Schiller Et Al-2014-Journal of Gastroenterology and Hepatology

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doi:10.1111/jgh.12392
W C O G 2 0 1 3 W O R K I N G PA RT Y R E P O RT
Gastro 2013 APDW/WCOG Shanghai Working Party Report:

Chronic diarrhea: Definition, classification, diagnosis
Lawrence R Schiller,* Darrell S Pardi, Robin Spiller, Carol E Semrad, Christina M Surawicz,
Ralph A Giannella,** Guenter J Krejs, Michael J G Farthing and Joseph H Sellin
*Baylor University Medical Center, Texas A&M University, Dallas, Texas, Mayo Clinic, Rochester, Minnesota, University of Chicago, Chicago,
Illinois, University of Washington, Seattle, Washington, **University of Cincinnati, Cincinnati, Ohio, and Baylor College of Medicine, Houston,
Texas, USA; Nottingham Digestive Diseases Centre, Queens Medical Centre, Nottingham, and University of Sussex, Brighton, UK and
Medical University of Graz, Graz, Austria
Key words
clinical intestinal disorders < gastroenterology,
diarrhea and malabsorption <
gastroenterology, intestinal disorders <
gastroenterology.
Accepted for publication 27 August 2013.
Correspondence
Dr Lawrence R. Schiller, Digestive Health
Associates of Texas, 712 North Washington
Avenue, #200, Dallas, TX 75248, USA. Email:
LRSMD@aol.com
Abstract
Diarrhea is best defined as passage of loose stools often with more frequent bowel
movements. For clinical purposes, the Bristol Stool Form Scale works well to distinguish
stool form and to identify loose stools. Laboratory testing of stool consistency has lagged
behind. Acute diarrhea is likely to be due to infection and to be self-limited. As diarrhea
becomes chronic, it is less likely to be due to infection; duration of 1 month seems to
work well as a cut-off for chronic diarrhea, but detailed scientific knowledge is missing
about the utility of this definition. In addition to duration of diarrhea, classifications by
presenting scenario, by pathophysiology, and by stool characteristics (e.g. watery, fatty, or
inflammatory) may help the canny clinician refine the differential diagnosis of chronic
diarrhea. In this regard, a careful history remains the essential part of the evaluation of a
patient with diarrhea. Imaging the intestine with endoscopy and radiographic techniques
is useful, and biopsy of the small intestine and colon for histological assessment provides
key diagnostic information. Endomicroscopy and molecular pathology are only now
being explored for the diagnosis of chronic diarrhea. Interest in the microbiome of the gut
is increasing; aside from a handful of well-described infections because of pathogens,
little is known about alterations in the microbiome in chronic diarrhea. Serological tests
have well-defined roles in the diagnosis of celiac disease but have less clearly defined
application in autoimmune enteropathies and inflammatory bowel disease. Measurement
of peptide hormones is of value in the diagnosis and management of endocrine tumors
causing diarrhea, but these are so rare that these tests are of little value in screening
because there will be many more false-positives than true-positive results. Chemical
analysis of stools is of use in classifying chronic diarrhea and may limit the differential
diagnosis that must be considered, but interpretation of the results is still evolving. Breath
tests for assessment of carbohydrate malabsorption, small bowel bacterial overgrowth,
and intestinal transit are fraught with technical limitations that decrease sensitivity and
specificity. Likewise, tests of bile acid malabsorption have had limited utility beyond
empirical trials of bile acid sequestrants.
Introduction
Diarrhea is a common symptom of many different disturbances of
gut function. It has been estimated that the average individual
living in an industrialized country has an episode of acute diarrhea
every 18 months. Chronic diarrhea is less frequent; 35% of the
population may have diarrhea lasting more than 1 month in any
given year.1,2 Incidence rates may be higher in places with less
advanced sanitation systems, but this point has not been well
studied.
6
The physicians goals are to mitigate the symptom and its potential complications, such as dehydration, to sort out the many conditions that may cause self-limited diarrhea from those that require
therapy and to provide effective treatment for the underlying
problem. These goals are particularly challenging when diarrhea
becomes chronic and therefore less likely to resolve spontaneously. Diagnosis is difficult in part because of the variety and
number of diagnostic studies that can be applied to these patients.
In an effort to help practitioners with the diagnosis of chronic
diarrhea, the American College of Gastroenterology proposed
Journal of Gastroenterology and Hepatology 29 (2014) 625

2013 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd
LR Schiller et al.
creation of a working party to the World Gastroenterology

Organisation for the 2013 World Congress of Gastroenterology in
Shanghai to examine the definition, classification, and diagnosis of
chronic diarrhea. One major goal of this working group was to
examine the evidence behind definitions of chronic diarrhea and to
develop consensus definitions for this symptom complex. Another
goal was to establish classification schemes for chronic diarrhea to
assist with more expeditious evaluation of patients. Finally, we
made an attempt to assess diagnostic tests used in patients with
chronic diarrhea to allow gastroenterologists to make an informed
selection of these tests, thereby leading to more cost-effective
management for these patients. Throughout this report, gaps
in knowledge and opportunities for clinical research will be
highlighted.
Definition of chronic diarrhea

The dictionary definition of diarrhea is an intestinal disorder
characterized by abnormal frequency and fluidity of fecal evacuations.3 Despite this fairly simple definition, diarrhea means different things to different individuals.
Most patients consider loose stoolsmore than frequencyas
the key characteristic of diarrhea.4 Patients may report diarrhea as
being present when stools are looser than normal (i.e. liquid or
unformed), even when stool frequency is not increased. The
Bristol Stool Form Scale (Fig. 1) works well in the clinic to assess
consistency and correlates roughly with intestinal transit times.5,6
Stool consistency is difficult to quantitate with laboratory tests
though and reports of the degree of looseness are subjective.4
Increased stool frequency is easier to quantitate, and this characteristic is often used by physicians as the sole definition of
Chronic diarrhea
diarrhea.1 Stool frequency depends in large part on diet and varies

considerably from person to person. On average, normal individuals on a typical American diet produce 25 bowel movements per
month.7 The range of normal is said to be from two or three bowel
movements per day to three bowel movements per week depending upon diet.1 Among patients presenting to a tertiary hospital for
evaluation of chronic diarrhea who were found to have normal
stool weights (< 200 g/24 h), some patients had high frequency
evacuations with minimal change in consistency, while others had
unformed stools with normal bowel movement frequency.8
Patients with higher stool weights tended to have both loose stools
and increased frequency. This suggests that while stool frequency
and consistency may be independently determined when stool
weight is low, the increased water content characteristic of more
voluminous diarrheas tends to change both measures.8
Stool weight is often used in scientific definitions of diarrhea.
On average, normal individuals in Western countries produce
approximately 100 g of stool per day, with the upper limit of the
95% confidence interval set at roughly 200 g/day. Higher stool
outputs can be normal if the diet is loaded with fiber as in other
parts of the world: outputs as high as 300 g may be normal when
a high-fiber diet is consumed.7 Conversely, about 20% of patients
referred to one tertiary referral center for chronic diarrhea had a
normal stool weight.8 This may reflect frequent small bowel movements, variation in daily frequency, or the presence of fecal incontinence. Urgency and fecal incontinence may drive patient
perception of the severity of diarrhea and often go unvoiced if
not specifically elicited by the physician.9 Because the leading
component of stool weight is stool water, increased stool weight is
largely driven by increased stool water output.4 This, in turn,
depends on the underlying pathophysiology-causing diarrhea, and
so stool weight is a surrogate for the severity of the abnormalitycausing diarrhea (but may not reflect the impact of the disease on
the patient).
This review focuses on chronic diarrhea. The duration of diarrhea may be used as a clue to etiology. Acute diarrhea typically is
due to bacterial or viral infections that run a course of a week or
less.1 Most of these cases are either self-limited or are easily
treated with antimicrobials. Persistent diarrhea (duration 24
weeks) has been distinguished mainly by pediatric gastroenterologists and raises the question of a protozoal infection.10 Even these
infections frequently abate within 1 month of onset. A duration of
4 weeks or more has been set arbitrarily as the threshold duration
for a diagnosis of chronic diarrhea by several sources.1,10 Although
some infections, such as those because of Clostridium difficile,
Aeromonas, or Yersinia, may last longer than 4 weeks, most
patients with diarrhea lasting longer than 4 weeks will be found to
have a non-infectious cause of their problem.
Most of the studies used to define a 4-week cut-off for a diagnosis of chronic diarrhea were done in industrialized countries.
Information from less developed parts of the world is needed to
evaluate how practical such a cut-off is in those regions.
Classification
Figure 1
Bristol Stool Form Scale.
The differential diagnosis for chronic diarrhea is enormous, with

a large number of diagnostic tests available that can be used to
evaluate these patients. Classifying the patient with chronic diarrhea into a subcategory helps to direct the diagnostic work-up,

Chronic diarrhea
Table 1
LR Schiller et al.
Classification of chronic diarrhea
Osmotic
Medications
Laxatives (Mg, SO4, PO4), elixirs
Undigested sugars
Diet foods/drinks/gum (sorbitol, mannitol, others)
Enzyme dysfunction (e.g. lactose, fructose)
Secretory
Medications
Non-osmotic laxatives, antibiotics, many others
Small intestinal bacterial overgrowth
Endocrine:
Tumors: carcinoid, gastrinoma, medullary thyroid cancer, VIPoma
Systemic: adrenal insufficiency, hyperthyroidism
Bile salt malabsorption (ileal resection, idiopathic, post
cholecystectomy)
Non-invasive infections: giardiasis, cryptosporidiosis
Steatorrhea
Maldigestion
Decreased bile salts (cirrhosis, bile duct obstruction, ileal resection)
Pancreatic dysfunction (chronic pancreatitis, cystic fibrosis, duct
obstruction)
Malabsorption
Celiac sprue, tropical sprue, giardiasis, Whipples disease
Chronic mesenteric ischemia
Short bowel syndrome
Bacterial overgrowth (diabetes mellitus, scleroderma, prior bowel
surgery)
Lymphatic obstruction
Inflammatory
Inflammatory bowel disease: ulcerative colitis, Crohns disease,
microscopic colitis
Malignancy: colon cancer, lymphoma
Radiation colitis/enteritis
Mastocytosis
Invasive or inflammatory infections: Clostridium difficile,
cytomegalovirus, Entamoeba histolytica, tuberculosis
Ischemia
Motility
Post-surgical (vagotomy, dumping)
Scleroderma
Diabetes mellitus
Hyperthyroidism
Miscellaneous
Irritable bowel syndrome
Functional diarrhea
Factitious
thereby limiting the number (and cost) of tests needed and increasing the efficiency of the evaluation.11,12 Pathophysiologically,
chronic diarrhea can be divided into six broad categories (Table 1).
Patients can be placed into one of these categories using clues
from the history (including details of onset, pattern, duration,
epidemiology, past medical history, family history, medications),
physical examination (e.g. rash, evidence of malnutrition), and the
diagnostic tests that will be discussed later. However, in practice,
such categorization is not always used when evaluating every
patient. For example, in a patient presenting with diarrhea, weight
loss, and dermatitis herpetiformis, the clinician will focus on a
8
diagnosis of celiac disease without first categorizing the patient.

Furthermore, some conditions that cause chronic diarrhea do not
fit cleanly into one of these categories. An example of this is small
intestinal bacterial overgrowth, which can cause secretory or
osmotic diarrhea and which can be caused by slow intestinal
transit or result in accelerated transit. Moreover, some causes of
diarrhea exploit more than one mechanism simultaneously. For
example, Crohns disease (CD) may produce diarrhea by both
inflammatory and secretory mechanisms.
On the other hand, in patients in whom a specific diagnosis is
not suggested by their clinical features, a systematic approach to
classification of the type of diarrhea as discussed later can be very
helpful. One step in classifying the type of chronic diarrhea is to
distinguish osmotic from non-osmotic causes. Osmotic diarrhea is
caused by the ingestion of a non-absorbable substance that results
in the presence of osmotically active compounds in the gastrointestinal (GI) tract, which obligate fluid retention within the lumen
to maintain osmotic equilibrium with plasma, resulting in diarrhea.
Osmotic diarrhea is suggested in a patient whose diarrhea is
clearly postprandial and resolves with fasting, and can be confirmed by measurement of stool electrolytes and calculation of the
osmotic gap as discussed later. Carbohydrate malabsorption is
further suggested by a low stool pH, indicating bacterial fermentation of the unabsorbed substrate.
Another step in classification is to determine the presence or
absence of steatorrhea, which is suggested by significant weight
loss and frankly greasy or oily stools that are malodorous and float
on the toilet water. Some patients may report oil droplets or fat
floating on the surface of the toilet water. Steatorrhea can be
confirmed by stool analysis, ideally with a timed fecal collection
while taking a known quantity of fat in the diet. Inflammatory
diarrhea is suggested by the presence of obvious blood or pus in
the stools, significant abdominal pain, or fever. It can be confirmed
by the presence of fecal leukocytes or leukocyte proteins (such as
lactoferrin or calprotectin), or the demonstration of inflammation
by direct visualization of the colonic mucosa by endoscopy or
histology.
Motility disorders cause diarrhea through either accelerated
GI transit (e.g. post-vagotomy diarrhea) or by slowing transit,
thereby predisposing to small intestinal bacterial overgrowth (e.g.
scleroderma). Motility-related diarrhea can be either secretory or
osmotic.
Secretory diarrhea is suggested in a patient with large-volume
watery diarrhea that persists despite fasting; it can be confirmed by
stool analysis showing increased stool volume with no increase in
the osmotic gap. Hormone secreting tumors are often considered
in a patient with secretory diarrhea, but these are relatively uncommon causes. Indiscriminant use of tests for these tumors results in
a large number of false-positive results and results in unnecessary
patient anxiety and cost because of further investigations.
Irritable bowel syndrome (IBS) and functional diarrhea are the
most common causes of chronic diarrhea in Western populations,
but the underlying pathophysiology remains poorly understood.13
IBS is defined by the Rome Committee as a chronic condition
characterized by abdominal pain and altered bowel habits; the pain
characteristically is in association with a change in stool form or
frequency, and is relieved by defecation.13 Studies have validated
this definition as identifying a cohort of patients who rarely
develop some other bowel condition. In contrast, functional

LR Schiller et al.
Chronic diarrhea
Microscopic Colitis
Irritable Bowel Syndrome
0.4
0.35
0.3
6
5
0.25
0.2
0.15
Figure 2 Age at diagnosis for microscopic

colitis (MC)16 (left panel) and for irritable
bowel syndrome (IBS)17 (right panel). Left
panel: ( ) MC male; ( ) MC female. Right
panel: ( ) IBS male; ( ) IBS female.
Cases per
1000 pop /
year
4
3
0.1
0.05
Cases per
1000 pop /
year
MC
0
039
4059
diarrheadefined as recurrent or continuous passage of loose or

watery stools without abdominal pain or discomfortis less well
distinguished from many other diarrheal diseases and easily can be
confused with these other conditions.13
Finally, factitious diarrhea is due to the intentional ingestion of
a substance that causes diarrhea or adulteration of a stool sample
with water or urine to exaggerate its volume.14 Factitious diarrhea
can fit into any of the proposed categories depending on which
substance is ingested or used to adulterate the stool.
Diagnosis
History and physical examination. While most cases of
chronic diarrhea will require detailed evaluation, the efficient use
of resources and optimum management will be facilitated by
obtaining a careful history and performing a thoughtful physical
examination. Key historical features to elicit are demographics,
mode of onset, patterns of symptoms, presence or absence of pain,
and clinical features, including associated comorbidity. Because
the commonest diagnosis in at least some areas is IBS, features
which are atypical for IBS are especially useful in indicating
whom to investigate more extensively. In addition, chronic diarrhea may be due to some systemic disease, and so the physician
must be alert to the presence of symptoms and disease outside of
the GI tract.2
Demographics. Age of onset and gender are important. Some
conditions, notably IBS, show a striking peak in the third and
fourth decade, average age ( standard deviation [SD]) at onset
was 38 14 years in one large study.15 In contrast, microscopic
colitis is much commoner in the seventh and eighth decade (see
Fig. 2), with an average ( SD) age at onset of 57 13 years in a
recent series.18 AIDS-related diarrhea is commoner in younger
patients, but most other etiologies can present at any age.
Female predominance is noted in patients with IBS, with a sex
ratio of 3 : 1 in those consulting with primary care physicians.17
The sex ratio is less dramatic in those with diarrhea-predominant
IBS.19 Microscopic colitis also has a female preponderance, while
most other conditions causing chronic diarrhea do not show as
striking an influence of gender when this has been examined.
6079
> 80
1524 2534 3544 4554 5564 6574 7584 85+
Age years
Table 2
Age years
Drugs causing diarrhea
Common causes
Antacids, Proton pump inhibitors24,25 Antineoplastic drugs
Broad spectrum antibiotics (especially cephalosporins26)
Colchicine
Metformin
Non-steroidal anti-inflammatory drugs, 5-aminosalicylates
Cholesterol-lowering agents
Rarer causes
Angiotensin converting enzyme inhibitor27
Angiotensin receptor blocking agents
Beta-adrenergic receptor antagonists, other antiarrhythmics
Carbamazepine28
Lipase inhibitors29,30
Lithium31
Prostaglandins
Vitamin and mineral supplements
Comorbidities and drug history. Prior to patient consultation, it is useful to have an overview of the patients previous
illnesses, comorbidities, and drug history. A good referral letter
listing prior consultations is helpful. The typical IBS patient may
have had multiple previous consultations in the last 5 years for both
GI and non-GI symptoms. This may reflect abnormalities of pain
processing sometimes associated with psychological distress that
adds to the severity of a multiplicity of symptoms.20,21 Patients with
celiac disease often have had previous iron deficiency anemia or
other autoimmune disorders.22 It is worth noting that the prodrome
before diagnosis may be years in CD that typically relapses and
remits.23 Systemic diseases, such as diabetes mellitus, hyperthyroidism, and Addisons disease, may produce chronic diarrhea as a
complication; careful review of the patients history is mandatory.2
Drug history and its relation to onset of diarrhea is important
because drugs can cause diarrhea through several mechanisms,
including direct pharmacological effects (e.g. -blockers, metformin, magnesium-containing antacids) or indirect effects (e.g.
proton pump inhibitors causing microscopic colitis or antibiotics
causing C. difficile colitis) (Table 2).14
Mode of onset. Many infectious illnesses that can be chronic
like giardiasismay begin with an acute illness, but some acute

Chronic diarrhea
LR Schiller et al.
infections can trigger presentation of different conditions including IBS,32 celiac disease, inflammatory bowel disease (IBD),33 and
rarely lactose intolerance.34 Whether the acute infection actually
initiates the condition or makes the underlying chronic condition
more obvious is uncertain for most, although at least for IBS, prior
sufferers have been excluded from most studies. Onset in association with acute infection can be confirmed by positive stool culture
demonstrating a pathogen, but this may not be available, especially
if diarrhea occurs while traveling. Other conditions like lymphoma
or celiac disease usually develop insidiously.
Pattern of diarrhea. Precise details of stool form using the
Bristol Stool Form scale (with visual aids if need be) are useful in
understanding the patients symptoms (Fig. 1). It is important to
recognize steatorrhea that significantly alters diagnostic possibilities.35 Fat laden stools are pale and bulky, often float and are sticky,
typically needing several flushes of the toilet, a useful feature that
patients may recognize, as most do not examine their stools
minutely. Erratic and unpredictable bowel movement are typical of
IBS patients, 81% of whom reported > 3 stool forms per week
compared with just 41% of those with organic causes of diarrhea.36
However, history is often unreliable, and in difficult cases, it may
be useful for the patient to complete a 1-week stool diary. A study
of IBS and diarrhea that recorded symptoms real-time using a
web-based system, which is less subject to bias than a diary,
showed that loose and watery stools were reported on just 29% of
days with normal consistency stool on 42% of days.37 Variable
stools also can be seen in patients with diet-driven diarrhea (e.g.
lactose intolerance), but clinical experience suggests that loose
stools occur nearly every day for many organic disorders, like
microscopic colitis, although there are no directly comparable
studies in these conditions.2,38
Another useful feature in the diagnosis of IBS is the periodicity
of symptoms with bouts lasting a few days and remitting for a
further few days.19,39 This short-lived fluctuation would be unusual
in most organic diseases, with CD, for example, typically waxing
and waning over weeks or months rather than days.40
Nocturnal diarrhea has been considered to be an alarm
feature, suggesting the likelihood of an organic process and the
need for more extensive investigations. However, more recent
studies suggest that nocturnal symptoms occur in similar proportions of patients with IBS and with a typical organic problem,
microscopic colitis (40% and 39%, respectively).38,41 Nocturnal
diarrhea is recognized as common in diarrhea associated
with diabetic autonomic neuropathy42 and also a feature of
postinfectious bile salt malabsorption.34,43
Of course, the key symptom of IBS is abdominal pain, the onset
of which is associated with a change in stool frequency or form
and which is relieved by defecation.13 Of course, Pain is not
specific for IBS, however. Painless diarrhea is no longer recognized as a form of IBS and should prompt a careful consideration
of other diagnoses.
Associated features suggesting need for further
investigations
Rectal bleeding. This is an indication for further examination,
usually by colonoscopy, although minor anal canal bleeding
because of trauma of frequent defecation is extremely common in
all diarrheal diseases.
10
Weight loss. This is common in many diarrheal diseases, often

induced by restrictive diets as patients learn to avoid certain foods
that aggravate the diarrhea. Weight loss is reported in over half of
patients with celiac disease44 and is more often due to food avoidance than malabsorption. This is likely to be also true in IBD when
eating induces pain. While IBS patients typically do not lose
weight, this was reported in 15% of IBS patients in one series45 and
so is not a reliable discriminator.
Age > 50 years. The incidence of colon cancer rises over the age
of 50, and so most patients presenting with new onset of diarrhea
over the age of 50 years will have a colonoscopy for screening
purposes, even though colon cancer is a rare cause of chronic
diarrhea and the incidence of colon cancer in such patients is low
(12%). A family history of colon cancer, especially presenting at
an early age, would also be a strong indication to perform a
colonoscopy, if only to relieve anxiety. Colonoscopy with mucosal
biopsy also may be indicated in older patients to look for microscopic colitis. Microscopic colitis is strongly age-related and
accounts for 10% of all cases of chronic diarrhea in patients over
70 years of age in Sweden.38
Pain. While many diarrheal diseases cause mild crampy abdominal pain, which may be relieved by defecation, pain in IBS is often
reported as very severe and incapacitating.19 Crohns ileocolitis is
often associated with pain localized to the right iliac fossa, while
most cases of malabsorption are associated with dull, poorly localized discomfort. Inflammatory diseases affecting the rectum may
be associated with tenesmus (painful defecation).
Associated psychological factors. While anxiety, panic disorders, and depression are well known to be associated with
IBS,21,45,46 being present in 67%,21 it is less well appreciated that
anxiety may prompt presentation to a physician for many illnesses.
For example, in a recent study comparing patients with celiac
disease to those with IBS (both presenting with diarrhea), anxiety
was equally increased in both groups, the Hospital Anxiety and
Depression Score being 10.2 1.0 and 9.3 0.9, respectively,
both significantly greater than healthy controls at 6.5 0.7.47 Thus,
anxiety may precipitate consultation without necessarily causing
the underlying condition. Similarly, it has been reported that diabetics have increased reporting of several GI symptoms, including
diarrhea in 18% (normal 12%) and early satiety in 12% (normal
5%).42 However, anxiety was present in 28% of diabetics (normal
20%), and when the dataset was controlled for anxiety, only early
satiety remained significantly more common, suggesting that some
symptoms were anxiety-driven.42
Somatization. Patients with chronic diarrhea may have symptoms related to other organ systems that may relate to their underlying illnesses. For example, dysuria might be a symptom related
to an enterovesical fistula in CD, and symptoms of pellagra might
be due to carcinoid syndrome. In other patients multiple, recurring
clinically significant complaints about pain and GI, neurological,
and sexual symptoms are related to somatization disorder, a
psychiatric syndrome.
Somatization may be a particularly difficult problem in
IBS patients. IBS patients often report multiple comorbidities,

LR Schiller et al.
including psychological disorders such as panic attacks; urinary

symptoms such as dysuria, nocturia, and frequency and urgency of
micturition; gynecological symptoms such as dyspareunia and
chronic pelvic pain; and musculoskeletal problems, including
chronic fatigue syndrome and fibromyalgia.48 PHQ12 Somatic
Symptoms scale (PHQ12SS) is a useful measure of non-GI symptoms.21 A PHQ12SS score > 6 identifies patients with IBS with a
sensitivity of 66.4% and specificity of 94.7%, and a positive likelihood ratio of 13.2. A low score makes IBS unlikely and should
prompt a search for other diagnoses.
Dietary causes of diarrhea. It is important to take a dietary
history to assess intake of foods that might cause diarrhea. A high
intake of wheat fiber and certain fruits can cause diarrhea, and
many patients with chronic diarrhea respond to dietary restriction
of these items. Recent work in Australia has emphasized the
importance of poorly absorbed carbohydrates and popularized
a diet that restricts FODMAPs (Fermentable Oligosaccharide,
Disaccharide and Monosaccharides, and Polyols). Foods containing these substances have been shown in double-blind, controlled
trials to trigger abdominal symptoms, such as flatulence, bloating,
abdominal discomfort, and diarrhea. FODMAPs include fructose,
lactose, fructo- and galacto-oligosaccharides (fructans and
galactans), and polyols (sorbitol, mannitol, xylitol, and maltitol)
that have limited or no absorption in the small intestine in many
individuals (polyols often are used as artificial sweeteners in
foods and beverages). When taken in excess, FODMAPs enter the
colon and are rapidly fermented, producing short-chain fatty
acids, carbon dioxide, hydrogen, and methane, which stimulate
colonic motility and can cause diarrhea.49,50 Carbohydrate malabsorption can be the major determinant of stool weight in malabsorption syndromes and is the main source of colonic gas
production.51
Fructose absorption in the small intestine is limited due to its
mechanism of absorption by facilitated diffusion.52 In recent years,
there has been a marked increase in consumption of fructose and
fructans, particularly in the United States, where high-fructose
corn syrup is widely used as a sweetener in commercial food
products. Fresh fruits also are now readily available throughout the
year, and many (particularly grapes and stoned fruits, such as
plums, mangos, and cherries) can cause diarrhea if ingested in
excess.
Lactose is a disaccharide that is the major carbohydrate in milk.
It must be hydrolyzed to glucose and galactose to be absorbed by
the mucosa. Mammals typically no longer ingest lactose after
weaning and so production of the lactase enzyme normally is
downregulated by adulthood in most mammals and most human
populations, rendering them lactose-intolerant. About 10 000
years ago, a mutation developed in the lactase promoter, T/C
(-13910), which prevents this normal post-weaning switch off.53
This mutation first developed in northwest Europe and has spread
southward and eastward, so that geographic and racial origin is
now a strong predictor of adult lactose tolerance. The prevalence
of lactose intolerance is lowest in northwest Europeans and their
descendants (10%), 40% in southern Mediterranean and Middle
Eastern patients, and up to 90% in patients from the Orient. A
separate mutation appears to account for lactase persistence in
southern Africa. Diarrhea is likely to be due to lactose intolerance
only if the patient ingests > 12 g/day (240 mL of milk or its
Chronic diarrhea
Table 3
Physical findings of interest in chronic diarrhea12
Findings
Potential Implications
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
Arthritis
Dehydration, neuropathy
Malnutrition
Mast cell disease (mastocytosis)
Lymphadenopathy
Abdominal bruit
Anal sphincter weakness
Amyloidosis
Addisons disease
Glucagonoma
Carcinoid syndrome
Kohlmeier-Degos disease
Celiac disease
Medullary carcinoma of the thyroid
Hyperthyroidism
Carcinoid syndrome
Endocrine tumor, amyloidosis
Inflammatory bowel disease,
yersinosis
HIV, lymphoma, cancer
Chronic mesenteric ischemia
Fecal incontinence
equivalent in other dairy foods).54 Milk ingested in large volumes

that may empty rapidly into the small intestine is more likely to
cause symptoms than when it is incorporated into solid foods.55
Excessive alcohol intake, particularly as beer, impairs intestinal
water absorption and can cause diarrhea.56 Prolonged alcohol
abuse can also cause chronic pancreatitis and lead to pancreatic
exocrine insufficiency leading to diarrhea secondary to malabsorption. Caffeine causes jejunal secretion57 and may be responsible
for diarrhea in some patients.58
Physical examination. Physical examination is of limited
value in most patients with chronic diarrhea beyond assessment of
hydration and nutritional status. General examination should
take note of evidence of weight loss and signs of malnutrition,
such as anemia, vitamin deficiency, clubbing, or lymphadenopathy. Abdominal examination is usually unremarkable apart from
vague tenderness. Abdominal masses are rare, but fullness in the
right iliac fossa may be felt in ileocolonic CD. Perineal inspection
and rectal examination is useful to exclude any induration or local
tenderness that might suggest CD or an anal fissure. Assessment of
voluntary squeeze is useful in assessing patients with urgency to
see if there is any sphincter defect because incontinence may lead
to a complaint of diarrhea. Table 3 lists rare physical findings that
can be of diagnostic value.
Radiology. Many types of radiological imaging studies are
useful in the diagnosis of chronic diarrhea in selected patients. The
choice of imaging study is based on history, clinical presentation,
and type of diarrhea. In addition, because of increasing concern for
exposure to ionizing radiation, it is incumbent to select these
studies with care and to avoid repetitive studies when possible.
When pancreatic insufficiency is suspected, a plain abdominal
radiograph that shows pancreatic calcifications is diagnostic of

11
Chronic diarrhea
LR Schiller et al.
established chronic pancreatitis (although computerized tomography [CT] scanning is more sensitive). In high-volume secretory
diarrheas, radiography may demonstrate intestinal air fluid levels
or a paucity of bowel gas, suggesting a fluid-filled bowel. Standard
abdominal CT scan is useful in detecting extraintestinal causes of
chronic diarrhea, such as neuroendocrine tumors and chronic pancreatitis, but is a poor test for small bowel mucosal disease.
Small bowel radiography. Small bowel barium studies have

historically been used in the diagnosis of chronic diarrhea and
abdominal pain. When bacterial overgrowth is suspected as a cause
of malabsorptive diarrhea, small bowel barium study is useful in
identifying multiple jejunal diverticula, altered small bowel
anatomy, blind loops, gastrocolic fistula, slow small bowel transit,
and small bowel strictures. It also allows localization of small
bowel lesions to guide further management. Findings that suggest
small bowel mucosal disease include jejunal dilation, fold thickening, and intussusceptions. These findings are non-specific and
are present in celiac disease, tropical sprue, scleroderma, and
hypoalbuminemia, as well as other mucosal diseases. Findings that
are more specific for celiac disease include decreased jejunal-fold
pattern and increased ileal-fold pattern (ilealization of jejunum or
so-called reversal of fold pattern). With the introduction of
abdominal CT scans, use of fluoroscopic barium studies has
declined. Classic radiographic findings are listed in Table 4.
Table 4 Radiographic findings in chronic diarrhea and malabsorption

syndromes
Condition
Classical findings
Celiac disease
Dilated caliber; increased fluid; thin, effaced

folds (moulage), segmentation of barium
column, painless intussusception
Normal caliber; thick, wild fold pattern;
patchy micronodularity
Dilated, esp. duodenum; delayed peristalsis,
hypomotility
Variable caliber; coarse folds; wall
infiltrated, stiff; extraluminal masses;
micronodularity
Normal caliber; symmetrical fold thickening,
no edema; stiff walls; micronodularity
Increased luminal fluid; thick, edematous
folds
Stenotic (string sign); deformed/thickened
folds; rigidity/ulceration of walls;
sometimes extraluminal mass
Increased luminal fluid; nodular lymphoid
hyperplasia
Dilated duodenum; thick duodenal folds;
spasm, rapid transit
Dilated duodenum; thick duodenal folds;
peptic ulcer; reticulated pattern
Thick folds; nodularity in duodenum
Fine mucosal graininess
Thick gut wall; mucosal nodularity
Whipples
disease
Scleroderma
Lymphoma
Amyloidosis
Lymphangiectasia
Crohns disease
Dysgammaglobulinemia
Giardiasis
ZollingerEllison
syndrome
Cystic fibrosis
Abetalipoproteinemia
Mastocytosis
12
CT and magnetic resonance enterography. CT and magnetic resonance (MR) enterography protocols using intravenous
and high-volume negative (or neutral) oral contrast have revolutionized radiological examination of the small bowel wall and also
allow examination of extraintestinal structures.5961 They are useful
in the diagnosis of chronic diarrhea because of small bowel CD,
particularly when out of reach of standard endoscopy. Findings in
active CD include mucosal enhancement, mural thickening, proliferation of mesenteric fat, and dilated vasa recta.61 Findings characteristic of active celiac disease include reversal of fold pattern,
intussusception, hyposplenism, and mesenteric adenopathy.62
Findings in eosinophilic gastroenteritis depend on the site of small
bowel involvement: fold-thickening, ulcers, and polyps are found
with mucosal involvement; bowel wall thickening, decreased distensibility, and strictures are found with muscle involvement; and
ascites, adenopathy, and omental thickening are found with serosal
involvement. CT enterography also is useful in the detection of
small bowel tumors, such as carcinoids, that can be detected when
they are as small as 5 mm in size. CT enterography is being used
in developing countries, but technical limitations in such settings
pose difficulties.63 MR enterography provides high-quality imaging without ionizing radiation but is more costly, time-consuming,
and more difficult to interpret because of motion artifacts from
bowel movement.60 These limitations are likely to change with
newer high-speed MR scanners. MR enterography is likely to
become more widely used as concerns with iatrogenic radiation
exposure grow. MR cholangiography and pancreatography largely
has supplanted endoscopic techniques as the diagnostic technique
of choice for pancreatobiliary disease.64
Nuclear medicine imaging. Neuroendocrine tumors are a rare
cause of secretory diarrhea. These tumors can be small and difficult to diagnose. Radioligand scintigraphy (e.g. OctreoScan) is
useful in diagnosing neuroendocrine tumors that express somatostatin receptors, such as gastrinomas and carcinoid tumors.65 The
newer tomographic hybrid scanner, single-photon emission computed tomography-CT provides better localization and may
increase accuracy.66 Use of higher doses of radioligands may
improve tumor detection rates.67 Positron emission tomography
combined with CT or MR is useful in detecting and localizing
small bowel lymphomas and for monitoring response to therapy.68
Endoscopy/enteroscopy/capsule enteroscopy
Endoscopy and colonoscopy. Endoscopy is a commonly
used diagnostic test in the evaluation of chronic diarrhea. Upper
endoscopy is indicated when there is a history of chronic diarrhea
with weight loss, positive celiac serologies, and/or vitamin and
mineral deficiencies to suggest small bowel mucosal disease
(chronic infection, celiac disease, tropical sprue, eosinophilic gastroenteritis, CD, radiation, amyloidosis, common variable immunodeficiency syndrome, lymphangiectasia, graft vs host disease).
Findings of nodularity, fissuring, or scalloping in the duodenum
are suggestive of villous atrophy from any cause. Endoscopic
visualization of villous atrophy is improved with water emersion,
zoom magnification, optical band imaging, and confocal microscopy.69,70 Systematic evaluation of the utility of endomicroscopy in
patients with chronic diarrhea is needed. The duodenum may

LR Schiller et al.
appear normal with milder degrees of inflammation (villous blunting or intraepithelial lymphocytosis with normal architecture) and
therefore should be biopsied when small bowel mucosal disease is
suspected. Duodenal biopsy may provide a specific diagnosis such
as in giardiasis and other protozoal infections, Whipples disease
and other infections, combined variable immunodeficiency, and
graft versus host disease. In other diseases, duodenal biopsy findings are non-specific, but suggestive, such as in celiac disease,
tropical sprue, and CD. In such cases, the diagnosis is made with
supporting serologies or in response to a specific treatment. In
celiac disease, diagnostic yield improves with targeted biopsies
of abnormal appearing mucosa, when four duodenal biopsies
are obtained and when both the bulb and distal duodenum are
biopsied.71,72 Upper endoscopy also permits collection of duodenal
aspirate for quantitative culture, the current gold standard for a
diagnosis of small intestinal bacterial overgrowth.
Colonoscopy with ileoscopy is indicated in patients with
watery, inflammatory, or elusive diarrhea to assess for IBD,
microscopic colitis, infections such as C. difficile, ischemia,
villous adenoma, or mastocytosis. Colonoscopy with ileoscopy
has highest specificity when compared with CT imaging and
capsule endoscopy in the diagnosis of CD.73 Ileoscopy is also
useful in the diagnosis of infections that cause chronic diarrhea
such as tuberculosis or yersinosis. The colon appears grossly
normal with microscopic colitis; a sufficient number of biopsies
should be obtained to increase the chances of making a diagnosis.
In contrast, C. difficile typically produces grossly apparent pseudomembranous colitis that is difficult to mistake for anything
else. Approximately 15% of cases of non-bloody chronic diarrhea
have histological findings in the colon; biopsies from the left
colon are sufficient to detect the causative condition in the vast
majority of these cases.74
Enteroscopy and capsule endoscopy. Most small bowel
mucosal diseases that cause chronic diarrhea can be diagnosed by
standard upper endoscopy and duodenal biopsy. Rarely, celiac
disease has a patchy distribution that is missed on duodenal biopsy
must be diagnosed by push enteroscopy with jejunal biopsy.
Newer technologies of wireless capsule endoscopy and deviceassisted (deep) enteroscopy allow complete examination of the
small bowel.
Capsule endoscopy is more sensitive than standard endoscopy
in the detection of villous atrophy with good interobserver agreement,75,76 but it misses milder inflammatory lesions. As tissue
sampling is not possible with capsule endoscopy, it cannot
provide a specific diagnosis for other small bowel mucosal
diseases that cause chronic diarrhea. The diagnostic yield is
particularly low in patients with chronic diarrhea and no laboratory or imaging studies to suggest organic disease. Capsule
endoscopy is useful in refractory celiac disease for the detection
of ulcerative jejunitis and enteropathy associated T-cell lymphoma (EATL).77 Capsule endoscopy has similar sensitivity as
CT enteroscopy, ileocolonoscopy, or small bowel radiography in
small bowel CD, but lower specificity limits its utility in that
setting.73 One of the risks of capsule endoscopy is retention
within the intestine. This occurred in 1.3% of patients in one
retrospective study from Sweden; risk factors included IBD and
tumors.78 The risk of capsule retention in known CD may be as
high as 13%.79
Chronic diarrhea
Device-assisted enteroscopy (balloon or spiral overtubes)

allows complete examination of the small bowel and has the
advantage of permitting tissue sampling but is invasive and timeconsuming. It is useful to assess for ulcerative jejunitis and EATL
in refractory celiac disease80 and for tissue diagnosis of other
causes of chronic diarrhea when suspicious lesions are identified at
capsule endoscopy or radiological small bowel imaging studies.
Endoscopic retrograde cholangiopancreatography and
endoscopic ultrasound. Detection of chronic pancreatitis and
neuroendocrine tumors of the pancreas that might cause chronic
diarrhea can be facilitated by endoscopic retrograde cholangiopancreatography (ERCP) or endoscopic ultrasound (EUS).81,82 EUS
permits biopsy of lesions and ERCP can be used to treat certain
forms of chronic pancreatitis.83
Pathology. Histopathology of the small bowel and colon has
an important role in the evaluation of patients with chronic diarrhea. Biopsy of both abnormal and normal appearing mucosa may
be indicated.
Colorectal and terminal ileal biopsy
Abnormal mucosa. Biopsy is essential in the diagnosis of colitis
to confirm inflammation, to identify its causes, and to identify
other abnormalities (Table 5). A common differential is between
infectious colitis and IBD. Some features such as crypt abscesses
are non-specific. The histological features of infectious or acute
self-limited colitis are preservation of normal crypt architecture
and predominantly acute inflammation in the lamina propria;
inflammation may be patchy. In contrast, features of active ulcerative colitis are contiguous mucosal inflammation with abnormal
crypt architecture with branched crypts, acute and chronic inflammatory cells in the lamina propria, increased inflammatory cells at
the crypt bases, and basilar plasmacytosis with basal lymphoid
aggregates.84,85 In fact, basilar plasmacytosis has been identified as
a predictor of clinical relapse. In ulcerative colitis, when inflammatory changes resolve (mucosal healing), crypt distortion often
remains.
The histological features of colitis in CD are focal inflammation
and architectural distortion, transmural inflammation, and epithelioid granulomas that can be found in 1020% of cases. While
diffuse inflammation can be seen, it is less common. The focal
nature of Crohns inflammation may be confused with infectious
colitis early in the course of disease. In approximately 10% of
patients with IBD, endoscopic and histological features are insufficient to distinguish ulcerative colitis and CD with confidence,
such patients are described as having indeterminate colitis. Segmental colitis associated with diverticulitis can show focal inflammation, granulomas, and may mimic CD or ulcerative colitis.86
Sometimes specific pathogens can be seen on biopsy, such as
ameba trophozoites, schistosomes with associated granulomas,
and viral inclusions because of cytomegalovirus (CMV) infection. Granulomas can be seen in tuberculosis, yersinosis, and
schistosomiasis.
Pseudomembranes on biopsy can be seen with C. difficile infection but also with ischemia and Shiga toxin Escherichia coli
infections. Other more common features of ischemia are loss of

13
Chronic diarrhea
Table 5
LR Schiller et al.
Interpretations of pathological findings on colorectal biopsy

Finding
Diagnosis
Normal
Infectious colitis
Microscopic colitis
Ulcerative colitis
Crohns disease
Infectious colitis
Architecture
Diffusely abnormal
Focally abnormal
Mucosa
Mucosal
inflammation
Predominantly acute
Diffuse, chronic
Basal plasmacytosis
Basal lymphoid
aggregates
Focally abnormal
Increased
intraepithelial
Lymphocytes (surface
and crypts)
Submucosal
inflammation
Granulomas
Infectious colitis
Ulcerative colitis
Ulcerative colitis
Ulcerative colitis
Crohns disease
Infectious colitis
Microscopic colitis
Crohns disease
Rare (found in
1020%)
Multiple
Organisms present
Crohns disease
Syphilis
Tuberculosis
Histoplasmosis
Chlamydia trachomatis
(LGV strains: proctitis)
Schistosomiasis
detect occult IBD, pseudomelanosis coli (a sign of laxative use),

and is necessary to diagnose microscopic colitis (both collagenous
colitis and lymphocytic colitis), eosinophilic colitis, and enteritis,
and may yield a diagnosis in 1030% of cases.87,88 In a series from
Brazil, histology was abnormal in 32.1% and identified occult
IBD, microscopic colitis, eosinophilic enterocolitis, spirochetosis,
and schistosomiasis in addition to findings of borderline significance.89 The histological features of collagenous colitis are normal
architecture, increased intraepithelial lymphocytes (IELs) (more
than 20 IELs per 100 absorptive cells) in the surface mucosa and
crypts, increased lamina propria lymphocytes, and a thickened
subepithelial collagen band (> 10 microns). Lymphocytic colitis
has the same features but no thickened collagen band.90 Other
changes that can be seen with microscopic colitis are surface
epithelial flattening, cryptitis, and Paneth cell metaplasia. Most
cases will be detected with biopsy of the left colon, but it is
important to obtain biopsies above the rectum. Usually four
random biopsies of left colon will be adequate. Biopsies of the
right colon are rarely necessary to make the diagnosis. One caution
in interpreting random colon biopsies from the cecum is to distinguish mild inflammatory changes that can be seen in normal individuals from true colitis. A reasonable practice is to obtain four to
five random biopsies from throughout the colon and place them in
a single bottle.91
Terminal ileal biopsies. Ileitis can be detected in patients with
CD, even without visible inflammatory changes and in some
patients with ulcerative colitis in whom it is termed backwash
ileitis.92 The yield of biopsy of the terminal ileum in patients with
diarrhea is highest in those with right lower quadrant pain; it may
aid diagnosis in 1020% of cases.93 In patients without right lower
quadrant pain, the yield will be much lower.
Viral inclusions
Intranuclear
Intranuclear and
cytoplasmic
Thickened
subepithelial
collagen layer
Epithelial surface
Pseudomembranes
Organisms present
Herpes simplex
Cytomegalovirus
Collagenous colitis
Clostridium difficile
Shigatoxin (+)
Escherichia
coli
Ischemia
Cryptosporidiosis
Entamoeba histolytica
Includes lymphocytic colitis and collagenous colitis

Less commonly, Crohns disease
mucosa in the upper lamina propria, hemorrhage, and a superficial

polymorphonuclear infiltrate. There is minimal inflammation;
necrosis can be seen later in severe cases. In radiation colitis, there
is ischemia and fibrosis, with scarring, neovascularization with
blood vessels in the upper mucosa, and hyalinized blood vessels.
Normal mucosa. Biopsy of normal colonic mucosa is important
in the evaluation of patients with chronic watery diarrhea. It may
14
Small bowel biopsy. Small bowel biopsy plays an important

role in the evaluation of patients with fat malabsorption as well as
the evaluation of chronic watery diarrhea. It can detect mucosal
disease such as celiac disease, CD, eosinophilic enteritis, tropical
sprue, and infections with organisms such as Mycobacterium
tuberculosis, Strongyloides stercoralis, Giardia intestinalis (formerly G. lamblia), Cystoisospora belli (formerly Isospora belli),
Cyclospora cayetanensis, and Cryptosporidium spp. Small bowel
biopsy in patients with HIV associated diarrhea who are immunosuppressed can detect any of the previously listed organisms and
also microsporidiosis and Mycobacterium avium intracellulare
(MAI). Uncommon small bowel diseases that can be recognized
by biopsy include Whipples disease, collagenous sprue, autoimmune enteropathy, and lymphoma. Classical findings of these conditions are listed in Table 6. In addition, finding normal small
bowel mucosa in a patient with malabsorption may point to pancreatic insufficiency as a cause.
Small bowel biopsies in some diseases are diagnostic
particularly for very rare diseases such as abetalipoproteinemia,
collagenous sprue, amyloid, and Whippless disease. Small bowel
biopsy can be suggestive but non-diagnostic in celiac disease and
CD. Flattened mucosa (i.e. villous atrophy or blunting) can be seen
in all of these conditions, as well as with viral gastroenteritis and
nonsteroidal anti-inflammatory drugs use; thus, clinical correlation
is always important. Histological characteristics that suggest

LR Schiller et al.
Table 6
Chronic diarrhea
Interpretation of pathological findings on small bowel biopsy
Brush border abnormalities

Sickle-shaped organisms
Basophilic dots
Inclusions
Abnormal enterocytes
Intracytoplasmic organisms
Foamy vacuolation
Lack of enteroendocrine cells
Abnormal basement
membrane
Collagenous band
Villous atrophy
Total or partial
Lamina propria abnormalities

Noncaseating granulomas
Infiltrating eosinophils
Infiltrating malignant
lymphocytes
Infiltrating mast cells
PAS-positive macrophages
Dilated lymphatics
Giardia intestinalis
Cryptosporidium
Microvillous inclusion disease
Cystoisosporiasis
Abetalipoproteinemia
Autoimmune polyglandular
syndrome
Collagenous sprue
Celiac disease, tropical sprue,
bacterial overgrowth,
dysgammaglobulinemia, dermatitis
herpetiformis, radiation enteritis,
immunoproliferative small
intestinal disease (IPSID), acute
viral infection, ischemia,
non-granulomatous ulcerative
jejunoileitis, microsporidiosis
Crohns disease
Eosinophilic gastroenteritis
Lymphoma, IPSID
Mastocytosis
Whipples disease (bacilli on EM),
Mycobacterium aviumintracellulare (acid-fast bacilli)
Lymphangiectasia
EM, electron microscopy; PAS, periodic-acid Schiff stain.
celiac disease are variable blunting or flattening of the villi that

can be patchy and IELs (more than 30 IELs/100 enterocytes).
However, these findings are non-specific and can be seen with
infections and other inflammatory diseases, such as CD.94
The current gold standard in biopsy diagnosis of celiac disease
is to take four to six biopsies in the duodenum; one should be from
the bulb and the others in the second and third portions of the
duodenum. While serology can suggest celiac disease, biopsy
remains mandatory to confirm the diagnosis. It is usually not
necessary to rebiopsy to document healing unless there is a poor
response to a gluten-free diet or there is doubt about the initial
diagnosis.
Eosinophilic gastroenteritis involves the stomach and small
bowel most commonly. There may be peripheral eosinophilia.
Histological characteristics are an eosinophilic infiltrate, > 1050/
high power field, that can be variable in location but is usually
in the mucosa. The small bowel is involved in 75% of cases.95
However, increased eosinophils can be seen in other situations,
such as parasitic infections and CD.
Pathological analysis of tissue samples is undergoing a renaissance as molecular techniques allow more information to be
extracted from specimens than just morphology. These techniques
include expanded special stains and genetic analysis of both
mucosa and associated microorganisms. Application of these

methods to samples from patients with chronic diarrhea is just
beginning.
Bacteriology/microbiology. In developed countries and
in the normal, immunocompetent host, infections are unusual
causes of chronic diarrhea. However, in developing countries
chronic bacterial, mycobacterial, and parasitic infections are
common. Additionally, there are special situations where intestinal
infections are more frequently responsible for chronic diarrhea.
Some of these situations include diarrhea in immigrants from
endemic areas, immunocompromised subjects, patients with HIV/
AIDS infection, men who have sex with men, and in individuals
with chronic travelers diarrhea.
Immunocompetent subjects in developed countries. In
immunocompetent individuals in developed countries, giardiasis,
amebiasis, yersinosis, and C. difficile infections may be chronic.
Strongyloides is occasionally seen but is quite unusual. In immunocompetent patients with chronic diarrhea, these five pathogens
should be sought if the cause of diarrhea is not readily apparent.
Giardia is most reliably detected with a stool enzyme-linked
immunosorbent assay (ELISA) assay. Ameba and Strongyloides
are sought with serological tests and stool examination for ova and
parasites; no more than three stool samples should be sent for
microscopic examination. C. difficile is most reliably detected
with a stool DNA amplification assay; only a single stool sample
need be done for that diagnosis.96 Less reliable tests include
enzyme-linked immunoassays for C. difficile toxins A and B that
suffer from poor sensitivity.
Immunocompromised subjects. In patients receiving immunosuppressant medications or those with HIV/AIDS infection, the
likelihood of chronic infections is much greater. Many common
enteropathogens that cause acute, self-limited diarrhea in immunologically normal individuals can cause chronic diarrhea in
these patients. These pathogens include Salmonella, Shigella,
Campylobacter, E. coli, Yersinia, and others. These infections can
last many weeks in the immunosuppressed host. Traditionally,
these infections have been sought with standard stool cultures;
however, new molecular techniques may prove to be better in time,
making standard stool cultures obsolete.97 Immunosuppression
may cause atypical presentations of infectious diarrhea. For
example, patients with subclinical Strongyloides infection may
develop hyperinfection syndrome or disseminated strongyloidiasis
when exposed to high-dose corticosteroids for treatment of asthma
or chronic obstructive pulmonary disease.
With HIV/AIDS potential infectious etiologies are related to the
degree of immunosuppression. With lesser degrees of immunosuppression (CD4 count > 200 cells/mm3), the usual pathogens mentioned in the preceding paragraph predominate. If the CD4 count is
< 200 cells/mm3, the potential spectrum is much wider. In addition
to the enteropathogens mentioned, mycobacterial and protozoan
infections become more likely. These include MAI, cryptosporidia, cyclospora, cystoisospora, and microsporidia. Viral
infections, such as CMV and Herpes simplex virus, and fungal
infections, such as candidiasis and histoplasmosis, should be
considered if other pathogens are not found.98

15
Chronic diarrhea
LR Schiller et al.
In immunocompromised subjects, a staged work-up is recommended. Initially, stools should be sent for routine bacterial culture
(to detect Salmonella, Shigella, and Campylobacter), a test for
C. difficile, ELISA testing for giardia and cryptosporidium, and for
ova and parasite examination to look for Stronglyoides and other
parasites. If these tests are unrevealing, upper GI endoscopy and
either flexible sigmoidoscopy or colonoscopy with biopsies should
be done.98 The biopsies should be examined microscopically and
cultured for viral pathogens.
Men who have sex with men. In men who have sex with men
(especially those who practice rectal intercourse), organisms that
cause proctitis need to be considered, especially when rectal or
anal pain, tenesmus, or rectal bleeding is present. These organisms
include Chlamydia trachomatis serovars L1, L2 and L3 (cause of
lymphogranuloma venereum99), amebiasis, Herpes simplex virus,
Neisseria gonorrhoeae, and Treponema pallidum. In addition to
stool cultures, sigmoidoscopy with biopsies should be done routinely in these individuals.
Chronic travelers diarrhea. Travelers diarrhea is usually
acute and self-limited. In approximately 3% of patients, the diarrhea is persistent and chronic.100 In this situation, chronic intestinal
infection must be excluded, and stool samples should be sent for
bacterial culture and microscopy, ELISA tests for giardiasis and
cryptosporidiosis, and a test for C. difficile, especially if the patient
previously received antibiotics. If these investigations are negative,
small intestinal biopsy should be considered to look for unusual
infections or tropical sprue. Tropical sprue should be included in
the differential diagnosis, especially if the traveler spent a long
time in an endemic region. If all of these tests are negative, some
suggest empirical treatment with antibiotics aimed at bacterial
enteropathogens and, if that does not work, a course of therapy for
protozoal pathogens.100 Others would proceed directly with small
bowel biopsy to look for tropical sprue.101 Some patients develop
IBS after a bout of travelers diarrhea.32
Chronic idiopathic secretory diarrhea (Brainerd diarrhea). There have been many outbreaks of diarrhea in which
some individuals developed chronic diarrhea. These outbreaks
have characteristics of a point-source epidemic, usually associated
with potential food or water contamination. One of the first outbreaks occurred in Brainerd, Minnesota, giving the condition its
common name, Brainerd diarrhea.102 Despite the obvious
concern for an infectious cause, state-of-the-art microbiological
evaluation of an ongoing outbreak failed to detect an agent for the
disease.103 An identical syndrome also can occur sporadically with
no indication of direct person-to-person spread.104 While this condition shares some similarity to postinfectious IBS, patients have
no pain, complain of continuous watery diarrhea that is moderately
voluminous, and eventually get better (after months or years). It is
unclear whether this represents ongoing infection with a novel
agent or some sort of long-lasting reaction to an acute infection or
a self-limited form of functional diarrhea.105
Serology. Serological testing is used to support specific diagnoses in many subspecialties, including rheumatology and
hepatology, but has had limited use in the diagnosis of chronic
16
diarrhea. There are three areas in which serological testing has

been considered: (i) celiac disease; (i) IBD; and (iii) autoimmune
enteropathy. The usefulness of serological tests in these conditions
is variable and ranges from indispensable (celiac disease) to just
suggestive (IBD).
Celiac disease. Serological tests are basic to the diagnosis of
celiac disease. Serological testing has provided new insights into
the epidemiology of celiac disease, expanding our understanding
of its worldwide prevalence. It has also given us a more comprehensive picture of the spectrum of the disease, with the recognition
of latent and silent celiac disease. Given the recent recognition of
an entity now termed non-celiac gluten sensitivity, serological
testing has assumed a greater importance in diagnosis of true
celiac disease.
Immunoglobin A anti-tissue transglutaminase (anti-TTG) and
anti-endomysial antibody (anti-EMSA) are very sensitive and specific for a diagnosis of celiac disease.106 Immunoglobulin A (IgA)
anti-TTG is the preferred single test for detection of celiac disease
in individuals over the age of 2 years and should be done, while the
patient is consuming gluten.106 Total serum IgA should be measured at the same time to exclude IgA deficiency that might cause
a falsely negative test (present in 23% of patients with celiac
disease). Antigliadin antibodies generally are positive in celiac
disease, but are not specific, and therefore not helpful for diagnosis. Anti-gliadin antibodies occur frequently (1015%) in patients
with IBS and other intestinal diseases, such as CD. Their presence
speaks to near universal exposure to gluten in the Western diet and
may reflect changes in intestinal permeability. Some patients with
positive anti-TTG or anti-EMSA tests have no symptoms and no
definite biopsy evidence of celiac disease; these individuals are
said to have potential or latent celiac disease. Patients with
potential celiac disease have no history of a previous diagnosis,
whereas those with latent celiac disease have had a previous diagnosis of celiac disease. Many of these patients have a family
history of celiac disease and also may have symptoms suggestive
of celiac disease, including chronic diarrhea, abdominal pain, and
anemia.107 The significance of these findings remains a subject of
debate.108,109
In an individual with steatorrhea, dermatitis herpetiformis, or
other signs/symptoms strongly suggestive of celiac disease, serological testing is indicated. Small intestinal biopsy should be considered in such patients, even if serological tests are negative. The
role of serological testing is less clear in individuals with a clinical
picture of diarrhea-predominant IBS or intermittent diarrhea.
Several studies have examined the question of how frequently
celiac disease presents as IBS and have reached different conclusions. A meta-analysis concluded that celiac disease (positive
serologies and biopsies) was fourfold more common among IBS
patients than normal, approximately 4%.110 A subsequent large
study from the United States found that positive serology tests for
celiac disease were common in both controls and non-constipated
IBS patients, and found no difference in the prevalence of biopsyproven celiac disease (0.44% and 0.41%, respectively).111 Routine
testing for celiac disease in diarrhea-predominant IBS may be
cost-effective in populations with a greater than 1% background
prevalence of celiac disease.112
HLA-DQ heterodimers DQ2 or DQ8 are present in almost all
patients with celiac disease. Therefore, the negative predictive

LR Schiller et al.
value of tests for these tissue types is > 99%.113 While HLA-DQ
testing should not be used for diagnosis of celiac disease because
of a high prevalence of these tissue types in most populations
(3040%), absence of HLA-DQ2/DQ8 can be used to exclude the
disorder when there are equivocal histological findings or conflicting serological and pathological results, or when a patient is on a
gluten-free diet and refuses to resume gluten consumption before
testing.106,114
IBD. Serological tests commonly used in managing IBD measure
antibodies targeting a yeast used in food production (antiSaccharomyces cerevisiae antibodies, directed against Saccharomyces cerevisiae, a yeast used in winemaking, baking, and
brewing), an intracellular neutrophil component (perinuclear antineutrophil cytoplasmic antibodies, directed against various proteins inside neutrophils), and bacterial components (anti-OmpC,
outer membrane porin C of E. coli, and anti-CBir-1, flagellin).
Reactivity to these antigens may represent cross-reactivity to a
molecular mimic, exposure to cell components normally inaccessible to the immune system, or altered permeability for these
antigens.115
Studies specifically examining the role of IBD serology in the
differential diagnosis of diarrhea are limited.116 The predictive
value of a test depends on the pretest probability of the diagnosis
in the patient being studied. In the setting of bloody diarrhea, fever,
and abnormal imaging, the likelihood of IBD is fairly high and so
the predictive value of a positive IBD serology is substantial, but
it is not clear that serological tests add much diagnostic certainty
to that provided by standard tests, such as colonoscopy or
enterography. Moreover, in a patient with watery diarrhea and no
other IBD alarm signs, the likelihood of IBD will be low and the
false-positive rate high. Using IBD serological testing in this clinical setting rarely is useful and frequently causes confusion and
additional unnecessary testing. It has been suggested that combining different serological tests with genetic and inflammatory
markers can improve the performance of blood tests for IBD,117 but
this remains to be established prospectively in a cohort with a
prevalence of IBD similar to the general population.
Autoimmune enteropathy. Autoimmune enteropathy is a
rare condition marked by intractable diarrhea, malabsorption, and
histological changes on small intestinal biopsy that resemble but
are not pathognomonic for celiac disease.118 It is often confused
with celiac disease but does not respond to gluten withdrawal or
other dietary manipulations, and the histology is subtly different
than that seen in celiac disease. Originally, it was considered a
pediatric disease, but it does occur in adults. Specialized research
laboratories offer serological testing, such as anti-enterocyte antibodies. These may be helpful in confirming the diagnosis, but
because this is such a rare and variable disease, performance
characteristics are not well defined and a positive test is not
necessary for establishing a diagnosis. Steroids and other
immunosuppressives frequently are required for treatment.
Peptide hormones. In a small number of patients secretory
diarrhea is caused by circulating agents that lead to water and
electrolyte secretion at the mucosal level and often also decrease
intestinal transit time.119 Many of these conditions are classic syndromes where a neuroendocrine tumor produces and releases a
Chronic diarrhea
peptide hormone or a neurotransmitter. The VernerMorrison syndrome (vasoactive intestinal polypeptide [VIP]oma or watery
diarrheahypokalemiahypochlorhydria syndrome) is caused
by excessive production of VIP;120,121 serotonin, substance P, and
tachykinins are the culprits in the malignant carcinoid syndrome.122 In gastrinoma (ZollingerEllison syndrome [ZES]) the
large amounts of gastric acid secretion overwhelm the absorptive
capacity of the intestine.119 Neuroendocrine tumors are rare, the
incidence is about 2.5 per 100 000 population per year,123 and
two-thirds are non-functioning and do not release a tumor product
into the circulation. The classic syndromes with endocrine activity
per se are thus much rarer: it is estimated that there is one VIPoma
per 10 million people per year and one ZES per 2 million people
per year.124
Radioimmunoassays (RIAs) are available to determine elevated
levels of many of these hormones (e.g. gastrin, VIP, calcitonin),
but because of the rarity of these syndromes, the rate of falsepositive laboratory results remains a problem.119 With an extended
panel of assays including motilin, neurotensin, pancreatic polypeptide, somatostatin, substance P, VIP, gastrin-releasing peptide,
and calcitonin, the high rate of false-positive results precludes any
clinical utility for the evaluation of patients with chronic diarrhea.125 Cholecystokinin (CCK) could now also be added to this
list.126 In other words, if peptide hormone levels were used as a
diagnostic tool for secretory diarrhea, the yield of true-positives
would be very low and false-positives very high. This changes
when secretory diarrhea accompanies a tumor mass found in the
pancreas, duodenal wall, ileum, or parathyroid. In this setting,
RIAs for VIP, gastrin, somatostatin, and calcitonin may be useful.
In the presence of small bowel tumors or symptoms, and signs
of flushing, hepatomegaly or valvular heart disease, the malignant
carcinoid syndrome should be suspected. Determination of the
serotonin metabolite, 5-hydroxyindoleacetic acid, in 24-h urine is
still the most reliable test. When the carcinoid syndrome is present
(e.g. diarrhea, flush) metastases of the primary tumor usually have
already increased total tumor mass and provided access for tumor
secretion to the systemic circulation.122
Chemical analysis of stool. Conceptually, chemical
analysis of stool in patients with chronic diarrhea can allow insight
into pathophysiology and could lead to expedited diagnosis. The
differential diagnosis of chronic diarrhea includes dozens of entities, and therefore, diarrhea can be daunting to evaluate. Different
etiologies cause different types of diarrhea. When an obvious
diagnosis is not evident, categorizing patients with chronic diarrhea as having watery diarrhea, fatty diarrhea, or inflammatory
diarrhea based on clinical presentation and simple stool analysis
can result in a less imposing differential diagnosis (Table 1).2 The
stool analysis involves inspecting the stool, measuring stool
weight, stool electrolytes, fecal pH, and fat content, and checking
for the presence of blood and white blood cells. Additional studies
that can be done selectively include measurement of carbohydrate
excretion, fecal chymotrypsin or elastase, and screening of stool
and urine for laxatives.
Measurement of stool weight gives guidance about the severity
of diarrhea and the need for fluid or electrolyte repletion. Stool
weight in functional diarrhea or IBS typically is < 500 g/24 h;
higher outputs suggest a more substantial disruption of normal
absorptive physiology. Assay of fecal electrolytes allows the

17
Chronic diarrhea
LR Schiller et al.
physician to distinguish osmotic and secretory diarrhea based on

calculation of the fecal osmotic gap.127 Secretory diarrhea produces stools that are rich in electrolytes because intraluminal fluid
retention is due to incomplete absorption of electrolytes. Electrolyte absorption is unaffected in osmotic diarrhea, and so stools
have low concentrations of absorbable electrolytes. The contribution of fecal electrolytes (sodium, potassium, and associated
anions) to stool osmolality can be judged by adding measured
fecal sodium and potassium concentrations, doubling that number
to account for unmeasured anions, and subtracting that number
from 290 mOsm/kg (the osmolality of intraluminal contents that
have equilibrated with body fluids) (measured stool osmolality is
affected by fermentation that occurs in the collection container and
should not be used for this determination). If the fecal osmotic gap
is small, most of the osmolality of stool water is accounted for by
electrolytes; this suggests that water and electrolyte absorption is
impaired. If the fecal osmotic gap is large, some non-electrolyte
contributes substantially to fecal osmolality. This usually is a
poorly absorbed substance that holds fluid within the gut lumen,
such as magnesium or carbohydrate. Experiments using laxatives
that produce either secretory or osmotic diarrhea suggest that a
fecal osmotic gap < 50 mOsm/kg is characteristic of a secretory
diarrhea and a fecal osmotic gap of > 75 mOsm/kg is characteristic
of osmotic diarrhea.127 Thus, calculation of the fecal osmotic gap
allows one to classify most cases of watery diarrhea into secretory
diarrhea or osmotic diarrhea that impacts on diagnosis and further
evaluation.
Fecal pH normally is close to 7.8,127 Fermentation of carbohydrate in the colon by the colonic flora produces short-chain fatty
acids that may lower fecal pH. This is particularly true in normal
volunteers given a large dose of lactulose by mouth.127 Thus, low
fecal pH may be a clue to the possibility of carbohydrate malabsorption. However, unlike normal subjects given lactulose, patients
with carbohydrate malabsorption may not always have a low fecal
pH probably because the amount of carbohydrate malabsorbed
may be less than in normal volunteers given lactulose or because
buffering by mucosal bicarbonate secretion may be more
effective.128
The presence of blood or pus in the stool raises the possibility of
an inflammatory diarrhea because of colitis or ileitis.2 Not every
inflammatory diarrhea causes blood or pus in the stool; however,
there has to be mucosal disruption as part of the inflammatory
process.
Stool fat content should be measured to see if steatorrhea is
present. Steatorrhea indicates a problem with fat absorption in the
small intestine because of either mucosal disease or luminal
factors, such as insufficient bile acid concentration, small bowel
bacterial overgrowth, or pancreatic exocrine insufficiency.35 While
it is helpful to measure stool fat output on a timed stool collection
so that steatorrhea can be quantitated, stool fat content (g/100 g
stool) tends to be elevated in many patients with steatorrhea. This
allows detection of steatorrhea on a spot stool specimen by means
of chemical tests or microscopic inspection of stool stained with a
lipophilic stain (e.g. Sudan III) if a timed collection cannot be
obtained.
There are few data regarding the utility of this sort of stool
analysis in the evaluation of chronic diarrhea. A recent study
looked at the value of measuring stool electrolytes, pH, and fat
content in a group of patients referred to one center with chronic
18
Table 7
Patterns of stool composition in chronic diarrhea8
Category/Findings
Implications
Stool weight < 200 g/24 h

No objective evidence of
diarrhea
Hyperdefecation (increased
frequency without excess
volume)
Abnormal consistency
(unformed to runny stools)
Elevated fecal osmotic gap
Steatorrhea
Secretory diarrhea without
steatorrhea (stool weight
> 200 g/24 h)
Carbohydrate malabsorption
without steatorrhea
High fecal osmotic gap
pH not always < 5.5
Steatorrhea with or without
carbohydrate malabsorption
Osmotic diarrhea
Unclassified (stool weight

> 200 g/24 h
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
Microscopic colitis or other cause
of secretory diarrhea
Ingestion of poorly absorbed

carbohydrates, malabsorption
Small bowel mucosal disease,
small intestinal bacterial
overgrowth, bile acid deficiency
Because of ingestion of poorly
absorbed ions (e.g. magnesium,
phosphate, sulfate) or
osmotically active polymers
(e.g. polyethylene glycol)
Blood or pus suggests
inflammatory causes of diarrhea
IBS, irritable bowel syndrome.
diarrhea that was difficult to diagnose or treat.8 This study suggested that results of stool analysis could be used to identify six
patterns of stool composition with important potential impacts on
diagnosis and the selection of tests for further evaluation (Table 7).
This might permit an algorithmic approach to the further evaluation of these patients.
A major limitation to this study is the selection of patients
included in the analysis. Many of these patients had previous
evaluations, and it is likely that the distribution of etiologies is
different than a population-based sample would be. It does point
out the potential for stool analysis to help with the evaluation of
these patients, however, and suggests avenues for further research.
Additional stool studies that can be done on a selective basis
include surrogate measures for fecal leukocytes (lactoferrin or
calprotectin) and pancreatic exocrine function (chymotrypsin or
elastase). Microscopy to look for fecal leukocytes is operatordependent and semiquantitative. Measurement of the leukocyte
enzymes, lactoferrin, or calprotectin is reproducible and quantitative, and can be used to follow the course of IBD.129 Technical
issues need to be addressed.130 Measurement of pancreatic enzyme
activity in stool is less predictive of pancreatic exocrine insufficiency than more traditional pancreatic function tests that involve

LR Schiller et al.
Table 8
Chronic diarrhea
Groups of patients with laxative abuse (2)
Group
Characteristics
Bulimia
Usually adolescent to young adult women;

concerned about weight or manifesting an
eating disorder; may binge eat, vomit, or
exercise excessively to neutralize excessive
food intake
Patients may have disability claim pending; illness
may induce concern or caring behavior in
others
Patients who relish being a diagnostic challenge;
may undergo extensive testing repeatedly
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
Munchausen
syndrome
Polles syndrome
(Munchausen
syndrome by
proxy)
duodenal intubation.131 At best, reduced fecal enzyme activity is

only suggestive of a diagnosis of exocrine pancreatic insufficiency
when steatorrhea is present.
Factitious diarrhea because of laxative ingestion remains a difficult clinical problem. It occurs in several scenarios that must be
recognized to facilitate diagnosis (Table 8). In theory, stool analysis can discover magnesium, phosphate, sulfate, polyethylene
glycol, senna, and bisacodyl abuse. Urine testing can be used to
find absorbed stimulant laxatives, such as senna or bisacodyl. The
performance of commercial stool assays for laxatives is not
ideal.132 Dilution of a stool sample with water can be detected by
measuring stool osmolality; because there is no mechanism to
dilute luminal contents below isotonicity, measured stool osmolality below 290 mOsm/kg is due to addition of water or dilute urine
to stool. Addition of urine to stool can be discovered by finding
substantial amounts of creatinine in stool water.14
Breath tests. Hydrogen breath tests (HBTs): The recognition
that hydrogen (H2) is produced in mammals only as a result of
bacterial metabolism of carbohydrate has led to the development
of novel technologies to detect malabsorption of carbohydrates
and/or small bowel bacterial overgrowth. Bacterial metabolism of
carbohydrate may occur under two circumstances: (i) if a carbohydrate normally absorbed by the small intestine is not absorbed
and passes into the colon, where bacteria ferment the carbohydrate
to short-chain fatty acids, CO2, CH4, and H2; and (ii) if there is a
significant increase in luminal bacteria in the small intestine that
degrades nutrients before they can be absorbed, again producing
short-chain fatty acids, CO2, and H2. Under either scenario, the
CH4 and H2 diffuse across the mucosa into the blood stream
and ultimately are excreted by the lungs. Hydrogen and CH4
in the exhaled breath can be easily quantified by a mass
spectrometer.54,133
The first clinical application of breath hydrogen tests was to
diagnose malabsorption of lactose. Lactase deficiency leads to the
failure to hydrolyze lactose into its component monosaccharides,
glucose, and galactose, with passage of lactose into the colon and
generation of H2 or CH4 by colonic bacteria. Other sugars and
sugar alcohols, such as fructose, lactulose, or sorbitol, can be used
as substrates and yield information about malabsorption or small

bowel transit time. Technical issues include the type of substrate
given, the dose of substrate, time course of sampling, and criteria
for a positive test.54
Breath hydrogen testing also can be used to assess small intestine bacterial overgrowth (SIBO). This condition is associated
with anatomic, functional, or motility abnormalities of the intestine, such as strictures, achlorhydria, motility disorders, or scleroderma. Symptoms related to SIBO include diarrhea, bloating,
weight loss, malabsorption, and anemia. The diagnostic gold
standard is quantitative culture of luminal fluid from small intestine. However, this test is uncommonly performed in clinical
practice. Bacteria in the small intestine can ferment carbohydrate
and different substrates for breath tests have been tested. The
14
C-D-xylose breath test (with measurement of radioactive CO2 in
the breath) has been the most rigorously tested and performs
fairly well, but it is only available in selected academic centers.
HBTs using glucose or lactulose as substrates, are the most commonly used tests for SIBO. The reported sensitivity and specificity for these tests varied from 27% to 93% and from 30% to 86%,
respectively, for glucose HBT, and from 17% to 89% and 44% to
100%, respectively, for lactulose HBT (compared with quantitative small bowel cultures from proximal small bowel).134140
The wide range in sensitivity and specificity suggest potential
problems with the reliability of these tests and pitfalls in basing
clinical decisions on them.
Many factors may affect the accuracy of HBTs. For example, in
addition to carbohydrate malabsorption, increased oral bacterial
flora or failure to adhere to a low-fiber diet can result in falsepositive tests. A false-negative result may also occur either because
of recent or concurrent antibiotic treatment or because of the lack
of H2-producing bacteria in an individuals microbiome. Variables
in the test protocols, such as dosage of carbohydrate administered,
method of collection, the amplitude of increase in H2 considered as
positive test can all affect the results.54,141
Rapid intestinal transit is the most important confounding variable in applying either glucose or lactulose breath hydrogen tests
to the diagnosis of SIBO. Because lactulose is a non-absorbable
disaccharide, it normally passes into the colon where it is quickly
fermented. Normally, the rise in exhaled H2 concentration signals
the arrival of lactulose in the cecum, and the time from ingestion of
lactulose represents the oral-cecal transit time (OCTT). If the
lactulose encounters bacteria in the small intestine an early or
double peak pattern may be recognized and has been interpreted
as indicating the presence of SIBO. The reliability of that interpretation has been questioned.141 A combined study linking a
glucose or lactulose breath hydrogen test with a scintigraphic
intestinal transit scan that provides an independent measure of
OCTT may improve the diagnostic accuracy of HBTs for SIBO.142
Such an approach improved the specificity of a lactulose HBT
from 70% to 100%, although the sensitivity was still limited.139,143
Therefore, the combination of a breath test and scintigraphy may
make it feasible to improve the reliability of the HBT, with either
lactulose or glucose. At this point in time, lactulose HBT by itself
should not be used to diagnose SIBO.
Bile acid testing. In normal subjects, more than 95% of the

bile acids secreted by the liver are reabsorbed in the ileum before

19
Chronic diarrhea
Table 9
Type 1
Type 2
Type 3
LR Schiller et al.
Three types of bile acid malabsorption

Category
Related conditions
Ileal dysfunction
Idiopathic
Miscellaneous
Ileal resection, disease of ileum, or bypass

No structural defect, ? transporter defect
Cholecystectomy, peptic ulcer
surgery/vagotomy, celiac disease,
diabetes mellitus, pancreatitis
reaching the cecum. When the enterohepatic circulation is disrupted, diarrhea may occur due to reduction of absorption or
stimulation of secretion by excess bile acid in the colon.
Classically, three types of bile acid malabsorption (BAM) have
been recognized as listed in Table 9. Type 1 malabsorption typically occurs in diseases of the ileum, most commonly CD, or after
surgical resection of the ileum. In general, > 50 cm of the ileum
needs to be lost before clinically significant BAM will occur. In
this situation, malabsorbed dihydroxy bile acids, such as chenodeoxycholic acid and deoxycholic acid, inhibit colonic sodium
absorption and stimulate chloride secretion causing diarrhea.144
Malabsorbed bile salt may also increase colonic permeability and
motility, thereby providing another mechanism for diarrhea.
Type 2 bile acid malabsorption is also known as idiopathic bile
acid malabsorption (IBAM); its prevalence is controversial. IBAM
was thought to be a rare cause of chronic diarrhea but has been
reported much more frequently since the introduction of SeHCAT
as a diagnostic tool (see later). The prevalence of BAM in patients
with chronic diarrhea ranges from 33% to 60% in several
reports.43,145149 In trying to sort out cause and effect, it is important
to recognize that diarrhea induced in normal subjects can cause
mild bile acid malabsorption, so some degree of BAM might result
from just the presence of diarrhea.150
Type 3 BAM is a grab-bag of diagnoses that have been associated with bile salt-induced diarrhea. Of these, the most common is
post-cholecystectomy diarrhea occurring in 1020% of individuals
after removal of the gallbladder. Sometimes, this may be described
as a loosening of stool consistency or an improvement in constipation rather than diarrhea. The pathophysiology is unclear.
Because bile acids are no longer stored in the gallbladder, they
may reside in the gut for a greater time and may be more subject
to bacterial dehydroxylation that would increase production of
diarrheogenic bile acids. Alternatively, altered motility may play a
role. Colonic transit time has been shown to be decreased after
cholecystectomy.151 The migrating motor complex may sweep
intestinal content including bile acids rapidly through the ileum
into the colon, leading to BAM type III. However, it is unclear how
frequently BAM actually occurs after cholecystectomy.152154
In most settings specific diagnostic tests for BAM are limited,
and therefore, a confident diagnosis may be difficult to obtain. The
14
C-glycocholate breath test has been abandoned because it is
laborious and neither very sensitive nor specific.155 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.150
In Europe measurement of whole body retention of a radioactive
bile acid, 84SeHCAT (selenium-75-homocholic acid taurine), is the
most widely available test for BAM. The radio-labeled bile acid is
20
absorbed and then excreted at the same rate as native cholic acid.
Following oral administration of the tracer, whole body counting
using a standard gamma camera is done after 3 h to establish a
baseline and again at 7 days to measure retention in the body. The
results usually are expressed as percentage retained at 7 days,
although half-life also can be calculated. Experts suggest that
patients with chronic diarrhea who have SeHCAT retention of
< 5% at 7 days (indicating severe bile acid malabsorption) often
respond to bile acid binding drugs, whereas patients with retention
of > 10% at 7 days (indicating more normal ileal bile acid absorption) are less likely to respond to those drugs.
There has been some controversy over the accuracy of SeHCAT
in the diagnosis of BAM. There is a wide variation of normal and
abnormal ranges in different centers and variable false-positive
and false-negative rates.156160 Some have suggested that the
SeHCAT test is of no value in the routine evaluation of chronic
diarrhea.161 Although that may be an extremely critical view, it is
important to recognize the limitations of the test. Given that BAM
may be a manifestation of diarrhea instead of the cause, it is
important to recognize that SeHCAT cannot delineate primary and
secondary BAM related to diarrhea.150 Nevertheless, it has gained
wide spread acceptance in Europe (the radioisotope is not available in the United States; consequently, American physicians have
no experience with this test).
The development of a simple blood test for bile acid malabsorption would be a major advance. Normally serum bile acid levels
are very low because of efficient clearance of bile acid from portal
blood by the liver and so it would be impossible to detect lower
than normal levels that might result from bile acid malabsorption.
When bile acid is malabsorbed by the ileum, however, the liver
compensates by increasing synthesis, which is reflected by
increased serum levels of C4 (7-hydroxy-4-cholesten-3-one), a
precursor in the bile acid synthetic pathway and a reliable reflection of CYP7A1 activity, the rate limiting step in bile acid synthesis. While increased serum C4 is consistent with ileal bile acid
malabsorption, this assay needs further validation before it can be
accepted for widespread use as a measure of BAM.155
For physicians outside Europe response to empirical treatment
with bile acid-binding drugs, such as cholestyramine, colestipol,
or colesevelam, may be a simpler diagnostic test. Failure to
respond to a therapeutic trial of bile acid binders makes BAM an
unlikely cause of diarrhea. However, if patients respond only to a
large amount of bile acid-binder (e.g. more than 12 g of cholestyramine), it is unclear whether this should be considered a positive
or a negative trial.145 One must recognize the possibility of a
falsely concluding that BAM is present because of the wellrecognized constipating effect of bile acid-binders.
Pancreatic function tests. The main reason to test pancreatic exocrine function in a patient with diarrhea is to determine
whether pancreatic exocrine insufficiency is the cause of diarrhea.
Historically, this was done by direct testing: intubating the
stomach to remove gastric acid and intubating the duodenum to
recover duodenal contents after stimulating pancreatic secretion
with secretin or a combination of secretin and CCK (secretin test
or secretin-CCK test). The test was cumbersome both for the
patient and technician, required fluoroscopy to position the
tubes properly, was poorly standardized, and was plagued by

LR Schiller et al.
intermittent shortages of the stimulants. Its performance characteristics were excellent, however, with 95% sensitivity when the
patient had advanced chronic pancreatitis.162 Intubation testing
survives in its original form at a few research centers and has
been modernized by collecting fluid directly from the pancreatic
duct at the time of endoscopic retrograde cholangiography or
EUS.162,163
Another form of direct testing does not involve intubation but
instead looks at fecal excretion of pancreatic enzymes. Measurement of fecal elastase 1, chymotrypsin, and lipase has been used
for this purpose.162,164 Fecal elastase 1 has the best performance
characteristics but is far from perfect, working best when the
pretest probability of pancreatic exocrine insufficiency is high.165
Test performance characteristics are such that these tests should
not be used for screening purposes.
One group of indirect tests of pancreatic function relies on
looking for the biochemical effects of maldigestion of natural or
synthetic substrates. For example, fat or nitrogen excretion in
stools collected for 4872 h will be elevated in patients with pancreatic exocrine insufficiency. These tests will be abnormal in
patients with advanced pancreatic exocrine insufficiency but may
not reflect lesser degrees of pancreatic exocrine dysfunction. They
also may be abnormal in any cause of malabsorption and therefore
are not specific for pancreatic exocrine insufficiency. Acceptability
is limited because these tests involve quantitative stool collection
over 2 or 3 days. Analyses of spot samples of stool for qualitative
fat excretion (using Sudan stain) or for acid steatocrit have been
proposed as alternatives, but sensitivity and specificity are
reduced.162,164,166 These excretory tests can be used to follow the
course of treatment but should not be used to make a diagnosis.
The other group of indirect tests involves ingestion of synthetic
substrates that can be cleaved by pancreatic enzymes and measures
recovery of the hydrolysis products in the urine or breath. The best
studied of these tests is the bentiromide (N-benzoyl-L-tyrosylparaaminobenzoic acid [NBT-PABA]) test. Chymotrypsin hydrolyzes the substrate, and PABA is recovered in the urine. In
advanced pancreatic insufficiency, the sensitivity is 8090% but is
much lower (3746%) with less severe impairment, making it no
better than the flip of a coin for diagnosis.162 The substrate is no
longer available in the United States. Similar results have been
seen with the dual-label Schilling test and fluorescein-dilaurate
(pancreolauryl) test.162 In contrast, good correlation of test results
with fecal fat excretion has been noted with 13C-labeled triglyceride breath tests.167169 Unfortunately, these tests are abnormal with
any cause of fat malabsorption because production of 13CO2
depends not only on hydrolysis but also absorption and metabolism of the labeled fatty acid.162
At present, there is no single, simple, reliable, and accurate test
for pancreatic exocrine insufficiency. Advanced disease is not difficult to diagnose with imaging studies, and these largely have
supplanted other forms of testing in most centers. MR imaging of
the pancreas before and after secretin is being evaluated as a test
that would combine both structural and functional elements and
eventually may prove to be useful.170 Currently, diagnosis of pancreatic exocrine insufficiency depends on clinical intuition based
on history, imaging of the pancreas, supportive evidence from
indirect testing for the consequences of maldigestion (e.g. steatorrhea), and the results of a therapeutic trial of pancreatic enzyme
replacement.
Chronic diarrhea
Conclusions
The definition of chronic diarrhea is still a matter of some
debate, with definitions of loose stool form, increased stool frequency or stool weight, and duration of symptoms at best arbitrary. It may be impossible (and perhaps unwise) to set more
stringent criteria for clinical purposes, as ultimately, evaluation
and management depends upon the patients definitions of diarrhea as much as ours.
Similarly, classification schemes need to be judged by their
utility in facilitating the care of individual patients who may not
always fit into distinct categories. This is subject to investigation,
however, and perhaps, this review will stimulate efforts to do so.
It would be ideal if the diagnostic evaluation and management
of chronic diarrhea could be reduced to a simple algorithm. At
present, this is impossible because of the number of possible
diagnoses, limited appreciation of the pretest probabilities of these
diagnoses (which depend in a critical way on geography and
specifics of individual patients), variability of test availability and
performance in different places, and the costs involved with diagnostic evaluations. In the future, researchand advances in our
ability to aggregate information about these patientsmay make
this task easier. For now taking a good history, thinking over
the more likely diagnoses and targeting testing is the best way
forward.
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Gastro 2013 APDW/WCOG Shanghai Working Party Report:

Medical University of Graz, Graz, Austria

Journal of Gastroenterology and Hepatology 29 (2014) 625

creation of a working party to the World Gastroenterology

Definition of chronic diarrhea

diarrhea.1 Stool frequency depends in large part on diet and varies

Bristol Stool Form Scale.

The differential diagnosis for chronic diarrhea is enormous, with

Journal of Gastroenterology and Hepatology 29 (2014) 625

Classification of chronic diarrhea

diagnosis of celiac disease without first categorizing the patient.

Journal of Gastroenterology and Hepatology 29 (2014) 625

Irritable Bowel Syndrome

Figure 2 Age at diagnosis for microscopic

diarrheadefined as recurrent or continuous passage of loose or

1524 2534 3544 4554 5564 6574 7584 85+

Drugs causing diarrhea

Journal of Gastroenterology and Hepatology 29 (2014) 625

Weight loss. This is common in many diarrheal diseases, often

Journal of Gastroenterology and Hepatology 29 (2014) 625

including psychological disorders such as panic attacks; urinary

Physical findings of interest in chronic diarrhea12

equivalent in other dairy foods).54 Milk ingested in large volumes

Journal of Gastroenterology and Hepatology 29 (2014) 625

Small bowel radiography. Small bowel barium studies have

Table 4 Radiographic findings in chronic diarrhea and malabsorption

Dilated caliber; increased fluid; thin, effaced

Journal of Gastroenterology and Hepatology 29 (2014) 625

Device-assisted enteroscopy (balloon or spiral overtubes)

Journal of Gastroenterology and Hepatology 29 (2014) 625

Interpretations of pathological findings on colorectal biopsy

detect occult IBD, pseudomelanosis coli (a sign of laxative use),

Includes lymphocytic colitis and collagenous colitis

mucosa in the upper lamina propria, hemorrhage, and a superficial

Small bowel biopsy. Small bowel biopsy plays an important

Journal of Gastroenterology and Hepatology 29 (2014) 625

Interpretation of pathological findings on small bowel biopsy

Brush border abnormalities

Lamina propria abnormalities

EM, electron microscopy; PAS, periodic-acid Schiff stain.

celiac disease are variable blunting or flattening of the villi that

mucosa and associated microorganisms. Application of these

Journal of Gastroenterology and Hepatology 29 (2014) 625

diarrhea. There are three areas in which serological testing has

Journal of Gastroenterology and Hepatology 29 (2014) 625

Journal of Gastroenterology and Hepatology 29 (2014) 625

physician to distinguish osmotic and secretory diarrhea based on

Patterns of stool composition in chronic diarrhea8

Stool weight < 200 g/24 h

Unclassified (stool weight

Change in stool frequency,

Ingestion of poorly absorbed

IBS, irritable bowel syndrome.

Journal of Gastroenterology and Hepatology 29 (2014) 625

Groups of patients with laxative abuse (2)

Usually adolescent to young adult women;

duodenal intubation.131 At best, reduced fecal enzyme activity is

as substrates and yield information about malabsorption or small

Bile acid testing. In normal subjects, more than 95% of the

Journal of Gastroenterology and Hepatology 29 (2014) 625

Three types of bile acid malabsorption

Ileal resection, disease of ileum, or bypass

Journal of Gastroenterology and Hepatology 29 (2014) 625