Diarrea PDF

CHAPTER
16
Diarrhea
LAWRENCE R. SCHILLER AND JOSEPH H. SELLIN
CHAPTER OUTLINE
Definition...................................................................................221
Pathophysiology.........................................................................222
Further Evaluation of Acute Diarrhea.......................................... 230

Further Evaluation of Chronic Diarrhea....................................... 231
Osmotic Diarrhea...................................................................... 222

Secretory Diarrhea.................................................................... 223
Complex Diarrhea...................................................................... 224
Treatment..................................................................................235
Clinical Classification.................................................................226
Selected Diarrheal Syndromes...................................................236
Acute versus Chronic Diarrhea................................................... 226

Large-Volume versus Small-Volume Diarrhea............................. 226
Osmotic versus Secretory Diarrhea............................................ 226
Watery versus Fatty versus Inflammatory Diarrhea...................... 226
Epidemiologic Features.............................................................. 226
IBS and Functional Diarrhea...................................................... 236

Microscopic Colitis.................................................................... 237
Postsurgical Diarrhea................................................................ 237
Bile AcidInduced Diarrhea........................................................ 238
Diarrhea in Hospitalized Patients................................................ 238
Factitious Diarrhea.................................................................... 239
Idiopathic Secretory Diarrhea..................................................... 240
Diarrhea of Obscure Origin........................................................ 240
Differential Diagnosis.................................................................227
Evaluation..................................................................................229
History...................................................................................... 229
Physical Examination................................................................. 229
Diarrhea is a universal human experience. The average American has an estimated 0.65 episodes of acute GI illness per
year.1 For most persons, episodes of diarrhea last a day or
2 and rapidly subside without medical intervention. For
others, diarrhea lasts for more than a few days or is complicated by fever, prostration, or rectal bleeding. Such persons
are likely to visit a health care provider. Over 3.5 million outpatient visits for diarrhea occur each year in the United States.2
Most patients can be managed successfully as outpatients,
but more than 150,000 hospital admissions each year are for
gastroenteritis. Over the course of a year, chronic diarrhea
(liquid stools for 4 weeks) may occur in 5% of the population
and is thus a major cause of disability for Americans.3 In
developing countries, acute infectious diarrhea remains an
important cause of morbidity and mortality, particularly
among children.
DEFINITION
Diarrhea is a symptom, not a disease, and therefore may occur
in dozens of conditions. Most patients consider increased fluidity of stool to be the essential characteristic of diarrhea.4
Stool consistency is difficult to quantitate, and visual scales
may be helpful for patients to use in describing their diarrhea.5
Researchers also have used stool frequency or stool weight as
a surrogate marker of diarrhea. Three or more bowel movements daily are considered to be abnormal, and the upper
limit of stool weight in Western countries is generally agreed
to be 200g daily.6 Although stool weight is often cited as a
scientific definition of diarrhea, diarrhea should not be
Empirical Therapy of Acute Diarrhea.......................................... 235

Empirical Therapy of Chronic Diarrhea....................................... 235
defined solely in terms of fecal weight. Some persons have

increased fecal weight as a result of fiber ingestion but do not
complain of diarrhea because their stool consistency is normal.
Stool output can be as great as 300g when a high-fiber diet is
consumed, as is customary in some developing countries.
Conversely, about 20% of patients referred for evaluation of
diarrhea may have a normal stool weight,7 more often the
result of a change in consistency (i.e., passage of small-volume
loose stools) than of hyperdefecation (i.e., more frequent
passage of formed stool).
In a study of the objective determinants of decreased fecal
consistency,4 the ability of water-insoluble fecal solids, such as
those derived from dietary fiber or bacterial cell walls, to hold
or bind fecal water correlated well with fecal consistency. Too
little water-holding capacity to bind all the water present
resulted in loose stools, but when fecal solids had sufficient
water-holding capacity to bind all the water present, stools
remained thick or formed. Fecal consistency correlated best
with the ratio of the water-holding capacity of insoluble solids
to the total amount of water present and not simply to the
amount of fecal water, further supporting the concept that
stool weight should not be the sole criterion for diarrhea.
Fecal incontinence may be reported as severe or troublesome diarrhea by some patients, especially older adults.8
Although many incontinent patients have loose stools, their
major problem is with the mechanisms of continence and not
with intestinal fluid or electrolyte absorption. Accordingly, all
patients who complain of diarrhea should be asked about the
presence of fecal incontinence. If incontinence is frequent,
especially in the absence of rectal urgency or loose stools, the
patient should be evaluated for incontinence and not for diarrhea (see Chapter 18).
221
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222 Section III Symptoms, Signs, and Biopsychosocial Issues
PATHOPHYSIOLOGY
Diarrhea frequently represents a protective response to a
variety of intestinal insults and assaults. Normally the intestine absorbs most of the fluid it secretes, and intestinal motility
provides a favorable milieu for water, electrolyte, and nutrient
absorption. When infectious agents, toxins, or other noxious
substances are present in the intestine, fluid secretion and
motility are stimulated to expel the unwanted material,
thereby producing diarrhea. This protective response is valuable acutely, but when chronic, it is inappropriate and no
longer serves an adaptive purpose. Historically, diarrhea was
thought to be primarily a motility disorder. An improved
understanding of intestinal electrolyte transport since 1970 has
shifted the emphasis to epithelial function rather than motility.
Clearly, however, epithelial and motor functions are altered
in a coordinated fashion to produce diarrhea.9
Diarrhea is usually due to an excess of stool water resulting from abnormal water and electrolyte transport.4 Normally
the small intestine and colon absorb 99% of both oral intake
and endogenous secretions from the salivary glands, stomach,
liver, and pancreasa total fluid load of roughly 9 to 10L
daily (Fig. 16-1). Diarrhea results from a disruption of this
normally fine-tuned mechanism; reduction of water absorption by as little as 1% can result in diarrhea.
Water itself is not actively transported; rather, it moves
across the intestinal mucosa via paracellular and transcellular
pathways secondary to osmotic forces generated by the transport of solutes (i.e., electrolytes, nutrients) (see Chapters 101
and 102). The molecular pathways of ion and nutrient transport across the mucosa have been well characterized and are
regulated by a complex communication system of extracellular and intracellular messengers that maintain fluid equilibrium throughout a wide range of physiologic conditions.
Normally, absorption and secretion take place simultaneously,
but absorption is quantitatively greater. Either a decrease in
absorption or an increase in secretion leads to additional fluid
within the lumen and thus diarrhea. Disruption of epithelial
electrolyte transport or its regulatory system by toxins, drugs,
hormones, and cytokines is a major cause of diarrhea.
Diarrhea due to disordered electrolyte transport is termed
secretory diarrhea, even though it is more commonly caused
by reduced absorption than by net secretion.10 Another major
cause of diarrhea is ingestion of some poorly absorbed osmotically active substance (e.g., magnesium ion, lactulose) that
retains fluid within the lumen to maintain osmotic equilibration with body fluids, thereby reducing water absorption.
Diarrhea resulting from this mechanism is known as osmotic
diarrhea (Table 16-1). Few clinical situations produce pure
secretory or osmotic diarrhea, but considering some conditions in which 1 or the other mechanism predominates is
useful before considering more complex processes.
Osmotic Diarrhea
Ingestion of poorly absorbed cations and anions or poorly
absorbed sugars or sugar alcohols (e.g., mannitol, sorbitol)
accounts for most osmotic diarrheas.11 Ions that are poorly
absorbed include magnesium, sulfate, and phosphate. These
ions are transported actively by mechanisms that are saturated
at low intraluminal ion concentrations and passively by mechanisms that are slow. Together, these processes limit total
absorption to a fraction of the amount ingested. Because
neither the small intestine nor colon can maintain an osmotic
gradient, unabsorbed ions (and their counter ions) that remain
in the intestinal lumen obligate retention of water to maintain
an intraluminal osmolality equal to that of body fluids
Upper tract
10 L
10 L
Volume
absorbed
Small intestine
6L
1.5 L
Jejunum
2.5 L
Ileum
Colon
1.5 L
1.4 L
0.1 L
FIGURE 16-1. Fluid loads along the GI tract. Each day, close to 10L
of fluid composed of ingested food and drink and secretions from
the salivary glands, esophagus, stomach, pancreas, bile duct,
and duodenum pass the ligament of Treitz. The jejunum absorbs
approximately 6L and the ileum 2.5L, leaving about 1.5L to
pass into the colon each day. The colon absorbs more than 90%
of this load, leaving about 0.1L in feces. Overall efficiency of
water absorption is 99%, and reduction of this efficiency by as
little as 1% may lead to diarrhea. (From Schiller LR. Chronic diarrhea. In: McNally P, editor. GI/Liver secrets. 2nd ed. Philadelphia:
Hanley & Belfus; 2001. p 411.)
(290mOsm/kg). Therefore, about 3.5mL of water (1000mL/

kg 290mOsm/kg) are retained for every 1mOsm of retained
ions or molecules (see Chapter 101).11-14
Sugars and sugar alcohols are the other major category of
substances that cause osmotic diarrhea.14 Monosaccharides
but not disaccharides can be absorbed intact across the apical
membrane of the intestine. When disaccharides like sucrose
and lactose are ingested, absence of the appropriate disaccharidase will preclude absorption of the disaccharide or its component monosaccharides (see Chapters 102 and 104). The most
common clinical syndrome of disaccharidase deficiency is
acquired lactase deficiency, which accounts for lactose intolerance in many adults.15 Lactase is present in the brush border
of the small intestine of most immature mammals but disappears in adult mammals, including 70% of adult humans.16
The main exceptions are persons from the northern European
gene pool and some areas of Africa, who typically maintain
lactase activity into adult life due to mutations in the promoter
region of the gene.17,18 Lactase activity often falls with age even
in these groups, however. Congenital deficiency of lactase is
rare and seems to be the result of a mutation in a gene distinct

Chapter 16 Diarrhea 223

TABLE 16-1 Secretory versus Osmotic Diarrhea
Type of Diarrhea
Causes
Examples
Secretory
Exogenous
secretagogues
Endogenous
secretagogues
Enterotoxins (e.g.,
cholera)
Neuroendocrine
tumors (e.g.,
carcinoid
syndrome)
Congenital
chloridorrhea
Intestinal resection,
diffuse intestinal
mucosal disease
Diffuse mesenteric
atherosclerosis
Intestinal hurry
following
vagotomy
Absence of ion
transporter
Loss of intestinal
surface area
Intestinal ischemia
Rapid intestinal
transit
Osmotic
Ingestion of poorly
absorbed agent
Reduced nutrient
transport
Magnesium
ingestion
Lactase deficiency
from that for lactase-phlorizin hydrolase (the gene affected in

adult lactase deficiency).19 Acquired deficiencies may also be
associated with mucosal diseases of the upper small intestine.
Congenital sucrase and trehalase deficiencies are rare and
prevent adequate digestion of sucrose (table sugar) and trehalose (a sugar found in mushrooms), respectively. Lactulose is
a synthetic disaccharide that cannot be hydrolyzed by the
human intestine and is not absorbed intact in more than trace
amounts. It causes an osmotic diarrhea when given in sufficient quantity to overwhelm the metabolic capacity of colonic
bacteria (80g/day).20 The number of foods that potentially
contribute to osmotic diarrhea has been expanded with the
recognition of fermentable oligosaccharides, disaccharides,
monosaccharides, and polyols (FODMAPs) (see later).
The essential characteristic of osmotic diarrhea is that it
resolves with fasting or cessation of ingestion of the offending
substance. This characteristic has been used clinically to differentiate osmotic diarrhea from secretory diarrhea, which
typically continues with fasting. Electrolyte absorption is not
impaired in osmotic diarrhea, and electrolyte concentrations
in stool water are usually low.12-14
Secretory Diarrhea
Secretory diarrhea has many causes. The mechanism of this
type of diarrhea is always net secretion of anions (chloride or
bicarbonate) or potassium or net inhibition of sodium absorption.21 The stimuli for secretion arise from the intestinal lumen,
subepithelial space, or systemic circulation and substantially
alter the messenger systems that regulate ion transport pathways. In rare cases, congenital absence of a specific transport
molecule limits sodium or chloride absorption and results in
diarrhea; in others, lack of sufficient absorptive surface area
critically limits electrolyte, particularly sodium, absorption.
The most common cause of secretory diarrhea is infection.21 Enterotoxins from various infectious agents (primarily
bacteria but also parasites and viruses) interact with receptors
that modulate intestinal transport and lead to increased anion
secretion. For example, Escherichia coli heat-stable enterotoxin
interacts with the guanylate cyclase C receptor on the luminal
surface of the enterocyte that normally mediates the effect of

guanylin, a luminally released peptide hormone that stimulates chloride secretion via the cystic fibrosis transmembrane
regulator.22 In addition to stimulating secretion, enterotoxins
may block specific absorptive pathways. Most enterotoxins
inhibit Na+-H+ exchange in the small intestine and colon,
thereby blocking 1 of the important driving forces for electrolyte and fluid absorption.23,24
Peptides produced by endocrine tumors (e.g., vasoactive
intestinal peptide) cause secretory diarrhea by stimulating
secretion by epithelial cells, as do peptides released from
subepithelial neurons and inflammatory cells (see Chapters 4
and 33).25 Neurotransmitters like acetylcholine or serotonin
(5-hydroxytryptamine [5-HT]) and other modulators like histamine and inflammatory cytokines are also potent secretory
stimuli.26,27 Most of these endogenous regulators of intestinal
transport elicit diarrhea by altering intracellular messengers,
such as cyclic adenosine monophosphate (cAMP), cyclic guanosine monophosphate (cGMP), and calcium, that control specific transport pathways.28 Peptides and other regulators may
also affect synthesis, localization, and degradation of individual transport proteins. Exogenous agents such as drugs
and some poisons lead to secretory diarrhea, presumably by
interacting with intracellular regulators or intracellular messengers of the enterocytes.
Molecular genetics has provided insight into rare diseases
and the potential for increased understanding of the mechanisms of diarrhea. The absence or disruption of a specific
absorptive pathway may cause diarrhea. For example, rare
congenital syndromes (e.g., congenital chloridorrhea, congenital sodium diarrhea) are caused by the absence of a specific
transport molecule.29 In chloridorrhea, the DRA (downregulated in adenoma) protein is absent and Cl-HCO3
exchange in the ileum and colon is defective, thereby
transforming chloride into a poorly absorbed ion. Diarrhea
resulting from chloridorrhea can be reduced by limiting oral
chloride intake or chloride secretion or by stimulating chloride
absorption in the colon by enhancing short-chain fatty acid
absorption.30 Another familial syndrome is due to a mutation
in the guanylate cyclase-C receptor that markedly increases
production of cGMP in enterocytes.31 Several transporter
defects have been proposed in congenital sodium diarrhea.32
A genome-wide association study in Bangladesh has identified genes that may provide a survival advantage for cholera
in an endemic region and are subject to natural selection.33
These genes include those associated with potassium channels
involved with cAMP-mediated chloride secretion and other
genes associated with nuclear factor (NF)-B-dependent pathways of the innate immune system. Such findings point the
way to improved understanding of the pathogenesis of diarrhea and potential targets for treatment.
For intestinal fluid and electrolyte absorption to be complete, the intestine must have an adequate surface area and
adequate contact time with luminal contents. Substantial loss
of surface area, as in celiac disease or inflammatory bowel
disease (IBD) or after resective surgery, may compromise
water absorption. Even though the reserve absorptive capacity
in the small intestine and colon is large, sufficiently long surgical resections inevitably cause diarrhea. In some cases, the
problem is temporary because, over time, the intestine may
improve its capacity for absorption by the process of adaptation.34 Such compensation is impossible following resection of
certain segments of the intestine with highly specific absorptive functions that simply cannot be assumed by other segments of the bowel. For example, ileocecal resection is followed
by permanent inability to absorb sodium chloride against a
concentration gradient that cannot be overcome by more distal
parts of the colon.35

Although classification of diarrhea as osmotic or secretory

may be instructive in thinking about the pathophysiology of
diarrhea, cases of pure secretory or pure osmotic diarrhea
are uncommon. Most clinically important diarrhea is complex
in pathogenesis, with several mechanisms involved. Causes
may include the effects of substances released by enteric
endocrine cells, cytokines released by local and remote immunologically reactive cells, activity of the enteric nervous
system, and peripherally released peptides and hormones
(autocrine, luminal, paracrine, immune, neural, and endocrine
systems [see Chapter 4]). The occurrence of significant crosstalk between the epithelial cells and luminal contents, including bacteria, nutrients, and minerals, has become increasingly
evident.47,48
Imm
une
Autocrine
Lu
mi
na
ine
racr
Pa
Systems
Endocrine
Complex Diarrhea
Further complicating an understanding of diarrhea is

the recognition that certain mediators affect not only epithelial
or muscle function but also each other; enteric nerves may
stimulate mast cells, and products released from mast cells
(particularly histamine) may alter enteric neuron functions.49
A single agonist like prostaglandin may have multiple simultaneous effects on epithelial function, muscle contraction, and
the paracellular pathway, thereby leading to effects on ion
transport, motility, and mucosal permeability.50 Therefore, a
number of modulators and effectors contribute to the final
clinical picture. A full appreciation of the pathophysiology of
diarrhea requires consideration of a regulatory system known
as ALPINES (autocrine, luminal, paracrine, immune, neural,
and endocrine systems [Fig. 16-2]).
An example of the complexity of the pathophysiology
of a diarrheal syndrome is cholera, often cited as the paradigm
of a pure secretory diarrhea. Cholera toxin targets the epithelial cell and increases the second messenger cAMP, which
opens apical chloride channels to stimulate chloride secretion
and results in diarrhea. However, the actual mechanism
whereby cholera induces diarrhea is far more complex.51
Cholera toxin stimulates endocrine cells and neural elements
that reinforce its direct secretory effect on enterocytes.52 In
addition, cholera toxin causes distinct changes in intestinal
motility. Other toxins produced by Vibrio cholerae target tight
junctions and thereby alter mucosal permeability (Fig. 16-3)
(see Chapter 110).53
l
ura
Ne
Abnormal motility may lead to diarrhea that has secretory

and osmotic components.10 For fluid and electrolyte absorption to be complete, the contact time between luminal contents
and the epithelium must be sufficient to permit absorption.
In some patients, abnormal motility produces intestinal
hurry.36,37 Because rapid transit prevents adequate time for
absorption, diarrhea results despite intact mucosal absorptive
capacity.10 In some patients with intestinal hurry, the oralcecal transit time may be as short as 10 minutes. Under such
circumstances, the diarrhea is exacerbated by malabsorption
of nutrients that produces an osmotic component to diarrhea.
In diabetes mellitus and postvagotomy diarrhea, intestinal
hurry has been linked to abnormal enteric nervous system
function.38 In other disorders (e.g., amyloidosis, postprandial
diarrhea, IBS), enteric nervous system dysfunction is suspected but unproved.39,40 Many endocrine diarrheas, such
as those caused by peptide-secreting tumors or hyperthyroidism, may lead to diarrhea not only by affecting intestinal
electrolyte transport but also by accelerating intestinal
motility.41
Slow intestinal transit may lead to a secretory diarrhea by
promoting small intestinal bacterial overgrowth.42,43 Excess
bacteria in the small intestine disrupt digestion and may alter
electrolyte transport. The best documented example of diarrhea related to this mechanism is scleroderma. Although diabetes mellitus is often suspected of causing diarrhea by slow
transit and stasis, as seen in scleroderma, such a pathophysiologic mechanism is not always established (see Chapter
105).44,45 Secretory diarrhea sometimes develops in patients
with colonic pseudo-obstruction due to active potassium
secretion in the colon, possibly related to autonomic or enteric
nervous dysfunction.46
Evaluation of the role of intestinal motility in the pathogenesis of diarrhea has been limited by the lack of tools necessary to measure the interactions among motility, propulsive
forces, and transit time. Except for intestinal perfusion studies,
during which the effect of motility on electrolyte transport is
eliminated, no methodology exists to dissociate the effects of
intestinal transport and motility on net absorption.10 Therefore, consensus has not been achieved on whether too much
or too little motility causes diarrhea, nor on how luminal
factors may alter intestinal smooth muscle function.
Reduced intestinal blood flow has an important but as
yet poorly defined role in diarrhea. Whether mesenteric ischemia has a direct effect on absorption or whether low blood
flow prompts secondary responses (e.g., via cytokines or
neurotransmitters) that affect fluid transport and produce a
secretory diarrhea is not clear. Radiation enteritis also produces an abnormal intestinal microcirculation associated
with persistent diarrhea that may be difficult to treat (see
Chapters 40 and 118).
ALPINES
Paracellular
pathway
Blood
flow
Epithelium
Permeability
Transport
Muscle
Motility
Metabolism
FIGURE 16-2. ALPINES regulatory system in the intestine. The

regulatory system of the intestine integrates autocrine, luminal,
paracrine, immune, neural, and endocrine systems and produces
coordinated changes in mucosal and muscular function that
permit adaptive responses to changing conditions. The regulatory system can widen or narrow the paracellular pathway that
governs passive transmucosal permeability of electrolytes, accelerate or retard transepithelial transport of nutrients and electrolytes by affecting membrane channels and pumps, alter motility
by relaxing or contracting the various muscle layers in the intestine, and increase or decrease mucosal blood flow, thereby influencing intestinal metabolism. Diarrhea may be an appropriate
response to acute infection. Maladaptive responses may be
responsible for chronic diarrhea. (Modified from Sellin JH. Functional anatomy, fluid and electrolyte absorption. In: Feldman M,
Schiller LR, editors. Gastroenterology and hepatology. The comprehensive visual reference, vol 7: Small intestine. Philadelphia:
Current medicine; 1997. p 1.11.)

Enterocyte
Lumen
ACE
V. cholerae
Subepithelial
space and
lamina propria
ZOT
Brefeldin A
CT
Adenylate
cyclase
Macrophage
Cl +
Na+
cAMP
PG
5HT
VIP
Cl
Myenteric
plexus
Enteric
neuron
EC cell
Smooth
muscle
cell
FIGURE 16-3. Pathophysiology of cholera. Vibrio cholerae produces several toxins that interact with adenylate cyclase in the enterocyte
and several elements of the regulatory system of the intestine, including enteric neurons and enterochromaffin (EC) cells, to produce
a secretory state and voluminous diarrhea. In addition to the classic enterotoxin, cholera toxin (CT), the bacterium produces zona
occludens toxin (ZOT), which increases the permeability of the tight junction between enterocytes, and accessory cholera enterotoxin
(ACE), which has unclear effects on enterocytes. In addition to cyclic adenosine monophosphate (cAMP) generated by adenylate
cyclase in response to CT, secretory stimuli include prostaglandin (PG), serotonin (5HT), and vasoactive intestinal polypeptide
(VIP) released by macrophages, EC cells, and enteric neurons. CT has been shown to activate adenylate cyclase on the basolateral
membrane of the cell in experiments in which the transcellular transport of CT to the basolateral membrane was inhibited by
Brefeldin A (jagged arrow). (From Sellin JH. Functional anatomy, fluid and electrolyte absorption. In: Feldman M, Schiller LR, editors.
Gastroenterology and hepatology. The comprehensive visual reference, vol 7: Small intestine. Philadelphia: Current medicine; 1997.
p 1.14.)
Another example of dysregulation of ALPINES is IBD.54

Diarrhea in patients with IBD involves more than just exudation into the lumen as a result of destruction of the mucosa.
Intact enterocytes are barraged by multiple secretagogues
released by immune cells in the intestine and by bacterial
toxins that may influence enterocyte function. Although
initial models of diarrhea in IBD suggested altered fluid transport driven by chloride secretion, subsequent studies have
demonstrated that the diarrhea in IBD is mediated by an antiabsorptive effect associated with down-regulation of sodium
channels and pumps.55-57 The pathophysiology of diarrhea in
IBD is even more complex if we consider the role of luminal
bacteria. Bacterial proteins (e.g., flagellin) may stimulate the
production of cytokines like interleukin (IL)-8, which further
attract inflammatory cells.58 Cytokines and immune cells
may also directly influence tight junction barrier function
and enterocyte secretory and absorptive pathways.59-62
Conversely, epithelial cells may secrete cytokines like IL-6
that enhance polymorphonuclear leukocyte (neutrophil)
function.63 Inflammation may induce significant changes in

motility as well (see Chapters 115 and 116).
IBS is another example of a disorder with a complex pathophysiology. A constellation of factors, such as altered motility,40 bile acid malabsorption,64 and compromised rectal
reservoir capacity,65 may aggravate symptoms in patients with
IBS. At a more fundamental level, alterations in mast cell or
enterochromaffin cell number, serotonin content, and serotonin reuptake and transport may contribute to the development of diarrhea (see Chapter 122).66-68
Complex pathophysiology may also be observed in malabsorption syndromes and functional disorders, particularly
those characterized by rapid transit. Failure to absorb carbohydrates may lead to osmotic diarrhea, but failure to absorb
long-chain fatty acids may complicate matters by impairing
electrolyte absorption by the colon.14,69 Common postprandial
functional diarrhea probably involves an interplay between
motility and transport functions. Diarrhea caused by food
allergy also involves activation of immunologic, paracrine,


and neural mechanisms that regulate vascular permeability,
electrolyte transport, and motility (see Chapters 10 and 104).70
CLINICAL CLASSIFICATION
Diarrhea can be classified in several ways: time course (acute
vs. chronic), volume (large vs. small), pathophysiology (secretory vs. osmotic), stool characteristics (watery vs. fatty vs.
inflammatory), and epidemiology.6 For the clinician, classification is useful only if it delineates a diagnostic and management approach in a given patient. In this regard, no single
scheme is perfect; the experienced physician uses all these
classifications to facilitate patient care.
Acute versus Chronic Diarrhea

The time course of diarrhea can help direct management.
Acute diarrhea (<4 weeks) is usually caused by an infection,
which is generally self-limited or easily treated.71 Most
common bacterial and viral causes of diarrhea run their course
within 7 days. Persistence of an acute diarrheal episode
beyond 7 days raises the possibility of a protozoal cause like
giardiasis or cryptosporidiosis. Although few infectious agents
(e.g., Aeromonas or Yersinia spp.) cause prolonged diarrhea in
an immunocompetent person, chronic diarrhea is usually not
caused by an infectious agent. Therefore, when confronted
with a patient with chronic diarrhea, the clinician must consider noninfectious causes (see later).
Large-Volume versus Small-Volume Diarrhea

Differentiation of the cause of diarrhea on the basis of the
volume of individual stools (rather than total daily stool
output) rests on the premise that the normal rectosigmoid
colon functions as a storage reservoir. When that reservoir
capacity is compromised by an inflammatory or motility disorder involving the left colon, frequent small-volume bowel
movements ensue. If the source of diarrhea is in the right colon
or small bowel and if the rectosigmoid reservoir is intact,
individual bowel movements are less frequent and larger. Frequent, small, painful stools may point to a distal colonic site
of pathology, whereas painless large-volume stools suggest a
right colonic or small bowel source. Although patients have
difficulty quantifying stool volume accurately, the distinction
between small- and large-volume stools may guide further
diagnostic studies.
Daily total stool output may also provide hints about the
cause. IBS often results in normal or only slightly elevated
24-hour stool weights, whereas diarrhea of other causes may
produce greater stool weights. Stool weight can be estimated
by the patients history; patients with diarrhea that produces
dehydration (in the absence of vomiting or limited oral intake)
typically have stool weights over 1000g and are unlikely to
have IBS.
Osmotic versus Secretory Diarrhea

Distinguishing diarrhea due to intestinal malabsorption of
ingested nonelectrolytes (osmotic diarrhea) from diarrhea due
to malabsorption or secretion of electrolytes (secretory diarrhea) helps separate the small number of cases of osmotic
diarrhea from the much larger number of cases of secretory
diarrhea. This distinction is based on the measurement of stool
electrolyte concentrations.12 In secretory diarrhea, sodium,
potassium, and accompanying anions account almost entirely
for stool osmolality, whereas in osmotic diarrhea, poorly
absorbable solutes within the intestinal lumen account for

much of the osmotic activity of stool water (see later). Because
osmotic diarrhea is caused by ingestion of some poorly
absorbed substance, it abates with fasting. Secretory diarrhea
typically continues during fasting, although stool output
may decrease modestly because of reduced endogenous
secretions.
Watery versus Fatty versus

Inflammatory Diarrhea
When diarrhea is chronic (4 weeks), the differential diagno
sis can overwhelm even the most experienced clinician. By
characterizing stools as watery, fatty, or inflammatory on the
basis of simple stool tests, evaluation of the patient can be
expedited by limiting the number of conditions that must be
considered in the differential diagnosis.3 Watery diarrhea
implies either secretory or osmotic diarrhea. Fatty diarrhea
implies defective absorption of fat and perhaps other nutrients
in the small intestine. Inflammatory diarrhea implies the presence of 1 of a limited number of inflammatory or neoplastic
diseases involving the GI tract.
Epidemiologic Features
One of the most useful clinical approaches to narrowing
the differential diagnosis is to relate diarrhea to its setting.
A soccer mom and a backpacker from Nepal could conceivably have the same cause of diarrhea but are more likely
to have different causes. Some common clinical scenarios
and the diagnoses that should be considered are shown in
Box 16-1.
BOX 16-1 Likely Causes of Diarrhea in Well-Defined

Patient Groups or Settings
Travelers
Bacterial infection (mostly acute)
Protozoal infections (e.g., amebiasis, giardiasis)
Tropical sprue
Epidemics and Outbreaks

Bacterial infection
Epidemic idiopathic secretory diarrhea (e.g., Brainerd
diarrhea)
Protozoal infection (e.g., cryptosporidiosis)
Viral infection (e.g., rotavirus)
Patients with Diabetes Mellitus

Altered motility (increased or decreased)
Associated diseases
Celiac disease
Pancreatic exocrine insufficiency
SIBO
Drug side effects (especially acarbose, metformin)
Patients with AIDS

Drug side effects
Lymphoma
Opportunistic infections (e.g., cryptosporidiosis,
cytomegalovirus, HSV, Mycobacterium avium complex)
Institutionalized and Hospitalized Patients

Clostridium difficile toxinmediated colitis
Drug side effects
Fecal impaction with overflow diarrhea
Ischemic colitis
Tube feeding


BOX 16-2 Differential Diagnosis of Diarrhea
Acute Diarrhea
Infection (see Box 16-3)
Bacteria
Parasites
Protozoa
Viruses
Food allergies
Food poisoning
Medications
Initial presentation of chronic diarrhea
Chronic Diarrhea
Fatty Diarrhea
Malabsorption syndromes
Mesenteric ischemia
Mucosal diseases (e.g., celiac disease, Whipples disease)
Short bowel syndrome
SIBO
Maldigestion
Inadequate luminal bile acid concentration
Inflammatory Diarrhea
Diverticulitis
Infectious diseases
Invasive bacterial infections (e.g., tuberculosis,
yersiniosis)
Invasive parasitic infections (e.g., amebiasis,
strongyloidiasis)
Pseudomembranous colitis (Clostridium difficile infection)
Ulcerating viral infections (e.g., cytomegalovirus, HSV)
Inflammatory bowel diseases
Crohns disease
UC
Ulcerative jejunoileitis
Ischemic colitis
Neoplasia
Colon cancer
Lymphoma
Radiation colitis
DIFFERENTIAL DIAGNOSIS
Many GI and systemic diseases can present with diarrhea. To
facilitate the differential diagnosis, the clinician should divide
diarrheal diseases into acute and chronic, and further subdivide chronic diarrhea by stool characteristicswatery, inflammatory, and fatty (Box 16-2).
Acute diarrhea is defined as lasting less than 4 weeks,
although many cases last fewer than 4 days.71 The usual cause
is infection by bacteria, viruses, protozoa, or multicellular
parasites (Box 16-3). Acute diarrhea can also be caused by food
poisoning, food allergies, and medications. Diseases that
lead to chronic diarrhea may present with an acute onset and
therefore must be considered when acute diarrhea becomes
persistent.
Chronic watery diarrhea may be caused by ingestion of
poorly absorbed, osmotically active substances (osmotic diarrhea) or, more commonly, conditions that cause secretory
diarrhea. Ingestion of any of a limited number of osmotic
agents, such as magnesium, phosphate, and sulfate laxatives
or poorly absorbed carbohydrates, causes osmotic diarrhea.
By contrast, chronic secretory diarrhea, in which electrolyte
Watery Diarrhea
Osmotic diarrhea
Carbohydrate malabsorption
Osmotic laxatives (e.g., Mg2+, PO43, SO42)
Secretory diarrhea
Bacterial toxins
Congenital syndromes (e.g., congenital chloridorrhea)
Disordered motility, regulation
Diabetic autonomic neuropathy
IBS
Postsympathectomy diarrhea
Postvagotomy diarrhea
Diverticulitis
Endocrinopathies
Addisons disease
Carcinoid syndrome
Gastrinoma
Hyperthyroidism
Mastocytosis
Medullary carcinoma of the thyroid
Pheochromocytoma
Somatostatinoma
VIPoma
Idiopathic secretory diarrhea
Epidemic secretory (Brainerd) diarrhea
Sporadic idiopathic secretory diarrhea
Ileal bile acid malabsorption
IBD
Crohns disease
Microscopic colitis
Collagenous colitis
Lymphocytic colitis
UC
Laxative abuse (stimulant laxatives)
Medications and toxins (see Box 16-4)
Neoplasia
Colon carcinoma
Lymphoma
Villous adenoma in rectum
Vasculitis
BOX 16-3 Infections That Cause Diarrhea

Bacteria
Aeromonas spp.
Campylobacter spp.
Clostridium difficile
Escherichia coli (enterotoxigenic, enteroinvasive,
enterohemorrhagic)
Pleisiomonas spp.
Salmonella spp.
Shigella spp.
Viruses
Adenovirus
Norovirus
Rotavirus
Parasites or Protozoa
Cryptosporidium
Cyclospora
Entamoeba histolytica
Giardia lamblia
Microsporidia


BOX 16-4 Medications and Toxins Associated
with Diarrhea
Acid-reducing agents (e.g., H2RAs, PPIs)
Antacids (e.g., those that contain magnesium)
Antiarrhythmics (e.g., quinidine)
Antibiotics (most)
Anti-inflammatory agents (e.g., 5-aminosalicylates, gold salts,
NSAIDs)
Antihypertensives (e.g., -adrenergic receptor blocking drugs)
Antineoplastic agents (many)
Antiretroviral agents
Colchicine
Heavy metals
Herbal products
Prostaglandin analogs (e.g., misoprostol)
Theophylline
Vitamin and mineral supplements
malabsorption leads to fluid retention within the lumen, is

associated with many clinical conditions (see Box 16-2).
Although IBD typically produces diarrhea characterized
by the presence of blood and pus, other diseases of inflammation without ulceration (e.g., microscopic colitis) may cause
diarrhea with the characteristics of chronic secretory diarrhea.
Diarrhea in such cases is mediated by secretion of cytokines
and other inflammatory mediators (see Chapter 128).
Chronic watery diarrhea can also be caused by ingestion
of drugs or poisons (Box 16-4).72-74 Identifying drugs as the
cause of diarrhea depends on recognizing that the initiation of
drug ingestion and the onset of diarrhea occurred coincidentally, but such a temporal correlation is not always easy to
identify and requires a detailed and carefully taken history.
The pathophysiology of drug-induced diarrhea is complex
and has not been well studied. Some drugs may activate specific receptors and transporters; for example, caffeine, like theophylline, may increase intracellular cAMP activity and fluid
secretion, as can be seen clinically in cases of what has been
called Starbucks diarrhea. Erythromycin interacts with the
motilin receptor, thereby stimulating propulsive motor activity in the GI tract. Other antibiotics may alter the bacterial flora
in the colon and lead to impaired colonic salvage of malabsorbed carbohydrate or overgrowth of toxin-producing Clostridium difficile. Some drugs (e.g., cocaine) may interfere with
blood flow to the intestine. Chemotherapeutic agents are associated with a high frequency of diarrhea, which may result
from disruption of the delicate balance between enterocyte
proliferation and apoptosis, leading to what has been termed
an apoptotic enteropathy (see Chapter 35). A diverse group of
drugs (e.g., aspirin, mycophenolate mofetil, gold) can incite an
inflammatory process in the intestine that may cause diarrhea.
Olmesartan can cause a sprue-like enteropathy (see Chapter
107). The problem of detecting drug-induced diarrhea is more
difficult in patients with surreptitious laxative abuse; these
patients deliberately conceal vital information about the cause
of their problem (see later).75
Another category of chronic watery diarrhea involves
disordered motility or dysregulation of intestinal function.
Problems such as postvagotomy diarrhea, postsympathectomy diarrhea, diabetic autonomic neuropathy, amyloidosis,
and probably diarrhea-predominant IBS belong in this category. In these situations, diarrhea has the characteristics of
a secretory diarrhea secondary to primary dysregulation of
electrolyte transport or altered motility that speeds luminal
fluid past absorptive sites in the intestine (see Chapters 36,

53, and 122).
Another large category of watery diarrhea is diarrhea
caused by endocrine dysfunction. Relatively common endocrine disturbances like hyperthyroidism and Addisons
disease can be complicated by chronic secretory diarrhea.
Much rarer endocrine tumors also produce diarrhea, typically
by altering electrolyte absorption or speeding intestinal transit.
The rarity of these tumors makes the pretest probability of
finding these conditions low, especially in the absence of liver
metastases, so screening tests are often falsely positive (see
later and Chapters 33 and 36).
Other tumors cause watery diarrhea by obstructing
bowel, blocking lymphatic drainage, interfering with absorption, or causing electrolyte secretion. Examples of such
conditions include colon carcinoma (bowel obstruction),
lymphoma (lymphatic obstruction in the small bowel and
mesentery), and villous adenomas of the rectum (secretion
of a large amount of potassium-rich gelatinous fluid into
the lumen). Villous adenomas found more proximally in
the colon rarely cause this type of diarrhea (see Chapters 31,
126, and 127).
The last category of chronic watery diarrhea is idiopathic
secretory diarrhea. This rubric includes 2 entities: epidemic
secretory diarrhea (also known as Brainerd diarrhea) and sporadic idiopathic secretory diarrhea. Both disorders are protracted but self-limited conditions (see later).76,77
Chronic inflammatory diarrhea is the designation for a
diverse group of infectious or idiopathic inflammatory and
neoplastic processes. Stools are characterized by the presence
of mucus and pus and are usually associated with ulceration
of the mucosa. Idiopathic IBD, including UC and Crohns
disease, typically produces such stools. Less commonly, other
inflammatory conditions such as diverticulitis or ulcerative
jejunoileitis may be associated with blood or pus in the stool,
as may infectious diseases that are invasive or ulcerating.
Infections that cause chronic inflammatory diarrhea include
bacterial infections (e.g., tuberculosis, yersiniosis, C. difficile
associated colitis), viral infections that ulcerate (e.g., cyto
megalovirus, herpes simplex virus), and invasive parasitic
infections (e.g., strongyloidiasis). In the immunocompromised
person, a broader range of infectious agents should be considered. Noninfectious diseases that cause chronic inflammatory
diarrhea include ischemic colitis and neoplasms (e.g., colon
cancer, lymphoma) that are complicated by ulceration of the
mucosa (see Chapters 31, 110 to 116, 118, 119, 121, and 127).
Chronic fatty diarrhea results from malabsorption or
maldigestion. Malabsorption syndromes caused by mucosal
diseasesmost commonly celiac disease but also rare entities
such as Whipples diseasetypically produce fatty diarrhea.
Short bowel syndrome or post-resection diarrhea can also
present with this pattern, although if the resection is relatively
limited, the diarrhea may be watery secondary to nutrient or
bile-acid malabsorption. Small intestinal bacterial overgrowth
causes steatorrhea by deconjugation of bile acids. Mesenteric
ischemia affecting the small intestine may impair intestinal
absorption of fat, but weight loss is more often due to sitophobia (fear of eating) secondary to postprandial pain. Maldigestion as a result of pancreatic exocrine insufficiency or
inadequate duodenal bile acid concentration produces steatorrhea. Although fatty, the stools may not be very loose in maldigestive conditions, because in the absence of fat digestion,
triglycerides remain intact and have little effect on colonic
electrolyte absorption. By contrast, malabsorption in the presence of normal digestion may produce fairly voluminous diarrhea because of the cathartic action of free fatty acids in the
colon (see Chapters 59, 104 to 109, and 118).74


BOX 16-5 Historical Features to Consider in Patients
Presenting with Diarrhea
Duration: acute (<4 weeks) vs. chronic (4 weeks)
Onset: congenital, abrupt, gradual
Pattern: continuous, intermittent
Epidemiology (see Box 16-1)
Iatrogenic factors: drugs (see Box 16-4), radiation, surgery
Factitious diarrhea (see Box 16-7)
Systemic diseases: endocrine, collagen vascular, neoplastic,
immunologic
Stool appearance: watery, bloody, fatty
Fecal incontinence: present, absent
Abdominal pain: location, relation to meals or bowel
movements, aggravating and relieving factors
Weight loss
Aggravating factors: diet, stress
Alleviating factors: diet, over-the-counter drugs, prescription
drugs
Previous evaluation
EVALUATION
History
A carefully taken medical history is crucial to evaluating a
patient presenting with diarrhea. A checklist for history findings is provided in Box 16-5. An essential feature is the duration of symptoms. Patients with acute diarrhea (<4 weeks in
duration) should be distinguished from those with chronic
diarrhea, in whom the differential diagnosis is much broader.
Severity of the diarrhea should be ascertained. Stool frequency
is the easiest characteristic of diarrhea for patients to define
but does not necessarily correlate with stool weight; some
persons pass small amounts of stool frequently, but others
have less frequent and more voluminous evacuations. Patients
have a poor notion of stool volume, but symptoms such as
dry mouth, increased thirst, decreased urine output, and
weakness suggest dehydration resulting from a high stool
output. Acute weight loss is also a good marker of severity.
Chronic weight loss may suggest intestinal malabsorption
or a serious constitutional process like malignancy, IBD, or
hyperthyroidism.
Stool characteristics are also important. Blood in the stool
signals the possibility of malignancy or IBD, although it is
often caused by hemorrhoids in patients with frequent evacuations. In patients with acute infectious diarrhea, visible blood
in the stool is highly specific for infection with an invasive
organism.78 Watery stools suggest an osmotic or secretory
process, and the presence of oil or food particles is suggestive
of malabsorption, maldigestion, or intestinal hurry. The phenomenon of floating stools generally represents an increase in
the gas content rather than the fat content of stools. The physician should also ask about the relationship of defecation to
meals or fasting, passage of stool during the day versus the
night, and presence of fecal urgency or incontinence. Urgency
and incontinence are not indicative of voluminous diarrhea
but suggest a problem with rectal compliance or the muscles
regulating continence. Nocturnal diarrhea that awakens the
patient from sleep strongly suggests an organic rather than a
functional disorder such as IBS. Other coexisting symptoms
like abdominal pain, flatulence, bloating or gaseous distention, cramps, fever, and weight loss should be noted. Excessive
flatus or bloating suggests increased fermentation of carbohydrate by colonic bacteria as a result of ingestion of poorly
absorbable carbohydrate or malabsorption of carbohydrate by

the small intestine.
Because iatrogenic causes of diarrhea (e.g., drugs, previous
surgery, radiation therapy) are common, the health care
provider should explore the history for prior abdominal surgeries and ingestion of prescription drugs and over-thecounter remedies, including nutritional and herbal therapies.
The patients diet should be reviewed thoroughly. Diarrhea
may be due to ingestion of large quantities of poorly absorbable carbohydrates like fructose or sugar alcohols like sorbitol
or mannitol, which may be consumed in fruit juices and soda
(which contain fructose and high-fructose corn syrup) or as
dietetic sugar-free candies and chewing gums (which contain
sorbitol and mannitol).79 Excessive consumption of coffee or
caffeine-containing energy drinks can also be associated with
diarrhea.
Epidemiologic clues should also be pursued (see Box 16-1).
Recent foreign travel, particularly to undeveloped countries,
makes the diagnosis of travelers diarrhea likely. The globalization of commerce has increased the frequency of once exotic
infections in those without grossly obvious exposures.80 The
physician should also consider whether the patient lives in a
rural or urban environment, the source of the patients drinking water, and the patients occupation, sexual orientation,
and use of alcohol or illicit drugs. Potential secondary gains
from illness or a history of attempted weight loss and fixation
on body image should raise the possibility of laxative abuse
(see later).
The patients history is essential in differentiating patients
with IBS from those with other functional disorders or organic
conditions that cause diarrhea. Current definitions of IBS
emphasize the presence of abdominal pain associated with
defecation.81 Additional factors that suggest a diagnosis of IBS
include a long history that usually extends back to adolescence
or young adulthood, passage of mucus, and exacerbation of
symptoms by stress. Factors that argue against a diagnosis of
IBS include recent-onset diarrhea, especially in older patients,
diarrhea that awakens the patient from sleep, weight loss,
presence of blood in the stool, and stool weights over 400 to
500g daily. Abnormal blood test results, such as a low hemoglobin level, low serum albumin concentration, or high erythrocyte sedimentation rate, also argue against a diagnosis of
IBS (see Chapter 122).
Painless diarrhea should no longer be considered a form
of IBS. The Rome III Consensus Committee has defined functional diarrhea as at least 3 months, which need not be consecutive, in the preceding 6 months of liquid (mushy) or
watery stools more than three-quarters of the time; and no
abdominal pain.81 Many patients with chronic diarrhea will
not have a readily defined cause of diarrhea identified when
first seen and could be characterized as having functional
diarrhea. Physicians should not rush to make this diagnosis
without exploring alternative possibilities, particularly those
that can produce episodic and variable diarrhea, such as small
intestinal bacterial overgrowth and carbohydrate malabsorption. Functional diarrhea must also be distinguished from
idiopathic secretory diarrhea (see later).
Physical Examination
Physical findings are usually more useful in determining the
severity of diarrhea than in determining its cause. The patients
volume status can be assessed by looking for orthostatic
changes in blood pressure and pulse. Fever and other signs of
toxicity should be noted. A careful abdominal examination is
important, with particular attention to the presence or absence


TABLE 16-2 Potential Implications of Physical Findings in
Patients with Chronic Diarrhea
TABLE 16-3 Management of Acute Diarrhea Based on

the Patients Appearance
Finding
Potential Implication
Orthostasis, hypotension
Muscle wasting, edema
Urticaria pigmentosa,
dermatographism
Pinch purpura, macroglossia
Hyperpigmentation
Migratory necrotizing erythema
Flushing
Malignant atrophic papulosis
Dermatitis herpetiformis
Thyroid nodule,
lymphadenopathy
Tremor, lid lag
Right-sided heart murmur,
wheezing
Hepatomegaly
Abdominal bruit
Arthritis
Dehydration, neuropathy
Malnutrition
Mast cell disease
(mastocytosis)
Amyloidosis
Addisons disease
Glucagonoma
Carcinoid syndrome
Kohlmeier-Degos disease
Celiac disease
Medullary carcinoma of the
thyroid
Hyperthyroidism
Carcinoid syndrome
Appearance
of Patient
Treatment
Nontoxic
Symptomatic therapy, rehydration
Toxic
Fluid and electrolyte repletion

Complete blood count
Serum electrolytes, blood urea nitrogen, serum
creatinine
Stool tests: culture (if fecal leukocytes positive),
ova and parasite examination, Giardia and
Cryptosporidium antigens, Clostridium
difficile testing or PCR multiplex panel
Sigmoidoscopy or colonoscopy
Lymphadenopathy
Anal sphincter weakness
Endocrine tumor, amyloidosis

Chronic mesenteric ischemia
IBD, yersiniosis, Whipples
disease
HIV infection, lymphoma,
cancer
Fecal incontinence
From Ref 202.
of bowel sounds, abdominal distention, localized or generalized tenderness, masses, and an enlarged liver. Rarely, the
physical examination may provide more direct evidence of the
cause of diarrhea. Characteristic physical findings that should
be sought are listed in Table 16-2.
Further Evaluation of Acute Diarrhea

Most cases of acute diarrhea are caused by infectious diseases
that have a limited course (a few days to a few weeks) and do
not require a physicians intervention unless the patients
immune system is compromised or the patient experiences
complications of volume depletion or other evidence of severe
toxicity, including inability to ingest fluid, frequent vomiting,
and debilitating muscle or joint pain.71 When these complications are present or when the diarrhea has persisted for more
than a few days, a more comprehensive evaluation is warranted. A complete blood count should be done to look for
anemia, hemoconcentration, or an abnormal white blood cell
count. Patients with a viral cause of diarrhea usually have
normal white blood cell and differential counts or lymphocytosis, but those with bacterial infectionsparticularly those
caused by organisms that invade the intestinal mucosa
have leukocytosis with an excess of immature white blood
cells. Neutropenia, however, can occur in patients with
salmonellosis. Measurements of serum electrolyte concentrations and blood urea nitrogen and serum creatinine levels can
be used to assess the extent of fluid and electrolyte depletion
and its effect on kidney function.
Stool samples should be examined for white blood cells to
identify inflammatory diarrhea.82 The standard method for
detecting white blood cells in stool is with a Wright stain and
microscopy. Test accuracy depends on the experience and skill
of the observer; false-positive and false-negative results are
common. Tests for the neutrophil products calprotectin and
lactoferrin are sensitive and specific for detecting neutrophils
in stool and may be a useful alternative to microscopy.83

Studies have suggested that stool cultures are unlikely to grow
pathogenic bacteria in the absence of fecal leukocytes, so a
Wright stain of stool or a fecal lactoferrin assay can be used to
decide which stool samples should be sent for bacterial culture,
thereby minimizing expense. This approach may be of more
value in outpatients than in patients hospitalized with diarrhea, because the latter have toxicity or have failed to resolve
spontaneously within a few days and must have stool cultures
sent. Routine stool cultures are of little use for hospitalized
patients in whom acute diarrhea develops while the patient is
in the hospital; testing for C. difficile infection is likely to be
more helpful. Advanced testing using molecular biological
techniques may speed the diagnosis of infectious diarrhea.84
The diagnostic value of examination of stool for ova and parasites depends on the pretest probability of a parasitic infection
and the experience of the observer. Enzyme-linked immunosorbent assays (ELISAs) for giardiasis and cryptosporidiosis
and serologic testing for amebiasis are more accurate tests
than stool microscopy and should be ordered even in the
absence of fecal leukocytes.85 Patients who have been treated
with antibiotics in the preceding 3 months or those in whom
diarrhea develops in an institutional setting should be tested
for C. difficile.86 With the increase in community-acquired C.
difficile infections, this treatable cause of acute diarrhea should
always be considered, even in the absence of a prior history
of antibiotic use (see Chapters 110 to 112).
Abdominal x-rays should be obtained in toxic-appearing
patients to assess for colitis and evidence of ileus or megacolon. Proctoscopy or flexible sigmoidoscopy should also be
considered in patients who are clearly toxic with infection,
have blood in the stool, or have persistent acute diarrhea.
Sigmoidoscopy is probably adequate as an early investigation
in such patients with severe acute diarrhea. In patients
with acquired immunodeficiency syndrome (AIDS)-related
diarrhea, colonoscopy is preferable because a substantial
proportion of infections and lymphomas may be present only
in the right colon,87 although this approach has been questioned (see Chapter 34).88 If sigmoidoscopy or colonoscopy
is done, mucosal biopsy specimens should be obtained
even if the mucosa does not appear to be grossly inflamed;
pathologic examination can identify important clues to facilitate a specific diagnosis.89 By contrast, biopsy of a normalappearing terminal ileum is generally unhelpful. A checklist
for evaluating patients with acute diarrhea is shown in
Table 16-3.


300
Because the differential diagnosis of chronic diarrhea is more

extensive than that of acute diarrhea, evaluation is more
complex.90,91 If a likely diagnosis cannot be established with
simple diagnostic tests or a therapeutic trial, the diarrhea
should be categorized as watery, inflammatory, or fatty by
stool analysis, thereby limiting the number of conditions to be
considered in the differential diagnosis. Stool analysis can be
obtained on a random sample or a timed (i.e., 24-, 48-, or
72-hour) stool collection. The value of analyzing a timed collection is that stool weight, and therefore the output of stool
components like fat, can be measured accurately. The daily
stool weight is perhaps the best clue to the diarrheas potential
impact on hydration. In the absence of a timed collection,
however, assessment of other stool characteristics on a random
or spot collection still provide many clues to the correct diagnosis.3,7 These assessments include stool sodium and potassium concentrations, stool pH, a fecal occult blood test, and
an examination of stool for white blood cells or a test for the
presence of a surrogate marker like fecal lactoferrin or calprotectin.83 In appropriate circumstances, stool samples can also
be analyzed for fat content and laxatives, including magnesium, phosphate, sulfate, bisacodyl, and anthraquinones
(see later).
Although stool collections are often viewed by patients
and physicians as messy and distasteful, they can usually be
done easily and successfully at home or in the hospital.
Perhaps the biggest hurdle is in dealing with laboratories that
are inexperienced or uninterested in stool analysis. Commercially available collection units that fit into a commode and
allow separation of stool and urine facilitate the collection, as
does the use of preweighed plastic or metal containers and a
small refrigerator or picnic cooler to keep the specimens cold.
Patients should continue their regular activities and should
consume a regular diet, including an intake of 80 to 100g of
fat daily, during the collection. Keeping a diary of food and
liquid ingested facilitates estimation of the patients fat and
calorie intake by a dietitian. When evaluating the results of
timed stool collections, it is important to recognize that
patients often do not eat diets sufficiently high in fat. During
the collection, diagnostic tests that might alter stool output or
composition, such as barium x-ray studies, should be avoided
and only essential medications given. Any antidiarrheal medications should be withdrawn. For most patients with diarrhea,
a 48-hour collection is sufficient. If stool output is not representative during that time, the collection can be extended.
Occasionally, stool output is measured during fasting; if the
diarrhea is caused by an ingested substance, fasting should
abolish the diarrhea. Persistence of diarrhea during fasting is
a criterion for secretory diarrhea.
Measurement of stool sodium and potassium concentrations allows calculation of an osmotic gap in stool water. The
osmotic gap is calculated by subtracting twice the sum of the
sodium and potassium concentrations from 290mOsm/kg,
the osmolality of stool in the body.12 (The sum of the concentrations is doubled to account for anions that accompany these
cations.) A small osmotic gap (<50mOsm/kg), which signifies
that the osmolality of stool water is due mostly to incompletely absorbed electrolytes, is characteristic of secretory
diarrhea (Fig. 16-4). A large gap (>100mOsm/kg) is characteristic of an osmotic diarrhea, usually resulting from ingestion of some poorly absorbed substance like magnesium salts
or nonelectrolytes. When the sum of sodium and potassium
concentrations doubled is higher than 290mOsm/kg, ingestion of a poorly absorbed multivalent anion (e.g., phosphate,
sulfate) is likely.12 The negative osmotic gap is the result of an
excess of cations obligated by multivalent anions. The actual
mmol/L
Further Evaluation of Chronic Diarrhea
250
Unmeasured
osmoles
200
Bicarbonate/
organic anions
150
Chloride
Potassium
100
Sodium
50
0
Secretory
diarrhea
Osmotic
diarrhea
FIGURE 16-4. Fecal electrolytes and the fecal osmotic gap. The
osmolality of colonic fluid and body fluids is in equilibrium and
is approximately 290mOsm/kg. Total concentration of electrolytes, therefore, cannot exceed 290mmol/L. In secretory diarrhea, almost all the osmotic activity of colonic contents is caused
by electrolytes, so the estimate of electrolyte content by the
formula 2 ([Na+] + [K+]) is approximately 290mmol/L. In osmotic
diarrhea, electrolytes account for only a small part of the osmotic
activity; unmeasured osmoles resulting from ingestion of a poorly
absorbed substance account for most of the osmotic activity, and
the calculated osmotic gap will be high. (From Schiller LR.
Chronic diarrhea. In: McNally P, editor. GI/liver secrets. 2nd ed.
Philadelphia: Hanley & Belfus; 2001. p 411.)
measurement of stool osmolality is of value only in detecting

samples that have been contaminated by the addition of water
or hypotonic urine. Such samples have an osmolality lower
than 290mOsm/kg. Continuing bacterial fermentation in
vitro tends to cause stool osmolality to rise once it has been
collected,14 so measured osmolality should not be used to calculate the fecal osmotic gap.
The pH of stool water provides useful information about
the possibility of carbohydrate malabsorption.12 Carbohydrate
that reaches the colon is promptly fermented by the bacterial
flora, with release of CO2 and H2 gases and short-chain
fatty acids (see Chapter 17). As a result of fermentation, the
pH is acidic, usually dropping to less than 6, a finding
that indirectly indicates excess carbohydrate fermentation in
the colon.
Fecal occult blood testing and examination of stool for
leukocytes allows identification of inflammatory diarrhea
resulting from colitis or malignancy. Other diarrheal conditions that cause occult bleeding include lymphoma of the
small intestine, celiac disease (fecal occult blood in 50%
of cases), and refractory sprue (fecal occult blood in 70%
of cases).92
Stool fat output can be measured quantitatively by chemical means on a timed (48- to 72-hour) collection or estimated
qualitatively by use of a Sudan stain on a random specimen.
Steatorrhea is defined as excessive loss of fat in the stool (>7g
or >9% of intake for 24 hours), but this definition may not
be valid for the diagnosis of fat malabsorption or maldigestion


in all patients with chronic diarrhea. In 1 study,93 diarrhea
induced with laxatives produced mild steatorrhea in 35% of
normal subjects. In patients with diarrhea, fat excretion in the
range of 7 to 14g/24hr has a low specificity for the diagnosis
of defective fat absorption, but fat excretion over 14g/24hr
strongly indicates a problem with fat absorption.93 Fat intake
during a quantitative collection should be estimated from diet
diaries because patients with diarrhea frequently have anorexia
or early satiation that may reduce their fat intakes substantially, thereby reducing fat excretion and potentially creating
a falsely negative test. For a valid study, patients should
consume 70 to 100g of fat daily for a few days before and
during the timed collection. Measurement of fat excretion as
a measure of malabsorption can also be compromised by
ingestion of the lipase inhibitor orlistat or the fat substitute
olestra.94
When only a random sample of stool is available, qualitative estimation of fat excretion by means of a Sudan stain of a
fecal smear may be helpful.95 Semiquantitative methods can
be applied to measure the number and size of fat globules, and
these methods produce results that correlate well with quantitative collections (see Chapters 102 and 104).
In patients in whom surreptitious laxative ingestion is suspected, stool water can be analyzed for laxatives by chemical
or chromatographic methods. As done commercially, this
analysis is subject to error.96 If positive, the test for the laxative
should be repeated on another stool sample to confirm the
finding before confronting the patient with this discovery (see
Chapter 23).
Stool samples can also be assayed with a chemical test for
carbohydrate (anthrone reagent)14 and for 1-antitrypsin clearance to detect protein-losing enteropathy (see Chapter 30).97
These tests have limited clinical usefulness and should not be
used routinely for initial evaluation of a patient with chronic
diarrhea.
Once stool analysis is completed, chronic diarrhea can be
categorized as watery (and secretory or osmotic), inflammatory, or fatty to help further differentiate its cause. A retrospective review of a series of stool analyses done at a tertiary
referral center showed findings clustered into 10 groups that
have diagnostic significance (Table 16-4).7
Chronic Watery Diarrhea

Secretory diarrhea has a broad differential diagnosis (see
Box 16-2), and a wide investigative net must be cast to identify
a specific cause (Box 16-6). Infection should be excluded by
stool culture for bacteria and special tests for other organisms.
The patients human immunodeficiency virus (HIV) status
should be clarified at this point because patients with AIDS
are more likely than others to have an infectious cause of
chronic diarrhea (see Chapter 34).98 Although most bacteria
that cause diarrhea are cleared spontaneously within 4 weeks,
some organisms (e.g., Aeromonas, Plesiomonas) may produce
chronic diarrhea.99,100 Special culture techniques may be
required to detect these organisms. Special microbiological
techniques are also required to find other pathogens like
coccidia and microsporidia.101 ELISA testing for Giardia and
Cryptosporidium antigens is more efficient than microscopy.85
Examination of mucosal biopsy specimens with special stains
or electron microscopy may be necessary to find pathogens
like cytomegalovirus.
Small intestinal bacterial overgrowth may result in secretory diarrhea, presumably caused by bacterial toxins, as well
as fatty diarrhea caused by bile salt deconjugation (see later).
The glucose-hydrogen breath test (see later) can be used to
screen for this condition, but the gold standard for diagnosis
of small intestinal bacterial overgrowth remains quantitative
culture of a small bowel aspirate if available (see Chapter
105).102 Structural diseases, such as short bowel syndrome,
gastrocolic or enteroenteric fistula, mucosal diseases, IBD, and
tumors including lymphomas, should be sought by means
of radiographic and endoscopic techniques. Small bowel
radiographs remain an important method for detecting structural small bowel diseases. CT or MRI, particularly CT or MRI
enterography, can detect small bowel and colonic diseases as
well as diseases extrinsic to the bowel (e.g., pancreatic tumors)
that can cause diarrhea.
Endoscopy is an important component of the evaluation
of chronic diarrhea. Colonoscopy has the highest diagnostic
yield, leading to a diagnosis in up to 30% of patients referred
for chronic diarrhea.103 Sigmoidoscopy or colonoscopy can be
used to visualize the colon and permit directed biopsies.
TABLE 16-4 Implications of Stool Characteristics in Patients with Chronic Diarrhea

Category/Findings
Implications
Stool Weight 200g/24h

No objective evidence of diarrhea
Hyperdefecation (increased frequency without excess volume)
Abnormal consistency (unformed to runny stools)
Elevated fecal osmotic gap
Steatorrhea
Change in stool frequency, intermittent diarrhea, fecal incontinence,

treatment with antidiarrheal drugs during collection
Possible IBS, proctitis, abnormal rectal reservoir function
Possible IBS
Presumed mild carbohydrate malabsorption or excess Mg intake
from supplements
Malabsorption or maldigestion
Stool Weight >200g/24h

Secretory diarrhea without steatorrhea
Carbohydrate malabsorption without steatorrhea
Steatorrhea with or without carbohydrate malabsorption
Osmotic diarrhea
Unclassified
Microscopic colitis or other cause of secretory diarrhea

Ingestion of poorly absorbed carbohydrates, malabsorption
Small bowel mucosal disease, SIBO, bile acid deficiency,
pancreatic insufficiency
Ingestion of poorly absorbed ions (e.g., magnesium, phosphate,
sulfate) or osmotically active polymers (e.g., polyethylene glycol)
Blood or pus suggests an inflammatory cause of diarrhea
From Ref. 7


BOX 16-6 Diagnostic Approach to the Patient with
Chronic Secretory Diarrhea

Osmotic Diarrhea
Exclusion of Infection
Measurement of stool magnesium output

Determination of stool pH; if <6 (consistent with carbohydrate
malabsorption):
Diet review
Breath hydrogen test with lactose; mucosal lactase assay if
available
Measurement of stool-reducing substances; anthrone
reaction
Measurement of stool phosphorus, sulfate, polyethylene glycol
Bacterial cultures (standard enteric pathogens, Aeromonas,

Plesiomonas)
Tests for other pathogens (microscopy for ova and parasites,
Giardia and Cryptosporidium antigens, special techniques for
Cyclospora, Coccidia, Microsporidia)
Exclusion of Structural Disease

CT or MRI of abdomen and pelvis
Sigmoidoscopy or colonoscopy with mucosal biopsies
Small bowel mucosal biopsy and aspirate for quantitative
culture
Capsule enteroscopy
Selective Testing
Plasma peptides: gastrin, calcitonin, VIP, somatostatin,
chromogranin A
Urine autocoids and metabolites: 5-HIAA, metanephrines,
histamine
Other tests: TSH, ACTH stimulation, serum protein
electrophoresis, immunoglobulins
Empirical Trial
Bile acidbinding agent
5-HIAA, 5 hydroxyindole acetic acid; TSH, thyroid-stimulating hormone;
VIP, vasoactive intestinal polypeptide.
Because colonic causes of chronic secretory diarrhea tend to

produce diffuse changes throughout the colon, sigmoidoscopy is usually adequate for this purpose.104 Colonoscopy is
preferable if the patient is older (and thus requires screening
for colon cancer), has blood in the stool, is suspected of
having right colonic or ileal disease, or has AIDS.87,103 Chronic
disorders that can be diagnosed by inspection of the colonic
mucosa include pseudomelanosis coli, polyps, tumors,
Crohns disease, UC amebiasis, and nonspecific ulceration. All
patients with undiagnosed chronic secretory diarrhea should
have mucosal biopsy specimens obtained from the colon, even
when the mucosa appears grossly normal.3 Random biopsies
should include multiple samples from several locations to give
the pathologist the best chance of making a diagnosis. Diseases in which colonic mucosa appears normal endoscopically, but which can be diagnosed histologically, include
microscopic colitis (lymphocytic and collagenous colitis [see
later]), amyloidosis, granulomatous infections, and schistosomiasis (see Chapters 36, 114, and 128).
Although upper GI endoscopy is routine in the evaluation of chronic diarrhea, no studies have been comparable
to those documenting a significant diagnostic yield for colonoscopy. Visualization and biopsy of the mucosa of the small
bowel by endoscopy or enteroscopy can be valuable, but
whether push enteroscopy adds much to standard esophagogastroduodenoscopy for evaluating diffuse small bowel
diseases is uncertain.105 Diseases that can be detected by
small intestinal biopsy include celiac disease, Crohns
disease, giardiasis, intestinal lymphoma, eosinophilic gastroenteritis, tropical sprue, Whipples disease, lymphangiectasia,
abetalipoproteinemia, amyloidosis, mastocytosis, and various
infectious processes. Patients with many of these dis
orders usually, but not always, present with steatorrhea (see
Chapters 29 to 31, 36, 104, and 107 to 115).
The role of wireless capsule endoscopy in the diagnosis of
diarrhea caused by small bowel disease is evolving rapidly.106
Subtle lesions not appreciated by other diagnostic modalities
can be seen, and new methods of deep enteroscopy allow

access to and biopsy of most of these abnormalities (see
Chapter 20).
Diarrhea caused by peptide-secreting tumors is an intellectually interesting form of chronic watery diarrhea that
is quite rare. The pretest probability of having a peptidesecreting tumor in a patient with chronic diarrhea is so low
that screening these patients with a panel of serum peptide
levels is far more likely to produce a false-positive than a
true-positive result.107 Testing for elevated serum peptide
levels or urinary metabolites of endocrine mediators like
5-hydroxyindoleacetic acid (5-HIAA), metanephrine, and
histamine should be limited to those patients who have
chronic diarrhea with symptoms and signs consistent with
a tumor syndrome (e.g., flushing or a large, hard liver in
carcinoid syndrome); ulcer disease suggestive of ZollingerEllison syndrome; headache, flushing, and urticaria pigmentosa in mastocytosis; or patients who have a CT that shows a
tumor.25 Scintigraphy using radiolabeled octreotide, especially
combined with positron emission tomography (PET) or CT,
can also be used to identify peptide-secreting tumors (see
Chapter 33).
More common endocrinologic diseases that cause diarrhea
are diabetes mellitus, hyperthyroidism, and Addisons disease.
In many cases, other symptoms and signs, such as an enlarged
thyroid or skin pigmentation characteristic of Addisons
disease, suggest the presence of these conditions. Blood
glucose, thyroid-stimulating hormone, and serum cortisol
levels before and after injection of an adrenocorticotropic
hormone analog should be measured selectively in patients
who might have 1 of these conditions. Other blood tests that
may be relevant in evaluating secretory diarrhea include
serum protein electrophoresis and immunoglobulin electrophoresis. Selective immunoglobulin A (IgA) deficiency may
present with recurrent intestinal infections such as giardiasis,
whereas combined variable immune deficiency can be associated with a variety of puzzling intestinal findings that sometimes mimic celiac disease.108 Testing for HIV and HIV-2 may
be appropriate (see Chapters 34 and 36).
Osmotic diarrhea has a much more limited differential
diagnosis, and its evaluation is much simpler (Box 16-7).11 For
practical purposes, osmotic diarrhea is caused by 1 of 3
conditionsingestion of exogenous magnesium, consumption of poorly absorbable carbohydrates, or carbohydrate malabsorption. Ingestion of other osmotically active substances is
unusual. Fortunately, these conditions can be differentiated by
taking a careful history and performing simple stool tests.
Magnesium can be measured directly in stool water by
atomic absorption spectrophotometry.13 Excretion of more
than 15mmol (30mEq) of magnesium daily or concentrations
in stool water of more than 44mmol/L (90mEq/L) strongly
suggests magnesium-induced diarrhea. The ingestion may be


intentional, as in a patient with surreptitious laxative ingestion, or accidental, as in a patient who uses magnesiumcontaining antacids or mineral supplements.
Ingestion of poorly absorbed carbohydrates or carbohydrate malabsorption typically leads to a low fecal pH because
of bacterial fermentation in the colon. A fecal pH lower than
6 is highly suggestive of carbohydrate malabsorption.12,14
More generalized malabsorption that involves fecal loss of
amino acids and fatty acids in addition to carbohydrate may
produce a somewhat higher pH (e.g., pH = 6 to 7.5). Isolated
carbohydrate malabsorption is usually due to ingestion of a
poorly absorbable carbohydrate, such as lactose in a person
with lactase deficiency. Other common causes include ingestion of poorly absorbed sugar alcohols that are used as artificial sweeteners (e.g., sorbitol, mannitol) or excessive ingestion
of sugars with a limited absorption capacity (e.g., fructose).79
Therapeutic use of inhibitors of carbohydrate absorption
(e.g., acarbose) may also lead to carbohydrate malabsorption.109 Because fermentation produces not only short-chain
fatty acids that acidify the stool but also carbon dioxide
and hydrogen, patient complaints of gas and bloating are
clinical clues to the presence of carbohydrate malabsorption,
although these symptoms are fairly nonspecific (see Chapters
17, 102, and 104).110
Once the clinical picture or stool analysis suggests carbohydrate malabsorption, a careful review of the patients diet
may indicate the likely source. FODMAPs, including fructose,
lactose, fructans, and polyols, which are found in many foods
and incompletely absorbed by many people, have been implicated in causing symptoms in many patients with IBS.111
Breath hydrogen tests can be used to implicate specific carbohydrates.20 In these tests, a previously fasting patient ingests
25g of carbohydrate dissolved in water, and exhaled breath is
assayed for hydrogen content at baseline and at intervals for
several hours. Because hydrogen is not a normal product of
human metabolism, any increase in breath hydrogen concentration is the result of bacterial fermentation and indicates that
unabsorbed carbohydrate has reached an area with high concentrations of intraluminal bacteria, typically the colon. Breath
hydrogen testing has been adapted to detect small intestinal
bacterial overgrowth with the use of glucose, a substrate that
ordinarily should be absorbed completely before reaching the
colon.102 Lactulose, a nonabsorbable but easily fermented
disaccharide, has also been used to detect small intestinal
bacterial overgrowth, but because of the wide variability of
intestinal transit time, use of lactulose for this purpose is problematic. Lactulose can be used as a substrate for determining
the oral-cecal transit time. Breath hydrogen testing after
administration of d-xylose has been advocated as a screening
test for generalized intestinal malabsorption.112 For most
purposes, breath hydrogen testing provides only supportive
evidence when the pretest likelihood of a particular diagnosis
is high (see Chapter 104). Once a specific cause of osmotic
diarrhea has been postulated, a therapeutic trial of an elimination diet can confirm the diagnosis.
Chronic Inflammatory Diarrhea

Patients with chronic diarrhea and white blood cells or blood
in the stool are classified as having inflammatory diarrhea.
These characteristics indicate that the mucosa is disrupted
and inflamed. Diagnostic considerations include IBD, infections, pseudomembranous enterocolitis, mesenteric ischemia,
radiation enteritis, and neoplasia. Because these conditions
may produce a secretory diarrhea without markers of inflammation in the stool, they must be considered in the differential
diagnosis of secretory diarrhea (see Chapters 40, 110 to 116,
118, 119, and 125 to 128).

Chronic Inflammatory Diarrhea
Sigmoidoscopy or colonoscopy with mucosal biopsies
Enteroscopy with mucosal biopsies
Exclusion of Tuberculosis, Parasites, and Viruses
Sigmoidoscopy or colonoscopy should be undertaken to

look initially for structural and histologic changes (Box 16-8).
Sigmoidoscopy can detect most causes of inflammatory diarrhea but may miss disorders localized to the right colon and
ileum. Because preparation for this test is simpler than that for
colonoscopy and the frequency of complications is lower, sigmoidoscopy is preferred by some physicians. Others prefer to
examine the entire colon and terminal ileum in patients with
inflammatory diarrhea, especially if occult blood is detected
in the stool.113 Whichever test is selected, biopsy specimens
must be obtained from the colon to aid in making the correct
diagnosis.
Infection can cause chronic inflammatory diarrhea or
aggravate existing inflammatory diarrhea caused by UC or
Crohns disease. The pathogens most likely to cause chronic
inflammatory diarrhea are C. difficile, cytomegalovirus, Entamoeba histolytica, Yersinia spp., and Mycobacterium tuberculosis;
C. difficile and cytomegalovirus are notorious for causing exacerbations of IBD (see Chapters 110 to 116).114 In addition to
biopsies, appropriate cultures and serologic tests should be
obtained to exclude these infections.
Chronic Fatty Diarrhea

Steatorrhea implies the disruption of fat solubilization,
digestion, or absorption in the small intestine. Evaluation
of chronic fatty diarrhea is designed to distinguish maldigestion (inadequate luminal breakdown of triglycerides) from
malabsorption (inadequate mucosal transport of the products
of digestion) (see Chapter 104).
The major causes of maldigestion are pancreatic exocrine
insufficiency (e.g., chronic pancreatitis) and lack of bile (e.g.,
advanced primary biliary cirrhosis). Mucosal diseases (e.g.,
celiac disease) are the usual causes of malabsorption. The
absolute amount of steatorrhea and the fecal fat concentration
(grams of fat/100g of stool) provide clues to the cause of
steatorrhea.115 The degree of steatorrhea tends to be higher
(often > 30g fat/day) with maldigestion, as in pancreatic
insufficiency, than with mucosal disease because of the greater
disruption of fat assimilation. Fecal fat concentration tends to
be higher with maldigestion than with mucosal disease. With
mucosal disease, fluid and electrolyte absorption may be
defective, and stool fat content is diluted by unabsorbed water.
Also, fat digestion usually is intact in mucosal disease, so
triglycerides are hydrolyzed to fatty acids that inhibit colonic
electrolyte and water absorption, further diluting the fat
content of stool.69 By contrast, triglyceride hydrolysis is
reduced in maldigestion and does not result in fatty acid
mediated inhibition of fluid and electrolyte transport, so in
maldigestion, unabsorbed fat is dispersed in a smaller stool
volume and is thus more concentrated. A fecal fat concentration over 9.5g/100g in a patient with suspected maldigestion
strongly suggests a pancreatic or biliary cause of steatorrhea.
Further evaluation of patients with chronic fatty diarrhea
is relatively straightforward (Box 16-9). The first step is to
look for a structural problem involving the small bowel or


Chronic Fatty Diarrhea
Small bowel biopsy and aspirate for quantitative culture
Exclusion of Pancreatic Exocrine Insufficiency

Empirical trial of pancreatic enzyme replacement therapy
Stool elastase or chymotrypsin concentration
Secretin test
Exclusion of Duodenal Bile Acid Deficiency

Empirical trial of bile acid replacement therapy
Postprandial duodenal aspirate for bile acid concentration
pancreas. The evaluation may include small bowel radiography or endoscopy with small bowel biopsy, CT, and MR
cholangiopancreatography. When a small bowel biopsy is performed, luminal contents should be aspirated and a sample
sent for quantitative culture to exclude small intestinal bacterial overgrowth. Because celiac disease is the most common
cause of mucosal disease that leads to malabsorption, tissue
transglutaminase antibodies and endomysial antibodies
should be determined (see Chapters 105 and 107).116
If no intestinal abnormalities are discovered or if radiographic evidence of chronic pancreatitis is detected, abnormal
pancreatic exocrine function should be considered. Available
tests of pancreatic function all have limitations (see Chapter
56). The secretin stimulation test, in which exogenous secretin
is used to stimulate the pancreas and bicarbonate output is
measured by aspiration of duodenal contents, is the most
time-honored of these tests but is rarely performed because
of its complexity.117 Combining the secretin stimulation test
with endoscopic retrograde cholangiopancreatography has
been attempted, but this modification has not been widely
adopted.118 Determination of pancreatic enzyme concentrations in stool has been advocated as a simpler screening test
for pancreatic exocrine insufficiency. Direct measurement of
stool chymotrypsin activity has poor sensitivity and specificity
in patients with chronic diarrhea.119 Measurement of fecal elastase has only somewhat better reliability.120 In reality, the best
way to determine pancreatic exocrine insufficiency may be a
therapeutic trial of pancreatic enzyme supplementation. If
such a trial is conducted, high doses of enzymes should be
prescribed, and some objective measurement like fecal fat
excretion or weight gain should be monitored to assess
response (see Chapter 59).121
Inadequate bile salt solubilization of dietary fat can usually
be inferred from the patients history or physical examination
(e.g., cholestatic jaundice, ileal resection, known enterocolic
fistula). If proof of the mechanism is required, analysis of a
postprandial duodenal aspirate can demonstrate reduced conjugated bile acid concentrations. This test may not be available
outside specialized centers, and a therapeutic trial of exogenous conjugated bile acids may be the best way of establishing
the diagnosis. Supplementation with bile acids reduces steatorrhea and can often improve the patients nutritional status
without aggravating diarrhea.122
TREATMENT
The most important treatment of diarrhea is to ensure that
fluid and electrolyte deficits are replenished with intravenous
fluids or oral rehydration therapy. Although oral rehydration
therapy is a convenient, inexpensive therapeutic option in
industrialized countries, its major impact has been in decreasing morbidity and mortality from cholera and other infectious
diarrheas in less developed countries.123 Because nutrient
absorption enhances sodium and fluid absorption in the
jejunum even when other forms of sodium absorption are
impaired, orally ingested saline solutions that contain glucose,
amino acids, or more complex nutrients that can be hydrolyzed at the brush border or intraluminally will be readily
absorbed. Although the earliest oral rehydration solutions
used glucose to accelerate sodium absorption, cereal-based
oral rehydration solutions are now thought to be superior.124
Modifications to the formula have included hypo-osmolarity
and use of amylase-resistant starch to enhance production of
short-chain fatty acids in the colon, thereby stimulating colonic
water and electrolyte absorption.125,126 Although oral rehydration solutions increase fluid and electrolyte absorption, they
do not reduce stool output, and stool weight may actually
increase with use of these solutions. Use of oral rehydration
solutions is precluded in patients who are vomiting frequently.
Most sport drinks (e.g., Gatorade) are designed to replenish
modest electrolyte losses from sweat and do not contain
enough sodium to adequately replace diarrheal losses. These
solutions can be used if additional sources of sodium and
absorbable nutrients (e.g., pretzels or crackers) are ingested
concomitantly. Solutions that more closely approximate the
World Health Organization oral rehydration solution or
cereal-based rehydration solutions are available commercially
(e.g., Rehydralyte, Resol, Ricalyte).
Empirical Therapy of Acute Diarrhea

Because infection is a frequent cause of acute diarrhea, empirical trials of antibiotic therapy are often considered by physicians.127 If the prevalence of bacterial or protozoal infection is
high in a community or a specific situation, empirical use of
an antibiotic is logical, as in the treatment of travelers diarrhea
with a fluoroquinolone or rifaximin, even without bacteriologic proof of infection.80 Empirical antibiotic therapy is often
used for more severely ill patients while bacterial culture
results are pending, but this approach has been called into
question. Patients in whom hemolytic-uremic syndrome
develops in response to infection with E. coli are more likely
to have received empirical antibiotic therapy than those
without hemolytic-uremic syndrome, although occurrence of
the syndrome may relate to the specific antibiotic and dose
prescribed.128 Experts also advise against empirical antibiotic
treatment of salmonellosis unless enteric fever is present.129
For patients with persistent diarrhea (lasting > 1 week),
an empirical trial of metronidazole or nitazoxanide for a
protozoal infection is sometimes considered (see Chapters
110 and 113).130
Nonspecific antidiarrheal agents can reduce stool frequency, stool weight, and coexisting symptoms like abdominal cramps (Table 16-5). Opiates such as loperamide or
diphenoxylate with atropine are frequently prescribed.131 The
concern that these antiperistaltic agents slow the clearance of
pathogens from the intestine has largely not been substantiated. Intraluminal agents such as bismuth subsalicylate
(Pepto-Bismol) and adsorbents (e.g., kaolin) may also help
reduce the fluidity of bowel movements. Racecadotril, a drug
that inhibits enkephalinase and thereby increases the effects
of endogenous opiates on the mu opiate receptor, is available
for the treatment of acute diarrhea in some countries.132
Empirical Therapy of Chronic Diarrhea

Empirical therapy is used in patients with chronic diarrhea
in 3 situations: (1) as temporizing or initial treatment before


TABLE 16-5 Nonspecific Drug Therapy for Chronic Diarrhea
Drug Class
Agent
Dose
Opiates (mu opiate receptor selective)
Codeine
Diphenoxylate
Loperamide
Morphine
Tincture of opium
15-60mg 4 times daily

2.5-5mg 4 times daily
2-4mg 4 times daily
2-20mg 4 times daily
2-20 drops 4 times daily
Enkephalinase inhibitor (delta opiate receptor effects)
Racecadotril* (acetorphan)
1.5mg/kg 3 times daily
2-Adrenergic agonist
Clonidine
0.1-0.3mg 3 times daily
Somatostatin analog
Octreotide
50-250g 3 times daily (subcutaneously)
Bile acidbinding resin
Cholestyramine
Colesevelam
Colestipol
4g 1 to 4 times daily
3 tabs twice daily
4g 1 to 4 times daily
Fiber supplement
Calcium polycarbophil
Psyllium
5-10g daily
10-20g daily
*Not yet approved in the United States.
diagnostic testing, (2) after diagnostic testing has failed to

confirm a diagnosis, and (3) when a diagnosis has been made
but no specific treatment is available or specific treatment has
failed to produce a cure. Generally, empirical antibiotic therapy
is less useful for chronic diarrhea than for acute diarrhea,
because infection is a much less likely cause. Although some
clinicians try an empirical course of metronidazole or a fluoroquinolone before committing a patient to extensive diagnostic testing, this approach is not supported by data and is not
recommended.
In the appropriate clinical setting, therapeutic trials of pancreatic enzyme replacement and conjugated bile acid supplementation in patients with unexplained steatorrhea may be
diagnostic and therapeutic (see earlier). By contrast, when
pancreatic enzyme supplements or bile acidbinding resins
are tried empirically for so-called idiopathic chronic diarrhea,
they rarely yield satisfactory results (see later).
Symptomatic treatment with an opiate is often necessary
in patients with chronic diarrhea, because specific treatment
may not be available.131 Potent opiates like codeine, opium, or
morphine are underused in the management of these patients,
largely because of fear of abuse. In fact, these agents are rarely
abused by patients with chronic diarrhea, especially if a few
simple measures are taken. First, the patient needs to be
informed about the abuse potential of the medication and
should be warned not to increase the dose without consulting
the physician. Second, the dose should be low initially and
titrated up until efficacy is achieved. Third, use of the opiate
should be monitored closely, and the prescription should not
be refilled until an interval appropriate with the anticipated
usage has passed.
Other agents sometimes used as nonspecific antidiarrheal
agents include octreotide and clonidine. Octreotide, a somatostatin analog, has been shown to improve diarrhea in
patients with the carcinoid syndrome and other endocrinopathies, dumping syndrome, chemotherapy-induced diarrhea,
and AIDS.133 The benefit in other diarrheal diseases is less
clear. Clonidine, an -adrenergic agent that has effects on
intestinal motility and transport,134 may have a special role in
diabetic diarrhea, but its hypotensive effect limits its usefulness in many patients with diarrhea.135 Crofelemer, an agent
approved by the U.S. Food and Drug Administration for
noninfectious diarrhea in AIDS patients on antiretroviral

therapy, inhibits 2 enterocyte chloride channelsthe cystic
fibrosis transmembrane regulator and calcium-activated chloride channeland thereby reduces chloride secretion.136
Whether or not crofelemer will be useful in other forms of
secretory diarrhea remains to be seen.
Interest in the use of probiotics as therapy for diarrhea
has been increasing, but evidence of effectiveness remains
limited.137 By modifying the colonic flora, these agents
may stimulate local immunity and speed resolution of travelers diarrhea, antibiotic-associated diarrhea, and infantile
diarrhea.138-140 Herbal remedies for diarrhea include those containing berberine (goldenseal, barberry), which appears to
stimulate fluid and electrolyte absorption, and arrowroot, the
mechanism of which is unknown.141,142
Stool-modifying agents such as psyllium alter stool consistency but do not reduce stool weight.143,144 They can be helpful
in patients with coexisting fecal incontinence and in some
patients with low stool weights (see earlier). The change from
watery to semiformed stools may be sufficient to alleviate
symptoms. In addition, pectin may delay transit through
the proximal intestine and increase luminal viscosity, thus
serving as an adjunctive empirical treatment. Calcium supplementation with 1 to 2g elemental calcium daily may be simple
and effective therapy.
SELECTED DIARRHEAL SYNDROMES

IBS and Functional Diarrhea
The most common diagnosis made in patients with chronic
diarrhea is IBS, yet only a fraction of patients with chronic
diarrhea actually meet the criteria for the diagnosis of IBS, for
which abdominal pain is a central feature.81,145 In the past,
painless diarrhea was considered to be a subtype of IBS,
but such patients are now classified as having functional
diarrhea.
Diarrhea in patients with IBS tends to be variable and
sometimes alternates with periods of constipation.81 When
measured, daily stool output is relatively low, typically less
than 400g/24hr. Consistency varies from loose to soft and


rarely is watery. The diarrhea does not awaken patients from
sleep. Rectal urgency and fecal incontinence may be pronounced, especially during periods of psychological stress.
Weight loss and evidence of chronic illness are uncommon
(see Chapter 122). In some patients, IBS seems to be a late
consequence of acute gastroenteritis.146
When typical features of IBS are absent, other diagnoses
should be considered. One alternative diagnosis is carbohydrate malabsorption, which can produce diarrhea of variable
severity depending on the amount of the malabsorbed carbohydrate consumed.147 Cramps, excessive flatus, and bloating
may also be present with carbohydrate malabsorption. A carefully taken dietary history may reveal specific dietary triggers,
but sometimes nonspecific dietary restriction, such as a diet
low in FODMAPs, can be helpful. Another condition that can
simulate IBS is small intestinal bacterial overgrowth. The diagnosis of this condition is complex and controversial (see
earlier).102 Bile acidinduced diarrhea can also vary in severity,
depending on the rate of delivery of bile acids to the colon.
Response to a therapeutic trial of a bile acidbinding resin may
be a reasonable diagnostic test for this condition (see later).
Celiac disease is another diagnosis often considered but is
found in only 3% to 5% of patients who meet criteria for a
diagnosis of IBS.148 Most patients with other causes of chronic
diarrhea have been misdiagnosed as having IBS at some point
before the correct diagnosis is discovered.
Microscopic Colitis
Microscopic colitis includes 2 entities: collagenous colitis and
lymphocytic colitis. These disorders are defined as a syndromes of watery diarrhea characterized by a normal colonoscopic appearance and histologic changes of lymphocytic and
plasmacytic inflammation in the lamina propria and intraepithelial lymphocytosis, with or without thickening of the subepithelial collagen table (see Chapter 128).149,150 Microscopic
colitis is a fairly common cause of chronic diarrhea of obscure
origin in the general population, as well as at referral centers.
At a tertiary referral center, microscopic colitis was discovered
in 10% of patients with chronic diarrhea, with an even division
between the lymphocytic and collagenous subtypes.107 A
population-based epidemiologic study in Sweden has shown
that the annual incidence of microscopic colitis is similar to
that of Crohns disease, and the disorder was diagnosed in
10% of patients who presented with chronic nonbloody diarrhea.151 Obtaining a sufficient number (6 to 10) of biopsies of
normal-appearing colonic mucosa in patients who present
with chronic watery diarrhea is critical to diagnosis.
The cause (or causes) of microscopic colitis remains
unknown. The disease occurs most frequently in middle-aged
women and often occurs in association with autoimmune diseases like arthritis and hypothyroidism. A history of nonsteroidal anti-inflammatory drug use is frequent. Most fascinating
is the tight linkage of lymphocytic and collagenous colitis with
human leukocyte antigen (HLA)-DQ2 and HLA-DQ1,3
(including the HLA-DQ1,3 subtypes HLA-DQ1,7, HLADQ1,8, and HLA-DQ1,9) as in celiac disease, suggesting
the possibility that the immune mechanisms involved in the
pathogenesis of microscopic colitis and celiac disease are
similar.152 In fact, microscopic colitis has been associated with
celiac disease and may be a cause of persistent diarrhea in
patients with celiac disease who are treated with a gluten-free
diet.153 Gluten is almost certainly not the causative antigen in
microscopic colitis, however, because many patients with
celiac disease continue to have histologic evidence of lymphocytic colitis despite treatment with a gluten-free diet, and
elimination of gluten from the diet is not effective in other
patients with microscopic colitis.154 Bacterial antigens in the

colonic lumen, rather than dietary antigens, may play an
important pathogenic role in microscopic colitis.
Whatever the cause, mucosal inflammation is largely
responsible for the diarrhea of microscopic colitis. Colonic
perfusion studies have shown that absorption of water and
salt is impaired in lymphocytic colitis and collagenous colitis.155
In vitro studies using human colon specimens have demonstrated decreases in sodium chloride absorption accompanied
by changes in diffusion and the function of tight junctions.156
Colonic water absorption correlates inversely with the cellularity of the lamina propria, but not with the thickness of the
collagen table. Net secretion of water and salt by the colon is
not noted frequently, however. Typical stool weights of 500 to
1000g/24hr are consistent with little or no fluid absorption
by the colon. Bile acid malabsorption may also play a role in
the pathogenesis of diarrhea in this condition.157
A Cochrane analysis of interventions for treating collagenous colitis has concluded that budesonide has the best
evidence for efficacy.158 Less well-established agents for the
treatment of collagenous colitis include bismuth subsalicylate, mesalamine, and prednisone. Studies of budesonide in
the treatment of lymphocytic colitis are fewer in number, and
the overall evidence in support of a benefit is weaker.159
Immunosuppressants such as azathioprine are recommended
for refractory cases.160 Microscopic colitis remits in most
patients with time, and symptomatic therapy with an antidiarrheal drug may be an appropriate option.161 Bile acid
sequestrants also may improve diarrhea in patients with this
condition.157
Postsurgical Diarrhea
GI and biliary tract surgical procedures produce a number of
changes in intestinal function that may lead to diarrhea.
Although surgery for peptic ulcer is performed much less
commonly now than in the past, other operations performed
on the GI and biliary tracts continue to be complicated by
diarrhea.
Diarrhea after Gastric Surgery

For many years, peptic ulcer was treated surgically by vagotomy with pyloroplasty or antrectomy (see Chapter 53). The
introduction of highly selective vagotomy in the 1980s led to
a decrease in the frequency of postoperative diarrhea. The
more traditional surgeries are still done for obstructing or
malignant ulcer disease. In addition, the use of gastric bypass
surgery for the treatment of obesity has increased dramatically
(see Chapter 8). This operation and other bariatric surgeries
are commonly associated with digestive symptoms, including
diarrhea.162 Diarrhea can also occur as a complication of laparoscopic antireflux surgery, presumably because of accidental
vagotomy (see Chapter 44).163
The most common syndrome seen after gastric surgery is
dumping syndrome, a condition characterized by postprandial
flushing, hypotension, diarrhea, and hypoglycemia (see
Chapter 53). This syndrome results from unregulated gastric
emptying, osmotic shifts, and the rapid release of peptide
hormones from the intestine164 and can be treated successfully
with a modified diet, antidiarrheal drugs, and the somatostatin analog octreotide.165 Gastric surgery may also predispose
patients to small intestinal bacterial overgrowth, abnormally
rapid intestinal transit, bile acid malabsorption, and pancreatic exocrine insufficiency as a result of poor stimulation of
pancreatic secretion and/or inadequate mixing of pancreatic
enzymes with intestinal contents.

Diarrhea after Bowel Resection

Loss of intestinal surface area promotes malabsorption of
fluid, electrolytes, or nutrients, depending on the portion
of bowel resected. The bowel is endowed with an excess of
absorptive surface for normal nutrient loads. Diarrhea develops when resection of the small intestine leaves insufficient
surface area for normal absorption, so-called short bowel syndrome (see Chapter 106).166 Intestinal adaptation may lead to
improved intestinal electrolyte absorption with time but
cannot overcome defects in specialized functions.167 For
example, removal of the ileocecal area limits the ability of the
intestine to absorb sodium against an electrochemical gradient, a defect that cannot be overcome elsewhere in the intestine (see Chapter 101).35 Ileal resection may also compromise
conjugated bile acid absorption and result in bile acid
mediated fluid and electrolyte secretion by the colon.168
Various approaches can be used to correct nutritional deficiencies and intestinal dysfunction in patients with short bowel
syndrome (see Chapter 106).
Ileostomy Diarrhea
Normally, 1 to 1.5L of fluid enters the colon from the small
intestine each day; an ileostomy diverts this fluid from the
body. Adaptation eventually results in a decrease in flow from
the small intestine to an average of 750mL daily, provided the
patient has a sufficient length of functioning small bowel. This
excess daily fluid loss is usually readily overcome by an
increase in oral intake, but patients with ileostomies tolerate
abnormally increased fluid losses poorly and are at risk of
dehydration under such circumstances. Ileostomy diarrhea is
said to be present when fluid losses exceed 1000mL daily (see
Chapter 117).169
Causes of ileostomy diarrhea include stomal stenosis,
partial small bowel obstruction, small intestinal bacterial overgrowth, recurrent IBD, recurrent tumor proximal to the stoma,
medication-associated diarrhea, and intraperitoneal infection.
In most cases, no specific cause is identified. A special circumstance occurs in patients with an ileal pouch formed to create
a continent ileostomy or an ileoanal anastomosis after colectomy for UC in whom inflammation of the pouch, so-called
pouchitis, caused by bacterial overgrowth or recurrent IBD
may develop.170 This condition is treated with an antibiotic
such as metronidazole, probiotics, or an anti-inflammatory
drug such as mesalamine.
Idiopathic ileostomy diarrhea is treated with antidiarrheal
drugs; high doses of potent opiates may be necessary. Octreotide is used if control with potent opiates is suboptimal. If
ileostomy output exceeds 2000mL daily, supplemental oral
rehydration solution or intravenous fluid may have to be provided to prevent dehydration and maintain normal urine
output.
Postcholecystectomy Diarrhea
Postcholecystectomy diarrhea is relatively common, occurring
in up to 20% of patients after cholecystectomy.171,172 It usually
occurs shortly after cholecystectomy, but the onset may be
delayed. The conventional explanation for postcholecystectomy diarrhea relates to changes in the enterohepatic cycling
of bile acids, but evidence in support of this mechanism is
limited. The gallbladder provides a nocturnal reservoir for bile
acids when they are not needed for digestion of fat. When the
gallbladder is removed, enterohepatic cycling of bile acids
continues at night, and a substantial portion of the bile acid
pool remains within the small bowel at all times. Every 90
minutes during fasting, the migrating myoelectric complex
passes through the small intestine and rapidly sweeps intestinal contents, including much of the bile acid pool in these
cases, past the specialized absorptive sites in the ileum and
into the colon. Increased concentrations of bile acids in the
colonic lumen may inhibit fluid and electrolyte absorption and
accelerate transit. Alternatively, bacterial deconjugation of bile
acids in the small bowel may increase and thereby decrease
ileal absorption. Some but not all studies have confirmed
increased fecal bile acid excretion in patients with postcholecystectomy diarrhea. Postcholecystectomy diarrhea is best
treated with bile acid binders taken at bedtime, and perhaps
at other times during the day as well. Opiate antidiarrheal
agents can also be helpful for refractory cases.
Bile AcidInduced Diarrhea

Bile acid malabsorption has been well described as the mechanism of diarrhea when ileal disease or resection allows excessive amounts of conjugated bile acid to enter the colon.
Concentrations of bile acid in the colon higher than 3 to
5mmol/L can inhibit electrolyte absorption and stimulate
secretion by the colonic mucosa.173 The importance of bile acid
malabsorption as a mechanism for producing chronic secretory diarrhea in the absence of ileal resection or disease is
controversial.174-176
In rare congenital cases, primary bile acid malabsorption
is caused by mutations in the ileal sodium-dependent bile acid
transporter gene (see Chapter 64), but most cases of adultonset bile acid malabsorption are not associated with a discrete molecular defect.177-179 Studies have suggested that bile
acid diarrhea is related to an expanded bile acid pool, with an
excess amount of bile acids overwhelming the absorptive
capacity of the ileum and causing colonic secretion.180 The
expanded bile acid pool may be due to decreased levels of
fibroblast growth factor (FGF)19, which normally represses
hepatic bile acid synthesis.181 Why FGF19 levels are abnormal
is unknown.
The clinical approach to possible bile acid diarrhea is problematic. In Europe, the selenium-75 labeled homotaurocholic
acid (SeHCAT) retention test can be used to test for bile acid
malabsorption. (This test is not available in the United States.)
If strict diagnostic criteria are used (<5% retention at 1 week),
the test can predict responsiveness to bile acidbinding drugs.6
The test is less reliable when less stringent criteria are
employed; diarrhea itself may make the test abnormal.182
Direct measurement of fecal bile acid output involves complicated research methods not applicable to clinical use and does
not predict response to bile acid binders in patients with
chronic diarrhea.183 In patients with undiagnosed idiopathic
diarrhea, it may be worthwhile to prescribe an empirical trial
of a bile acidsequestering resin. If the medication controls the
diarrhea, bile acid malabsorption may be playing a role.
Because such agents may also bind toxins or other luminal
agonists, the possibility of a nonspecific effect must be
considered.
Diarrhea in Hospitalized Patients

Diarrhea frequently develops during hospitalization, particularly in severely ill patients hospitalized for protracted periods.
Common causes of diarrhea in this setting include medications (especially antibiotics), tube feedings, intestinal ischemia, and fecal impaction.
Diarrhea is a side effect of many medications, including
those frequently used in hospitalized patients (see Box 16-4).72
Antibiotic therapy is particularly likely to cause diarrhea by
at least 2 mechanisms: impairing carbohydrate metabolism
by the colonic bacterial flora and facilitating overgrowth of


C. difficile and production of toxins by the bacteria.184 In some
cases, erythromycin produces diarrhea by its motilin-like
effect on GI transit.
Impaired bacterial metabolism can cause diarrhea by
allowing carbohydrates and associated water to remain in the
intestinal lumen.185 Ordinarily, all dietary fiber and about 20%
of wheat starch evade digestion and intestinal absorption and
reach the colon. Colonic bacteria ferment these carbohydrates
to short-chain fatty acids, hydrogen, and carbon dioxide.
These fermentation products and associated water are rapidly
absorbed by the colon, so diarrhea does not result. By contrast,
when an antibiotic kills some of the normal colonic flora, fermentation decreases; undigested fiber and carbohydrates as
well as water are retained in the lumen, leading to an osmotic
diarrhea. In some persons, intestinal transit may be modified
by illness or by other drugs given concomitantly, leading to
greater delivery of carbohydrate to the colon and further
aggravating the diarrhea. Such diarrhea should subside when
the patient is fasting.
C. difficilerelated diarrhea is a more serious concern.186
Hospitalized patients and residents of nursing homes are
likely to be colonized by this organism; some 20% of hospitalized patients become colonized with C. difficile. Physical proximity and poor hand hygiene are major factors in its spread
within institutions. Factors precipitating diarrhea in this condition include antibiotic therapy, chemotherapy, and altered
immunity, including reduced gastric acidity resulting from
administration of a proton pump inhibitor.187 C. difficilerelated
disease ranges in severity from modest diarrhea to lifethreatening colitis, particularly when patients are colonized
with a virulent strain of C. difficile or have underlying IBD (see
Chapter 112). Patients may have severe abdominal pain, tenderness, and marked polymorphonuclear leukocytosis, with
an increased percentage of immature forms. In less severely
ill patients suspected of having this infection, stool should be
tested for C. difficile, and if the result is positive, appropriate
antibiotic therapy should be initiated. In more severely ill
patients, analysis of stool samples for C. difficile may not be
sufficient,188 and sigmoidoscopy is performed to identify the
characteristic findings of pseudomembranous colitis. Occasionally the colitis is evident only more proximally in the
colon, and colonoscopy is required to confirm the diagnosis.
Therapy with metronidazole, vancomycin, or fidaxomicin
often suppresses the diarrhea, but recurrence is common
because the organism forms spores.189 Probiotics, toxinabsorbing resins, and vaccines are being studied as ways to
reduce recurrence.86 Fecal bacteriotherapy (fecal microbiota
transplantation) has had remarkable success in clearing recurrent disease in initial clinical trials (see Chapter 130).190
Diarrhea can be a complication of enteral nutrition,
although it is often the result of coexisting problems.191 Tube
feeding, although more physiologic than parenteral nutrition,
is still different from the normal presentation of nutrients to
the intestine by oral ingestion of food, and the regulatory
system of the GI tract may not adapt. Some tube feeding formulas are hypertonic and may induce diarrhea by a mechanism similar to that of dumping syndrome. In such cases, a
change in formula to one that is isotonic may be of benefit. In
other cases, slowing the rate of infusion and thereby decreasing the delivery of nutrients to the intestine may be helpful,
but this approach may be of limited value if the patients
nutritional needs are not being met at the slower rate of infusion. Addition of an antidiarrheal agent such as loperamide or
tincture of opium to the tube feeding may be necessary,
although this approach has limitations, especially for patients
in whom ileus is a risk (see Chapter 124).
Intestinal ischemia may develop in some hospitalized
patients, especially those with hypotension or shock.192 These
patients are at risk of developing bloody diarrhea caused by

ischemic colitis or more profound diarrhea if small intestinal
ischemia develops (see Chapter 118).
The risk of fecal impaction is increased in older adults,
patients on prolonged bowel rest, and those taking constipating drugs. Paradoxical or overflow diarrhea with incontinence
may be the first clue to an impaction. Hospitalized patients in
whom diarrhea develops should undergo a digital rectal
examination to exclude fecal impaction (see Chapter 18).8
Factitious Diarrhea
Surreptitious laxative abuse should be considered for persons
in whom diarrhea remains undiagnosed, especially in those
who fit into 1 of the following 4 categories (Table 16-6): (1)
patients with anorexia nervosa or bulimia who use laxatives
as a way of adjusting body weight (see Chapter 9), (2) those
who use laxative-induced illness for secondary gain (e.g., disability income) or to generate concern in other persons, (3)
patients with Munchausens syndrome who feign illness to
confound physicians, and (4) persons who are being poisoned
with laxatives by their caregivers (see Chapter 23).193,194
A high index of suspicion is required for detecting laxative
abuse. Physicians usually assume patients are being truthful,
but up to 15% of patients who undergo evaluation for chronic
diarrhea may be surreptitiously abusing laxatives.195 Clues to
laxative abuse may be found during the evaluation for chronic
diarrhea. For example, hypokalemia may suggest ingestion of
stimulant laxatives like senna. Detection of pseudomelanosis
coli, a brownish pigmentation of the colonic mucosa, suggests
chronic ingestion of anthraquinone laxatives like senna or
cascara (see Chapter 128). Presence of a large fecal osmotic gap
suggests magnesium ingestion. A negative osmotic gap may
indicate ingestion of poorly absorbed polyvalent anions like
phosphate or sulfate.
In patients who belong to 1 of the groups listed in Table
16-6 and in those with diarrhea that remains undiagnosed
after evaluation, stool samples should be analyzed for laxatives with standardized methods. Most laxatives can be
detected by spectrophotometry or chromatography, but the
accuracy of commercial analysis has been called into question.96 Because some patients exaggerate stool volume by
TABLE 16-6 Conditions in Patients Predisposed to
Laxative Abuse
Condition
Characteristics
Bulimia
Usually adolescent to young women;

concerned about weight or manifesting
an eating disorder; may binge eat,
vomit, or exercise excessively to
neutralize excessive food intake
Munchausens
syndrome
Patients who relish being a diagnostic

challenge; may repeatedly undergo
extensive testing
Polles syndrome
(Munchausens
syndrome by proxy)
Dependent child or adult poisoned with

laxatives by parent or caregiver to
show effectiveness as caregiver; may
have history of sibling who died with
chronic diarrhea
Secondary gain
Patients may have disability claim

pending; illness may induce concern or
caring behavior in others


adding urine or water, stool osmolality should be measured
as well; a value lower than 290mOsm/kg suggests dilution
of the stool with water or hypotonic urine. Admixture of stool
with hypertonic urine often leads to an impossibly high fecal
osmolality (typically > 600mOsm/kg) and to a negative fecal
osmotic gap because of high concentrations of sodium and
potassium in the urine. A negative fecal osmotic gap can also
be noted when phosphate or sulfate osmotic laxatives are
ingested. In the current legal environment, unauthorized
room searches for laxatives should not be conducted.
When a diagnosis of laxative abuse is made, an effort
should be made to confirm the diagnosis with repeated stool
analyses before discussion with the patient or family. The
patient should be confronted with the findings, but not before
plans for the aftermath are made. Psychiatric consultation
should follow the discussion with the patient; some persons
who abuse laxatives become suicidal after being discovered,
and all patients who abuse laxatives need counseling. In cases
of laxative administration by a parent or caregiver, legal proceedings should be instituted to separate the patient from the
abuser (see Chapter 23).
Few outcome studies of the effect of discovery of laxative
abuse are available. In 1 small study of 11 patients, 6 said they
were improved, and 5 claimed no benefit; 4 of the 5 unimproved patients sought further medical attention elsewhere
for chronic diarrhea.196
Idiopathic Secretory Diarrhea

When an exhaustive evaluation fails to reveal a cause of
chronic diarrhea and stool analysis suggests a secretory diarrhea, the diagnosis of idiopathic secretory diarrhea is made.
This condition often starts suddenly in a previously healthy
person and is differentiated from the many similar acute diarrheal illnesses by persisting beyond 4 weeks. It occurs in 2
forms, epidemic and sporadic.76,77
The epidemic form of secretory diarrhea occurs in outbreaks seemingly linked to contaminated food or drink.76,197-201
The initial description of this condition resulted from an outbreak in Brainerd, Minnesota, thus its common appellation
Brainerd diarrhea. Several outbreaks have been described in the
literature in different communities and even on a cruise ship.
Although the epidemiology suggests an infectious cause, no
causative agent has been identified in these outbreaks.
Sporadic idiopathic secretory diarrhea affects persons in a
fashion identical to that of the epidemic form but does not
seem to be acquired easily by family members or others.77
Many affected persons give a history of travel, but to destinations not usually associated with travelers diarrhea. Diarrhea
begins abruptly and reaches its maximum intensity soon after
onset. Weight loss of up to 20 pounds is characteristic and
almost always occurs within the first few months of illness and
not thereafter. Empirical trials of antibiotics and bile acid
binding resins are ineffective. Nonspecific opioid antidiarrheal
agents may provide symptomatic improvement.
Both forms of idiopathic secretory diarrhea have a selflimited course and usually resolve within 2 years of onset. The
resolution of idiopathic secretory diarrhea occurs gradually
over 2 to 3 months. Understanding this natural history can be
a solace to patients, who may otherwise feel mired in an
unending illness. Idiopathic secretory diarrhea may share
several clinical characteristics with functional diarrhea but in
general has a more discrete onset and is associated with higher
stool volumes.
Diarrhea of Obscure Origin

Physicians sometimes fail to make a specific diagnosis in
patients with chronic diarrhea, despite an elaborate
BOX 16-10 Frequent Diagnoses in Patients with Diarrhea

of Obscure Origin
Bile acidinduced diarrhea
Carbohydrate malabsorption
Chronic idiopathic secretory diarrhea
Fecal incontinence
Functional diarrhea
Iatrogenic diarrhea (drugs, surgery, radiation)
IBS
Microscopic colitis
Peptide-secreting tumors
SIBO
Surreptitious laxative ingestion
evaluation, and may refer these patients to centers interested

in this condition. Common diagnoses resulting from reevaluation of these patients are shown in Box 16-10.
Although unusual or obscure conditions that require
special tests may be expected to predominate in this group of
patients, most eventual diagnoses are straightforward and
might have been made sooner.107 Fecal incontinence and iatrogenic diarrhea could be recognized with a careful history.
Surreptitious laxative ingestion and microscopic colitis could
be diagnosed with an appropriate index of suspicion and
testing (laxative screen and colonic biopsies, respectively). Bile
acidinduced diarrhea, small intestinal bacterial overgrowth,
pancreatic exocrine insufficiency, and carbohydrate malabsorption could be discovered with a detailed history and a
properly conducted therapeutic trial. Peptide-secreting tumors
are rare, but serum peptide assays and imaging techniques
(e.g., CT, octreotide scanning) are widely available. Failure to
make a diagnosis typically results from failure to appreciate
the evidence at hand and to think through the differential
diagnosis of chronic diarrhea.
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CHAPTER

Further Evaluation of Acute Diarrhea.......................................... 230

Osmotic Diarrhea...................................................................... 222

Selected Diarrheal Syndromes...................................................236

Acute versus Chronic Diarrhea................................................... 226

IBS and Functional Diarrhea...................................................... 236

Empirical Therapy of Acute Diarrhea.......................................... 235

defined solely in terms of fecal weight. Some persons have

Descargado de ClinicalKey.es desde Univ Antioquia julio 20, 2016.

222 Section III Symptoms, Signs, and Biopsychosocial Issues

(290mOsm/kg). Therefore, about 3.5mL of water (1000mL/

Descargado de ClinicalKey.es desde Univ Antioquia julio 20, 2016.

Chapter 16 Diarrhea 223

from that for lactase-phlorizin hydrolase (the gene affected in

surface of the enterocyte that normally mediates the effect of

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224 Section III Symptoms, Signs, and Biopsychosocial Issues

Although classification of diarrhea as osmotic or secretory

Further complicating an understanding of diarrhea is

Abnormal motility may lead to diarrhea that has secretory

FIGURE 16-2. ALPINES regulatory system in the intestine. The

Descargado de ClinicalKey.es desde Univ Antioquia julio 20, 2016.

Chapter 16 Diarrhea 225

Another example of dysregulation of ALPINES is IBD.54

function.63 Inflammation may induce significant changes in

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226 Section III Symptoms, Signs, and Biopsychosocial Issues

Acute versus Chronic Diarrhea

Large-Volume versus Small-Volume Diarrhea

Osmotic versus Secretory Diarrhea

absorbable solutes within the intestinal lumen account for

Watery versus Fatty versus

BOX 16-1 Likely Causes of Diarrhea in Well-Defined

Epidemics and Outbreaks

Patients with Diabetes Mellitus

Patients with AIDS

Institutionalized and Hospitalized Patients

Descargado de ClinicalKey.es desde Univ Antioquia julio 20, 2016.

Chapter 16 Diarrhea 227

BOX 16-3 Infections That Cause Diarrhea

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228 Section III Symptoms, Signs, and Biopsychosocial Issues

malabsorption leads to fluid retention within the lumen, is

fluid past absorptive sites in the intestine (see Chapters 36,

Descargado de ClinicalKey.es desde Univ Antioquia julio 20, 2016.

Chapter 16 Diarrhea 229

absorbable carbohydrate or malabsorption of carbohydrate by

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230 Section III Symptoms, Signs, and Biopsychosocial Issues

TABLE 16-3 Management of Acute Diarrhea Based on

Symptomatic therapy, rehydration

Fluid and electrolyte repletion

Endocrine tumor, amyloidosis

From Ref 202.

Further Evaluation of Acute Diarrhea

in stool and may be a useful alternative to microscopy.83

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Chapter 16 Diarrhea 231

Because the differential diagnosis of chronic diarrhea is more

Further Evaluation of Chronic Diarrhea

measurement of stool osmolality is of value only in detecting

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232 Section III Symptoms, Signs, and Biopsychosocial Issues