Basal metabolic rate

From Wikipedia, the free encyclopedia

Basal metabolic rate (BMR) is the amount of energy expended while at rest in a neutrally temperate environment, in the post-absorptive state (meaning that the digestive system is inactive, which requires about twelve hours of fasting in humans). The release of energy in this state is sufficient only for the functioning of the vital organs, such as the heart, lungs, brain and the rest of the nervous system, liver, kidneys, sex organs, muscles and skin. BMR decreases with age and with the loss of lean body mass. Increasing muscle mass increases BMR. Aerobic fitness level, a product of cardiovascular exercise, while previously thought to have effect on basal or resting metabolic rate (RMR), has been shown in the 1990s not to correlate with BMR, when fat-free body mass was adjusted for. New research has however come to light which suggests aerobic exercise does increase resting energy consumption (see "Aerobic vs. anaerobic exercise"). Illness, previously consumed food and beverages, environmental temperature, and stress levels can affect one's overall energy expenditure as well as one's BMR.

BMR is measured under very restrictive circumstances when a person is awake, but at complete rest. An accurate BMR measurement requires that the person's sympathetic nervous system not be stimulated. A more common and closely related measurement, used under less strict conditions, is resting metabolic rate (RMR).^[1]

BMR and RMR are measured by gas analysis through either direct or indirect calorimetry, though a rough estimation can be acquired through an equation using age, sex, height, and weight. Studies of energy metabolism using both methods provide convincing evidence for the validity of the respiratory quotient (R.Q.), which measures the inherent composition and utilization of carbohydrates, fats and proteins as they are converted to energy substrate units that can be used by the body as energy.

[edit] Nutrition and dietary considerations

Basal metabolic rate is usually by far the largest component of total caloric expenditure. However, the Harris-Benedict equations are only approximate and variation in BMR (reflecting varying body composition), in physical activity levels, and in energy expended in thermogenesis make it difficult to estimate the dietary consumption any particular individual needs in order to maintain body weight. 2000 kilocalories is often quoted but is no more than a guideline.

[edit] Physiology

Both basal metabolic rate and resting metabolic rate are usually expressed in terms of daily rates of energy expenditure. The early work of the scientists J. Arthur Harris and Francis G. Benedict showed that approximate values could be derived using body surface area (computed from height and weight), age, and sex, along with the oxygen and carbon dioxide measures taken from calorimetry. Studies also showed that by eliminating the sex differences that occur with the accumulation of adipose tissue by expressing metabolic rate per unit of "fat-free" or lean body weight, the values between sexes for basal metabolism are essentially the same^{[citation needed]}. Exercise physiology textbooks have tables to show the conversion of height and body surface area as they relate to weight and basal metabolic values.

The primary organ responsible for regulating metabolism is the hypothalamus. The hypothalamus is located on the brain stem and forms the floor and part of the lateral walls of the third ventricle of the cerebrum. The chief functions of the hypothalamus are:

control and integration of activities of the autonomic nervous system (ANS)
- The ANS regulates contraction of smooth muscle and cardiac muscle, along with secretions of many endocrine organs such as the thyroid gland (associated with many metabolic disorders).
- Through the ANS, the hypothalamus is the main regulator of visceral activities, such as heart rate, movement of food through the gastrointestinal tract, and contraction of the urinary bladder.
production and regulation of feelings of rage and aggression
regulation of body temperature
regulation of food intake, through two centers:
- The feeding center or hunger center is responsible for the sensations that cause us to seek food. When sufficient food or substrates have been received and leptin is high, then the satiety center is stimulated and sends impulses that inhibit the feeding center. When insufficient food is present in the stomach and ghrelin levels are high, receptors in the hypothalamus initiate the sense of hunger.
- The thirst center operates similarly when certain cells in the hypothalamus are stimulated by the rising osmotic pressure of the extracellular fluid. If thirst is satisfied, osmotic pressure decreases.

All of these functions taken together form a survival mechanism that causes us to sustain the body processes that BMR and RMR measure.

[edit] BMR estimation formulas

Several prediction equations exist. Historically most notable was Harris-Benedict equation, which was created in 1919.

The original equations from Harris and Benedict are:

for men, $P = \left ( \frac {13.7516 m} {1 ~ \mbox {kg}} + \frac {5.0033 h} {1 ~ \mbox {cm}} - \frac {6.7550 a} {1 ~ \mbox {year}} + 66.4730 \right ) \frac {\mbox {kcal}} {\mbox {day}}$
for women, $P = \left ( \frac {9.5634 m} {1 ~ \mbox {kg}} + \frac {1.8496 h} {1 ~ \mbox {cm}} - \frac {4.6756 a} {1 ~ \mbox {year}} + 655.0955 \right ) \frac {\mbox {kcal}} {\mbox {day}}$

where P is total heat production at complete rest, m is the weight, h is the stature (height), and a is the age, and with the difference in BMR for men and women being mainly due to differences in body weight. ^[2] For example, a 55 year old woman weighing 130 lb (59 kg) and 5 feet 6 inches (168 cm) tall would have a BMR of 1272 kcal per day or 53 kcal/h (61.3 watts).

It was the best prediction equation until recently, when MD Mifflin and ST St Jeor in 1990 created new equation:

$P = \left ( \frac {9.99 m} {1 ~ \mbox {kg}} + \frac {6.25 h} {1 ~ \mbox {cm}} - \frac {4.92 a} {1 ~ \mbox {year}} + s \right ) \frac {\mbox {kcal}} {\mbox {day}},$ where s is +5 for males and −161 for female. According to this formula, the woman in the example above has a BMR of 1208 kcal per day.

During the last 100 years, lifestyles have changed and a survey in 2005 showed it to be about 5% more accurate.

These formulae are based on body weight, which does not take into account the difference in metabolic activity between lean body mass and body fat. A more accurate formula is the Katch-McArdle formula based on lean body mass:

$P = 370 + \left( {21.6 \cdot LBM} \right) ,$ where LBM is the lean body mass in kg.^[3] According to this formula, if the woman in the example has a body fat percentage of 30%, her BMR would be 1263 kcal per day.

To calculate daily calorie needs, this BMR value is multiplied by a factor with a value between 1.2 and 1.9, depending on the person's activity level.

[edit] Animal BMR

Kleiber's law relates the BMR for animals of different sizes and the observations indicate that the BMR is proportional to the 3/4 power of body mass. Warm blooded, cold blooded and unicellular animals fit on different curves.

[edit] Biochemistry

Energy expenditure breakdown
liver	27%
brain	19%
heart	7%
kidneys	10%
skeletal muscle	18%
other organs	19%

About 70% of a human's total energy expenditure is due to the basal life processes within the organs of the body (see table). About 20% of one's energy expenditure comes from physical activity and another 10% from thermogenesis, or digestion of food (postprandial thermogenesis).^[4] All of these processes require an intake of oxygen along with coenzymes to provide energy for survival (usually from macronutrients like carbohydrates, fats, and proteins) and expel carbon dioxide, which is explained by the Krebs cycle.

What enables the Krebs cycle to perform metabolic changes to fats, carbohydrates, and proteins is energy which can be defined as the ability or capacity to do work. The breakdown of large molecules into smaller molecules associated with release of energy is catabolism. The building up process is termed anabolism. The breakdown of proteins into amino acids is an example of catabolism while the formation of proteins from amino acids is an anabolic process.

Exergonic reactions are energy-releasing reactions and are generally catabolic. Endergonic reactions require energy and include anabolic reactions and the contraction of muscle. Metabolism is the total of all catabolic, exergonic, anabolic, endergonic reactions.

Adenosine Triphosphate (ATP) is the intermediate molecule that drives the exergonic transfer of energy to switch to endergonic anabolic reactions used in muscle contraction. This is what causes muscles to work which can require a breakdown, and also to build in the rest period, which occurs during the strengthening phase associated with muscular contraction. ATP is composed of adenine, a nitrogen containing base, ribose, a five carbon sugar (collectively called adenosine), and three phosphate groups. ATP is a high energy molecule because it stores large amounts of energy in the chemical bonds of the two terminal phosphate groups. The breaking of these chemical bonds in the Krebs Cycle provides the energy needed for muscular contraction.

[edit] Glucose

Because the ratio of hydrogen to oxygen atoms in all carbohydrates is always the same as that in water — that is, 2 to 1 — all of the oxygen consumed by the cells is used to oxidize the carbon in the carbohydrate molecule to form carbon dioxide. Consequently, during the complete oxidation of a glucose molecule, six molecules of carbon dioxide are produced and six molecules of oxygen are consumed.

The overall equation for this reaction is:

C₆H₁₂O₆ + 6 O₂ → 6 CO₂ + 6 H₂O

Because the gas exchange in this reaction is equal, the respiratory quotient for carbohydrate is unity or 1.0:

R.Q. = 6 CO₂ / 6 O₂

[edit] Fats

The chemical composition for fats differs from that of carbohydrates in that fats contain considerably fewer oxygen atoms in proportion to atoms of carbon and hydrogen. When listed on nutritional information tables, fats are generally divided into six categories: total fats, saturated fatty acid, polyunsaturated fatty acid, monounsaturated fatty acid, dietary cholesterol, and trans fatty acid. From a basal metabolic or resting metabolic perspective, more energy is needed to burn a saturated fatty acid than an unsaturated fatty acid. The fatty acid molecule is broken down and categorized based on the number of carbon atoms in its molecular structure. The chemical equation for metabolism of the twelve to sixteen carbon atoms in a saturated fatty acid molecule shows the difference between metabolism of carbohydrates and fatty acids. Palmitic acid is a commonly studied example of the saturated fatty acid molecule.

The overall equation for the substrate utilization of palmitic acid is:

C₁₆H₃₂O₂ + 23 O₂ → 16 CO₂ + 16 H₂O

Thus the R.Q. for palmitic acid is 0.696:

R.Q. = 16 CO₂ / 23 O₂ = 0.696

[edit] Proteins

Proteins are composed of carbon, hydrogen, oxygen, and nitrogen arranged in a variety of ways to form a large combination of amino acids. Unlike fat the body has no storage deposits of protein. All of it is contained in the body as important parts of tissues, blood hormones, and enzymes. The structural components of the body that contain these amino acids are continually undergoing a process of breakdown and replacement. The respiratory quotient for protein metabolism can be demonstrated by the chemical equation for oxidation of albumin:

C₇₂H₁₁₂N₂O₂₂S + 77 O₂ → 63 CO₂ + 38 H₂O + SO₃ + 9 CO(NH₂)₂

The R.Q. for albumin is 63 CO₂/ 77 O₂ = 0.818

The reason this is important in the process of understanding protein metabolism is that the body can blend the three macronutrients and based on the mitochondrial density, a preferred ratio can be established which determines how much fuel is utilized in which packets for work accomplished by the muscles. Protein catabolism (breakdown) has been estimated to supply 10% to 15% of the total energy requirement during a two hour training session. However, if a person's muscle glycogen supplies are low from previous exercise sessions, the amount of energy derived from protein catabolism could increase from 15% to 45%. This process could severely degrade the protein structures needed to maintain survival such as contractile properties of proteins in the heart, cellular mitochondria, myoglobin storage, and metabolic enzymes within muscles.

The oxidative system (aerobic) is the primary source of ATP supplied to the body at rest and during low intensity activities and uses primarily carbohydrates and fats as substrates. Protein is not normally metabolized significantly, except during long term starvation and long bouts of exercise (greater than 90 minutes.) At rest approximately 70% of the ATP produced is derived from fats and 30% from carbohydrates. Following the onset of activity, as the intensity of the exercise increases, there is a shift in substrate preference from fats to carbohydrates. During high intensity aerobic exercise, almost 100% of the energy is derived from carbohydrates, if an adequate supply is available.

[edit] Aerobic vs. anaerobic exercise

Studies published in 1992^[5] and 1997^[6] indicate that the level of aerobic fitness of an individual does not have any correlation with the level of resting metabolism. Both studies find that aerobic fitness levels do not improve the predictive power of Fat Free Mass for resting metabolic rate.However recent research suggests that endurance training does indeed result in an increase in energy consumption. A recent study^[7] has shown that the resting energy consumption of men who run for four hours a week is 54% higher than sedentary men.

This means it is unclear whether aerobic or anaerobic exercise are more effective in raising the resting metabolic rate (Basal Metabolic Rate). Anaerobic exercise, such as weight lifting, builds additional muscle mass, which is Fat Free Mass. Additional Fat Free Mass will lead to a higher resting metabolic rate according to the above studies. Also, while aerobic exercise is beneficial for cardiovascular reasons as well as direct calorie burning, recent studies seem to suggest that heavy endurance exercise is also good for increasing resting metabolism it is however unclear if light cardiovascular training has the same effect.

[edit] Longevity

[edit] Organism Longevity and Basal Metabolic Rate

In allometric scaling maximum potential life span (MPLS) is directly related to metabolic rate (MR), where MR is the recharge rate of a biomass made up of covalent bonds subject to deterioration over time from thermodynamic, entropic pressure. Metabolism is essentially about redox coupling, and has nothing to do with thermogenesis. Metabolic efficiency (ME) is then expressed as the efficiency of this coupling, a ratio of amperes captured and used by biomass (W), to the amperes available for that purpose. MR is measured in watts, W is measured in grams. These factors are combined in a power law, an elaboration on Kleiber's Law relating MR to W and MPLS, that appears as MR = W^ (4ME-1)/4ME. When ME is 100%, MR = W^3/4, what is known popularly as quarter power scaling, a version of allometric scaling premised upon unreal estimations of biological efficiency.

The equation reveals that as ME drops below 20%, for W < one gram, MR/MPLS increases so dramatically as to endow W with virtual immortality by 16%. The smaller W is to begin with, the more dramatic is the increase in MR as ME diminishes. All of the cells of an organism fit into this range, i.e., less than one gram, and so this MR will be referred to as BMR.

But the equation reveals that as ME increases over 25%, BMR approaches zero. The equation also shows that for all W > one gram, where W is the organization of all of the BMRs of the organism's structure, but also includes the activity of the structure, as ME increases over 25%, MR/MPLS increases rather than decreases, as it does for BMR. An MR made up of an organization of BMRs will be referred to as an FMR. As ME decreases below 25%, FMR diminishes rather than increases as it does for BMR.

The antagonism between FMR and BMR is what marks the process of aging of biomass W in energetic terms. The ME for the organism is the same as that for the cells, such that the success of the organism's ability to find food (and lower its ME), is key to maintaining the BMR of the cells driven, otherwise, by starvation, to approaching zero; while at the same time a lower ME diminishes the FMR/MPLS of the organism.^{[citation needed]}

[edit] Medical considerations

Each person's metabolism is unique due to his unique physical makeup and physical behavior. For some, this makes weight management a very difficult undertaking requiring sophisticated expertise. There are a number of medical adjustments to natural human processes that can affect one's metabolism.

Menopause affects metabolism but in different ways for different people, thus hormones are sometimes used to minimize the effects of menopause. Weight training can have a longer impact on metabolism than aerobic training, but there are no formulas currently written which can predict the length and duration of a raised metabolism from trophic changes with anabolic neuromuscular training. Gastric bypass surgery is used to reduce the content capacity of the stomach, bringing caloric intake down and lowering thermogenesis. Because the surgery significantly reduces caloric consumption, it will decrease BMR and RMR over time in the same fashion as aging, because the volume of the stomach is reduced. The stomach along with the rest of the digestive tract is a major contributor to BMR and RMR. Celiac disease, which reduces the ability of the stomach to digest food, may also reduce BMR and RMR. Celiac disease is fairly common, occurring in 1% of the U.S. population, with 2 million undiagnosed.^[11]^{[citation needed]}

[edit] Cardiovascular implications

Heart rate is determined by the medulla oblongata and part of the pons, two organs located inferior to the hypothalamus on the brain stem. Heart rate is important for basal metabolic rate and resting metabolic rate because it drives the blood supply, stimulating the Krebs cycle. During exercise that achieves the anaerobic threshold, it is possible to deliver substrates that are desired for optimal energy utilization. The anaerobic threshold is defined as the energy utilization level of heart rate exertion that occurs without oxygen during a standardized test with a specific protocol for accuracy of measurement, such as the Bruce Treadmill protocol (see Metabolic equivalent). With four to six weeks of targeted training the body systems can adapt to a higher perfusion of mitochondrial density for increased oxygen availability for the Krebs cycle, or tricarboxylic cycle, or the glycolitic cycle. This in turn leads to a lower resting heart rate, lower blood pressure, and increased resting or basal metabolic rate.

Knowing what the body burns at rest or through exercise yields (via heart rate monitoring) a targeted program of energy utilization based on metabolic performance. The resting heart rate is correlated to the resting metabolic rate because of the singular contribution made by the heart to survival. By measuring heart rate we can then derive estimations of what level of substrate utilization is actually causing biochemical metabolism in our bodies at rest or in activity. This in turn can help a person to maintain an appropriate level of consumption and utilization by studying a graphical representation of the anaerobic threshold. This can be confirmed by blood tests and gas analysis using either direct or indirect calorimetry to show the effect of substrate utilization. The measures of basal metabolic rate and resting metabolic rate are becoming essential tools for maintaining a healthy body weight.

[edit] See also

[edit] Notes

^ CaloriesPerHour.com. "Diet and Weight Loss Tutorial". Calculating BMR and RMR. http://www.caloriesperhour.com/tutorial_BMR.php. Retrieved on 2008-01-26.
^ Harris J, Benedict F (1918). "A Biometric Study of Human Basal Metabolism". Proc Sci U S a 4 (12): 370–3. doi:10.1073/pnas.4.12.370. PMID 16576330.
^ Tom Venuto (2003). Burn the Fat, Feed the Muscle. ISBN 0-9724132-0-0. http://www.burnthefat.com.
^ Template:Exercise Physiology. McArdle, William D. 2nd edition. 1986. Lea & Febigier, Philadelphia.
^ CE Broeder, KA Burrhus, LS Svanevik and JH Wilmore (1992). "American Journal of Clinical Nutrition". The effects of aerobic fitness on resting metabolic rate. http://www.ajcn.org/cgi/content/abstract/55/4/795. Retrieved on 2007-11-23.
^ D. A. Smith, J. Dollman, R. T. Withers, M. Brinkman, J. P. Keeves, and D. G. Clark(1997). "Journal of Applied Physiology". Relationship between maximum aerobic power and resting metabolic rate in young adult women. http://jap.physiology.org/cgi/content/abstract/82/1/156. Retrieved on 2007-11-23.
^ http://www.pnas.org/content/105/43/16701
^ Miquel J, Lundgren PR, Bensch KG, Atlan H (1976). "The effects of temperature on the aging process have been investigated in approximately 3500 imagoes of male Drosophila melanogaster". Mechanisms of Aging and Development 5 (5): 347–370. doi:10.1016/0047-6374(76)90034-8. PMID 823384.
^ Ragland SS, Sohal RS (1975). "Ambient temperature, physical activity and aging in the housefly, Musca domestica". Experimental Gerontology 10 (5): 279–289. doi:10.1016/0531-5565(75)90005-4. PMID 1204688.
^ Speakman JR, Selman C, McLaren JS, Harper EJ (2002). "Living fast, dying when? The link between aging and energetics". The Journal of Nutrition 132 (6, Supplement 2): 1583S–1597S. PMID 12042467. http://jn.nutrition.org/cgi/content/full/132/6/1583S.
^ "MedlinePlus: Celiac Disease". http://www.nlm.nih.gov/medlineplus/celiacdisease.html. Retrieved on 2006-09-15.

[edit] References

Tsai, Adam Gilden, MD and Wadden, Thomas A. PhD. Systematic Review: An Evaluation of Major Commercial Weightloss Programs in the United States. Ann Intern Med. 2005, 142:56-66.
Gustafson, Deborah, PhD; Rothenburg, Elisabet, PhD; Blennow, Kaj, PhD; Steen, Bertil, MD,PhD; Skoog, Ingmar, MD, PhD. An 18-Year Follow-Up of Overweight and Risk of Alzheimer Disease. Arch Intern Med: Vol. 163, July 14, 2003, pgs 1524 through 1528.
Expert Panel on the Identification, Evaluation and Treatment of Overweight in Adults. Clinical Guidelines on the Identification, Evaluation, and Treatment of Overweight and Obesity in Adults: Executive Summary. Downloaded from www.ajcn.org on July 9, 2006, Am J Clin Nutr 1998; 68:899-917.
Segal, Arthur C. A Linear Diet Model. The College Mathematics Journal, January 1987.
Pike, R.L., and Brown, M. Nutrition: An Integrated Approach, 2nd edition New York: Wiley. 1975
Sahlin, K., Tonkonogy, and Soderlund, K. Energy Supply and muscle fatigue in humans. Acta Physiol. Scand. 162:261-266. 1998
Saltin, B, and Gollnick. Skeletal muscle adaptability: Significance for metabolism and performance. In Handbook of Physiology, L.D. Peachey, R.H. Adrian, and S.R. Geiger, eds. Baltimore: Williams & Wilkins. 1983. pg 540 - 555.
Thorstensson, P. Muscle strength, fiber types and enzymes in man. Acta Physiol. Scand. 102: 443. 1976
Thorstensson, P. , Sjodin, B. Actinomyosin ATPase, myokinase, CPK and LDH in human fast and slow twitch muscle fibers. Acta Physiol. Scand. 99: 225-229. 1975
VanHelder, W., Radomski, Goode, R. and Casey, K. Hormonal and metabolic response to three types of exercise of equal duration and external work output. Eur. J. of Appl. Physiol. 54:337-342. 1985
Wells, J., Balke, B. and Van Fossan, D. Lactic Acid accumulation during work. A suggested standardization of work classification. J Appl. Physiol. 10: 51-55. 1957.
McArdle, W. Exercise Physiology: Energy, Nutrition, and Human Performance. Lea & Febiger. Philadelphia, PA. 1986.

[edit] External links

The original 1918 Harris-Benedict article (free full text)
Harris-Benedict study. Detailed discussion of antecedents, data, measurements, statistics (Published by The Carnegie Institution of Washington 1919)
BMR Calculator with Calorie Requirements and Macronutrient Ratio Adjustor
Harris-Benedict Calculator
What do BMR and RMR stand for?
Dietary Guidelines from the U.S. Government
Food Consumption patterns in the U.S.
[1] Body composition Explained
[2]Harvard University's explanation of Metabolic Equivalent Tables
[3] Temporal Trend Shifts and the Ecological Perspectives on Weight Gain in the US
[4] Information on the National Weight Control Registry.
[5] Health Trends in the United States
[6] BMR as affected by alcohol and nicotine
[7] DoD Body Fat Estimation Equation using neck and waist girth measurements.

[0] CaloriesPerHour.com. "Diet and Weight Loss Tutorial". Calculating BMR and RMR. http://www.caloriesperhour.com/tutorial_BMR.php. Retrieved on 2008-01-26.

[Harris1918-1] Harris J, Benedict F (1918). "A Biometric Study of Human Basal Metabolism". Proc Sci U S a 4 (12): 370–3. doi:10.1073/pnas.4.12.370. PMID 16576330.

[BFFM-2] Tom Venuto (2003). Burn the Fat, Feed the Muscle. ISBN 0-9724132-0-0. http://www.burnthefat.com.

[3] Template:Exercise Physiology. McArdle, William D. 2nd edition. 1986. Lea & Febigier, Philadelphia.

[4] CE Broeder, KA Burrhus, LS Svanevik and JH Wilmore (1992). "American Journal of Clinical Nutrition". The effects of aerobic fitness on resting metabolic rate. http://www.ajcn.org/cgi/content/abstract/55/4/795. Retrieved on 2007-11-23.

[5] D. A. Smith, J. Dollman, R. T. Withers, M. Brinkman, J. P. Keeves, and D. G. Clark(1997). "Journal of Applied Physiology". Relationship between maximum aerobic power and resting metabolic rate in young adult women. http://jap.physiology.org/cgi/content/abstract/82/1/156. Retrieved on 2007-11-23.

[6] ttp://www.pnas.org/content/105/43/16701

[7] Miquel J, Lundgren PR, Bensch KG, Atlan H (1976). "The effects of temperature on the aging process have been investigated in approximately 3500 imagoes of male Drosophila melanogaster". Mechanisms of Aging and Development 5 (5): 347–370. doi:10.1016/0047-6374(76)90034-8. PMID 823384.

[8] Ragland SS, Sohal RS (1975). "Ambient temperature, physical activity and aging in the housefly, Musca domestica". Experimental Gerontology 10 (5): 279–289. doi:10.1016/0531-5565(75)90005-4. PMID 1204688.

[9] Speakman JR, Selman C, McLaren JS, Harper EJ (2002). "Living fast, dying when? The link between aging and energetics". The Journal of Nutrition 132 (6, Supplement 2): 1583S–1597S. PMID 12042467. http://jn.nutrition.org/cgi/content/full/132/6/1583S.

[10] "MedlinePlus: Celiac Disease". http://www.nlm.nih.gov/medlineplus/celiacdisease.html. Retrieved on 2006-09-15.

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