Pierre L Martin-Hirsch MRCOG

• Consultant Gynaecological Oncologist, Central Lancashire
• Teaching Hospitals, Preston

These new epithelial cells spread outward over the luminal surfaces of the intestines infantile spasms 4 months order sumatriptan overnight. While still in the deep folds spasms gums order sumatriptan 50 mg with mastercard, the epithelial cells secrete sodium chloride and water into the intestinal lumen muscle relaxant online sumatriptan 25 mg order online. This secretion spasms kidney area cheap sumatriptan amex, in turn spasms 1983 download 25 mg sumatriptan order free shipping, is reabsorbed by the older epithelial cells outside the folds, thus providing flow of water for absorbing intestinal digestates. The toxins of cholera and of some other types of diarrheal bacteria can stimulate the epithelial fold secretion so greatly that this secretion often becomes much greater than can be reabsorbed, thus sometimes causing a loss of 5 to 10 liters of water and sodium chloride as diarrhea each day. Within 1 to 5 days, many severely affected patients die of this loss of fluid alone. Extreme diarrheal secretion is initiated by entry of a subunit of cholera toxin into the epithelial cells. This subunit stimulates formation of excess cyclic adenosine monophosphate, which opens tremendous numbers of chloride channels, allowing chloride ions to flow rapidly from inside the cell into the intestinal crypts. In turn, this action is believed to activate a sodium pump that pumps sodium ions into the crypts to go along with the chloride ions. Finally, all this extra sodium chloride causes extreme osmosis of water from the blood, thus providing rapid flow of fluid along with the salt. All this excess fluid washes away most of the bacteria and is of value in combating the disease, but too much of a good thing can be lethal because of serious dehydration of the whole body that might ensue. In most instances, the life of a person with cholera can be saved by the administration of tremendous amounts of sodium chloride solution to make up for the loss. By far the most abundant of the absorbed monosaccharides is glucose, which usually accounts for more than 80% of the carbohydrate calories absorbed. The reason for this high percentage is that glucose is the final digestion product of our most abundant carbohydrate food, the starches. The remaining 20% of absorbed monosaccharides is composed almost entirely of galactose and fructose-the galactose derived from milk and the fructose as one of the monosaccharides digested from cane sugar. Virtually all the monosaccharides are absorbed by a secondary active transport process. In the absence of sodium transport through Active Absorption of Calcium, Iron, Potassium, Magnesium, and Phosphate. Calcium ions are actively ab- sorbed into the blood, especially from the duodenum, and the amount of calcium ion absorption is exactly controlled to supply the daily need of the body for calcium. One important factor controlling calcium absorption is parathyroid hormone secreted by the parathyroid glands, and another is vitamin D. Parathyroid hormone activates vitamin D, and the activated vitamin D in turn greatly enhances calcium absorption. Potassium, magnesium, phosphate, and probably still other ions can also be actively absorbed through the intestinal mucosa. Bivalent ions are normally absorbed in only small amounts; for example, maximum absorption of calcium ions is only 1/50th as great as the normal absorption of sodium ions. Fortunately, only small quantities of the bivalent ions are normally required daily by the body. The transport of sodium and glucose through the intestinal membrane occurs in two stages. First is active transport of sodium ions through the basolateral membranes of the intestinal epithelial cells into the interstitial fluid, thereby depleting sodium inside the epithelial cells. Second, a decrease of sodium inside the cells causes sodium from the intestinal lumen to move through the brush border of the epithelial cells to the cell interiors by a process of secondary active transport. Thus, the low concentration of sodium inside the cell literally "drags" sodium to the interior of the cell, and glucose is dragged along with it. To summarize, it is the initial active transport of sodium through the basolateral membranes of the intestinal epithelial cells that provides the eventual force for moving glucose through the membranes as well. Galactose is Absorption of Fats Earlier in this chapter, we pointed out that when fats are digested to form monoglycerides and free fatty acids, both of these digestive end products first become dissolved in the central lipid portions of bile micelles. Because the molecular dimensions of these micelles are only 3 to 6 nanometers in diameter, and because of their highly charged exterior, they are soluble in chyme. In this form, the monoglycerides and free fatty acids are carried to the surfaces of the microvilli of the intestinal cell brush border and then penetrate into the recesses among the moving, agitating microvilli. Here, both the monoglycerides and fatty acids diffuse immediately out of the micelles and into the interior of the epithelial cells, which is possible because the lipids are also soluble in the epithelial cell membrane. This process leaves the bile micelles still in the chyme, where they function again and again to help absorb still more monoglycerides and fatty acids. Thus, the micelles perform a "ferrying" function that is highly important for fat absorption. In the presence of an abundance of bile micelles, about 97% of the fat is absorbed; in the absence of the bile micelles, only 40% to 50% can be absorbed. Here, they are mainly used to form new triglycerides that are subsequently released in the form of chylomicrons through the base of the epithelial cell, to flow upward through the thoracic lymph duct and empty into the circulating blood. Instead, fructose is transported by facilitated diffusion all the way through the intestinal epithelium and is not coupled with sodium transport. It is then converted to glucose and finally transported in the form of glucose the rest of the way into the blood. Because fructose is not co-transported with sodium, its overall rate of transport is only about one-half that of glucose or galactose. Absorption of Proteins as Dipeptides, Tripeptides, or Amino Acids As explained earlier, most proteins, after digestion, are absorbed through the luminal membranes of the intestinal epithelial cells in the form of dipeptides, tripeptides, and a few free amino acids. The energy for most of this transport is supplied by a sodium co-transport mechanism in the same way that sodium co-transport of glucose occurs. After binding, the sodium ion then moves down its electrochemical gradient to the interior of the cell and pulls the amino acid or peptide along with it. A few amino acids do not require this sodium co-transport mechanism but instead are transported by special membrane transport proteins in the same way that fructose is transported, by facilitated diffusion. At least 10 different types of transport proteins for amino acids and peptides have been found in the intestinal epithelial cells. This multiplicity of transport proteins is required because of the diverse binding properties of different amino acids and peptides. Small quantities of short- and medium-chain fatty acids, such as those from butterfat, are absorbed directly into the portal blood rather than being converted into triglycerides and absorbed by way of the lymphatics. The cause of this difference between short- and long-chain fatty acid absorption is that the short-chain fatty acids are more water soluble and mostly are not reconverted into triglycerides by the endoplasmic reticulum. This phenomenon allows diffusion of these short-chain fatty acids from the intestinal epithelial cells directly into the capillary blood of the intestinal villi. Most of the water and electrolytes in this chyme are absorbed in the colon, usually leaving less than 100 ml of fluid to be excreted in the feces. Also, essentially all the ions are absorbed, leaving only 1 to 5 mEq each of sodium and chloride ions to be lost in the feces. Most of the absorption in the large intestine occurs in the proximal half of the colon, giving this portion the name absorbing colon, whereas the distal colon functions principally for feces storage until a propitious time for feces excretion and is therefore called the storage colon. The mucosa of the large intestine, like that of the small intestine, has a high capability for active absorption of sodium, and the electrical potential gradient created by sodium absorption causes chloride absorption as well. The tight junctions between the epithelial cells of the large intestinal epithelium are much tighter than those of the small intestine. This characteristic prevents significant amounts of back-diffusion of ions through these junctions, thus allowing the large intestinal mucosa to absorb sodium ions far more completely-that is, against a much higher concentration gradient-than can occur in the small intestine. This is especially true when large quantities of aldosterone are available because aldosterone greatly enhances sodium transport capability. Absorption of sodium and chloride ions creates an osmotic gradient across the large intestinal mucosa, which in turn causes absorption of water. The feces normally are about three-fourths water and one-fourth solid matter that is composed of about 30% dead bacteria, 10% to 20% fat, 10% to 20% inorganic matter, 2% to 3% protein, and 30% undigested roughage from the food and dried constituents of digestive juices, such as bile pigment and sloughed epithelial cells. The brown color of feces is caused by stercobilin and urobilin, derivatives of bilirubin. The actual odoriferous products include indole, skatole, mercaptans, and hydrogen sulfide. Gehart H, Clevers H: Tales from the crypt: new insights into intestinal stem cells. Kunzelmann K, Mall M: Electrolyte transport in the mammalian colon: mechanisms and implications for disease. When the total quantity entering the large intestine through the ileocecal valve or by way of large intestine secretion exceeds this amount, the excess appears in the feces as diarrhea. As noted earlier, toxins from cholera or certain other bacterial infections often cause the crypts in the terminal ileum and large intestine to secrete 10 or more liters of fluid each day, leading to severe and sometimes lethal diarrhea. Numerous bacteria, especially colon bacilli, are present even normally in the absorbing colon. They are capable of digesting small amounts of cellulose, in this way providing a few calories of extra nutrition for the body. In herbivorous animals, this source of energy is significant, although it is of negligible importance in human beings. The bacteria-formed vitamin K is especially important because the amount of this vitamin in the daily ingested foods is normally insufficient to maintain adequate blood coagulation. The purpose of this chapter is to discuss a few representative types of gastrointestinal malfunction that have special physiological bases or consequences. Damage to the fifth, ninth, or tenth cerebral nerve can cause paralysis of significant portions of the swallowing mechanism. In addition, a few diseases, such as poliomyelitis or encephalitis, can prevent normal swallowing by damaging the swallowing center in the brain stem. Paralysis of the swallowing muscles, as occurs in persons with muscle dystrophy or as a result of failure of neuromuscular transmission in persons with myasthenia gravis or botulism, can also prevent normal swallowing. When the swallowing mechanism is partially or totally paralyzed, the abnormalities that can occur include the following: (1) complete abrogation of the swallowing act so that swallowing cannot occur, (2) failure of the glottis to close so that food passes into the lungs instead of the esophagus, and (3) failure of the soft palate and uvula to close the posterior nares so that food refluxes into the nose during swallowing. One of the most serious instances of paralysis of the swallowing mechanism occurs when patients are in a state of deep anesthesia. While on the operating table, they sometimes vomit large quantities of materials from the stomach into the pharynx; then, instead of swallowing the materials again, they simply suck them into the trachea because the anesthetic has blocked the reflex mechanism of swallowing. Achalasia is a condition in which the lower esophageal sphincter fails to relax during swallowing. As a result, food swallowed into the esophagus fails to pass from the esophagus into the stomach. Pathophysiological studies have shown damage in the neural network of the myenteric plexus in the lower two-thirds of the esophagus. As a result, the musculature of the lower esophagus remains spastically contracted, and the myenteric plexus has lost its ability to transmit a signal to cause "receptive relaxation" of the gastroesophageal sphincter as food approaches this sphincter during swallowing. When achalasia becomes severe, the esophagus often cannot empty the swallowed food into the stomach for many hours, instead of the few seconds that is the normal time. Over months and years, the esophagus becomes tremendously enlarged until it often can hold as much as 1 liter of food, which often becomes putridly infected during the long periods of esophageal stasis. The infection may also cause ulceration of the esophageal mucosa, sometimes leading to severe substernal pain or even rupture and death. Considerable benefit can be achieved by stretching the lower end of the esophagus with a balloon inflated on the end of a swallowed esophageal tube. Disorders of the Stomach Gastritis-Inflammation of the Gastric Mucosa Mild to moderate chronic gastritis is especially common in the middle to later years of adult life. The inflammation of gastritis may be only superficial and therefore not very harmful, or it can penetrate deeply into the gastric mucosa, in many long-standing cases causing almost complete atrophy of the gastric mucosa. Research suggests that gastritis often is caused by chronic bacterial infection of the gastric mucosa. This condition often can be treated successfully with an intensive regimen of antibacterial therapy. In addition, certain ingested irritant substances can be especially damaging to the protective gastric mucosal barrier-that is, to the mucous glands and to the tight epithelial junctions between the gastric lining cells-often leading to severe acute or chronic gastritis. This low level of absorption is mainly due to two specific features of the gastric mucosa: (1) it is lined with highly resistant mucous cells that secrete viscid and adherent mucus, and (2) it has tight junctions between the adjacent epithelial cells. These two features together plus other impediments to gastric absorption are called the "gastric barrier. The hydrogen ions then diffuse into the stomach epithelium, creating additional havoc and leading to a vicious circle of progressive stomach mucosal damage and atrophy. It also makes the mucosa susceptible to digestion by the peptic digestive enzymes, thus frequently resulting in a gastric ulcer. Chronic Gastritis Can Lead to Gastric Atrophy and Loss of Stomach Secretions Causes: 1. In many people who have chronic gastritis, the mucosa gradually becomes more and more atrophic until little or no gastric gland digestive secretion remains. It is also believed that in some people autoimmunity develops against the gastric mucosa, which also leads eventually to gastric atrophy. Loss of the stomach secretions in gastric atrophy leads to achlorhydria and, occasionally, to pernicious anemia. Achlorhydria means that the stomach fails to secrete hydrochloric acid; it is diagnosed when the pH of the gastric secretions fails to decrease below 6. Even when it is secreted, the lack of acid prevents it from functioning because pepsin requires an acid medium for activity. Normal gastric secretions contain a glycoprotein called intrinsic factor, secreted by the same parietal cells that secrete hydrochloric acid. Intrinsic factor must be present for adequate absorption of vitamin B12 from the ileum. That is, intrinsic factor combines with vitamin B12 in the stomach and protects it from being digested and destroyed as it passes into the small intestine.

The complexity of the situation is not completely understood but is the target of extensive research in vivo spasms around heart generic sumatriptan 50 mg without a prescription, in vitro spasms muscle pain purchase generic sumatriptan from india, and in long-term clinical studies spasms sphincter of oddi sumatriptan 25 mg purchase without prescription. Birth weight and rate of postnatal growth (ie muscle relaxant tv 4096 purchase sumatriptan now, catch-up growth)-not prematurity alone-are inversely related to cardio vascular mortality and the prevalence of the metabolic syndrome muscle relaxant 5859 discount generic sumatriptan uk. Unfortunately, excessive growth soon after birth can also lead to obesity and its comorbidities later in life. There are two periods characterized by brief growth spurts in childhood: the infant-childhood growth spurt between 1 Y2 years and 3 years and the mid-childhood growth spurt between 4 and 8 years. The mid-childhood growth spurt does not occur in all children, is more frequent in boys than girls, and its presence is hereditary. After another plateau, the striking increase in stature, the pubertal growth spurt follows, causing a second peak growth velocity. The final decrease in growth rate then ensues, until the epiphyses of the long bones fuse and growth ceases. An early adiposity rebound is a risk factor for the development of obesity later in childhood and thereafter. Further research as needed to determine the optimal growth rate for newborns experiencing poor intrauterine growth or premature delivery. On the other hand, macrosomic infants born to mothers with diabetes mellitus often develop childhood obesity and insulin resistance in later childhood even if they have a period of normal weight between 1 and 5 years of age. In sum, prenatal and early postnatal growth affects the older child and adult in many ways. J I 1 /V 1/ 115 f- 46 f- 44 f- 42 f- 40 f- 38 f- 36 f- 34 f- 32 110 1 05 1 00 95 90 85 80 co m. Values are higher in the immedi ate neonatal period, decrease through childhood, and rise again as a result of increased pulse amplitude (but not frequency) during puberty. Post-translational processing produces the 70-amino acid mature form; alternative splicing mechanisms produce structural variants of the molecule. Sex steroids Gonadal sex steroids exert an important influence on the pubertal growth spurt, whereas absence of these eb oo ks fre sf. Thyroid hormone As noted earlier, newborns with con genital hypothyroidism are of normal length, but if untreated, they manifest exceedingly poor growth soon after birth. Infants with untreated congenital hypothyroidism suffer permanent developmental delay so early treatment is necessary. Newborn screening for congenital hypothyroidism is universal in the United States and most countries. Acquired hypothyroidism with onset after 3 years leads to a markedly decreased growth rate but no permanent intellectual defects. G l ucocorticoids Endogenous or exogenous glucocorti coids in excess quickly decrease growth rate; this effect occurs more quickly than weight gain. The absence of glucocorticoids has little effect on growth if the individual is clinically well in other respects (eg, in the absence of hypotension or hypoglycemia). Gonadal and adrenal sex steroids in excess can cause a sharp increase in growth rate as well as the premature appearance and progression of secondary sexual features. If unabated, increased sex steroids will cause advancement of skeletal age, premature epiphyseal fusion, and short adult stature all mediated by estrogen. The g rowth veloc ity and the degree of skeleta l maturation a re some co 50th percentile for the U. Socioeconomic factors Worldwide, the most common cause of short stature is poverty and its effects. Thus, poor nutri tion, poor hygiene, and poor health influence growth both before and after birth. Parasitic infection is prevalent in less developed countries and severely stunts growth and depletes energy. In people of the same ethnic group and in the same geographic location, variations in stature are often attributable to socioeconomic factors. Conversely, when other factors are equal, the differ ences in average height between various ethnic groups are mainly genetic. The data for the construction of these charts is derived from well-nourished breastfed infants. Other fac tors may be blamed for poor growth when nutritional deficien cies are actually responsible. For example, Sherpas were thought to have short stature mainly because of genetic factors or the effects of high altitude living on the slopes of Mount Everest; however, nutritional supplementation increased stature in this group, demonstrating the effects of adequate nutrition. The developed world places a premium on appearance, and women portrayed as beautiful in the media are characteristically thin. Significant numbers of children, chiefly teenagers, voluntarily decrease their caloric intake even if they are not obese; this accounts for some cases of poor growth. For example, bronchopulmonary dysplasia decreases growth to some degree because it increases metabolic demands, shifting nutrient usage away from growth; improved nutrition increases growth in these patients. Celiac disease is another common gastrointestinal disorder that impairs growth, pubertal development, menstrua tion, and bone acquisition. Feeding problems in infants, resulting from inexperience of parents or poor child-parent interactions (so-called maternal deprivation), may account for poor growth. Fad diets, such as poorly constructed vegan diets that put children at risk for vitamin B 1 2 or iron deficiency, as well as major dietary manipulation, such as a severely low-fat diet, may place children at risk for deficiency of fat-soluble vitamins. Deliberate starvation of children by care givers is an extreme form of child abuse that may be first discov ered because of poor growth. N utritional factors fre fre fre eb oo ks ks oo ks oo re ks fre fre ks f ok s oo oo eb o eb eb Accurate measurement of height is an essential part of the physical examination of children and adolescents. The onset of a chronic disease may often be determined by an inflection point in the growth chart. In other cases, a detailed growth chart indicates a normal constant growth rate in a child observed to be short for age. Catch-up growth is usually short-lived and is followed by a more typical growth rate. Chronic disease Many chronic systemic diseases interfere with growth independent of poor nutrition. For example, conges tive heart failure and asthma, if uncontrolled, are associated with decreased stature; in some cases, adult height is in the normal range because growth continues over a longer period of time. In addition, thyroid dysfunction may develop, further complicating the growth pattern. Psychologic factors Aberrant intrafamilial dynamics, psychologic stress, or psychiatric disease can inhibit growth either by altering endocrine function or by secondary effects on nutrition (psychosocial dwarfism or maternal deprivation). It is essential to diagnose those situations that might suggest organic disease states, as the management approach is very different in malnutrition. Instead, the examining physician should determine which short children warrant further evaluation and which ones (and their parents) require only reassurance that they are healthy. When parents see that their child is below the 3rd percentile and in a section of the chart colored differently from the normal area, they assume that there is a serious problem. Thus, the format of the chart can dictate parental reaction to height, because all parents want their children to be in the normal range. Pathologic short stature is defined by different authorities in different manners. However, a diagnosis of pathologic short stature should not be based on a single measure ment. Serial measurements are required because they allow deter mination of growth velocity, which is a more sensitive index of the growth process than a single determination. A very tall child who develops a postnatal growth problem will not fall below the 3rd percentile for years but will fall below the mean in growth velocity soon after the onset of the disorder. In children under 4 years of age, normal growth velocity changes more strikingly with age. Growth charts for special populations are also available at that website; thus growth charts for achondroplasia, Down syndrome, Noonan syndrome, Williams syndrome, Turner syndrome, Russell-Silver syndrome, and other conditions can also be found. Healthy term newborns tend to be clustered in length measure ments around 2 1 inches (often owing to mistakes in obtaining accurate measurements). Thus, a child with constitu tional delay in growth or genetic short stature, whose height is at the mean at birth and gradually falls to the 1 Oth percentile at 1 year of age and to the 5th percentile by 2 years of age, may in fact be healthy in spite of crossing percentile lines in the journey to a growth channel at the 5th percentile. Although the growth rate may decrease during these years, it should not be less than the 5th percentile for age. Every physician treating children should record supine length (<2 years of age) or standing height (>2 years of age) as well as weight at every office visit. Failure to recognize a change in measurement technique as the child moves from lying to standing may falsely suggest a growth problem. Patients who cannot be measured in the standing position (eg, because of cerebral palsy) require other approaches. The use of arm span is a possible surrogate for the measurement of height, and there are formulas available for the calculation of height based on the measurement of upper arm length, tibial length, and knee length (see later). How ever, it is reported that screening examinations in the real world fall short of that ideal. Forty-one percent of a presumably normal population screened at a school in England met the criteria for evaluation of abnormal growth (approximately two-thirds grew faster than the normal growth category and one-third were in the slower than normal category), leading to an unreasonable size of a referral population, all due to simple measuring errors. Infants must be measured on a firm horizontal surface with a permanently attached rule, a stationary plate per pendicular to the rule for the head, and a movable perpendicular plate for the feet. One person should hold the head stable while another makes sure the knees are straight and the feet are firm against the movable plate. There are calipers-like devices (eg, infantometer) that can be used for such accurate measurements. Standing measurements cannot be accurately performed with the measuring rod that projects above the common weight scale; the rod is too flexible, and the scale footplate will in fact drop lower when the patient stands on it. There is an average 5-inch height difference between adult men and women in the United States. In effect, this cor rects the North American growth charts for the particular family being considered. This method is useful only in the absence of disease affecting growth, and the prediction is more valid when the parents are of similar rather than of widely different heights. When there is a large discrepancy between the heights of the mother and the father, prediction of target height becomes difficult. A child may follow the growth pattern of the shorter parent more closely than the midparental height. A boy may, for example, follow the growth pattern of a short mother rather than a taller father. A parent who spent the growing years in poverty, with chronic disease, or in an area of political unrest might have shorter adult height, due to nutritional factors or disease, that may not be passed on to the children. Height is measured at the top of the head by a sliding perpendicular plate (or square wooden block). A Harpenden sta diometer is a mechanical measuring device capable of such accu rate measurement. It is preferable to measure in the metric system, because the smaller gradations make measurements more accurate by minimizing the effect of rounding off numbers. Growth is not constant but is characterized by short spurts and periods of slowed growth. The interval between growth measure ments should be adequate to allow an accurate evaluation of growth velocity. Appropriate sampling intervals vary with age but should not be less than 3 months in childhood, with a 6-month interval being optimal. The problem of measuring the growth rate of children with orthopedic deformities or contractures is significant, because these patients may have nutritional and/or endocrine disorders as well. The measurement of knee height, tibial length, or upper arm length correlates well with standing height (r 0. Specialized laser-calibrated devices to measure tibial length (kneeometry) are reported to be accurate for assessment of short-term growth down to weekly intervals. Sitting height is used in some clinical studies of growth, but the sitting stadiom eter is rarely available. The following discussion covers only the more common conditions, emphasizing those that might be fre fre sf re. Shorter than aver age stature need not be considered a disease, because variation in stature is a normal feature of human beings, and a normal child should not be burdened with a misdiagnosis. Although the classifica tions described later may apply to most patients, some will still be resistant to definitive diagnosis. For example, menarche is better correlated with a bone age of 1 3 years than with a given chronologie age. Patients with aromatase deficiency, who cannot convert testoster one to estradiol, and patients with estrogen receptor defects, who cannot respond to estrogen, grow taller well into their twenties without having epiphysial fusion. Bone age indicates remaining growth available to a child and can be used to predict adult height. However, bone age is not a definitive diagnostic test of any disease; it can assist in diagnosis only when considered along with other factors. The Greulich and Pyle Atlas of radiographs of the left hand and wrist is most commonly used in the United States, but other methods of skeletal age determination, such as Tanner and White house maturity scoring, are preferred in Europe. Further, there appear to be ethnic differences in bone age maturation that is not reflected in the guidelines for interpretation. For newborn infants, knee and foot radiographs are compared with an appro priate bone age atlas. For late pubertal children, just before epiphyseal fusion, the knee atlas reveals whether any further growth can be expected or whether the epiphyses are fused.

The remaining one-third are caused by thrombosis or hemorrhage of vessels in other organs of the body spasms throughout my body 50 mg sumatriptan order overnight delivery, especially the brain (causing strokes) spasms or twitches sumatriptan 100 mg with amex, but also the kidneys spasms left abdomen discount sumatriptan 100 mg with visa, liver spasms down legs when upright 25 mg sumatriptan buy amex, gastrointestinal tract spasms prozac discount sumatriptan uk, limbs, and so forth. Roles of Cholesterol and Lipoproteins in Atherosclerosis Increased Low-Density Lipoproteins. Patients with full-blown familial hypercholesterolemia may have blood cholesterol concentrations of 600 to 1000 mg/dl, levels that are four to six times normal. If untreated, many of these people die before age 30 years because of myocardial infarction or other sequelae of atherosclerotic blockage of blood vessels throughout the body. Heterozygous familial hypercholesterolemia is relatively common and occurs in about 1 in 500 people. The more severe form of this disorder caused by homozygous mutations is much rarer, occurring in only about one of every million births on average. Whether or not these mechanisms are true, epidemiological studies indicate that when a person has a high ratio of high-density to low-density lipoproteins, the likelihood of developing atherosclerosis is greatly reduced. A, Attachment of a monocyte to an adhesion molecule on a damaged endothelial cell of an artery. The monocyte then migrates through the endothelium into the intimal layer of the arterial wall and is transformed into a macrophage. The macrophage then ingests and oxidizes lipoprotein molecules, becoming a macrophage foam cell. The foam cells release substances that cause inflammation and growth of the intimal layer. B, Additional accumulation of macrophages and growth of the intima cause the plaque to grow larger and accumulate lipids. Eventually, the plaque may occlude the vessel or rupture, causing the blood in the artery to coagulate and form a thrombus. Some of the factors that are known to predispose to atherosclerosis are (1) physical inactivity and obesity, (2) diabetes mellitus, (3) hypertension, (4) hyperlipidemia, and (5) cigarette smoking. Hypertension, for example, increases the risk for atherosclerotic coronary artery disease by at least twofold. Likewise, persons with diabetes mellitus have, on average, more than a twofold increased risk of developing coronary artery disease. When hypertension and diabetes mellitus occur together, the risk for coronary artery disease is increased by more than eightfold. When hypertension, diabetes mellitus, and hyperlipidemia are all present, the risk for atherosclerotic coronary artery disease is increased almost 20-fold, suggesting that these factors interact in a synergistic manner to increase the risk of developing atherosclerosis. In many overweight and obese patients, these three risk factors do occur together, greatly increasing their risk for atherosclerosis, which in turn may lead to heart attack, stroke, and kidney disease. In early and middle adulthood, men are more likely to develop atherosclerosis than are women of comparable age, suggesting that male sex hormones might be atherogenic or, conversely, that female sex hormones might be protective. Others, such as hypertension, lead to atherosclerosis by causing damage to the vascular endothelium and other changes in the vascular tissues that predispose to cholesterol deposition. To add to the complexity of atherosclerosis, experimental studies suggest that excess blood levels of iron can lead to atherosclerosis, perhaps by forming free radicals in the blood that damage the vessel walls. The statins may also have other beneficial effects that help prevent atherosclerosis, such as attenuating vascular inflammation. These drugs are now widely used to treat patients who have increased plasma cholesterol levels. Therefore, appropriate preventive measures are valuable in decreasing heart attacks. Hammarstedt A, Gogg S, Hedjazifar S, Nerstedt A, Smith U: Impaired adipogenesis and dysfunctional adipose tissue in human hypertrophic obesity. Scheja L, Heeren J: the endocrine function of adipose tissues in health and cardiometabolic disease. Zechner R, Madeo F, Kratky D: Cytosolic lipolysis and lipophagy: two sides of the same coin. The most important measures to protect against the development of atherosclerosis and its progression to serious vascular disease are (1) maintaining a healthy weight, being physically active, and eating a diet that contains mainly unsaturated fat with a low cholesterol content; (2) preventing hypertension by maintaining a healthy diet and being physically active, or effectively controlling blood pressure with antihypertensive drugs if hypertension does develop; (3) effectively controlling blood glucose with insulin treatment or other drugs if diabetes develops; and (4) avoiding cigarette smoking. Several types of drugs that lower plasma lipids and cholesterol have proved to be valuable in preventing atherosclerosis. Most of the cholesterol formed in the liver is converted into bile acids and secreted in this form into the duodenum; then, more than 90% of these same bile acids is reabsorbed in the terminal ileum and used over and over again in the bile. Therefore, any agent that combines with the bile acids in the gastrointestinal tract and prevents their reabsorption into the circulation can decrease the total bile acid pool in the circulating blood. Resin agents can also be used to bind bile acids in the gut and increase their fecal excretion, thereby reducing cholesterol synthesis by the liver. These proteins include structural proteins, enzymes, nucleoproteins, proteins that transport oxygen, proteins of the muscle that cause muscle contraction, and many other types that perform specific intracellular and extracellular functions throughout the body. The basic chemical properties that explain the diverse functions of proteins are so extensive that they constitute a major portion of the entire discipline of biochemistry. For this reason, the current discussion is confined to a few specific aspects of protein metabolism that are important as background for other discussions in this text. Basic Properties of Proteins Amino Acids Are the Principal Constituents of Proteins the principal constituents of proteins are amino acids. Twenty of these amino acids are present in the body proteins in significant quantities. The amino acids of proteins are aggregated into long chains by means of peptide linkages. After the peptide linkage has been formed, an amino radical and a carboxyl radical are still at opposite ends of the new, longer molecule. Each of these radicals is capable of combining with additional amino acids to form a peptide chain. Some complicated protein molecules have many thousands of amino acids combined by peptide linkages, and even the smallest protein molecule usually has more than 20 amino acids combined by peptide linkages. Transport and Storage of Amino Acids Blood Amino Acids Note in this reaction that the nitrogen of the amino radical of one amino acid bonds with the carbon of the carboxyl radical of the other amino acid. A hydrogen ion the normal concentration of amino acids in the blood is between 35 and 65 mg/dl, which is an average of about 2 mg/dl for each of the 20 amino acids, although some are present in far greater amounts than are others. They actually account for 2 to 3 milliequivalents of the negative ions in the blood. The precise distribution of the different amino acids in the blood depends to some extent on the types of proteins eaten, but the concentrations of at least some individual amino acids are regulated by selective synthesis in the different cells. The 10 essential amino acids cannot be synthesized in sufficient quantities in the body; these amino acids must be obtained, already formed, from food. The products of protein digestion and absorption in the gastrointestinal tract are almost entirely amino acids; only rarely are polypeptides or whole protein molecules absorbed from the digestive tract into the blood. Second, after entering the blood, the additional amino acids are absorbed within 5 to 10 minutes by cells throughout the body, especially by the liver. Therefore, large concentrations of amino acids almost never accumulate in the blood and tissue fluids. Nevertheless, the turnover rate of the amino acids is so rapid that many grams of proteins can be carried from one part of the body to another in the form of amino acids each hour. The molecules of all the amino acids are much too large to diffuse readily through the pores of the cell membranes. Therefore, significant quantities of amino acids can move 866 Chapter 70 Protein Metabolism either inward or outward through the membranes only by facilitated transport or active transport using carrier mechanisms. The nature of some of the carrier mechanisms is not completely understood, but a few are discussed in Chapter 4. In the kidneys, the different amino acids that are filtered by the glomerular capillaries can be reabsorbed through the proximal tubular epithelium by secondary active transport, which returns them to the blood. However, as is true of other active transport mechanisms in the renal tubules, there is an upper limit to the rate at which each type of amino acid can be transported. For this reason, when the concentration of a particular type of amino acid becomes too high in the plasma and glomerular filtrate, the excess that cannot be actively reabsorbed is lost into the urine. Storage of Amino Acids as Proteins in the Cells are replenished by degradation of proteins from other cells of the body, especially from liver cells. These effects are particularly noticeable in relation to protein synthesis in cancer cells. Cancer cells are often prolific users of amino acids; therefore, the proteins of the other cells can become markedly depleted. Each type of cell has an upper limit with regard to the amount of proteins it can store. After all the cells have reached their limits, the excess amino acids still in the circulation are degraded into other products and used for energy, as discussed subsequently, or they are converted to fat or glycogen and stored in these forms. Functional Roles of the Plasma Proteins the major types of protein present in the plasma are albumin, globulin, and fibrinogen. A major function of albumin is to provide colloid osmotic pressure in the plasma, which prevents plasma loss from the capillaries, as discussed in Chapter 16. The globulins perform several enzymatic functions in the plasma, but equally important, they are principally responsible for both the natural and acquired immunity of the body against invading organisms, as discussed in Chapter 35. Fibrinogen polymerizes into long fibrin threads during blood coagulation, thereby forming blood clots that help repair leaks in the circulatory system, as discussed in Chapter 37. Essentially all the albumin and fibrinogen of the plasma proteins, as well as 50% to 80% of the globulins, are formed in the liver. The remaining globulins, which are formed almost entirely in lymphoid tissues, are mainly gamma globulins that constitute antibodies used in the immune system. The rate of plasma protein formation by the liver can be extremely high-as much as 30 g/day. Certain disease conditions cause rapid loss of plasma proteins; for example, severe burns that denude large surface areas of the skin can cause the loss of several liters of plasma through the denuded areas each day. The rapid production of plasma proteins by the liver is valuable in preventing death in such states. Occasionally, a person with severe renal disease loses as much as 20 grams of plasma protein in the urine each day for months, and this plasma protein is continually replaced mainly by liver production of the required proteins. As discussed in Chapter 25, liver cirrhosis leads to decreased plasma colloid osmotic pressure, which causes generalized edema. Therefore, the concentration of free amino acids inside most cells usually remains low, and storage of large quantities of free amino acids does not occur in the cells; instead, they are stored mainly in the form of actual proteins. However, many of these intracellular proteins can be rapidly decomposed again into amino acids under the influence of intracellular lysosomal digestive enzymes. Special exceptions to this reversal process are the proteins in the chromosomes of the nucleus and the structural proteins such as collagen and muscle contractile proteins. These proteins do not participate significantly in this reverse digestion and transport back out of the cells. Some tissues of the body participate in the storage of amino acids to a greater extent than do others. For example, the liver, which is a large organ and has special systems for processing amino acids, can store large quantities of rapidly exchangeable proteins, which is also true of the kidneys and the intestinal mucosa to a lesser extent. Amino Acid Release From Cells as a Means of Regulating Plasma Amino Acid Concentration. Whenever plasma amino acid concentrations fall below normal levels, the required amino acids are transported out of the cells to replenish their supply in the plasma. In this way, the plasma concentration of each type of amino acid is maintained at a reasonably constant value. Some of the hormones secreted by the endocrine glands are able to alter the balance between tissue proteins and circulating amino acids. For example, growth hormone and insulin increase the formation of tissue proteins, whereas adrenocortical glucocorticoid hormones increase the concentration of plasma amino acids. Because cellular proteins in the liver (and, to a much less extent, in other tissues) can be synthesized rapidly from plasma amino acids, and because many of these proteins can be degraded and returned to the plasma almost as rapidly, constant interchange and equilibrium occurs between the plasma amino acids and labile proteins in virtually all cells of the body. For example, if a particular tissue requires proteins, it can synthesize new proteins from amino acids of the blood; in turn, blood amino acids plasma proteins can act as a source of rapid replacement. Indeed, whole plasma proteins can be imbibed in toto by tissue macrophages through the process of pinocytosis; once in these cells, they are split into amino acids that are transported back into the blood and used throughout the body to build cellular proteins wherever they are needed. In this way, the plasma proteins function as a labile protein storage medium and represent a readily available source of amino acids whenever a particular tissue requires them. Reversible equilibrium among the tissue proteins, plasma proteins, and plasma amino acids. On the basis of radioactive tracer studies, it has been estimated that normally about 400 grams of body protein are synthesized and degraded each day as part of the continual state of flux of amino acids, which demonstrates the general principle of reversible exchange of amino acids among the different proteins of the body. Even during starvation or severe debilitating diseases, the ratio of total tissue proteins to total plasma proteins in the body remains relatively constant at about 33:1. Because of this reversible equilibrium between plasma proteins and the other proteins of the body, one of the most effective therapies for severe, acute whole-body protein deficiency is intravenous transfusion of plasma protein. Within a few days, or sometimes within hours, the amino acids of administered protein are distributed throughout the cells of the body to form new proteins as needed. This second group of amino acids that cannot be synthesized is called the essential amino acids. Use of the word "essential" does not mean that the other 10 "nonessential" amino acids are not required for the formation of proteins but only that the others are not essential in the diet because they can be synthesized in the body. Synthesis of the nonessential amino acids depends mainly on the formation of appropriate -keto acids, which are the precursors of the respective amino acids. For example, pyruvic acid, which is formed in large quantities during the glycolytic breakdown of glucose, is the keto acid precursor of the amino acid alanine. Then, by the process of transamination, an amino radical is transferred to the -keto acid, and the keto oxygen is transferred to the donor of the amino radical.

In a person with poor liver function muscle relaxant 751 discount sumatriptan 25 mg on-line, blood glucose concentration after a meal rich in carbohydrates may rise two to three times as much as in a person with normal liver function spasms right arm purchase sumatriptan from india. Gluconeogenesis in the liver is also important in maintaining a normal blood glucose concentration because gluconeogenesis occurs to a significant extent only when the glucose concentration falls below normal spasms from catheter sumatriptan 100 mg on line. Large amounts of amino acids and glycerol from triglycerides are then Although most cells of the body metabolize fat muscle relaxant medication over the counter buy generic sumatriptan on line, certain aspects of fat metabolism occur mainly in the liver spasms homeopathy right side cheap sumatriptan 25 mg on line. In fat metabolism, the liver performs the following specific functions, as summarized from Chapter 69: 1. Synthesis of large quantities of cholesterol, phospholipids, and most lipoproteins 3. Synthesis of fat from proteins and carbohydrates To derive energy from neutral fats, the fat is first split into glycerol and fatty acids. The fatty acids are then split by betaoxidation into two-carbon acetyl radicals that form acetyl coenzyme A (acetyl-CoA). Acetyl-CoA can enter the citric acid cycle and be oxidized to liberate large amounts of energy. Beta-oxidation can take place in all cells of the body, but it occurs especially rapidly in the hepatic cells. The liver cannot use all the acetyl-CoA that is formed; instead, it is converted by the condensation of two molecules of acetyl-CoA into acetoacetic acid, a highly soluble acid that passes from the hepatic cells into the extracellular fluid and is then transported throughout the body to be absorbed by other tissues. These tissues reconvert the acetoacetic acid into acetyl-CoA and then oxidize it in the usual manner. About 80% of the cholesterol synthesized in the liver is converted into bile salts, which are secreted into the bile; the remainder is transported in the lipoproteins and carried by the blood to the tissue cells of the body. Phospholipids are likewise synthesized in the liver and transported principally in the lipoproteins. Both cholesterol and phospholipids are used by the cells to form membranes, intracellular structures, and multiple chemical substances that are important to cellular function. Almost all the fat synthesis in the body from carbohydrates and proteins also occurs in the liver. After fat is synthesized in the liver, it is transported in the lipoproteins to the adipose tissue to be stored. The most important functions of the liver in protein metabolism, as summarized from Chapter 70, are the following: 1. Interconversions of the various amino acids and synthesis of other compounds from amino acids Deamination of amino acids is required before they can be used for energy or converted into carbohydrates or fats. A small amount of deamination can occur in the other tissues of the body, especially in the kidneys, but it is much less important than the deamination of amino acids by the liver. Therefore, if the liver does not form urea, the plasma ammonia concentration rises rapidly and results in hepatic coma and death. Indeed, even greatly decreased blood flow through the liver-as occurs occasionally when a shunt develops between the portal vein and the vena cava-can cause excessive ammonia in the blood, an extremely toxic condition. Essentially all the plasma proteins, with the exception of part of the gamma globulins, are formed by the hepatic cells, accounting for about 90% of all the plasma proteins. The remaining gamma globulins are the antibodies formed mainly by plasma cells in the lymph tissue of the body. Therefore, even if as much as half the plasma proteins are lost from the body, they can be replenished in 1 or 2 weeks. Plasma protein depletion causes rapid mitosis of the hepatic cells and growth of the liver to a larger size; these effects are coupled with rapid output of plasma proteins until the plasma concentration returns to normal. Among the most important functions of the liver is its ability to synthesize certain amino acids and other important chemical compounds from amino acids. For example, the so-called nonessential amino acids can all be synthesized in the liver. To perform this function, a keto acid having the same chemical composition (except at the keto oxygen) as that of the amino acid to be formed is synthesized. An amino radical is then transferred through several stages of transamination from an available amino acid to the keto acid to take the place of the keto oxygen. The liver has a particular propensity for storing vitamins and has long been known as an excellent source of certain vitamins in the treatment of patients. The vitamin stored in greatest quantity in the liver is vitamin A, but large quantities of vitamin D and vitamin B12 are normally stored there as well. Sufficient quantities of vitamin A can be stored to prevent vitamin A deficiency for as long as 10 months. Sufficient quantities of vitamin D can be stored to prevent deficiency for 3 to 4 months, and enough vitamin B12 can be stored to last for at least 1 year and perhaps for several years. Except for the iron in the hemoglobin of the blood, by far the greatest proportion of iron in the body is stored in the liver in the form of ferritin. The hepatic cells contain large amounts of a protein called apoferritin, which is capable of combining reversibly with iron. Therefore, when iron is available in the body fluids in extra quantities, it combines with apoferritin to form ferritin and is stored in this form in the hepatic cells until needed elsewhere. When the iron in the circulating body fluids reaches a low level, the ferritin releases the iron. Thus, the apoferritin-ferritin system of the liver acts as a blood iron buffer, as well as an iron storage medium. Other functions of the liver in relation to iron metabolism and red blood cell formation are considered in Chapter 33. In the absence of vitamin K, the concentrations of all these substances decrease markedly and almost prevent blood coagulation. The liver is well known for its ability to detoxify or excrete many drugs into the bile, including sulfonamides, penicillin, ampicillin, and erythromycin. Several of the hormones secreted by the endocrine glands are also either chemically altered or excreted by the liver, including thyroxine and essentially all the steroid hormones, such as estrogen, cortisol, and aldosterone. Liver damage can lead to excess accumulation of one or more of these hormones in the body fluids and therefore cause overactivity of the hormonal systems. Finally, one of the major routes for excreting calcium from the body is secretion by the liver into the bile, which then passes into the gut and is lost in the feces. Measurement of Bilirubin in the Bile as a Clinical Diagnostic Tool Formation of bile by the liver and the function of bile salts in the digestive and absorptive processes of the intestinal tract are discussed in Chapters 65 and 66. In addition, many substances are excreted in the bile and then eliminated in the feces. One of these substances is the greenish-yellow pigment bilirubin, which is a major end product of hemoglobin degradation, as pointed out in Chapter 33. However, bilirubin also provides an exceedingly valuable tool for diagnosing both hemolytic blood diseases and various types of liver diseases. Briefly, when the red blood cells have lived out their life span (on average, 120 days) and have become too fragile to exist in the circulatory system, their cell membranes rupture, and the released hemoglobin is phagocytized by tissue macrophages (also called the reticuloendothelial system) throughout the body. The hemoglobin is first split into globin and heme, and the heme ring is opened to give (1) free iron, which is transported in the blood by transferrin, and (2) a straight chain of four pyrrole nuclei, which is the substrate from which bilirubin will eventually be formed. The first substance formed is biliverdin, but this substance is rapidly reduced to free bilirubin, also called unconjugated bilirubin, which is gradually released from the macrophages into the plasma. This form of bilirubin immediately combines strongly with plasma albumin and is transported in this combination throughout the blood and interstitial fluids. Within hours, the unconjugated bilirubin is absorbed through the hepatic cell membrane. In passing to the inside of the liver cells, it is released from the plasma albumin and soon thereafter conjugated about 80% with glucuronic acid to form bilirubin glucuronide, about 10% with sulfate to form bilirubin sulfate, and about 10% with a multitude of other substances. In these forms, the bilirubin is excreted from the hepatocytes by an active transport process into the bile canaliculi and then into the intestines. Once in the intestine, about half of the "conjugated" bilirubin is converted by bacterial action into urobilinogen, which is highly soluble. Some of the urobilinogen is reabsorbed through the intestinal mucosa back into the blood, and most is re-excreted by the liver back into the gut, but about 5% is excreted by the kidneys into the urine. After exposure to air in the urine, urobilinogen becomes oxidized to urobilin; alternatively, in the feces, it becomes altered and oxidized to form stercobilin. These two types of jaundice are called, respectively, hemolytic jaundice and obstructive jaundice. In hemolytic jaundice, the excretory function of Jaundice-Excess Bilirubin in the Extracellular Fluid Jaundice refers to a yellowish tint to the body tissues, including a yellowness of the skin and deep tissues. The usual cause of jaundice is large quantities of bilirubin in the extracellular fluids-either unconjugated or conjugated bilirubin. The normal plasma concentration of bilirubin, which is almost entirely the unconjugated form, averages 0. In certain abnormal conditions, this amount can rise to as high as 40 mg/ dl, and much of it can become the conjugated type. The skin usually begins to appear jaundiced when the concentration rises to about three times normal-that is, above 1. The common causes of jaundice are (1) increased destruction of red blood cells, with rapid release of bilirubin into the blood, and (2) obstruction of the bile ducts or the liver is not impaired, but red blood cells are hemolyzed so rapidly that the hepatic cells simply cannot excrete the bilirubin as quickly as it is formed. Likewise, the rate of formation of urobilinogen in the intestine is greatly increased, and much of this urobilinogen is absorbed into the blood and later excreted in the urine. In obstructive jaundice that is caused either by obstruction of the bile ducts (which most often occurs when a gallstone or cancer blocks the common bile duct) or by damage to the hepatic cells (which occurs in hepatitis), the rate of bilirubin formation is normal, but the bilirubin formed cannot pass from the blood into the intestines. The unconjugated bilirubin still enters the liver cells and becomes conjugated in the usual way. This conjugated bilirubin is then returned to the blood, probably by rupture of the congested bile canaliculi and direct emptying of the bile into the lymph leaving the liver. Cordero-Espinoza L, Huch M: the balancing act of the liver: tissue regeneration versus fibrosis. Fabris L, Fiorotto R, Spirli C et al: Pathobiology of inherited biliary diseases: a roadmap to understand acquired liver diseases. Gracia-Sancho J, Marrone G, Fernández-Iglesias A: Hepatic microcirculation and mechanisms of portal hypertension. Lefebvre P, Cariou B, Lien F, et al: Role of bile acids and bile acid receptors in metabolic regulation. Chemical laboratory tests can be used to differentiate between unconjugated and conjugated bilirubin in the plasma. In hemolytic jaundice, almost all the bilirubin is in the "unconjugated" form; in obstructive jaundice, it is mainly in the "conjugated" form. A test called the van den Bergh reaction can be used to differentiate between the two. When total obstruction of bile flow occurs, no bilirubin can reach the intestines to be converted into urobilinogen by bacteria. Therefore, no urobilinogen is reabsorbed into the blood, and none can be excreted by the kidneys into the urine. Consequently, in total obstructive jaundice, tests for urobilinogen in the urine are completely negative. Also, stools become clay-colored owing to a lack of stercobilin and other bile pigments. Another major difference between unconjugated and conjugated bilirubin is that the kidneys can excrete small quantities of the highly soluble conjugated bilirubin but not the albumin-bound unconjugated bilirubin. Therefore, in severe obstructive jaundice, significant quantities of conjugated bilirubin appear in the urine. This phenomenon can be demonstrated simply by shaking the urine and observing the foam, which turns an intense yellow. Thus, by understanding the physiology of bilirubin excretion by the liver and by the use of a few simple tests, it is often possible to differentiate among multiple types of hemolytic diseases and liver diseases, as well as to determine the severity of the disease. Dietary Balances Energy Available in Foods Although considerable variation exists among different individuals, and even in the same person from day to day, the usual diet of Americans provides about 15% of the total energy intake from protein, 40% from fat, and 45% from carbohydrate. In most non-Western countries, the quantity of energy derived from carbohydrates far exceeds that derived from proteins and fats. Indeed, in some parts of the world where meat is scarce, the energy received from fats and proteins combined may be no greater than 15% to 20%. Table 72-1 lists the compositions of selected foods, especially demonstrating the high proportions of fat and protein in meat products and the high proportion of carbohydrate in most vegetable and grain products. Fat is deceptive in the diet because it usually exists as nearly 100% fat, whereas proteins and carbohydrates are mixed in watery media, so that each of these normally represents less than 25% of the total weight. Therefore, the fat of one pat of butter mixed with an entire helping of potato sometimes contains as much energy as the potato itself. Twenty to 30 grams of the body proteins are the energy liberated from each gram of carbohydrate as it is oxidized to carbon dioxide and water is 4. The energy liberated from metabolism of the average dietary protein as each gram is oxidized to carbon dioxide, water, and urea is 4. Also, these substances vary in the average percentages that are absorbed from the gastrointestinal tract: about 98% of carbohydrate, 95% of fat, and 92% of protein. Therefore, the average physiologically available energy in each gram of these three foodstuffs is as follows: Calories Carbohydrate Fat Protein 4 9 4 degraded daily and used to produce other body chemicals. Therefore, all cells must continue to form new proteins to take the place of those that are being destroyed, and a supply of protein is necessary in the diet for this purpose. An average person can maintain normal stores of protein if the daily intake is greater than 30 to 50 grams. Some proteins have inadequate quantities of certain essential amino acids and therefore cannot be used to replace the degraded proteins. Such proteins are called partial proteins, and when they are present in large quantities in the diet, the daily protein requirement is much greater than normal. In general, proteins derived from animal foodstuffs are more complete than are proteins derived from vegetable and grain sources.

Sumatriptan 50 mg amex. Japanese Massage-Full Body Massage Oil relaxing muscle *3.

This causes a natriuresis which produces some contraction of the extra cellular fluid volume muscle relaxant 5mg buy sumatriptan 50 mg without prescription, decreased glomerular filtration rate muscle relaxant for joint pain sumatriptan 50 mg low cost, decreased delivery of fluid to the collecting duct muscle relaxant medicines order sumatriptan 100 mg with mastercard, and a decreased urine volume muscle relaxant xylazine generic sumatriptan 50 mg on-line. Amiloride is especially recommended in this setting because it is potassium-sparing spasms gums discount sumatriptan 25 mg fast delivery. Amiloride may also have some advantage in lithium-induced nephrogenic diabetes insipidus because amiloride decreases lithium entrance into cells in the distal tubule. Indomethacin has an antidiuretic action that especially prolongs the action of vasopressin and administered desmopressin. It also decreases urine volume in nephrogenic diabetes insipidus, but there is concern about gastrointestinal bleeding. When diabetes insipidus occurs in patients who also have ante rior pituitary deficiency, adequate treatment with thyroid hor mone and hydrocortisone is essential to maintain normal renal response to desmopressin. Clinical situations such as surgical procedures, treatments that require a saline diuresis, and periods when patients are not allowed fluids by mouth require careful bal ance of antidiuretics (often a low dose of vasopressin by infusion), administered fluid, and sodium. Occasionally, when the serum sodium concentration is mea sured by flame photometry the measured sodium is artifactually low because flame photometry calculates the sodium in a fixed volume of plasma. If a large proportion of the plasma volume is taken up by extremely elevated levels of lipid or protein, sodium determined by flame photometry is low. Plasma osmolality deter mined by freezing point or vapor pressure is a direct measure of particles in solution and will be normal in these situations. So the low level of sodium by flame photometry is referred to as pseudo hyponatremia. Hyperglycemia will produce hyponatremia because of the shift of water from the intracellular fluid to the extracellular fluid; however, the calculated osmolality will be normal. When true hypo-osmolality is found to exist, the differential diagnosis is of hyponatremia as illustrated in Table 5-1. The dis order is divided into four major subgroups based on the extracel lular fluid volume status and the measured urinary sodium. If the patient is dehydrated and the urinary sodium is low, this indicates normal physiologic response to extra-renal sodium loss such as vomiting or diarrhea with continued intake of water. The appropriate therapy is to replace the sodium and fluid deficiency with normal saline. If the patient is dehydrated but the urinary sodium is increased, this indicates a renal loss of sodium inappro priate to the decreased volume and hyponatremia. This may be due to intrinsic renal disease, diuretic use, aldosterone deficiency. Continued ingestion of water (part A) produces an expansion of extracellular and intracellular volume. The body attempts to bring the extracellular fluid volume back to normal by natriure sis (part B) of isotonic urine. The mechanism of natriuresis is complex and involves increased glomerular filtration; pressure natriuresis; and natriuretic factors, especially atrial natriuretic peptide and brain natriuretic peptide. This natriuresis decreases total body water and total body sodium but because it is o tonic, it contributes little to the degree of hyponatremia. Next, the body attempts to return intracellular fluid volume to normal by (part C) excreting from the intracellular fluid potassium and organic osmolytes such as glutamine, glutamate, myoinositol, aspartate, and N-acetylaspartate. In spite of the attempt to nor malize extracellular and intracellular fluid, there remains a ten dency for these compartments to be slightly expanded. The last adaptation (part D) is caused by this tendency for volume expansion and produces changes in the kidney to make it less responsive to the chronic inappropriate excess of vasopressin and to allow an increase in water excretion. Vasopressin retains water by stimulating V2 receptors on the principal cells of the collect ing duct. This stimulation both increases the synthesis of aqua porin-2 molecules and the insertion of aquaporins into the cell membrane. With chronic excess of vasopressin, the density of aquaporins in the membrane increases dramatically, producing a state of chronic increase in water retention. Appropriate therapy is to replace the sodium and fluid loss with normal saline but also with appropriate treatment of the underlying defect. If the extracellular fluid volume is expanded with edema or ascites and the urinary sodium is low, this indicates hyperaldosteronism, secondary to reduced or ineffective plasma volume as in cirrhosis or congestive heart failure, and the appropriate therapy is treatment of the underlying condition. Where the extracellular fluid volume appears to be normal with increased urinary sodium, this indicates the pathophysiology of inappropriate secretion of antidiuretic hormone. Note that the urine osmolality will not be maximally dilute and that measured vasopressin will not be maximally sup pressed in any of the four categories in Table 5- 1. Although not appropriate to the osmolality, in the first three categories, the ele vation of vasopressin is appropriate to the real or perceived decreased plasma volume. Copeptin, the inactive glycopeptide that is cleaved from the provasopressin molecule and secreted with vaso pressin and neurophysin, was mentioned earlier. Some studies have indicated that measurement of levels of this peptide might be useful in evaluating various causes of hyponatremia. In this new state (part E), ingestion of sodium will somewhat re-expand the extracellular fluid volume and be excreted, while ingestion of water will be more easily excreted because of the renal adaptation of decreased aquaporins-therefore a new steady state. Of the diagnoses of hyponatremia shown in Table 5- l, the two categories that are most difficult to differentiate are those with elevated urinary sodium concentrations. On physical examina tion, it may be difficult to differentiate moderately low extracel lular fluid volume from normal extracellular fluid volume. In this situation, the differential diagnosis may be aided by a volume challenge of normal saline infused at a modest rate over a few hours while following urinary and plasma sodium determinations. If the patient is in cate gory 2 with a renal loss of sodium, sodium from the administered m saline will be retained, and the water excreted will somewhat dilute urinary sodium. This will result in a decrease in urinary sodium while the serum sodium concentration will rise. This vol ume challenge in difficult cases is not considered therapy, but only an assist to make the appropriate diagnosis, which will then lead to the initiation of appropriate therapy. Measured plasma volume in subarachnoid hemorrhage is difficult to interpret because of the lack of sensitivity of readily available clinical measures. As noted earlier, the baroreceptors consist of a diffuse system of receptors in the chest and synapses in the brain. Lesions which disrupt the flow of signals in the lung or in the brain may decrease this inhibitory signal and produce inappropri ate secretion of vasopressin. When hyponatremia is known to have occurred rapiclly and is severe and symptomatic, the patient should be treated quickly. Acute hyponatremia is arbitrarily defined as having developed over less than 48 hours. Discontinuing the administration of any hypotonic fluid and the administration of hypertonic NaCl (eg, 3%), possibly with the addition of a diuretic, should be promptly considered. Often acute disorders occur in the hospital in a surgical or obstetrical setting and children and young women are at the greatest risk. For chronic hyponatremia, overly aggressive treatment may cause new and addi tional pathology. Sym ptoms of hyponatremia the symptoms of hypona tremia are largely dependent on the rapidity of the development of hyponatremia. When hyponatremia develops rapidly and is severe (serum sodium level < 1 20 mEq/L), patients are at risk for cerebral edema with herniation of the brain stem (especially chil dren and young women). Other complications include neurogenic pulmonary edema, seizures, coma, and respiratory arrest. Hypona tremia that develops slowly over a long period of time is surpris ingly well-tolerated even at very low levels of serum sodium. Neurologic symptoms usually do not occur with sodium values above 1 20 mEq/L, but any degree of hyponatremia might exacer bate other comorbid conditions. Hyponatremia is usually consid ered chronic if hyponatremia has developed slowly and persisted for greater than 48 hours. This has been reported in several cases of children with traumatic brain injury or brain surgery. The acute massive diuresis and natriuresis is accompanied by definitive volume contraction by the measures listed earlier. Brain shrink age is thought to be the cause of a syndrome of myelinolysis which was first described in the pons-hence the term central pontine myelinolysis. The cause may be disruption of the blood-brain barrier and influx of plasma components that are toxic to the oligodendrocytes. The syndrome consists of neurologic deterioration over several days with fluctuating consciousness, convulsions, hypoventilation, and hypo tension. Eventually, these patients may develop pseudobulbar palsy with difficulty in swallowing and inability to speak, even leading to quadriparesis. Recovery from this syndrome is variable, and many neurologic complications are permanent. Chronic alcoholics, patients with malnutrition or liver disease and patients with profound hyponatre mia or hypokalemia are at increased risk to develop osmotic demyelination. In chronic hyponatremia that is asymptomatic, the safest ther apy is restriction of free water intake and slow correction of the hyponatremia over days. For chronic hyponatremia that has central nervous system symptoms, carefully controlled and limited increases in the osmolality should be undertaken. Coma or convul sions are obvious signs of neurologic symptoms that may be pro duced by hyponatremia, but nausea, vomiting, and confusion may be less specific signs of neurologic impairment. There is consider able debate in the literature about the exact rate of correction of the sodium concentration in these cases, and one should review the most up to date recommendations prior to initiating therapy. Gen eral parameters of therapy are that the increase of serum sodium might be accomplished at a rate of 0. For those at high risk for osmotic demyelinating the total should not exceed 8 mEq/L in the first 24 hours. Further treatment is undertaken with fluid restriction as for asymptomatic hyponatremia. When overly rapid increases in serum sodium occur, especially in persons at high risk for osmotic demyelination, some experts have given dilute fluids, sometimes with desmopressin, to acutely re-lower the serum sodium. Benefit is supported by some animal studies, but there are no controlled studies documenting that this is beneficial in patients. Dosages of 600 to 1 200 mg/d in divided doses decrease urine osmolality (this use is off-label). Azotemia and neph rotoxicity have been reported with demeclocycline especially in patients with cirrhosis. Fluid restriction is the preferred therapy in pediatrics although in young children restricting fluids may not provide adequate calories. When the volume stimulus is removed, there is again an increase in the density of membrane water channels, and the kidney becomes more efficient in retaining water. This accounts for the common clinical observa tion that fluid restriction that is initially effective may have to be increasingly severe to maintain a beneficial effect. There are recently approved vasopressin receptor antagonists, vaptans, which enhance renal free water excretion (aquaresis) without sodium excretion (natriuresis). Conivaptan is a combined vlA and v2 receptor antago nist that is available for intravenous administration to hospitalized patients. Tolvaptan is a selective V2 receptor antagonist that can be administered orally and is approved to treat severe hyponatremia (serum Na < 1 25 mEq/L) in patients who are symptomatic or patients who have failed to correct with fluid restriction. Vaptans should not be used in conjunction with other therapy, for exam ple, hypertonic saline or fluid restriction. The risk of brain myelolysis caused by too rapid correction of sodium with these agents is the same as with other therapies, so the same recommendations about rates of correction of serum sodium described earlier will apply as physi cians gain further experience with these agents. The hypothalamic/pituitary hormones critical to lactation are prolactin and oxytocin. Prolactin secretion from the anterior pituitary is described in Chapter 4, and its primary activity is to promote milk production. While there are a number of central nervous sys tem actions that have been attributed to oxytocin (probably acting as a neurotransmitter), the physiologic functions of this posterior pituitary hormone are limited to lactation and parturition. The milk-producing unit of the breast is the alveolar system in which clusters of milk-producing cells are surrounded by specialized myoepithelial cells. Oxytocin receptors are localized on glandular cells and on myoepithelial cells along the duct. Oxytocin stimulates the cells along the duct to shorten and the ducts to widen, enhancing milk flow through the ducts to the nipple. Suckling at the breast stimulates mechanoreceptors or tactile receptors that ascend through the spinal cord to the lateral cervical nucleus and eventually to the oxytocinergic magnocellular. Renal Na+ Joss (diuretics, Addison disease, renal disease, cerebral salt wasting). Brain dehydration and neurologic deterio ration after rapid correction of hyponatremia. The uterine myometrial cells have intrinsic contraction activity and are responsive to oxytocin. During pregnancy, oxyto cin is released, but oxytocinase decreases the plasma level of oxy tocin, and progesterone and relaxin decrease the intrinsic contractility of the myometrium. In humans, there is a dramatic increase in uterine responsiveness to oxytocin as parturition approaches. Several hormones other than oxytocin including pros taglandins, endothelins, adrenergic agonists, corticotropin-releas ing hormone, glucocorticoids, and cytokines also participate in the initiation and completion of labor. The most specific role of oxytocin may be the release of oxytocin brought about by vaginal and cervical dilatation produced by the descending head and body, known as the Fergusson reflex. This may be important in stimulating uterine muscle to contract maximally and clamp down blood vessels to decrease blood loss. It is perhaps not sur prising that parturition, which is so important to survival of the species, is controlled by many different pathways of cross-stimula tion and feed-forward activity. Oxytocin remains the strongest stimulant to myometrial contraction, explaining its value as a therapeutic agent in inducing parturition and the interest in oxy tocin antagonists to delay parturition. Physiologic changes during brain stem death-lessons for management of the organ donor.

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