One of the gastrointestinal tract’s most important functions is for the ingestion of nutrients—carbohydrate, protein, lipid, minerals, vitamins, and water—that the organism uses for production of energy, creation of complex proteins and lipid moieties, and maintenance of electrolytes and total body water stores. The production of energy involves the oxidation of nutrients (carbohydrates, fats, and proteins) that results in creation of high-energy phosphate bonds in which energy is stored for life processes, with carbon dioxide and water produced as side products. The most important high-energy phosphate bond is adenosine triphosphate (ATP) (Fig. 33-1). This ubiquitous molecule is the energy storehouse for the body, providing the energy necessary for essentially all physiologic processes and chemical reactions. Probably the most important intracellular process that requires energy from hydrolysis of ATP is formation of peptide linkages between amino acids during protein synthesis. Likewise, skeletal muscle contraction cannot occur without energy derived from ATP hydrolysis. Metabolism of nutrients is necessary for creation of ATP that when hydrolyzed provides energy for transport of ions across cell membranes. Active transport is required to maintain the distribution of ions necessary for multiple cellular processes including the propagation of nerve impulses. In renal tubules, as much as 80% of ATP is used for membrane transport of ions. In addition to its function in energy transfer, ATP is also the precursor of cyclic adenosine monophosphate (cAMP), an important signaling molecule.
For adults, total energy expenditure averages 39 kcal/kg in males and 34 kcal/kg in females. Approximately 20 kcal/kg is expended as basal metabolism necessary to maintain integrity of the cell membrane and other energy-requiring tasks essential for life. In the resting state, the basal expenditure of calories is equivalent to approximately 1.1 kcal per minute, which requires approximately 200 to 250 mL per minute of oxygen in a 70-kg man for oxidation of nutrients. As the level of activities increase above the basal state, the caloric (and oxygen) requirements increase in proportion to the energy expenditure required (Table 33-1). The caloric values of carbohydrates, fats, and proteins are approximately 4.1 kcal/g, 9.3 kcal/g, and 4.1 kcal/g, respectively. Fat forms the major energy storage depot because of its greater mass and high caloric value (Fig. 33-2).1 As a consequence, the primary form in which potential chemical energy is stored in the body is fat (triglyceride). The high caloric density and hydrophobic nature of triglycerides permit efficient energy storage without adverse osmotic consequences.
Carbohydrate Metabolism
Carbohydrates comprise a group of organic compounds that include sugars and starches and, in addition to carbon, contain hydrogen and oxygen in the same ratio as water (2:1). Three disaccharides are important in human biology—sucrose: glucose and fructose; lactose: glucose and galactose; and maltose: glucose and glucose. Starch, found in grains such as wheat, rice, and barley and other plants, including potatoes and corn, consists of many units of glucose joined by glycosidic bonds. Sugars are an important energy source for the body and the sole source of energy for the brain.
The liver is the site of carbohydrate metabolism where regulation, storage, and production of glucose takes place. The liver is the only organ that contains glucose kinase, an enzyme that has a high reaction rate (Km), capable of phosphorylating glucose, but only when its concentration is high. Adequate concentrations appear immediately after a meal when glucose concentration in the portal vein is increased. At least 99% of all the energy derived from carbohydrates is used by mitochondria to form ATP in the cells (Fig. 33-3). The final products of carbohydrate digestion in the gastrointestinal tract are glucose, fructose, and galactose. After absorption into the circulation, fructose and galactose are rapidly converted to glucose. As a result, glucose is the predominant molecule used to produce ATP. This glucose must be transported through cell membranes into cellular cytoplasm before it can be used by cells. This transport uses a protein carrier in carrier-mediated diffusion, which is enhanced by insulin. Resistance to insulin, and thus transport of glucose into the cell in diabetes mellitus or sepsis,2 results in hyperglycemia with associated adverse sequelae. Immediately upon entering cells, glucose is converted to glucose-6-phosphate under the influence of the enzyme hexose kinase. Phosphorylated glucose is ionized at pH 7 and, because plasma membranes are not permeable to the ions, the phosphorylated glucose cannot pass back through the membrane and is effectively trapped within the cell.
The fetus derives almost all its energy from glucose obtained from the maternal circulation. Immediately after birth, the infant stores of glycogen are sufficient to supply glucose for only a few hours. Furthermore, gluconeogenesis is limited in the neonate. As a result, the neonate is vulnerable to hypoglycemia if feeding is not initiated.
Glycogen
After entering cells, glucose can be used immediately for release of energy to cells or it can serve as a substrate for glycogen synthase. Dephosphorylation of the enzyme, glycogen synthase by protein phosphatase-1, which in turn is regulated by insulin and glucagon, activates the enzyme. Activated glycogen synthase combines molecules of glucose into a long polymer, similar to the way plants store carbohydrate as starch. Glycogen synthase is deactivated when it is phosphorylated—by glycogen synthase kinase-3, 5′-adenosine monophosphate–activated protein kinase, and protein kinase-A. The liver and skeletal muscles are particularly capable of storing large amounts of glycogen, but all cells can store at least some glucose as glycogen, and the glycogen in these cells is increasingly recognized as having important roles in both health and disease.3 The liver stores glycogen for release of glucose during fasting, and muscle, which can store as much as 90% of the glucose contained in a meal, catabolizes glycogen during strenuous exercise.4 The ability to form glycogen makes it possible to store substantial quantities of glucose without significantly altering the osmotic pressure of intracellular fluids. Glucose is cleaved from glycogen between meals, during fasting, and during exercise by glycogen phosphorylase and by a debranching enzyme.
Gluconeogenesis
Gluconeogenesis is the formation of glucose from amino acids and the glycerol portion of fat. Amino acids are first deaminated before entering the citric acid (Krebs) cycle (see Fig. 33-3). This process occurs when body stores of glycogen decrease below normal levels. An estimated 60% of the amino acids in the body’s proteins can be converted easily to pyruvate and glucose, whereas the remaining 40% have chemical configurations that make this conversion difficult.
Gluconeogenesis is stimulated by hypoglycemia. Particularly in the liver, simultaneous release of cortisol mobilizes proteins, making them available for breakdown to amino acids used in gluconeogenesis. Thyroxine is also capable of increasing the rate of gluconeogenesis.
Energy Release from Glucose
Glucose is progressively broken down into two molecules of pyruvate, both of which can enter the citric acid cycle (Fig. 33-4), and the resulting energy is used to form ATP. For each mole of glucose that is completely degraded to carbon dioxide and water, a total of 38 moles of ATP is ultimately formed. The most important means by which energy is released from the glucose molecule is by glycolysis and the subsequent oxidation of the end products of glycolysis. Glycolysis is the splitting of the glucose molecule into two molecules of pyruvate, which enter the mitochondria where the pyruvate is converted to acetyl-coenzyme A (CoA), which enters the citric acid cycle and is converted to carbon dioxide and hydrogen ions with the formation of ATP (oxidative phosphorylation). Oxidative phosphorylation occurs only in the mitochondria and in the presence of adequate amounts of oxygen.
Anaerobic Glycolysis
In the absence of adequate amounts of oxygen, a small amount of energy can be released by anaerobic glycolysis, also known as fermentation in plants, fungi, and bacteria because conversion of glucose to pyruvate does not require oxygen. Indeed, glucose is the only nutrient that can serve as a substrate for the formation of ATP without oxygen. This release of glycolytic energy to cells can be lifesaving for a few minutes should oxygen become unavailable.
During anaerobic glycolysis, most pyruvic acid is converted to lactic acid, which diffuses rapidly out of cells into extracellular fluid. When oxygen is again available, this lactic acid can be reconverted to glucose. This reconversion occurs predominantly in the liver. Indeed, severe liver disease may interfere with the ability of the liver to convert lactic acid to glucose, leading to metabolic acidosis.
Lipid Metabolism
Lipids are hydrophobic organic molecules that include waxes, sterols, fat-soluble vitamins, triglycerides (fats), phospholipids, and other substances. Lipids contain a high amount of potential energy, but are also important as structural components of cell membranes, in signaling pathways, and as precursors to a number of cytokines. Fatty acids and their derivatives as well as molecules that contain sterols such as cholesterol are also considered lipids. Although there are biosynthetic pathways to synthesize and degrade lipids, some fatty acids are essential and must be ingested in the diet. Fatty acids are carboxylic acids consisting of a long hydrocarbon chain ending in a carboxyl group; the hydrocarbon chain can be saturated or unsaturated (Fig. 33-5). Humans can desaturate carbon atoms no closer than the 9th carbon from the tail of the aliphatic chain. However, humans require fatty acids (that are therefore essential) that are desaturated as close as the 6th and as close as the 3rd carbon to the terminus of the aliphatic chain—ω6 and ω3 fatty acids, respectively. Twenty carbon chain fatty acids are stored in the second position of phospholipids (see the following text), and when released, serve as substrates for a group of very important cytokines, the eicosanoids—prostaglandins, thromboxanes, and leukotrienes. Arachidonic acid (see Fig. 33-5), a 20 carbon chain v6 fatty acid (C20:4ω6) is a precursor for prostaglandins and thromboxanes of the two series and leukotrienes of the four series, whereas eicosapentaenoic acid, C20:5ω3, is a precursor for prostaglandins and thromboxanes of the three series and leukotrienes of the five series.
A glycerol stem to which three fatty acid molecules are bound is known as a triglyceride (Fig. 33-6). A triglyceride molecule to which one of the terminal fatty acids is replaced with a phospate ion is known as a phospholipid (Fig. 33-7). Phospholipids are the building blocks of cell membranes (Fig. 33-8), form myelin, and, because of their unique structure and functions, are being used in other scientific applications.
Triglycerides, after absorption from the gastrointestinal tract, are transported in the lymph and then, by way of the thoracic duct, into the circulation in droplets known as chylomicrons. Chylomicrons are rapidly removed from the circulation and stored as they pass through capillaries of adipose tissue and skeletal muscles. Triglycerides are used in the body mainly to provide energy for metabolic processes similar to those fueled by carbohydrates.
Cholesterol does not contain fatty acids, but it is a lipid, because it is composed of carbon and hydrogen, not as aliphatic chains of carbon but with four rings made up of carbon (Fig. 33-9). Seventy-five percent of cholesterol is produced in the liver in a synthetic process that involves 37 steps; the other 25% of cholesterol is ingested in the diet.
Molecules that are part lipid and part protein, lipoproteins, are also synthesized primarily in the liver (Table 33-2). The presumed function of lipoproteins is to provide a mechanism of transport for lipids throughout the body. Lipoproteins are classified according to their density, which is inversely proportional to their lipid content. All the cholesterol in plasma is found in lipoprotein complexes, with low-density lipoproteins (LDLs) representing the major cholesterol component in plasma. These LDLs provide cholesterol to tissues, where it is an essential component of cell membranes and is used in the synthesis of corticosteroids and sex hormones. In the liver, LDLs are taken up by receptor-mediated endocytosis. An intrinsic feedback control system increases the endogenous production of cholesterol when exogenous intake is decreased, explaining the relatively modest lowering effect on plasma cholesterol concentrations produced by low-cholesterol diets. If this endogenous increase in cholesterol synthesis is blocked by drugs that inhibit hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase, then there is an appreciable decrease in the plasma cholesterol concentration.
Drugs that selectively inhibit HMG-CoA are known as statins. Statins effectively lower plasma LDL cholesterol concentrations and seem to provide protection against acute cardiac events, perhaps reflecting antiinflammatory effects. In addition, statins lower plasma triglyceride concentrations and modestly increase high-density lipoprotein (HDL) cholesterol concentrations. Drugs that bind bile salts (cholestyramine, colestipol) prevent cholesterol from reentering the circulation as part of the enterohepatic circulation. A disadvantage of using drugs that bind bile salts to lower plasma cholesterol concentrations is an associated increase in plasma triglyceride concentrations.
The first step in the use of triglycerides for energy is hydrolysis into fatty acids and glycerol and subsequent transport of these products to tissues, where they are oxidized. Almost all cells, except for brain cells, can use fatty acids interchangeably with glucose for energy. Degradation and oxidation of fatty acids occur only in mitochondria, resulting in progressive release of two carbon fragments (β-oxidation) in the form of acetyl-CoA (Fig. 33-10). These acetyl-CoA molecules enter the citric acid cycle in the same manner as acetyl-CoA formed from pyruvate during the metabolism of glucose, ultimately leading to formation of ATP. In the liver, two molecules of acetyl-CoA formed from the degradation of fatty acids can combine to form acetoacetic acid (see Fig. 33-10). A substantial amount of acetoacetic acid is converted to β-hydroxybutyric acid and small amounts of acetone. In the absence of adequate carbohydrate metabolism (starvation or uncontrolled diabetes mellitus), large quantities of acetoacetic acid, β-hydroxybutyric acid, and acetone accumulate in the blood to produce ketosis because almost all the energy of the body must come from metabolism of lipids.
In contrast to glycogen, large amounts of lipids can be stored in adipose tissue and in the liver. A major function of adipose tissue is to store triglycerides until they are needed for energy. Epinephrine and norepinephrine activate triglyceride lipase in cells, leading to mobilization of fatty acids.
Protein Metabolism
Approximately 75% of the solid constituents of the body are proteins (Table 33-3). All proteins are composed of the same 20 amino acids, and several of these must be supplied in the diet because they cannot be formed endogenously (essential amino acids) (Table 33-4). Dietary proteins must be digested into amino acids and di- and tripeptides before they can be absorbed. The process begins in the stomach where pepsinogen is converted to pepsin in the acidic pH. The process continues in small intestine into which the pancreas secretes trypsin and chymotrypsin and carboxypeptidases. These gastric and pancreatic proteases hydrolyze proteins into medium and small chain peptides. Peptidases in the brush border of the small intestine hydrolyze these medium and small chain peptides into free amino acids and di- and tripeptides. These end products of digestion, formed on the surface of the enterocyte, are ready for absorption by sodium-dependent amino acid transporters.
Nonessential amino acids can be synthesized from the appropriate α-keto acid. For example, pyruvate formed during the glycolytic breakdown of glucose is the keto acid precursor of alanine. Each amino acid has an acidic carboxyl group (COOH) and an amino group (NH3R), (Fig. 33-11). Proteins are formed by amino acids connected one to another by an amide bond, a covalent chemical bond between the carboxyl group of one amino acid with the amino group of another amino acid. The resulting C(O)NH bond is called a peptide bond, and the resulting molecule is an amide. The four-atom functional group -C(=O)NH- is called a peptide link (Fig. 33-12). Even the smallest proteins characteristically contain more than 20 amino acids connected by peptide linkages, whereas complex proteins have as many as 100,000 amino acids. In addition, more than one amino acid chain in a protein may be bound to another amino acid chain by hydrogen bonds, hydrophobic bonds, or electrostatic forces.
Amino acids are relatively strong acids and exist in the blood principally in the ionized form. After a meal, the blood amino acid concentration increases only a few milligrams, reflecting rapid tissue uptake, especially by the liver. Passage of amino acids into cells requires active transport mechanisms because these substances are too large to pass by diffusion or through channels in cell membranes. In proximal renal tubules, amino acids that have entered the glomerular filtrate are actively transported back into the blood. These transport mechanisms have maximums above which amino acids appear in the urine. In the normal person, however, loss of amino acids in the urine each day is negligible. Failure to transport amino acids into the blood is indicative of renal disease.
Storage of Amino Acids
Immediately after entry into cells, amino acids are conjugated under the influence of intracellular enzymes into cellular proteins. As a result, concentrations of amino acids inside cells remain low. The concentration of amino acids within cells is low as the cell uses them as substrate to create proteins within the liver, kidneys, and gastrointestinal mucosa. Nevertheless, these proteins can be rapidly decomposed again into amino acids under the influence of intracellular liposomal digestive enzymes. The resulting amino acids can then be transported out of cells into blood to maintain optimal plasma amino acid concentrations. Tissues can synthesize new proteins from amino acids in blood. This response is especially apparent in relation to protein synthesis in cancer cells. Cancer cells are prolific users of amino acids, and, simultaneously, the proteins of other tissues become markedly depleted, contributing to cachexia.
Plasma Proteins
Plasma proteins are represented by (a) albumin, which provides colloid osmotic pressure; (b) globulins necessary for innate and acquired immunity; and (c) fibrinogen, which polymerizes into long fibrin threads during coagulation of blood. Essentially, all plasma albumin and fibrinogen and 60% to 80% of the globulins are formed in the liver. Additional globulins are formed in lymphoid tissues and other cells of the reticuloendothelial system. The rate of plasma protein formation by the liver can be greatly increased in situations, such as severe burns, where there is loss of large amounts of fluid and protein.
The hepatic synthetic rate of proteins depends on the blood concentration of amino acids. Even during starvation or severe debilitating diseases, the ratio of total tissue proteins to total plasma proteins in the body remains relatively constant at approximately 33:1. Because of the reversible equilibrium between plasma proteins and other proteins of the body, one of the most effective of all therapies for acute protein deficiency is the intravenous administration of plasma proteins. Within hours, amino acids of the administered protein become distributed throughout cells of the body to form proteins where they are needed.
Albumin
Albumin is the most abundant plasma protein and is principally responsible for maintaining plasma osmotic pressure. In addition, albumin is important as a transporter of plasma-bound substances often including exogenously administered drugs. Normal daily synthesis of albumin is about 10 g and the half-life for this protein may be as long as 22 days. Therefore, serum albumin concentrations may not be noticeably decreased in early states of acute hepatic failure. However, within hours of the onset of a critical illness or injury, albumin levels decrease by as much as 33% due to changes in the distribution between intravascular and extravascular compartments and rates of synthesis and degradation of protein. Despite the fact that low serum albumin is a poor prognostic factor in critical illness, supplementation has not been shown to improve prognosis.
Coagulation Factors
Hepatocytes synthesize all coagulation factors with the exception of von Willebrand factor and factor VIIIC. Coagulation may be rapidly impaired by acute liver failure, reflecting the short plasma half-life for many critical components (factor VII 100 to 300 minutes). Vitamin K (uptake dependent on bile salts) is necessary for modification of several of the clotting factors (prothrombin, antithrombin, protein S, and protein C) and may be deficient in malabsorptive states and malnutrition.
Use of Proteins for Energy
Once cells contain a maximum amount of amino acids, any additional amino acids are deaminated (oxidative deamination) to keto acids that can enter the citric acid cycle to become ATP or the keto acids are released into the bloodstream, taken up by adipocytes, and converted to and stored as fat. Ammonia resulting from deamination is converted to urea in the liver for excretion by the kidneys. Indeed, acute hepatic failure manifests by accumulation of toxic concentrations of ammonia. Certain deaminated amino acids are similar to the breakdown products that result from glucose and fatty acid metabolism. For example, deaminated alanine is pyruvic acid, which can be converted to glucose or glycogen, or it can become acetyl-CoA, which is polymerized to fatty acids. The conversion of amino acids to glucose or glycogen is gluconeogenesis, and the conversion of amino acids into fatty acids is ketogenesis. In the absence of protein intake, approximately 20 to 30 g of endogenous protein are degraded into amino acids daily. In severe starvation, cellular functions deteriorate because of protein depletion. Carbohydrates and lipids spare protein stores to a certain extent because they are used in preference but not exclusively to proteins for energy.
Growth hormone and insulin promote the synthetic rate of cellular proteins, possibly by facilitating the transfer of amino acids into cells. Glucocorticoids increase the breakdown rate of extrahepatic proteins, thereby making increased amino acids available to the liver. This allows the liver to synthesize increased amounts of cellular proteins and plasma proteins. Testosterone increases protein deposition in tissues, particularly the contractile proteins of skeletal muscles.
Effects of Stress on Metabolism
Carbohydrate, lipid, and protein metabolism are significantly altered by stress. In response to stress, the body increases secretion of cortisol, catecholamines, and glucagon, resulting in increased endogenous glucose production (hepatic gluconeogenesis) and hyperglycemia (to provide glucose to cells for ATP production in those cells involved in the fight or flight response. Stress-induced β-adrenergic stimulation increases the breakdown of fats (lipolysis). The products of lipolysis can be used for gluconeogenesis or directly by cells to produce ATP. Likewise, a predictable response to stress is catabolism of proteins in skeletal muscles, releasing keto acids that can be used for ATP production or for gluconeogenesis.
Exogenous glucose administered to injured or septic patients has a minimal effect on gluconeogenesis and lipolysis. Conversely, administration of glucose in the presence of starvation decreases gluconeogenesis and lipolysis.
Obesity
Given the importance of energy stores to individual survival and reproductive capacity, the ability to conserve energy in the form of adipose tissue would at one time have conferred a survival advantage.5 For this reason, human genes that favor energy intake and storage are presumed to be present although not yet identified. Nevertheless, the combination of easy access to calorically dense foods and a sedentary lifestyle has made the metabolic consequences of these presumed genes maladaptive. In addition, certain medications are commonly associated with weight gain (Table 33-5).6
Obesity is the most common and costly nutritional problem in the United States. Based on body mass index (BMI) (weight in kilograms divided by the square of the height in meters), 67% of adult males and 62% of adult females are overweight (BMI ≥25) and 27.5% of adult males and 34% of adult females (BMI ≥30; class I obesity) are obese.7 Individuals with a BMI >35 have class II obesity, and class III obesity if the BMI is >40. The prevalence of obesity peaks between 60 and 69 years of age but even 5-year-old children are increasingly found to be obese for their age.8 A BMI of ≥28 is associated with a three to four times increase in the risk of ischemic heart disease, stroke, and diabetes mellitus compared with the general population. Increased waist circumference (>102 cm in adult males and >88 cm in adult females) is associated with an increased risk for ischemic heart disease, diabetes mellitus, and systemic hypertension. In this regard, an overweight person with a predominant abdominal fat distribution (common in elderly males with impaired glucose tolerance) may be at high risk for these diseases even if not considered obese by BMI criteria. The increased risk for morbidity and mortality extend beyond measurements of BMI and fat distribution, as reflected by the diagnosis of metabolic syndrome, which is present if a patient has three of the following five risk factors: increased waist circumference (as described previously), low levels of HDL cholesterol, increased triglycerides, hypertension, and glucose intolerance (Table 33-6). The risk of anesthesia may be increased in classes II and III obese patients, reflecting mechanical difficulties (airway, positioning, and ventilation) and increased incidence of comorbid conditions (diabetes mellitus, systemic hypertension).
Treatment of obesity by decreasing caloric intake and increasing metabolic rate (exercise) directed toward a long-term decrease in body weight is largely ineffective, and 90% to 95% of persons who lose weight subsequently regain it.9 Both proteins and carbohydrates can be metabolically converted to fat, and there is no evidence that changing the relative proportions of protein, carbohydrate, and fat in the diet without decreasing caloric intake will promote weight loss.10 However, fat has a higher caloric density than protein and carbohydrate, and its contribution to the palatability of foods promotes its ingestion and increases the intake of calories.
Pharmacologic Treatment
Phentermine is an appetite suppressant that is utilized for short-term therapy intended to induce weight loss. In the past, this drug was frequently used in combination with fenfluramine (the latter induces the development of valvular heart disease, similar to that seen with carcinoid syndrome). It has been replaced by another combination drug, phentermine and topiramate, which is also somewhat effective; however, it may also be associated with heart problems. Orlistat inhibits lipases in the gastrointestinal lumen, thus antagonizing triglyceride hydrolysis and decreasing fat absorption by about 30%. Because orlistat is not absorbed, its ability to cause weight loss likely reflects the resulting low-fat diet and lower caloric intake. Weight loss with orlistat is modest, an average of 2.9 kg (6.4 lb) at 1 to 4 years.11Gastrointestinal side effects (abdominal discomfort, flatus, fecal urgency) reflecting the increased fat content in stool are dose limiting and occur in the majority of patients treated with orlistat. Concerns have also been raised about its negative effects on the kidneys.12 It is recommended that orlistat not be prescribed for patients with known malabsorptive conditions, and daily multivitamin supplementation is useful. Lorcaserin is a third drug currently used in the United States, associated with a mean weight loss of 3.1 kg over 1 year compared to a placebo over a year.13Lorcaserin is a selective 5-HT2C agonist, which activates proopiomelanocortin production and promotes weight loss through satiety.
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