Posture

In an adult, a change from a lying to an upright position results in a reduction of the person’s blood volume of about 10% (≈600 to 700 mL). Because only protein-free fluid passes through the capillaries to the tissue, this change in posture results in a reduction of the plasma volume of the blood and an increase (≈8 to 10%) in the plasma protein concentration. Normally, the decrease with the change from lying to standing is complete in 10 minutes. However, an interval of 30 minutes is required for the reverse change to occur when one goes from standing to lying.

The typical pressure at the arterial end of a capillary is 24 mm Hg (3.2 kPa), and at the venous end 10 mm Hg (1.3 kPa), although this varies with the distance of the capillary from the heart.⁷⁴ Transfer of fluid and solute across a capillary wall depends on a complex interaction of hydrostatic and osmotic pressures of capillary and interstitial fluids. Fluid moves into the interstitial space at the arteriolar end of the capillary and returns to the capillary at the venular end. A greater volume of fluid leaves the capillary at the arteriolar end than is returned to the venous end. Excess fluid drains into the lymphatic system. When an individual lies down, fluid return to the capillaries is increased, because capillary pressure is reduced. The volume of fluid returning to capillaries progressively declines when an individual is recumbent for a long time. Heart rate and systolic and diastolic blood pressures are greater in the upright than in the recumbent individual. Change in posture from lying to standing increases the secretion of catecholamines, aldosterone, angiotensin II, renin, and antidiuretic hormone (vasopressin). Epinephrine and norepinephrine concentrations in plasma may double within 10 minutes, but no change in their urinary excretion is noted. The increase in plasma aldosterone and plasma renin activity is slower, but their concentrations may still double within 1 hour. Concentrations of other hormones may also increase as a result of the relative hemoconcentration induced by standing. Typically, a 5 to 15% increase in the concentrations of most cellular elements and protein-bound molecules is also noted with a change from lying to an erect position.

Substantial changes also take place with a change from lying to a sitting position, or from standing to a supine or sitting position.¹⁶ Reduction of the extracellular fluid volume with standing reduces the renal blood flow and causes a reduction in the glomerular filtration rate (GFR) and in urine production. Changes are apparent in 1 hour. Within 2 hours of becoming recumbent, an individual’s hemoglobin and hematocrit may decrease by as much as 6.5% as the result of hypervolemia. This is associated with a reduction in the concentration of plasma protein on the order of 8% and of protein-bound constituents.³⁸ Although postural changes affect urinary sodium excretion, its plasma concentration is only slightly affected. Urinary excretion of sodium and lithium (used to treat some forms of schizophrenia) is reduced in response to increased aldosterone secretion, but the normal diurnal variation persists.⁴¹ When an individual stands, his urinary pH decreases and excretion of bicarbonate is reduced as hydrogen ions are exchanged for sodium. Excretion of protein is reduced in most individuals with reduction of the glomerular filtration rate that occurs with standing. Orthostatic proteinuria is a condition in which protein is present when individuals are standing but is essentially absent when they are recumbent. This phenomenon may be caused by increased glomerular permeability from increased venous pressure. The incidence of orthostatic proteinuria is probably less than 5%.

Changes in concentration of proteins and protein-bound constituents in serum with postural changes are greater in hypertensive patients than in normotensive patients, in individuals with a low plasma protein concentration than in those with a normal concentration, and in the elderly compared with the young.25,26 Most of the plasma oncotic pressure is attributable to albumin because of its high concentration, so that protein malnutrition—with its associated reduction in plasma albumin concentration—reduces the retention of fluid within the capillaries. Conversely, the impact of postural changes is less in individuals with abnormally high concentrations of protein, such as those with a monoclonal gammopathy (multiple myeloma). In general, the concentrations of freely diffusible constituents with molecular weights of less than 5000 Da are unaffected by postural changes. However, a significant increase in potassium (≈0.2 to 0.3 mmol/L) occurs after an individual stands for 30 minutes.²⁷ This increase in K⁺ has been attributed to the release of intracellular potassium from muscle. Changes in the concentration of some major serum constituents with changes in posture are listed in Table 6-1.

Application of a tourniquet at the time of blood collection mimics the effect of a change from a lying to a standing position, raising the plasma concentrations of proteins and protein-bound constituents, the activities of enzymes and the counts of blood cells, and the blood hematocrit and hemoglobin concentrations.

Prolonged Bed Rest

Plasma and extracellular fluid volumes decrease within a few days of the start of bed rest. Consequently, the blood hematocrit may increase by as much as 10% within 4 days. Usually a slight reduction in total body water is noted, but with 2 weeks’ bed rest the plasma volume reverts to its pre-bed rest value.³⁸

Concentrations of protein-bound constituents are also reduced, although mobilization of calcium from bones with an increased free ionized fraction compensates for the reduced protein-bound calcium, so serum total calcium is less affected. Indeed, a paradoxical increase in the total plasma calcium concentration may occur. Plasma 1,25-dihydroxyvitamin D and 25-hydroxyvitamin D concentrations may decrease by as much as 20%. Plasma aspartate aminotransferase activity is usually slightly less in individuals confined to bed than in those undertaking normal physical activity. Initially and paradoxically, CK activity is increased as a result of its release from skeletal muscles, but ultimately, CK activity may be less than in active, healthy individuals. Serum potassium may be reduced by up to 0.5 mmol/L over 3 weeks in association with a reduction in skeletal muscle mass.

Prolonged bed rest is associated with increased urinary nitrogen excretion, which increases by up to 15% after 2 weeks. Calcium excretion steadily increases up to 7 weeks of rest, increasing by a maximum of about 60%. Excretion of sodium, potassium, phosphate, and sulfate is also increased but to a much smaller extent; hydrogen ion excretion is reduced, and this is presumably caused by decreased metabolism of skeletal muscle.²² The amplitude of circadian variation of plasma cortisol is reduced by prolonged immobilization, and urinary excretion of catecholamines may be reduced to one third of the concentration in an active individual. Vanillylmandelic acid (VMA) excretion is reduced by one fourth after 2 to 3 weeks of bed rest.

When an individual becomes active after a period of bed rest, longer than 3 weeks is required before calcium excretion reverts to normal, and another 3 weeks before positive calcium balance is achieved. A period of several weeks is required before positive nitrogen balance is restored.

Exercise

In considering the effects of exercise, the nature and extent of the exercise should be taken into account.⁸⁶ Static or isometric exercise, usually of short duration but of high intensity, uses previously stored ATP and creatine phosphate, whereas more prolonged exercise must use ATP generated by normal metabolic pathways. Changes in concentrations of analytes that result from exercise are largely due to shifts of fluid between intravascular and interstitial compartments and changes in hormone concentrations stimulated by the change in activity and by the loss of fluid due to sweating. Plasma concentrations of β-endorphin and catecholamines may more than double within a minute of initiation of strenuous exercise. Hemoconcentration, affecting high molecular weight constituents, follows strenuous exercise. The physical fitness of an individual may also affect the extent of change in the concentration of a constituent; the length of time after exercise when a specimen was collected also influences the concentrations of measured analytes. Such factors account for sometimes conflicting reports in the literature.

With moderate exercise, the provoked stress response causes an increase in blood glucose, which stimulates insulin secretion. The arteriovenous difference in glucose concentration is increased more than 5-fold from about 14 mg/dL (0.8 mmol/L) at rest, depending on the duration and intensity of exercise in association with greater tissue demand for glucose.⁹⁷ Plasma pyruvate and lactate are increased by increased metabolic activity of skeletal muscle. Even mild exercise may increase the plasma lactate twofold. Arterial pH and PCO₂ are reduced by exercise. Reduced renal blood flow causes a slight increase in the serum creatinine concentration. Competition for renal excretion between urate, lactate, and products of increased tissue catabolism causes the plasma urate concentration to increase. Exercise causes a reduction in cellular ATP, which increases cellular permeability. Increased permeability causes slight increases in the serum activities of enzymes originating from skeletal muscle, such as AST, LD, CK, and aldolase.⁹⁴ The increase in CK is largely attributable to its CK-MM isoform, although small increases in CK-MB may also be observed. The increase in enzyme activity tends to be greater in unfit than in fit individuals. Performing normal daily activities over 4 hours may increase serum CK activity by as much as 50% in some healthy individuals.⁴⁸ Mild exercise produces a slight decrease in serum cholesterol and triglyceride concentrations that may persist for several days. Those who walk for about 4 hours each week have an average cholesterol concentration 5% lower and HDL concentration 3.4% higher than inactive individuals.

In general, the effects of strenuous exercise are exaggerations of those occurring with mild exercise. Thus hypoglycemia and increased glucose tolerance may occur. Plasma lactate may be increased tenfold during exercise but soon returns to normal in fit individuals. Severe exercise increases the concentration of plasma proteins owing to an influx of protein from interstitial spaces, which occurs after an initial loss of both fluid and protein through the capillaries. Plasma concentrations of total proteins increase by about 9% and renal glomerular permeability increases, leading to increased proteinuria.⁷⁵ Plasma fibrinolytic activity is also increased. Strenuous exercise may more than double CK activity, but the activity of enzymes with primarily liver or kidney origin is little changed, although hepatic and renal blood flow is reduced.

Strenuous exercise for 10 minutes increases plasma renin activity by 400%. Cortisol secretion is stimulated, and the normal diurnal variation may be abolished.²¹ Urinary free cortisol excretion and plasma concentrations of cortisol, aldosterone, growth hormone (somatotropin), and prolactin are also increased by exercise. Plasma insulin concentration is decreased by exercise. Strenuous exercise increases both plasma and urinary concentrations of catecholamines. Changes in concentrations of cortisol and other stress-stimulated increased hormone concentrations are presumed to release leukocytes, primarily neutrophils, from the bone marrow into the peripheral circulation. Following strenuous exercise, the leukocyte count has been observed to increase to about 25,000 cells/µL.⁴¹

Blood pH, oxygen saturation, and venous bicarbonate concentrations are decreased by strenuous exercise. The concentration of triglycerides is reduced briefly by exercise, but the free fatty acid concentration is greatly increased; serum creatinine and urea nitrogen concentrations are also increased. Although the creatinine concentration returns rapidly to normal on cessation of exercise, the increased urea nitrogen concentration persists for some time. Reversible, benign hematuria and proteinuria with increased excretion of leukocytes and erythrocytes occur commonly with exercise and worsen in proportion to the extent of exercise. These may persist for 3 days following strenuous sports, but this does not warrant investigation. Urinary steroid excretion increases in response to the stress of exercise.

Some representative changes in concentration or activity of serum constituents induced by exercise are listed in Table 6-2.

Physical Training

Athletes generally have a higher serum activity of enzymes of skeletal muscular origin at rest than do nonathletes. However, the response of these enzymes to exercise is less in athletes than in other individuals. Reduced release of enzymes from skeletal muscle in well-trained individuals has been attributed to an increase in the number and size of mitochondria, allowing the muscle to better metabolize glucose, fatty acids, and ketone bodies. The proportion of CK that is CK-MB is much greater in trained than in untrained individuals.¹⁴ Serum concentrations of urea, urate, creatinine, and thyroxine are higher in athletes than in comparable untrained individuals. Urinary excretion of creatinine is also increased. These changes are probably related to increased muscle mass and greater turnover of muscle mass in athletes.

Body fat is reduced by physical training. This is associated with increased HDL-cholesterol and decreased LDL-cholesterol and triglyceride concentrations, the extent of which varies with the intensity and duration of training.

Circadian Variation

Many constituents of body fluids exhibit cyclical variation throughout the day.95,100 Factors contributing to such variation include posture, activity, food ingestion, stress, daylight or darkness, and sleep or wakefulness. The cyclical pattern tends to be similar among individuals who work during the day and sleep at night, although it is different in night workers. These cyclical variations may be quite large; therefore the timing of specimen collection must be strictly controlled. For example, the concentration of serum iron may increase by as much as 50% from 0800 to 1400, and that of cortisol by a similar amount between 0800 and 1600. Serum potassium has been reported to decline from 5.4 mmol/L at 0800 to 4.3 mmol/L at 1400.^88,89 The typical total variation in several commonly measured serum constituents over 6 hours is illustrated in Table 6-3. Total variation is contrasted with analytical error.

Hormones are secreted in bursts, and this, together with the cyclical variation to which most hormones are subject, may make it very difficult to interpret their plasma concentrations properly.⁹⁹ Corticotropin secretion is influenced by cortisol-like steroids, but it is also affected by posture and by light, darkness, and stress. Its secretion is increased threefold to fivefold from its minimum between afternoon and midnight to its maximum around waking. Growth hormone and epinephrine concentrations exhibit similar change throughout the day. Cortisol concentrations are greatest around 0600 to 0800 hours, and one study reported mean minima and maxima of 15.8 µg/dL and 111 µg/dL, respectively, at different times during the day.⁵²

Maximum renin activity normally occurs early in the morning during sleep; its minimum occurs late in the afternoon. The plasma aldosterone concentration shows a similar pattern. GFR varies inversely with the secretion of renin, probably through constriction of renal efferent arterioles.⁴² GFR is least at the time of maximum renin secretion and is 20% greater in the afternoon, when renin activity is at a minimum. Excretion of 17-ketosteroids and 17-hydroxycorticosteroids is low at night and reaches a maximum about midafternoon.

No circadian variation in plasma concentrations of FSH and LH is noted in men, but a 20 to 40% increase in plasma testosterone occurs during the night. Prolactin is secreted, similar to other hormones such as LH and FSH, in multiple bursts; prolactin concentration is greatest during sleep.⁹⁹ The pituitary gland regulates hormone secretion primarily through negative feedback generated by increased circulating concentrations of circulating hormones. To perform a precise assessment of the concentration of a hormone, several measurements may be required.

Serum TSH is at a maximum between 0200 and 0400, and is at a minimum between 1800 and 2200. The variation is on the order of 50 to 206%.⁵² Variations in serum thyroxine concentrations also occur, but these appear to be related to changes in the concentration of binding protein brought about by changes in posture. These variations are maximal at between 1000 and 1400. Total protein concentration may vary by as much as 10% over 24 hours, but variation in individual proteins may be even greater.

Growth hormone secretion is greatest shortly after sleep commences. Conversely, basal plasma insulin is higher in the morning than later in the day, and its response to glucose is also greatest in the morning and least at about midnight. When a glucose tolerance test is given in the afternoon, higher glucose values occur than when the test is given early in the day. Higher plasma glucose occurs in spite of a greater insulin response, which is nevertheless delayed and less effective.

Urinary excretion of catecholamines and their metabolites is less at night than during the day. The effect is related to activity, because in night workers, excretion is less during the day.

Peak urinary excretion of sodium and potassium occurs about noon, whereas excretion of calcium and magnesium is greatest during the night. Urinary phosphate excretion is low at night, with the result that serum phosphate is as much as 30% higher at night than during the morning. Urinary volume and creatinine excretion are low during the night. Creatinine clearance may be reduced by up to 10% during the night. Night urine contains excess ammonia, and its titratable acidity is high.⁹⁰

Blood cell concentrations are affected by circadian rhythms, with neutrophil and lymphocyte counts increasing by 61% and 67%, respectively, at their peaks from their nadir concentrations.⁵²

Travel

Travel across several time zones affects the normal circadian rhythm. Five days is required to establish a new stable diurnal rhythm after travel across 10 time zones. Changes in laboratory test results are attributable to altered pituitary and adrenal function. Urinary excretion of catecholamines is usually increased for 2 days, and serum cortisol is reduced. During a 20-hour flight, serum glucose and triglyceride concentrations increase, while glucocorticoid secretion is stimulated. During such a prolonged flight, fluid and sodium retention occurs, but urinary excretion returns to normal after 2 days.¹¹

Space travel is associated with a decrease in blood and plasma volumes and is further associated with increases in plasma antidiuretic hormone, atrial natriuretic peptide, growth hormone, cortisol, and corticotropin concentrations.⁶⁰ In contrast, the plasma renin activity may be decreased by as much as 50%. Plasma aldosterone may also decrease but to a lesser extent. In spite of the stress of space travel, plasma concentrations of catecholamines are usually unaffected. Space travel leads to bone demineralization and a negative calcium and phosphate balance, primarily caused by increased excretion of these minerals. However, concentrations of commonly measured analytes generally do not exceed the reference range when astronauts adapt to space travel.¹⁰²

Diet

Diet has considerable influence on the composition of plasma. Studies with synthetic diets have shown that day-to-day changes in the amount of protein are reflected within a few days in the composition of nitrogenous components of plasma and in the excretion of end products of protein metabolism.

Four days after the change from a normal diet to a high-protein diet, doubling of the plasma urea concentration occurs, along with an increase in its urinary excretion.⁹ Serum cholesterol, phosphate, urate, and ammonia concentrations are also increased. High protein intake increases both serum and urinary urea and urate. A high-fat diet, in contrast, depletes the nitrogen pool because of the requirement for excretion of ammonium ions to maintain acid-base homeostasis. A high-fat diet increases the serum concentration of triglycerides but reduces serum urate. Reduction of fat intake reduces serum lactate dehydrogenase activity. Ingestion of very different amounts of cholesterol has little effect on its serum concentration; an increase in intake of 50% may affect the serum concentration by only 5 to 10 mg/dL (0.13 to 0.26 mmol/L).⁵⁴ Ingestion of monounsaturated fat instead of saturated fat reduces cholesterol and LDL-cholesterol concentrations. When polyunsaturated fat is substituted for saturated fat, the concentrations of triglycerides and HDL-cholesterol are reduced. Notwithstanding the conclusions of previous studies, a 2009 report suggests that different types of diets have a similar influence on the plasma concentrations of lipids, and that total caloric ingestion is the primary influence on an individual’s body mass and blood lipid concentrations, with total and LDL-cholesterol and triglyceride concentrations decreasing and HDL-cholesterol increasing similarly when volunteers were fed different weight-loss diets.⁸¹

When dietary carbohydrates consist mainly of starch or sucrose rather than other sugars, the serum activities of ALP and LD are increased. AST and ALT activities are also influenced by the type of sugar ingested, being higher with a sugar diet than with a starch-based diet.⁵¹ Plasma triglyceride concentration is reduced when sucrose intake is decreased. Peak glucose concentration tends to be less during a glucose tolerance test in individuals habitually ingesting a bread diet than when a high-sucrose diet is ingested. A high-carbohydrate diet decreases the serum concentrations of LDL-cholesterol, triglycerides, cholesterol, and protein. Individuals who eat many small meals throughout the day tend to have total LDL- and HDL-cholesterol concentrations that are lower than when food of the same type and amount is eaten in three meals.²

In addition to the types of foods and drinks ingested, specific food-related situations influence plasma composition. These include vegetarianism, obesity, malnutrition, fasting, and starvation.

Food Ingestion

The concentration of certain plasma constituents is affected by the ingestion of a meal, with the time between ingestion of a meal and collection of blood affecting the plasma concentrations of many analytes. For example, fasting overnight for 10 to 14 hours before blood collection noticeably decreases the variability in concentration of many analytes and is seen as the optimal time for fasting around which to standardize blood collections.²⁴ The biggest increases in serum concentration that occur after a meal are noted for glucose and triglycerides.¹³ The increase in ALP (mainly intestinal isoenzyme) is greater when a fatty meal is ingested and is influenced by the blood group of the individual and the substrate used for the enzyme assay. Activities of alanine and aspartate aminotransferases may increase by 10 to 20% following a meal.⁴⁹ In addition, lipemia following a meal may affect some analytical methods used to measure serum constituents. Ultracentrifugation or the use of serum blanks can reduce the adverse analytical effects of lipemia.

The effects of a meal may be long lasting. Thus ingestion of a protein-rich meal in the evening may cause increases in concentration of serum urea nitrogen, phosphorus, and urate that are still apparent 12 hours later.¹ Nevertheless, these changes may be less than the typical intraindividual variability. Large protein meals at lunch or in the evening increase serum cholesterol and growth hormone concentrations for at least 1 hour after a meal. The effect of carbohydrate meals on blood composition is less than that of protein meals. No change in the cortisol concentration is noted when breakfast is taken, probably because cortisol completely occupies all cortisol binding sites on its binding protein in the early morning. Glucagon and insulin secretions are stimulated by a protein meal, and insulin is also stimulated by carbohydrate meals.

In response to a meal, the stomach secretes hydrochloric acid, causing a reduction in the plasma chloride concentration. Venous blood from the stomach contains an increased amount of bicarbonate. This condition reflects a mild metabolic alkalosis (“alkaline tide”) and increased PCO₂. The metabolic alkalosis is sufficient to reduce serum-free ionized calcium by 0.2 mg/dL (0.05 mmol/L). After ingestion of a meal, the liver becomes the prime site for metabolism of ingested substances. Ingestion of therapeutic drugs with meals may have considerable influence on the characteristic absorption and metabolism of each drug.

The effects of ingestion of a 700-kcal (2.93-MJ) meal on some commonly measured blood constituents are illustrated in Table 6-4. These effects differ with different meals. Thus the glucose increase is often greater and phosphate is usually decreased after a carbohydrate meal.⁹⁰

Ingestion of one glass of water leads to statistically, but not clinically, significant alterations in the concentration of several commonly measured test constituents. When 75 g glucose is ingested with water, as in a glucose tolerance test, the concentration of glucose is increased. This stimulates the secretion of insulin. Insulin causes the release of sodium from cells and stimulates the transport of potassium into cells.

Ingestion of Specific Foods and Beverages

Constituents of food and drink affect the composition of plasma. Bran, serotonin, and caffeine are examples of such constituents.

Vegetarianism

In long-standing vegetarians, the concentration of VLDL-cholesterol is reduced, typically by 12%, compared with nonvegetarians. Total lipid and phospholipid concentrations are reduced, and concentrations of cholesterol and triglycerides may be only two thirds of those in individuals on a mixed diet. Both HDL- and LDL-cholesterol concentrations are affected. In strict vegetarians, the LDL-cholesterol concentration may be 37% less and the HDL-cholesterol concentration 12% less than in nonvegetarians. The cholesterol : HDL-cholesterol ratio is decreased. Effects are less notable in individuals who have been on a vegetarian diet for only a short time. Lipid concentrations are also less in individuals who eat only a vegetable diet than in those who consume eggs and milk as well. Little difference is seen in the concentration of protein or the activities of enzymes in the serum of long-standing vegetarians and individuals on a mixed diet. A vegetarian diet does not appear to affect liver function in that liver function tests are similar in vegans and nonvegans.³⁷ The serum creatinine concentration may be slightly reduced in vegetarians because of reduced ingestion of protein, but urinary excretion of creatinine and its clearance may be almost 40% less than in meat-eaters.⁶¹ Plasma concentrations of trace elements tend to be reduced in vegans. For example, serum copper may be reduced by 20%, selenium by 10%, and zinc by more than 10% after individuals have consumed a lactovegetarian diet for 3 months.⁸⁷ Although the plasma concentration of many vitamins is increased, that of vitamin B₁₂ may be reduced in vegetarians to a concentration approaching that observed in deficiency. An explanation for the low vitamin B₁₂ and the high bilirubin still has to be established. Differences in the composition of serum of vegetarians and nonvegetarians are shown in Table 6-5. Urinary pH is usually higher in vegetarians than in meat-eaters as the result of reduced intake of precursors of acid metabolites.

Malnutrition

In malnutrition, the plasma concentrations of most proteins, including total protein, albumin, prealbumin, and β-globulin, are reduced. The frequently increased concentration of γ-globulin does not fully compensate for the decrease in other proteins. Concentrations of complement C3, retinol-binding globulin, transferrin, and prealbumin decrease rapidly with the onset of malnutrition and are measured to define the severity of the condition.⁷² Plasma concentrations of lipoproteins are reduced, and serum cholesterol and triglycerides may be only 50% of the concentrations in healthy individuals. In spite of severe malnutrition, glucose concentration is maintained close to that in healthy individuals. However, the concentrations of serum urea nitrogen and creatinine are greatly reduced as a result of decreased skeletal mass, and creatinine clearance is decreased.

The plasma cortisol concentration is increased, largely as the result of an increase in the free cortisol moiety, but also possibly because of decreased metabolic clearance. Plasma concentrations of total T₃ and T₄ are considerably reduced, with the thyroxine concentration being most affected. This is due in part to reduced concentrations of TBG and prealbumin.

Erythrocyte and plasma folate concentrations are reduced in protein-calorie malnutrition, but the serum vitamin B₁₂ concentration is unaffected or may even be slightly increased.⁵⁵ Plasma concentrations of vitamins A and E are reduced, but the extent depends on the cause and duration of the malnutrition (e.g., dietary or iatrogenic, such as bariatric surgery). The blood hemoglobin concentration is reduced, but the serum iron concentration initially is little affected by malnutrition, although decreased plasma transferrin concentrations ultimately lead to reduced iron concentrations.

The activity of most of the commonly measured enzymes is reduced but increases with restoration of good nutrition.

Long-Term Fasting and Starvation

Withdrawal of most caloric intake has been used to treat certain cases of obesity. Such withdrawal provokes many metabolic responses. The body attempts to conserve protein at the expense of other sources of energy, such as fat. The blood glucose concentration decreases by as much as 18 mg/dL (1 mmol/L) within 3 days of the start of a fast, in spite of the body’s attempts to maintain glucose production.⁶⁷ Insulin secretion is greatly reduced, whereas glucagon secretion may double in an attempt to maintain normal glucose concentration. Lipolysis and hepatic ketogenesis are stimulated. Amino acids are released from skeletal muscle, and the plasma concentration of branched-chain amino acids may increase by as much as 100% with 1 day of fasting, but the urea concentration decreases. Ketoacids and fatty acids become the principal sources of energy for muscle. This results in an accumulation of organic acids that leads to a metabolic acidosis with reduction of blood pH, PCO₂, and plasma bicarbonate concentrations. In addition, the concentrations of ketone bodies (acetoacetic acid, β-hydroxybutyric acid, and acetone), fatty acids, and glycerol in serum rise considerably. When individuals are fasted for 60 hours compared with the usual 12 hours typically used in clinical practice to obtain baseline laboratory values, plasma insulin concentrations are reduced by half and those of C-peptide by more than one third. In contrast, concentrations of glucagon, epinephrine, and norepinephrine are doubled, and that of growth hormone is increased fivefold.¹⁰

The breakdown of fat leads to a transient increase in body water. Typically, however, an osmotic diuresis soon reduces the blood volume. Fasting for 6 days increases plasma concentrations of cholesterol and triglycerides but causes a decrease in HDL-cholesterol concentration.⁸² After individuals lived for 4 weeks on a 400-kcal diet, the concentrations of urea and triglycerides and the activity of gamma-glutamyltransferase decreased by 20 to 50%, whereas concentrations of urate, derived from nucleoprotein, and creatinine and the activity of AST increased by 20 to 40%.⁹⁶ Reduced GFR and competition for excretion from lactate and ketoacids contribute to the increased urate concentration.

Hepatic blood supply may be reduced with starvation. BSP retention is increased, and serum bilirubin rises; unconjugated bilirubin more than doubles within 48 hours.³ Slight increases in the serum activities of aspartate and alanine aminotransferase and of lactate dehydrogenase are observed within 2 weeks of the start of a fast, but return to baseline within 4 to 6 weeks.³⁴ Enzyme changes may be linked more to focal necrosis of the liver than to general circulatory impairment.

In spite of the catabolism of tissue induced by starvation, the serum protein concentration is little affected initially; ultimately, a reduction occurs. With the onset of starvation, aldosterone secretion increases, leading to increased urinary excretion and decreased plasma concentration of potassium. Magnesium, calcium, and phosphate are affected similarly, although the urinary excretion of phosphate gradually declines. Although the plasma urea concentration is not significantly affected by 10 days of starvation, the absolute urinary excretion of urea, total nitrogen, and creatinine is increased over the first few days of starvation.¹⁵

Plasma growth hormone concentration may rise by as much as 15 times at the start of a fast but may return to normal after 3 days. Reduced energy expenditure is associated with decreased concentrations of thyroid hormones. Free and total triiodothyronine is decreased by up to 50% within 3 days of the start of a fast. Free thyroxine concentration is also affected, but to a lesser extent; total thyroxine is little changed. Urinary free cortisol is decreased by fasting, and the plasma cortisol concentration (free and total) shows a slight increase, together with loss of the normal diurnal variation.

Early in refeeding, sodium retention occurs as a result of decreased sodium and chloride excretion in the urine.⁷⁷ The reduction in potassium excretion takes longer. These events are associated with an even greater secretion of aldosterone than occurs during the period of fasting. Abnormal concentrations of most constituents rapidly revert to normal with refeeding. Nitrogen balance soon becomes positive, especially if the nonprotein calories are derived mainly from carbohydrate.