Documente Academic
Documente Profesional
Documente Cultură
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
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
LR Schiller et al.
Chronic diarrhea
Classification
Figure 1
Chronic diarrhea
Table 1
LR Schiller et al.
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
LR Schiller et al.
Chronic diarrhea
Microscopic Colitis
0.4
0.35
0.3
6
5
0.25
0.2
0.15
Cases per
1000 pop /
year
4
3
0.1
0.05
Cases per
1000 pop /
year
MC
0
039
4059
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
Age years
Table 2
Age years
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
LR Schiller et al.
Chronic diarrhea
Table 3
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
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.
Classical findings
Celiac disease
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
13
Chronic diarrhea
Table 5
LR Schiller et al.
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
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
LR Schiller et al.
Table 6
Chronic diarrhea
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
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
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.
Table 7
Category/Findings
Implications
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
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
Group
Characteristics
Bulimia
Secondary gain
Munchausen
syndrome
Polles syndrome
(Munchausen
syndrome by
proxy)
19
Chronic diarrhea
Table 9
Type 1
Type 2
Type 3
LR Schiller et al.
Related conditions
Ileal dysfunction
Idiopathic
Miscellaneous
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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