Fundamentals of Human Nutrition/Niacin
Niacin, also known as Vitamin B3, is one of the eight, water-soluble B vitamins that is involved in the metabolism of glucose, fat, and alcohol to produce energy. Niacin serves this role as an intermediate of nicotinamide adenine dinucleotide (NAD), and the phosphate form of NAD, NADP; these compounds function in helping oxidation-reduction reactions occur in the body (Higdon 2013).
Niacin is a water-soluble B3 vitamin. It encompasses both nicotinic acid and nicotinamide, with the latter being the main source present in the blood. It has two coenzyme forms, which are NAD and NADP otherwise known as nicotinamide adenine dinucleotide and the phosphate form respectively. Both function primarily in energy metabolic redox reactions of the breakdown of carbs, proteins, alcohol, and fats, serving as coenzymes to over 400 enzymes. Specifically, NAD hinders neurological degeneration and also parallels riboflavin coenzymes during metabolism as it takes hydrides from the citric acid cycle to the electron transport chain (Rolfes & Whitney 2013).
Sufficient amounts of the vitamin can either be obtained from the diet or be made in the body from the amino acid tryptophan if satisfactory protein synthesis requirements have been met. Tryptophan metabolism via the kynurenine pathway is relatively inefficient in providing the recommended amounts of niacin because it also depends on certain enzyme availability along with the presence of other B vitamins such as vitamin B6 and riboflavin. Specifically, to create 1 milligram of niacin, 60 milligrams of dietary tryptophan is required. Recommendations are expressed as niacin equivalents (NE), whereby the amount of tryptophan is converted to niacin using the 60 mg standard (Harper, Henderson, & Horwitt 1981). For example, a food comprised of 1 milligram of niacin and 120 milligrams of tryptophan essentially provides the equivalent of 3 milligrams of total niacin.
Niacin is naturally found in protein-rich foods and some vegetables such as meat, fish, poultry, enriched whole grains, legumes, potatoes, tomatoes, and mushrooms. However, corn is a bad source of niacin because 70% of its niacin is connected to peptides and complex carbs that inhibit its proper absorption. In fact, several studies have been performed comparing a “corn” versus “wheat” based diet. After several weeks and urinary excretion assessments, findings show that those subjects fed a “corn” based diet developed a niacin deficiency at a much faster rate, most likely due to the low tryptophan content of corn and an inhibitory factor in corn which results in an amino acid imbalance (Gibbens, Goldsmith, Rosenthal, & Tjnglaub, 1955). RDA requirements are 16 mg NE/day for men and 14 mg NE/day for women with the maximum acceptable dosage (UL) being 35 mg/day. In some cases, large doses of nicotinic acid can be helpful as in the case of fighting heart disease. A particular study tracked the progression of increased niacin dosages over the course of several weeks and results show that total cholesterol to HDL-cholesterol ratio decreased by one-thrid. In fact, by week 96, participant LDL-cholesterol levels reduced by 20%, HDL cholesterol levels increased by 28%, and triglyceride levels declined by 40% (Brody, Brusco, Capuzzi, Goldberg, Guyton, Kreisberg, & Morgan 1998).
However, if an individual were to exceed such recommendations by abusing niacin supplements they can potentially induce harm, changing niacin’s effect in the body from being solely physiological to pharmological- a transition where by the extra amount of the vitamin acts as a drug raising blood concentrations to unusually high levels. For example, if intake of nicotinic acid exceeds 3-4 times the RDA recommendation daily dose, a niacin flush may ensue. Symptoms include headaches, reddened extremities and chest, and temporary burning, tingling, and itching sensations due to capillary dilation. In order to avoid toxicity, the use of niacin as a drug needs to be monitored and should be abstained from use as treatment in people with liver disease, peptic ulcers, inflammatory bowel syndrome, diabetes, and alcoholism (Rolfes & Whitney 2013).
On the other extreme, in low protein diets, a niacin deficiency can result in pellagra otherwise known as primary pellagra. Secondary pellagra exists when there is sufficient niacin intake yet an obstacle such as liver cirrhosis, alcoholism, ulcerative colitis, or Hartnup disease prevents its proper absorption (Burton, Champion, Ebling, Rook, & Wilkinson, 1992). Rarely seen in industrialized nations, it remains primarily prevalent among developing countries. Originally, it was thought of as an infection and only through medical discovery was it realized that it actually resulted from diet inadequacies (Carpenter, 1985, J. Lewin, 1985). Symptoms include dermatitis resulting in thick, hard, scaly spots, itching and burning sensations, and sporadic lesions on the body. It can also lead to gastrointestinal discomfort such as diarrhea, poor appetite, nausea, and vomiting as well as dementia which results in fatigue, delusions, headaches, confusion, and disorientation (Burton, Champion, Ebling, Rook, & Wilkinson, 1992). If left untreated this disease can result in premature death.
Brody Jerome, Brusco O.A, CapuzziDavid M, Goldberg Anne C, Guyton John R, Kreisberg Robert A, & Morgan John M. (1998). Efficacy and safety of an extended-release niacin (Niaspan): a long-term study. The American Journal of Cardiology, Volume 82, Issue 12, Supplement 1, 74U-81U.
Burton JL, Champion RH, Ebling FJB, Rook A, & Wilkinson DS. (1992). Textbook of Dermatology. Fifth Edition. Blackwell Scientific Publications.
Carpenter KJ, Lewin WJ. (1985). A reexamination of the composition of diets associated with pellagra. The Journal of Nutrition, 115, 543–552.
Food and Nutrition Board & National Academies Press, Institute of Medicine (US) Standing Committee on the Scientific Evaluation of Dietary Reference Intakes and its Panel on Folate, Other B Vitamins, and Choline. Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline (1998). doi:http://www.ncbi.nlm.nih.gov/books/NBK114304/
Horwitt MK, Harper AE, Henderson LM. (1981). Niacin-tryptophan relationships for evaluating niacin equivalents. The American Journal of clinical Nutrition, 34, 423–427.
Gibbens, Janis, Goldsmith, Grace, G. Tjnglaub, Walter, & Rosenthal, Harold (1955). Studies of Niacin Requirement in Man ii. Requirement on Wheat and Corn Diets Low in Tryptophan. Nutritional Research Laboratory, Departments of Medicine and Biochemistry, Tulane University School of Medicine and the Charity Hospital of Louisiana at New Orleans, Louisiana, 371-385.
Rolfes Sharon Rady & Whitney Eleanor Noss. (2013). Understanding Nutrition, 14th Edition [Cengage Brain Learning Digital Ebook]. doi: http://ng.cengage.com/static/nb/ui/index.html?nbId=196342&nbNodeId=58604887&deploymentId=4842767387588213997397576#!&parentId=58604888
Food sources of niacin include:
- Whole-grain and enriched breads and cereals
Instead of dietary niacin, the human body is also able to convert dietary tryptophan into niacin. In this case, 60 mg of tryptophan is equal to 1 mg of niacin (Meštrović, 2014).
In terms of supplements, niacin exists as nicotinamide or nicotinic acid. Reasons to take niacin supplements would be to better control cholesterol levels, as well as reduce cardiovascular risks.
Niacin functions as an intermediate for nicotinamide adenine dinucleotide (NAD) and a phosphate form of NAD, NADP. These coenzymes are required by hundreds of enzymes in the body to move electrons and help undergo oxidation-reduction reactions. These redox reactions are involved in catabolizing glucose, fat, and alcohol to ultimately produce energy (Higdon, 2013). In general, B-vitamins help maintain a healthy liver, skin, hair, eyes, and a properly working nervous system. Also, niacin aids in increasing amounts of HDL (high-density lipoproteins), in the body; this augmentation helps in lowering levels of bad, LDL (low-density lipoproteins) in the bloodstream (Ehrlich, 2015). This is especially important in reducing risks of coronary heart disease.
8.3.3 Absorption and Transport
Nicotinamide and nicotinic acid are absorbed rapidly from the intestines and stomach. Absorption is mediated by different processes depending on the concentration of niacin. When the concentration is high, absorption is mediated by passive diffusion. On the other hand, at lower concentrations absorption is mediated by facilitated diffusion that is dependent on sodium-ions (Institute of Medicine Standing Committee, 1998). Niacin doses ranging from 3 to 4 grams are almost fully absorbed. Enzymes in the intestines and liver catalyze NAD to release nicotinamide, and it is transported to the tissues where it is used to make NAD when necessary. Both forms of niacin use simple diffusion to enter cells, and both also use facilitated transport when entering erythrocytes (Institute of Medicine Standing Committee, 1998).
Niacin (vitamin B₃) deficiency is generally uncommon in developed countries, but tends to reside in the homeless or impoverished populations. These populations tend to have poor diet and high alcohol consumption, which impact niacin absorption. Many processed foods, such as bread and cereal, found in the United States are fortified with niacin as well as other B-vitamins to prevent dietary inadequacies. If niacin is not available, tryptophan can be synthesized in small amounts to produce niacin for the body.
Inadequate niacin and/or tryptophan dietary intake can create a dietary deficiency. General causes of inadequate levels of B₃ include diarrhea, alcoholism, obesity, eating disorders, and malnutrition. Niacin deficiency typically accompanies other B-vitamin deficiencies, such as B₆ or B₁₂. This makes it difficult to determine the exact cause of symptoms and thus makes it more difficult to treat. Inadequate intake of niacin is more common among those with corn-based diets. This is because the niacin present in corn is not available for humans to utilize unless it is alkalized first. People who live in Mexico generally do not have issues with niacin deficiency because corn tortillas, which are treated with alkali (soaked), are a dietary staple. Once the corn tortillas are treated with alkali, the niacin becomes biologically available to humans. Corn proteins are also very low in tryptophan thus increasing the risk of niacin deficiency.
The symptoms of B₃ deficiency range in severity, but generally impact the stomach and skin first. The disease associated with severe niacin deficiency is called Pellagra and is characterized by the three D’s: dermatitis, diarrhea, and dementia. Pellagra changes the texture and appearance of skin and causes lesions to develop. Skin may become cracked, scaly, and sometimes darkened if exposed to the sun. Skin conditions may or may not appear in conjunction with other symptoms, or even at all. The gastrointestinal tract can also be impacted by a lack of niacin. Primarily, Pellagra causes stomach pain, nausea, and diarrhea. Pain in the mouth can also result and may even lead to a swollen and reddened tongue. Low levels of B₃ can impact the nervous system if left untreated. Problems such as dizziness, headaches, anxiety, depression, and Dementia (which is mental degradation) can result. If these problems persist and are not supplemented with niacin and/or tryptophan, death could be the ultimate result. Treatment of mild niacin deficiency usually just entails regular doses of niacin, within the RDA (see section 8.3.3). Severe deficiency, called Pellagra, is often treated with nicotinamide. Nicotinamide is used because it can be taken in higher doses without the risk of niacin toxicity (see section 8.3.5). Niacin deficiencies are usually treating with a multi-complex B-vitamin. This is done to help treat deficiencies in all of the B-vitamins, which commonly accompany B₃ deficiency.
The intake of too much niacin could result in a niacin flush, which leads to the dilation of the capillaries and could be painful. Symptoms may include: painful flush and rash, itching, nausea, excessive sweating, blurred vision, liver damage, and impaired glucose tolerance. If taken in large doses, hepatotoxicity may occur, which is where liver cells are damaged. Jaundice has also been known to be a result in too much niacin. Dry skin, skin rashes, low blood pressure, and headaches are also common occurrences when niacin is taken in large amounts. Other than hepatotoxicity, extremely large amounts of niacin in the body can cause gout, an irregular heartbeat, and ulcers in the digestive tract (Higdon, 2013). Also, a study found that those who consume high levels of niacin are twice as susceptible to a stroke. With all these side effects and risks, the upper level of 35 mg of niacin each day is recommended; not surpassing this amount is likely to result in no health risks.
Niacin is only about 30% available in developed cereal grains because it is largely bound, but with alkali treatment the absorption percentage is increased (Institute of Medicine Standing Committee, 1998). In meats, niacin appears in its NAD/NADP form and is notably more abundant. Also, in the cases where niacin is added to foods during fortification or enrichment, it is done so in its free form and so is greatly available. Food sources like liver and beans contain niacin in its free form. Below the bioavailability of niacin in its nicotinic acid and nicotinamide forms is discussed.
The Council for Responsible Nutrition (2013) noted that the uptake of nicotinic acid in the intestines was rapid and almost total. After being absorbed, 15-30 % of the plasma nicotinic acid is bound to protein. When the intake is at lower levels nutritional functions related to coenzymes containing NM occur; whereas at higher levels of intake (> 50 mg/day) a flushing effect with undesirable vasodilation can occur (MacKay, Hathcock, & Guarneri, 2012). At much higher levels of intake (500 – 3000 mga/day) serum lipid profiles report beneficial outcomes (CRN, 2013).
Nicotinamide is abundantly bioavailable and is capable of defending against pellagra, which is one of the definitive signs of a niacin deficiency. The beneficial changes with plasma lipids or flushing effect are not seen with nicotinamide as it is not converted to nicotinic acid sufficiently. In a certain study female students in college were given 51 mg of NM and in the end it was found that nearly half was excreted as metabolites in urine (MacKay et al., 2012). In CRN (2013) it was noted that intensifying doses (3g – 10g) of NM presented a linear correlation between the dose amount and the maximum recorded concentration of plasma.
The bioavailability of Niacin differs among the several forms it can take. These forms are nicotinic acid, nicotinamide, and any other derivatives that can be converted into nicotinic acid once absorbed in the body. There are some that may argue that the derivatives might not technically be considered niacin, however it really depends on the biological effects the derivatives have after absorption. If the derivatives, such as inositol hexanicotinate, uptake has a similar chemical reaction and affects the metabolism of the organism similar to that of the primary form of niacin, it can be used as evidence to properly identify it as niacin.
When niacin is absorbed as nicotinic acid, it is typically transported through the intestines. Nicotinic acid is absorbed through the intestinal lining and it is described as rapid and nearly total. For example, if there is a large dose of 3 – 4 grams of nicotinic acid, it will be almost completely absorbed by an average, adult body and 30% of the plasma nicotinic acid is bounded to plasma protein (Institute of Medicine, 1998). There is usually a “flushing effect” that occurs when consumption exceeds 50 mg per day.
To avoid the flushing effect, there is now investigations regarding an extended release nicotinic acid that slowly releases nicotinic acid. It is being researched to see if its benefits and efficiency outweigh free flowing nicotinic acid. Extended released forms are being produced using ion exchange methods and using wax materials that melt slowly with body temperature. The extended release time depends on the delivery matrix, and it has been seen thus far that absorption of nicotinic acid is much slower than it free flowing counterpart, however it is still achieve effective levels needed.
The bioavailability of nicotinamide is a little different from nicotinic acid. In 1995, Kim Dragovic conducted an experiment with seven healthy individuals, giving them different doses of nicotinamide that was taken orally. It took about 30 minutes for maximum plasma levels to be reached, seen in most patients after taking 6 grams of nicotinamide. The other dosage levels that patients all could tolerate well were 3, 4, 5, and 6 grams. The final dosage level tested was 10 grams, which was not tolerated as well, however maximum plasma levels were achieved for at least 4 hours straight (Dragovic 1995).
Niacin is best absorbed through food sources such as yeast, meat, poultry, and red fish. It has been seen though that in mature cereal grains, niacin binds to the sugar glucose molecules, therefore decreasing niacin bioavailability.
Niacin in ordinary cereal grains has a relatively low 30% bioavailability that gets absorbed into the body. Bioavailability factors with niacin often affect the metabolism of tryptophan commonly seen in individuals with pellagra. Niacin however has a higher bioavailability in milk, meat, beans, and eggs. Some niacin containing foods, such as corn, contain Vitamin B3 chemically bound to it thus inhibiting its absorption and metabolism throughout digestion. Foods with high concentrations of leucine are also known to disrupt the metabolism of tryptophan followed by the metabolic inhibition of niacin thereafter.1 Niacin can be found in many forms like nicotinic acid that has a very rapid and almost stoichiometric intestinal uptake. Bolus doses of 3-4g nicotinic acid are almost completely absorbed by adults. After absorption in the intestine 15-30% of the nicotinic acid is bounded to proteins. Nicotinamide another form of Niacin, has coenzymes that function at lower levels of niacin intake, around 15–18 mg/day. (Mackay, 2012) At higher levels, over 50 mg/day, niacin intake can have a vasodilative flushing effect. An extended release form of nicotinic acid has been developed as a result of the flushing. The extended release form of nicotinic acid has been under research to explore their potential benefits on serum lipids that usually occurs at much higher levels of intake around 500-3,000 mg/day. Nicotinamide and its coenzymes don’t require much intake because it is readily bioavailable making it also an effective treatment for preventing pellagra. Female college students were administered 51 mg of nicotinamide, of which 52% was excreted as urinary metabolites. Nicotinamide is not sufficiently converted to NA to produce either the undesirable flushing effect or the beneficial changes in plasma lipids. Another form of niacin called inositol hexanicotinate. This chemical compound consists of six nicotinic acid molecules all bonded to an inositol molecule at the center of the structure. Often referred to as “No-Flush Niacin” inositol hexanicotinate also inhibits the flushing affect that most people find unacceptable.2 Inositol hexanicotinate is hydrolyzed at a slow rate throughout the body freeing up the nicotinic acid molecules and the inositol. Its unique properties allow it to be metabolized providing true niacin activity but without the flushing individuals may experience. However there are still a lot of grey areas to be clarified regarding inositol hexanicotinate. Being one of the forms of niacin with the least adverse affects there is still very little data on how well inositol hexanicotinate benefits serum lipids. There is a debate on whether the chemistry behind inositol hexanicotinate is really interchangeable or not. Recent studies on the effects of inositol hexanicotinate on blood lipids have been depicting bioavailability levels for nicotinic acid to be too low to be even considered a form of niacin. (Mackay, 2012) - K.G 2015
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Institute of Medicine (US) Standing Committee on the Scientific Evaluation of Dietary Reference Intakes and its Panel on Folate, Other B Vitamins, and Choline. (1998). 6, Niacin. Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline. Washington (DC): National Academies Press (US). Retrieved from: http://www.ncbi.nlm.nih.gov/books/NBK114304/
MacKay, D., Hathcock, J., and Guarneri, E. (2012). Niacin: chemical forms, bioavailability, and health effects. Nutrition Rev. 70: 357–366. Retrieved from: http://nutritionreviews.oxfordjournals.org/content/nutritionreviews/70/6/357.full.pdf
Council for Responsible Nutrition (CRN). (2013). Niacin: Nicotinic Acid, Nicotinamide, and Inositol Hexanicotinate. Vitamin and Mineral Safety 3rd Edition. Retrieved from: http://www.crnusa.org/safety/updatedpdfs/13-CRNVMS3-NIACIN.pdf