CKD

The science behind the CKD is simple. Carbohydrates in the diet cause an insulin (a "storage" hormone) output in the pancreas. It is used to store glycogen, amino acids into muscles, while causing excess calories to be stored as fat. So common sense asks me, "How can one try to break down fat, when your body is in a storage-type mode?" Difficult to do, indeed. That is why it makes perfect sense for step one to be cutting carbs.

The next thing that happens in your body is the rise in catecholamines (a "fat mobilizing" hormone), cortisol (a "breakdown" hormone), and growth hormone. Now your body realizes there’s no more carbs to burn for energy, so it must find another energy source: fat.

This usually happens during a metabolic condition called "ketosis." This is when your liver is out of glycogen and starts to produce ketones (by-products of fatty acids). You can check your status of whether or not you are in ketosis with urinalysis strips you can pick up at any local drug store called "Ketostix." Just urinate and see if it turns color. If so, you have ketones in the urine.

When the body is fed fat and protein, it will use dietary fat along with bodyfat for energy with protein going towards repair.

As a side note, there is another reason why this diet makes the most sense to use while keeping muscle. When one follows a high carbohydrate, low-fat, reduced-calorie diet, there’s a point when some bodyfat is burned, but when the body is still in a carbohydrate burning metabolism while trying to lose "weight," it will strip down precious body protein to convert to glucose for energy.

On the other hand, during fat metabolism, protein cannot be converted into free-fatty acids for energy. Although there is no scientific research done on this, there have been reports from followers that there truly is a "protein-sparing" effect. It makes sense doesn’t it? Where else would the body look for fat energy when all dietary fat is burned? Bodyfat.

Diet Requirements Mon. to Fri.

The phrase "working smarter, not harder" applies here more than any diet one has tried. One must fully understand what they must do in order to optimize their goal. To set a CKD up, one cannot just expect to cut all carbs in the diet, train hard, and lose fat! Although some have come up with variations to this plan, the one stated in this article, I have found, has worked for myself (it got me to 6% BF), and other clients I’ve trained to the leanest, hardest they’ve ever been.

First, to set up the diet, write down your lean mass weight. Not your total weight, dough boy. If you weigh 200, but have 20% bodyfat, your lean mass weight would be around 160 pounds. Multiply this by one, getting your grams of protein requirements for a day. Make sure you eat at least one gram of protein/pound of lean mass! This is important in recovery from workouts and enough nitrogen retention to keep muscle. Next, multiply by four, to get your protein calories. Here, it is 640.

The rest of your caloric requirements for the day should be fat. Here is the catch: you must eat fat to burn fat. There’s no way around it. There are many advantages to dietary fat on this diet: Feeling of fullness since fat digestion is slow (less hunger), tastes great, and lowers blood glucose levels (lowering insulin and allow all the fat burning hormones to do their job).

So how much fat? I always recommend starting out with a 500 calorie deficit from your maintenance calories. If you don’t know, it is usually 15 times body weight (full body weight here) depending on an individuals metabolic rate. So here, the example would need 3000 calories a day to maintain weight, and 2500 calories to begin fat loss.

2500 minus 640 (protein calories) is 1860 which works out to be around 206 fat grams a day. Now as you go deeper into the diet, and find the need to restrict calories more, you must cut fat calories, not protein.

The Weekend Carb Load

Since muscle glycogen is the main source of energy for anaerobic exercise such as weight training, we cannot simply deplete all stores while working out and not fill them back up. If that does happen, be rest-assured that the body WILL use protein for fuel then. But this won’t happen on the CKD.

Your one and a half days of "freedom" allow you to do two things: First, reward your carb cravings from the previous days, allowing you to enjoy pleasures like pizza, pasta, breads, etc. Second, eating these things are physiologically rewarding as insulin levels run high, storing amino acids and carbs, as glycogen, into the depleted muscle allowing you to be able to workout again the following week.

Your "carb-up" should begin Friday night and last until around midnight Saturday. Now the next important issue to address is how many carbs. Some lucky individuals find that they eat whatever they want for the 24-30 hour time interval and receive perfect glycogen compensation, while others rely on a better statistical number.

What has been recommended by other authors of the CKD is 10-12 grams of carbs per kilogram of lean mass. Again, time to do math. Our example had 160 pounds of lean mass, so divide that by the conversion factor of 2.2, and we get roughly 73 kg.

100 Grams of easily digested liquid carbs along with around half as many grams of carbs in protein (here 50) as a whey shake or something of that nature should be taken right after the last workout (which I will address in the workout section of the article) when insulin sensitivity will be at its greatest.

A few hours later this individual will start to spread the remaining 630 grams of carbs, along with the important number of 160 grams of protein (remember, keep this constant) during the remainder of the compensation period.

So what about dietary fat? I know you’re reminding yourself, "Didn’t this guy mention pizza?" Yes, I did. And here’s why. During the first 24-30 hours of carbing up, the body will use all dietary carbohydrates to refill glycogen, protein for rebuilding, and get this: fat for energy. Still?

Just like the previous five and a half days. Makes sense. When all the carbohydrates are being used for more important functions (muscle), what else is there to be used? However, you can’t just eat all the fat you want. Keep grams of fat intake below your body weight in kilograms. Again, here our example will keep is fat below 73 during the carb-fest.

By anecdotal reports, this should keep fat regain minimal to nil. Keeping fat intake extremely low has even caused some extra fat burning during the carb up!

As stated before, some dietary fat should be eaten to slow digestion and keep sugar levels stable. Whether it be saturated, unsaturated, or essential fats, is the dieter’s decision. All have nine calories per gram. (Note: there is a claim that essential fatty acids such as flax seed oil increase insulin sensitivity within the muscle cells, in turn, increasing glycogen intake.)

In Case You Missed It

So here’s how it breaks down during the week: Sunday through Friday afternoon , you will follow the low carb diet outlined above. Eat fat and protein all day everyday except on workout days because after workouts, you will need to consume strictly just protein—no fat or carbs.

Some have found to enjoy a protein shake afterwards because they are easily digested. Do whatever works for you. But fat is not logical since you want the protein to fuel the healing process as quickly as possible and fat will only slow it down.

Friday afternoon, around two hours before your last workout of the week, eat two to three pieces of fruit. This will get your body/liver ready to start the carb loading and give you some energy for that final, dreadful workout (trust me, during the first few weeks, you will not want to do that final workout, but you must). Then from Friday night until Saturday at midnight or until bed, eat those carbs!

CKD Workout

Now, the question is, how do we workout to optimize muscle preservation and keep our metabolism up while dieting? Before we get into that, one must realize that during any dieting scheme there is one thing that must be done, and one thing that must not be done.

First, you must keep training volume lower than your usual routine. Overtraining is probably the number one killer in motivation, it deprives sleep, and hinders fat loss.

Second, you must not fall into the myth of lighter weights with higher reps. You got your muscle by benching 240, and you have to bench 240 to keep that same muscle! Or at least around that area! Okay, now that we have that established, here’s what we do:

On Monday and Tuesday we will work our weaker body parts, rest or cardio on Wednesday and Thursday mornings, Thursday do our strongest body parts, and Friday a combination of the Monday/Tuesday workouts in a loop format. The workout I have found to work optimally for myself and my clients is this:

(Note: You may feel free to tweak, shake, and turn this example upside down.

Everybody is different, so find what works for you.)

MONDAY: Chest, Back, Abs

High intensity workouts with 60 sec rest between sets, 90 sec rest between

each exercise

(this excludes all warm up sets)

Bench 3 sets, 6-10 reps

T-bar Row 3 sets, 6-10 reps

Incline bench 3 sets, 6-10 reps

Latpulldown to front 3 sets, 6-10 reps

Dips or Decline bench 3 sets, 6-10 reps

Shrugs 3 sets, 6-10 reps

Flys (any type) 2 sets, 10-12 reps

Reverse flys 2 sets, 10-12 reps

Stiff-leg deadlift 3 sets, 10-12 reps

Rope ab crunch 3 sets, 10-15 reps

Reverse crunch 3 sets, 10-20 reps

TUESDAY: Shoulders, Arms

Same intensity mentioned before

Behind the neck shoulder press 3 sets, 8-10 reps

Military press 3 sets, 8-10 reps

Preacher curls 3 sets, 8-10 reps

French press or "skull-crushers" 3 sets, 8-10 reps

Shoulder raises (any type) 2 sets, 8-10 reps

Hammers 3 sets, 8-10 reps

V-bar tricep press 3 sets, 8-10 reps

Forearm curls 2 sets, 8-10 reps

Reverse forearm curls 2 sets, 8-10 reps

Wednesday: Rest or Cardio

Thursday morning: Rest or Cardio

Later on Thursday: Legs

Same intensity mentioned before

Squat or Leg press 4 sets, 6-10 reps

Lying leg curl 4 sets, 6-10 reps

Standing calf raise 4 sets 6-10 reps

Leg extensions 4 sets, 10-12 reps

Seated leg curl 4 sets, 10-12 reps

Seated calf raise 4 sets, 10-12 reps

Friday night: Final Workout

Same intensity mentioned before

Bench 2 sets, 6-10 reps

T-bar Row 2 sets, 6-10 reps

Incline bench 2 sets, 6-10 reps

Latpulldown to front 2 sets, 6-10 reps

Behind the neck shoulder press 1 set, 8-10 reps

Military press 1 set, 8-10 reps

Either curl exercise 2 sets, 8-10 reps

Either tricep exercise 2 sets, 8-10 reps

Stiffleg deadift 1 set, 8-10 reps

Normal floor ab crunch 2 sets, 10-20 reps

Reverse crunches 2 sets, 10-20 reps

Start the carb up for 24-30 hours!


Aerobics

Before we go on, I want to address the cardio/aerobics issue. Some people find that for the first month on a CKD, cardio/aerobics is not needed. However when fat loss does start to slow down a bit, that is when most start adding 30 min. sessions on their off days. Be careful though, you do not want to hinder your Thursday leg workout. So experiment and try to only add aerobic sessions if you feel you have to.

Supplements

So we have the basic diet outline stated, the workout, now what about supplements? Things that can extremely optimize this diet regime. Well, I have to admit no allegiance to any supplement company on this one: Water. Water is important on any diet, especially low carb since there is a diuretic effect, and more importantly during the carbing period. Glycogen is stored with water! You need as much water as possible to hydrate the depleted muscle. Trust me, you will feel a huge "pump" on Sunday morning from all the stored carbs and water INSIDE your muscle.

Speaking of muscle, the god of all sports supplement right now: Creatine. It can still be used on a low carb diet. Usually 10 grams a day during the low carb days, and around 20-30 grams during the carbing period should work for most everybody. I highly recommend it for everybody who doesn’t get an upset stomach using it.

Finally, one that everyone that’s dieted before knows about: The ECA stack. Most have not used pure ECA, but mainly herbal extracts in thermogenic products sold by sports supplement companies. For a pre-work out boost and increased fat burning through thermogenics (heat), this is my favorite supplement. It does its job, you feel it happening, and it can help you psychologically when you don’t feel like working out that day.

Conclusion

With all this said, I will throw my personal opinion, thanks and motivation on or for the cyclical ketogenic diet. First of all, to me, it is the greatest diet every developed. It makes sense, works and isn’t as hard to follow as one might think. Just stay motivated and concentrate on your goal.

When you have a craving during the week for that cupcake or pasta, just go eat a delicious serving of some pepperoni and melted mozzarella cheese. Or how about a hamburger patty covered in cheddar cheese and some strips of bacon? Foods that are delicious and that can satiate hunger.

I followed this exact plan this past summer for eight weeks and loss 18 pounds of fat without any loss in muscle. It was the leanest and most vascular I had ever seen myself.

And I must give thanks where thanks are due since I did not come up with this diet. Dan Duchaine, who recently passed away, brought my attention to a CKD with his book BodyOpus and Lyle McDonald has done deep research and wrote his book The Ketogenic Diet: A Complete Guide for the Dieter and Practitioner.

This diet can be for you. Oh you’re only a mass builder? Well, lower bodyfat percentages even make you look bigger! Give it some thought and decide. Then achieve your goal. It’s worth it: A diet with true fat loss.

What are Ketoacidosis?

Ketoacidosis is a type of metabolic acidosis which is caused by high concentrations of ketone bodies, formed by the deamination of amino acids, and the breakdown of fatty acids. This is most common in untreated type 1 diabetes mellitus, when the liver breaks down fat and proteins in response to a perceived need for respiratory substrate. It can also occur with people undergoing hunger strikes, fasting over 3 days, or people starving to death as the body is forced to break down fat for sustenance due to their lack of outside nutrition.

Ketoacidosis should not be confused with ketosis, which is one of the body's normal processes for the metabolism of body fat. In ketoacidosis, the accumulation of keto acids is so severe that the pH of the blood is substantially decreased.

Metabolic Pathway

Most medical resources regard ketosis as a physiological state associated with chronic starvation. Glucose is regarded as the preferred energy source for all cells in the body with ketosis being regarded as a crisis reaction of the body to a lack of carbohydrates in the diet. In recent years this viewpoint, both the body's preference for glucose and the dangers associated with ketosis, has been challenged by some doctors.

Ketone bodies, from the breakdown of fatty acids to acetyl groups, are also produced during this state, and are burned throughout the body. Excess ketone bodies will slowly decarboxylate into acetone. That molecule is excreted in the breath and urine. When glycogen stores are not available in the cells (glycogen is primarily created when carbohydrates such as starch and sugar are consumed in the diet), fat (triacylglycerol) is cleaved to give 3 fatty acid chains and 1 glycerol molecule in a process called lipolysis. Most of the body is able to utilize fatty acids as an alternative source of energy in a process where fatty acid chains are cleaved to form acetyl-CoA, which can then be fed into the Krebs Cycle. During this process a high concentration of glucagon is present in the serum and this inactivates hexokinase and phosphofructokinase-1 (regulators of glycolysis) indirectly, causing most cells in the body to use fatty acids as their primary energy source. At the same time, glucose is synthesized in the liver from lactic acid, glucogenic amino acids, and glycerol, in a process called gluconeogenesis. This glucose is used exclusively for energy by cells such as neurons and red blood cells.

What is Ketosis?

Ketosis (pronounced /kiːˈtoʊsɪs/) is a stage in metabolism occurring when the liver converts fat into fatty acids and ketone bodies which can be used by the body for energy. It was identified by Dr. Stephen Moody in 1969.
Adipose tissue consists of highly specialized cells which store energy in the form of a triglyceride and release it upon hydrolysis in a process known as lipolysis, yielding three fatty acids and one glycerol molecule. Ketoacidosis is the accumulation of excessive keto acids in the blood stream (specifically acetoacetate and beta-hydroxy butyrate), these ketone bodies are a by-product of the lipid metabolic pathway after the fat is converted to energy.

Potassium

Potassium is an essential dietary mineral that is also known as an electrolyte. The term electrolyte refers to a substance that dissociates into ions (charged particles) in solution making it capable of conducting electricity. The normal functioning of our bodies depends on the tight regulation of potassium concentrations both inside and outside of cells.

Function

Maintenance of membrane potential

Potassium is the principal positively charged ion (cation) in the fluid inside of cells, while sodium is the principal cation in the fluid outside of cells. Potassium concentrations are about 30 times higher inside than outside cells, while sodium concentrations are more than 10 times lower inside than outside cells. The concentration differences between potassium and sodium across cell membranes create an electrochemical gradient known as the membrane potential. A cell's membrane potential is maintained by ion pumps in the cell membrane, especially the sodium, potassium-ATPase pumps. These pumps use ATP (energy) to pump sodium out of the cell in exchange for potassium (diagram). Their activity has been estimated to account for 20%-40% of the resting energy expenditure in a typical adult. The large proportion of energy dedicated to maintaining sodium/potassium concentration gradients emphasizes the importance of this function in sustaining life. Tight control of cell membrane potential is critical for nerve impulse transmission, muscle contraction, and heart function.

Cofactor for enzymes

A limited number of enzymes require the presence of potassium for their activity. The activation of sodium, potassium-ATPase requires the presence of sodium and potassium. The presence of potassium is also required for the activity of pyruvate kinase, an important enzyme in carbohydrate metabolism.

Deficiency

An abnormally low plasma potassium concentration is referred to as hypokalemia. Hypokalemia is most commonly a result of excessive loss of potassium, e.g., from prolonged vomiting, the use of some diuretics, some forms of kidney disease, or disturbances of metabolism. The symptoms of hypokalemia are related to alterations in membrane potential and cellular metabolism. They include fatigue, muscle weakness and cramps, and intestinal paralysis, which may lead to bloating, constipation, and abdominal pain. Severe hypokalemia may result in muscular paralysis or abnormal heart rhythms (cardiac arrhythmias) that can be fatal.

Conditions that increase the risk of hypokalemia

    * The use of potassium-wasting diuretics (e.g., thiazide diuretics or furosemide)
    * Alcoholism
    * Severe vomiting or diarrhea
    * Overuse or abuse of laxatives
    * Anorexia nervosa or bulimia
    * Magnesium depletion
    * Congestive heart failure (CHF)

In rare cases, habitual consumption of large amounts of black licorice has resulted in hypokalemia. Licorice contains a compound (glycyrrhizic acid) with similar physiologic effects to those of aldosterone, a hormone that increases urinary excretion of potassium. Low dietary intakes of potassium do not generally result in hypokalemia. However, recent research indicates that insufficient dietary potassium increases the risk of a number of chronic diseases (see Disease Prevention).

Adequate Intake (AI)

In 2004, the Food and Nutrition Board of the Institute of Medicine established an adequate intake level (AI) for potassium based on intake levels that have been found to lower blood pressure, reduce salt sensitivity, and minimize the risk of kidney stones.

Disease Prevention

The diets of western industrialized cultures are quite different from those of prehistoric cultures and the few remaining isolated primitive cultures. Among other differences, the daily intake of sodium chloride (salt) in western industrialized cultures is about 3 times higher than the daily intake of potassium on a molar basis, while salt intakes in primitive cultures are about 7 times lower than potassium intakes. The relative deficiency of dietary potassium in the modern diet may play a role in the pathology of some chronic diseases.

Stroke

Several large epidemiological studies have suggested that increased potassium intake is associated with decreased risk of stroke. A prospective study of more than 43,000 men followed for 8 years found that men in the top quintile (1/5)of dietary potassium intake (averaging 4,300 mg/day) were only 62% as likely to have a stroke than those in the lowest quintile of potassium intake (averaging 2,400 mg/day). The inverse association was especially high in men with hypertension. However, a similar prospective study of more than 85,000 women followed for 14 years found a much more modest association between potassium intake and the risk of stroke. Another large study that followed more than 9,000 people for an average of 16 years found that potassium intake was inversely related to stroke only in black men and men with hypertension. However, black men and women reported significantly lower potassium intakes than white men and women (1,606 mg/day vs. 2,178 mg/day). More recent data from the same population indicates that those with potassium intakes higher than 1,352 mg/day were only 72% as likely to have a stroke as those with potassium intakes lower than 1,352 mg/day. Taken together, the epidemiological data suggest that a modest increase in fruit and vegetable intake (rich sources of dietary potassium), especially in those with hypertension and/or relatively low potassium intakes, could significantly reduce the risk of stroke.

Osteoporosis

Four cross-sectional studies have reported significant positive associations between dietary potassium intake and bone mineral density (BMD) in populations of premenopausal, perimenopausal, and postmenopausal women and elderly men. The average dietary potassium intakes of the study participants ranged from about 3,000 to 3,400 mg/day, while the highest potassium intakes exceeded 6,000 mg/day and the lowest intakes ranged from 1,400 to 1,600 mg/day. In all of these studies, BMD was also positively and significantly associated with fruit and vegetable intake. The only study to examine changes in BMD over time found that higher dietary potassium intakes (and fruit and vegetable intakes) were associated with significantly less decline in BMD at the hip in men, but not in women over a period of four years. Potassium-rich foods, such as fruits and vegetables are also rich in precursors to bicarbonate ions, which serve to buffer acids in the body. The modern western diet tends to be relatively low in sources of alkalai (fruits and vegetables) and high in sources of acid (fish, meats, cheeses). When the quantity of bicarbonate ions is insufficient to maintain normal pH, the body is capable of mobilizing alkaline calcium salts from bone in order to neutralize acids consumed in the diet and generated by metabolism (14). Increased consumption of fruits and vegetables reduces the net acid content of the diet and may preserve calcium in bones, which might otherwise be mobilized to maintain normal pH. Support for this theory was provided by a study of 18 postmenopausal women, which found that potassium bicarbonate supplementation decreased urinary acid and calcium excretion, while increasing biomarkers of bone formation and decreasing biomarkers of bone resorption.

Kidney stones

Abnormally high urinary calcium (hypercalciuria) increases the risk of developing kidney stones. In individuals with a history of developing calcium-containing kidney stones, increased dietary acid load was significantly associated with increased urinary calcium excretion. Increasing dietary potassium (and alkalai) intake by increasing fruit and vegetable intake or by taking potassium bicarbonate supplements has been found to decrease urinary calcium excretion. Additionally, potassium deprivation has been found to increase urinary calcium excretion. A large prospective study of more than 45,000 men followed for 4 years found that men whose potassium intake averaged more than 4,042 mg/day were only half as likely to develop symptomatic kidney stones as men whose intake averaged less than 2,895 mg per day. A similar study that followed more than 90,000 women over a period of 12 years found that women in the highest quintile of potassium intake (averaging 3,458 mg/day) were only 65% as likely to develop symptomatic kidney stones as women in the lowest quintile of potassium intake (averaging 2,703 mg/day). In both these prospective studies, dietary potassium intake was derived almost entirely from potassium-rich foods, such as fruits and vegetables.

Disease Treatment

High blood pressure (hypertension)

A number of studies indicate that groups with relatively high dietary potassium intakes have lower blood pressures than comparable groups with relatively low potassium intakes. Data on more than 17,000 adults who participated in the Third National Health and Nutritional Examination Survey (NHANES III) indicated that higher dietary potassium intakes were associated with significantly lower blood pressures. The results of the Dietary Approaches to Stop Hypertension (DASH) trial provided further support for the beneficial effects of a potassium-rich diet on blood pressure. Compared to a control diet providing only 3.5 servings/day of fruits and vegetables and 1,700 mg/day of potassium, consumption of a diet that included 8.5 servings/day of fruits and vegetables and provided 4,100 mg/day of potassium lowered blood pressure by an average of 2.8/1.1 mm Hg (systolic BP/diastolic BP) in people with normal blood pressure and by an average of 7.2/2.8 mm Hg in people with hypertension. Increasing dietary calcium intake by 800 mg/day in the DASH trial lowered systolic and diastolic BP still further (see Calcium). More information about the DASH diet is available from the National Institutes of Health (NIH) Web site.

 In 1997, a meta-analysis of 33 randomized controlled trials including 2,609 individuals assessed the effects of increased potassium intake, mostly in the form of potassium chloride (KCl) supplements, on blood pressure. Increased potassium intake (2,300-3,900 mg/day) resulted in slight but significant blood pressure reductions that averaged 1.8/1.0 mm Hg in people with normal blood pressure and 4.4/2.5 mm Hg in people with hypertension. Subgroup analysis indicated that the blood pressure-lowering effect of potassium was more pronounced in individuals with higher salt intakes and in trials where black individuals were a majority of the participants. A recent clinical trial in 150 Chinese men and women with borderline to mild hypertension found that moderate supplementation with 500 mg/day of potassium chloride for 12 weeks resulted in a significant 5 mm Hg reduction in systolic BP but not diastolic BP compared to placebo. Like many Western diets, the customary diet of this population was high in sodium and low in potassium.

Sources

Food sources

The richest sources of potassium are fruits and vegetables. People who eat large amounts of fruits and vegetables have a high potassium intake (8-11 grams/day). A recent dietary survey in the U.S. indicated that the average dietary potassium intake is about 2,300 mg/day for adult women and 3,100 mg/day for adult men. The potassium content of some relatively potassium-rich foods is listed in milligrams (mg) in the table below. For more information on the nutrient content of foods you eat frequently, search the USDA food composition database.

 

Supplements

Multivitamin/mineral supplements in the U.S. do not contain more than 99 mg of potassium per serving. Higher doses of supplemental potassium are generally prescribed to prevent and treat potassium depletion and hypokalemia. The use of more potent potassium supplements in potassium deficiency requires close monitoring of serum potassium concentrations. Potassium supplements are available as a number of different salts, including potassium chloride, citrate, gluconate, bicarbonate, aspartate and orotate. Because of the potential for serious side effects the decision to use a potent potassium supplement should be made in collaboration with one's health care provider (see Safety).

Safety

Toxicity (excess)

Abnormally elevated serum potassium concentrations are referred to as hyperkalemia. Hyperkalemia occurrs when potassium intake exceeds the capacity of the kidneys to eliminate it. Acute or chronic renal (kidney) failure, the use of potassium-sparing diuretics, and insufficient aldosterone secretion (hypoaldosteronism) may result in the accumulation of excess potassium due to decreased urinary potassium excretion. Oral doses greater than 18 grams taken at one time in individuals not accustomed to high intakes may lead to severe hyperkalemia, even in those with normal kidney function. Hyperkalemia may also result from a shift of intracellular potassium into the circulation, which may occur with the rupture of red blood cells (hemolysis) or tissue damage (e.g., trauma or severe burns). Symptoms of hyperkalemia may include tingling of the hands and feet, muscular weakness, and temporary paralysis. The most serious complication of hyperkalemia is the development of an abnormal heart rhythm (cardiac arrhythmia), which can lead to cardiac arrest. See Drug interactions for a discussion of the medications that increase the risk of hyperkalemia.

Adverse reactions to potassium supplements

Gastrointestinal symptoms are the most common side effects of potassium supplements, including nausea, vomiting, abdominal discomfort, and diarrhea. Intestinal ulceration has been reported after the use of enteric-coated potassium chloride tablets. Taking potassium with meals or taking a microencapsulated form of potassium may reduce gastrointestinal side effects. The most serious adverse reaction to potassium supplementation is hyperkalemia (see Toxicity). Individuals with abnormal kidney function and those on potassium-sparing medications (see Drug interactions) should be monitored closely to prevent hyperkalemia.

Linus Pauling Institute Recommendation

There is considerable evidence that a diet supplying at least 4.7 grams/day of potassium is associated with decreased risk of stroke, hypertension, osteoporosis, and kidney stones. Fruits and vegetables are among the richest sources of dietary potassium, and a large body of evidence supports the association of increased fruit and vegetable intakes with reduced risk of chronic disease. Consequently, the Linus Pauling Institute recommends increasing potassium intake to at least 4.7 grams/day by increasing consumption of potassium-rich foods, especially fruits, vegetables, and nuts.

Adults over the age of 65

A diet supplying at least 4.7 grams/day of potassium is also appropriate for healthy older adults since such diets are associated with decreased risk of stroke, hypertension, osteoporosis, and kidney stones. This recommendation does not apply to individuals who have been advised to limit potassium consumption by a health care professional.

References: http://lpi.oregonstate.edu/infocenter/minerals/potassium/

Pantothenic Acid

Pantothenic acid, also known as vitamin B5, is essential to all forms of life (1). Pantothenic acid is found throughout living cells in the form of coenzyme A (CoA), a vital coenzyme in numerous chemical reactions.

Function

Coenzyme A

Pantothenic acid is a component of coenzyme A (CoA), an essential coenzyme in a variety of reactions that sustain life. CoA is required for chemical reactions that generate energy from food (fat, carbohydrates, and proteins). The synthesis of essential fats, cholesterol, and steroid hormones requires CoA, as does the synthesis of the neurotransmitter, acetylcholine, and the hormone, melatonin. Heme, a component of hemoglobin, requires a CoA-containing compound for its synthesis. Metabolism of a number of drugs and toxins by the liver requires CoA.

Coenzyme A was named for its role in acetylation reactions. Most acetylated proteins in the body have been modified by the addition of an acetate group that was donated by CoA. Protein acetylation affects the 3-dimensional structure of proteins, potentially altering their function, the activity of peptide hormones, and appears to play a role in cell division and DNA replication. Protein acetylation also affects gene expression by facilitating the transcription of mRNA. A number of proteins are also modified by the attachment of long-chain fatty acids donated by CoA. These modifications are known as protein acylation, and appear to play a central role in cell signaling.

Acyl-carrier protein

The acyl-carrier protein requires pantothenic acid in the form of 4'-phosphopantetheine for its activity as an enzyme. Both CoA and the acyl-carrier protein are required for the synthesis of fatty acids. Fatty acids are a component of some lipids, which are fat molecules essential for normal physiological function. Among these essential fats are sphingolipids, which are a component of the myelin sheath that enhances nerve transmission, and phospholipids in cell membranes.

Deficiency

Naturally occurring pantothenic acid deficiency in humans is very rare and has been observed only in cases of severe malnutrition. World War II prisoners in the Phillipines, Burma, and Japan experienced numbness and painful burning and tingling in their feet, which was relieved specifically by pantothenic acid. Pantothenic acid deficiency in humans has been induced experimentally by administering a pantothenic acid antagonist together with a pantothenic acid deficient diet. Participants in this experiment complained of headache, fatigue, insomnia, intestinal disturbances, and numbness and tingling of their hands and feet. In a more recent study, participants fed only a pantothenic acid free diet did not develop clinical signs of deficiency, though some appeared listless and complained of fatigue. Homopantothenate is a pantothenic acid antagonist with cholinergic effects (similar to those of the neurotransmitter, acetylcholine). It was used in Japan to enhance mental function, especially in Alzheimer's disease. A rare side effect was the development of hepatic encephalopathy, a condition of abnormal brain function resulting from the failure of the liver to eliminate toxins. The encephalopathy was reversed by pantothenic acid supplementation suggesting, but not proving, it was due to pantothenic acid deficiency caused by the antagonist.

Because it is so rare, most information regarding the effects of pantothenic acid deficiency comes from experimental research in animals. The diversity of symptoms emphasizes the numerous functions of pantothenic acid in its coenzyme forms. Pantothenic acid deficient rats developed damage to the adrenal glands, while monkeys developed anemia due to decreased synthesis of heme, a component of hemoglobin. Dogs with pantothenic acid deficiency developed low blood glucose, rapid breathing and heart rates, and convulsions. Chickens developed skin irritation, feather abnormalities, and spinal nerve damage associated with the degeneration of the myelin sheath. Pantothenic acid deficient mice showed decreased exercise tolerance and diminished storage of glucose (in the form of glycogen) in muscle and liver. Mice also developed skin irritation and graying of the fur, which was reversed by giving pantothenic acid. This finding led to the idea of adding pantothenic acid to shampoo, although it has not been successful in restoring hair color in humans.

The Adequate Intake (AI)

The Food and Nutrition Board of the Institute of Medicine felt the existing scientific evidence was insufficient to calculate an RDA for pantothenic acid, so they set an adequate intake level (AI). The AI for pantothenic acid was based on estimated dietary intakes in healthy population groups.

Disease Treatment

Wound healing

Administration of pantothenic acid orally and application of pantothenol ointment to the skin have been shown to accelerate the closure of skin wounds and increase the strength of scar tissue in animals. Adding calcium-D-pantothenate to cultured human skin cells given an artificial wound increased the number of migrating skin cells and their speed of migration, effects likely to accelerate wound healing. However, little data exists in humans to support the findings of accelerated wound healing in cell culture and animal studies. A randomized, double blind study examining the effect of supplementing patients undergoing surgery for tattoo removal with 1,000 mg of vitamin C and 200 mg of pantothenic acid could not document any significant improvement in the wound healing process in those that received the supplements.

High cholesterol

A pantothenic acid derivative called pantethine has been reported by a number of investigators to have a cholesterol lowering effect. Pantethine is actually two molecules of pantetheine joined by a disulfide bond (chemical bond between two molecules of sulfur). In the synthetic pathway of coenzyme A (CoA), pantethine is closer to CoA than pantothenic acid, and is the functional component of CoA and acyl carrier proteins. Several studies found doses of 900 mg of pantethine daily (300 mg, three times daily) to be significantly more effective than placebo in lowering total cholesterol and triglyceride levels in the blood of both diabetic and non-diabetic individuals. Pantethine was also found to lower cholesterol and triglyceride levels in diabetic patients on hemodialysis without adverse side effects. The low side effect profile of pantethine was especially attractive for hemodialysis patients because of the increased risk of drug toxicity in patients with renal (kidney) failure. Pantethine is not a vitamin; it is a derivative of pantothenic acid. The decision to use pantethine to treat elevated blood cholesterol or triglycerides should be made in collaboration with a qualified health care provider, who can provide appropriate follow up.

Intestinal bacteria

The bacteria that normally colonize the colon (large intestine) are capable of making their own pantothenic acid. It is not yet known whether humans can absorb the pantothenic acid synthesized by their own intestinal bacteria in meaningful amounts. However, a specialized process for the uptake of biotin and pantothenic acid was recently identified in cultured cells derived from the lining of the colon, suggesting that humans may be able to absorb pantothenic acid and biotin produced by the bacteria normally present in the colon.

Supplements

Pantothenic acid

Supplements commonly contain pantothenol, a more stable alcohol derivative, which is rapidly converted by humans to pantothenic acid. Calcium and sodium D-pantothenate, the calcium and sodium salts of pantothenic acid are also available as supplements.

Pantethine

Although it is used as a cholesterol-lowering agent in Europe and Japan, pantethine is available in the U.S. as a dietary supplement.

Safety

Toxicity

Pantothenic acid is not known to be toxic in humans. The only adverse effect noted was diarrhea resulting from very high intakes of 10 to 20 grams/day of calcium D-pantothenate. However, there is one case report of life-threatening eosinophilic pleuropericardial effusion in an elderly woman who took a combination of 10 mg/day of biotin and 300 mg/day of pantothenic acid for two months. Due to the lack of reports of adverse effects when the Dietary Reference Intakes (DRI) for pantothenic acid were established in 1998, the Food and Nutrition Board of the Institute of Medicine did not establish a tolerable upper level of intake (UL) for pantothenic acid. Pantethine is generally well tolerated in doses up to 1,200 mg/day. However gastrointestinal side effects like nausea and heartburn have been reported.

Drug interactions

Oral contraceptives (birth control pills) containing estrogen and progestin may increase the requirement for pantothenic acid. Use of pantethine in combination with HMG-CoA reductase inhibitors (statins) or nicotinic acid may produce additive effects on blood lipids.

Linus Pauling Institute Recommendation

Little is known regarding the amount of dietary pantothenic acid required to promote optimal health or prevent chronic disease. The Linus Pauling Institute supports the recommendation by the Food and Nutrition Board of 5 mg/day of pantothenic acid for adults. A varied diet should provide enough pantothenic acid for most people. Following the Linus Pauling Institute recommendation to take a daily multivitamin-mineral supplement, containing 100 % of the Daily Value (DV), will ensure an intake of at least 5 mg/day of pantothenic acid.

Older adults (65 years and older)

Presently there is little evidence that older adults differ in their intake or requirement for pantothenic acid. Most multivitamin/multimineral supplements provide at least 5 mg/day of pantothenic acid.

Reference: http://lpi.oregonstate.edu/infocenter/vitamins/pa/

Niacin

Niacin is a water-soluble vitamin, which is also known as nicotinic acid or vitamin B3. Nicotinamide is the derivative of niacin and used by the body to form the coenzymes nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP). The chemical structure of the various forms of niacin are shown in the diagram. None of the forms are related to the nicotine found in tobacco, although their names are similar.

Function

Oxidation-reduction (redox) reactions

Living organisms derive most of their energy from oxidation-reduction (redox) reactions, which are processes involving the transfer of electrons. As many as 200 enzymes require the niacin coenzymes, NAD and NADP, mainly to accept or donate electrons for redox reactions. NAD functions most often in energy producing reactions involving the degradation (catabolism) of carbohydrates, fats, proteins, and alcohol. NADP functions more often in biosynthetic (anabolic) reactions, such as in the synthesis of fatty acids and cholesterol.

Non-redox reactions

The niacin coenzyme, NAD, is the substrate (reactant) for two classes of enzymes (mono-ADP-ribosyltransferases and poly-ADP-ribose polymerase) that separate the niacin moiety from NAD and transfer ADP-ribose to proteins (diagram). Mono-ADP-ribosyltransferase enzymes were first discovered in certain bacteria, where they were found to produce toxins, such as cholera and diptheria. These enzymes and their products, ADP-ribosylated proteins, have also been found in the cells of mammals and are thought to play a role in cell signaling by affecting G-protein activity. G-proteins are proteins that bind guanosine-5'-triphosphate (GTP) and act as intermediaries in a number of cell-signaling pathways. Poly-ADP-ribose polymerases (PARPs) are enzymes that catalyze the transfer of many ADP-ribose units from NAD to acceptor proteins. PARPs appear to function in DNA replication and repair as well as in cell differentiation, suggesting a possible role for NAD in cancer prevention. At least five different PARPs have been identified, and although their functions are not yet well understood, their existence indicates a potential for considerable consumption of NAD. A third class of enzymes (ADP-ribosyl cyclase) catalyzes the formation of cyclic ADP-ribose, a molecule that works within cells to provoke the release of calcium ions from internal storage sites and probably also plays a role in cell signaling.

Deficiency

Pellagra

The late stage of severe niacin deficiency is known as pellagra. Early records of pellagra followed the widespread cultivation of corn in Europe in the 1700's. The disease was generally associated with poorer social classes whose chief dietary staple consisted of cereals like corn or sorghum. Pellagra was also common in the southern United States during the early 1900's where income was low and corn products were a major dietary staple. Interestingly, pellagra was not known in Mexico, where corn was also an important dietary staple and much of the population was also poor. In fact, corn contains appreciable amounts of niacin, but it is present in a bound form that is not nutritionally available to humans. The traditional preparation of corn tortillas in Mexico involves soaking the corn in a lime (calcium oxide) solution, prior to cooking. Heating the corn in an alkaline solution results in the release of bound niacin, increasing its bioavailability.

The most common symptoms of niacin deficiency involve the skin, digestive system, and the nervous system. The symptoms of pellagra were commonly referred to as the four D's: dermatitis, diarrhea, dementia, and death. In the skin, a thick, scaly, darkly pigmented rash develops symmetrically in areas exposed to sunlight. In fact, the word "pellagra" comes from the Italian phrase for rough or raw skin. Symptoms related to the digestive system include a bright red tongue, vomiting, and diarrhea. Neurologic symptoms include headache, apathy, fatigue, depression, disorientation, and memory loss. If untreated, pellagra is ultimately fatal.

Nutrient interactions (tryptophan and niacin)

In addition to its synthesis from dietary niacin, NAD may also be synthesized in the liver from the dietary amino acid, tryptophan. The synthesis of niacin from tryptophan also depends on enzymes that require vitamin B6 and riboflavin as well as an enzyme containing heme (iron). On average, 1 mg of niacin can be synthesized from the ingestion of 60 mg of tryptophan. Thus, 60 mg of tryptophan are considered to be 1 mg of niacin equivalents (NE). However, studies of pellagra in the southern U.S. during the early twentieth century indicated that the diets of many individuals who suffered from pellagra contained enough NE to prevent pellagra, challenging the idea that 60 mg of dietary tryptophan are equivalent to 1 mg of niacin. In particular, one study in young men found that the tryptophan content of the diet had no effect on the decrease in red blood cell niacin content that resulted from low dietary niacin.

Causes of niacin deficiency

Niacin deficiency or pellagra may result from inadequate dietary intake of niacin and/or tryptophan. As mentioned above, other nutrient deficiencies may also contribute to the development of niacin deficiency. For instance, patients with Hartnup's disease, a hereditary disorder resulting in defective tryptophan absorption, have developed pellagra. Carcinoid syndrome, a condition of increased secretion of serotonin and other catecholamines by carcinoid tumors, may also result in pellagra due to increased utilization of dietary tryptophan for serotonin rather than niacin synthesis. Further, prolonged treatment with the anti-tuberculosis drug, Isoniazid, has resulted in niacin deficiency.

Disease Prevention

Cancer

Studies of cultured cells (in vitro) provide evidence that NAD content influences the cellular response to DNA damage, an important risk factor in cancer development. Cellular NAD is consumed in the synthesis of ADP-ribose polymers, which play a role in DNA repair, and cyclic ADP-ribose may also mediate cell-signaling pathways important in cancer prevention. Additionally, cellular depletion of NAD has been found to decrease levels of the tumor suppressor protein, p53, in human breast, skin, and lung cells. Neither the cellular NAD content nor the dietary intake of NAD precursors (niacin and tryptophan) necessary for optimizing protective responses following DNA damage has been determined, but both are likely to be higher than that required for the prevention of pellagra. Niacin deficiency was found to decrease bone marrow NAD and poly-ADP-ribose levels and increase the risk of chemically induced leukemia. Moreover, one study reported that niacin supplementation decreased the risk of ultraviolet light-induced skin cancers in mice. However, little is known regarding cellular NAD levels and the prevention of DNA damage or cancer in humans. One study in two healthy individuals involved elevating NAD levels in blood lymphocytes by supplementation with 100 mg/day nicotinic acid/day for eight weeks. Compared to non-supplemented individuals, the supplemented individuals had reduced DNA strand breaks in lymphocytes exposed to free radicals in a test tube assay. More recently, nicotinic acid supplementation of up to 100 mg/day in 21 healthy smokers failed to provide any evidence of a decrease in cigarette smoke-induced genetic damage in blood lymphocytes compared to placebo.

Generally, relationships between dietary factors and cancer are established first in epidemiological studies and followed up by basic cancer research at the cellular level. In the case of niacin, research on biochemical and cellular aspects of DNA repair has stimulated an interest in the relationship between niacin intake and cancer risk in human populations. Recently, a large case-control study found increased consumption of niacin, along with antioxidant nutrients, to be associated with decreased incidence of oral (mouth), pharyngeal (throat), and esophageal cancers in northern Italy and Switzerland. An increase in niacin intake of 6.2 mg was associated with about a 40% decrease in cases of cancers of the mouth and throat, while a 5.2 mg increase in niacin intake was associated with a similar decrease in cases of esophageal cancer.

Insulin-dependent diabetes mellitus (IDDM)

Insulin-dependent diabetes mellitus in children, often called type I diabetes, is known to result from the autoimmune destruction of insulin-secreting beta-cells in the pancreas. Prior to the onset of symptomatic diabetes, specific antibodies, including islet cell antibodies (ICA), can be detected in the blood of high-risk individuals. The ability to detect individuals at high risk for the development of IDDM led to the enrollment of high-risk siblings of children with IDDM into trials designed to prevent its onset. Evidence from in vitro and animal research indicates that high levels of nicotinamide protect beta-cells from damage by toxic chemicals, inflammatory white blood cells, and reactive oxygen species. Pharmacologic doses of nicotinamide (up to 3 grams/day) were first used to protect beta-cells in patients shortly after the onset of IDDM. An analysis of ten published trials (five placebo-controlled) found evidence of improved beta-cell function after one year of treatment with nicotinamide, but the analysis failed to find any clinical evidence of improved glycemic (blood glucose) control. Recently, high doses of nicotinamide were found to decrease insulin sensitivity in high-risk relatives of IDDM patients, which might explain the finding of improved beta-cell function without concomitant improvement in glycemic control. Several pilot studies for the prevention of IDDM in ICA-positive relatives of patients with IDDM yielded conflicting results, whereas a large randomized trial in school children that was not placebo-controlled found a significantly lower incidence of IDDM in the nicotinamide-treated group. A large multi-center randomized controlled trial of nicotinamide in ICA-positive siblings of IDDM patients between three and 12 years of age recently failed to find a difference in the incidence of IDDM after three years. Another large multicenter trial of nicotinamide in high-risk relatives of IDDM patients is presently in progress. Unlike nicotinamide, nicotinic acid has not been found effective in the prevention of IDDM.

Disease Treatment

High cholesterol and cardiovascular disease

Pharmacologic doses of nicotinic acid, but not nicotinamide, have been known to reduce serum cholesterol since 1955. Today, niacin is commonly prescribed with other lipid-lowering medications. However, one randomized, placebo-controlled, multicenter trial examined the effect of nicotinic acid therapy (three grams daily), alone, on outcomes of cardiovascular disease. Specifically, the Coronary Drug Project (CDP) followed over 8,000 men with a previous myocardial infarction (heart attack) for six years. Compared to the placebo group, the group that took three grams of nicotinic acid daily experienced an average 10% reduction in total blood cholesterol, a 26% decrease in triglycerides, a 27% reduction in recurrent nonfatal myocardial infarction, and a 26% reduction in cerebrovascular events (stroke + transient ischemic attacks). Although nicotinic acid therapy did not decrease total deaths or deaths from cardiovascular disease during the six-year study period, post-trial follow up nine years later revealed a 10% reduction in total deaths with nicotinic acid treatment. Four out of five major cardiovascular outcome trials found nicotinic acid in combination with other therapies to be of statistically significant benefit in men and women. Nicotinic acid therapy markedly increases HDL-cholesterol levels, decreases serum Lp(a) (lipoprotein-a) concentrations, and shifts small, dense LDL particles to large, buoyant LDL particles; all of these changes in the blood lipid profile are considered cardioprotective.

Because of the adverse side effects associated with high doses of nicotinic acid (see Safety), it has most recently been used in combination with other lipid-lowering medications in slightly lower doses. A recent randomized controlled trial found that a combination of nicotinic acid (2 to 3 grams/day) and a cholesterol-lowering drug (simvastatin) resulted in greater benefits on serum HDL levels and cardiovascular events, such as heart attack and stroke, than placebo in patients with coronary artery disease and low HDL levels. However, an antioxidant combination (vitamin E, vitamin C, selenium, and beta-carotene) appeared to blunt the beneficial effects of niacin plus simvastatin. The effects of niacin are dose-dependent. A placebo-controlled study in 39 patients taking statins (cerivastatin, atorvastatin, or simvastatin) found that a very low dose of niacin, 100 mg daily, increased HDL cholesterol by only 2.1 mg/dL, and the combination had no effect on LDL cholesterol, total cholesterol, or triglyceride levels. Doses of niacin higher than 1 gram/day are typically used to treat hyperlipidemia. A few case reports have raised concerns that concurrent use of niacin and statins may result in myopathy; however, clinical trials have not confirmed such adverse effects.

Although it is a nutrient, at the pharmacologic dose required for cholesterol-lowering effects, the use of nicotinic acid should be approached as if it were a drug. Individuals should only undertake cholesterol-lowering therapy with nicotinic acid under the supervision of a qualified health care provider in order to minimize potentially adverse effects and maximize therapeutic benefits.

HIV/AIDS

It has been hypothesized that infection with human immunodeficiency virus (HIV), the virus that causes acquired immmunodeficiency syndrome (AIDS), increases the risk of niacin deficiency. Interferon-gamma (IF-g) is a cytokine produced by cells of the immune system in response to infection. IF-g levels are elevated in individuals infected with HIV, and higher IF-g levels have been associated with poorer prognoses. By stimulating the enzyme, indoleamine 2,3 dioxygenase (IDO), IF-g increases the breakdown of tryptophan, a niacin precursor, thus supporting the idea that HIV infection increases the risk of niacin deficiency. In a very small, uncontrolled study, treatment of four HIV positive individuals with 1,000 to 1,500 mg/day of nicotinamide for two months resulted in 40% increases in plasma tryptophan levels. An observational study of 281 HIV-positive men found that higher levels of niacin intake were associated with decreased progression rate to AIDS and improved survival.

Safety

Toxicity

Niacin from foods is not known to cause adverse effects. Although one study noted adverse effects following consumption of bagels with 60 times the normal amount of niacin fortification, most adverse effects have been reported with pharmacologic preparations of niacin.

Nicotinic acid

Common side effects of nicotinic acid include flushing, itching, and gastrointestinal disturbances such as nausea and vomiting. Hepatotoxicity (liver cell damage), including elevated liver enzymes and jaundice, has been observed at intakes as low as 750 mg of nicotinic acid/day for less than three months. Hepatitis has been observed with timed-release nicotinic acid at dosages as little as 500 mg/day for two months, although almost all reports of severe hepatitis have been associated with the timed-release form of nicotinic acid at doses of 3 to 9 grams per day used to treat high cholesterol for months or years. Immediate-release (crystalline) nicotinic acid appears to be less toxic to the liver than extended release forms. Immediate-release nicotinic acid is often used at higher doses than timed-release forms, and severe liver toxicity has occurred in individuals who substituted timed-release niacin for immediate-release niacin at equivalent doses. Skin rashes and dry skin have been noted with nicotinic acid supplementation. Transient episodes of low blood pressure (hypotension) and headache have also been reported. Large doses of nicotinic acid have been observed to impair glucose tolerance, likely due to decreased insulin sensitivity. Impaired glucose-tolerance in susceptible (pre-diabetic) individuals could result in elevated blood glucose levels and clinical diabetes. Elevated blood levels of uric acid, occasionally resulting in attacks of gout in susceptible individuals, have also been observed with high-dose nicotinic acid therapy. Nicotinic acid at doses of 1.5 to 5 grams/day has resulted in a few case reports of blurred vision and other eye problems, which have generally been reversible upon discontinuation. People with abnormal liver function or a history of liver disease, diabetes, active peptic ulcer disease, gout, cardiac arrhythmias, inflammatory bowel disease, migraine headaches, and alcoholism may be more susceptible to the adverse effects of excess nicotinic acid intake than the general population.

Nicotinamide

Nicotinamide is generally better tolerated than nicotinic acid. It does not generally cause flushing. However, nausea, vomiting, and signs of liver toxicity (elevated liver enzymes, jaundice) have been observed at doses of 3 grams/day. Nicotinamide has resulted in decreased insulin sensitivity at doses of 2 grams/day in adults at high risk for insulin-dependent diabetes.

The tolerable upper intake level (UL)

Flushing of the skin primarily on the face, arms, and chest is a common side effect of nicotinic acid and may occur initially at doses as low as 30 mg/day. Although flushing from nicotinamide is rare, the Food and Nutrition Board set the tolerable upper intake level (UL) for niacin (nicotinic acid and nicotinamide) at 35 mg/day to avoid the adverse effect of flushing. The UL applies to the general population and is not meant to apply to individuals who are being treated with a nutrient under medical supervision, as should be the case with high-dose nicotinic acid for elevated blood cholesterol levels.

Drug interactions

Coadministration of nicotinic acid with lovastatin (another cholesterol lowering medication) may have resulted in rhabdomyolysis in a small number of case reports. Rhabdomyolysis is a relatively uncommon condition in which muscle cells are broken down, releasing muscle enzymes and electrolytes into the blood, sometimes resulting in kidney failure. A 3-year randomized controlled trial in 160 patients with documented coronary heart disease (CHD) and low HDL levels found that a combination of simvastatin (Zocor) and niacin increased HDL2 levels, inhibited the progression of coronary artery stenosis (narrowing), and decreased the frequency of cardiovascular events such as myocardial infarction and stroke. However, concurrent therapy with antioxidants (1000 mg/d vitamin C, 800 IU/d alpha-tocopherol, 100 mcg/d of selenium, and 25 mg/d beta-carotene) diminished the protective effects of the simvastatin-niacin combination. Although the mechanism for these effects is not known, some scientists have questioned the benefit of concurrent antioxidant therapy in patients on lipid lowering agents.

Several other medications may interact with niacin therapy or with absorption and metabolism of the vitamin. Sulfinpyrazone is a medication for the treatment of gout that promotes excretion of uric acid from the blood into urine. Nicotinic acid may inhibit this "uricosuric" effect of sulfinpyrazone. Long-term administration of the cancer chemotherapy agent, 5-Fluorouracil (5-FU), has been reported to cause symptoms of pellagra, and thus niacin supplementation may be needed. Niacin supplementation is also recommended during long-term treatment of tuberculosis with isoniazid, a niacin antagonist, because such treatment has resulted in pellagra-like symptoms. Further, estrogen and estrogen-containing oral contraceptives increase the efficiency of niacin synthesis from tryptophan, resulting in a decreased dietary requirement for niacin.

Linus Pauling Institute Recommendation

The optimum intake of niacin for health promotion and chronic disease prevention is not yet known. The RDA (16 mg NE/day for men and 14 mg NE/day for women) is easily obtainable in a varied diet and should prevent deficiency in most people. Following the Linus Pauling Institute recommendation to take a daily multivitamin-mineral supplement, containing 100% of the Daily Value (DV) for niacin, will provide at least 20 mg of niacin daily.

Older adults (65 years and older)

Dietary surveys indicate that 15% to 25% of older adults do not consume enough niacin in their diets to meet the RDA (16 mg NE/day for men and 14 mg NE/day for women), and that dietary intake of niacin decreases between the ages of 60 and 90 years. Thus, it is advisable for older adults to supplement their dietary intake with a multivitamin/multimineral supplement, which will generally provide at least 20 mg of niacin daily.

Reference: http://lpi.oregonstate.edu/infocenter/vitamins/niacin/

Folic Acid

The terms folic acid and folate are often used interchangeably for this water-soluble B-complex vitamin. Folic acid, the more stable form, occurs rarely in foods or the human body but is the form most often used in vitamin supplements and fortified foods. Naturally occurring folates exist in many chemical forms. Folates are found in foods as well as in metabolically active forms in the human body. In the following discussion forms found in food or the body will be referred to as "folates", while the form found in supplements or fortified foods will be referred to as "folic acid".

Function

One-carbon metabolism

The only function of folate coenzymes in the body appears to be in mediating the transfer of one-carbon units. Folate coenzymes act as acceptors and donors of one-carbon units in a variety of reactions critical to the metabolism of nucleic acids and amino acids.

Nucleic acid metabolism

Folate coenzymes play a vital role in DNA metabolism through two different pathways. 1) The synthesis of DNA from its precursors is dependent on folate coenzymes. 2) A folate coenzyme is required for the synthesis of methionine, and methionine is required for the synthesis of S-adenosylmethionine (SAM). SAM is a methyl group (one-carbon unit) donor used in many biological methylation reactions, including the methylation of a number of sites within DNA and RNA. Methylation of DNA may be important in cancer prevention (see Disease Prevention).

Amino acid metabolism

Folate coenzymes are required for the metabolism of several important amino acids. The synthesis of methionine from homocysteine requires a folate coenzyme as well as a vitamin B12-dependent enzyme. Thus, folate deficiency can result in decreased synthesis of methionine and a buildup of homocysteine. Increased levels of homocysteine may be a risk factor for heart disease as well as several other chronic diseases (see Disease Prevention).

Nutrient interactions

Vitamin B12 and vitamin B6

The metabolism of homocysteine, an intermediate in the metabolism of sulfur-containing amino acids, provides an example of the interrelationships among nutrients necessary for optimium physiological function and health. Healthy individuals utilize two different pathways to metabolize homocysteine (see diagram). One pathway (methionine synthase) synthesizes methionine from homocysteine and is dependent on a folate coenzyme and a vitamin B12-dependent enzyme. The other pathway converts homocysteine to another amino acid, cysteine, and requires two vitamin B6-dependent enzymes. Thus, the amount of homocysteine in the blood is regulated by three vitamins: folate, vitamin B12, and vitamin B6.

Deficiency

Causes

Folate deficiency occurs in a number of situations. For example, alcoholism is associated with low dietary intake and diminished absorption of folate, which can lead to folate deficiency. Additionally, certain conditions such as pregnancy or cancer result in increased rates of cell division and metabolism, causing an increase in the body's demand for folate. Several medications may also contribute to deficiency (see Drug interactions).

Symptoms

Individuals in the early stages of folate deficiency may not show obvious symptoms, but blood levels of homocysteine may increase (see Prevention). Rapidly dividing cells are most vulnerable to the effects of folate deficiency; thus, when the folate supply to the rapidly dividing cells of the bone marrow is inadequate, blood cell division becomes abnormal resulting in fewer but larger red blood cells. This type of anemia is called megaloblastic or macrocytic anemia, referring to the enlarged, immature red blood cells. Neutrophils, a type of white blood cell, become hypersegmented, a change which can be found by examining a blood sample microscopically. Because normal red blood cells have a lifetime in the circulation of approximately four months, it can take months for folate deficient individuals to develop the characteristic megaloblastic anemia. Progression of such an anemia leads to a decreased oxygen carrying capacity of the blood and may ultimately result in symptoms of fatigue, weakness, and shortness of breath. It is important to point out that megaloblastic anemia resulting from folate deficiency is identical to the megaloblastic anemia resulting from vitamin B12 deficiency, and further clinical testing is required to diagnose the true cause of megaloblastic anemia.

The Recommended Dietary Allowance (RDA)

Determination of the RDA

Traditionally, the dietary folate requirement was defined as the amount needed to prevent a deficiency severe enough to cause symptoms like anemia. The most recent RDA (1998) was based primarily on the adequacy of red blood cell folate concentrations at different levels of folate intake, which have been shown to correlate with liver folate stores. Maintenance of normal blood homocysteine levels, an indicator of one-carbon metabolism, was considered only as an ancillary indicator of adequate folate intake. Because pregnancy is associated with a significant increase in cell division and other metabolic processes that require folate coenzymes, the RDA for pregnant women is considerably higher than for women who are not pregnant. However, the prevention of neural tube defects (NTD) was not considered when setting the RDA for pregnant women. Rather, reducing the risk of NTD was considered in a separate recommendation for women capable of becoming pregnant (see Prevention), because the crucial events in the development of the neural tube occur before many women are aware that they are pregnant.

Dietary Folate Equivalents (DFE)

When the Food and Nutrition Board of the Institute of Medicine set the new dietary recommendation for folate, they introduced a new unit, the Dietary Folate Equivalent (DFE). Use of the DFE reflects the higher bioavailability of synthetic folic acid found in supplements and fortified foods compared to that of naturally occurring food folates.

1 microgram (mcg) of food folate provides 1 mcg of DFE
1 mcg of folic acid taken with meals or as fortified food provides 1.7 mcg of DFE
1 mcg of folic acid (supplement) taken on an empty stomach provides 2 mcg of DFE
For example, a serving of food containing 60 mcg of folate would provide 60 mcg of DFE, while a serving of pasta fortified with 60 mcg of folic acid would provide 1.7 x 60 = 102 mcg DFE due to the higher bioavailability of folic acid. A folic acid supplement of 400 mcg taken on an empty stomach would provide 800 mcg of DFE.

Genetic variation in folate requirements

A common polymorphism or variation in the gene for the enzyme methylene tetrahydrofolate reductase (MTHFR), known as the C677T MTHFR polymorphism, results in a less stable enzyme. Depending on the population, 50% of individuals may have inherited one copy (C/T), and 5% to 25% of individuals may have inherited two copies (T/T) of the abnormal MTHFR gene. MTHFR plays an important role in maintaining the specific folate coenzyme required to form methionine from homocysteine (see diagram). When folate intake is low, individuals who are homozygous (T/T) for the abnormal gene have lower levels of the MTHFR enzyme and thus higher levels of homocysteine in their blood. Improved folate nutritional status appears to stabilize the MTHFR enzyme, resulting in improved enzyme levels and lower homocysteine levels. An important unanswered question about folate is whether the present RDA is enough to normalize MTHFR enzyme levels in individuals who are homozygous for the C677T polymorphism, or whether those individuals have a higher folate requirement than the RDA.

Disease Prevention

Pregnancy complications

Neural tube defects

Fetal growth and development are characterized by widespread cell division. Adequate folate is critical for DNA and RNA synthesis. Neural tube defects (NTD) result in either anencephaly or spina bifida, which are devastating and sometimes fatal birth defects. The defects occur between the 21st and 27th days after conception, a time when many women do not realize they are pregnant. The risk of NTD in the United States prior to fortification of foods with folic acid was estimated to be one per 1000 pregnancies. Results of randomized trials have demonstrated 60% to 100% reductions in NTD cases when women consumed folic acid supplements in addition to a varied diet during the periconceptional period (about one month before and one month after conception). The results of these and other studies prompted the U.S. Public Health Service to recommend that all women capable of becoming pregnant consume 400 mcg of folic acid daily to prevent NTD. The recommendation was made to all women of childbearing age because adequate folic acid must be available very early in pregnancy, and because many pregnancies in the U.S. are unplanned. Despite the effectiveness of folic acid supplementation, it appears that less than half of women who become pregnant follow the recommendation. To decrease the incidence of NTD, the FDA implemented legislation in 1998 requiring the fortification of all enriched grain products with folic acid (see Sources). The required level of folic acid fortification in the U.S. was estimated to provide 100 mcg of additional folic acid in the average person's diet, though it probably provides even more due to overuse of folic acid by food manufacturers. The Centers for Disease Control and Prevention reported that the frequency of NTD in the U.S. has decreased 26% since the mandate. However, studies in Canada, where fortification is nearly identical to that in the U.S. (1.5 and 1.4 mg of folic acid/kg of grain, respectively), have reported greater reductions in the incidence of NTD. In fact, it was recently proposed that the fortification legislation has prevented approximately 50% of NTD in Canada and the U.S, but improvements in the U.S. have been largely underestimated.

Other pregnancy complications

Adequate folate status may also prevent the occurrence of other types of birth defects, including certain heart defects and limb malformations. However, the support for these findings is not as consistent or clear as support for NTD prevention. Additionally, low levels of dietary folate during pregnancy have been associated with increased risks of premature delivery and infant low infant birth weights. More recently, elevated blood homocysteine levels, considered an indicator of functional folate deficiency, have been associated with increased incidence of miscarriage as well as pregnancy complications like preeclampsia and placental abruption. Thus, it is reasonable to maintain folic acid supplementation throughout pregnancy, even after closure of the neural tube in order to decrease the risk of other problems during pregnancy.

Cardiovascular disease

Homocysteine and cardiovascular disease

The results of more than 80 studies indicate that even moderately elevated levels of homocysteine in the blood increase the risk of cardiovascular diseases. An analysis of the observational studies on blood homocysteine and vascular disease indicated that a prolonged decrease in plasma homocysteine level of only 1 micromole/liter resulted in about a 10% risk reduction. The mechanism by which homocysteine increases the risk of vascular disease remains the subject of a great deal of research, but it may involve adverse effects of homocysteine on blood clotting, arterial vasodilation, and thickening of arterial walls. Although increased homocysteine levels in the blood have been consistently associated with increased risk of cardiovascular diseases, it is not yet clear whether lowering homocysteine levels will reduce cardiovascular disease risk (see below, Folate and homocysteine). Consequently, the American Heart Association recommends screening for elevated total homocysteine levels only in "high risk" individuals, for example those with personal or family history of premature cardiovascular disease, malnutrition or malabsorption syndromes, hypothyroidism, kidney failure, lupus, or individuals taking certain medications (nicotinic acid, theophylline, bile acid-binding resins, methotrexate, and L-dopa). Most research indicates that a plasma homocysteine level of < 10 micromoles/liter is associated with a lower risk of cardiovascular disease and a reasonable treatment goal for individuals at high risk.

Folate and homocysteine

Folate-rich diets have been associated with decreased risk of cardiovascular disease. A study that followed 1,980 Finnish men for ten years found that those who consumed the most dietary folate had a 55% lower risk of an acute coronary event when compared with those who consumed the least dietary folate. Of the three vitamins that regulate homocysteine levels, folic acid has been shown to have the greatest effect in lowering basal levels of homocysteine in the blood when there is no coexisting deficiency of vitamin B12 or vitamin B6 (see Nutrient interactions). Increasing folate intake through folate-rich foods or supplements has been found to lower homocysteine levels. Moreover, blood homocysteine levels have declined since the FDA mandated folic acid fortification of the grain supply. A recent meta-analysis of 25 randomized controlled trials found that supplementation with 0.8 mg folic acid daily maximally reduced plasma homocysteine concentrations; daily doses of 0.2 mg and 0.4 mg of folic acid were associated with 60% and 90% reductions, respectively, in plasma homocysteine. A supplement regimen of 400 mcg of folic acid, 2 mg of vitamin B6, and 6 mcg of vitamin B12 has been advocated by the American Heart Association if an initial trial of a folate-rich diet (see Sources) is not successful in adequately lowering homocysteine levels. Although increased folic acid intake has been found to decrease homocysteine levels, it is presently not clear whether increasing folic acid intake results in decreased risk of cardiovascular diseases. Several randomized placebo-controlled trials have been conducted or are ongoing to determine whether homocysteine lowering through folic acid and other B vitamin supplementation reduces the incidence of cardiovascular diseases. A preliminary meta-analysis of data from four of the ongoing trials, including about 14,000 subjects, showed that B vitamin supplementation had no significant effect on risk of coronary heart disease or stroke. Similarly, another meta-analysis of 12 randomized controlled trials, including data from 16,958 individuals with preexisting cardiovascular or renal disease, found that folic acid supplementation had no effect on coronary heart disease, stroke, or all-cause mortality despite 13%-52% reductions in plasma homocysteine concentrations. Consequently, the American Heart Association removed its recommendation for using folic acid to prevent cardiovascular diseases in high-risk women. Completion of the ongoing clinical trials should provide a more definitive answer whether folic acid is beneficial for the prevention or treatment of heart disease or stroke.

Cancer

Cancer is thought to arise from DNA damage in excess of ongoing DNA repair and/or the inappropriate expression of critical genes. Because of the important roles played by folate in DNA and RNA synthesis and methylation, it is possible for folate intake to affect both DNA repair and gene expression. The consumption of at least five servings of fruits and vegetables daily has been consistently associated with a decreased incidence of cancer. Fruits and vegetables are excellent sources of folate, which may play a role in their anti-carcinogenic effect. Observational studies have found diminished folate status to be associated with cancers of the cervix, colon and rectum, lung, esophagus, brain, pancreas, and breast. Intervention trials of folic acid supplementation in humans have been conducted mainly with respect to cervical and colorectal (colon and rectal) cancer. While the results in cervical cancer have been inconsistent, randomized intervention trials regarding colorectal cancer have been more promising.

Colorectal cancer

A recent meta-analysis of seven cohort and nine case-control studies found that folate from foods was inversely associated with colorectal cancer risk; however, total folate from foods and folic acid supplements was not associated with colorectal cancer risk. It is important to note that the case-control studies examined in this meta-analysis were highly heterogeneous, and that the authors stated that dietary fiber or other vitamins could have confounded their results. Overall, the role of folate in the possible prevention of colorectal cancer provides an example of the complexity of the interactions between genetics and nutrition. In general, observational studies have found that relatively low folate intake and high alcohol intake are associated with increased incidence of colorectal cancer. Alcohol interferes with the absorption and metabolism of folate. In a prospective study of more than 45,000 male health professionals, current intake of more than two alcoholic drinks per day doubled the risk of colon cancer. The combination of high alcohol and low folate intake yielded an even greater risk of colon cancer; however, increased alcohol intake in individuals who consumed 650 mcg or more of folate per day was not associated with an increased risk of colon cancer. In some studies, individuals who are homozygous for the C677T MTHFR polymorphism (TT) have been found to be at decreased risk for colon cancer when folate intake is adequate. However, when folate intake is low and/or alcohol intake is high, individuals with the (T/T) genotype have been found to be at increased risk of colorectal cancer.

Breast cancer

Studies investigating whether folate intake affects breast cancer risk have reported mixed results. The results of two prospective studies suggest that increased folate intake may reduce the risk of breast cancer in women who regularly consume alcohol; moderate alcohol intake has been associated with increased risk of breast cancer in women in several studies. Interestingly, a very large prospective study in more than 88,000 nurses reported that folic acid intake was not associated with breast cancer in women who consumed less than one alcoholic drink per day. However, in women consuming at least one alcoholic drink per day, folic acid intake of at least 600 mcg daily resulted in about half the risk of breast cancer compared with women who consumed less that 300 mcg of folic acid daily.

Alzheimer's disease and cognitive impairment

The role of folate in nucleic acid synthesis and methylation reactions is essential for normal brain function. Over the past decade several investigators have described associations between decreased folate levels and cognitive impairment in the elderly. A large cross-sectional study in elderly Canadians found that those individuals with low serum folate levels were more likely to have dementia, be institutionalized, and be depressed. However, these findings could reflect the poorer nutritional status of institutionalized elderly and individuals with dementia. In the same study, low serum folate levels were associated with an increased likelihood of short-term memory problems in elderly individuals who hand no signs of dementia. A study in 30 elderly nuns, who lived in the same convent, ate the same diet, and had similar lifestyles, reported a strong association between decreased blood folate levels and the severity of brain atrophy related to Alzheimer's disease. More recent studies have reported conflicting results as to whether folate status impacts Alzheimer's disease risk. One study in elderly people of predominantly Hispanic and African-American ethnicity with a high prevalence of vascular risk factors reported that a higher folate intake, from diet and folic acid supplements, was associated with a decreased risk for Alzheimer's disease. In contrast, a prospective study in elderly individuals reported that dietary folate is not associated with Alzheimer's disease, whereas another prospective study reported that a high folate intake, from foods and from folic acid supplements, was associated with increased rates of cognitive decline in the elderly. Moderately increased homocysteine levels, as well as decreased folate and vitamin B12 levels, have been associated with Alzheimer's disease and vascular dementia. One study in 370 elderly men and women, who were followed over three years, associated low serum levels of vitamin B12 (< 150 pmol/L) or folate (< 10 nmol/L) with a doubling of the risk of developing Alzheimer's disease. In a sample of 1,092 men and women without dementia followed for an average of ten years, those with higher plasma homocysteine levels at baseline had a significantly higher risk of developing Alzheimer's disease and other types of dementia. Those with plasma homocysteine levels greater than 14 micromoles/liter had nearly twice the risk of developing Alzheimer's disease.

Safety

Toxicity

No adverse effects have been associated with the consumption of excess folate from foods. Concerns regarding safety are limited to synthetic folic acid intake. Deficiency of vitamin B12, though often undiagnosed, may affect a significant number of people, especially older adults (see Vitamin B12). One symptom of vitamin B12 deficiency is megaloblastic anemia, which is indistinguishable from that associated with folate deficiency (see Deficiency). Large doses of folic acid given to an individual with an undiagnosed vitamin B12 deficiency could correct megaloblastic anemia without correcting the underlying vitamin B12 deficiency, leaving the individual at risk of developing irreversible neurologic damage. Such cases of neurologic progression in vitamin B12 deficiency have been mostly seen at folic acid doses of 5,000 mcg (5 mg) and above. In order to be very sure of preventing irreversible neurological damage in vitamin B12 deficient individuals, the Food and Nutrition Board of the Institute of Medicine advises that all adults limit their intake of folic acid (supplements and fortification) to 1,000 mcg (1 mg daily). The board also noted that vitamin B12 deficiency is very rare in women in their childbearing years, making the consumption of folic acid at or above 1000 mcg/day unlikely to cause problems; however, there are limited data on the effects of large doses.

Drug interactions

When nonsteroidal anti-inflammatory drugs (NSAIDs), such as aspirin or ibuprofen, are taken in very large therapeutic dosages (i.e., to treat severe arthritis), they may interfere with folate metabolism. In contrast, routine low dose use of NSAIDs has not been found to adversely affect folate status. The anticonvulsant, phenytoin, has been shown to inhibit the intestinal absorption of folate, and several studies have associated decreased folate status with long-term use of the anticonvulsants, phenytoin, phenobarbital, and primidone. However, few studies controlled for differences in dietary folate intake between anticonvulsant users and nonusers. Also, taking folic acid at the same time as the cholesterol-lowering agents, cholestyramine and colestipol, may decrease the absorption of folic acid. Methotrexate is a folic acid antagonist used to treat a number of diseases, including rheumatoid arthritis and psoriasis. Some of the side effects of methotrexate are similar to those of severe folate deficiency, and increased dietary folate or supplemental folic acid may decrease side effects without reducing the efficacy of methotrexate. A number of other medications have been shown to have antifolate activity, including trimethoprim (an antibiotic), pyrimethamine (an antimalarial), triamterene (a blood pressure medication), and sulfasalazine (a treatment for ulcerative colitis). Early studies of oral contraceptives (birth control pills) containing high doses of estrogen indicated adverse effects on folate status; however, this finding has not been supported by more recent studies on low dose oral contraceptives that controlled for dietary folate.

Linus Pauling Institute Recommendation

The available scientific evidence shows that adequate folate intake prevents neural tube defects and other poor outcomes of pregnancy, is helpful in lowering the risk of some forms of cancer, especially in genetically susceptible individuals, and may lower the risk of cardiovascular diseases. The Linus Pauling Institute recommends that adults take a 400 mcg supplement of folic acid daily, in addition to folate and folic acid consumed in the diet. A daily multivitamin-mineral supplement, containing 100% of the Daily Value (DV) for folic acid provides 400 mcg of folic acid. Even with a larger than average intake of folic acid from fortified foods, it is unlikely that an individual's daily folic acid intake would regularly exceed the tolerable upper intake level of 1,000 mcg/day established by the Food and Nutrition Board (see Safety).

Older adults (65 years and older)

The recommendation for 400 mcg/day of supplemental folic acid as part of a daily multivitamin-multimineral supplement, in addition to a folate-rich diet, is especially important for older adults because blood homocysteine levels tend to increase with age (see Disease Prevention).

Reference: http://lpi.oregonstate.edu/infocenter/vitamins/fa/

Biotin

Biotin is a water-soluble vitamin, generally classified as a B-complex vitamin. After the initial discovery of biotin, nearly forty years of research were required to establish it as a vitamin. Biotin is required by all organisms but can only be synthesized by bacteria, yeasts, molds, algae, and some plant species.

Function

In its physiologically active form biotin is attached at the active site of four important enzymes, known as carboxylases. Each carboxylase catalyzes an essential metabolic reaction.

Enzyme cofactor

Acetyl-CoA carboxylase catalyzes the binding of bicarbonate to acetyl-CoA to form malonyl-CoA. Malonyl-CoA is required for the synthesis of fatty acids.

Pyruvate carboxylase is a critical enzyme in gluconeogenesis, the formation of glucose from sources other than carbohydrates, for example, amino acids and fats.

Methylcrotonyl-CoA carboxylase catalyzes an essential step in the metabolism of leucine, an indispensable (essential) amino acid.

Propionyl-CoA carboxylase catalyzes essential steps in the metabolism of amino acids, cholesterol, and odd chain fatty acids (fatty acids with an odd number of carbon molecules).

Histone biotinylation

Histones are proteins that bind to DNA and package it into compact structures to form chromosomes. The compact packaging of DNA must be relaxed somewhat for DNA replication and transcription to occur. Modification of histones through the attachment of acetyl or methyl groups (acetylation or methylation) has been shown to affect the structure of histones, thereby affecting replication and transcription of DNA. The attachment of biotin to another molecule, such as a protein, is known as "biotinylation".  The enzyme biotinidase has recently been shown to catalyze the biotinylation of histones, suggesting that biotin may play a role in DNA replication and transcription.

Deficiency

Although biotin deficiency is very rare, the human requirement for dietary biotin has been demonstrated in two different situations: prolonged intravenous feeding without biotin supplementation and consumption of raw egg white for a prolonged period (many weeks to years). Avidin is a protein found in egg white, which binds biotin and prevents its absorption. Cooking egg white denatures avidin, rendering it susceptible to digestion, and unable to prevent the absorption of dietary biotin.

Symptoms

Symptoms of overt biotin deficiency include hair loss and a scaly red rash around the eyes, nose, mouth, and genital area. Neurologic symptoms in adults have included depression, lethargy, hallucination, and numbness and tingling of the extremities. The characteristic facial rash, together with an unusual facial fat distribution, have been termed the "biotin deficient face" by some experts. Individuals with hereditary disorders of biotin metabolism resulting in functional biotin deficiency have evidence of impaired immune system function, including increased susceptibility to bacterial and fungal infections.

Predisposing conditions

Two hereditary disorders, biotinidase deficiency and holocarboxylase synthetase (HCS) deficiency, result in an increased biotin requirement. Biotinidase is an enzyme that catalyzes the release of biotin from small proteins and the amino acid, lysine, thereby recycling biotin. There are several ways in which biotinidase deficiency leads to biotin deficiency. Intestinal absorption is decreased because a lack of biotinidase inhibits the release of biotin from dietary protein. Recycling of one's own biotin bound to protein is impaired, and urinary loss of biotin is increased because the kidneys appear to excrete biotin that is not bound to biotinidase more rapidly. Biotinidase deficiency sometimes requires supplementation of as much as 5 to 10 milligrams (mg) of oral biotin/day, though smaller doses are often sufficient. HCS is an enzyme that catalyzes the attachment of biotin to all four carboxylase enzymes (see Function). HCS deficiency results in decreased formation of all carboxylases at normal blood levels of biotin, and requires high-dose supplementation of 40 to 100 mg of biotin/day. In general, the prognosis of both disorders is good if biotin therapy is introduced early (infancy or childhood) and continued for life.

Aside from prolonged consumption of raw egg white or intravenous feedings lacking biotin, other conditions may increase the risk of biotin depletion. The rapidly dividing cells of the developing fetus require biotin for DNA replication and synthesis of essential carboxylases, thereby increasing the biotin requirement in pregnancy. Recent research suggests that a substantial number of women develop marginal or subclinical biotin deficiency during normal pregnancy. Some types of liver disease may also increase the requirement for biotin. A recent study of 62 children with chronic liver disease and 27 healthy controls found serum biotinidase activity to be abnormally low in those with severely impaired liver function due to cirrhosis (10). Anticonvulsant medications, used to prevent seizures in individuals with epilepsy, increase the risk of biotin depletion. See Safety for more information on biotin and anticonvulsants.

Disease Prevention

Birth defects

Recent research indicates that biotin is broken down more rapidly during pregnancy and that biotin nutritional status declines during the course of pregnancy. In 6 out of 13 women studied biotin excretion dropped below the normal range during late pregnancy, suggesting that their biotin status was abnormally low. Approximately half of pregnant women have abnormally high excretion of a metabolite (3-hydroxyisovaleric acid) thought to reflect decreased activity of a biotin-dependent enzyme. A recent study of 26 pregnant women found that biotin supplementation decreased the excretion of this metabolite compared to placebo, suggesting that marginal biotin deficiency is relatively common in pregnancy. Although the level of biotin depletion was not severe enough to cause symptoms, it was reason for concern because subclinical biotin deficiency has been shown to cause birth defects in several animal species. There exists no direct evidence that marginal biotin deficiency causes birth defects in humans. However, the potential risk for biotin depletion makes it prudent to ensure adequate biotin intake throughout pregnancy.  Since pregnant women are advised to consume supplemental folic acid prior to and during pregnancy (see Folic Acid) to prevent neural tube defects, it would be easy to consume supplemental biotin (at least 30 mcg/day) in the form of a multivitamin that also contains at least 400 mcg of folic acid.

Disease Treatment

Diabetes mellitus

It has been known for many years that overt biotin deficiency results in impaired utilization of glucose. Blood biotin levels were significantly lower in 43 patients with non-insulin dependent diabetes mellitus (NIDDM) than in non-diabetic control subjects, and lower fasting blood glucose levels were associated with higher blood biotin levels. After one month of biotin supplementation (9 mg/day) fasting blood glucose levels decreased by an average of 45%. Reductions in blood glucose levels were also found in 7 insulin-dependent diabetics after 1 week of supplementation with 16 mg of biotin daily. Several mechanisms could explain the glucose-lowering effect of biotin. As a cofactor of enzymes required for fatty acid synthesis, biotin may increase the utilization of glucose to synthesize fats. Biotin has been found to stimulate glucokinase, an enzyme in the liver, resulting in increased synthesis of glycogen, the storage form of glucose. Biotin has also been found to stimulate the secretion of insulin in the pancreas of rats, which also has the effect of lowering blood glucose. An effect on cellular glucose (GLUT) transporters is also currently under investigation. Presently, studies of the effect of supplemental biotin on blood glucose levels in humans are extremely limited, but they highlight the need for further research.

Brittle fingernails

The finding that biotin supplements were effective in treating hoof abnormalities in horses and swine led to speculation that biotin supplements might also be helpful in strengthening brittle fingernails in humans. Three uncontrolled trials examining the effects of biotin supplementation (2.5 mg/day for up to six months) in women with brittle fingernails have been published. In two of the trials, subjective evidence of clinical improvement was reported in 67-91% of the participants available for follow-up at the end of the treatment period. One trial that used scanning electron microscopy to assess fingernail thickness and splitting found that fingernail thickness increased by 25% and splitting decreased after biotin supplementation. Although the results of these small uncontrolled trials suggest that biotin supplements may be helpful in strengthening brittle nails, larger placebo-controlled trials are needed to assess the efficacy of high-dose biotin supplementation for the treatment of brittle fingernails.

Hair loss

Although hair loss is a symptom of severe biotin deficiency (see Deficiency), there are no published scientific studies that support the claim that high-dose biotin supplements are effective in preventing or treating hair loss in men or women.

Safety

Toxicity

Biotin is not known to be toxic. Oral biotin supplementation has been well-tolerated in doses up to 200 mg/day in people with hereditary disorders of biotin metabolism. In people without disorders of biotin metabolism, doses of up to 5 mg/day for two years were not associated with adverse effects. However, there is one case report of life-threatening eosinophilic pleuropericardial effusion in an elderly woman who took a combination of 10 mg/day of biotin and 300 mg/day of pantothenic acid for two months. Due to the lack of reports of adverse effects when the Dietary Reference Intakes (DRI) were established for biotin in 1998, the Institute of Medicine did not establish a tolerable upper level of intake (UL) for biotin. Note: 1 mg = 1,000 mcg.

Drug interactions

Individuals on long-term anticonvulsant (anti-seizure) therapy have been found to have reduced levels of biotin in their blood, and urinary excretion of organic acids consistent with decreased carboxylase activity. The anticonvulsants, primidone and carbamazepine, inhibit biotin absorption in the small intestine. Phenobarbital, phentyoin, and carbamazepine appear to increase urinary excretion of biotin. Use of the anti-convulsant, valproic acid, has been associated with decreased biotinidase activity in children. Long-term treatment with sulfa drugs or other antibiotics may decrease bacterial synthesis of biotin, potentially increasing the requirement for dietary biotin. Large doses of the nutrient, pantothenic acid, have the potential to compete with biotin for intestinal and cellular uptake due to their similar structures. Very high (pharmacologic) doses of lipoic acid have been found to decrease the activity of biotin-dependent carboxylases in rats, but such an effect has not been demonstrated in humans.

Linus Pauling Institute Recommendation

Little is known regarding the amount of dietary biotin required to promote optimal health or prevent chronic disease. The Linus Pauling Institute supports the recommendation by the Food and Nutrition Board of 30 micrograms (mcg) of biotin/day for adults. A varied diet should provide enough biotin for most people.  However, following the Linus Pauling Institute recommendation to take a daily multivitamin/multimineral supplement will generally provide an intake of at least 30 mcg of biotin/day.

Older adults (65 years and older)

Presently, there is no indication that older adults have an increased requirement for biotin. If dietary biotin intake is not sufficient, a daily multivitamin/multimineral supplement will generally provide an intake of at least 30 mcg of biotin/day.

Reference: http://lpi.oregonstate.edu/infocenter/vitamins/biotin/