostasis of selenium in tissues.[27]   

Testing

Carbohydrates

Measuring the amount of glucose in plasma is one of the most important ways to screen for and manage diabetes. To clinically test and monitor blood glucose, blood is drawn from a vein, usually when the patient has fasted for at least 8 hours. The level of glucose is measured in milligrams glucose per deciliter plasma. A healthy, fasting blood glucose level is less than or equal to 99 mg/dL. Someone who has an increased risk for diabetes, or prediabetes, falls in the range of fasting blood glucose of 100 to 125 mg/dL. If a patient has a fasting blood glucose of 126 mg/dL or greater on two separate occasions, they can receive a diagnosis of diabetes.[61][62][61]

Proteins 

Nitrogen balance is the gold standard for testing the protein status of the body. Nitrogen balance can serve as a marker of adequate nutrition and physiological stress. Nitrogen balance is equal to the grams of nitrogen consumed minus the grams of nitrogen excreted. The grams of nitrogen consumed is calculated by the grams of protein consumed divided by 6.25 grams of protein per 1 gram of nitrogen. The grams of nitrogen excreted is calculated by extrapolating losses with grams of nitrogen in urinary urea plus 4 grams, which accounts for losses in feces, sweat, skin, and wounds. Under normal conditions, an individual should be at nitrogen equilibrium, or nitrogen balance equals zero. Critically ill patients often have negative nitrogen, so the goal with them is to increase the protein intake to achieve a positive nitrogen balance for healing.[63]

Lipids

To test the amount of lipids in the body, a sample of blood is taken via venipuncture in tubes and analyzed for serum or plasma total cholesterol, triglycerides, and lipoproteins. Cholesterol levels remain fairly constant so that sampling is possible at any time. In contrast to cholesterol levels, triglyceride levels fluctuate throughout the day, so blood collection should occur after a 12-hour fasting period because, at that point, chylomicrons should have cleared from the circulation. To separate and quantify lipoproteins from the plasma sample, ultracentrifugation, precipitation, and electrophoresis are performed. High vs. low plasma lipid levels are determined based on the bell-shaped distribution of the general population. Cholesterol levels are determined based on risk for coronary atherosclerosis. Cholesterol levels below 200 mg/dl are considered desirable, levels from 200 to 239 mg/dl are considered borderline high cholesterol, and levels that are 240 mg/dl or greater are considered high cholesterol.[64]

Vitamin B1 (Thiamin)

Thiamin status is measurable via urinary thiamin excretion, erythrocyte thiamin, and erythrocyte transketolase activity. Erythrocyte transketolase activity is considered the gold standard functional test of thiamin status.[9]

Vitamin B2 (Riboflavin)

Riboflavin status is measured via erythrocyte glutathione reductase activity, erythrocyte flavin, and urinary flavin. Erythrocyte glutathione reductase activity is the most common method to determine riboflavin status.[9]

Vitamin B3 (Niacin)

Niacin status can be measured using urinary 1-methyl nicotinamide excretion, plasma concentrations of 2-pyridone, erythrocyte pyridine nucleotides, and transfer of adenosine diphosphate ribose as a functional measurement. Urinary 1-methyl nicotinamide is the most reliable and sensitive measure of niacin status.[9]

Vitamin B5 (Pantothenic Acid)

Pantothenic acid status can be measured using urinary pantothenic acid excretion and whole blood pantothenic acid concentration.[9]

Vitamin B6 (Pyridoxine) 

Vitamin B6 status assessment is best with plasma PLP. A plasma PLP of <20 nmol/L indicates a vitamin B6 deficiency.[9]

Vitamin B7 (Biotin)

Biotin status is measurable with urinary biotin and 3-hydroxyisovalerate excretion. Decreased urinary excretion of biotin along with increased urinary excretion of 3-hydroxyisovalerate indicates biotin deficiency.[9]

Vitamin B9 (Folate) 

The primary test used to measure folate status is erythrocyte folate. Given folate is taken up by developing erythrocytes in the bone marrow, erythrocyte folate concentration is an ideal indicator of long-term folate status. Plasma homocysteine can also be useful as an indicator of folate status given in inadequate quantities of folate, not as much homocysteine can undergo conversion to methionine. Serum folate can also be tested as an indicator of dietary folate intake but is limited and should be used in conjunction with additional folate status indicators.[9]

Vitamin B12 (Cobalamin) 

The primary test to measure vitamin B12 status is serum vitamin B12, which reflects both intake and stores. The lower limit of serum vitamin B12 for adults is 170 to 250 pg/mL. Serum methylmalonic acid concentration is another specific and functional indicator of vitamin B12 status because serum methylmalonic acid concentrations become elevated during vitamin B12 deficiency. Serum total homocysteine concentration is a functional but non-specific indicator of vitamin B12 status due to elevation during vitamin B12 deficiency.[9]

Vitamin C (Ascorbic Acid)

Vitamin C status testing is via plasma vitamin C and leukocyte vitamin C. Plasma vitamin C concentration is sensitive to a recent diet, while leukocyte vitamin C reflects tissue stores. A plasma vitamin C concentration of less than 0.2 mg/dL is considered deficient.[10][65]

Vitamin A (Retinol)

The gold standard for testing vitamin A status is through a liver biopsy because the liver is vitamin A's major storage organ. However, this measure is not very feasible in humans. Retinol status is testable with plasma retinol concentration, but it only indicates low status if there is a severe deficiency. Vitamin A status may also be tested with a relative dose-response test, which measures the magnitude of increase RBP following supplementation.[66]

Vitamin D (Cholecalciferol)

Vitamin D status is tested by using serum 25-hydroxyvitamin D concentrations. A serum 25-hydroxyvitamin D concentration that is less than 20 ng/mL represents a vitamin D deficiency and a need for supplementation.[34] 

Vitamin E (Tocopherol)

Vitamin E status is difficult to test because serum concentrations of vitamin E are largely age-dependent and are influenced by blood lipids. In the general population, α-tocopherol plasma levels can range from 19.9 micromoles/L to 34.2 micromoles. More research needs to be done to adjust specific requirements to an individual's bioavailability.[67]

Vitamin K (Phylloquinone; Menaquinone)

Vitamin K status is difficult to assess due to its being lipophilic and not very abundant. However, functional tests such as prothrombin time or Gla protein measurement can be useful to assess vitamin K status indirectly.[37] 

Calcium

Calcium status is difficult to assess in individuals because there is not a reliable indicator that can establish a relationship between calcium and a particular disease state. Total body calcium is not useful to assess calcium intake because the body regulates calcium in a very tight range and will adapt to conserve it. Bone-mass measurements may indicate long-term calcium status by assessing changes in bone density.[68]  

Magnesium

Magnesium status can be tested with serum magnesium. Serum magnesium is maintained at a tight range of 1.7 to 2.6 mg/dL. A serum value of under 1.7 mg indicates a magnesium deficiency. A serum value of over 2.6 mg/dL indicates magnesium toxicity.[15][14]

Phosphorus

Serum phosphorus is the most common way to assess phosphorus status. Serum phosphorus is maintained in a relatively narrow range of 2.5 to 4.5 mg/dL. Although serum phosphorus does not reflect the full body stores, serum phosphorus is crucial for various cellular processes in the body. Serum phosphorus below or above the normal range can indicate a deficiency and toxicity, respectively.[14]   

Sodium

Sodium balance is tested via plasma sodium concentration. A plasma sodium concentration greater than 150 mmol/L indicates sodium toxicity or hypernatremia. A plasma sodium concentration of less than 136 mmol/L indicates sodium deficiency or hyponatremia.[69][70]

Potassium

Potassium balance is tested via serum potassium. The body maintains normal serum potassium levels in a narrow range of 3.5 to 5.5 mmol/L. Potassium toxicity, or hyperkalemia, occurs at serum potassium concentrations greater than 5.5 mmol/L. Potassium deficiency, or hypokalemia, occurs at concentrations less than 3.5 mmol/L.[19]  

Chloride

Since chloride serves as an important diagnostic indicator for various diseases, it can be tested for in serum, sweat, urine, and feces. Serum and urine chloride concentrations are used in the diagnosis of acid-base and osmolar disorders and used in formulas like the anion gap, strong anion gap, strong ion difference, and chloride/sodium ratio. Sweat chloride concentration is used in the diagnosis of cystic fibrosis when it is above 60 mmol/L.[54] 

Iron

Iron is tested via serum-based indicators of iron status, such as hemoglobin, plasma ferritin, and plasma transferrin saturation. Hemoglobin is routinely measured to indicate anemia but is not specific for iron. Plasma ferritin is the gold standard of iron status because it is the most specific indicator of iron stores. A plasma ferritin concentration of less than 20 ng/L indicates iron deficiency. High plasma ferritin values can indicate iron overload. Transferrin saturation indicates the ratio of iron to transferrin to reflect transport iron. Transferrin saturation is low cost but shows a pronounced diurnal variation.[71] 

Zinc

Zinc status testing is via serum zinc. A concentration of zinc below the lower value of the reference range of 10 to 18 micromol/L is considered a deficiency.[72]  

Copper

Copper status evaluation is via serum copper or serum ceruloplasmin. A concentration of serum copper below the lower value of the reference range of 12 to 20 micromol/L is considered a deficiency.[72][45][72]  

Iodine

Iodine status can be assessed with four different methods: urinary iodine concentration, goiter rate, serum TSH, and serum Tg. Urinary iodine, serum Tg, and goiter rate are complementary tests given urinary iodine are sensitive to recent iodine intake in a matter of days, serum Tg shows an intermediate response in a matter of weeks or months, and goiter rate changes reflect iodine nutrition in a matter of months or years. TSH can be used to assess iodine status reflecting on the level of circulating thyroid hormone but is a relatively insensitive indicator of iodine status in adults. However, TSH is a sensitive indicator of iodine status in newborns.[46]   

Selenium

Selenium status is tested via serum selenium. A concentration of selenium below the lower value of the reference range of 0.75 to 1.85 micromol/L is considered a deficiency.[72]  

Clinical Significance

Carbohydrates

Diabetes refers to a group of metabolic diseases of disordered glucose metabolism. Diabetes is characterized by hyperglycemia, or high blood sugar, and premature vascular disease. Symptoms of diabetes-related hyperglycemia include polydipsia, polyuria, weight loss, polyphagia, and blurred vision. Acute and life-threatening complications of uncontrolled diabetes include hyperglycemia with diabetic ketoacidosis or nonketotic hyperosmolar syndrome. Long-term complications of uncontrolled diabetes include macrovascular and microvascular complications that lead to loss of vision, renal failure, neuropathy, and cardiovascular disease. There are three types of diabetes: type 1, type 2, and gestational. Type 1 diabetes occurs in 5 to 10% of cases and is characterized by absolute insulin deficiency and pancreatic beta-cell destruction. Insulin is a hormone produced by pancreatic beta cells that stimulates the uptake of sugar in the blood by cells. Insulin therapy is required to treat type 1 diabetes. Type 2 diabetes occurs in 90 to 95% of cases and is characterized by insulin resistance and impaired beta-cell function. In some individuals with type 2 diabetes, blood glucose control can be managed with lifestyle changes like diet, weight reduction, and exercise, and/or oral glucose-lowering medications. However, some individuals may need insulin therapy. Gestational diabetes occurs in 9% of pregnant women during the second or third trimester of pregnancy. Glucose tolerance usually returns to normal after delivery, but this increases the risk for type 2 diabetes later in life.[73]

Proteins 

Protein-energy malnutrition is a problem for children in both developing and developed countries around the world and contributes to acute and chronic childhood illness. In cases of extreme protein-energy malnutrition, marasmus and kwashiorkor are the two main clinical syndromes seen. Marasmus is more common and is characterized by muscle wasting and depletion of subcutaneous fat stores without edema as a result of deprivation of calories and nutrients. In addition, there is poor growth, little disease resistance, slowed metabolism, and impaired brain development. This usually occurs in children under the age of 5, due to their increased caloric requirements. Kwashiorkor is characterized by normal weight with edema, poor growth, low blood albumin, little disease resistance, and apathy as a result of a diet with an adequate caloric intake but inadequate protein. This commonly occurs in older infants or toddlers who are displaced from breastfeeding due to the birth of a younger sibling and have to wean rapidly but are unable to increase protein intake enough.[74]

Lipids

Lipids in abnormal concentrations attract clinical attention. Abnormal levels of lipids can occur due to abnormalities in synthesis, degradation, and transport of lipoprotein particles. Hyperlipidemia is defined as elevated levels of lipids or lipoproteins in the blood. Hyperlipidemia is very clinically relevant due to its association with an increased risk of atherosclerotic cardiovascular disease. Other clinical manifestations of hyperlipidemia include ischemic vascular disease, acute pancreatitis, and visible accumulations of lipid deposits. Increase plasma lipid levels can be related to genetic disorders, dietary factors, certain drugs, and as a secondary symptom of certain diseases.[64] 

Vitamin B1 (Thiamin)

Thiamin deficiency is historically known as a disease called beriberi. Currently, in developed nations, thiamin deficiency mainly occurs with chronic alcoholism and is called Wernicke-Korsakoff syndrome. Symptoms of thiamin deficiency are nonspecific and include anorexia, weight loss, apathy, short-term memory issues, confusion, irritability, muscular weakness, and enlargement of the heart.[9]  

Vitamin B2 (Riboflavin)

The symptoms of riboflavin deficiency include sore throat, angular stomatitis, glossitis, dermatitis, and weakness. It is rare but can occur with diseases such as cancer, diabetes, cardiac disease, and alcoholism.[9]

Vitamin B3 (Niacin)

The classic clinical manifestation of severe niacin deficiency is a disease called pellagra. Pellagra is characterized by a symmetrical, pigmented rash that develops in sunlight exposed areas, GI symptoms such as vomiting, constipation, or diarrhea, a bright red tongue, and neurological problems such as depression, fatigue, apathy, headache, and loss of memory. Pellagra was common in the United States and Europe in areas where corn was a dietary staple in the early twentieth century. Pellagra has disappeared from developed countries except for cases of chronic alcoholism. It still persists in parts of India, China, and Africa.[9]

Vitamin B5 (Pantothenic Acid)

Pantothenic acid deficiencies are extremely rare but have been shown in individuals fed diets devoid of pantothenic acid. Symptoms of deficiency include irritability, fatigue, apathy, sleep disturbances, GI complaints, numbness, paresthesias, muscle cramps, and hypoglycemia with increased insulin sensitivity.[9]

Vitamin B6 (Pyridoxine) 

Vitamin B6 deficiency is rare in healthy individuals. Symptoms of vitamin B6 deficiency include seborrheic dermatitis, microcytic anemia, convulsions, and confusion. Microcytic anemia occurs due to PLP’s role as a cofactor in the first step in heme biosynthesis.[9]

Vitamin B7 (Biotin)

Biotin deficiency is rare but can occur in specific scenarios. Biotin deficiency can occur in people who ingest raw eggs due to the protein avidin which inhibits biotin absorption. It can also occur in people with genetic defects in the enzyme biotinidase. Symptoms of biotin deficiency include thinning of hair, loss of hair color, dermatitis, depression, lethargy, and hallucinations.[9]

Vitamin B9 (Folate) 

Folate deficiency results in impaired synthesis of DNA and RNA which can manifest clinically megaloblastic anemia and developmental disorders in utero. Megaloblastic, or macrocytic, anemia occurs when red blood cell development is halted in the early erythroblast stage due to a lack of folate allowing DNA synthesis to continue and erythroblasts to divide and mature. Early erythroblasts are large and do not contain much hemoglobin. Inadequate maternal folate status during pregnancy can result in neural tube defects such as spina bifida and anencephaly. Neural tube defect risk reduction has been achieved with daily supplementation of 400 mcg of folate in women of childbearing age. In addition, there is some evidence that might suggest folate reduces the risk of cardiovascular disease, certain cancers, and psychiatric disorders.[9]

Vitamin B12 (Cobalamin) 

The major cause of clinical effects of vitamin B12 deficiency is pernicious anemia, which is caused by a lack of functional intrinsic factor in the stomach due to autoimmune destruction of gastric parietal cells. Malabsorption of food-bound vitamin B12 can also occur due to non-autoimmune atrophic gastritis which causes loss of stomach acid and mainly affects the elderly. The hematological effects of vitamin B12 deficiency are clinically indistinguishable from those of folate deficiency causing macrocytic, or megaloblastic, anemia. Vitamin B12 deficiency can also result in impaired neurological function and increased neural tube defect risk.[9]

Vitamin C (Ascorbic Acid)

Vitamin C deficiency is clinically and historically known as scurvy. Vitamin C deficiency is currently rare and only seen in malnourished populations with chronic conditions, poor diet, malabsorption, or substance dependency. Symptoms of vitamin C deficiency include gingival inflammation, fatigue, petechiae, bruising, and joint pain.[10][65] 

Vitamin A (Retinol)

Vitamin A deficiency affects 20-40 million children worldwide in regions with low-fat, plant-based diets and protein-calorie malnutrition. Vitamin A deficiency more commonly causes death than blindness in children in high-risk regions due to its role in the immune system. Vitamin A deficiency can also cause an increased risk of respiratory and diarrheal infections, decreased growth rate, slow bone development, and decreased survival from a serious illness.[59] 

Vitamin D (Cholecalciferol)

Vitamin D deficiency can lead to rickets and osteomalacia due to its critical role in bone and mineral metabolism. Rickets occurs in infants and children as a result of the failure of the bone to mineralize. The symptoms of rickets include growth retardation and bowing of the long bones of the legs. Osteomalacia occurs in adults, as a result, inadequate amounts of calcium and phosphate causing demineralization of the bone. Vitamin D may have extraskeletal effects and play a role in cardiovascular diseases, autoimmune diseases, neurological diseases, cancer, asthma, and pregnancy complications.[34] 

Vitamin E (Tocopherol)

Vitamin E deficiency is very rare but can occur in certain individuals. Symptoms of vitamin E deficiency include oxidative damage of tissues, membrane damage of cells, neurological abnormalities such as peripheral neuropathy, muscular functional abnormalities like ataxia, and hemolytic anemia. Vitamin E deficiency most commonly occurs in premature babies of very low birthweight, people with fat-malabsorption disorders like Crohn’s disease and cystic fibrosis, and those who have a rare neurodegenerative disease called ataxia with vitamin E deficiency (AVED) that is caused by mutations in the gene for αβ-tocopherol transfer protein.[75] 

Vitamin K (Phylloquinone; Menaquinone)

Vitamin K deficiency is uncommon in healthy adults but may be seen in those with gastrointestinal malabsorptive disorders. However, newborns are at high risk for vitamin K deficiency. Newborns are at risk given milk is low in vitamin K, their stores are low since vitamin K does not pass the placenta, and their intestines are not yet populated with vitamin K synthesizing bacteria. Infants born in the United States and Canada routinely receive 0.5 to 1 mg of intramuscular phylloquinone within 6 hours of birth to prevent vitamin K deficiency bleeding, or VKDB. VKDB can affect infants up to 3 to 4 months of age and cause intracranial hemorrhage, central nervous system damage, and liver damage.[76] 

Calcium

Hypocalcemia, or calcium deficiency, can result from inadequate calcium intake, poor calcium absorption, or excessive calcium losses. Poor calcium absorption can occur due to inadequate vitamin D status. Excessive calcium losses can occur due to a lack of PTH. Symptoms of hypocalcemia can include muscle spasms, cramps, paresthesia, tetany, and seizures. Long term hypocalcemia can impact bone health and result in reduced bone mass and osteoporosis. Hypercalcemia can occur due to increased bone resorption, increased intestinal absorption, and decreased renal excretion of calcium. Syndromes that increase PTH production can result in excessive calcium reabsorption and calcitriol production in the kidney. Excess PTH and calcitriol production can result in increased bone resorption. Excess calcitriol also can increase intestinal absorption. Symptoms of hypercalcemia include fatigue, confusion, polydipsia, frequent urination, upset stomach, bone pain, muscle weakness, and cardiac arrhythmia.[14][77][78] 

Magnesium

Magnesium deficiency, or hypomagnesemia, can occur due to chronic inadequate magnesium intake, chronic diarrhea, magnesium malabsorption, alcoholism, and use of medications like diuretics, antacids, proton pump inhibitors, and aminoglycoside antibiotics. Symptoms of hypomagnesemia are nonspecific and include muscle weakness, cramps, spasms, and tremors. Magnesium toxicity, or hypermagnesemia, can occur with supplemental magnesium, especially in those with intestinal or renal disease. Symptoms of hypermagnesemia include diarrhea, nausea, vomiting, headaches, lethargy, and flushing. At very high serum concentrations of magnesium, cardiac and electrocardiogram changes can occur, as well as coma, respiratory depression, and cardiac arrest.[15][14] 

Phosphorus

Phosphorus deficiency, or hypophosphatemia, is relatively rare in healthy individuals. However, hypophosphatemia can occur due to conditions that cause a shift of phosphorous from extracellular fluid to intracellular fluid, decreased intestinal absorption of phosphorus, or increased renal excretion of phosphorus. Hypophosphatemia may also occur in individuals with rare genetic disorders that decrease renal reabsorption and increase the excretion of phosphorus. Hypophosphatemia can appear asymptomatic until serum levels reach <1.5 mg/dL where symptoms of anorexia, confusion, seizures, and paralysis can present. Respiratory depression can occur at serum levels <1 mg/dL. Treatment of hypophosphatemia includes oral or intravenous supplementation depending on the severity of deficiency. Phosphorus toxicity, or hyperphosphatemia, can occur in those with chronic kidney disease due to decreased excretion of phosphorus. Hyperphosphatemia is associated with increased death from cardiovascular disease due to vascular calcification in individuals with and without chronic kidney disease. Hyperphosphatemia is treated first by dietary restriction of phosphate, then by protein restriction, and if the latter fail, dialysis. Hyperphosphatemia can also be treated with oral phosphate binders that block dietary phosphorus absorption.[14][79]

Sodium

Given the pervasiveness of sodium in a variety of foods, sodium deficiency is highly unlikely in healthy individuals. Sodium deficiency, or hyponatremia, can only occur in pathological conditions such as adrenal insufficiency, kidney disease that results in excessive sodium losses, excessive burns, diabetic ketoacidosis, and additional conditions that cause excessive sodium losses such as vomiting, diarrhea, prolonged sweating, and excessive diuretic use. Symptoms of hyponatremia include hypovalemia, lethargy, confusion, and weakness. Sodium toxicity, or hypernatremia, can occur with dehydration, hyperaldosteronemia, and renal failure. Symptoms of hypernatremia include hypervolemia, hypertension, convulsions, or coma. Even under normal conditions, continuous excessive intake of sodium can result in hypertension in certain individuals. [19][18] 

Potassium

Potassium is considered to be a shortfall nutrient in the American diet according to the 2010 Dietary Guidelines for American’s Advisory Committee because most Americans are unable to consume the AI of 4,700 mg/day. There is moderate evidence of an association between blood pressure reduction and potassium intake in adults, which influences cardiovascular disease risk. Hypokalemia usually occurs due to inadequate potassium intake and/or excessive potassium losses. Hypokalemia can clinically manifest in symptoms such as muscle weakness, smooth muscle dysfunction, cardiac complications, and glucose intolerance. Hyperkalemia usually occurs due to impaired renal excretion. Hyperkalemia will manifest in excitatory tissues and present symptoms such as neuromuscular symptoms such as paresthesias and fasciculations, cardiac arrest, and impaired renal function.[19][41][19]

Chloride

Hypochloremia, or chloride deficiency, is related to clinical situations that cause excessive chloride losses due to gastrointestinal or renal conditions such as vomiting and renal failure. When serum chloride levels fall, bicarbonate reabsorption increases proportionately resulting in metabolic alkalosis. Symptoms of hypochloremia are concurrent with those of metabolic alkalosis and include confusion, apathy, cardiac arrhythmias, and neuromuscular irritability. Hyperchloremia, or chloride toxicity, is related to clinical situations that cause excessive gastrointestinal or renal bicarbonate losses such as severe diarrhea and medications that promote bicarbonate excretion. When serum bicarbonate levels fall, chloride reabsorption increases proportionately resulting in metabolic acidosis.[54]

Iron

The World Health Organization (WHO) indicates iron deficiency to be the most common form of malnutrition in the world, affecting 25% of the global population. Iron deficiency is highly prevalent in both developing and developed countries. Iron deficiency is most commonly caused by inadequate intake of dietary iron, inadequate iron utilization due to diseases, impaired iron absorption, or excess iron loss. Iron deficiency can often be avoided and reversed with iron supplementation and/or reducing iron losses. Untreated iron deficiency can result in microcytic anemia, poor cognitive performance, impaired immune function, impaired growth in children, poor pregnancy outcomes, and reduced endurance capacity. On the other hand, iron overload can be caused by a disease called hereditary hemochromatosis, which is due to a C282Y mutation in the HFE gene. Hereditary hemochromatosis can be treated with iron removal therapy.[71][22][42] 

Zinc

Zinc deficiency can present clinically with symptoms such as dermatitis, alopecia, decreased appetite, frequent diarrhea, frequent upper respiratory infection, stunted growth in children, and hypogonadism. Zinc deficiency can occur due to diarrheal illness, kidney failure, and genetic diseases acrodermatitis enteropathica (AE). AE is a fatal disease of zinc malabsorption due to a mutation in the ZIP4 gene which encodes the major intestinal zinc uptake protein. AE is treated with lifelong zinc supplementation of 100 mg/kg per day. Zinc toxicity is rare due to the tight regulation of zinc concentrations in the body. However, long-term zinc supplementation above the tolerable upper intake level of 40 mg/day can decrease copper absorption and cause copper deficiency. This occurs because zinc induced the formation of the intestinal cell protein metallothionein, which binds to metals and prevents their absorption by trapping them in the intestinal cell. Metallothionein has a stronger affinity for copper than zinc, thus trapping copper in the intestinal cell and halting absorption.[23]  

Copper

Copper deficiency manifests generally in systems such as bone marrow hematopoiesis, optic nerve function, and the nervous system. Copper deficiency causes symptoms such as fatigue and weakness. Copper deficiency can occur due to excessive zinc supplementation and the genetic disorder of copper malabsorption called Menkes disease. Menkes disease is caused by a mutation in the ATP7A gene which causes copper to accumulate in the enterocyte making it unable to reach the blood or any other organ systems. Another genetic disease of copper metabolism is Wilson’s disease, which is a genetic disease of accumulation of copper mainly in the liver and the brain due to a mutation in the ATP7B gene responsible for the ATP7B exporter.[45][24]  

Iodine

Iodine deficiency will cause a compensatory response of the thyroid gland. When iodine intake falls below approximately 100 mcg/day, the pituitary increases secretion of TSH, which increases plasma iodine clearance by the thyroid. Thus, plasma iodine levels decreases and thyroid hormone synthesis decreases resulting in hypothyroidism. The increase in TSH also increases the thyroid cell number and cell size resulting in an enlarged thyroid gland, or goiter. The goiter can be treated with iodine supplementation gradually reducing the size or a thyroidectomy. If left untreated, the goiter may cause tracheal and esophageal pressure. Thyroid deficiency during pregnancy can lead to neurological cretinism in the offspring.[46] 

Selenium

Selenium deficiency has been known to appear in humans after severe and prolonged cases of selenium deprivation. Selenium deficiency is known as Keshan disease and occurs in areas where selenium content in the soil is low, like China. Symptoms of Keshan disease include cardiomyopathy, peripheral myopathy, decreased muscle tone and function, hair thinning, opacification of nails, and anemia.[27] 


References

[1] Ward E, Addressing nutritional gaps with multivitamin and mineral supplements. Nutrition journal. 2014 Jul 15;     [PubMed PMID: 25027766]
[2] Kim M,Basharat A,Santosh R,Mehdi SF,Razvi Z,Yoo SK,Lowell B,Kumar A,Brima W,Danoff A,Dankner R,Bergman M,Pavlov VA,Yang H,Roth J, Reuniting overnutrition and undernutrition, macronutrients, and micronutrients. Diabetes/metabolism research and reviews. 2019 Jan;     [PubMed PMID: 30171821]
[3] Guenther PM,Jensen HH, Estimating energy contributed by fiber using a general factor of 2 vs 4 kcal/g. Journal of the American Dietetic Association. 2000 Aug;     [PubMed PMID: 10955054]
[4] Cummings JH,Stephen AM, Carbohydrate terminology and classification. European journal of clinical nutrition. 2007 Dec;     [PubMed PMID: 17992187]
[5] Trumbo P,Schlicker S,Yates AA,Poos M, Dietary reference intakes for energy, carbohydrate, fiber, fat, fatty acids, cholesterol, protein and amino acids. Journal of the American Dietetic Association. 2002 Nov;     [PubMed PMID: 12449285]
[6] Pasiakos SM,Agarwal S,Lieberman HR,Fulgoni VL 3rd, Sources and Amounts of Animal, Dairy, and Plant Protein Intake of US Adults in 2007-2010. Nutrients. 2015 Aug 21;     [PubMed PMID: 26308049]
[7] Acheson KJ, Diets for body weight control and health: the potential of changing the macronutrient composition. European journal of clinical nutrition. 2013 May;     [PubMed PMID: 23187953]
[8] Del Razo Olvera FM,Melgarejo Hernández MA,Mehta R,Aguilar Salinas CA, Setting the Lipid Component of the Diet: A Work in Process. Advances in nutrition (Bethesda, Md.). 2017 Jan;     [PubMed PMID: 28096140]
[9] 1998;     [PubMed PMID: 23193625]
[10] Lykkesfeldt J,Michels AJ,Frei B, Vitamin C. Advances in nutrition (Bethesda, Md.). 2014 Jan 1;     [PubMed PMID: 24425716]
[11] Krinsky NI, Human requirements for fat-soluble vitamins, and other things concerning these nutrients. Molecular aspects of medicine. 2003 Dec;     [PubMed PMID: 14585302]
[12] Kiela PR,Ghishan FK, Physiology of Intestinal Absorption and Secretion. Best practice     [PubMed PMID: 27086882]
[13] Ross AC,Manson JE,Abrams SA,Aloia JF,Brannon PM,Clinton SK,Durazo-Arvizu RA,Gallagher JC,Gallo RL,Jones G,Kovacs CS,Mayne ST,Rosen CJ,Shapses SA, The 2011 Dietary Reference Intakes for Calcium and Vitamin D: what dietetics practitioners need to know. Journal of the American Dietetic Association. 2011 Apr;     [PubMed PMID: 21443983]
[14] Blaine J,Chonchol M,Levi M, Renal control of calcium, phosphate, and magnesium homeostasis. Clinical journal of the American Society of Nephrology : CJASN. 2015 Jul 7;     [PubMed PMID: 25287933]
[15] Costello R,Wallace TC,Rosanoff A, Magnesium. Advances in nutrition (Bethesda, Md.). 2016 Jan;     [PubMed PMID: 26773023]
[16] Calvo MS,Lamberg-Allardt CJ, Phosphorus. Advances in nutrition (Bethesda, Md.). 2015 Nov;     [PubMed PMID: 26567206]
[17] Karppanen H,Karppanen P,Mervaala E, Why and how to implement sodium, potassium, calcium, and magnesium changes in food items and diets? Journal of human hypertension. 2005 Dec;     [PubMed PMID: 16302005]
[18] Strazzullo P,Leclercq C, Sodium. Advances in nutrition (Bethesda, Md.). 2014 Mar 1;     [PubMed PMID: 24618759]
[19] Yin J,Hu Y,Yoon J, Fluorescent probes and bioimaging: alkali metals, alkaline earth metals and pH. Chemical Society reviews. 2015 Jul 21;     [PubMed PMID: 25317749]
[20] Bohn AA,de Morais HA, A Quick Reference on Chloride. The Veterinary clinics of North America. Small animal practice. 2017 Mar;     [PubMed PMID: 28007306]
[21] Finnamore HE,Whelan K,Hickson M,Shovlin CL, Top dietary iron sources in the UK. The British journal of general practice : the journal of the Royal College of General Practitioners. 2014 Apr;     [PubMed PMID: 24686867]
[22] Cook JD, Parenteral trace elements: iron. Bulletin of the New York Academy of Medicine. 1984 Mar;     [PubMed PMID: 6426560]
[23] Huang L,Drake VJ,Ho E, Zinc. Advances in nutrition (Bethesda, Md.). 2015 Mar;     [PubMed PMID: 25770261]
[24] Livingstone C, Review of Copper Provision in the Parenteral Nutrition of Adults [Formula: see text]. Nutrition in clinical practice : official publication of the American Society for Parenteral and Enteral Nutrition. 2017 Apr;     [PubMed PMID: 28362575]
[25] Ma J,Betts NM, Zinc and copper intakes and their major food sources for older adults in the 1994-96 continuing survey of food intakes by individuals (CSFII). The Journal of nutrition. 2000 Nov;     [PubMed PMID: 11053529]
[26] Zimmermann M,Trumbo PR, Iodine. Advances in nutrition (Bethesda, Md.). 2013 Mar 1;     [PubMed PMID: 23493543]
[27] Mehdi Y,Hornick JL,Istasse L,Dufrasne I, Selenium in the environment, metabolism and involvement in body functions. Molecules (Basel, Switzerland). 2013 Mar 13;     [PubMed PMID: 23486107]
[28] Goodman BE, Insights into digestion and absorption of major nutrients in humans. Advances in physiology education. 2010 Jun;     [PubMed PMID: 20522896]
[29] Dashty M, A quick look at biochemistry: carbohydrate metabolism. Clinical biochemistry. 2013 Oct;     [PubMed PMID: 23680095]
[30] Wu G, Amino acids: metabolism, functions, and nutrition. Amino acids. 2009 May;     [PubMed PMID: 19301095]
[31] Barter P, Lipoprotein metabolism and CKD: overview. Clinical and experimental nephrology. 2014 Apr;     [PubMed PMID: 24052157]
[32] Li E,Tso P, Vitamin A uptake from foods. Current opinion in lipidology. 2003 Jun;     [PubMed PMID: 12840654]
[33] Goodman DS, Overview of current knowledge of metabolism of vitamin A and carotenoids. Journal of the National Cancer Institute. 1984 Dec;     [PubMed PMID: 6096622]
[34] Pilz S,Zittermann A,Trummer C,Theiler-Schwetz V,Lerchbaum E,Keppel MH,Grübler MR,März W,Pandis M, Vitamin D testing and treatment: a narrative review of current evidence. Endocrine connections. 2019 Feb 1;     [PubMed PMID: 30650061]
[35] Christakos S,Dhawan P,Verstuyf A,Verlinden L,Carmeliet G, Vitamin D: Metabolism, Molecular Mechanism of Action, and Pleiotropic Effects. Physiological reviews. 2016 Jan;     [PubMed PMID: 26681795]
[36] Herrera E,Barbas C, Vitamin E: action, metabolism and perspectives. Journal of physiology and biochemistry. 2001 Mar;     [PubMed PMID: 11579997]
[37] Fusaro M,Gallieni M,Rizzo MA,Stucchi A,Delanaye P,Cavalier E,Moysés RMA,Jorgetti V,Iervasi G,Giannini S,Fabris F,Aghi A,Sella S,Galli F,Viola V,Plebani M, Vitamin K plasma levels determination in human health. Clinical chemistry and laboratory medicine. 2017 May 1;     [PubMed PMID: 27732556]
[38] Iheagwara OS,Ing TS,Kjellstrand CM,Lew SQ, Phosphorus, phosphorous, and phosphate. Hemodialysis international. International Symposium on Home Hemodialysis. 2013 Oct;     [PubMed PMID: 23279081]
[39] Wright EM,Loo DD, Coupling between Na , sugar, and water transport across the intestine. Annals of the New York Academy of Sciences. 2000;     [PubMed PMID: 11193601]
[40] Agarwal R,Afzalpurkar R,Fordtran JS, Pathophysiology of potassium absorption and secretion by the human intestine. Gastroenterology. 1994 Aug;     [PubMed PMID: 8039632]
[41] Palmer BF,Clegg DJ, Physiology and pathophysiology of potassium homeostasis. Advances in physiology education. 2016 Dec;     [PubMed PMID: 27756725]
[42] Saito H, METABOLISM OF IRON STORES. Nagoya journal of medical science. 2014 Aug;     [PubMed PMID: 25741033]
[43] Santiago P, Ferrous versus ferric oral iron formulations for the treatment of iron deficiency: a clinical overview. TheScientificWorldJournal. 2012;     [PubMed PMID: 22654638]
[44] Miret S,Simpson RJ,McKie AT, Physiology and molecular biology of dietary iron absorption. Annual review of nutrition. 2003;     [PubMed PMID: 12626689]
[45] Myint ZW,Oo TH,Thein KZ,Tun AM,Saeed H, Copper deficiency anemia: review article. Annals of hematology. 2018 Sep;     [PubMed PMID: 29959467]
[46] Zimmermann MB, Iodine deficiency. Endocrine reviews. 2009 Jun;     [PubMed PMID: 19460960]
[47] Hou Y,Wu Z,Dai Z,Wang G,Wu G, Protein hydrolysates in animal nutrition: Industrial production, bioactive peptides, and functional significance. Journal of animal science and biotechnology. 2017;     [PubMed PMID: 28286649]
[48] Burdge GC,Calder PC, Introduction to fatty acids and lipids. World review of nutrition and dietetics. 2015;     [PubMed PMID: 25471798]
[49] Kelly GS, Pantothenic acid. Monograph. Alternative medicine review : a journal of clinical therapeutic. 2011 Sep;     [PubMed PMID: 21951027]
[50] Greenway FL,Ingram DK,Ravussin E,Hausmann M,Smith SR,Cox L,Tomayko K,Treadwell BV, Loss of taste responds to high-dose biotin treatment. Journal of the American College of Nutrition. 2011 Jun;     [PubMed PMID: 21896875]
[51] Stahl W,Sies H, Antioxidant activity of carotenoids. Molecular aspects of medicine. 2003 Dec;     [PubMed PMID: 14585305]
[52] Sklan D, Vitamin A in human nutrition. Progress in food     [PubMed PMID: 3303134]
[53] Mustacich DJ,Bruno RS,Traber MG, Vitamin E. Vitamins and hormones. 2007;     [PubMed PMID: 17628169]
[54] Berend K,van Hulsteijn LH,Gans RO, Chloride: the queen of electrolytes? European journal of internal medicine. 2012 Apr;     [PubMed PMID: 22385875]
[55] Rivera-Mancía S,Pérez-Neri I,Ríos C,Tristán-López L,Rivera-Espinosa L,Montes S, The transition metals copper and iron in neurodegenerative diseases. Chemico-biological interactions. 2010 Jul 30;     [PubMed PMID: 20399203]
[56] Saari JC, Vitamin A and Vision. Sub-cellular biochemistry. 2016;     [PubMed PMID: 27830507]
[57] Beijer MR,Kraal G,den Haan JM, Vitamin A and dendritic cell differentiation. Immunology. 2014 May;     [PubMed PMID: 24843870]
[58] Hogarth CA,Griswold MD, The key role of vitamin A in spermatogenesis. The Journal of clinical investigation. 2010 Apr;     [PubMed PMID: 20364093]
[59] Bates CJ, Vitamin A. Lancet (London, England). 1995 Jan 7;     [PubMed PMID: 7799706]
[60] Petkovich M, Regulation of gene expression by vitamin A: the role of nuclear retinoic acid receptors. Annual review of nutrition. 1992;     [PubMed PMID: 1323983]
[61] Barr RG,Nathan DM,Meigs JB,Singer DE, Tests of glycemia for the diagnosis of type 2 diabetes mellitus. Annals of internal medicine. 2002 Aug 20;     [PubMed PMID: 12186517]
[62] Patel P,Macerollo A, Diabetes mellitus: diagnosis and screening. American family physician. 2010 Apr 1;     [PubMed PMID: 20353144]
[63] Hoffer LJ, Human Protein and Amino Acid Requirements. JPEN. Journal of parenteral and enteral nutrition. 2016 May;     [PubMed PMID: 26796095]
[64] Cox RA,García-Palmieri MR, Cholesterol, Triglycerides, and Associated Lipoproteins 1990;     [PubMed PMID: 21250192]
[65] Frei B,Birlouez-Aragon I,Lykkesfeldt J, Authors' perspective: What is the optimum intake of vitamin C in humans? Critical reviews in food science and nutrition. 2012;     [PubMed PMID: 22698272]
[66] Tanumihardjo SA, Vitamin A: biomarkers of nutrition for development. The American journal of clinical nutrition. 2011 Aug;     [PubMed PMID: 21715511]
[67] Galmés S,Serra F,Palou A, Vitamin E Metabolic Effects and Genetic Variants: A Challenge for Precision Nutrition in Obesity and Associated Disturbances. Nutrients. 2018 Dec 4;     [PubMed PMID: 30518135]
[68] Weaver CM, Assessing calcium status and metabolism. The Journal of nutrition. 1990 Nov;     [PubMed PMID: 2243290]
[69] Hoorn EJ,Zietse R, Diagnosis and Treatment of Hyponatremia: Compilation of the Guidelines. Journal of the American Society of Nephrology : JASN. 2017 May;     [PubMed PMID: 28174217]
[70] Barsoum NR,Levine BS, Current prescriptions for the correction of hyponatraemia and hypernatraemia: are they too simple? Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association. 2002 Jul;     [PubMed PMID: 12105238]
[71] Pfeiffer CM,Looker AC, Laboratory methodologies for indicators of iron status: strengths, limitations, and analytical challenges. The American journal of clinical nutrition. 2017 Dec;     [PubMed PMID: 29070545]
[72] Papamargaritis D,Aasheim ET,Sampson B,le Roux CW, Copper, selenium and zinc levels after bariatric surgery in patients recommended to take multivitamin-mineral supplementation. Journal of trace elements in medicine and biology : organ of the Society for Minerals and Trace Elements (GMS). 2015;     [PubMed PMID: 25271186]
[73] Diagnosis and classification of diabetes mellitus. Diabetes care. 2013 Jan;     [PubMed PMID: 23264425]
[74] Grover Z,Ee LC, Protein energy malnutrition. Pediatric clinics of North America. 2009 Oct;     [PubMed PMID: 19931063]
[75] Traber MG,Sies H, Vitamin E in humans: demand and delivery. Annual review of nutrition. 1996;     [PubMed PMID: 8839930]
[76] Marchili MR,Santoro E,Marchesi A,Bianchi S,Rotondi Aufiero L,Villani A, Vitamin K deficiency: a case report and review of current guidelines. Italian journal of pediatrics. 2018 Mar 14;     [PubMed PMID: 29540231]
[77] Fong J,Khan A, Hypocalcemia: updates in diagnosis and management for primary care. Canadian family physician Medecin de famille canadien. 2012 Feb;     [PubMed PMID: 22439169]
[78] Minisola S,Pepe J,Piemonte S,Cipriani C, The diagnosis and management of hypercalcaemia. BMJ (Clinical research ed.). 2015 Jun 2;     [PubMed PMID: 26037642]
[79] Askar AM, Hyperphosphatemia. The hidden killer in chronic kidney disease. Saudi medical journal. 2015 Jan;     [PubMed PMID: 25629999]