Download A Scientific Approach to the Assessment of Chronic Diarrhea and

A Scientific Approach to the Assessment of Chronic Diarrhea and Malabsorption
Ralph A. Giannella, MD
DIARRHEA
General Approach
A useful clinical classification of diarrhea includes five
categories: (1) secretory; (2) osmotic; (3) inflammatory;
(4) fatty; and (5) functional. When faced with a patient
complaining of diarrhea, two major clinical distinctions
need to be made: is the diarrhea inflammatory or noninflammatory; if non-inflammatory, is it secretory or osmotic
or fatty. These decisions can be usually made easily on both
clinical grounds and with simple diagnostic tests.
Clinical criteria distinguish between inflammatory and noninflammatory diarrhea (Fig. 1). Non-inflammatory diarrhea
is characterized by watery stools, frequently large volume
(>1L/day), without blood or pus, and the absence of
abdominal pain and fever. The stool does not demonstrate
fecal leukocytes (or only a few) or occult blood.
Inflammatory diarrhea is characterized by frequent mucoid
and/or bloody stools and may be accompanied by tenesmus,
fever, or severe abdominal pain. The stool may demonstrate
many fecal leukocytes and frequently, occult blood. Thus
the simplest test is the examination of the stool smear for
both the presence of fecal leukocytes and occult blood. Fecal
leukocytes indicate the existence of an acute inflammatory
focus somewhere in the gastrointestinal tract. The more
numerous the polys, the lower in the GI tract is the
inflammatory focus. Thus, when sheets of polys are seen,
the disease almost always represents a colitis.
Fatty diarrhea, the malabsorption of fat, should be suspected
when the patient reports oil droplets or “fat” floating on the
surface of the toilet water. Less reliable indicators of the
possibility of fat malabsorption are description of bulky,
foul smelling, greasy stools.
Inflammatory Diarrheal Disorders
Various entities, primarily infectious agents, can cause
inflammation-induced diarrheal disorders. (see Figure 2)
The epithelium is stimulated to secrete by various substances
elaborated by neutrophils, immune cells, or an activated
enteric nervous system. The latter also results in increased
propulsive contractions of the bowel. Products of the
inflammatory reaction can also lead to mucosal destruction,
increased permeability, and nutrient maldigestion and
malabsorption. Causes of an inflammatory diarrheal disease
are ulcerative colitis and Crohn’s disease, antibioticassociated colitis, radiation colitis, diverticulitis, and
infectious causes of colitis such as shigella, campylobacter,
salmonella and enterohemorrhagic E. coli and occasionally
amebiasis.
The second decision is to determine whether the diarrhea
is osmotic or secretory. Secretory diarrhea tends to be of
large volume (>1L/Day) and continues during fasting, while
osmotic diarrhea tends to be smaller volume which ceases
or markedly diminishes with fasting. The distinction is best
made by history and by examination of fecal electrolytes.
(see Figure 3)
Secretory Diarrheas
Secretory diarrheas are caused by stimuli which drive the
epithelium to secrete electrolytes and water. Increased
concentration of various mediators, caused by a variety of
stimuli, cause small intestinal enterocytes to secrete. These
include cyclic AMP, cyclic GMP, and intracellular calcium.
Causes of secretory diarrhea include: intestinal infections
and bacterial enterotoxins (cholera toxin, E. coli toxins,
etc,), neurohumoral agents (VIP, serotonin, calcitonin,
gastrin, etc.), and detergents or laxatives. A number of
detergents are intestinal secretagogues and include bile
acids, long-chain fatty acids, and certain laxatives. When
the terminal ileum has been resected or is severely damaged,
bile salts and fatty acids emptying into the colon are potent
intestinal secretagogues, resulting in the colonic secretion
of electrolytes and water and diarrhea (see Ileal Resection
Syndromes below).
Osmotic Diarrheas
Osmotically-induced diarrhea results when non-absorbable
ions or solutes are ingested or produced in the intestinal
lumen. Since they can not be absorbed, they exert an osmotic
force on the enterocytes resulting in water being drawn into
the lumen and obligatory excretion. Causes of osmotic
diarrhea include the ingestion of poorly absorbed solutes
(magnesium, phosphate-containing laxatives, antacids,
dietetic sugar substitutes [sorbitol, mannitiol] and sulfates),
maldigestion (pancreatic insufficiency and disaccharidase
deficiency), and malabsorptive disorders. When carbohydrate is being malabsorbed, a variety of factors determine
whether diarrhea occurs.
Chronic Traveler’s Diarrhea
The most common causes of persistent diarrhea in the
returned traveler are listed in Figure 4.
Diabetic Diarrhea (see Figure 5)
Diabetic diarrhea, unfortunately, is common. It occurs in
patients with long-standing insulin-requiring diabetes. These
patients always have evidence of end organ damage such
as retinopathy, nephropathy, and neuropathy especially
auotnomic neuropathy (impotence, lack of reflex
tachycardia, diminished sweating, gastroparesis, etc.). In
diabetics with diarrhea other causes of diarrhea must be
vigorously pursued and eliminated, especially potentially
treatable causes. Subjects with diabetes have an increased
likelihood of pancreatic insufficiency, celiac sprue, and
small intestinal bacterial overgrowth. These should be
investigated by examining the stool for fat, performing a
glucose hydrogen breath test, and serum tTG antibody
determinations.
The mechanism of diabetic diarrhea is not well understood
but may result from sympathetic denervation of the intestine.
The diarrhea is unpredictable, may alternate with
constipation, and spontaneously waxes and wanes. It is
usually watery, can be of very large volume, nocturnal, and
frequently is associated with urgency and fecal incontinence.
Treatment is problematic. However, some patients respond
well to therapy with diphenoxylate or loperamide and these
agents, given on schedule around the clock, should be tried
initially. Some patients will respond to the alpha-adrenergic
agonist, clonidine. The dose should be gradually increased
since it may provoke postural hypotension. Octreotide may
be helpful in some patients. If these fail, codeine, on
schedule, may be very helpful.
Hospital-Acquired Diarrhea
Diarrhea developing in the hospital is a common problem.
The major causes are C. difficile infection, complication of
a medication (particularly elixir formulations which may
contain sorbitol and mannitol), and tube feedings. Diarrhea
developing after three days in the hospital is rarely due to
either the common enteric pathogens (campylobacter,
salmnonella, or shigella) or to parasites. Therefore, stool
samples for these are rarely positive in any patient who
develops diarrhea after three days in the hospital.
Microscopic Colitis
Microscopic colitis is a common and frequently
undiagnosed cause of chronic diarrhea. It is comprised of
two entities, lymphocytic colitis and collagenous colitis.
The diagnosis requires colonic biopsy. However, the
findings may be subtle and overlooked by the pathologist
who frequently reads the specimen as “non-specific chronic
inflammation.” The key pathologic feature is an increase
in the number of intraepithelial lymphocytes. In any patient
with unexplained diarrhea and this reading, the slides should
be reviewed by a pathologist familiar with the pathologic
features of microscopic colitis. Characteristics of
microscopic colitis are listed in Figure 6.
Drugs and Diarrhea
In any patient complaining of diarrhea, a careful drug history
should be obtained. A large number of different drug classes
can cause chronic diarrhea. The patient may not have made
the connection between his complaint of diarrhea ands
taking a particular medication. Drugs having the potential
to cause diarrhea are listed in Figure 7.
Post-cholecystectomy Diarrhea
Alteration in number of bowel movements may occur in up
to 30% of patients after a cholecystectomy but only
approximately 10% have a troubling increase in the number
of bowel movements. Post-cholecystectomy diarrhea is a
bone fide entity that is poorly understood. We have no way
of predicting which patients will be so affected although it
may occur more frequently in women. Some patients may
respond to binding of bile salts, i.e., colesevelam HCI
(WelChol®) two tabs three times daily. Only by trial and
error can one determine which patients will respond.
Ileal resection Syndromes (Bile acid and
Fatty Acid Diarrheas)
Some causes of ileal resection include Crohn’s disease,
resection of carcinoid tumors, vascular accidents, etc.
Two diarrheal-malabsorptive syndromes may occur, bile salt
diarrhea and fatty acid diarrhea, both attributable to the
partial or complete interruption of the enterohepatic
circulation of bile salts, depending upon the magnitude of
the ileal resection (see Figure 8). In general, when less than
100 cm of terminal ileum are resected, the reduction of bile
salt absorption is modest and the liver can compensate by
increasing the synthesis and secretion of conjugated bile
salts. Fat malabsorption is modest. The malabsorbed bile
salts and their metabolites stimulate colonic secretion of
electrolytes and water with resultant diarrhea. Diagnosis
should be suspected in anyone who develops diarrhea in
the post-operative period following ileal resection or bypass.
Treatment is simple and effective. Cholestyramine or
colesevelam bind bile salts and prevents their wastage into
the colon in active form. Patients usually respond promptly
and the dose can then be reduced should constipation ensue.
Side effects of cholestyramine include steatorrhea,
hypoprothrombinemia, and hyperchloremic acidosis. The
possibility of drug binding by the resin should also be
considered in patients taking medications.
If greater than a 100 cm of the ileum are removed, the active
absorptive surface for bile salts is absent resulting in a
massive loss of bile salts into the colon. This loss exceeds
the capacity of the liver to compensate by increasing bile
salt synthesis and results in a diminished bile salt pool,
resulting in a low postprandial intraluminal bile salt
concentration (<CMC) and steatorrhea. In contrast to bile
salt diarrhea, the secretogogues in this case are malabsorbed
fatty acids which enter the colon, undergo hydroxylation,
and cause diarrhea. Steatorrhea can be severe and lead to
malnutrition. Treatment is difficult and generally requires
a low fat diet, calcium supplements, antidiarrheals, and
vitamin supplements. Cholestyramine or other bile salt
binders are of no benefit and may worsen the steatorrhea
and diarrhea.
Other consequences of this massive interruption of
enterohepatic circulation of bile salts include cholelithiasis
and renal stones. Because of the increased concentration
of fatty acids in the lumen of the small bowel, calcium is
complexed to the malabsorbed negatively-charged fatty acid
molecules. The reduction in the concentration of
intraluminal calcium results in the unopposed colonic
absorption of dietary oxalates resulting in increased
excretion of oxalate in urine, (so-called enteric
hyperoxaluria) and the formation of calcium oxalate kidney
stones. Because of the decreased bile salt pool, cholesterol
gallstones may occur.
Severe and elusive diarrheas
After a thorough work-up, the diagnosis may remain elusive.
In this circumstance, the following entities should be
particularly considered, i.e., microscopic colitis,
eosinophilic gastroenteritis, diabetic diarrhea, chronic
idiopathic diarrhea, factitious diarrhea, villous adenoma,
and hormone-secreting tumors.
MALABSORPTION
Malabsorption Disorders
The commonest causes of malabsorption seen include
pancreatic insufficiency, small bowel bacterial overgrowth
syndromes, ileal resection, and celiac disease. Less common
causes include giardiasis and short bowel syndrome. Rare
causes include Whipple’s disease, lymphangiectasia,
agammaglobulinemia, and abetalipoproteinemia.
Classification of Malabsorption
Since there are so many potential causes of malabsorption,
a simple classification is necessary. A useful classification,
which allows virtually all causes of malabsorption to be
placed in one of four categories is: 1) decreased pancreatic
secretion; 2) decreased bile salts; 3) mucosal diseases; and
4) lymphatic disease. (see the slide presentation)
Useful Tests in the Workup of Malabsorption
Several tests are very helpful in the differential diagnosis
of malabsorption disorders. These include a stool Sudan
stain for fat, d-xylose test, small intestinal biopsy, celiac
serology, Vitamin B12 level, and the glucose hydrogen
breath tests. The specific usefulness and limitations of each
is shown in the slide presentation.
Mucosal diseases
The number of illnesses that alter the mucosa of the small
intestine is large and varied. Specific diseases that directly
involve the small bowel are listed below according to the
value of the small intestinal biopsy in their diagnosis (see
Figure 9).
Celiac Disease
Celiac disease is an illness which presents in infancy or
later in life most commonly with diarrhea and malabsorption
and is a consequence of an immune mediated process
induced by gluten from cereals, especially wheat. There is
a genetic susceptibility and a strong association with
particular HLA haplotypes, HLA-DQ2, or DQ8. In Western
societies, approximately 95% of celiacs are either haplotype
DQ2 or DQ8.
In recent years new concepts have emerged regarding celiac
sprue. Celiac disease is not a rare disease and is much
commoner than previously believed, i.e., 1 in 150 inmost
Western populations. Surveys of normal blood donors in
the United States suggest similar frequencies. Secondly, we
now appreciate that a large body of patients with the typical
mucosal lesion, discussed below, have few if any symptoms.
This state has been called latent sprue. Feeding such patients
large amounts of gluten induces symptoms. Thirdly,
although the usual manifestations are diarrhea and
malabsorption, the illness may manifest as a selective
malabsorption of single nutrients, i.e., iron, vitamin D etc.,
or even without prominent gastrointestinal symptoms or
with vague non-specific symptoms. The symptoms do not
bear a reliable relationship to the severity of the mucosal
lesion, i.e., mild symptoms or even no obvious symptoms
can occur in the face of subtotal villus atrophy. In fact,
patients can present with extra-intestinal manifestations in
the absence of gastrointestinal symptoms. Such extraintestinal manifestations include anemia, osteopenia,
neuropathy, amenorrhea, infertility, and various skin lesions.
We also know that 25-50% of patients with celiac disease
have hemoccult positive stools probably representing blood
loss from the histopathologic lesion. Thus, celiac disease
can manifest itself in three forms listed in figure 10. These
days, most cases of celiac disease are detected before full
blown malabsorption and striking nutrient deficiencies are
apparent.
Associated Conditions
Celiac sprue occurs with increased frequency in patients
with various conditions including dermatitis herpetiformis,
diabetes mellitus (type 1), Down’s syndrome, and IgA
deficiency. Conversely, a number of conditions occur more
frequently in the patient with celiac sprue. Some of these
include Diabetes mellitus, Sjogren’s syndrome, autoimmune
thyroid disease, and epilepsy.
High Risk Groups
A number of conditions have an increased likelihood of
being complicated by celiac sprue. The approximately
frequency of celiac disease in these conditions are listed in
Figures 11 and 12.
Diagnosis
In addition to the signs, symptoms, and laboratory
abnormalities mentioned above, the diagnosis should also
be suggested by an abnormal appearance of the duodenum
on upper GI endoscopy. The abnormalities suggesting celiac
disease, and mandating biopsy, include a reduced number
of duodenal folds, scalloping of folds, mucosal grooves,
and a mosaic pattern. However, these endoscopic findings
have a positive predictive value of only 60-70%.
Furthermore, “all that scallops is not celiac disease.”
The usual cardinal diagnostic maneuver is the small
intestinal biopsy which is usually consistent with the
diagnosis. Serological tests are available which can aid the
diagnosis of celiac sprue. The various antibodies available
include anti-gliadin antibodies, anti-reticulin antibodies,
anti-endomysial antibodies and tissue transglutaminase
(tTG). They can be obtained individually or as a package.
I recommend obtaining tTG and if positive the antiendomysial antibody, which is highly specific for celiac
sprue, nearly 100%. Thus, a positive test strongly suggests
the diagnosis and can be used as an indication for a small
intestinal biopsy. Either tTG and anti-EMA, however, are
not quite as sensitive, i.e., only approximately 70%. It can
be negative in patients who are IgA deficient, children less
than two years of age, and in celiacs who have a mild
enteropathy. Thus, a negative tTG or anti-EMA, does not
absolutely exclude the diagnosis of celiac sprue. Thus, when
suspicion is high, one should proceed to the small intestinal
biopsy. Another value of tTG and anti-EMA is to follow
the course of sprue and the effectiveness of excluding gluten
from the diet. In the patient strictly observing a gluten-free
diet, tTG and anti-EMA becomes negative. This may take
as much as a year of a strict gluten free diet, however.
It should be remembered that both these tests are IgA tests
and that if a subject can not make IgA, the tests can be
falsely negative. Thus, a simultaneous serum IgA should
be drawn.
A positive anti-EMA or positive tTG Elisa does not obviate
the need for a small bowel biopsy to confirm the diagnosis
of celiac disease. A small bowel biopsy is still the “gold
standard” in diagnosis.
Histopathology of Celiac Sprue
One of the most dramatic morphologic pictures of small
intestinal disease is the so-called “flat” mucosa or total
villous atrophy characteristic of advanced celiac sprue. In
contrast to the normal, villi may be absent. Other features
include deep, hyperplastic crypts, alteration of the surface
epithelium from the normal columnar to a cuboidal
epithelium infiltrated with lymphocytes, i.e., intraepithelial
lymphocytes, and a lamina propria containing increased
infiltration with lymphocytes and plasma cells. Formerly,
it was thought that this lesion and appearance was
characteristic of and perhaps diagnostic of celiac sprue. We
have learned that celiac sprue can exist with a less severe
lesion, i.e., villous structure evident and even near normal.
A “flat’ biopsy (subtotal villous atrophy) is NOT required
for the diagnosis of celiac sprue. The “minimal” lesion
consistent with celiac sprue is a preserved villous
architecture but with an increased number of intra-epithelial
lymphocytes. We have also learned that “all that flattens is
not sprue.” A list of disorders that can result in a “flat”
mucosal biopsy is given in (see Figure 13).
Treatment
Treatment with a gluten-free diet which must be strictly
observed. It is highly recommended that newly diagnosed
patients consult with a dietician knowledgeable in the
intricacies of this diet. Patients should also be encouraged
to join a celiac disease support group. Symptomatic
improvement begins in as soon as a week. However, it may
take as long as a year or more for the anti -EMA test to
become normal and for the intestinal lesion to return to
normal. The differential diagnosis of a patient who fails to
respond or in whom symptoms recur is given in Figure 14.
Complications of Celiac Sprue
Unfortunately, not all patients respond well to a gluten free
diet and not all patients remain in remission. A number of
patients are initially resistant to gluten withdrawal and do
not improve. These have been called unclassified sprue and
more recently auto-immune enteropathy. Some resistant
cases initially present with or evolve with time into
collagenous sprue, a lesion characterized as a sub epithelial
band of collagen. Such patients do poorly. Other
complications of sprue include intestinal lymphoma, which
initially may be mistaken for celiac sprue, steroid resistant
ulcerative jejuno-ileitis, and osteopenia.
SMALL INTESTINAL BACTERIAL
OVERGROWTH SYNDROMES
The blind loop syndrome is usually manifest by gas,
bloating, abdominal distress, diarrhea, steatorrhea, and
frequently macrocytic anemia. Other clinical manifestations
seen more rarely include protein-losing enteropathy
malnutrition, peripheral neuropathy, gastrointestinal blood
loss, arthritis, and abdominal pain. The blind loop syndrome
occurs as the result of proliferation of aerobic and anaerobic
bacteria along the length of the small intestine. Lesions
predisposing to bacterial overgrowth include motor or
structural abnormalities of the small intestine that result in
intestinal stasis (Figs. 15 and 16). When normal small bowel
motor activity (migrating myoelectric complex, MMC) is
absent, ingested bacteria colonize and proliferate to reach
population levels of 106 to 109 organisms/ml. The flora is
also qualitatively different from normal with colonization
by E. coli and other enteric organisms as well as anaerobes
such as bacteroides, clostridia, etc. Structural disorders
predisposing to small intestinal bacterial overgrowth include
Billroth II anastomosis (stasis in the afferent limb), multiple
jejunal diverticula, enteroenteric fistula, intestinal stricture,
or anastomosis with bypassed segments of intestine.
Predisposing motility disorders include intestinal
scleroderma, idiopathic pseudo-obstruction, and diabetic
enteropathy. Small intestinal bacterial overgrowth may also
occur in the elderly without obvious structural
abnormalities. Some of these patients may have abnormal
motor activity, i.e., absence of the MMC.
Pathophysiology
Two major manifestations of the disorder, macrocytic
anemia and diarrhea-steatorrhea, are a direct consequence
of bacterial metabolic activity (see Figure 17). The anemia
is a consequence of the intraluminal competition of bacteria
for ingested vitamin B12. The intraluminal bacteria consume
vitamin B12 bound to intrinsic factor thereby making it
unavailable to the host. Steatorrhea occurs because of bile
salt metabolism by the anaerobic flora of the small intestine
which deconjugate and dehydroxylate bile salts, rendering
them inefficient detergents for the emulsification and
absorption of fat as well as decreasing their concentration
below the critical micellar concentration. Unconjugated bile
salts may also injure the mucosa, resulting in morphologic
abnormalities. In addition, glycosidases and proteases
secreted by the bacteria directly injure the microvillus
membrane of the small bowel resulting in malfunction of
various enzymes and transporters.
Diagnosis
The diagnosis of bacterial overgrowth in the small intestine
should be suspected in any patient with diarrhea,
malnutrition, malabsorption, macrocytic anemia or vitamin
B12 deficiency or increased serum folate levels (see Figure
18). The possibility of bacterial overgrowth should be
considered particularly in patients with the structural or
motor lesions of the small intestine enumerated above.
Vitamin B12 deficiency should be suspected with macrocytic
anemia and peripheral neuropathy and documentation
should be sought with measurement of serum vitamin B12
level. Increased serum folate levels occur because of
bacterial production of folates. Small intestinal x-rays
should be done to exclude one of the aforementioned
anatomical lesions. The gold standard for diagnosis is the
demonstration of increased concentrations of bacteria in
the lumen of the proximal small intestine. Quantitative and
qualitative jejunal microbiology is not readily available in
most hospital laboratories. Detailed enumeration and
quantitation of the individual species is not required for
routine clinical purposes. Quantitation of total aerobic and
anaerobic flora suffice. If quantitative culture of the jejunal
aspirate is not possible, the diagnosis can be made by the
use of various breath tests. (see below and Figure 19)
Breath Tests
Several breath tests are useful in confirming the diagnosis
of the blind loop syndrome. Measurement of hydrogen
breath excretion after lactulose or glucose ingestion (an
early rise in H2 concentration 30 to 60 minutes after
ingestion) are the easiest to perform and the most widely
available. The C13 or C14 xylose breath test can also be used.
However, in the face of short bowel, ileal disease (resection
or bypass), these tests can be falsely positive due to rapid
intestinal transit. While these tests are non-invasive, both
false positive and false negative results can limit their
reliability. However, in spite of this limitation, the glucosehydrogen breath test is a useful test to search for and
document small intestinal bacterial overgrowth and to follow
the response to therapy. It is thought to be subject to fewer
false positive results than is the lactulose breath test.
Treatment
The treatments of the bacterial overgrowth syndrome are
multi faceted, should be both supportive and specific, and
depend upon the underlying disorder. In all cases, strict
attention to nutrition, and replacement of vitamins, minerals
etc. must be done. If possible, surgical correction of the
underlying intestinal lesion should be considered, i.e.,
strictures, entero-enteric fistulae. Unfortunately, these are
uncommon and the more common causes are not amenable
to surgical correction. Antibiotic therapy, to control the
bacterial flora, is the mainstay of therapy. A single course
of antibiotics (ciprofloxacin 500 mg BID for 7 days and
metronidazole 250 mg tid for 7 days) sometimes has a longlasting beneficial effect. However, frequently repeated
courses are required and sometimes, cyclical antibiotic
therapy may be necessary, one week on one week off. Since
the anatomical lesions may not be amenable to correction,
repopulation of the gut by bacteria occurs and thus repetitive
cycles of antibiotics may be required. If the response to
antibiotic treatment is suboptimal, which it frequently may
be, reducing fat intake, especially long chain fatty acids
and replacement with medium chain triglycerides (MCT’s)
may be helpful. Parenteral replacement of fat soluble
vitamins may be required. In some cases TPN may be
required.
Figure 1: Two major clinical diarrhea syndromes
Inflammatory
Mucoid, blood stools
Tenesmus, fever, severe cramps
Small volume, frequent BM’s
Dehydration unusual
Fecal leukocytes, occult blood
Salmonella, Shigella, E. coli
Campylobacter, C. difficile, IBD, radiation
Ischemic colitis
Non-inflammatory.
Watery stools
No blood, pus, fever, or tenesmus
Large volume
Dehydration frequent
No fecal leukocytes or occult blood
Viruses, protozoa, toxigenic bacteria
Drugs, IBS, microscopic colitis etc.
Figure 2: Causes of Inflammation-induced diarrhea
Bacterial infections
Other infections (esp in hospital)
Inflammatory bowel disease
Other colitides
Radiation, Ischemia
Figure 3: Features of osmotic and secretory diarrhea
Osmotic
Small volume
Stops or markedly reduces with fasting
Osmotic gap > 50
Secretory
Large volume, watery
Diarrhea continues with fasting
Minimal osmotic gap
Salmonella, Campylobacter, Shigella, E. coli
C. difficile
Figure 4: Causes of persistent diarrhea in the returned traveler (“Chronic traveler’s Diarrhea”)
Persistent infection (giardia, ameba, salmonella, campylobacter, yersinia)
C. difficile colitis
Lactose intolerance
Tropical sprue
Unmasked celiac disease
Small bowel bacterial overgrowth
Unmasked IBD
Post-infectious IBS
Figure 5: Characteristics of Diabetic Diarrhea
Occurs in 1-5% of diabetics
Usually type 1 diabetics with autonomic neuropathy or other complications
Variable clinical course—episodic and may alternate with constipation
Correlates poorly with state of glycemia
Probably due to sympathetic denervation
25% may have steatorrhea, exclude celiac disease, bacterial overgrowth, pancreatic insufficiency
most common cause –Metformin
Treatment—Anti-diarrheals, alpha adrenergic agonists (clonidine), sandostatin, codeine
Figure 6: Characteristics of microscopic colitis
A common cause of chronic diarrhea
Starts abruptly, watery diarrhea and frequently weight loss
Normal colonoscopy, diagnosis by random biopsies
Sigmoidoscopic biopsies are usually adequate
Can co-exist with celiac disease
May be caused by drugs, i.e. NSAIDs, ranitidine, flutamide, ? PPI’s
May spontaneously abate in 2 + years
Treatment is anti-diarrheals, budesonide
Figure 7: Drugs that can cause diarrhea
Antibiotics
Anti-cancer drugs
Anti-depressants
Anti-hypertensives
Anti-convulsants
Cholesterol-lowering drugs
Oral hypoglycemics (biguanides)
GI drugs (H2RA, PPI’s, 5-ASA, PG analogs, Mg).
Colchicine
Diuretics
Theophylline
Farthing MJG, Kelly CP: AGA Postgraduate course, May 2000
Figure 8: Comparison of bile acid and fatty acid diarrheas
(Adapted from Chang EB and Binder HJ: AGA-UTP Unit # 25. Diarrheal Diseases. 1992).
Bile salt diarrhea
Fatty acid diarrhea
Length of resection
small (<100 cm)
large (> 100 cm)
BA pool size
normal
decreased
Duodenal BA concentration
normal
decreased
Steatorrhea
none or minimal
> 20 gms/day
Responds to low fat diet
no
yes
Responds to cholestyramine
yes
no
Figure 9: Diagnostic value of the small intestinal biopsy
A. Disorders in which biopsy is diagnostic: diffuse lesions
Whipple’s disease
agammaglobulinemia
abetalipoproteinemia
B. Disorders in which biopsy may be diagnostic; patchy lesions
Celiac disease
intestinal lymphoma
intestinal lymphangiectasia
eosinophilic enteritis
mastocytosis
amyloidosis
Crohn’s disease
collagenous sprue
Giardiasis
Coccidiosis
cryptosporidiosis
mycobacterium avium intracellulare (MAI)
C. Disorders in which biopsy is abnormal but not diagnostic
celiac sprue
unclassified sprue
tropical sprue
viral gastroenteritis
bacterial overgrowth
radiation enteritis
folate of vitamin B12 deficiency
Modified from: Trier JS: Intestinal malabsorption: differentiation of cause. Hosp Prac 1988;23:195-211.
Figure 10: Forms of Celiac Disease
Classic (GI symptoms)
Atypical (no GI symptoms)
Asymptomatic (silent)
Figure 11: Prevalence of Celiac Disease
Dermatitis herpetiformis
First degree relative
Down’s syndrome
Type 1 diabetics
Primary biliary cirrhosis
Autoimmune thyroid disease
Sjogren’s disease
Selective IgA deficiency
in High Risk Groups
100%
5-20%
4-14%
6%
6%
4%
3%
1-3%
Figure 12: Prevalence of celiac disease in the United States
Not at risk individuals
1:133
Symptomatic individuals
1:56
First degree relatives
1:22
Second degree relatives
1:39
Figure 13: Causes of a “Flat” small intestinal Biopsy
celiac sprue
collagenous sprue
giardiasis
lymphoma
tropical sprue
cow’s mild allergy
bacterial overgrowth
eosinophilic enteritis
viral gastroenteritis
Zollinger Ellison syndrome
Figure 14: Differential Diagnosis of Non-responsive Celiac Disease
Incorrect diagnosis
Continuing gluten intake
Refractory sprue
Lymphoma
Autoimmune enteropathy
Ulcerative jejuno-ileitis
Other illnesses (microscopic colitis, pancreatic insufficiency, bacterial overgrowth)
Figure 15. Motor disorders predisposing to bacterial overgrowth syndromes
Diabetic enteropathy
Scleroderma
Idiopathic intestinal pseudoobstruction
SBBO of the elderly
Figure 16. Structural lesions predisposing to the bacterial overgrowth syndrome
Blind intestinal pouch
Multiple jejunal diverticula
Afferent loop syndrome (Billroth 2 anastomosis)
Stricture of small intestine
Side to side entero-enteric anastomoses
Bypassed small intestine
Entero-enteric or colo-enteric fistulae
Figure 17. Pathophysiology and consequences of bacterial overgrowth
Steatorrhea
Anaerobes deconjugate bile salts
Vitamin B12 malabsorption
Bacterial competition for B12 and consumption of B12
Protein loss
Mucosal damage, protein-losing, bacterial catabolism
Carbohydrate malabsorption
Bacterial catabolism, mucosal damage
Figure 18: Diagnosis of the bacterial overgrowth syndrome
Clinical suspicion-anemia, steatorrhea, diarrhea, predisposing lesions
Document malabsorption-of fat, xylose, or vitamin B12
Rule out-mucosal disease, pancreatic disease, ileal disease
Specific tests
Figure 19: Specific diagnostic tests for the bacterial overgrowth syndrome
Small bowel culture—THE GOLD STANDARD
Breath tests— Glucose hydrogen, Lactulose-hydrogen (unreliable), 13C-xylose
(not generally available)
Therapeutic trial—monitor breath test