Chapter 10 Nutrients Important for Metabolism and Blood Function

Nutrients In

Once absorbed from the small intestine, all nutrients require transport to cells in need of their support. Additionally, molecules manufactured in other cells sometimes require delivery to other organ systems. Blood is the conduit and blood vessels are the highway that support nutrient and molecule transport to all cells. Water-soluble molecules, such as some vitamins, minerals, sugars, and many proteins, move independently in blood. Fat-soluble vitamins, triglycerides, cholesterol, and other lipids are packaged into lipoproteins that allow for transport in the watery milieu of blood. Many proteins, drugs, and hormones are dependent on transport carriers, primarily albumin. In addition to transporting all of these molecules, blood must transfer the oxygen breathed in by the lungs to all cells in the body. As discussed, the iron-containing hemoglobin molecule in red blood cells accomplishes this.

Wastes Out

Figure 10.1 The Capillary Exchange: Nutrients In and Wastes Out

In the metabolism of macronutrients to energy, cells produce the waste products carbon dioxide and water. As blood travels through smaller and smaller vessels, the rate of blood flow is dramatically reduced allowing for efficient exchange of nutrients and oxygen for cellular waste products. The kidneys remove any excess water in the blood, and blood delivers the carbon dioxide to the lungs where it is exhaled. Also, the liver produces the waste product urea from the breakdown of amino acids, and detoxifies many harmful substances, all of which require transport in the blood to the kidneys for excretion.

All for One, One for All

We are not going to talk about the three musketeers, but we will talk about the way our bodies function and work harmoniously to sustain life. The eleven organ systems in the body completely depend on each other for continued survival as a complex organism. Blood allows for transport of nutrients, wastes, water, and heat, and is also a conduit of communication between organ systems. Blood’s importance to the rest of the body is aptly presented in its role in glucose delivery, especially to the brain. The brain metabolizes, on average, 6 grams of glucose per hour. In order to avert confusion, coma, and death, glucose must be readily available to the brain at all times. To accomplish this task, cells in the pancreas sense glucose levels in the blood. If glucose levels are low, the hormone glucagon is released into the blood and is transported to the liver where it communicates the signal to ramp-up glycogen breakdown and glucose synthesis. The liver does just that, and glucose is released into the blood, which transports it to the brain. Concurrently, blood transports oxygen to support the metabolism of glucose to energy in the brain. Healthy blood conducts its duties rapidly, avoiding hypoglycemic coma and death. This is just one example of the body’s survival mechanisms exemplifying life’s mantra, “All for one, one for all.”

What Makes Blood Healthy?

Maintaining healthy blood, including its continuous renewal, is essential to support its vast array of vital functions. Blood is healthy when it contains the appropriate amount of water and cellular components, and proper concentrations of dissolved substances, such as albumin and electrolytes. As with all other tissues, blood needs macro- and micronutrients to optimally function. In the bone marrow, where blood cells are made, amino acids are required to build the massive amount of hemoglobin packed within every red blood cell, along with all other enzymes and cellular organelles contained in each blood cell. Red blood cells, similar to the brain, use only glucose as fuel, and it must be in constant supply to support red-blood-cell metabolism. As with all other cells, the cells in the blood are surrounded by a plasma membrane, which is composed of mainly lipids. Blood health is also acutely sensitive to deficiencies in some vitamins and minerals more than others, a topic that will be explored in this chapter.

Energy Storage

In contrast, in the “fed” state (when energy levels are high), extra energy from nutrients will be stored. Glucose can be stored only in muscle and liver tissues. In these tissues it is stored as glycogen, a highly branched macromolecule consisting of thousands of glucose monomers held together by chemical bonds. The glucose monomers are joined together by an anabolic pathway called glycogenesis. For each molecule of glucose stored, one molecule of ATP is used. Therefore, it costs energy to store energy. Glycogen levels do not take long to reach their physiological limit and when this happens excess glucose will be converted to fat. A cell in positive-energy balance detects a high concentration of ATP as well as acetyl-CoA produced by catabolic pathways. In response, catabolism is shut off and the synthesis of triglycerides, which occurs by an anabolic pathway called lipogenesis, is turned on. The newly made triglycerides are transported to fat-storing cells called adipocytes. Fat is a better alternative to glycogen for energy storage as it is more compact (per unit of energy) and, unlike glycogen, the body does not store water along with fat. Water weighs a significant amount and increased glycogen stores, which are accompanied by water, would dramatically increase body weight. When the body is in positive-energy balance, excess carbohydrates, lipids, and protein are all metabolized to fat.

Thiamine (B₁)

Thiamine is especially important in glucose metabolism. It acts as a cofactor for enzymes that break down glucose for energy production (Figure 10.3). Additionally, thiamine plays a role in the synthesis of ribose from glucose and is therefore required for RNA, DNA, and ATP synthesis. The brain and heart are most affected by a deficiency in thiamine. Thiamine deficiency, also known as beriberi, can cause symptoms of fatigue, confusion, movement impairment, pain in the lower extremities, swelling, and heart failure. It is prevalent in societies whose main dietary staple is white rice. During the processing of white rice, the bran is removed, along with what were called in the early nineteenth century, “accessory factors,” that are vital for metabolism. Dutch physician Dr. Christiaan Eijkman cured chickens of beriberi by feeding them unpolished rice bran in 1897. By 1912, Sir Frederick Gowland Hopkins determined from his experiments with animals that the “accessory factors,” eventually renamed vitamins, are needed in the diet to support growth, since animals fed a diet of pure carbohydrates, proteins, fats, and minerals failed to grow.Encyclopedia Brittanica Blog. “Frederick Gowland Hopkins and his “Accessory Food Factors.” Accessed October 1, 2011. http://www.britannica.com/blogs/2011/06/frederick-gowland-hopkins-accessory-food-factors/. Eijkman and Hopkins were awarded the Nobel Prize in Physiology (or Medicine) in 1929 for their discoveries in the emerging science of nutrition.

Riboflavin (B₂)

Riboflavin is an essential component of flavoproteins, which are coenzymes involved in many metabolic pathways of carbohydrate, lipid, and protein metabolism. Flavoproteins aid in the transfer of electrons in the electron transport chain. Furthermore, the functions of other B-vitamin coenzymes, such as vitamin B₆ and folate, are dependent on the actions of flavoproteins. The “flavin” portion of riboflavin gives a bright yellow color to riboflavin, an attribute that help lead to its discovery as a vitamin. Riboflavin deficiency, sometimes referred to as ariboflavinosis, is often accompanied by other dietary deficiencies (most notably protein) and can be common in people that suffer from alcoholism. Its signs and symptoms include dry, scaly skin, mouth inflammation and sores, sore throat, itchy eyes, and light sensitivity.

Niacin (B₃)

Niacin is a component of the coenzymes NADH and NADPH, which are involved in the catabolism and/or anabolism of carbohydrates, lipids, and proteins. NADH is the predominant electron carrier and transfers electrons to the electron-transport chain to make ATP. NADPH is also required for the anabolic pathways of fatty-acid and cholesterol synthesis. In contrast to other vitamins, niacin can be synthesized by humans from the amino acid tryptophan in an anabolic process requiring enzymes dependent on riboflavin, vitamin B₆, and iron. Niacin is made from tryptophan only after tryptophan has met all of its other needs in the body. The contribution of tryptophan-derived niacin to niacin needs in the body varies widely and a few scientific studies have demonstrated that diets high in tryptophan have very little effect on niacin deficiency. Niacin deficiency is commonly known as pellagra and is characterized by diarrhea, dermatitis, dementia, and sometimes death (see Note 10.24 "Video 10.3").

Pantothenic Acid (B₅)

Figure 10.4

Vitamin B₅ makes up coenzyme A, which carries the carbons of glucose, fatty acids, and amino acids into the citric acid cycle as Acetyl-CoA.

Pantothenic acid forms coenzyme A, which is the main carrier of carbon molecules in a cell. Acetyl-CoA is the carbon carrier of glucose, fatty acids, and amino acids into the citric acid cycle (Figure 10.4). Coenzyme A is also involved in the synthesis of lipids, cholesterol, and acetylcholine (a neurotransmitter). Vitamin B₅ deficiency is exceptionally rare. Signs and symptoms include fatigue, irritability, numbness, muscle pain, and cramps. You may have seen pantothenic acid on many ingredients lists for skin and hair care products; however there is no good scientific evidence that pantothenic acid improves human skin or hair.

Pyroxidine (B₆)

Pyroxidine is the coenzyme involved in nitrogen transfer between amino acids and therefore plays a role in amino-acid synthesis and catabolism. Also, it functions to release glucose from glycogen in the catabolic pathway of glycogenolysis and is required by enzymes for the synthesis of multiple neurotransmitters and hemoglobin. A deficiency in vitamin B₆ can cause signs and symptoms of muscle weakness, dermatitis, mouth sores, fatigue, and confusion.

Vitamin B₆ is a required coenzyme for the synthesis of hemoglobin. A deficiency in vitamin B₆ can cause anemia, but it is of a different type than that caused by insufficient folate, cobalamin, or iron; although the symptoms are similar. The size of red blood cells is normal or somewhat smaller but the hemoglobin content is lower. This means each red blood cell has less capacity for carrying oxygen, resulting in muscle weakness, fatigue, and shortness of breath.

Biotin

Biotin is required as a coenzyme in the citric acid cycle and in lipid metabolism. It is also required as an enzyme in the synthesis of glucose and some nonessential amino acids. A specific enzyme, biotinidase, is required to release biotin from protein so that it can be absorbed in the gut. There is some bacterial synthesis of biotin that occurs in the colon; however this is not a significant source of biotin. Biotin deficiency is rare, but can be caused by eating large amounts of egg whites over an extended period of time. This is because a protein in egg whites tightly binds to biotin making it unavailable for absorption. A rare genetic disease-causing malfunction of the biotinidase enzyme also results in biotin deficiency. Symptoms of biotin deficiency are similar to those of other B vitamins, but may also include hair loss when severe.

Folate

Folate is a required coenzyme for the synthesis of the amino acid methionine, and for making RNA and DNA. Therefore, rapidly dividing cells are most affected by folate deficiency. Red blood cells, white blood cells, and platelets are continuously being synthesized in the bone marrow from dividing stem cells. A consequence of folate deficiency is macrocytic, also called megaloblastic, anemia. Macrocytic and megaloblastic mean “big cell,” and anemia refers to fewer red blood cells or red blood cells containing less hemoglobin. Macrocytic anemia is characterized by larger and fewer red blood cells. It is caused by red blood cells being unable to produce DNA and RNA fast enough—cells grow but do not divide, making them large in size.

Figure 10.5

Spina bifida is a neural-tube defect that can have severe health consequences.

Folate is especially essential for the growth and specialization of cells of the central nervous system. Children whose mothers were folate-deficient during pregnancy have a higher risk of neural-tube birth defects. Folate deficiency is causally linked to the development of spina bifida, a neural-tube defect that occurs when the spine does not completely enclose the spinal cord. Spina bifida can lead to many physical and mental disabilities (Figure 10.5). Observational studies show that the prevalence of neural-tube defects was decreased after the fortification of enriched cereal grain products with folate in 1996 in the United States (and 1998 in Canada) compared to before grain products were fortified with folate (Figure 10.5). Additionally, results of clinical trials have demonstrated that neural-tube defects are significantly decreased in the offspring of mothers who began taking folate supplements one month prior to becoming pregnant and throughout the pregnancy. In response to the scientific evidence, the Food and Nutrition Board of the Institute of Medicine (IOM) raised the RDA for folate to 600 micrograms per day for pregnant women. Some were concerned that higher folate intakes may cause colon cancer, however scientific studies refute this hypothesis.

Cobalamin (B₁₂)

Cobalamin contains cobalt, making it the only vitamin that contains a metal ion. Cobalamin is an essential part of coenzymes. It is necessary for fat and protein catabolism, for folate coenzyme function, and for hemoglobin synthesis. An enzyme requiring cobalamin is needed by a folate-dependent enzyme to synthesize DNA. Thus, a deficiency in cobalamin has similar consequences to health as folate deficiency. In children and adults cobalamin deficiency causes macrocytic anemia, and in babies born to cobalamin-deficient mothers there is an increased risk for neural-tube defects. In order for the human body to absorb cobalamin, the stomach, pancreas, and small intestine must be functioning properly. Cells in the stomach secrete a protein called intrinsic factor that is necessary for cobalamin absorption, which occurs in the small intestine. Impairment of secretion of this protein either caused by an autoimmune disease or by chronic inflammation of the stomach (such as that occurring in some people with H.pylori infection), can lead to the disease pernicious anemia, a type of macrocytic anemia. Vitamin B₁₂ malabsorption is most common in the elderly, who may have impaired functioning of digestive organs, a normal consequence of aging. Pernicious anemia is treated by large oral doses of vitamin B₁₂ or by putting the vitamin under the tongue, where it is absorbed into the blood stream without passing through the intestine. In patients that do not respond to oral or sublingual treatment vitamin B₁₂ is given by injection.

A summary of the prominent functions of the B vitamins in metabolism and blood function, and their deficiency syndromes is given in Table 10.3 "B-Vitamin Functions in Metabolism and Blood, and Deficiency Syndromes".

Dietary Reference Intakes and Sources of B Vitamins

B vitamins are water-soluble and are not stored in significant amounts in the body. Therefore, they must be continuously obtained from the diet. Fortunately, B vitamins are generally well-absorbed in the gut. The Recommended Dietary Allowances (RDA) or Adequate Intakes (AI) set by the IOM, for the B vitamins are listed in Table 10.4 "Dietary Reference Intakes and Food Sources for B Vitamins", which also gives some dietary sources for these micronutrients. It should be noted that B vitamins are lost from foods during storage, processing, and cooking. To maximize B vitamin uptake, fruits and vegetables should not be stored for long periods of time, should be eaten more as whole foods, and vegetables should be steamed rather than boiled. Also, alcohol disrupts intestinal absorption of B vitamins. The US Department of Agriculture has reports of the nutrient contents in foods, including all B vitamins, available at their website. (See Note 10.25 "Interactive 10.2".)

Vitamin K: Functions in Metabolism and Blood

There is emerging evidence that vitamin K may play a role in energy metabolism, but currently the exact functions of vitamin K-dependent enzymes in energy metabolism remain elusive. Recall from Chapter 9 "Nutrients Important for Bone Health", vitamin K is required for optimal bone metabolism. Vitamin K is also critical for blood function. It is a coenzyme for enzymes involved in blood clotting. Blood-clotting proteins are continuously circulating in the blood. Upon injury to a blood vessel, platelets stick to the wound forming a plug. The clotting factors circulating close by respond in a series of protein-protein interactions resulting in the formation of the fibrous protein, fibrin, which reinforces the platelet plug (see Note 10.26 "Video 10.4" for an animation of the blood-clotting cascade of events).

A deficiency in vitamin K causes bleeding disorders. It is relatively rare, but people who have liver or pancreatic disease, celiac disease, or malabsorption conditions are at higher risk for vitamin K deficiency. Signs and symptoms include nosebleeds, easy bruising, broken blood vessels, bleeding gums, and heavy menstrual bleeding in women. The function of the anticoagulant drug warfarin is impaired by excess vitamin K intake from supplements. Calcium additionally plays a role in activation of blood-clotting proteins as discussed in the previous chapter.

Magnesium

Magnesium is the eleventh most abundant element in the human body and is known to participate as a cofactor in hundreds of metabolic reactions. ATP exists as a complex with magnesium and therefore this mineral is involved in all reactions that synthesize or require ATP including carbohydrate, lipid, protein, RNA, and DNA synthesis. Many Americans do not get the recommended intake of magnesium from their diets. Some observational studies suggest mild magnesium deficiency is linked to increased risk for cardiovascular disease. Signs and symptoms of severe magnesium deficiency may include tremor, muscle spasms, loss of appetite, and nausea.

Iron

Red blood cells contain the oxygen-carrier protein hemoglobin. It is composed of four globular peptides, each containing a heme complex. In the center of each heme, lies iron (Figure 10.6). Iron is a key component of hundreds of metabolic enzymes. Many of the proteins of the electron-transport chain contain iron–sulfur clusters involved in the transfer of high-energy electrons and ultimately ATP synthesis. Iron is also involved in numerous metabolic reactions that take place mainly in the liver and detoxify harmful substances. Moreover, iron is required for DNA synthesis. The great majority of iron used in the body is that recycled from the continuous breakdown of red blood cells.

Figure 10.6

Hemoglobin is composed of four peptides. Each contains a heme group with iron in the center.

The iron in hemoglobin binds to oxygen in the capillaries of the lungs and transports it to cells where the oxygen is released (see Note 10.30 "Video 10.5"). If iron level is low hemoglobin is not synthesized in sufficient amounts and the oxygen-carrying capacity of red blood cells is reduced, resulting in anemia. When iron levels are low in the diet the small intestine more efficiently absorbs iron in an attempt to compensate for the low dietary intake, but this process cannot make up for the excessive loss of iron that occurs with chronic blood loss or low intake. When blood cells are decommissioned for use, the body recycles the iron back to the bone marrow where red blood cells are made. The body stores some iron in the bone marrow, liver, spleen, and skeletal muscle. A relatively small amount of iron is excreted when cells lining the small intestine and skin cells die and in blood loss, such as during menstrual bleeding. The lost iron must be replaced from dietary sources.

The bioavailability of iron is highly dependent on dietary sources. In animal-based foods about 60 percent of iron is bound to hemoglobin, and heme iron is more bioavailable than nonheme iron. The other 40 percent of iron in animal-based foods is nonheme, which is the only iron source in plant-based foods. Some plants contain chemicals (such as phytate, oxalates, tannins, and polyphenols) that inhibit iron absorption. Although, eating fruits and vegetables rich in vitamin C at the same time as iron-containing foods markedly increases iron absorption. A review in the American Journal of Clinical Nutrition reports that in developed countries iron bioavailability from mixed diets ranges between 14 and 18 percent, and that from vegetarian diets ranges between 5 and 12 percent.Centers for Disease Control and Prevention. “Iron and Iron Deficiency.” Accessed October 2, 2011. http://www.cdc.gov/nutrition/everyone/basics/vitamins/iron.html. Vegans are at higher risk for iron deficiency, but careful meal planning does prevent its development. Iron deficiency is the most common of all micronutrient deficiencies and will be explored in depth in Section 10.5 "Iron-Deficiency Anemia".

Zinc

Zinc is a cofactor for over two hundred enzymes in the human body and plays a direct role in RNA, DNA, and protein synthesis. Zinc also is a cofactor for enzymes involved in energy metabolism. As the result of its prominent roles in anabolic and energy metabolism, a zinc deficiency in infants and children blunts growth. The reliance of growth on adequate dietary zinc was discovered in the early 1960s in the Middle East where adolescent nutritional dwarfism was linked to diets containing high amounts of phytate. Cereal grains and some vegetables contain chemicals, one being phytate, which blocks the absorption of zinc and other minerals in the gut. It is estimated that half of the world’s population has a zinc-deficient diet.Prasad, Ananda. “Zinc deficiency.” BMJ 2003 February 22; 326(7386): 409–410. doi: 10.1136/bmj.326.7386.409. Accessed October 2, 2011. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1125304/?tool=pmcentrez. This is largely a consequence of the lack of red meat and seafood in the diet and reliance on cereal grains as the main dietary staple. In adults, severe zinc deficiency can cause hair loss, diarrhea, skin sores, loss of appetite, and weight loss. Zinc is a required cofactor for an enzyme that synthesizes the heme portion of hemoglobin and severely deficient zinc diets can result in anemia.

Iodine

Recall from Chapter 1 "Nutrition and You" the information about the discovery of iodine and its use as a means of preventing goiter, a gross enlargement of the thyroid gland in the neck. Iodine is essential for the synthesis of thyroid hormone, which regulates basal metabolismMetabolic pathways necessary to support and maintain the basic functions of the body (e.g. breathing, heartbeat, liver, and kidney function) while at rest., growth, and development. Low iodine levels and consequently hypothyroidism has many signs and symptoms including fatigue, sensitivity to cold, constipation, weight gain, depression, and dry, itchy skin and paleness. The development of goiter may often be the most visible sign of chronic iodine deficiency, but the consequences of low levels of thyroid hormone can be severe during infancy, childhood, and adolescence as it affects all stages of growth and development. Thyroid hormone plays a major role in brain development and growth and fetuses and infants with severe iodine deficiency develop a condition known as cretinism, in which physical and neurological impairment can be severe. The World Health Organization (WHO) estimates iodine deficiency affects over two billion people worldwide and it is the number-one cause of preventable brain damage worldwide.World Health Organization. “Iodine Status Worldwide.” Accessed October 2, 2011. http://whqlibdoc.who.int/publications/2004/9241592001.pdf.

Selenium

Selenium is a cofactor of enzymes that release active thyroid hormone in cells and therefore low levels can cause similar signs and symptoms as iodine deficiency. The other important function of selenium is as an antioxidant, which was discussed in detail in Chapter 8 "Nutrients Important As Antioxidants".

Copper

Copper, like iron, assists in electron transfer in the electron-transport chain. Furthermore, copper is a cofactor of enzymes essential for iron absorption and transport. The other important function of copper is as an antioxidant, which was also discussed in Chapter 8 "Nutrients Important As Antioxidants". Symptoms of mild to moderate copper deficiency are rare. More severe copper deficiency can cause anemia from the lack of iron mobilization in the body for red blood cell synthesis. Other signs and symptoms include growth retardation in children and neurological problems, because copper is a cofactor for an enzyme that synthesizes myelin, which surrounds many nerves.

Manganese

Manganese is a cofactor for enzymes involved in glucose production (gluconeogenesis) and amino-acid catabolism in the liver. Manganese deficiency is uncommon.

Chromium

The functioning of chromium in the body is less understood than that of most other minerals. It enhances the actions of insulin so plays a role in carbohydrate, fat, and protein metabolism. Currently, the results of scientific studies evaluating the usefulness of chromium supplementation in preventing and treating Type 2 diabetes are largely inconclusive. More research is needed to better determine if chromium is helpful in treating certain chronic diseases and, if so, at what doses.

A summary of the prominent functions of minerals in metabolism and their related deficiency syndromes is given in Table 10.8 "Mineral Functions in Metabolism and Blood and Deficiency Syndrome".

Dietary Reference Intakes for Minerals and Dietary Sources

The RDA set by the IOM for minerals involved in metabolism are listed for adults in Table 10.9 "Dietary Reference Intakes and Food Sources for Minerals Important for Metabolism". The table also lists dietary sources for these micronutrients. The mineral content of foods is greatly affected by the soil from which it grew, and thus geographic location is the primary determinant of the mineral content of foods. For instance, iodine comes mostly from seawater so the greater the distance from the sea the lesser the iodine content in the soil.

Bioavailability

Minerals are not as efficiently absorbed as most vitamins and so the bioavailability of minerals can be very low. Plant-based foods often contain factors, such as oxalate and phytate, that bind to minerals and inhibit their absorption. In general, minerals are better absorbed from animal-based foods. In most cases, if dietary intake of a particular mineral is increased, absorption will decrease. Some minerals influence the absorption of others. For instance, excess zinc in the diet can impair iron and copper absorption. Conversely, certain vitamins enhance mineral absorption. For example, vitamin C boosts iron absorption, and vitamin D boosts calcium and magnesium absorption. As is the case with vitamins, certain gastrointestinal disorders and diseases, such as Crohn’s disease and kidney disease, as well as the aging process, impair mineral absorption, putting people with malabsorption conditions and the elderly at higher risk for mineral deficiencies.

At-Risk Populations

Infants, children, adolescents, and women are the populations most at risk worldwide for iron-deficiency anemia by all causes. Infants, children, and even teens require more iron because iron is essential for growth. In these populations, iron deficiency (and eventually iron-deficiency anemia) can also cause the following signs and symptoms: poor growth, failure to thrive, and poor performance in school, as well as mental, motor, and behavioral disorders. Women who experience heavy menstrual bleeding or who are pregnant require more iron in the diet. One more high-risk group is the elderly. Both elderly men and women have a high incidence of anemia and the most common causes are dietary iron deficiency and chronic disease such as ulcer, inflammatory diseases, and cancer. Additionally, those who have recently suffered from traumatic blood loss, frequently donate blood, or take excessive antacids for heartburn need more iron in the diet.