Approach to the Patient with Gastrointestinal Disease Don W

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					APPROACH TO THE PATIENT WITH GASTROINTESTINAL DISEASE
Don W. Powell

Epidemiology
Diseases of the gastrointestinal tract and liver together account for about 10% of the total burden of illness, more than 50 million office visits, and nearly 10 million hospital admissions annually in the United States. Colorectal cancer (Chapter 200) is the second most common cause of cancer in men and women, and, when all of the gastrointestinal organs are combined, gastrointestinal malignancies are the most common of any organ system. The cost of gastrointestinal diseases depends on their prevalence, direct cost (professional fees, hospital charges, pharmaceutical costs), and indirect cost (time lost from work). The most prevalent gastrointestinal diseases are the non–food-borne infections and food-borne illnesses (combined, greater than one episode per year per U.S. citizen) (Chapter 323), gastroesophageal reflux disease (GERD) (Chapter 136), gallbladder disease (Chapter 158), and irritable bowel syndrome (IBS) (Chapter 135), with each occurring in 10% or more of the U.S. population. The most costly diseases (total cost in 2000 dollars) are GERD ($10.1 billion), gallbladder disease ($6.5 billion), colorectal cancer ($5.3 billion), peptic ulcer disease ($3.4 billion; Chapter 138), and diverticular disease ($2.7 billion; Chapter 143). Finally, gastrointestinal diseases as a group account for approximately 10% of all deaths in the United States each year.

Overview of the Gastrointestinal Tract
The major function of the gastrointestinal tract is to process and absorb water and nutrients while food moves physically from mouth to colon, where nonabsorbable wastes are stored for periodic elimination. Dysfunction of the epithelial absorptive function and of the smooth muscle contractile function causes the major pathologic processes related to the gastrointestinal tract. The epithelial lining of the gastrointestinal tract is a huge surface area, greater than that of a tennis court; it interacts with the food, water, and xenobiotics of the external environment and with the intestinal microflora. The epithelium allows the absorption of fluid, electrolytes, and nutrients in health and the secretion of huge volumes of fluid and electrolytes in disease. The rapid turnover of the epithelial cells, which have a life span of 3 to 7 days, allows environmental interaction with genes that may lead to the development of neoplasia. Some of the most common diseases affecting the gastrointestinal tract are disorders of integrated function controlled by secreted hormones, paracrine mediators, and the enteric nervous system. Disruption of this neuroendocrine control is much more likely to cause symptom-complexes (e.g., functional diseases such as IBS and nonulcer dyspepsia) than anatomically defined disease. However, it would be a mistake to view the gastrointestinal tract only as a muscular tube with an epithelial lining. The enteric nervous system contains between 10 and 100 million neurons, a conglomerate equal to the total number in the spinal cord. If the total number of enteroendocrine cells were put together into a

single organ, it would probably be the largest endocrine gland in the body. The gastrointestinal tract’s immune cells, which make up the gastrointestinal-associated lymphoid system (GALT), constitute the largest immune organ of the body. These three systems allow the smooth integration of the function of this complex organ, but they also represent points of dysfunction, which can cause both local and even systemic disease. The enteric nervous system is, for all intents and purposes, an independent nervous system. A growing body of evidence suggests that interaction of the sensory nerves with the spinal cord and brain causes functional gastrointestinal disorders. Current lack of understanding of the enteric nervous system may compromise the management of the 15 to 20% of the population who present with IBS and/or non-ulcer dyspepsia (Chapter 135). The enteroendocrine system of the gastrointestinal tract is unique because it responds to intraluminal stimuli as well as to systemic stimuli presented to it from either the nervous system or the blood. The secretions of these endocrine cells not only affect epithelial, smooth muscle, and vascular function but also have poorly understood effects on distal organs such as the liver, pancreas, and brain. The GALT is part of a common mucosa-associated lymphoid tissue (MALT) that exists also in the lung, the breast, and the genitourinary tract. The major function of the GALT is to recognize the myriad of antigens presented to the gastrointestinal tract, differentiating between those that should be ignored (e.g., the proteins of nutrients and commensal microflora) and those that should excite a major immune response (e.g., the proteins of pathogenic bacteria). The enteric immune system may play a role in systemic autoimmune diseases and in the development of immune tolerance.

Clinical Approach to Gastrointestinal Disease
The diagnosis of gastrointestinal diseases derives predominantly from the patient’s history and, to a lesser extent, from the physician’s physical examination. Laboratory tests and imaging studies can provide objective evidence for or against a given disease among those included in the differential diagnosis raised by an accurate and expert history and physical examination. Diagnoses arise out of specific symptoms (e.g., dysphagia) or from pairing gastrointestinal complaints (e.g., diarrhea) with extraintestinal symptoms or physical findings (e.g., the arthritis of inflammatory bowel disease or the flushing of carcinoid syndrome). However, gastrointestinal symptoms arise not only from disease or dysfunction of the gastrointestinal tract but also through the brain-gut axis and blood stream and from dysfunction or disease of other organs, especially the central nervous system (CNS). For example, a cardinal symptom of gastrointestinal disease, nausea and vomiting, is just as likely to result from stimuli that affect the CNS as from stimuli arising in the gastrointestinal tract. Other cardinal symptoms are abdominal pain, weight loss, bleeding, diarrhea, and constipation. CARDINAL SYMPTOMS Nausea and Vomiting To understand nausea and vomiting, it is first necessary to differentiate these symptoms from closely related phenomena such as hunger, appetite, satiety, and anorexia. Both hunger and appetite refer to the

desire to eat. The determinants of hunger are usually physiologic signals coming from the complex interaction between adrenergic receptors in the medial hypothalamus of the CNS and the serotoninergic, dopaminergic, and β-adrenergic receptors in the lateral hypothalamus. Appetite is closely related to hunger, but it is thought to be influenced predominantly by environmental and psychological processes (e.g., the aroma, appearance, and taste of food, as well as the patient’s mood). Satiety refers to the gratification of hunger and appetite, mediated in part by cholecystokinin and bombesin, which appear to act both peripherally through the vagus nerve and centrally in the hypothalamic satiety center. The discovery of the Ob gene and its peptide hormone leptin in adipocytes has improved our understanding of the homeostasis of body mass. Leptin and insulin act on the hypothalamus to inhibit release of anabolic substances such as neuropeptide Y and peptides called orexins that promote feeding and weight gain. Leptin also stimulates release of catabolic substances such as melanocortin and corticotropin-releasing factor, which reduce feeding behavior. Anorexia is a clinical symptom characterized by the absence of hunger or appetite. It may be caused by CNS, systemic, or gastrointestinal disease or by emotional processes that initiate functional disorders. Satiety and anorexia must be differentiated from nausea, which is the unpleasant feeling that one is about to vomit, and vomiting (or emesis), which is the forceful ejection of contents of the upper gut through the mouth. In contrast, retching involves coordinated, voluntary muscle activity of the abdomen and thorax—in effect, a forced respiratory inspiration against a closed mouth and glottis without discharge of gastric contents from the mouth. Regurgitation is the effortless return of gastric or esophageal contents into the mouth without nausea, and it occurs without spasmodic abdominal, thoracic, or gastrointestinal muscular contractions. Rumination (merycism) is the effortless but purposeful regurgitation of food from the stomach into the mouth, where it is rechewed and reswallowed, often several times during or after a meal. The coordinated events that allow the process of vomiting begin in the reticular areas of the medulla and include the dorsal vagal complex nuclei, which was formerly called the ―vomiting center.‖ More recent investigations indicate that multiple brain stem sites mediate emesis, and there is no single ―vomiting center.‖ Indeed, several brain stem nuclei are necessary to integrate the various responses of the gastrointestinal, respiratory, pharyngeal, and somatic systems in the act of vomiting. The brain stem control of nausea and vomiting has sensory input from at least four additional areas: (1) the chemoreceptor trigger zone; (2) the vestibular nucleus mediating input from the inner ear and through the cerebellum; (3) the gastrointestinal tract itself, as well as other viscera within the peritoneal cavity; and (4) the upper cortical regions of the CNS. These four areas, through various neurons and receptors of the serotoninergic (5-HT3), dopaminergic (D2), histaminergic (H1), muscarinic (M1), and vasopressinergic (V1) type, respond to environmental and internal stimuli to signal and then activate the vomiting center(s). The chemoreceptor trigger zone is in the area postrema in the floor of the fourth ventricle. This area lacks a tight blood-brain barrier, so blood-borne agents can penetrate it. The chemoreceptor trigger zone also receives neural input from the upper centers of the brain and the peripheral nerves, and it responds to certain systemic medications and to metabolic diseases. Motion sickness and inner ear disease, such as Ménière’s disease (Chapter 470), act through the vestibular nucleus, which contains H1 and M1 receptors. The vagus and sympathetic nerves, via the nodosum ganglion and the nucleus tractus solitarius, mediate nausea that arises from gastric irritants such as salicylates or staphylococcal enterotoxin; gastric, small intestinal, colonic, or bile duct distention; and inflammation or ischemia of bowel, liver, pancreas, and

peritoneum. Higher cortical centers also may affect the vomiting center and mediate nausea and vomiting induced by intense emotions or stress, as well as the classic anticipatory nausea and vomiting seen with administration of cancer chemotherapy. To understand the causes of nausea and vomiting, stimuli arising from the CNS must be differentiated from those originating in the gastrointestinal tract. Historical information concerning the duration, precipitation, and pattern of nausea and vomiting as well as the nature of the vomitus is not sufficient; the physician must also seek signs and symptoms of gastrointestinal diseases (e.g., abdominal pain, diarrhea, constipation, bleeding, or weight loss) and of CNS diseases (e.g., headache, changes in mental status, change in neuromuscular function, symptoms related to the inner ear, drug ingestion, or a history of emotional or environmental stress). Medications are among the most common causes of nausea and vomiting. Apomorphine, opiates, digitalis, levodopa, bromocriptine, and anticancer drugs act on the chemoreceptor trigger zone. Drugs that frequently cause nausea through other mechanisms include nonsteroidal anti-inflammatory drugs, erythromycin, cardiac antiarrhythmic medications, antihypertensive drugs, diuretics, oral antidiabetic agents, oral contraceptives, and gastrointestinal medications such as sulfasalazine. Chemotherapeutic agents most likely to induce vomiting are cisplatin, nitrogen mustard, and dacarbazine (Chapter 191). Gastrointestinal and systemic infections, both viral and bacterial, are probably the second most common cause of nausea and vomiting. Infections may be at fault through the release of bacterial enterotoxins or the inflammation initiated by the pathogen. Obstruction of the gastrointestinal tract or organs—stomach, small intestine, colon, pancreas, or biliary tract—and ischemia or inflammation of these organs or the liver or peritoneum are the third most common cause. In addition to labyrinthine disorders (motion sickness, space sickness, viral labyrinthitis, acoustic tumors, and Ménière’s disease; Chapter 470), a major CNS cause of nausea and vomiting is diseases that increase intracranial pressure (Chapter 428). Emotional responses to unpleasant smells or taste and severe psychogenic stress are additional CNS causes. Metabolic causes such as uremia, diabetic ketoacidosis, hypercalcemia, hypoxemia, hyperthyroidism, Addison’s disease, and radiation therapy cause nausea by stimulating the chemoreceptor trigger zone. The first trimester of pregnancy causes vomiting in approximately 70% of pregnant women. Postoperative nausea and vomiting complicate up to 40% of surgical operations. Effective antiemetics for nausea and vomiting include those that block the major receptors of (1) the area postrema (D2, 5-HT3, H1, and M1 receptors) and (2) the H1, M1, 5-HT1A, and 5-HT3 receptors of brain stem nuclei (the vomiting center) that receive input from the vestibular nucleus, the vagus, and the sympathetic nerves. Phenothiazines act on D1, H1, and M1 receptors; metoclopramide, domperidone, and ondansetron affect 5-HT3 and 5-HT4 receptors; scopolamine is an M1-receptor antagonist; and diphenhydramine (Dramamine) and cyclizine (Marezine) are H1 antagonists. The most effective of the antinausea drugs for chemotherapy-induced vomiting are the 5-HT3 receptor antagonists ondansetron, granisetron, and dolasetron. In the chemotherapy setting, a 5-HT3 receptor antagonist may be combined with other medications (a corticosteroid, phenothiazine/butyrophenone, substituted benzamide, or cannabinoid) for maximal antiemetic action. Abdominal Pain

This symptom complex arises from intra-abdominal, nociceptive impulses that are variously modulated by input from the spinal cord and the CNS. Abdominal pain is either acute or chronic; when chronic, it may be intermittent (e.g., recurrent biliary colic), unrelenting (e.g., chronic pancreatitis or pancreatic cancer), or intractable but of unclear cause (e.g., the functional abdominal pain syndromes). In the gastrointestinal tract, nociceptive pain receptors are present in the walls (lamina propria and muscle layers) of the hollow organs, in serosal structures (the visceral peritoneum and the capsules of the solid organs), and within the mesentery that supports and surrounds the abdominal organs. These receptors respond to distention, contraction, traction, compression, torsion, and stretch; to inflammatory mediators such as bradykinin, substance P, serotonin, histamine, and prostaglandins; and to chemicals such as hydrochloric acid, potassium chloride, and hypertonic saline. These receptors do not respond to classic nociceptive stimuli such as pinching, burning, stabbing, or cutting or to electrical or thermal stimulation. As a result, the gastroenterologist can biopsy or thermally coagulate the gastrointestinal mucosa with impunity, yet a patient notes severe pain with contraction or distention of the viscera or with traction and pulling on the mesentery and abdominal organs. The cell bodies of the sensory receptors of the gut and viscera are in the dorsal root ganglion of the spinal cord. These neurons synapse in the dorsal horn and then either cross the cord to ascend in the contralateral spinal thalamic tract or ascend in the contralateral posterior column to reach the reticular formation of the brain stem or the thalamus, where they synapse and project to the limbic system and frontal lobe or to the somatosensory cortex, respectively. In the embryo, the gut and organs are present in the midline and receive innervation from both sides of the spinal canal. Thus, stimuli arising in the gastrointestinal tract (e.g., from inflammation, ischemia) are often perceived as midline pain until the process (e.g., appendicitis or cholecystitis) extends to the adjacent parietal peritoneum, where laterally localizing nerves project the pain to the brain. The synapses of the pain fibers from the viscera and the dorsal horn of the spinal cord allow the CNS and somatic nerves to modulate the perception of visceral pain. Descending inhibitory neurons arising in the CNS, when activated, stimulate interneurons in the cord that inhibit the firing of the second-order and visceral pain neurons, which travel up the cord to the brain. The balance of these excitatory and inhibitory forces determines the degree to which the nociceptive information is transmitted to the CNS. This process is called the gate control theory of pain; it explains how acupuncture might inhibit the perception of visceral pain. A new and important concept is the role of sensitization in the pathophysiology of the functional gastrointestinal diseases (Chapter 135). Inflammation and/or prolonged and excessive motor events in the gut are thought to induce molecular changes, both in the periphery (enteric nervous system) and centrally (in the spinal cord and brain), that lead the patient to experience a greater than normal amount of discomfort for a given stimulus (hyperalgesia) or a perception of pain with gut stimuli that normally are not perceived as painful (allodynia). The location of painful sensations is determined by the spinal segments in which the afferent nerves from the abdominal viscera enter the spinal cord. For example, foregut structures, such as the esophagus, stomach, proximal duodenum, liver, biliary tree, and pancreas, are innervated at T5 to T9; pain from these structures is perceived between the xiphoid and the umbilicus. Pain from midgut structures, such

as the small intestine, appendix, and ascending and proximal two thirds of the transverse colon, is transmitted from T8 to L1 and is perceived as periumbilical. Pain from hindgut structures, which include the distal one third of the transverse colon, the descending colon, and the rectosigmoid, is transmitted from T11 to L1 and is perceived between the umbilicus and the pubis. Referred pain is pain perceived in the skin or muscle in the same cutaneous dermatomes as those nerve roots where the innervation of the abdominal organ enters the spinal cord. Referred pain is a helpful phenomenon to diagnose the cause of acute abdominal pain: gallbladder pain may be perceived in the right shoulder or scapula, and pain from retroperitoneal processes such as pancreatitis is referred to the back. In addition to the location of pain and the presence of referred pain, the character of the pain (burning, steady, or colic), its duration, its time to reach peak intensity, and its relieving and aggravating factors (such as eating or passing gas or stool) are helpful components of the medical history. Esophagitis is classically described as substernal burning pain relieved by antacids and aggravated by lying down (Chapter 136). Peptic ulcer pain occurs when the stomach is empty (often 4 AM), and it is relieved by eating or taking antacids (Chapter 138). Gallbladder colic (Chapter 158) is perceived either in the midline or right upper quadrant, reaches a peak intensity within minutes to an hour, and usually persists for 1 to 4 hours. In contrast, the pain of cholecystitis and pancreatitis (Chapter 145) reaches its peak more slowly, becomes sustained, and lasts for days. Intestinal obstruction causes colicky pain that waxes and wanes over the course of minutes and is usually periumbilical (Chapter 143). Chronic intermittent abdominal pain may be due to obstructed viscera, such as in recurrent cholelithiasis or intestinal obstruction; to metabolic or genetic diseases, such as acute intermittent porphyria (Chapter 223) or familial Mediterranean fever (Chapter 181); to neurologic diseases, such as diabetic reticulopathy (Chapter 462), abdominal migraine (Chapter 428), or vertebral nerve root compression (Chapter 429); or to miscellaneous inflammatory diseases, such as Crohn’s disease (Chapter 142), endometriosis (Chapter 250), lead poisoning (Chapter 20), and mesenteric ischemia (Chapter 144). Functional abdominal pain, now thought to result from visceral hyperalgesia, includes three major types: (1) IBS, in which recurrent abdominal pain is accompanied by changes in gastrointestinal function (constipation, diarrhea, or alternating constipation and diarrhea; Chapter 135); (2) nonulcer dyspepsia, which is defined as ulcer-like symptoms in the absence of endoscopically definable anatomic or histologic evidence of inflammation (Chapter 135); and (3) chronic, intractable abdominal pain, in which pain is not accompanied by other symptoms of organ dysfunction. These functional diseases are quite common and may account for up to 50% of patients who present with gastrointestinal symptoms to either the primary care physician or gastroenterologist. Weight Loss Continued, unexplained weight loss greater than 5% of body weight is of concern to the patient and physician. Contrary to usual thought, malignancy is not the most common cause and, when it is, it is usually diagnosed early in the course of evaluation. Gastrointestinal disorders, with their attendant anorexia, fear of eating (sitophobia), malabsorption and/or inflammation, and psychogenic causes, are at least as common as cancer. Diseases of the other organ systems make up the remainder of the diverse etiologies. In the elderly, weight loss often can be attributed to the 10 ―D‖s: dentition, dysgeusia, dysphagia, diarrhea, disease (chronic), depression, dementia, dysfunction, drugs, and ―don’t know.‖ In

the young, eating disorders (anorexia nervosa and bulimia; Chapter 232) must be considered. Evaluation in both the young and old requires a careful history and physical examination with attention to clues or findings that suggest systemic or organ system disease. A careful neuropsychiatric evaluation should also be performed, with appropriate input from caregivers and friends. Screening laboratory tests are useful: complete blood cell count, urinalysis, metabolic panel, chest radiograph, thyroid-stimulating hormone assay, erythrocyte sedimentation rate, celiac disease antibody test, HIV tests (if risk factors are present), and fecal occult blood test. If cancer is suspected but there are no localizing clues, helpful tests include a cervical Pap smear and mammography in women, a prostate-specific antigen in men, and colonoscopy/barium enema or abdominal/pelvic computed tomography in either gender. Gastrointestinal Bleeding Bleeding from a gastrointestinal tract may be occult, that is, requires testing of the stool to be detected, or gross and evident as hematemesis, melena, or hematochezia (Chapter 133). It is always a serious symptom that requires investigation. Hemoccult, the most commonly used test to detect occult bleeding, requires blood loss of 10 mL/day to give a positive test 50% of the time. Endoscopy is the most effective way to diagnose occult bleeding (Chapters 132 and 133). Upper endoscopy should be performed first if the patient’s symptoms suggest upper tract disease; colonoscopy should be performed first in those with lower tract symptoms or in those who are asymptomatic. Melena, which requires 150 mL of blood in the gastrointestinal tract to be manifest, and hematemesis occur when the bleeding site is proximal to the ligament of Treitz. Upper endoscopy is indicated for these signs. Hematochezia may occur after massive upper tract bleeding or minor bleeding from anorectal sources. Hematochezia should be investigated with colonoscopy after an urgent bowel preparation if the bleeding has been significant. Diarrhea Death from fluid and electrolyte losses may be the outcome of diarrhea in developing countries but, in developed nations, it is usually more of economic significance due to loss of time from work. For diagnostic purposes, diarrhea (Chapter 141) may be categorized as watery, malabsorption (steatorrhea), or inflammatory. However, the causes in each case may be due to either the presence of ingested, poorly absorbed osmotic substances in the bowel, stimulation of water and electrolyte secretion, or malabsorption of nutrients. Constipation Constipation is so common a complaint that it is often not considered to be a symptom of disease. It may occur secondary to endocrine, metabolic, neurologic, or anorectal diseases. More commonly, it is idiopathic. When severe and intractable, two general pathophysiologic mechanisms are sought: colonic inertia (slow transit) and functional outlet obstruction. PHYSICAL EXAMINATION In acute abdominal pain, the physical examination is targeted quite differently than in patients with chronic gastrointestinal complaints. The goal of the examination in acute abdominal pain is to determine the presence of surgical disease. Observation of facial expression is key to determining the presence

and severity of pain. Distention, particularly if tympanic, suggests bowel obstruction, but simple obesity and ascites are more likely causes of distention without tympany. The character of bowel sounds (absent in peritonitis, high-pitched tinkles in intestinal obstruction) can be important, but any bowel sounds that are hypoactive, hyperactive, or present in one quadrant or another are of little consequence. The most useful part of the examination is palpation, which gives clues to the presence of severe peritoneal inflammation, as manifested by involuntary guarding, abdominal rigidity, or rebound tenderness; when these symptoms are accompanied by absent bowel sounds, perforation and peritonitis must be suspected (Chapter 143). Palpation with the stethoscope rather than with the hand can sometimes differentiate true abdominal rebound tenderness from a response that is either feigned or imagined. In the patient with chronic gastrointestinal complaints, the goal of the physical examination is to determine the presence or absence of other systemic findings that might suggest the underlying disease, to determine the size of the abdominal viscera, and to detect any abnormal masses. For example, the presence of jaundice and spider telangiectasia suggests liver disease (Chapter 156) and perhaps varices as a cause of gastrointestinal bleeding. Large joint arthritis and aphthous ulcers of the mouth might suggest celiac disease (Chapter 141) or inflammatory bowel disease (Chapter 142). The abdominal examination might reveal epigastric, right upper quadrant, right lower quadrant, or left lower quadrant tenderness to complement a compatible history for peptic ulcer disease (Chapter 138), cholecystitis (Chapter 158), Crohn’s disease (Chapter 142), or diverticulitis (Chapter 143), respectively. An epigastric mass might suggest a pancreatic neoplasm (Chapter 201) or pseudocyst (Chapter 145), whereas right lower quadrant and left lower quadrant masses suggest abscess due to inflammatory bowel disease and diverticulitis, respectively, or colonic cancer. Examination of the liver (Chapter 148) should focus primarily on its breadth and consistency. Auscultation is useful to determine the presence of bruits indicative of vascular disease or friction rubs that suggest pancreatic or hepatic cancer (Chapters 201 and 202). The physical examination is not complete without a digital rectal examination. The examiner should not forget to sweep the finger posterially to search for anorectal carcinoma and masses in the pouch of Douglas and anteriorly to determine the size and consistency of the prostate (Chapter 129). Tenderness and masses laterally can occur in appendicitis (Chapter 143), inflammatory bowel disease, or diverticulitis, as well as abdominal cancers. The character and color of the stool and the presence of fecal occult blood should be assessed. LABORATORY TESTS AND IMAGING PROCEDURES A complete blood cell count, liver chemistries, and erythrocyte sedimentation rate can be useful screening tests in assessing gastrointestinal disease. The choice of endoscopy versus barium contrast radiographs depends on the acuteness of the gastrointestinal disease and the diseases being sought (Chapters 131 and 132). Although endoscopy is relatively expensive and should never be used indiscriminately, it often can expedite definitive diagnosis and provide definitive therapy.

SUGGESTED READINGS
Bonen DK, Cho JH: The genetics of inflammatory bowel disease. Gastroenterology 2003;124:521–536. New concepts of the genetic factors that play a role in the susceptibility to develop inflammatory bowel disease, particularly the NOD2/CARD15 gene, are reviewed.

Braverman IM: Skin signs of gastrointestinal disease. Gastroenterology 2003;124: 1595–1614. Excellent photographs of the more common external manifestations of gastrointestinal diseases. Grady WH: Genetic testing for high-risk colon cancer patients. Gastroenterology 2003;124:1574–1594. About 20 to 30% of all colon cancers have a potentially definable genetic cause. Quigley EMM, Hasler WL, Parkman HP: AGA technical review on nausea and vomiting. Gastroenterology 2001;120:261–263. This is an authoritative review on the causes, diagnosis, and treatment of nausea and vomiting. Schiller LR: Review article: The therapy of constipation. Aliment Pharmacol Ther 2001;15:749–763. This review focuses on the treatment of constipation, rather than its pathophysiology and causes.

131 章

DIAGNOSTIC IMAGING PROCEDURES IN GASTROENTEROLOGY
Gerhard R. Wittich

Long-established techniques, such as plain film radiography and barium studies, continue to play an important role as efficient and cost-effective imaging methods in gastroenterology. In addition, ultrasonography, nuclear medicine, computed tomography (CT), and magnetic resonance imaging (MRI) have greatly improved gastroenterologic diagnosis and have stimulated a number of image-guided interventions.

Plain Film Radiography
Plain film radiography remains a valuable tool for the diagnosis of several abdominal disorders. The acute abdominal series, consisting of supine and upright views of the abdomen, readily provides information regarding abnormal gas patterns. Demonstration of gas/fluid levels within dilated loops of bowel may suggest obstruction or adynamic ileus. This technique is a reliable method to confirm or exclude the presence of intraperitoneal bowel perforation, since as little as 5 mL of air can be detected with proper radiographic technique. Plain film radiography of the abdomen is also useful to detect abnormal calcifications such as calcified gallstones (Chapter 158), pancreatic calcifications (Chapter 145), calcified aneurysms (Chapter 75), and calcified hydatid cysts of the liver.

Barium Studies
Barium studies of the upper gastrointestinal tract allow diagnosis of inflammatory, neoplastic, and motility disorders and of lesions that cause stenosis or obstruction. In the hands of experienced investigators who take advantage of the diagnostic capabilities of optimized single- and double-contrast studies, the sensitivity of barium studies for the detection of gastric ulcers or esophageal or gastric neoplasms approaches that of endoscopic examination. In the esophagus, barium studies cannot quite match the

almost 100% sensitivity of diagnostic endoscopy. However, the lower cost of barium studies and their noninvasive nature make them excellent initial tests for many suspected disorders of the upper gastrointestinal tract. For example, in a subgroup of immunocompromised patients with dysphagia, double-contrast evaluation of the esophagus allows detection of candida esophagitis (Chapter 136), characterized by a granular mucosa and plaquelike lesions, in about 90% of cases. Alternatively, barium study of the esophagus may reveal ulcerative changes suggesting herpes esophagitis or infection with cytomegalovirus or human immunodeficiency virus. Although endoscopy is more sensitive and may allow a specific diagnosis by obtaining samples for microbial cultures, it may be more economical to reserve endoscopy for patients with equivocal or negative radiographic studies. In patients with symptoms of reflux esophagitis (Chapter 136), double-contrast barium examination demonstrates ulcerations and possible stricture formation in advanced cases, but barium studies are inferior to endoscopy in the earlier stages of the disease, and barium studies cannot diagnose or follow Barrett’s esophagus. High-quality double-contrast techniques remain a reasonable alternative as initial imaging studies for the evaluation of the stomach and duodenum, because the vast majority of gastric and duodenal ulcers (Chapter 138) are readily displayed radiographically, and barium studies are safer and less expensive than endoscopy. An indication for primary, endoscopic evaluation is acute upper gastrointestinal hemorrhage: whereas barium studies may reveal the source of bleeding in 70 to 80% of cases, the ability to control hemorrhage by endoscopic intervention clearly makes it the preferred method (Chapter 133). Because routine endoscopy of the small bowel is not feasible, the most common techniques to image this organ are the small bowel follow-through study with intermittent fluoroscopic evaluation and enteroclysis, which is intubation of the proximal jejunum followed by infusion of contrast material. Enteroclysis, which should be restricted to patients with a high level of suspicion of small bowel disease, has several advantages over the small bowel follow-through study. It is independent of the activity of the pylorus, so a high-quality study can usually be completed in less than 30 minutes. Double-contrast enteroclysis, which includes the use of barium and methylcellulose, allows complete evaluation of all loops of small bowel, including ileal loops that often are superimposed on one another within the pelvis. Common indications for enteroclysis include partial mechanical small bowel obstruction, suspected peritoneal neoplasms (Chapter 146), suspected radiation enteritis (Chapter 143), unexplained, intermittent lower gastrointestinal bleeding (Chapter 133), Crohn’s disease being considered for surgery (Chapter 142), and malabsorption possibly due to small bowel disease (Chapter 141). Endoscopic and radiographic studies play a complementary role in evaluation of the colon. Single-contrast studies are sufficient for documentation of large colon carcinomas, but double-contrast enemas are required for detection of more subtle lesions, such as small polyps or early mucosal changes in patients with inflammatory bowel disease (Chapters 142 and 200). With meticulous double-contrast technique, the detection rate of colonic polyps is approximately 90% and approaches the sensitivity of colonoscopy (Fig. 131–1). Typical indications for barium enemas include symptoms of colon carcinoma (Chapter 200), diverticular disease (Chapter 143), and inflammatory bowel disease (Chapter 142). In addition, double-contrast barium enema is part of one of the alternate strategies to screen asymptomatic patients for colon cancer (Chapter 200).

Ultrasonography

Ultrasonography has many applications in patients with gastroenterologic disorders, but a disadvantage is its inability to penetrate gas-filled structures. For example, ultrasonography can yield exquisite images of the pancreatic parenchyma and the pancreatic duct in thin patients, but it may be difficult to evaluate this retroperitoneal organ in obese patients with a large amount of bowel gas within the transverse colon and stomach. The sensitivity of ultrasonography for detection of gallbladder stones is greater than 90%. In the jaundiced patient (Chapter 149), ultrasonography allows quick differentiation of obstruction of the intrahepatic and extrahepatic bile ducts (Fig. 131–2) from other causes of jaundice, such as hepatitis. Both the level of obstruction and its cause often can be determined. For example, lesions in the pancreatic head or the porta hepatis or a stone within the common bile duct can be detected. Because of its anatomic position posterior to the pancreatic head, the distal common bile duct may be obscured by gas within the duodenum, transverse colon, or gastric antrum. Additional studies such as magnetic resonance cholangiography, endoscopic retrograde cholangiopancreatography, or percutaneous transhepatic cholangiography may be necessary. Ultrasonography is also an excellent imaging tool for the evaluation of the hepatic parenchyma. It allows detection of fatty liver (Chapter 155) as well as textural changes of cirrhosis (Chapter 156), and it has a sensitivity between 80 and 90% for detection of hepatic neoplasms (Chapter 202). Cystic lesions within the liver and hepatic abscesses are easily detected. The spleen is readily imaged by ultrasonography to determine its size as well as to image intrasplenic or perisplenic fluid collections or mass lesions. Doppler and color Doppler studies can evaluate portal venous flow in patients with portal hypertension before and after placement of a transjugular intrahepatic portosystemic shunt (TIPS).

Computed Tomography
The development of fast CT scanners, which use helical scanning techniques, has enhanced the role of CT for evaluation of abdominal organs. Single images can be obtained in 100 to 500 msec (depending on the scanner), and the abdomen can be imaged in a single breath-hold in less than 30 seconds. This speed permits optimal utilization of contrast material. For example, the entire liver can be imaged during the arterial phase after injection of a contrast bolus to detect hypervascular lesions such as hepatomas (Chapter 202) that typically enhance more than normal hepatic parenchyma (Fig. 131–3). Less vascular lesions such as metastases from a colon carcinoma can typically be detected as low-density lesions during the portal venous phase because they receive significantly less blood than normal parenchyma through the portal system. An additional benefit of rapid-sequence CT scanning is the possibility to use specialized software for three-dimensional display of organ systems such as the vascular system. This technique, called CT angiography, is of particular value for the noninvasive evaluation of liver transplant recipients (Chapter 157). Application of this technique to the colon has been termed virtual colonoscopy (Fig. 131–4). Initial results indicate that this is a useful noninvasive screening test for colonic polyps—at the least in patients in whom conventional colonoscopy has failed.

Computed tomography is also an essential tool for evaluating and staging abdominal mass lesions; for diagnosis of hepatic, pancreatic, and splenic abscesses; and for detecting abscesses associated with disorders of the bowel such as appendicitis, diverticulitis, or Crohn’s disease (Chapters 142 and 143). In patients with biliary obstruction, CT is very useful to determine the cause of obstruction, including carcinoma of the pancreatic head or the ampulla (Chapters 158 and 201), particularly when ultrasonographic evaluation remains inconclusive. Another important use of CT is to guide abdominal interventions such as percutaneous needle aspiration of mass lesions or abnormal fluid collections, placement of needles and probes for percutaneous tumor ablation, and drainage of abdominal abscesses.

Magnetic Resonance Imaging
The more water and hence the more protons a specific tissue contains, the greater is its signal intensity. This property results in a contrast resolution that is superior to that of CT and ultrasonography. Additional advantages of MRI include its noninvasiveness, the absence of ionizing radiation, and the ability to obtain images in multiple planes, such as cross-sectional, sagittal, and coronal displays. Drawbacks of MRI compared with ultrasonography and CT are the significantly higher cost of equipment, the longer imaging times, the need to exclude patients with ferromagnetic intracranial metallic clips or cardiac pacemakers, and the tunnel-like gantry design of conventional scanners that causes some patients to become claustrophobic (Chapter 7). Low-and mid-field scanners (0.5 to 1.0) have reduced the cost of equipment and provide good-quality images, albeit still at relatively long scanning times. Magnetic resonance cholangiography has evolved as an alternative to diagnostic endoscopic retrograde cholangiopancreatography or percutaneous transhepatic cholangiography. Magnetic resonance angiography, which can image the vascular supply of the liver, is of particular value in liver transplant patients (Chapter 157). It produces images similar to CT angiography and is of particular value if patients cannot receive iodinated contrast material because of a history of allergies or renal failure. Magnetic resonance imaging is often used when ultrasonography or CT is inconclusive. For example, MRI can differentiate cavernous hemangiomas (Chapter 202) from other liver lesions, owing to their very long T2 value. The use of contrast agents such as gadolinium-diethylenetriaminepenta-acetic acid gives MRI a high sensitivity for detecting hepatic tumors, but its specificity has not reached a level that would obviate the need for percutaneous biopsies, except in certain lesions such as hemangiomas.

Radionuclide Imaging
Scintigraphic studies are rarely used as the primary method to image abdominal disorders, but they are indicated to solve certain diagnostic problems. Cavernous hemangiomas (Chapter 202), which are found in 1 to 7% of autopsies, must be differentiated from hepatomas, metastases, or other lesions. Technetium-99m (
99m

Tc)–labeled red blood cell studies represent a noninvasive, economic method to
99m

diagnose a cavernous hemangioma. The sensitivity for detection of small lesions (less than 2 cm) has been increased with the introduction of single-photon emission computed tomography. Tc pertechnetate allows detection of ectopic gastric musosa in patients with symptomatic Meckel’s diverticulum, which is of particular value in pediatric patients. Of clinical importance is localization of the

source of gastrointestinal hemorrhage (Chapter 133) with labeled red cell scintigraphy. This study is often indicated before angiography for patients in whom endoscopy has failed to localize and control bleeding. Biliary scintigraphy with
99m

Tc-HIDA is often useful in patients with clinical symptoms of acute

cholecystitis (Chapter 158). In a normal patient, radionuclide uptake can be seen in the liver, bile ducts, gallbladder, and bowel within 60 minutes after intravenous injection. The absence of radionuclide uptake in the region of the gallbladder despite the presence of radionuclide within the remainder of the biliary system suggests obstruction of the cystic duct and supports the diagnosis of acute cholecystitis. Positron emission tomography, has evolved from an expensive research tool to a widely accepted economical and clinically useful tool for oncologic imaging. Applications of this imaging technique include tumor staging in patients with esophageal or colorectal cancer.

Vascular Interventions
Although noninvasive imaging by ultrasonography, CT, or MRI has largely replaced angiography for the diagnostic evaluation of hepatic and pancreatic masses, angiography remains valuable for tumor therapy (Chapter 202). Catheter delivery systems are useful for chemoembolization to palliate unresectable primary or secondary liver tumors, particularly large tumors, which may not be suitable for percutaneous ablation with radiofrequency. Selective angiography of the celiac and mesenteric vessels has long been important for the management of acute and chronic ischemia due to vascular stenosis, thrombosis, and embolism (Chapter 144). Local, catheter-directed thrombolysis may revascularize branches of the superior mesenteric artery if an embolic event is suspected and diagnosed within a few hours of the acute event and before irreversible ischemic damage mandates surgical intervention. Balloon angioplasty and stenting may obviate the need for surgical correction of a hemodynamically significant stenosis. Catheter angiography also remains an important tool for management of acute gastrointestinal hemorrhage (Chapter 133); it should be considered when endoscopic attempts to control gastroduodenal bleeding fail. Selective embolization of arteries that feed bleeding sources in the stomach and duodenum is highly effective in controlling active hemorrhage with a low risk of tissue infarction. The role of angiography in acute and massive lower gastrointestinal hemorrhage is primarily for precise preoperative localization of the bleeding source and to temporize surgery by local infusion of a vasoconstrictor. Bleeding is controlled in more than 70% of patients, thereby making them candidates for elective rather than more risky emergency surgery. In a subgroup of patients who remain at high risk for surgery, selective embolization may be considered. This method is also highly effective in controlling lower gastrointestinal hemorrhage but carries about a 10% risk of bowel infarction. Patients with coagulopathy should be considered for transjugular liver biopsy if a tissue diagnosis is required for management. Refinements in biopsy devices allow retrieval of adequate tissue samples in more than 90% of cases with minimal morbidity. The use of TIPS has rapidly evolved as standard treatment for patients with complications of cirrhosis (Chapter 156), such as refractory ascites or hemorrhage from esophageal varices after failure of endoscopic sclerotherapy. The technical success rate of this method is more than 90%, and its rates of

morbidity and mortality are lower than those of emergency surgical portacaval shunts. Although the long-term success of this method is currently somewhat limited by shunt stenosis or occlusion, close surveillance with periodic visits (3- to 6-month intervals) and color Doppler ultrasonography can often discover shunt stenosis before recurrent episodes of bleeding. Angiographic reintervention may be required to maintain portal decompression (Fig. 131–5). Although the primary patency rate of TIPS at 1 year is approximately 50%, reinterventions such as balloon dilatation of stenotic shunts can result in a secondary patency rate of more than 90% after 1 year and more than 80% after 3 years. Early results of clinical trials with coated stents suggest that longer patency of shunts can be achieved in the future.

Nonvascular Interventions
Percutaneous ultrasonography or CT guided biopsy of hepatic, pancreatic, or other abdominal mass lesions has become standard practice. The sensitivity of fine needle biopsy of abdominal neoplasms is greater than 90%, with a complication rate that is less than 1%. Similar techniques can be used for nerve blocks, such as celiac ganglion blocks in patients with intractable pain secondary to advanced pancreatic carcinoma (Chapter 201) or chronic pancreatitis (Chapter 145). Percutaneous catheter drainage combined with antibiotic treatment has been accepted as first-line therapy of hepatic and other abdominal abscesses, with success rates exceeding 90%. For example, patients who have diverticular abscesses without peritonitis (which requires emergency surgical exploration) can undergo diagnostic CT scanning with intravenous contrast, followed by percutaneous CT-guided abscess drainage. After the septic episode is controlled, patients may undergo endoscopic evaluation or a barium enema to determine the extent of disease of the colon and to exclude an underlying perforated neoplasm. Subsequently, most patients will be referred for elective bowel resection. This approach reduces morbidity and mortality when compared with a two- or three-step surgical approach consisting of emergency surgical drainage and colostomy followed by bowel resection and reversal of colostomy. Similarly, patients with appendiceal abscesses may benefit from percutaneous drainage followed by elective appendectomy. Primary surgical intervention can usually be reserved for very complex infectious processes such as infected pancreatic necrosis or multiloculated collections combined with high output bowel fistulae. Percutaneous tumor ablation may be indicated in patients who are at high risk for surgery. Techniques include percutaneous alcohol injection and ablation with radiofrequency, laser, or cryotherapy probes. Three-year survival rates greater than 50% have been achieved. Percutaneous biliary interventions (Chapter 158) under fluoroscopic control are complementary to endoscopic and surgical procedures. Transhepatic techniques are of particular value when endoscopic techniques fail or are contraindicated, such as in patients whose prior surgical interventions in the biliary system make endoscopic access impossible. Transhepatic insertion of an indwelling expandable metallic prosthesis is well established as palliation for malignant biliary obstructions and may avoid endoscopic treatment or palliative surgery. Emergency percutaneous biliary drainage may be necessary in patients with acute cholangitis. Transhepatic stone removal is useful in patients with hepatolithiasis. Transhepatic balloon dilation has a greater than 70% long-term success rate in patients with benign biliary strictures. Percutaneous cholecystostomy is useful for initial decompression of the gallbladder in patients with acute calculous or acalculous cholecystitis, particularly if patients are considered to be at high risk for

emergency surgery, and permits subsequent elective cholecystectomy. Alternatively, percutaneous methods can be used for fragmentation and removal of stones from the gallbladder in patients who remain at high risk for surgery. Gastrointestinal interventions such as balloon dilation of benign strictures of the esophagus or placement of an endoprosthesis for palliative treatment of malignant obstructions of the esophagus (Chapter 132) or colon (Chapter 139) can be performed by interventional endoscopists or interventional radiologists. Similarly, percutaneous radiologic gastrostomy has a high success rate because high-grade or complete esophageal obstruction is not a contraindication to this method.

SUGGESTED READINGS
Balthazar EJ: Acute pancreatitis: Assessment of severity with clinical and CT evaluation. Radiology 2002;223:603–613. The role of contrast-enhanced CT for management of acute pancreatitis. Ruers TJ, Langenhoff BS, Neeleman N, et al: Value of positron emission tomography with (F-18) fluorodeoxyglucose in patients with colorectal liver metastases: A prospective study. J Clin Oncol 2002;20:388–395. Fluorodeoxyglucose positron emission tomography staging improves therapeutic management of these patients. Solbiati L, Livraghi T, Goldberg SN, et al: Percutaneous radio-frequency ablation of hepatic metastases from colorectal cancer: Long-term results in 117 patients. Radiology 2001;221:159–166. Radiofrequency ablation is an effective method to treat hepatic metastases, with a 3-year survival rate of 46%. Svensson MH, Svensson E, Lasson A, et al: Patient acceptance of CT colonography and conventional colonoscopy: Prospective comparative study in patients with or suspected of having colorectal disease. Radiology 2002;222:337–345. CT colonography was less painful than conventional colonoscopy.

132 章

GASTROINTESTINAL ENDOSCOPY
Pankaj Jay Pasricha

Technological advances in radiologic and endoscopic imaging have transformed medicine in the past few decades. With its remarkable accessibility, the gastrointestinal tract, perhaps more than any other organ system, has particularly benefited from the endoscopic approach. The major advantages of endoscopy over contrast radiography in evaluation of diseases of the alimentary tract include direct visualization, resulting in a more accurate and sensitive evaluation of mucosal lesions; the ability to obtain biopsy specimens from superficial lesions; and the ability to perform therapeutic interventions. These advantages make endoscopy the procedure of choice in most cases in which mucosal lesions or growths are suspected. Conversely, contrast radiography may be indicated when extrinsic or intrinsic distortions of anatomy are suspected, such as volvulus, intussusception, subtle strictures, or complicated postsurgical changes. For most upper gastrointestinal lesions, however, the sensitivity (about 90%) and

specificity (nearly 100%) of endoscopy are far higher than those of barium radiography (about 50 and 90%, respectively). Diagnostic endoscopy (Table 132–1) is usually a remarkably safe and well-tolerated procedure. However, complications do occur and need to be carefully explained to the patient as part of the informed consent process; patients must also be prepared appropriately to reduce complication rates (Table 132–2).

LUMINAL ENDOSCOPY: SPECIFIC INDICATIONS
Most indications for gastrointestinal endoscopy are based on the presenting symptoms of the patient (e.g., dysphagia, bleeding, diarrhea). In other instances, endoscopy is required to evaluate specific lesions found by other diagnostic imaging, such as a gastric ulcer or colon polyp discovered by barium radiography. Finally, screening endoscopy is often performed in asymptomatic individuals on the basis of their risk for commonly occurring and preventable conditions such as colon cancer (see later). Implicit in the decision to perform endoscopy is the assumption that it will have a bearing on future management strategy. In dealing with the evaluation of gastrointestinal symptoms, several questions need to be addressed by the referring physician and the endoscopist: Which patients need endoscopy? When should the endoscopy be done? What is the endoscopist looking for? What endoscopic therapy, if any, should be planned? GASTROESOPHAGEAL REFLUX AND HEARTBURN (Chapters 135 and 136). Gastroesophageal reflux disease (GERD) is an extremely common condition in the general population. The fact that its cardinal symptom, heartburn, is relatively specific for this condition justifies an empirical approach of treatment using a combination of lifestyle modifications and over-the-counter or even prescription drugs. Endoscopy is not therefore necessary to make the diagnosis of GERD. Indeed, a negative endoscopy does not rule out the diagnosis of GERD because the overall sensitivity of endoscopy in GERD is only about 70%. If necessary, further evaluation with ambulatory pH monitoring may be indicated to establish the diagnosis. However, there are several circumstances in which endoscopy should be considered for patients with reflux, including patients with associated warning symptoms (―red flags‖) such as dysphagia, odynophagia, regurgitation, weight loss, gastrointestinal bleeding, or frequent vomiting (Fig. 132–1). These symptoms imply either the development of a GERD-related complication (erosive esophagitis, stricture, or adenocarcinoma) or another disorder masquerading as GERD (esophageal cancer or a gastric-duodenal lesion such as cancer or peptic ulcer). Another group of patients who are candidates for endoscopy are those with severe or persistent or frequently recurrent symptoms that suggest significant esophagitis and hence a risk for complications. Finally, if Barrett’s esophagus is discovered (see Fig. 132–1), most experts recommend some form of periodic surveillance endoscopy as these patients are at increased risk for the development of adenocarcinoma. Barrett’s esophagus, once established, does not generally regress despite adequate control of reflux. Because of the small but definite risk of cancer associated with this lesion, various methods to ablate this epithelium have been attempted, with the rationale that under conditions of acid suppression the esophageal lining is reconstituted by squamous epithelium. Ablation can be achieved by a variety of thermal means that include techniques such as electrical cautery, argon plasma coagulation, and high-energy lasers. Other techniques include mucosal resection and photodynamic therapy, which

involves the destruction of tumor tissue through the interplay between a tumor-sensitizing drug, usually derived from hematoporphyrins (such as porfimer sodium [Photofrin]), and an activating low-energy laser. For patients who have high-grade dysplasia and who are at high risk for surgery, such procedures may be curative and are considered to be reasonable alternatives to esophagectomy. In patients without dysplasia, the benefit (i.e., reduction in the risk of cancer) remains to be established, and ablation should be considered experimental in this setting. Endoscopic techniques for the therapy of GERD have been introduced, with the common principle of narrowing of the gastroesophageal junction. One technique uses radio frequency energy to produce a scar at the gastroesophageal junction; another relies on an innovative suturing device to restructure this area. Other procedures under development include variations on these themes as well as injection of polymers to ―bulk up‖ the gastroesophageal junction. It should be cautioned that clinical trials of these procedures have been performed only in small numbers of carefully selected patients, and it is too soon to know whether they are safe and effective for general use. In contrast to that in the general population, heartburn in immunocompromised patients often indicates an esophageal infection. The most common causes in patients with human immunodeficiency virus (HIV) infection are Candida, cytomegalovirus (CMV), herpesvirus, and idiopathic esophageal ulcers. Because most patients with the acquired immunodeficiency syndrome and esophagitis have candidiasis, an empirical 1- to 2-week course of antifungal therapy may be justified. Patients who do not respond to this approach, however, should almost always have an endoscopy and biopsy so that more specific therapy can be instituted. DYSPHAGIA (Chapter 136). Dysphagia can often be categorized as oropharyngeal on the basis of the clinical features of nasal regurgitation, laryngeal aspiration, or difficulty in moving the bolus out of the mouth. These symptoms are usually associated with a lesion in the central or peripheral nervous system. Although endoscopy is often performed in these patients, videofluoroesophagography (modified barium swallow or cine-esophagogram) is the procedure of choice as it allows a frame-by-frame evaluation of the rapid sequence of events involved in transfer of the bolus from the mouth to the esophagus. Common causes of esophageal dysphagia include malignant as well as benign processes (peptic strictures secondary to reflux, Schatzki’s rings) and motility disturbances of the esophageal body or the lower esophageal sphincter. Endoscopic examination is considered mandatory in all patients with esophageal dysphagia. However, contrast esophagography may also be helpful; it can provide guidance for an endoscopy that is anticipated to be difficult (e.g., a patient with a complex stricture), suggest a disturbance in motility, and occasionally detect subtle stenoses that are not appreciated on endoscopy (the scope diameter is typically 10 mm or less, whereas some symptomatic strictures can be considerably wider). Endoscopic treatment options are available for many causes of esophageal dysphagia. Tumors may be dilated mechanically, ablated by thermal means (cautery or laser), or stented with prosthetic devices. Metallic expandable stents have become the palliative procedure of choice for most patients with symptomatic esophageal cancer. Benign lesions of the esophagus, such a strictures or rings, can also be dilated endoscopically, usually with excellent results. Finally, some motility disturbances such as achalasia are best approached endoscopically with the use of large balloon dilators for the lower esophageal sphincter or sometimes with the local injection of botulinum toxin.

DYSPEPSIA (Chapter 135). Dyspepsia, which is chronic or recurring pain or discomfort centered in the upper abdomen, is a common condition that can be caused by a variety of disorders, including peptic ulcer, reflux esophagitis, gallstones, gastric dysmotility, and, rarely, gastric or esophageal cancer. However, up to 60% of patients with chronic (>3 months) dyspepsia belong to the so-called functional category in which there is no definite structural or biochemical explanation for the symptoms. Although Helicobacter pylori gastritis is found frequently in these patients, there is no definite evidence to prove a cause-and-effect relationship between these two findings. The optimal diagnostic approach to dyspepsia is somewhat controversial and is still evolving (see Fig. 135–2). If a diagnostic test is to be performed, endoscopy, sometimes with biopsies to detect H. pylori, is clearly the procedure of choice, with an accuracy of about 90% (compared with about 65% for double-contrast radiography). There has been a move toward empirical approaches to dyspepsia because only a minority of patients with dyspepsia have peptic ulcers and gastric cancer is extremely rare in Western countries. However, dyspepsia is a recurrent condition, and patients who do not respond to empirical therapy eventually almost always undergo endoscopy. Many gastroenterologists therefore opt for early endoscopy, if only for the reassurance that a negative examination provides. UPPER GASTROINTESTINAL BLEEDING (Chapter 133). Acid-peptic disease (including ulcers, erosions, and gastritis), variceal bleeding, and Mallory-Weiss tears account for the vast majority of all cases of upper gastrointestinal bleeding. Other less common but important lesions include angiomas or the rarer Dieulafoy’s lesion (a superficial artery that erodes through the gut mucosa). Finally, upper gastrointestinal cancers are occasionally associated with significant bleeding. Endoscopy is mandatory in all patients with upper gastrointestinal bleeding, with the rare exception being the terminally ill patient in whom the outcome is unlikely to be affected. Endoscopy is able to detect and localize the site of the bleeding in 95% of cases and is clearly superior to contrast radiography (with an accuracy of only 75 to 80%). The endoscopic appearance of bleeding lesions can also help predict the risk of rebleeding, thus facilitating the triage and treatment process. Bleeding can be effectively controlled during the initial endoscopy itself in the majority of cases. The risk of recurrent bleeding is diminished, resulting in a shorter duration of hospital stay as well as a reduction in the need for surgery. In general, endoscopy should be performed only after adequate stabilization of hemodynamic and respiratory parameters. The role of gastric lavage before endoscopy is controversial; some endoscopists prefer that it be done, occasionally even using a large-bore tube, whereas others avoid such preparation because of the fear of producing artifact. The timing of subsequent endoscopy is dependent on two factors: the severity of the hemorrhage and the risk status of the patient. Patients with active, persistent, or severe bleeding (>3 units of blood) require urgent endoscopy. Endoscopy in these patients is best performed in the intensive care unit because they are at particular risk for aspiration and may require emergent intubation for respiratory protection and ventilation. Patients with slower or inactive bleeding may be evaluated by endoscopy in a ―semielective‖ manner (usually within 12 to 20 hours), but a case can be made to perform endoscopy early even in these stable patients (perhaps in the emergency department itself) to allow more confident triage and efficient resource management. Most bleeding from upper gastrointestinal lesions can be effectively controlled endoscopically. The endoscopist considers factors such as age (older patients have a higher risk of rebleeding) and the severity of the initial hemorrhage (which has a direct correlation with the risk of rebleeding) in addition to the appearance of the lesion when determining the need for endoscopic therapy. Nonvariceal bleeding

vessels can be treated by a variety of means including injections of various substances (epinephrine, saline, sclerosants), thermal coagulation (laser or electrocautery), or mechanical means (clipping). In the United States, the most popular approach to a bleeding peptic ulcer lesion is a combination of injection with dilute epinephrine and electrocoagulation. Initial hemostasis can be achieved in 90% or more of cases; rebleeding, which may recur in up to 20% of cases, responds about half of the time to a second endoscopic procedure. Patients who continue to bleed (typically patients with large ulcers in the posterior wall of the duodenal bulb) are usually managed angiographically (with embolization of the bleeding vessel) or surgically. Variceal bleeding is also effectively managed endoscopically, with a success rate similar to that with bleeding ulcers (Fig. 132–2). Hemostasis is achieved using band ligation (Fig. 132–3), sclerotherapy, or a combination of both. Increasingly, patients who do not respond to endoscopic treatment are considered candidates for a transjugular intrahepatic portosystemic shunt (TIPS); traditional shunt surgery for bleeding varices is rarely performed. Even if initial endoscopic hemostasis is successful, long-term prevention of rebleeding requires a program of ongoing endoscopic sessions until variceal obliteration is complete. Ligation is the preferred approach in this setting because it is associated with fewer side effects. An ongoing area of investigation is whether endoscopic therapy, in the form of ligation, should be performed in patients with large esophageal varices who have never bled (primary prophylaxis). Meta-analysis of the published literature suggests that such therapy may offer some advantages over the current mainstay of treatment, β-blocker drugs. ACUTE LOWER GASTROINTESTINAL BLEEDING (Chapter 133). The most common cause of acute lower gastrointestinal bleeding is angiodysplasia, followed by diverticulosis, neoplasms, and colitis. In about 10% of patients presenting with hematochezia, a small bowel lesion may be responsible. In contrast to upper gastrointestinal bleeding, there is no single best test for acute lower gastrointestinal bleeding (Fig. 132–4). In young patients (<40 years) with minor bleeding, features that are highly suggestive of anorectal origin (e.g., blood on the surface of the stool or on the wipe) may warrant only a flexible sigmoidoscopy. Conversely, patients presenting with hemodynamic compromise may need an upper endoscopy first to exclude a lesion in the upper gastrointestinal tract (typically postpyloric) that is bleeding so briskly that it arises as hematochezia. Colonoscopy has traditionally been recommended after bleeding has slowed or stopped and the patient has been given an adequate bowel purge. However, a disadvantage of delaying endoscopy is that when a pathologic lesion such as an arteriovenous malformation (see Fig. 132–4) or diverticulum is found, it may be impossible to implicate it confidently as the site of bleeding (complementary information by radiography or scintigraphy becomes particularly important in this situation). Some experts therefore recommend an urgent diagnostic endoscopy with little or no preparation for acute lower gastrointestinal hemorrhages and have reported success rates of 50%. OCCULT GASTROINTESTINAL BLEEDING OR IRON DEFICIENCY ANEMIA (Chapter 133). Normal fecal blood loss is usually less than 2 to 3 mL/day. Most standard fecal occult blood tests detect only blood loss of 10 mL/day or more. Therefore, even if this test is negative, patients with iron deficiency anemia and no other obvious source of blood loss should always undergo aggressive gastrointestinal evaluation, which uncovers a gastrointestinal lesion in the majority of cases. Although most lesions that cause overt gastrointestinal bleeding can also cause occult blood loss, occult bleeding should almost never be ascribed to diverticulosis or hemorrhoids. Endoscopy is always preferable to radiographic studies for evaluation of occult blood loss or iron deficiency anemia because of its ability to detect flat

lesions, particularly vascular malformations, which may be found in 6% or more of patients. If both upper and lower endoscopies are negative, a small bowel radiographic series (preferably an enteroclysis) to look for gross lesions often completes the evaluation. If the patient continues to have symptomatic bleeding, enteroscopy (the use of a very long upper endoscope to intubate the small bowel) and capsule endoscopy (see later) may be helpful to detect small bowel lesions such as tumors or angiomas. An innovation has been the development of ―capsule endoscopy,‖ which consists of a disposable capsule that can be swallowed and that takes color video images as it travels through the digestive tract. These images are received and recorded by a device that the patient wears as a belt while carrying out his or her routine activities. At the end of the procedure, the information is downloaded to a computer, processed, and scanned for detectable abnormalities. The capsule itself passes out harmlessly in the stool. The capsule is not useful, in its present form, as a method for imaging the upper gastrointestinal tract or the colon; further, it has no therapeutic utility. Nevertheless, with the help of this procedure, physicians can now visualize the mucosa of the entire small bowel in detail, facilitating the detection of uncommon but important lesions such as vascular malformations or small tumors that can be missed by alternative imaging methods. COLORECTAL NEOPLASMS (Chapter 200). Colonoscopy is the most accurate test for detecting mass lesions of the large bowel that are suspected on clinical or radiologic grounds. However, the greatest impact of endoscopy on colorectal neoplasia may be in the area of screening and prevention. The adenoma-to-carcinoma sequence of progression in colorectal cancer provides a relatively unique opportunity for prophylaxis. Thus, if screening programs can identify patients with polyps and if these polyps are removed, cancer can largely be prevented. Various techniques are available for safe and effective polypectomy, depending upon the size, presence of a stalk, and location (Fig. 132–5). Colonoscopy is being increasingly accepted as the procedure of choice for screening patients at average risk, that is, anybody older than 50 years. When patients have been found to harbor adenomatous polyps, they should be entered into a surveillance program; the frequency of colonoscopic examinations is still not settled but varies in practice from 1 to 3 years. More aggressive screening strategies are required for patients considered at high risk for colorectal cancer, including patients with well-defined hereditary syndromes as well as those with a history of colorectal cancer in a first-degree relative. In addition, patients with ulcerative colitis with long-standing (more than 8 years) disease affecting the entire colon have an increased risk for developing colon cancer, about 0.5 to 3% after 20 years. Periodic colonoscopic surveillance (every 1 to 2 years with biopsies) is therefore recommended for patients with long-standing disease (8 years with pancolitis, 12 to 15 years with left-sided colitis); the discovery of dysplasia or cancer is an indication for colectomy. ―Virtual colonoscopy,‖ which involves the digital construction of an endoluminal view of the colon on the basis of data from abdominal computed tomography (CT), is quite sensitive but currently has a prohibitively high false-positive rate, preventing its adoption for general screening. CHRONIC DIARRHEA (Chapter 141). Endoscopy may be a valuable aid in the evaluation of patients with persistent diarrhea. The timing of the endoscopy in these patients often depends on the clinical features of the illness. Patients with bloody diarrhea should have lower endoscopy as part of their initial evaluation to look for inflammatory bowel disease (Chapter 142). In most patients with chronic diarrhea,

endoscopy is often done when initial routine testing does not yield a specific diagnosis. Both upper and lower endoscopies may be used, depending on the clinical presentation. Thus, the patient suspected of having a malabsorptive process may require an upper endoscopy with jejunal or duodenal biopsies to look for celiac sprue or rarer lesions such as lymphoma or Whipple’s disease (endoscopic biopsy has largely replaced blind intestinal biopsies for these conditions). Conversely, patients suspected to have a secretory cause of diarrhea require a colonoscopy with biopsies to look for overt inflammatory bowel disease or more subtle variants such as microscopic or lymphocytic colitis, in which cases the diagnosis requires careful examination of the biopsy specimens. The endoscopic approach to diarrhea in immunocompromised patients, such as those with HIV infection, is guided by the degree of immunosuppression and the need to find treatable infections. When routine stool tests are negative, patients with CD4 counts less than 100/mm should undergo endoscopic evaluation to detect pathogens such as CMV, Mycobacterium avium complex, and microsporidiosis. Small-volume stools with tenesmus suggest a proctocolitis, for which sigmoidoscopy (rather than a full colonoscopy) with biopsies is usually adequate. In patients with upper gastrointestinal symptoms (large-volume diarrhea, bloating, and dyspepsia), an upper endoscopy with biopsy may be attempted first. MISCELLANEOUS INDICATIONS. The upper endoscope has provided a relatively quick and noninvasive means for removal of accidentally or deliberately ingested foreign bodies. Timing is critical for removal, however, because objects are usually beyond endoscopic retrieval when they reach the small bowel. Any foreign object that is causing symptoms should be removed, as should potentially dangerous devices such as batteries or sharp objects. In general, objects greater than 2.5 cm in width or 13 cm in length are unlikely to leave the stomach and so should also be removed. Occasionally, patients with food impacted in the esophagus require endoscopic removal (Fig. 132–6). This condition almost always indicates an underlying functional or structural problem (Chapter 136) and should prompt a thorough diagnostic evaluation after the acute problem has been addressed. Because of the relatively poor correlation between oropharyngeal lesions and more distal visceral injury, upper endoscopy is usually recommended urgently in patients with corrosive ingestion (Chapter 106). Endoscopy allows patients to be divided into high- or low-risk groups for complications, with institution of appropriate monitoring and therapy. Among the myriad causes of nausea and vomiting, a few, such as mucosal lesions or unsuspected reflux disease, are amenable to endoscopic diagnosis. Patients with new-onset constipation (Chapter 134), particularly those who are older than 40 years, should also undergo a colonoscopic evaluation to exclude an obstructing carcinoma. Colonoscopy is also useful in patients with pseudo-obstructive (nonobstructive) colonic dilation or Ogilvie’s syndrome (Chapter 134); such patients are at risk for colonic rupture at diameters above 9 to 12 cm, and colonoscopic decompression is often required, sometimes on an emergent basis. Malignant obstruction of the gastrointestinal lumen including the esophagus (Fig. 132–7), pylorus or duodenum, and colon can now be safely and effectively palliated endoscopically using expandable metal stents, avoiding the need for surgery in these patients. A major advance in enteral feeding has been the introduction of percutaneous endoscopic gastrostomy (PEG), a relatively quick, simple, and safe
3

endoscopic procedure that has virtually eliminated surgical placement of gastric tubes. A variation of PEG is percutaneous endoscopic jejunostomy (PEJ), in which a long tube is passed through the gastric tube, past the pylorus, and into the jejunum. The most common indication for these procedures is the need for sustained nutrition in patients with neurologic impairment of swallowing or with head and neck cancers. Patients with a very short life expectancy are not suitable candidates for PEG and can be managed by nasoenteral tubes. PEJ was originally introduced to prevent aspiration, but it does not prevent this complication; the major indication for PEJ is significant impairment of gastric emptying. Retrograde tube migration with PEJ is quite common, however, and PEJ may require frequent replacement.

PANCREATOBILIARY ENDOSCOPY (IMAGING)
Endoscopic retrograde cholangiopancreatography (ERCP) involves a special side-viewing endoscope (the duodenoscope) that is used to gain access to the second part of the duodenum. A small catheter is then introduced into the bile or pancreatic duct, and radiographic contrast medium is injected under fluoroscopic monitoring. Successful cannulation and imaging can be achieved in up to 95% of cases. In some centers, a very fine caliber ―baby‖ endoscope can also be introduced into the duct of interest (cholangioscopy or pancreaticoscopy), allowing the direct visualization of intraductal pathology. ERCP is perhaps the technically most demanding of gastrointestinal endoscopic procedures, and it is associated with the highest risk of serious complications (notably pancreatitis, in about 5% of cases). SUSPECTED BILIARY PATHOLOGY (Chapters 148 and 158). The diagnostic approach to patients with cholestasis begins with an attempt to differentiate obstructive from hepatocellular causes. The most common causes of obstructive jaundice are common bile duct stones and tumors of the pancreatic and bile ducts. Less invasive conventional imaging with ultrasonography, CT, or magnetic resonance imaging (MRI) demonstrates dilated bile ducts and mass lesions but is not very sensitive or specific in detecting or delineating pathology in the distal common bile duct and pancreas, two regions where the majority of obstructing lesions are found. Furthermore, some biliary diseases, such as sclerosing cholangitis, do not result in dilated ducts but have a characteristic appearance on cholangiography. Finally, the ability to use devices such as cytology brushes and biopsy forceps during cholangiography provides an additional aid in the diagnosis of biliary lesions. Both percutaneous and endoscopic cholangiographic techniques are associated with a high rate of success in experienced hands, but the endoscopic approach allows visualization of the ampullary region and the performance of sphincterotomy, and it also avoids the small risk of a biliary leak associated with puncture of the liver capsule. In the last few years, magnetic resonance cholangiopancreatography (MRCP), a digital reconstruction technique based on an abdominal MRI scan, has become popular as an imaging modality for the pancreatobiliary system, with excellent sensitivity and specificity. Because of its relative safety, many experts now advocate this procedure for screening patients with a low likelihood of disease. In those with a higher probability, ERCP is still the procedure of choice because of its therapeutic options. Of the approximately 600,000 patients undergoing cholecystectomy in this country, 5 to 10% may present with bile duct stones before or after the surgery. Endoscopic stone removal is successful in 90% or more of these cases and usually requires a sphincterotomy (Fig. 132–8). The sphincter of Oddi is a band of muscle that encircles the distal common bile duct and pancreatic duct in the region of the

ampulla of Vater; cutting of this muscle, or sphincterotomy, is one of the mainstays of endoscopic biliary treatment and is accomplished using a special tool called a papillotome or sphincterotome. This procedure is often sufficient for the treatment of small stones in the bile ducts, but larger stones may require additional procedures, such as mechanical, electrohydraulic, or laser lithotripsy, all of which can be performed endoscopically. In addition to stone disease, sphincterotomy can be curative for patients with papillary stenosis or muscle spasm (termed sphincter of Oddi dysfunction). Finally, by enlarging the access to the bile duct, sphincterotomy facilitates the passage of stents and other devices into the bile duct. Sphincterotomy carries an additional small risk of bleeding, but its associated morbidity is about one third that of surgical exploration and its cost is only about 20% as high. Endoscopic therapy has also revolutionized the palliative approach to malignant biliary obstruction. The technique, which requires the placement of indwelling stents, is superior to both radiologic and surgical techniques. Plastic stents have been the mainstay of treatment, but metal stents last longer and are perhaps preferred in patients with longer life expectancies. PANCREATIC DISEASE (Chapters 145 and 201). ERCP is also useful in patients with pancreatic diseases that do not always arise with obstructive jaundice, such as pancreatic cancer of the body and tail and, less commonly, chronic pancreatitis. It is also indicated for patients with acute or recurrent pancreatitis without any obvious risk factors on history or routine laboratory evaluation. Imaging of the pancreatic duct may delineate anatomic abnormalities that may be responsible for the pancreatitis, such as congenital variants (pancreas divisum, annular pancreas), intraductal tumors, or possibly sphincter of Oddi dysfunction. In such cases, bile can be collected from the bile duct for microscopic examination for crystals (so-called microlithiasis) that can result in pancreatitis in some patients even in the absence of macroscopic stones. In patients with chronic pancreatitis, which is most often due to excessive alcohol intake, pancreatography can confirm the diagnosis, provide useful information about the severity of the disease, and identify ductal lesions that may be amenable to therapy by either endoscopic (see later) or surgical means. In more subtle cases, collection and analysis of pancreatic juice after stimulation with secretin may be useful in establishing exocrine impairment and hence in confirming chronic pancreatic injury. ERCP also has a role in some patients with acute pancreatitis (Chapter 145) that is probably caused by obstructing biliary stones. Patients presenting with severe biliary pancreatitis may benefit from an urgent ERCP early in their course, with the intention of detecting and removing stones from the common bile duct. Similarly, patients who have smoldering acute pancreatitis that does not appear to be improving satisfactorily with conservative treatment may require ERCP to identify and treat any obstructing lesions in the pancreatic or distal biliary duct. Therapeutic endoscopy for pancreatic disease is still evolving. Relief of ductal obstruction (e.g., by endoscopic removal of pancreatic stones or dilation of strictures) can provide short to intermediate pain relief in some patients with chronic pancreatitis. Endoscopic pseudocyst drainage by a variety of techniques is now technically feasible, with results that appear to be comparable to those of surgical or radiologic techniques. Patients with ductal disruptions (e.g., those with pancreatic ascites) can often be treated with endoscopic stent placement. Pancreatic papillotomy may also be useful for selected cases of recurrent pancreatitis, such as those with pancreas divisum or pancreatic sphincter dysfunction. Although the ability to approach these difficult clinical entities by the relatively less invasive endoscopic techniques

represents a major accomplishment, the exact role of the various treatment modalities (surgical, radiologic, and endoscopic) in the treatment of pancreatic diseases remains to be determined.

TRANSLUMINAL IMAGING: ENDOSCOPIC ULTRASONOGRAPHY
The development of endoscopic ultrasonography (EUS), or endosonography, has been a major technological achievement in gastroenterology. The incorporation of an ultrasonic transducer in the tip of a flexible endoscope or the use of stand-alone ultrasound probes has now made it possible to obtain images of gastrointestinal lesions that are not apparent on superficial views, including lesions within the wall of the gut as well those that lie beyond (e.g., pancreatic or lymph node lesions). A further role of EUS is to guide fine-needle aspiration, which often provides pathologic confirmation of suspicious lesions (Fig. 132–9). In many cases, this approach appears to be even more accurate than conventional radiologic techniques such as abdominal ultrasonography or CT. Thus, EUS is probably the single best test for diagnosing pancreatic tumors (Chapter 201), particularly the small endocrine varieties, with sensitivities approaching 95%. It is also the procedure of choice for imaging submucosal and other wall lesions of the gastrointestinal tract (overall accuracy of 65 to 70%) as well as for staging of a variety of gastrointestinal tumors (overall accuracy of 90% or more). Preoperative staging is a critical element in the management strategy for tumors such as esophageal and pancreatic cancer, and EUS can complement more conventional radiologic tests to help determine the resectability and curative potential of surgery in these cases. In addition to its valuable diagnostic role, EUS is rapidly emerging as a therapeutic tool. One example is EUS-directed celiac plexus neurolysis, a technique that appears to be effective for the treatment of pain in patients with pancreatic cancer. Unfortunately, this approach does not appear to work as well in patients with chronic pancreatitis.

FUTURE DIRECTIONS
Traditional endoscopy, encompassing the procedures described here, is based on the simple reflection of light from tissue. However, light interacts with tissue in many other ways, including fluorescence, absorbance, and scatter. Many instruments are being developed that take advantage of these diverse interactions and provide information on the biology of the tissue that goes beyond a simple endoscopic image. These techniques, termed optical biopsy (Fig. 132–10) or bioendoscopy, are rapidly undergoing testing as complementary modalities to current endoscopic techniques and promise to take this already valuable technique to new levels of accuracy.

SUGGESTED READINGS
Keymling M: Colorectal stenting. Endoscopy 2003;35:234–238. Endoscopic stents can relieve malignant colorectal obstruction and avoid high-risk emergency laparotomy and resection. Pearce CB, Duncan HD: Enteral feeding. Nasogastric, nasojejunal, percutaneous endoscopic gastrostomy, or jejunostomy: Its indications and limitations. Postgrad Med J 2002;78:198–204. Review of the current status of enteral feeding.

Ransohoff DF, Sandler RS: Screening for colorectal cancer. N Engl J Med 2002;346: 40–44. Evidence supporting various strategies for colorectal cancer screening, followed by a review of formal guidelines. Triadafilopoulos G: Endoscopic therapies for gastroesophageal reflux disease. Curr Gastroenterol Rep 2002;4:200–204. Review of new endoscopic treatments.

133 章

GASTROINTESTINAL HEMORRHAGE AND OCCULT GASTROINTESTINAL BLEEDING
David J. Bjorkman

Gastrointestinal hemorrhage is a common clinical disorder. Bleeding from the gastrointestinal tract may present clinically as acute upper tract bleeding (proximal to the ligament of Treitz), acute lower tract bleeding (distal to the ligament of Treitz), or as evidence of occult blood loss either by iron deficiency anemia or a positive stool test for blood.

UPPER GASTROINTESTINAL BLEEDING
Upper gastrointestinal bleeding (proximal to the ligament of Treitz) is responsible for 250,000 to 300,000 hospital admissions and $2.5 billion in costs in the United States each year. The most common causes of upper gastrointestinal bleeding are peptic ulcers (Chapter 138) and esophagogastric varices. Variceal bleeding (Fig. 133–1) most commonly occurs in the setting of portal hypertension (Chapter 156). Less common causes of upper gastrointestinal bleeding are Mallory-Weiss tears (Fig. 133–2), malignancy, erosive disease, and vascular abnormalities (Table 133–1).

Diagnosis
Most cases of acute upper gastrointestinal bleeding present as hematemesis, although brisk bleeding can present as hematochezia. Gastrointestinal endoscopy (Chapter 132) remains both the diagnostic and therapeutic procedure of choice for upper gastrointestinal bleeding. Despite progressive advances in diagnosis, the mortality from acute upper gastrointestinal bleeding requiring hospitalization remains near 4% for young patients and has been reported to be as high as 15% in the elderly. EMERGENCY EVALUATION AND TREATMENT. The initial focus for any patient with significant blood loss should be the evaluation and restoration of intravascular volume, which begins with careful evaluation of blood pressure and pulse, including special attention to any orthostatic changes. Blood hemoglobin concentration and hematocrit are unreliable markers of acute blood loss, but they are helpful as baseline values. Intravenous access and vigorous volume replacement decrease the morbidity of acute upper gastrointestinal bleeding and should be initiated immediately in all patients with significant gastrointestinal bleeding. Initial volume restoration can be accomplished with the infusion of isotonic

electrolyte solutions until vital signs become stable. Blood products should be based on the patient’s clinical condition. ASSESSING THE LEVEL OF BLEEDING. Endoscopy (Chapter 132) is the method of choice for establishing the site of gastrointestinal bleeding. An upper gastrointestinal source can be assumed when there is a history of hematemesis with frank blood or coffee grounds–like material. A history of melena alone is suggestive but not pathognomonic of a bleeding source proximal to the ligament of Treitz. In patients with a small bowel or a proximal colonic source of bleeding, delayed colonic transit may result in dark stool that may be difficult to distinguish from melena. Hematochezia is more suggestive of a bleeding site in the lower gastrointestinal tract, but, in as many as 10% of cases, it may also result from vigorous upper gastrointestinal bleeding. When an acute bleeding source is suspected to be in the upper gastrointestinal tract, nasogastric aspiration is 80% sensitive for the presence of an actively bleeding lesion, and evidence of blood in a nasogastric aspirate suggests bleeding proximal to the ligament of Treitz. False-negative aspirates may occur in 20% of patients because the tube is improperly positioned or the reflux of blood from the duodenum is prevented by pylorospasm or obstruction. Nasogastric suction is also useful to determine whether bleeding is persistent or recurrent and to estimate the rapidity of bleeding. DIAGNOSTIC ENDOSCOPY. After hemodynamic stabilization, endoscopy is indicated in consenting patients unless the risks of the procedure outweigh its potential benefits, at least temporarily (e.g., patients in shock) or its results would not alter the outcome or care of the patient. Endoscopy has a sensitivity of 92% for identifying the site of upper gastrointestinal bleeding, with a specificity that approaches 100%. The sensitivity of endoscopy may be limited by retained blood and clots in the stomach. In this situation, vigorous gastric lavage using a large-bore orogastric tube is critical prior to the procedure. Endoscopy has the added advantage of guiding biopsies to test for Helicobacter pylori infection (Chapters 137 and 138) and to diagnose malignancy (Chapter 199). By comparison, barium radiography has a sensitivity of only 54%. Barium radiography is contraindicated in acute upper gastrointestinal bleeding because it interferes with subsequent endoscopy, angiography, or surgery. Careful endoscopic examination not only identifies the source of upper gastrointestinal bleeding but also is the most accurate predictor of prognosis (probability of rebleeding, morbidity, and mortality). Additional clinical risk factors for higher morbidity and mortality include older age, shock, volume of bleeding, need for transfusion, onset of bleeding in the hospital, and the presence of comorbid clinical conditions. A scoring system (Table 133–2), which uses clinical factors to predict rebleeding and mortality, has been developed and validated. Endoscopic classification of ulcers has been shown repeatedly to predict accurately the rates of rebleeding, morbidity, and mortality (Table 133–3). Patients without high-risk stigmata (those with a clean ulcer base or flat, pigmented, spots) have an extremely low rate of rebleeding and a negligible mortality.

Endoscopic Triage: Cost-Effective Care for Low-Risk Patients
Although it may seem intuitively obvious that endoscopy would improve outcomes, randomized trials have indicated that diagnostic endoscopy alone does not improve mortality, rebleeding rates, the need

for surgery, or hospital stay. The overwhelming majority (75 to 80%) of patients with bleeding ulcers stop bleeding spontaneously, limiting the impact of early endoscopy for these patients. Nevertheless, recent prospective studies show that urgent endoscopy in all patients with acute nonvariceal upper gastrointestinal bleeding identifies 20 to 30% of patients who meet both clinical and endoscopic criteria for a low risk of rebleeding and morbidity (see Tables 133–2 and 133–3); these patients can be safely treated as outpatients, thereby dramatically reducing the cost of care. Conversely, patients with a high risk of rebleeding, using the same criteria, can undergo early endoscopic therapy, ideally prior to admission, and be triaged to more intensive hospital care. Urgent endoscopy as a triage tool is rapidly becoming the standard of cost-effective care in upper gastrointestinal bleeding (Fig. 133–3).
1

Treatment
ENDOSCOPIC THERAPY. In the 20% of patients with nonvariceal upper gastrointestinal bleeding who have persistent or recurrent bleeding as determined by nasogastric lavage or endoscopy, endoscopic therapy reduces both morbidity and mortality. All available endoscopic techniques appear to have similar results but vary in their approach to sealing the bleeding vessel and maintaining hemostasis. The major methods may be divided into thermal coagulation, injection therapy, and mechanical compression. The most common thermal methods use electrical current (multipolar or bipolar electrode) or direct application of a heated device (heater probe) to seal the vessel with thermal energy. Using these methods, hemostasis can be achieved in 90% of patients with active bleeding, and rebleeding rates are significantly reduced by more than 50%.
2

The least expensive method of endoscopic therapy for upper gastrointestinal bleeding is to inject the bleeding site with saline or diluted epinephrine. This approach yields initial results that are generally similar to those of thermal therapy but may not be as effective for long-term hemostasis.
3,4

Thermal

therapy and injection can be combined to control bleeding and to treat the lesion definitively. Mechanical methods to treat bleeding include hemostatic clips and the use of rubber band ligation. Both of these methods appear to have an efficacy similar to thermal therapy. In the few patients who have recurrent bleeding after initial endoscopic therapy, a second attempt has a significant success rate and can reduce the need for surgery.
5

MEDICAL THERAPY. The most common causes of peptic ulcer disease are H. pylori infection and anti-inflammatory drug (NSAID) use (Chapter 138). NSAIDs should be discontinued and H. pylori infection should be treated in all patients with bleeding ulcers. Data are now compelling that profound acid suppression reduces rebleeding in patients with high-risk endoscopic stigmata for rebleeding. Studies using high doses of both intravenous and oral omeprazole have demonstrated a significant improvement in outcome (rebleeding, hospital stay, transfusion requirement) compared with H2-receptor antagonists. This effect is likely due to improvement of coagulation and platelet aggregation by increasing intragastric pH. Vigorous acid suppression should be provided to all patients with acute upper gastrointestinal bleeding.
6

NONULCER ACUTE UPPER GASTROINTESTINAL BLEEDING. Variceal bleeding is the most common cause of nonulcer upper gastrointestinal hemorrhage. The approach to variceal bleeding is a

combination of pharmacologic (octreotide, somatostatin), endoscopic (band ligation, sclerotherapy), and mechanical (balloon tamponade) approaches (see Fig. 156–2). Most non–peptic ulcer, nonvariceal causes of upper gastrointestinal bleeding can be treated using the same endoscopic modalities described earlier with similar success. The most common of these causes is a tear at the gastroesophageal junction, called a Mallory-Weiss (Chapter 136) tear, which accounts for 5 to 14% of upper gastrointestinal bleeding. Mallory-Weiss bleeding usually stops spontaneously, but persistent bleeding should be treated in a manner similar to bleeding from peptic ulcers. Dieulafoy’s lesion, which is an aberrant submucosal artery that erodes into the lumen of the stomach, is a rare cause of recurrent vigorous upper gastrointestinal bleeding. Tumors also are rare (<1%) causes of acute upper gastrointestinal bleeding. Vascular lesions may rarely present as acute bleeding, but more commonly they cause chronic, low-grade blood loss. Bleeding from diffuse gastric erosions, which can occur in critically ill patients, does not respond to endoscopic therapy but can usually be prevented by prophylactic treatment.
7

LOWER GASTROINTESTINAL BLEEDING
Lower gastrointestinal bleeding occurs at a rate of 20 : 100,000 population, which is about one fifth as frequently as upper gastrointestinal bleeding. Hematochezia, which is the most common presenting symptom for lower gastrointestinal hemorrhage, can be variously described as bloody diarrhea, blood and clots per rectum, maroon-colored stool, or blood mixed with the stool. Hematochezia can occur from bleeding anywhere in the gastrointestinal tract, and, noted previously, about 10% of patients who present with hematochezia have an upper gastrointestinal source of bleeding. The most common causes of lower gastrointestinal bleeding are colonic diverticula (Chapter 143), vascular ectasias (Chapter 144), and tumors (Chapter 200), all of which increase in prevalence with age (Table 133–4). As a result, lower gastrointestinal bleeding is most commonly a disorder of the elderly, with a dramatically increased incidence with advancing age. The initial approach to the patient should be the same as in upper gastrointestinal bleeding, with careful assessment of vital signs and vigorous volume replacement. A history of prior bleeding, inflammatory bowel disease, radiation therapy, and NSAID use may be helpful but does not identify the bleeding lesion. Identification and treatment of the bleeding lesion should be attempted after the patient is hemodynamically stable (Fig. 133–4). It may be difficult to diagnose colonic angiodysplasia, which is now thought to be about as common a cause of lower gastrointestinal bleeding as are colonic diverticula. Since many elderly patients have colonic diverticula, bleeding due to undiagnosed angiodysplasia may sometimes be mistakenly attributed to diverticula. Urgent colonoscopy after a vigorous cleansing of the colon can help determine whether the bleeding is from diverticula or angiodysplasia. In many cases, the bleeding lesion may be identified by the presence of a fresh clot or active bleeding. Endoscopic therapy of these lesions, similar to the methods described earlier for upper gastrointestinal bleeding, reduces the rate of rebleeding and the need for surgery. Vascular lesions can be treated with injection, contact thermal methods, or endoscopic laser therapy. There is no role for barium enema in the setting of acute lower gastrointestinal bleeding, because it is unlikely to provide a definitive diagnosis and prevents or delays more accurate diagnostic modalities with potential therapeutic benefits.

When urgent colonoscopy does not identify a bleeding source or if bleeding is too rapid to permit colonoscopy, angiography may identify the bleeding site. The yield of angiography ranges from 40 to 80%, but, to be successful, angiography requires a bleeding rate of at least 1 mL/min. When a bleeding site is identified, the bleeding can be slowed or stopped by local infusion of vasoconstrictors or by selective embolization of the bleeding artery, with success rates exceeding 80%. Both approaches carry a substantial (>10%) risk of causing local ischemia. In settings in which bleeding is not rapid enough for angiography, nuclear scintigraphy may be helpful in identifying the site but not the cause of the lesion. The bleeding rate required for identification is at least 0.1 mL/min. In optimal conditions, the sensitivity of scintigraphy is 85%, and its specificity is 70%. One advantage of tagged red blood cell scintigraphy is the ability to detect intermittent bleeding by performing serial scans over the lifetime of the radionuclide. Surgical consultation and comanagement are appropriate in all cases of gastrointestinal bleeding and are most critical in the setting of severe lower gastrointestinal bleeding. Vigorous efforts should be made to diagnose the bleeding lesion, and if that is not possible, at least the involved segment of the colon to guide surgical therapy. Surgery directed at a lesion identified endoscopically or radiographically is often curative. Empirical total or right hemicolectomy should be reserved for life-threatening bleeding that could not be localized and has not responded to available therapeutic approaches.

OCCULT AND OBSCURE GASTROINTESTINAL BLEEDING
Occult bleeding is defined as the detection of asymptomatic blood loss from the gastrointestinal tract, generally by routine fecal occult blood testing (FOBT) or the presence of iron deficiency anemia. Obscure gastrointestinal bleeding is defined as bleeding of unknown origin that persists or recurs after a negative initial endoscopic evaluation of both the upper and lower gastrointestinal tracts. Both of these entities may be presentations of recurrent or chronic bleeding. The initial approach to evidence of occult gastrointestinal blood loss should be endoscopic evaluation. In the setting of an isolated positive FOBT, colonoscopy is indicated as the first test (Chapter 200). The yield of colonoscopy in these patients is approximately 2% for cancer and 30% for one or more colonic polyps. The initial approach to a patient with iron deficiency anemia depends on the presence of symptoms referable to either the upper or lower gastrointestinal tract. Regardless of the findings on the initial upper or lower endoscopic examination, all patients should have both upper and lower endoscopy because the complementary endoscopic examination has a yield of 6% even if the first one was positive. For premenopausal women, a positive FOBT requires full evaluation, as does iron deficiency anemia. Barium radiographs of the upper and lower gastrointestinal tract have limited utility in the setting of occult bleeding because of their inability to biopsy or treat lesions that are identified. The evaluation of obscure gastrointestinal bleeding is often frustrating. Angiodysplasia is the most common cause in most recent series (Fig. 133–5). Initial endoscopic examination should focus on any symptoms reported by the patient. Potential causative agents, such as NSAIDs and aspirin, should be discontinued. Disorders associated with bleeding, such as hereditary hemorrhagic telangiectasia

(Osler-Weber-Rendu syndrome), inflammatory bowel disease, or a bleeding diathesis should be considered. A repeat endoscopic evaluation may be appropriate, because approximately one third of cases reveal a cause of bleeding overlooked during the initial endoscopy. When upper endoscopy and colonoscopy are both unrevealing, evaluation of the small bowel is indicated. Radiographic evaluation of the small bowel is noninvasive but relatively insensitive, with a less than 6% yield from small bowel follow-through and a 10 to 21% yield from enteroclysis. By comparison, the diagnostic yield of endoscopic enteroscopy of the small bowel in obscure gastrointestinal bleeding is 38 to 75%. Traditional videoendoscopes can evaluate only the proximal small bowel (≤ 150 cm), whereas longer scopes, which are passed through the entire small bowel and then withdrawn while visualizing the mucosa (sonde enteroscopy), are limited in their ability to visualize the entire mucosa and cannot be used to perform diagnostic or therapeutic maneuvers. When endoscopic evaluation does not detect the cause of blood loss, radiographic procedures such as scintigraphy and angiography should be considered. Provocative angiography using heparin or thrombolytic agents has been suggested by some authorities, but this approach has the potential risk of precipitating major bleeding. In the face of continued blood loss and no identified etiology, intraoperative endoscopy may provide simultaneous diagnosis and therapy. During the procedure, the surgeon plicates the bowel over the endoscope. As the scope is withdrawn, endoscopic findings can be identified for surgical resection or treatment. The yield of this procedure exceeds 70%. In some clinical situations, the site of bleeding cannot be identified, and the patient requires long-term transfusion therapy.

FUTURE DIRECTIONS
A new device for visualizing the entire gastrointestinal mucosa consists of a small camera in an ingestable capsule that transmits images to receivers attached to the patient’s abdomen and mapped to identify the location of the image. The diagnostic yield of capsule enteroscopy is not yet clear, but this approach may potentially visualize segments of the small bowel that were previously inaccessible. No therapeutic maneuvers are possible with the device.

SUGGESTED READINGS
Jensen DM, Machicado GA, Jutabha R, et al: Urgent colonoscopy for the diagnosis and treatment of severe diverticular hemorrhage. N Engl J Med 2000;342:78–82. A trial of urgent colonoscopy in the setting of lower gastrointestinal bleeding using historical controls as a comparison. Lee KK, You JH, Wong IC, et al: Cost-effectiveness analysis of high-dose omeprazole infusion as adjuvant therapy to endoscopic treatment of bleeding peptic ulcer. Gastrointest Endosc 2003;57:160–164. This effective therapy is also worth the cost. Lewis JD, Brown A, Localio AR, et al: Initial evaluation of rectal bleeding in young persons: A cost-effectiveness analysis. Ann Intern Med 2002;136:99–110. Evaluation of the colon of persons 25 to 45 years of age with otherwise asymptomatic rectal bleeding increases the life expectancy at a cost comparable to that of colon cancer screening.

134 章

DISORDERS OF GASTROINTESTINAL MOTILITY
Michael Camilleri

Motility disorders result from impaired control of the neuromuscular apparatus of the gastrointestinal tract. Associated symptoms include recurrent or chronic nausea, vomiting, bloating, abdominal discomfort, and constipation or diarrhea in the absence of intestinal obstruction.

PHYSIOLOGY OF GASTROINTESTINAL MOTOR FUNCTION
NEUROENTERIC CONTROL. Motor function of the gastrointestinal tract depends on the contraction of smooth muscle cells and their integration and modulation by enteric and extrinsic nerves. Neurogenic modulators of gastrointestinal motility include the central nervous system, autonomic nerves, and enteric nervous system. Extrinsic neural control of gastrointestinal motor function consists of the cranial and sacral parasympathetic outflow (excitatory to nonsphincteric muscle) and the thoracolumbar sympathetic supply (excitatory to sphincters, inhibitory to nonsphincteric muscle). The cranial outflow is predominantly through the vagus nerve, which innervates the gastrointestinal tract from the stomach to the right colon. Sympathetic fibers to the stomach and small bowel arise from T5 to T10 of the intermediolateral column of the spinal cord. The prevertebral ganglia play an important role in the integration of afferent impulses between the gut and the central nervous system and in the reflex control of abdominal viscera. The enteric nervous system is an independent nervous system consisting of approximately 100 million neurons organized into ganglionated plexuses. The larger myenteric, or Auerbach’s, plexus is situated between the longitudinal and circular muscle layers of the muscularis externa; this plexus contains neurons responsible for gastrointestinal motility. The submucosal, or Meissner’s, plexus controls absorption, secretion, and mucosal blood flow. The enteric nervous system also plays an important role in visceral afferent function. Myogenic factors regulate the electrical activity generated by gastrointestinal smooth muscle cells. Interstitial cells of Cajal form a non-neural pacemaker system located at the interface of the circular and longitudinal muscle layers of the intestine and function as intermediaries between the neurogenic enteric nervous system and myogenic control system. Electrical control activity spreads through the contiguous segments of the gut through neurochemical activation by excitatory (e.g., acetylcholine, substance P) and inhibitory (e.g., nitric oxide, somatostatin) transmitters. GASTRIC AND SMALL BOWEL MOTILITY. The motor functions of the stomach and small intestine are characterized by distinct manometric patterns of activity in the fasting and postprandial periods (Fig. 134–1). The fasting or interdigestive period is characterized by a cyclic motor phenomenon, the interdigestive migrating motor complex. In healthy individuals, one cycle of this complex is completed every 60 to 90 minutes. The complex has three phases: a period of quiescence (phase I), a period of

intermittent pressure activity (phase II), and an activity front (phase III) during which the stomach and small intestine contract at highest frequencies (3 per minute in the stomach, 12 per minute in the duodenum, 8 per minute in the ileum). Another characteristic interdigestive motor pattern seen in the distal small intestine is the giant migrating complex, or power contraction, which empties residue from the ileum into the colon in bolus transfers. With eating, the proximal stomach accommodates food by reduction in its tone, facilitating the ingestion of food without an increase in pressure. This reflex is vagally mediated and involves an intrinsic nitrergic neuron. Liquids empty from the stomach in an exponential manner. The half-emptying time for non-nutrient liquids in healthy individuals is usually less than 20 minutes. Solids are retained selectively in the stomach until particles have been triturated to a size of less than 2 mm in diameter. Gastric emptying of solids is characterized by an initial lag period followed by a linear postlag emptying phase. The small intestine transports solids and liquids at approximately the same rate. As a result of the lag phase for the transport of solids from the stomach, liquids typically arrive in the colon before solids. Chyme moves from ileum to colon intermittently in boluses. In the postprandial period, the interdigestive migrating motor complex is replaced by an irregular pattern of variable amplitude and frequency. This pattern, which enables mixing and absorption, is observed in the regions in contact with food. The maximum frequency of contractions is lower than during phase III of the interdigestive motor complex, and the duration of this period is proportional to the number of calories consumed during the meal (about 1 hour for each 200 kcal ingested). Segments of the small intestine that are not in contact with food continue with interdigestive motor patterns. Vomiting is characterized by a stereotypic sequence of motor events, including contractions of the stomach, abdominal muscles, and diaphragm. In humans, this sequence is followed immediately by a process similar to the migrating motor complex in the proximal small bowel. COLONIC MOTILITY. The normal colon displays short-duration (phasic) contractions and a background contractility or tone. Nonpropagated phasic contractions have a role in segmenting the colon into haustra, which compartmentalize the colon and facilitate mixing, retention of residue, and formation of solid stool. High-amplitude propagated contractions, which are characterized by an amplitude greater than 75 mm Hg, propagation over a distance of at least 15 cm, and a propagation velocity of 0.15 to 2.2 cm/sec, contribute to the mass movements in the colon. In health, these contractions occur on average five to six times per day, most often postprandially and between 6
AM

and 2 PM.

Colonic transit is a discontinuous process, slow most of the time and rapid at other times. Residue may be retained for prolonged periods in the right colon, and a mass movement may deliver the contents to the sigmoid colon in seconds. Movement of colonic content is stimulated by feeding (gastrocolonic response). In health, the average mouth-to-cecum transit time is about 6 hours, and transit times through the right colon, left colon, and sigmoid colon are about 12 hours each. As dietary fiber is increased, mean colonic transit time decreases, stool frequency increases, and stool consistency becomes softer. Decreased caloric intake slows colonic transit. Outlet obstruction in patients with pelvic floor dysfunction or voluntary suppression of defecation often is associated with slow colonic transit and decreased motor response to feeding.

Fluid reabsorption influences gastrointestinal transit. Approximately 9 L of fluid enter the gut from oral intake and endogenous secretions. The small intestine delivers about 1.5 L of fluid to the colon, where most is reabsorbed, leaving a maximum of 200 mL of water excreted in normal stool. Up to 3 L of fluid can be reabsorbed by the colon in a 24-hour period, unless the rate of ileocolonic flow or colonic motility overwhelms the colon’s capacity and/or reabsorptive ability. DEFECATION AND CONTINENCE. Normal defecation requires a series of coordinated actions of the colon, rectum, pelvic floor, and anal sphincter muscles (Fig. 134–2). Filling of the rectum by a volume of 10 mL may be sensed, although the rectum can accommodate 300 mL before a sense of fullness and urge to defecate develop. Distention of the rectum results in the relaxation of the internal anal sphincter (rectoanal inhibitory reflex) and simultaneous contraction of the external anal sphincter to maintain continence. The anal transition zone can sense the difference between solid or liquid stool compared with gas.

DISEASES OF SLOW TRANSIT THROUGH THE STOMACH AND SMALL BOWEL
Gastrointestinal motility disturbances (Table 134–1) result from disorders of the extrinsic nervous system, enteric nervous system, interstitial cells of Cajal (or intestinal pacemakers), or smooth muscle. Combined disorders occur in systemic sclerosis, amyloidosis, and mitochondrial cytopathy, which initially can present with neuropathic patterns and later display myopathic characteristics with disease progression. Genetic defects include abnormalities of cRet, the gene that encodes for the tyrosine kinase receptor; the endothelin B system, which tends to retard development of neural elements, facilitating colonization of the entire gut from the neural crest; Sox10, a transcription factor that enhances maturation of neural precursors; and ckit, a marker for the interstitial cells of Cajal. cRet, endothelin B, and Sox10 defects are associated with the phenotypic picture recognized as Hirschsprung’s disease, whereas ckit defects have been associated with idiopathic hypertrophic pyloric stenosis and congenital megacolon.

EXTRINSIC NEUROPATHIC DISORDERS
Extrinsic neuropathic processes include vagotomy, trauma, Parkinson’s disease (Chapter 443), diabetes (Chapter 242), amyloidosis (Chapter 290), and a paraneoplastic syndrome usually associated with small cell carcinoma of the lung. Another common ―neuropathic‖ problem in clinical practice results from the effect of medications, such as α2-adrenergic agonists and anticholinergics, on neural control. Damage to the autonomic nerves by trauma, infection, neuropathy, and neurodegeneration may lead to motor, secretory, and sensory disturbances, most frequently resulting in constipation. Patients with spinal cord injury above the level of the sacral segments have delayed proximal and distal colonic transit attributable to parasympathetic denervation. In these patients, fasting colonic motility and tone are normal, but the response to feeding generally is reduced or absent. Spinal cord lesions involving the sacral segments and/or damage to the efferent nerves from these segments disrupt the neural integration of rectosigmoid expulsion and anal sphincter control. In patients with these injuries, there is loss of contractile activity in the left colon and decreased rectal tone and sensitivity, which may lead to dilation and fecal impaction. Parkinson’s disease and multiple sclerosis frequently are associated with

constipation. Diabetes mellitus is associated with gastroparesis (see later), pylorospasm, intestinal pseudo-obstruction, diarrhea, constipation, and fecal incontinence. All of these manifestations may be caused by autonomic dysfunction, although more recent evidence points to the importance of acute changes in glycemia and, more importantly, to changes in the structure and function of the enteric nervous system. The prevalence of constipation is 22% among diabetic patients with neuropathy but only 9.2% in diabetic patients without neuropathy, a rate that is not significantly different from healthy controls.

ENTERIC AND INTRINSIC NEUROPATHIC DISORDERS
Disorders of the enteric nervous system are usually the result of a degenerative, immune, or inflammatory process. Viral-induced gastroparesis (e.g., rotavirus, Norwalk virus, cytomegalovirus, or Epstein-Barr virus) is associated with infiltration of the myenteric plexus with inflammatory cells. In idiopathic chronic intestinal pseudo-obstruction, there is no disturbance of the extrinsic neural control and no identified cause for the enteric nervous system abnormality. Full-thickness biopsy specimens of the intestine may be required to evaluate the myenteric plexus and interstitial cells of Cajal.

SMOOTH MUSCLE DISORDERS
Disturbances of smooth muscle may result in significant disorders of gastric emptying and of transit through the small bowel and colon. These disturbances include, in descending order of prevalence, systemic sclerosis, amyloidosis, dermatomyositis, dystrophia myotonica, and metabolic muscle disorders. Motility disturbances may be the result of metabolic disorders, such as hypothyroidism and hyperparathyroidism, but these patients more commonly present with constipation. Scleroderma may result in focal or general dilation, diverticula, and delayed transit. The amplitude of contractions is reduced, and bacterial overgrowth may result in steatorrhea or pneumatosis intestinalis. Mitochondrial neurogastrointestinal encephalomyopathy, or familial visceral myopathy type II, is an autosomal recessive condition that may present with hepatic failure in neonates, seizures or diarrhea in infants, and hepatic failure or chronic intestinal pseudo-obstruction in adults.

GASTROPARESIS AND PSEUDO-OBSTRUCTION
The clinical features of gastroparesis and chronic intestinal pseudo-obstruction are similar and include nausea, vomiting, early satiety, abdominal discomfort, distention, bloating, and anorexia. In severe cases, there may be considerable weight loss, with depletion of mineral and vitamin stores. Diarrhea and constipation indicate that the motility disorder extends beyond the stomach. Vomiting may be complicated by aspiration pneumonia or Mallory-Weiss esophageal tears, and patients with a generalized motility disorder may have abnormal swallowing or delayed colonic transit. A careful family and medication history is essential. Review of systems may reveal an underlying collagen vascular disease (e.g., scleroderma) or disturbances of extrinsic neural control, including orthostatic dizziness, difficulties with erection or ejaculation, recurrent urinary tract infections, dry mouth, dry eyes, dry vagina, difficulties with visual accommodation in bright lights, and absence of sweating. On physical examination, a succussion splash indicates stasis, typically in the stomach. The hands and mouth may show signs of Raynaud’s phenomenon or scleroderma. Testing of pupillary responses (to

light and accommodation), external ocular movements, blood pressure in the lying and standing positions, and general features of a peripheral neuropathy can identify patients with an associated neurologic disturbance (e.g., diabetic neuropathy) or with the oculogastrointestinal dystrophy that typically is found with mitochondrial cytopathies (see under smooth muscle disorders). The differential diagnosis includes mechanical obstruction, functional gastrointestinal disorders, anorexia nervosa, and the rumination syndrome, which typically presents as early (0 to 30 minutes) postprandial, effortless regurgitation of undigested food after virtually every meal.

Diagnosis
A motility disorder of the stomach or small bowel should be suspected whenever large volumes are aspirated from the stomach, particularly after an overnight fast, or when undigested solid food or large volumes of liquids are observed during an esophagogastroduodenoscopy. The clinician should assess the acuity of the symptoms and the patient’s state of hydration and nutrition. The goals of the evaluation are to determine what regions of the digestive tract are malfunctioning and whether the symptoms are due to a neuropathy or a myopathy (Fig. 134–3). Key steps include the following: 1. Suspect and exclude mechanical obstruction. In symptomatic patients with pseudo-obstruction, plain radiographs of the abdomen typically show dilated loops of small bowel with associated air-fluid levels. Mechanical obstruction should be excluded by upper gastrointestinal endoscopy and barium studies, including a small bowel follow-through. Barium studies may suggest the presence of a motor disorder, particularly if there is gross dilation, dilution of barium, or retained solid food within the stomach. These studies rarely identify the cause, however, except for systemic sclerosis, which is characterized by megaduodenum and packed valvulae conniventes in the small intestine. 2. Assess gastric and small bowel motility. After mechanical obstruction and alternative diagnoses such as Crohn’s disease (Chapter 142) have been excluded, a transit profile of the stomach and/or small bowel should be performed. In a gastric emptying study, ingestion of a radiolabeled meal is followed by scanning at 0, 1, 2, 3, 4, and 6 hours. If the cause of the motility disturbance is obvious, such as gastroparesis in a patient with long-standing diabetes mellitus, it is usually unnecessary to pursue further diagnostic testing. If the cause is unclear, gastroduodenal manometry using a multilumen tube with sensors in the distal stomach and proximal small intestine can differentiate a neuropathic process (normal amplitude contractions, but abnormal patterns of contractility) from a myopathic process (low-amplitude contractions in the affected segments). 3. Identify the pathogenesis (Table 134–1). In patients with neuropathic causes of uncertain origin, tests should assess autonomic dysfunction (Chapter 460), measure type 1 antineuronal nuclear autoantibodies (ANNA-1) associated with paraneoplastic syndromes, and consider the possibility of a brainstem lesion. In patients with a myopathic disorder of unclear cause, the evaluation should consider amyloidosis (immunoglobulin electrophoresis, fat aspirate, or rectal biopsy; Chapter 290), systemic sclerosis (topoisomerase I; Chapter 281), and thyroid disease (Chapter 239). In appropriate settings, porphyria (Chapter 223) and Chagas’ disease (Chapter 394) may need to be excluded. In refractory cases, referral to a specialized center may result in genetic testing and/or full-thickness biopsy of the small intestine to identify metabolic muscle disorders and mitochondrial myopathies.

4.

Identify complications of the motility disorder, including bacterial overgrowth, dehydration, and malnutrition. In patients presenting with diarrhea, it is important to assess nutritional status and to exclude bacterial overgrowth by culture of small bowel aspirates (Chapter 143). Bacterial overgrowth is relatively uncommon in neuropathic disorders but is found more often in myopathic conditions, such as scleroderma, that are associated more often with dilation or low-amplitude contractions. An empirical trial of antibiotics (see later) often is used instead of formal testing.

Treatment
Rehydration, electrolyte repletion, and nutritional supplementation are particularly important during acute exacerbations of gastroparesis and chronic intestinal pseudo-obstruction. Initial nutritional measures include low-fiber supplements with the addition of iron, folate, calcium, and vitamins D, K, and B 12 at the usually recommended daily levels. In patients with more severe symptoms, enteral or parenteral supplementation may be required. If it is anticipated that enteral supplementation may be needed for more than 3 months, a jejunostomy tube is recommended. Gastrostomy tubes should be avoided in patients with gastroparesis except for venting purposes. Medications increasingly are being used to treat neuromuscular motility disorders, but there is little evidence of effectiveness in myopathic disturbances except for the rare case of dystrophia myotonica affecting the stomach and for small bowel systemic sclerosis. Metoclopramide is a dopamine antagonist with prokinetic and antiemetic properties. Antiemetic effects are due in part to its anti–5-hydroxytryptamine type 3 (HT3) antagonist actions. Long-term use of metoclopramide is limited by the side effects of tremor and Parkinson-like symptoms. It is available in tablet or elixir form and typically is taken 30 minutes before meals and at bedtime. Usual doses are 5 to 20 mg four times daily, but patients may experience side effects (changes in affect, anxiety) at relatively low doses (30 to 40 mg/day). Erythromycin, a macrolide antibiotic that stimulates motilin receptors at higher doses (250 to 500 mg) and cholinergic mechanisms at lower doses (40 to 80 mg), results in the dumping of solids from the stomach, accelerates gastric emptying in gastroparesis, increases the amplitude of antral contractions, and improves antroduodenal coordination. Erythromycin is most effective when it is used intravenously (3 mg/kg every 8 hours) during acute exacerbations of gastroparesis. For oral erythromycin, tolerance and gastrointestinal side effects often prevent use for longer than 1 month, but sometimes liquid erythromycin can be tolerated at 40 to 80 mg three times daily before meals. Octreotide, a cyclized analogue of somatostatin, induces small intestinal activity that mimics phase III of the interdigestive migrating motor complex. It retards gastric emptying, decreases postprandial gastric motility, and inhibits small bowel transit. Octreotide seems to be useful in the treatment of dumping syndromes associated with accelerated transit. Octreotide may be used at night to induce migrating motor complex activity and avoid bacterial overgrowth. If required during the daytime, octreotide often is combined with oral erythromycin to ―normalize‖ the gastric emptying rate. Antiemetics, including diphenhydramine, trifluoperazine, and metoclopramide, can treat nausea and vomiting in patients with gastroparesis and intestinal pseudo-obstruction. The more expensive serotonin
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5-HT3 antagonists (e.g., ondansetron) have not proved to be of greater benefit than these less expensive alternatives. Antibiotic therapy is indicated in patients with documented, symptomatic bacterial overgrowth. Although formal clinical trials have not been conducted, it is common practice to use different antibiotics for 7 to 10 days each month, in an attempt to avoid resistance. Common antibiotics include doxycycline, 100 mg twice daily; metronidazole, 500 mg three times daily; ciprofloxacin, 500 mg twice daily; and double-strength trimethoprim-sulfamethoxazole, two tablets twice daily. Use of antibiotics in patients with diarrhea and fat malabsorption secondary to bacterial overgrowth results in significant symptomatic relief. Surgical decompression is rarely necessary in patients with chronic pseudo-obstruction. Venting enterostomy (jejunostomy) is effective, however, in relieving abdominal distention and bloating and in reducing the frequency with which nasogastric intubations and hospitalizations are required for acute exacerbations relative to the period before vent placement. Access to the small intestine by enterostomy also provides nutrients and should be considered in patients with intermittent symptoms. Surgical treatment should be considered whenever the motility disorder is localized to a resectable portion of the gut: duodenojejunostomy or duodenoplasty for patients with megaduodenum, completion gastrectomy for patients with post–gastric surgical stasis syndrome, and colectomy with ileorectostomy for intractable constipation associated with chronic colonic pseudo-obstruction. Gastric electrical stimulation, an approved treatment, may improve gastric emptying and symptoms in patients with severe gastroparesis, but data on efficacy are inconclusive. Small bowel transplantation currently is limited to patients with intestinal failure who have reversible liver disease induced by total parenteral nutrition or have life-threatening or recurrent catheter-related sepsis.

DISEASES OF RAPID TRANSIT THROUGH STOMACH AND SMALL BOWEL
DUMPING SYNDROME AND ACCELERATED GASTRIC EMPTYING
Dumping syndrome and accelerated gastric emptying typically follow truncal vagotomy and gastric drainage procedures (Chapter 139). With the widespread use of highly selective vagotomy and the advent of effective anti–acid secretory therapy, these problems are becoming rare. A high caloric (usually carbohydrate) content of the liquid phase of the meal evokes a rapid insulin response with secondary hypoglycemia. These patients also may have impaired antral contractility and gastric stasis of solids, which paradoxically may result in a clinical picture of gastroparesis (for solids) and dumping (for liquids). The management of dumping syndrome and accelerated gastric emptying emphasizes dietary maneuvers, such as avoidance of high-nutrient liquid drinks and possibly addition of guar gum or pectin to retard gastric emptying of liquids. Rarely, pharmacologic treatment with octreotide, 25 to 100 μg subcutaneously before meals, is needed to retard intestinal transit and inhibit the hormonal responses that lead to hypoglycemia.

RAPID TRANSIT DYSMOTILITY OF THE SMALL BOWEL

Rapid transit of material through the small bowel may occur in the setting of the irritable bowel syndrome (Chapter 135), postvagotomy diarrhea (Chapter 139), short bowel syndrome (Chapter 141), diabetic diarrhea (Chapter 242), and carcinoid diarrhea (Chapter 245). With the exception of irritable bowel syndrome, these conditions may cause severe diarrhea and result in significant losses of fluid and electrolytes. Idiopathic bile acid catharsis may represent an inability of the distal ileum to reabsorb bile acids because of rapid transit and reduced contact time with the ileal mucosa; this condition may induce colonic secretion and secondary diarrhea. Accelerated transit may be confirmed by scintigraphic studies. Treatment goals are to restore hydration and nutrition and to slow small bowel transit. Dietary interventions include avoiding hyperosmolar drinks and replacing them with iso-osmolar or hypo-osmolar oral rehydration solutions. The fat content in the diet should be reduced to approximately 50 g/day to avoid delivery of unabsorbed fat to the colon. All electrolyte and nutritional deficiencies of calcium, magnesium, potassium, and water-soluble and fat-soluble vitamins should be corrected. In patients with less than 1 m of residual small bowel, it may be impossible to maintain fluid and electrolyte homeostasis without parenteral support. In patients with a longer residual segment, oral nutrition, pharmacotherapy, and supplements are almost always effective. The opioid agent loperamide (4 mg 30 minutes before meals and at bedtime for a total dose of 16 mg/day) suppresses the motor response to feeding and improves symptoms but may be ineffective or cause side effects (e.g., hypotension). Verapamil (40 mg twice daily) and/or clonidine (0.1 mg twice daily) may be used in addition to loperamide. Octreotide (50 μg subcutaneously three times daily before meals) may be used in patients for whom the oral agents are ineffective or poorly tolerated. 5-HT3 antagonists (e.g., alosetron) may be efficacious in the treatment of carcinoid diarrhea and diarrhea-predominant irritable bowel syndrome.

COLONIC MOTILITY DISORDERS
CONSTIPATION Epidemiology and Pathophysiology
Constipation is a common clinical problem, reported by about 20% of the population, and 40% of Americans report needing to strain excessively to pass their bowel movements. It is essential to distinguish an evacuation disorder, also called functional outlet obstruction (Table 134–2), from constipation resulting from slow transit or other causes. In one study in a tertiary center, 50% of 70 patients with severe, unresponsive constipation had impaired evacuation, and the remainder had constipation associated with either normal transit (also called functional constipation) or delayed colonic transit (also called slow transit constipation). In functional constipation, transit is normal, and there is no evacuation disorder. These patients may have pain in association with constipation, and there may be overlap with constipation-predominant irritable bowel syndrome (Chapter 135). In patients with acquired slow transit constipation, unassociated with colonic dilation, the number of interstitial cells of Cajal in the different layers of the sigmoid colon is reduced compared with controls.

Idiopathic megarectum and megacolon can be either congenital or acquired; an enteric nervous system defect is suspected. In megacolon, the dilated segment shows normal phasic contractility but decreased colonic tone, with smooth muscle hypertrophy and fibrosis of the muscularis mucosa, circular muscle, and longitudinal muscle layers. Acquired defects in the enteric nervous system may result in constipation in Chagas’ disease (Chapter 394), which is caused by infection with Trypanosoma cruzi and results in the destruction of myenteric neurons. Acquired aganglionosis also has been reported with circulating antineuronal antibodies, with or without associated neoplasm.

Diagnosis and Treatment
Characterization of constipated patients (Fig. 134–4) relies on the measurement of transit with radiopaque markers. It is important to identify evacuation disorders because a biofeedback treatment program with muscle relaxation of the anal sphincters and pelvic floor results in a 70% or greater cure rate for the constipation. The response to this treatment program is influenced by comorbidity, such as the coexistence of eating disorders or a psychological or psychiatric diagnosis. Surgical strategies used in the past for evacuation disorders have been shown to be either unnecessary or damaging to patients, resulting in incontinence. An evacuation disorder frequently is associated, however, with delayed overall colonic transit, not simply delayed transit in the distal colon. The average daily fiber intake is around 12 g/day. In patients with slow transit constipation, drug-induced constipation, or evacuation disorders, supplementation of 30 g of fiber per day does not result in any improvement in constipation. In patients with normal transit constipation, however, 12 to 30 g/day is effective in relief of constipation. By definition, 50% of people have fiber intake less than 12 g/day; the first line of therapy in all patients presenting with constipation is to increase fiber intake to at least 12 g/day. A second step is to add an osmotic laxative, such as a magnesium salt, to enhance the retention of fluid within the lumen by osmotic forces, to increase the fluidity, and to ease aboral transport of colonic content. Polyethylene glycol solutions (such as GoLYTELY, NuLytely, MiraLax, OCL solution) are used frequently as a second-line therapy. If these measures do not suffice, a prokinetic or stimulant agent, such as bisacodyl (5 to 10 mg every 1 to 2 days) may be added. When these approaches do not work, the patient should be reassessed to exclude an evacuation disorder. Newer medications include the 5-HT4 agonist, prucalopride, which accelerates colonic transit in healthy participants and in patients with functional constipation. It significantly increased the number of spontaneous and complete bowel movements in phase III trials of patients with functional constipation. Recombinant human analogues of neurotrophins (e.g., r-met-Hu) can accelerate colonic transit time and relieve constipation.
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In patients whose constipation is not associated with an evacuation disorder and does not respond to aggressive medical therapies (including combinations described earlier), subtotal colectomy with ileorectostomy is effective in relieving constipation. During the first postoperative year, bowel frequency may be increased up to eight times during the daytime and once or twice at night; from the second postoperative year onward, bowel frequency is reduced to one to three times per day with few or no

nocturnal episodes. Laparoscopic colectomy with ileorectostomy may achieve the same success rate with less morbidity compared with open colectomy with ileorectostomy.

HIRSCHSPRUNG’S DISEASE
Epidemiology and Pathophysiology
Hirschsprung’s disease occurs in 1 in 5000 live births. It is characterized by a localized segment of narrowing of the distal colon as a result of failure of local development of intrinsic nerves in the myenteric plexus. A relative deficiency of c-kit-positive interstitial cells of Cajal has been reported in Hirschsprung’s disease and chronic intestinal pseudo-obstruction. Hirschsprung’s disease is usually present from birth and is identified in childhood; onset of symptoms and diagnosis after the age of 10 is rare. Hirschsprung’s disease is well characterized histologically by the absence of ganglion cells in the myenteric and submucosal plexus and the presence of hypertrophied nerve trunks in the space normally occupied by the ganglion cells. The lack of nerve growth factor receptors in the muscle layers of the colon involved with Hirschsprung’s disease has been shown. The narrowing and failure of relaxation in the aganglionic segment are thought to be due to the lack of neurons containing nitric oxide synthase.

Diagnosis and Treatment
Diagnosis is based on the typical focal narrowing of the colon, the absence of the rectoanal inhibitory reflex (relaxation of anal sphincter pressure at rest during distention of a balloon in the rectum depends on natural preservation and maturation of intrinsic nerves in the distal bowel), and a deep rectal biopsy specimen showing absence of submucosal neurons with hypertrophied nerve trunks. Treatment involves excision of the affected bowel segment or a pull-through procedure by which normal bowel is anastomosed to the cuff of the rectum, just above the anal sphincters.

SUGGESTED READINGS
Bytzer P, Talley NJ, Leemon M, et al: Prevalence of gastrointestinal symptoms associated with diabetes mellitus: A population-based survey of 15,000 adults. Arch Intern Med 2001;161:1989–1996. Population-based epidemiologic study of gastrointestinal symptoms in patients with diabetes mellitus. Camilleri M: Enteric nervous system disorders: Genetic and molecular insights for the neurogastroenterologist. Neurogastroenterol Motil 2001;13:277–295. Review of genetic and molecular disorders resulting in gastrointestinal syndromes secondary to disturbed function of enteric nerves. Camilleri M: Advances in diabetic gastroparesis. Rev Gastroenterol Disord 2002;2:47–56. Review of the mechanisms and manifestations of upper gastrointestinal syndromes in patients with diabetes mellitus. Chaussade S, Minic M: Comparison of efficacy and safety of two doses of two different polyethylene glycol-based laxatives in the treatment of constipation. Aliment Pharmacol Therap 2003;17:165–172. A well-sructured trial comparing different formulations and doses of osmotic laxatives that are commonly used in clinical practice.

Maleki D, Locke GR III, Camilleri M, et al: Gastrointestinal tract symptoms among persons with diabetes mellitus in the community. Arch Intern Med 2000;160:2808–2816. Population-based epidemiologic study of gastrointestinal symptoms in patients with diabetes mellitus. Talley NJ, Spiller R: Irritable bowel syndrome: A little-understood organic bowel disease. Lancet 2002;360:555–564. Overview of a condition affecting up to 10% of the population.


				
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