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`Lecture 11. Elements of Body CompositionLecture 11. Elements of Body CompositionL. J. Hoffer REVISED May 15, 2007IntroductionThe composition of the human body changes in most serious diseases, and the detection and evaluation of these changes is an essential part of physical diagnosis. In this chapter the subdivisions of body composition are described, their medical importance is discussed, and the use of physical findings and laboratory tests to evaluate them demonstrated. We will look in special detail into the structure of a crucial body constituent, protein.The Body CompartmentsThe human body consists of 4 compartments: (1) fat, (2) lean soft tissues, (3) free fluids, and (4) skeleton.1. FatFat is the body's chief energy store. Its size is the most variable of all the body's compartments. What we regard as a &quot;normal&quot; body fat content - conventionally taken as ~ 20% of body weight for a normal young man and ~ 30% for a normal young woman - is rather arbitrary. Fat can make up as little as 5% of weight, and it seems to have no upper limit. There are cases on record of persons whose body weight exceeded 1000 pounds, most of the excess weight being fat. Excess body fat is associated with an increased risk of death and a greater risk of several important diseases, including high blood pressure, diabetes mellitus, and blood lipid disorders; these risks increase with increasing obesity. How is body fat content measured? In the research setting, the contribution of pure fat to body weight is usually measured by densitometry. The density of water is 1.000 kg/L, while the density of fat is 0.900. The density of the remainder of the body, called the &quot;fat-free mass&quot; or lean body mass (LBM), is 1.100. The more fat there is in a body the closer the body's density is to 0.900. Each value of fat/total body weight corresponds to a unique total body density value. According to the Siri equation: Fraction of body weight that is pure fat = 4.95/D minus 4.50 In this equation, D is whole body density, i.e. weight divided by volume. Body weight is easily measured. Volume is calculated from body weight measured on land minus body weight measured under water.Lecture 11. Elements of Body CompositionLecture 11. Elements of Body CompositionArchimedes was the first to realize that an object, when under water, displaces a volume equal to its own volume, while its weight is reduced by the weight of the water it has displaced. A person who weighs 90 kg on land and 2 kg under water must have displaced 88 kg (= 88 L) of water. Therefore the volume of his body is 88 L, and his D is 90/88 = 1.02 kg/L. (The small amounts of air in his airways, stomach and intestines add slightly to his total volume, and in real studies a correction is made for this using techniques that go beyond the scope of this chapter.) The fat mass in this example is 0.35 X 90 = 31.5 kg and the lean body mass is 90 - 31.5 = 58.5 kg. Thus, this person is 35% pure fat by weight. The Siri equation was derived by W.E. Siri, &quot;Body composition from fluid spaces and density; in: Techniques for Measuring Body Composition, J Brozedk and A. Henschel, Eds. National Academy of Sciences, Washington, 1961, pp 223-4. For a very interesting and enjoyable experience and a graphic demonstration of the Archimedes principle and derivation of the Siri equation, you may please visit http://nutrition.uvm.edu/nfs/htm/interactive_learning/index.htm and click on the button entitled &quot;body composition.&quot; Other useful information at this site includes a calculator of how much energy is expended in different activities, and a diet analyzer that indicates the energy values of different foods. A good store of fat could be useful for a weak swimmer since buoyancy reduces the amount of work needed to keep from sinking. Ignoring the minor effect of air in the airways, etc., can you calculate the percent body fat necessary to be weightless in fresh water? (Solve this yourself.) Body fat can also be approximately calculated from total body water (TBW). The lean body mass is approximately 73% water over a wide range of body fat contents. TBW can be determined, either by water isotope dilution or by using bioelectrical impedance (described later in this chapter).  From this information the percent of body weight that is fat can be calculated. Example: A patient weighs 75 kg and her TBW is found to be 30 kg. Her LBM may be estimated as follows: LBM = 30/0.73 = 41 kg. Fat mass = 75 kg - 41 kg = 34 kg Conclusion: fat makes up (34/75) · 100 = 45% of the patient's body weight. Be aware that the &quot;fat&quot; which these techniques indicate is pure fat. Pure fat is not the same as the &quot;fat&quot; one sees and touches when examining a patient, which is adipose tissue. Adipose tissue is only ~ 85% pure fat, because fat is located within fat cells (adipocytes) which contain some water, and they require a supporting structure of connective tissue and blood vessels which have water associated with them. When people gain or lose body fat they gain or lose adipose tissue. For precise calculations, one should factor in the gain or loss of body water that accompanies the fat. For example, when a person gains or loses 1 kg of pure fat, he/she will actually gain or lose 1/0.85 = 1.18 kg of adipose tissue and his/her body weight will increases or decrease by 1.18 kg. Clinical assessment of body fatLecture 11. Elements of Body CompositionLecture 11. Elements of Body CompositionUnderwater weighing is impractical and unnecessarily precise for clinical medicine. TBW is sometimes estimated in health clubs using bioelectrical impedance, and the per cent body fat calculated as shown above. In clinical medicine one can assess body fatness by simple examination of the patient and measurement of the body mass index (BMI). BMI = weight (in kg)/height2 (in m) To calculate BMI you must know (memorize) that 1 kg = 2.2 lb and 1 inch = 2.54 cm A BMI that is greater or less than normal usually means body fat is increased or decreased. What is a normal BMI? According to current guidelines adult BMI normally ranges between 18.5 and 25, but this norm is to some extent culturally determined. In Thailand the BMI might normally range from 18 to 22. BMI predicts body fat reasonably well because, in health, the other body compartments tend to be constant and, in any case, they are relatively constrained in their range of variation. But doctors often see the extremes, and they typically see people who are not healthy. When using the BMI to estimate body fatness of sick patients, therefore, one assesses the other body compartments for deviations from normal and makes approximate corrections for changes that are detected. For example, some professional athletes and body builders are overweight because of an increased muscle mass, and often have a percent body fat that is lower than normal. Body weight is often increased in sick patients because they accumulate fluid in their extracellular space (described later in this chapter). Bearing these precautions in mind, it is generally the case that a BMI &gt; 26 implies body fat content is increased and a BMI &lt; 20 means it is reduced. A BMI &gt; 30 is associated with an increased health risk that increases in rough proportion to the rising BMI. The identification of the health risks associated with mild and moderate obesity is an area of active research and considerable controversy.2. Lean soft tissuesMore simply called the &quot;lean tissues,&quot; the lean soft tissues are the living, metabolically active part of the body. It is here that the body's biochemical reactions occur (adipose tissue has metabolic activity, but far less than that of lean tissues). The lean tissues are the body's repository of nonstructural protein, watersoluble vitamins, and many minerals (potassium, zinc, iron, and nonskeletal phosphorus and magnesium). Caution: do not to confuse lean tissue mass with lean body mass (LBM) as defined in the previous section. The lean tissues normally account for ~50% of the weight of a non-obese person. About 80% of the lean tissue compartment is accounted for by skeletal muscle. The remaining 20% consists of all the other non-adipocyte cells of the body, including those of the blood and immune system, and the organs, such as liver, kidneys, spleen, intestines, lungs, heart and nervous system. Unlike fat, the lean tissue compartment is constrained in size. Reduction by more than 10-15% (typically due to loss of skeletal muscle mass) is associated with reduced strength, feeling unwell, and a variety of physiological derangements which will be discussed in subsequent lectures this year. For an adult patient, a reduction in lean tissue mass &gt; 25% is associated with severe disability and an increased risk of death from several possible complications. It is for this reason that a 25% or greater depletion of lean tissue mass is commonly used to trigger the medical decision to initiate forced feeding of a patient with anorexia nervosa. Lean tissue loss &gt; 45% is often incompatible with survival.Lecture 11. Elements of Body CompositionLecture 11. Elements of Body CompositionAssessment of the lean tissue mass Two measurable indicators of the lean tissue mass are whole-body body nitrogen (N) and wholebody potassium (K). In clinical research, body N can be measured from the radiation emitted from the body after neutron activation. Protein is distinguished from other body constituents by its N content, so total body N provides specific information about the protein content of the living body. When interpreting neutron activation data it is important to recognize that almost half the body's protein is found in the connective tissue of the extracellular compartment and hence is irrelevant to the lean tissue store. However, since extracellular protein (mostly collagen) turns over very slowly, changes in body N that occur over periods of weeks do represent true changes in the lean tissue mass. Body K (atomic mass 39) can be measured from the low-level radiation emitted by the naturallyoccurring isotope 40K or by injecting the radioactive isotope 42K and measuring its dilution (specific radioactivity) in the predominant isotope, 39K. Approximately 95% of the body's K is located within lean tissue cells, and in healthy people the body's K content predicts the lean tissue mass quite accurately. There is no disease caused by lean tissue gain. What interests physicians is whether the patient's lean tissue mass is reduced, and if it is, by how much. For this purpose BMI, along with a inspection of the patient's muscle bulk and adipose tissue is quite adequate. In a patient whose BMI is normal or below normal, body fat cannot account for more than 20-30% of body weight. If the BMI of such a person falls below this value, we can conclude that lean tissue losses must be contributing importantly to the weight loss, since there just isn't very much fat to lose. The following general rule applies in situations in which BMI falls from normal values to lower ones: Percent reduction in body weight = Percent loss of lean tissue mass Problem: A normal man (height 1.75 m) weighs 70 kg. He develops a chronic infection and over the ensuing 6 months his weight decreases by 25 kg. How much lean tissue did he lose? Solution: His initial BMI was 22.9, a normal value. After 6 months of illness he lost nearly 36% of his initial body weight. Therefore (using the rule above) he has lost ~ 36% of his lean tissue mass. This is severe lean tissue wasting. Note that his BMI is now only 14.7. Studies of hospitalized patients indicate that the risk of death increases as the BMI falls progressively below about 18. Death is almost inevitable when the BMI falls below 14. Note that this analysis assumes there has been no change in the free fluid (extracellular) compartment. As will be explained later, changes in extracellular water content commonly occur in starvation and need to be recognized and accounted for when assessing a patient. How does one detect lean tissue (protein) loss in very obese people? This can be a problem. IN fact protein malnutrition not infrequently goes undetected in such patients. We will consider methods for diagnosing lean tissue loss in these patients subsequently. The range of body composition we term as &quot;normal&quot; is very wide, and somewhat culturally determined. A BMI of 18 is compatible with health if it represents the person's norm. It is not unusual for a healthy woman 5 feet 7 inches tall to weigh only 115 pounds. (Questions to ask such persons: Were you this weight all your adult life? Are your healthy parents, brothers and sisters, orLecture 11. Elements of Body CompositionLecture 11. Elements of Body Compositiongrown children, as thin as you? Does this represent a change from normal?) If a person's normal BMI is 18, you may be confident that he or she has less muscle mass/kg of body weight than another person whose BMI is 23, but this, in itself, does not imply disease. If a person's BMI was normally 23 but has now dropped to 18 you can be confident that lean tissue loss accounted for a major component of the weight loss (see rule above), and may confirm this by examining the size of his/her various muscle groups. (Fat mass or may not have occurred as well, depending on the reason for the weight loss; see later discussion.) As will be discussed later, a proper assessment of the medical significance of a borderline low BMI requires learning whether the current BMI represents a change from usual, and whether weight loss is continuing. Changes in lean tissue mass and body weight are related to changes in body N Adipose tissue is 15% water by weight, whereas the lean tissues are approximately 80% water by weight. The remaining 20% of the weight of lean tissues is protein. (It is on this basis that &quot;wet weight&quot; and &quot;dry weight&quot; of tissues are measured in biochemistry research. A small sample of &quot;fresh&quot; tissue is weighed immediately after excision and weighed again after prolonged dry heating in an oven. The dry weight of liver or muscle is very close to its protein content. You may do the experiment yourself on a sample of fresh lean beef muscle.) The lean tissues can be envisioned as a solution of potassium, phosphates, magnesium, zinc, and vitamins dissolved in protein soup. When the body loses lean tissue the amino acids in it are oxidized and their N excreted, chiefly as urinary urea. Since protein is 16% N, one can calculate how fast lean tissues are being lost by measuring N excretion. Problem: A person with a severe catabolic (protein-losing) illness is losing 15 g N/day from his body. He is not receiving any protein nutrition. What is the rate of lean tissue loss?  Solution: Ignore the possibility that N is being lost from extracellular proteins, since their metabolism is far too slow to contribute importantly to short-term changes in N gain or loss. On that assumption, 1 g N lost from the body implies a 6.25 g loss of protein from lean tissues. Each g protein lost is equivalent to a loss of 5 g of lean &quot;wet&quot; tissues. Therefore, the patient is losing (15 x 6.25 x 5) = 469 g of lean tissue mass/day. If this catabolic loss is not reduced the patient will lose more than 3 kg of lean tissues in a week, with potentially serious adverse consequences. It is convenient to lump all the lean tissue cells together as if they are one entity, but it ignores their considerable functional, metabolic and even compositional differences. For example, the metabolic activity of the &quot;central&quot; lean tissue cells (liver, kidney, intestines) is about twenty times faster than that of skeletal muscle cells, and their potassium content is about half that of skeletal muscle.3. Extracellular (&quot;free&quot;) fluidsExtracellular fluid (ECF) makes up approximately 20% of normal body weight. Almost all the body's sodium (Na) is located in the ECF space, which consists of two isotonic compartments in osmotic equilibrium: the interstitial space and the intravascular space. The interstitial spaceLecture 11. Elements of Body CompositionLecture 11. Elements of Body CompositionInterstitial space accounts for 3/4 of the total ECF, or nearly 11 liters in a man who weighs 70 kg. Edema (a palpable and often visible swelling of the body due to extracellular fluid accumulation) is the characteristic and specific sign of an increased interstitial compartment. Clinical edema is an insensitive sign of increased interstitial volume, since as much as 10 pounds (4.5 kg) of interstitial fluid can accumulate (largely within the skin) before edema becomes clinically apparent. The most sensitive way to detect interstitial fluid accumulation is by frequent weighing of patients at risk of developing it.  Increased interstitial volume is usually associated with an increased intravascular space, but this is not always the case. (The most common example of increased ECF in the presence of a reduced intravascular space is when the patient has a severely lowered serum albumin concentration, which lowers plasma oncotic pressure. In this situation the interstitial space is increased but the intravascular space can be normal or even reduced. This topic is covered in detail elsewhere in the curriculum. ) When the interstitial space is depleted, skin loses its juiciness (the medical term for &quot;skin juiciness&quot; is turgor). If the skin over the deltoid muscle or sternum is pinched up it will remain tented, like a piece of putty, for a few moments: this is proof of a &quot;loss of skin turgor.&quot; Moisture inside of the mouth decreases, and the small pool of saliva normally present under the tongue disappears. Reduction of the interstitial space is invariably associated with a reduced intravascular space. The symptoms of a reduced intravascular compartment will therefore be found as well. The intravascular space Blood is 60-65% water and 35-40% cells (and the blood cells themselves are 80% water). Blood volume is normally about 8% of body weight. For a 70 kg person that is about 6 L (of which 3.5 L is plasma and 2.5 L is blood cells). If the blood volume falls by 50% or more (as in severe hemorrhage) the patient will no longer be able to perfuse his/her organs and will go into hypovolemic shock and, if not fluid resuscitated, will die. Typical findings in less severe but still important intravascular volume depletion (&gt;15%) are low blood pressure (especially upon assuming the upright position), rapid heart rate (which accelerates further upon standing or sitting up), the collapse of normally visible veins, such as the jugular veins (low venous pressure), reduced urine excretion rate, and feeling terrible. Because blood flow to the kidneys is reduced urea is not cleared as effectively from the circulation and its serum concentration rises. If the cause of intravascular depletion is fluid loss (rather than whole blood loss, as occurs in acute hemorrhage) the hematocrit (percent of blood made up of cells) will rise, and the findings of interstitial fluid depletion will be present. If the cause is acute hemorrhage the hematocrit will initially be normal, since blood cells and plasma have been lost in equal proportions, but over the next several hours the hematocrit will fall as fluid enters the intravascular space from the interstitial space. If your patient in shock and the hematocrit is normal, hemorrhage (which may be internal!) is still a distinct possibility because it may have occurred very recently and even be ongoing at that moment. Expansion of the intravascular space is typically associated with a normal or high blood pressure, swollen jugular veins and an expanded interstitial compartment. A typical finding is edema of the dependent parts of the body (ankles, lower legs: why there? -- because of gravity) but if the expansion is very rapid there will not have been sufficient time for edema to accumulate. In severe cases fluid accumulates in the pulmonary interstitial space and may extravasate into the alveoli, interfering with gas exchange, causing hypoxemia and even lactic acidosis. This life-threateningLecture 11. Elements of Body CompositionLecture 11. Elements of Body Compositioncondition is termed &quot;pulmonary edema.&quot; Pulmonary edema also occurs in hospitalized patients with limited cardiac function who were infused with blood products or salty solutions at too rapid a rate. The &quot;third space&quot; Extracellular fluid is sometimes drawn into a local area of severe disease hidden within the body. If this occurs rapidly, the volume shift can come at the expense of the intravascular space and create the clinical picture of intravascular volume depletion. This may occur, for example, in pancreatitis and other intra-abdominal catastrophes. The patient demonstrates the findings of decreased intravascular volume, but no external reason for it, such as visible hemorrhage, severe diarrhea, or excessive urine loss, is apparent. The missing intravascular volume must therefore have gone somewhere else, into a &quot;third space,&quot; either because of unrecognized internal hemorrhage (for example, ruptured spleen or aortic aneurysm, or hemorrhage into chest cavity, retroperitoneum, or hip joint space) or because of diffusion into a new interstitial fluid space. Slow third space accumulations can occur within the abdominal cavity in some forms of liver disease and in inflammatory diseases of the peritoneum. This accumulation is called ascites.4. SkeletonBy this I refer to the bones and all the connective tissue in the body (largely collagen). Changes in adult skeletal mass are important, but only over months and years, so they are not considered further in these lectures.Total Body WaterWater flows freely within and between the body's intracellular and extracellular compartments, but it contributes very differently to each of them. The ECF is ~ 100% water. The lean tissues are 80% water. Whole blood is ~ 92% water. (How do we know this? Because whole blood is normally 60% plasma and 40% cells which are themselves 80% water, so 0.6 + (0.8)(0.4) = 0.92.) Adipose tissue is ~ 15% water. The TBW of a young man with normal body composition (~ 20% fat) is ~ 60% of body weight. The TBW of a young woman (~ 30% fat) TBW is ~ 50% of body weight. With increasing age the contribution of fat to body weight increases because as people age their muscle mass decreases and their absolute fat mass usually increases. TBW may be assumed to be 50% of the body weight of an older person (&gt; age 50) whose BMI is normal. You can readily derive these values yourself using the relationship LBM = 73% water, but most doctors simply memorize the relationship: TBW = 0.5 X adult body weight, and apply it to everyone.) It is important to estimate TBW when diagnosing and treating water deficiency states, which occur frequently in clinical medicine. Water moves freely between the cells (which accounts for approximately 40% of normal body weight) and the ECF (20% of normal body weight), whereas sodium remains in the ECF. In an idealized condition of pure water deficiency the amount of sodium in the body is constant, merely being dissolved in a smaller amount of water. The patient's water deficit can be calculated using the measured body weight and serum sodium concentration [Na]. Methods for calculating the free water deficit of a dehydrated patient are covered in other sections of the curriculum.Lecture 11. Elements of Body CompositionLecture 11. Elements of Body CompositionIn research, TBW is measured by having the subject swallow a known amount of an isotope of water, then, after equilibration, measuring its dilution in a sample of serum, urine, or even saliva. TBW can also be measured by the method of bioelectrical impedance. This is a simple measurement of the body's resistance to a low voltage electrical current run through it.  Fat is a poor conductor of electricity, whereas salty water (which is what most of the LBM consists of) is an excellent conductor. For a person of given weight and height, a lower resistance corresponds to a greater water mass, and, by inference, lower fat mass. Empiric formulas have been developed by correlating electrical resistance, body weight; age, sex, and height with TBW as measured by the gold standard isotope dilution method. These formulas are reasonably accurate.Reference ManThis figure summarizes the body composition of normal &quot;reference man.&quot; Note that reference man is 5 feet, 9 inches tall (1.75 m) and his BMI is 22.8. These reference values are very approximate but provide useful benchmarks. &quot;Reference woman&quot; is ~ 30% body fat. She is 5 feet, 4 inches tall and weighs 60 kg. What is her BMI? With increasing old age, fat increases and lean tissues decrease, so the fraction of body weight that is water decreases.In the interests of simplicity, this figure ignores the difference between pure fat and adipose tissue pointed out earlier. Reference man as depicted here is 19% pure fat, because pure fat is what is measured by densitometry. But the nearly 2 L of water which should go along with his 13 kg of pure fat is not indicated anywhere. This small amount of adipose tissue-related intracellular and extracellular water may be assumed to be mixed into the general ECF and lean tissue compartments.Lecture 11. Elements of Body CompositionLecture 11. Elements of Body CompositionStructure of Proteins and Amino AcidsThe material which follows summarizes Chapters 1, 2 and 4 in Biochemistry, 3rd ed. Please review these chapters (omitting the section on buffers which is covered in your renal physiology lectures). Proteins, are the most structurally and functionally diverse of all molecules in nature. Proteins are polymers of -amino acids in peptide linkage. The defining features of an -amino acid are its COOH group on carbon-1 and its NH2 group on carbon-2, also known as the  carbon. In peptides a bond is formed between C1 of one amino acid and the -NH2 of another one, with loss of a molecule of water. The space-filling and chemical properties (such as water solubility) of the side chains of the amino acids determine how the polypeptide chain folds and occupies space. The 20 amino acids found in proteins are conceptually grouped according to their side chains, as nonpolar (9 amino acids), uncharged polar (6), acidic (2) and basic (3). The ­SH group of cysteine is important because different cysteine molecules in the same chain (or different chains) frequently form a disulfide bond that confers structural features. Also, structural and functional modifications occur after the protein is formed (termed post-translational modifications). For example, methyl groups are post-translationally added to specific histidine and arginine molecules in certain proteins and some tyrosine residues of other proteins are sulfated. Let us summarize the known biological functions of the amino acids and proteins The -amino acids obviously occur spontaneously in nature since they existed in the primordial soup from which life emerged. In addition to being fuel, some of them have primordial signaling functions. Evolution is very inventive. For example, the freshwater coelenterate Hydra recognizes its prey by sensing the tripeptide, glutathione, which exists in a high concentration in cells and is released from them when they are ruptured. However, the quantitatively most important function of amino acids is to link up to form proteins. Protein Functions 1. Structure. (Approximately 50% of human body protein is connective tissue, hair, fur and feathers. Well, not feathers, they are only found on birds and dinosaurs. 2. Motive function (muscles) 3. Regulatory function as enzymes 4. Transport proteins 5. Immune function 6. Antioxidant function It was not until the middle of the 20th Century that it came to be appreciated that diseases can be caused simply by simple alterations in the primary structure of of proteins. The American chemist Linus Pauling,defined a new branch of medicine which he called &quot;molecular biology&quot; after he identified the cause of sickle cell anemia as the pathological replacement of a one specific GLULecture 11. Elements of Body CompositionLecture 11. Elements of Body Compositionresidue with a VAL in one of the two polypeptide chains of hemoglobin by VAL (See Biochemistry 3rd ed., p 35-6). This seemingly small change in the primary structure of the molecule causes a drastic alteration in the tertiary structure and function of the whole molecule. Pauling was also opened up the field of tertiary structure of proteins by specifying collagen's triple helical structure. To be functional, the collagen polypeptide needs to be post-translationally modified by hydroxylation of certain proline and lysine residues. These reactions require ascorbic acid. Since humans cannot synthesize ascorbic acid (vitamin C), deficiency of which leads to abnormal collagen synthesis and the construction of leaky blood capillaries (causing bruises), teeth that do not stay firmly rooted in the gums, a peculiar shape of hair follicles, and the reopening of wound scars. The disease, called scurvy, was once a feared scourge of sailors and explorers. See textbook page 47.Body Composition, Nutrition, and Disease InteractionsWe are what we eat and drink, and are diminished by what we oxidize and excrete. Nutrients (and water) are what the body is made of, and nutrients and water balance determine its composition. Among other things, the assessment of body composition consists of an evaluation of the severity of nutritional protein deficiency, and of energy excess (obesity) or deficiency (starvation). Disease also affects body composition. Many, if  not most of the important chronic diseases you will encounter in medicine leave their mark on body composition, either by affecting what and how much patients eat, or through &quot;catabolic&quot; effects that stimulate body protein breakdown and cause &quot;wasting&quot; of the lean tissues. These are the topics of subsequent lectures.Lecture 11. Elements of Body Composition`

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