Niacin, also called nicotinic acid, is an natural compound and a type of vitamin B3, a necessary human nutrient.[3] It may be manufactured by crops and animals from the amino acid tryptophan.[4] Niacin is obtained within the food regimen from a wide range of complete and processed meals, with highest contents in fortified packaged meals, meat, poultry, pink fish similar to tuna and salmon, lesser quantities in nuts, legumes and seeds.[3][5] Niacin as a dietary complement is used to deal with pellagra, a illness brought on by niacin deficiency. Indicators and signs of pellagra embody pores and skin and mouth lesions, anemia, complications, and tiredness.[6] Many nations mandate its addition to wheat flour or different meals grains, thereby decreasing the danger of pellagra.[3][7]
The amide spinoff nicotinamide (niacinamide) is a element of the coenzymes nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP+). Though niacin and nicotinamide (niacinamide) are an identical of their vitamin exercise, nicotinamide doesn’t have the identical pharmacological, lipid-modifying results or unintended effects as niacin, i.e., when niacin takes on the -amide group, it doesn’t scale back ldl cholesterol nor trigger flushing.[8][9] Nicotinamide is really helpful as a therapy for niacin deficiency as a result of it may be administered in remedial quantities with out inflicting the flushing, thought of an antagonistic impact.[10]
Niacin can be a prescription medicine.[11] Quantities far in extra of the really helpful dietary consumption for vitamin features will decrease blood triglycerides and low density lipoprotein ldl cholesterol (LDL-C), and lift blood excessive density lipoprotein ldl cholesterol (HDL-C, also known as “good” ldl cholesterol). There are two types: immediate-release and sustained-release niacin. Preliminary prescription quantities are 500 mg/day, elevated over time till a therapeutic impact is achieved. Fast-release doses could be as excessive as 3,000 mg/day; sustained-release as excessive as 2,000 mg/day.[11] Regardless of the confirmed lipid adjustments, niacin has not been discovered helpful for lowering the danger of heart problems in these already on a statin.[12] A 2010 evaluate had concluded that niacin was efficient as a mono-therapy,[13] however a 2017 evaluate incorporating twice as many trials concluded that prescription niacin, whereas affecting lipid ranges, didn’t scale back all-cause mortality, cardiovascular mortality, myocardial infarctions, nor deadly or non-fatal strokes.[14] Prescription niacin was proven to trigger hepatotoxicity[15] and improve danger of sort 2 diabetes.[16][17] Niacin prescriptions within the U.S. had peaked in 2009, at 9.4 million, declining to 1.3 million by 2017.[18]
Niacin has the system C6H5NO2 and belongs to the group of the pyridinecarboxylic acid.[3] Because the precursor for nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP), niacin is concerned in DNA restore.[19]
Contents
Definition[edit]
Niacin is each a vitamin, i.e., a necessary nutrient, marketed as a dietary complement, and within the US, a prescription medication. As a vitamin, it’s precursor of the coenzymes nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP). These compounds are coenzymes for a lot of dehydrogenases, collaborating in lots of hydrogen switch processes. NAD is necessary in catabolism of fats, carbohydrate, protein, and alcohol, in addition to cell signaling and DNA restore, and NADP principally in anabolism reactions similar to fatty acid and ldl cholesterol synthesis.[20] Vitamin consumption suggestions made by a number of nations are that intakes of 14–18 mg/day are enough to fulfill the wants of wholesome adults.[4][21][22] Niacin or nicotinamide (niacinamide) are used for prevention and therapy of pellagra, a illness brought on by lack of the vitamin.[6][20] When niacin is used as a medication to deal with elevated ldl cholesterol and triglycerides, every day doses vary from 500 to three,000 mg/day.[23][24] Excessive-dose nicotinamide doesn’t have this medicinal impact.[20]
Vitamin deficiency[edit]
Extreme deficiency of niacin within the food regimen causes the illness pellagra, characterised by diarrhea, sun-sensitive dermatitis involving hyperpigmentation and thickening of the pores and skin (see picture), irritation of the mouth and tongue, delirium, dementia, and if left untreated, dying.[6] Widespread psychiatric signs embody irritability, poor focus, anxiousness, fatigue, lack of reminiscence, restlessness, apathy, and melancholy.[20] The biochemical mechanism(s) for the noticed deficiency-caused neurodegeneration are usually not nicely understood, however could relaxation on: A) the requirement for nicotinamide adenine dinucleotide (NAD+) to suppress the creation of neurotoxic tryptophan metabolites, B) inhibition of mitochondrial ATP technology, leading to cell harm; C), activation of the poly (ADP-ribose) polymerase (PARP) pathway, as PARP is a nuclear enzyme concerned in DNA restore, however within the absence of NAD+ can result in cell dying; D) decreased synthesis of neuro-protective brain-derived neurotrophic issue or its receptor tropomyosin receptor kinase B; or E) adjustments to genome expression straight as a result of niacin deficiency.[25]
Niacin deficiency isn’t seen in developed nations, and it’s extra usually related to poverty, malnutrition or malnutrition secondary to power alcoholism.[26] It additionally tends to happen in much less developed areas the place individuals eat maize (corn) as a staple meals, as maize is the one grain low in digestible niacin. A cooking method referred to as nixtamalization i.e., pretreating with alkali components, will increase the bioavailability of niacin throughout maize meal/flour manufacturing.[27] For that reason, individuals who eat corn as tortillas or hominy are at much less danger of niacin deficiency.
For treating deficiency, the World Well being Group (WHO) recommends administering niacinamide as an alternative of niacin, to keep away from the flushing facet impact generally brought on by niacin. Pointers counsel utilizing 300 mg/day for 3 to 4 weeks.[10] Dementia and dermatitis present enchancment inside every week. As a result of deficiencies of different B-vitamins could also be current, the WHO recommends a multi-vitamin along with the niacinamide.[10]
Hartnup illness is a hereditary dietary dysfunction leading to niacin deficiency.[28] It’s named after an English household with a genetic dysfunction that resulted in a failure to soak up the important amino acid tryptophan, tryptophan being a precursor for niacin synthesis. The signs are much like pellagra, together with pink, scaly rash and sensitivity to daylight. Oral niacin or niacinamide is given as a therapy for this situation in doses starting from 50 to 100 mg twice a day, with an excellent prognosis if recognized and handled early.[28] Niacin synthesis can be poor in carcinoid syndrome, due to metabolic diversion of its precursor tryptophan to type serotonin.[3]
Measuring vitamin standing[edit]
Plasma concentrations of niacin and niacin metabolites are usually not helpful markers of niacin standing.[4] Urinary excretion of the methylated metabolite N1-methyl-nicotinamide is taken into account dependable and delicate. The measurement requires a 24-hour urine assortment. For adults, a worth of lower than 5.8 μmol/day signify poor niacin standing and 5.8 to 17.5 μmol/day represents low.[4] In accordance with the World Well being Group, another imply of expressing urinary N1-methyl-nicotinamide is as mg/g creatinine in a 24-hour urine assortment, with poor outlined as <0.5, low 0.5-1.59, acceptable 1.6-4.29, and high >4.3[10] Niacin deficiency happens earlier than the indicators and signs of pellagra seem.[4] Erythrocyte nicotinamide adenine dinucleotide (NAD) concentrations probably present one other delicate indicator of niacin depletion, though definitions of poor, low and sufficient haven’t been established. Lastly, plasma tryptophan decreases on a low niacin food regimen as a result of tryptophan converts to niacin. Nevertheless, low tryptophan may be brought on by a food regimen low on this important amino acid, so it isn’t particular to confirming vitamin standing.[4]
Dietary suggestions[edit]
The U.S. Institute of Drugs (renamed Nationwide Academy of Drugs in 2015) up to date Estimated Common Necessities (EARs) and Beneficial Dietary Allowances (RDAs) for niacin in 1998, additionally Tolerable higher consumption ranges (ULs). In lieu of an RDA, Satisfactory Intakes (AIs) are recognized for populations for which there’s not enough proof to determine a dietary consumption degree that’s enough to fulfill the nutrient necessities of most individuals.[31] (see desk).
The European Meals Security Authority (EFSA) refers back to the collective set of knowledge as Dietary Reference Values (DRV), with Inhabitants Reference Consumption (PRI) as an alternative of RDA, and Common Requirement as an alternative of EAR. For the EU, AIs and ULs have the identical definition as within the US, besides that items are milligrams per megajoule (MJ) of power consumed fairly than mg/day. For ladies (together with these pregnant or lactating), males and youngsters the PRI is 1.6 mg per megajoule. Because the conversion is 1 MJ = 239 kcal, an grownup consuming 2390 kilocalories must be consuming 16 mg niacin. That is akin to US RDAs (14 mg/day for grownup girls, 16 mg/day for grownup males).[21]
ULs are established by figuring out quantities of nutritional vitamins and minerals that trigger antagonistic results, after which choosing as an higher restrict quantities which might be the “maximum daily intake unlikely to cause adverse health effects.”[31] Regulatory businesses from totally different nations don’t at all times agree. For the US, 30 or 35 mg for youngsters and adults, much less for youngsters.[4] The EFSA UL for adults is about at 10 mg/day – about one-third of the US worth. For the entire authorities ULs, the time period applies to niacin as a complement consumed as one dose, and is meant as a restrict to keep away from the pores and skin flush response. This explains why for EFSA, the really helpful every day consumption could be larger than the UL.[32]
Each the DRI and DRV describe quantities wanted as niacin equivalents (NE), calculated as 1 mg NE = 1 mg niacin or 60 mg of the important amino acid tryptophan. It’s because the amino acid is utilized to synthesize the vitamin.[4][21]
For U.S. meals and dietary complement labeling functions the quantity in a serving is expressed as a p.c of Every day Worth (%DV). For niacin labeling functions 100% of the Every day Worth is 16 mg. Previous to 27 Might 2016 it was 20 mg, revised to deliver it into settlement with the RDA.[33][34]
Compliance with the up to date labeling rules was required by 1 January 2020 for producers with US$10 million or extra in annual meals gross sales, and by 1 January 2021 for producers with decrease quantity meals gross sales.[35][36] A desk of the outdated and new grownup every day values is supplied at Reference Every day Consumption.
Sources[edit] – “vitamin b3 name”
Niacin is present in a wide range of complete and processed meals, together with fortified packaged meals, meat from varied animal sources, seafoods, and spices.[3][37] Generally, animal-sourced meals present about 5–10 mg niacin per serving, though dairy meals and eggs have little. Some plant-sourced meals similar to nuts and grains present about 2–5 mg niacin per serving, though this naturally current niacin is basically sure to polysaccharides and glycopeptides, making it solely about 30% bioavailable. Fortified meals components similar to wheat flour have niacin added, which is bioavailable.[5] Amongst complete meals sources with the very best niacin content material per 100 grams:
Vegetarian and vegan diets can present sufficient quantities if merchandise similar to dietary yeast, peanuts, peanut butter, tahini, brown rice, mushrooms, avocado and sunflower seeds are included. Fortified meals and dietary dietary supplements may also be consumed to make sure sufficient consumption.[5][40]
Meals preparation[edit]
Niacin naturally present in meals is vulnerable to destruction from excessive warmth cooking, particularly within the presence of acidic meals and sauces. It’s soluble in water, and so may be misplaced from meals boiled in water.[41]
Meals fortification[edit]
International locations fortify meals with vitamins to handle recognized deficiencies.[7] As of 2020, 54 nations required meals fortification of wheat flour with niacin or niacinamide; 14 additionally mandate fortification of maize flour, and 6 mandate fortification of rice.[42] From nation to nation, niacin fortification ranges from 1.3 to six.0 mg/100 g.[42]
As a dietary complement[edit]
In the US, niacin is bought as a non-prescription dietary complement with a spread of 100 to 1000 mg per serving. These merchandise usually have a Construction/Operate well being declare[43] allowed by the US Meals & Drug Administration (FDA). An instance can be “Supports a healthy blood lipid profile.” The American Coronary heart Affiliation strongly advises towards the substitution of dietary complement niacin for prescription niacin due to probably severe unintended effects, which signifies that niacin ought to solely be used below the supervision of a well being care skilled, and since manufacture of dietary complement niacin is just not as well-regulated by the FDA as prescription niacin.[44] Greater than 30 mg niacin consumed as a dietary complement could cause pores and skin flushing. Face, arms and chest pores and skin turns a reddish coloration due to vasodilation of small subcutaneous blood vessels, accompanied by sensations of warmth, tingling and itching. These indicators and signs are usually transient, lasting minutes to hours; they’re thought of disagreeable fairly than poisonous.[5]
As lipid-modifying medicine[edit]
In the US, prescription niacin, in immediate-release and slow-release types, is used to deal with main hyperlipidemia and hypertriglyceridemia.[23][24] It’s used both as a monotherapy or together with different lipid-modifying medicine. Dosages begin at 500 mg/day and are sometimes progressively elevated to as excessive as 3000 mg/day for fast launch or 2000 mg/day for gradual launch (additionally known as sustained launch) to attain the focused lipid adjustments (decrease LDL-C and triglycerides, and better HDL-C).[23][24] Prescriptions within the US peaked in 2009, at 9.4 million and had declined to 1.3 million by 2017.[18] In late 2017, Avondale, having acquired the rights to Niacor from Upsher Smith, raised the value of the drug by greater than 800%.[45]
Systematic opinions discovered no impact of prescription niacin on all-cause mortality, cardiovascular mortality, myocardial infarctions, nor deadly or non-fatal strokes regardless of elevating HDL ldl cholesterol.[12][46] Reported unintended effects embody an elevated danger of new-onset sort 2 diabetes.[14][16][17][47]
Mechanisms[edit]
Niacin reduces synthesis of low-density lipoprotein ldl cholesterol (LDL-C), very low-density lipoprotein ldl cholesterol (VLDL-C), lipoprotein(a) and triglycerides, and will increase high-density lipoprotein ldl cholesterol (HDL-C).[48] The lipid-therapeutic results of niacin are partly mediated by way of the activation of G protein-coupled receptors, together with hydroxycarboxylic acid receptor 2 (HCA2)and hydroxycarboxylic acid receptor 3 (HCA3), that are extremely expressed in physique fats.[49][50] HCA2 and HCA3 inhibit cyclic adenosine monophosphate (cAMP) manufacturing and thus suppress the discharge of free fatty acids (FFAs) from physique fats, decreasing their availability to the liver to synthesize the blood-circulating lipids in query.[51][52][53] A lower in free fatty acids additionally suppresses liver expression of apolipoprotein C3 and PPARg coactivator-1b, thus growing VLDL-C turnover and decreasing its manufacturing.[54] Niacin additionally straight inhibits the motion of diacylglycerol O-acyltransferase 2 (DGAT2) a key enzyme for triglyceride synthesis.[53]
The mechanism behind niacin growing HDL-C is just not completely understood, however appears to happen in varied methods. Niacin will increase apolipoprotein A1 ranges by inhibiting the breakdown of this protein, which is a element of HDL-C.[55][56] It additionally inhibits HDL-C hepatic uptake by suppressing manufacturing of the ldl cholesterol ester switch protein (CETP) gene.[48] It stimulates the ABCA1 transporter in monocytes and macrophages and upregulates peroxisome proliferator-activated receptor gamma, leading to reverse ldl cholesterol transport.[57]
Mixed with statins[edit]
Prolonged launch niacin was mixed with the lovastatin trade-named Advicor, and with simvastatin, trade-named Simcor as prescription drug combos. Advicor was authorised by the U.S. Meals and Drug Administration (FDA) in 2001.[58] Simcor was authorised in 2008.[59] Subsequently, massive end result trials utilizing these niacin and statin therapies have been unable to reveal incremental good thing about niacin past statin remedy alone.[60] The FDA withdrew approval of each medicine in 2016. The explanation given: “Based on the collective evidence from several large cardiovascular outcome trials, the Agency has concluded that the totality of the scientific evidence no longer supports the conclusion that a drug-induced reduction in triglyceride levels and/or increase in HDL-cholesterol levels in statin-treated patients results in a reduction in the risk of cardiovascular events.” The drug firm discontinued the medicine.[61]
Contraindications[edit]
Prescription fast launch (Niacor) and prolonged launch (Niaspan) niacin are contraindicated for individuals with both lively or a previous historical past of liver illness as a result of each, however particularly Niaspan, have been related to situations of significant, now and again deadly, liver failure.[24][62] Each merchandise are contraindicated for individuals with current peptic ulcer illness, or different bleeding issues as a result of niacin lowers platelet rely and interferes with blood clotting.[23][24][62] Each merchandise are additionally contraindicated for girls who’re pregnant or anticipating to turn into pregnant as a result of security throughout being pregnant has not been evaluated in human trials. These merchandise are contraindicated for girls who’re lactating as a result of it’s recognized that niacin is excreted into human milk, however the quantity and potential for antagonistic results within the nursing toddler are usually not recognized. Girls are suggested to both not nurse their youngster or discontinue the drug. Excessive-dose niacin has not been examined or authorised to be used in kids below 16 years.[23][24][62]
Adversarial results[edit]
The most typical antagonistic results of medicinal niacin (500–3000 mg) are flushing (e.g., heat, redness, itching or tingling) of the face, neck and chest, headache, stomach ache, diarrhea, dyspepsia, nausea, vomiting, rhinitis, pruritus and rash.[3][5][62] These could be minimized by initiating remedy at low dosages, growing dosage progressively, and avoiding administration on an empty abdomen.[62]
The acute antagonistic results of high-dose niacin remedy (1–3 grams per day) – which is often used within the therapy of hyperlipidemias – can additional embody hypotension, fatigue, glucose intolerance and insulin resistance, heartburn, blurred or impaired imaginative and prescient, and macular edema.[3][5] With long-term use, the antagonistic results of high-dose niacin remedy (750 mg per day) additionally embody liver failure (related to fatigue, nausea, and lack of urge for food), hepatitis, and acute liver failure;[3][5] these hepatotoxic results of niacin happen extra usually when extended-release dosage types are used.[3][5] The long-term use of niacin at better than or equal to 2 grams per day additionally considerably will increase the danger of cerebral hemorrhage, ischemic stroke, gastrointestinal ulceration and bleeding, diabetes, dyspepsia, and diarrhea.[5]
Flushing[edit]
Flushing – a short-term dilatation of pores and skin arterioles, inflicting reddish pores and skin coloration – normally lasts for about 15 to half-hour, though generally can persist for weeks. Usually, the face is affected, however the response can lengthen to neck and higher chest. The trigger is blood vessel dilation[3][5] as a result of elevation in prostaglandin GD2 (PGD2) and serotonin.[63][64][65][66] Flushing was usually thought to contain histamine, however histamine has been proven to not be concerned within the response.[63] Flushing is usually accompanied by a prickly or itching sensation, particularly, in areas coated by clothes.[5]
Prevention of flushing requires altering or blocking the prostaglandin-mediated pathway.[5][67] Aspirin taken half an hour earlier than the niacin prevents flushing, as does ibuprofen. Taking niacin with meals additionally helps scale back this facet impact.[5] Acquired tolerance will even assist scale back flushing; after a number of weeks of a constant dose, most individuals now not expertise flushing.[5] Sluggish- or “sustained”-release types of niacin have been developed to minimize these unintended effects.[68][69]
Liver harm[edit]
Niacin in medicinal doses could cause modest elevations in serum transaminase and unconjugated bilirubin, each biomarkers of liver damage. The will increase normally resolves even when drug consumption is sustained.[15][70][71] Nevertheless, much less generally, the sustained launch type of the drug can result in severe hepatotoxicity, with onset in days to weeks. Early signs of significant liver harm embody nausea, vomiting and stomach ache, adopted by jaundice and pruritus. The mechanism is regarded as a direct toxicity of elevated serum niacin. Decreasing dose or switching to the fast launch type can resolve signs. In uncommon situations the damage is extreme, and progresses to liver failure.[15]
Diabetes[edit]
The excessive doses of niacin used to deal with hyperlipidemia have been proven to raise fasting blood glucose in individuals with sort 2 diabetes.[16] Lengthy-term niacin remedy was additionally related to a rise within the danger of new-onset sort 2 diabetes.[16][17]
Different antagonistic results[edit]
Excessive doses of niacin may also trigger niacin maculopathy, a thickening of the macula and retina, which results in blurred imaginative and prescient and blindness. This maculopathy is reversible after niacin consumption ceases.[72] Niaspan, the slow-release product, has been related to a discount in platelet content material and a modest improve in prothrombin time.[24]
Pharmacology[edit]
Pharmacodynamics[edit]
Niacin and nicotinamide are each transformed into the coenzyme NAD.[73] NAD converts to NADP by phosphorylation within the presence of the enzyme NAD+ kinase. NAD and NADP are coenzymes for a lot of dehydrogenases, collaborating in lots of hydrogen switch processes.[74] NAD is necessary in catabolism of fats, carbohydrate, protein, and alcohol, in addition to cell signaling and DNA restore, and NADP principally in anabolism reactions similar to fatty acid and ldl cholesterol synthesis.[74] Excessive power necessities (mind) or excessive turnover charge (intestine, pores and skin) organs are normally essentially the most vulnerable to their deficiency.[75]
Activating HCA2 has results aside from decreasing serum ldl cholesterol and triglyceride concentrations: antioxidative, anti-inflammatory, antithrombotic, improved endothelial perform and plaque stability, all of which counter improvement and development of atherosclerosis.[76][77]
Niacin inhibits cytochrome P450 enzymes CYP2E1, CYP2D6 and CYP3A4.[78] Niacin produces an increase in serum unconjugated bilirubin in regular people and in these with Gilbert’s Syndrome. Nevertheless, within the Gilbert’s Syndrome, the rise in bilirubin is larger and clearance is delayed longer than in regular individuals.[79] One check used to assist in diagnosing Gilbert’s Syndrome includes intravenous administration of nicotinic acid (niacin) in a dose of fifty mg over a interval of 30 seconds.[70][71]
Pharmacokinetics[edit]
Each niacin and niacinamide are quickly absorbed from the abdomen and small gut. Absorption is facilitated by sodium-dependent diffusion, and at larger intakes, by way of passive diffusion. In contrast to another nutritional vitamins, the p.c absorbed doesn’t lower with growing dose, in order that even at quantities of 3-4 grams, absorption is almost full.[20] With a one gram dose, peak plasma concentrations of 15 to 30 μg/mL are reached inside 30 to 60 minutes. Roughly 88% of an oral pharmacologic dose is eradicated by the kidneys as unchanged niacin or nicotinuric acid, its main metabolite. The plasma elimination half-life of niacin ranges from 20 to 45 minutes.[23]
Niacinamide is the most important type within the bloodstream. Within the liver, niacinamide is transformed to storage nicotinamide adenine dinucleotide (NAD). As wanted, liver NAD is hydrolyzed to niacinamide and niacin for transport to tissues, there reconverted to NAD to function an enzyme cofactor.[20] Extra niacin is methylated within the liver to N1-methylnicotinamide (NMN) and excreted in urine as such or because the oxidized metabolite N1-methyl-2-pyridone-5-carboxamide (2-pyridone). Decreased urinary content material of those metabolites is a measure of niacin deficiency.[20]