Niacin (Vitamin B-3):
Sources and Physiologic Functions Sources: Niacin is found in unrefined and enriched grain and cereal, milk, and lean meats, especially the liver. Yeast, poultry, saltwater fish, nuts, legumes, coffee, tea, dairy products, and potatoes are good sources of Niacin.
Populations at risk: In alcoholics, deficiency may be caused by decreased intake, reduced absorption, or impaired ability to use the absorbed vitamin. Chronic diarrhea, liver cirrhosis, diabetes mellitus, and malignant disease can result in niacin deficiency. Niacin deficiencies are rare in developed countries, as the body can make niacin from the amino acid tryptophan. However, the antituberculosis drug isoniazid impairs the conversion of tryptophan to niacin and may produce symptoms of niacin deficiency. Patients with Tuberculosis receiving INH therapy should be supplemented with niacin.
Signs and Symptoms of Deficiency: Severe niacin deficiency can result in Pellagra disease. Severe dermatitis and fissured scabs, diarrhea, and mental depression characterize this disease. The condition is associated with “the four Ds”: dermatitis, diarrhea, dementia, and, eventually, death. Another sign of Pellagra is Casal’s collar, which is a rough red dermatitis. Achlorhydria, retarded growth, and pigmentation of the tongue are other symptoms.
Safety: Many clinicians have extensive experience with the use of niacin for the treatment of hyperlipidemia. The adverse events associated with niacin can be divided into the side effects: flushing, diarrhea, indigestion, nausea, and vomiting. The more severe adverse events are hepatotoxicity, exacerbation of gout, and possible worsening of glucose intolerance. There are three available forms of niacin: short-acting or crystalline, intermediate-acting, and long-acting. In general, the flushing and gastrointestinal side effects tend to occur with the short or intermediate-acting conditions at doses as low as 50 to 100mgs and usually resolve with continued use of the drugs. The more severe toxicity is generally seen with the longer-acting conditions in 2-6 gm/day doses. From the clinical trial data, it would appear that an intake of less than 500mg is associated with no identifiable risk.
Toxicity is usually seen in patients treated with high doses of hypercholesterolemia. Hypotension and dermatitis are the most common symptoms. Other symptoms of toxicity include increased pulse and respiratory rate, increased cerebral blood flow, and central nervous system stimulation. Peripheral vasodilation, fatty liver, and decreased serum cholesterol may also be seen.
Biochemistry: The term niacin refers to both nicotinic acid and niacinamide. The biologically active coenzyme forms are niacinamide adenine dinucleotide (NAD+) and its phosphorylated derivative, niacinamide adenine dinucleotide phosphate (NADP+). NAD and NADP are used in the catalysis of oxidation and reduction reactions. The coenzyme functions to accept and donate electrons. NAD is used in energy-producing reactions involving the degradation of carbohydrates, fatty acids, ketone bodies, amino acids, and alcohol. NADP is involved in biosynthetic reactions like the pentose phosphate pathway, fatty acid biosynthesis, cholesterol synthesis, and ribonucleotide reductase. Niacin is also essential for growth, conversion of vitamin A to retinal, and prevention of Pellagra. Nicotinic acid is often used as a vasodilator.
Recommendations: Recommendations: RDA in mg
Infants birth to 6 mos – 5 mg
Infants 6 mos to 1 yr – 9 mg
Children 1 yr to 3 yr – 9 mg
Children 4 yr to 6 yr – 12 mg
Children 7 yr to 10 yr – 13 mg
Adolescent males 11yr to 14 yr – 17 mg
Adolescent females 11 yr to 14 yr – 15 mg
Adolescent males 15 yr to 18 yr – 20 mg
Adolescent females 15 yr to 18 yr – 15 mg
Adult males 19 yr to 50 yr – 19 mg
Adult females 19 yr to 50 yr – 15 mg
Adult males 51 yr plus – 15 mg
Adult females 51 yr plus – 13 mg
Pregnant Women – 17 mg
Lactating Mothers (1st six months) – 20 mg
Lactating Mothers (2nd six months) – 20 mg
Niacin B3
Food Source Serving Size/Amount # of mg/serving
Wheat Flour (whole wheat) 1 cup 7.6 mg
Wheat Flour (white enriched) 1 cup 7.4 mg
Milk 2% fat 8 fl. oz 0.2 mg
Liver (beef braised) 3.5 oz 10.7 mg
Yeast (brewer’s) 1.0 oz 10.7 mg
Turkey (dark meat) 3.5 oz 3.6 mg
Chicken (dark meat) 3.5 oz 1.26 mg
Chicken (light meat) 3.5 oz 1.03 mg
Atlantic cod (raw) 3 oz 1.8 mg
Atlantic salmon (uncooked) 3 oz 6.7 mg
Almonds (lightly roasted) 1 oz 1.0 mg
Literature: Cholesterol:
Niacin is used in the treatment of hypercholesterolemia. The efficacy and safety of lovastatin and niacin were compared in a controlled, randomized, open-label study of a 26-week duration in 136 patients with primary hypercholesterolemia. Lovastatin and niacin both exerted favorable dose-dependent changes on plasma lipids and lipoproteins concentrations. Lovastatin was more effective in reducing LDL cholesterol concentrations, whereas niacin increased high-density lipoprotein cholesterol concentrations and reduced the Lp(a) lipoprotein level. Lovastatin was better tolerated than niacin, in large part because of the common cutaneous side effects of niacin. The dosages used were lovastatin 20mg/d and niacin 1.5 g/d for ten weeks. Similar results were seen in another study where the two drugs reduced low-density lipoprotein-high-density lipoprotein ratios to an equivalent level. However, these effects were obtained differently. In this study, 27 out of 37 patients finished the trial with a dose of 4.5 g/d of nicotinic acid. In another study in renal transplant patients, nicotinic acid significantly reduced the total cholesterol and the low-density lipoprotein cholesterol and significantly increased the high-density lipoprotein cholesterol. The triglyceride level was decreased by about 100 but was not significant (P = 0.09). There were no substantial changes in the lovastatin-treated group’s triglyceride and high-density lipoprotein cholesterol levels. Flushing developed in 67%, but no dropouts were due to side effects.
The long-term safety and efficacy of a new extended-release once-a-night niacin preparation, Niaspan, in the treatment of hypercholesterolemia was determined. Niaspan produced favorable changes in LDL and HDL cholesterol, triglycerides, and lipoprotein(a). Adverse hepatic effects were minor and occurred at rates similar to those reported for statin therapy. Intolerance to flushing, leading to discontinuation of Niaspan, occurred in 4.8% of patients.
In one study conducted on 110 patients seen in a private medical clinic during 5 years, 43% of individuals given regular nicotinic acid and 42% of those shown sustained-release nicotinic acid were forced to discontinue the medication because of side effects. However, some of these side effects necessitating stopping nicotinic acid did not occur until the patient took the drug for 1 or 2 years.
In the Coronary Drug Project, Niacin treatment showed modest benefit in decreasing definite nonfatal recurrent myocardial infarction but did not decrease total mortality. With a mean follow-up of 15 years, nearly nine years after termination of the trial, mortality from all causes in the niacin group was 11% lower than in the placebo group (52.0 versus 58.2%; p = 0.0004). This late benefit of niacin, occurring after discontinuation of the drug, maybe result in a translation into a mortality benefit over subsequent years of the early favorable effect of niacin in decreasing nonfatal reinfarction or a result of the cholesterol-lowering effect of niacin, or both.
Lipoprotein(a)
Seman et al. discussed the importance of treating elevated Lipoprotein (a) levels. Recent data have supported Lp(a) as an independent risk factor for coronary heart disease (CHD). In vitro studies suggest that Lp(a) contributes to atherogenesis directly by cholesterol uptake and indirectly by inhibiting fibrinolysis. A study by the Mayo Clinic demonstrated the association between electrophoretic detection of Lp(a) from fresh plasma and CHD in both men and women, resulting in relative risks for men and women of 1.9 and 1.6, respectively. Framingham Heart Study further supports this. In some studies, Lp(a) is proven to be a risk factor for CHD in men but not in women. In both studies, less than half as many new cases of CHD occurred in women as in men, which may have affected these results. The Scandinavian Simvastatin Survival Study demonstrated that Lp(a) predicted significant coronary events and death in secondary prevention in both simvastatin and in controls. This somewhat contrasts with other studies that suggest that Lp(a) attributes risk only when the LDL cholesterol is high. Angiographic studies also suggest that Lp(a) can predict lumen diameter, but only in the setting of either high LDL cholesterol or low HDL cholesterol. Cross-sectional data on Lp(a) and CHD have provided some insight into the relationship between elevated Lp(a) levels and vascular disease in blacks versus whites, with a positive correlation between Lp(a) and CHD in some black populations.
Lp(a) levels, however, did not seem helpful in predicting post-procedure outcomes. Lp(a) did not predict occlusion over 6 months in high-pressure coronary artery stenting, percutaneous transluminal coronary angioplasty, or over 5 years following coronary artery bypass grafting. Furthermore, a role for accelerating atherogenesis in patients with type 2 diabetes has not been successfully linked to Lp(a).
Mechanisms that are thought to be involved in Lp(a) and CHD include the uptake of Lp(a) by foam cells, selective trapping of Lp(a) by artery wall proteoglycans, and aggregation of LDL with Lp(a). Accelerated atherogenesis involves inhibiting plasmin formation on the endothelial surface: hence, reducing the activation of transforming growth factor may result in the migration and proliferation of smooth muscle cells into the vascular intima. Plasmin suppression may be caused in part by the transcription regulation of plasminogen activator inhibitor-1 by the uptake of Lp(a) and very low-density lipoprotein (VLDL) in the endothelial cells. In addition, Lp(a) induced endothelial dysfunction may promote vascular occlusion.
In patients with CHD or a significant risk for CHD, one should consider measuring Lp(a) and treating with either niacin or estrogen if the patient has Lp(a) cholesterol levels of more than 10 mg/dL or an Lp(a) mass of more than 30 mg/dL.
Diabetes:
Treatment with nicotinamide may prevent or delay the onset of insulin-dependent diabetes mellitus. In a population-based diabetes prevention trial, 20,195 schoolchildren were screened for islet cell antibodies. Risk can be determined by measuring the ratio of antibodies to islet cells (ICA antibody test). Of these, 185 had islet cell antibodies and met the criteria for treatment with nicotinamide. One hundred seventy-three received this treatment. The study population has an average follow-up time of 7.1 years. The incidence of diabetes in children who tested positive for ICA antibodies and who were given niacinamide was reduced by about 60%. Nicotinamide has a protective effect against the development of insulin-dependent diabetes in this setting, but the size of the product has a wide confidence interval. In recent-onset type 1 diabetes, niacinamide may prolong the “honeymoon period.” Another study showed that nicotinamide improves insulin secretion and metabolic control in lean type 2 diabetic patients with secondary failure to sulphonylureas. Nicotinamide improves C-peptide release in type 2 diabetic patients with secondary loss of sulphonylureas, leading to a metabolic control similar to patients treated with insulin.
Peripheral vascular disease:
Several double-blind studies showed that inositol hexaniacinate could improve walking distance in patients with intermittent claudication. In one of the studies, 120 patients received either a placebo or 2 g of inositol hexaniacinate daily. Over 3 months, the inositol hexaniacinate-treated group showed a significant improvement in walking distance.
Raynaud’s disease:
The effects of 4 g/day of Hexopal (Hexanicotinate inositol) or placebo were examined in 23 patients with primary Raynaud’s disease during cold weather. The Hexopal group felt subjectively better and had demonstratively shorter and fewer attacks of vasospasm during the trial period. Serum biochemistry and rheology were not significantly different between the two groups. Although the mechanism of action remains unclear, Hexopal is safe and effectively reduces the vasospasm of primary Raynaud’s disease during the winter months.
Osteoarthritis:
In a double-blind, placebo-controlled study, 72 patients with osteoarthritis were randomized for treatment with niacinamide or an identical placebo for 12 weeks. Niacinamide improved the global impact of osteoarthritis, improved joint flexibility, reduced inflammation, and allowed for a reduction in standard anti-inflammatory medications when compared to placebo. This study indicates that niacinamide may have a role in treating osteoarthritis.
Summary: Vitamin B3 (Niacin) is found in unrefined and enriched grain and cereal, milk, and lean meats, especially the liver. Yeast, poultry, saltwater fish, nuts, legumes, coffee, tea, dairy products, and potatoes are good sources of Niacin. Chronic diarrhea, alcoholism, liver cirrhosis, diabetes mellitus, and malignant disease can result in niacin deficiency. Niacin deficiencies are rare in developed countries, as the body can make niacin. Significant research shows that Niacin can increase HDL levels and reduce LP(a), improving one’s cardiac risk profile. Research shows the benefit of Niacin supplementation has a protective effect against the development of insulin-dependent diabetes (Type I) and, in Type II diabetics, improves C-peptide release in patients with secondary failure of sulphonylureas, leading to a metabolic control similar to patients treated with insulin. Additional research shows potential benefits in treating Raynaud’s disease, peripheral vascular disease, and osteoarthritis.
Hypotension and dermatitis are the most common symptoms of hypervitaminosis. Other symptoms of toxicity include increased pulse and respiratory rate, increased cerebral blood flow, and central nervous system stimulation. Peripheral vasodilation, fatty liver, and decreased serum cholesterol may also be seen.
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