APPROACH TO THE PATIENT WITH GASTROINTESTINAL
Don W. Powell
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 cos t 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
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
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 e xists 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.
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 (D 2), histaminergic (H 1), 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 H 1 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 an d 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 dur ation,
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 m ustard, 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. Ob struction 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 lab yrinthine 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. Metab olic 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 are a
postrema (D 2, 5-HT3, H1, and M1 receptors) and (2) the H 1, 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 D 1, H 1, 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 H 1 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.
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 corte x,
In the embryo, the gut and organs are present in the midline and receive innervation from bo th 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 neur ons 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 n ormally 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 l ying 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.
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, a nd ―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.
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.
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 purpos es, 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 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.
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 soun ds (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 b e
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 ima gined.
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 exa miner 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.
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 susceptib ility to develop inflammatory b owel
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.
DIAGNOSTIC IMAGING PROCEDURES IN
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
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, readil y 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 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 ear lier
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 vas t 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 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
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 li ver (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).
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 l ess 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, calle d 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 obstru ction, 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
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 ultrasonograp hy. 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.
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 (99mTc)–labeled red blood cell studies represent a noninvasive, economic method to
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 Tc-HID A 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, bi le 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 techniqu e include
tumor staging in patients with esophageal or colorectal cancer.
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 surge ry. 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 evol ved 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.
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 techniqu es 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 m ay 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 wi th acute
calculous or acalculous cholecystitis, particularly if patients are considered to be at high risk for
emergency surgery, and permits subsequent elective cholecystectomy. Alternativel y, 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 obstructi ons of the esophagus (Chapter 132) or
colon (Chapter 139) can be performed by interventional endoscopists or interventional ra diologists.
Similarly, percutaneous radiologic gastrostomy has a high success rate because high -grade or complete
esophageal obstruction is not a contraindication to this method.
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
ab lation 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.
Pankaj Jay Pasricha
Technological advances in radiologic and endoscopic imaging have transformed medicine in the p ast 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
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 peri pheral 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 o r 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
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
Helicob acter 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 GASTROINTES TINAL 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 significa nt 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, endos copy 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. Pati ents 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 associate d 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 LOW ER 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 (typical ly 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 down loaded 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 o f d ysplasia 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 3 should undergo endoscopic
evaluation to detect pathogens such as CMV, Mycob acterium 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
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 o n an
Malignant obstruction of the gastrointestinal lumen including the esophagus (Fig. 132–7), pylorus or
duodenum, and colon can now be safely and effectively palliated endoscopi cally 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
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 fre quent
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 i ts 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 mai nstays 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 exa mination 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
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 determ ined.
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
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.
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. Man y 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.
Keymling M: Colorectal stenting. Endoscopy 2003;35:234–238. Endoscopic stents can relieve malignant
colorectal ob struction 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 b y a revie w of formal guidelines.
Triadafilopoulos G: Endoscopic therapies for gastroesophageal reflux disease. Curr Gastroenterol Rep
2002;4:200–204. Review of new endoscopic treatments.
GASTROINTESTINAL HEMORRHAGE AND OCCULT
David J. Bjorkman
Gastrointestinal hemorrhage is a common clinical disorder. Bleeding from the gas trointestinal 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).
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 bleed ing. 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 TREATM ENT. 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. B lood
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 p atient’s
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 p ylorospasm 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 gas trointestinal 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
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 a vailable 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) o r 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 recur rent
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 H 2-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 va riceal 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
LOWER GASTROINTESTINAL BLEEDING
Lower gastrointestinal bleeding occurs at a rate of 20 : 100,000 population, which is about one fi fth 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 disorde r 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 va soconstrictors 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 scin tigraphy 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. Ob scure
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
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 ob scure gastrointestinal b leeding 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 telangi ectasia
(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.
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.
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 b leeding 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 b leeding increases the life expectancy at a cost
comparable to that of colon cancer screening.
DISORDERS OF GASTROINTESTINAL MOTILITY
Motility disorders result from impaired control of the neuromuscular apparatus of the gastrointestinal tra ct.
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
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 o xide, somatostatin) transmitters.
GASTRIC AND SMALL BOW EL 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 res idue 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 intrins ic 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 resu lt 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 mos t 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. Mo vement 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 decreas ed 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 volum e 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
DISEASES OF SLOW TRANSIT THROUGH THE STOMACH AND SMALL
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 comm on ―neuropathic‖ problem in clinical practice results from the
effect of medications, such as α 2-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 d egenerative, 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 e yes, dry vagina, difficulties with visual accommodation in bright lights, and absence of sweati ng.
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 fo und
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 e very meal.
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 evalua tion
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 gastroin testinal 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 b owel 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 radiolabele d
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
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
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
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 co ntractions, and
improves antroduodenal coordination. Erythromycin is most effective when it is used intravenously
(3 mg/kg every 8 hours) during acute exacerbations of gastroparesis. 1 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
5-HT3 antagonists (e.g., ondansetron) have not proved to be of greater benefit than these less expensive
Antib iotic 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 localize d 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
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 gas tric 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 significan t 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 segme nt, 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
COLONIC MOTILITY DISORDERS
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 ob struction (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. Surg ical 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 trans port
of colonic content. Polyethylene glycol solutions (such as GoLYTELY, NuLytel y, 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.2 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
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.
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
A relative deficiency of c-kit-positive interstitial cells of Cajal has been reported in Hirschsprung’s disease
and chronic intestinal pseudo-ob struction. Hirschsprung’s diseas e 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.
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 diab e tes 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 diab etes 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.