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11.1 Pathogenesis The four
basic mechanisms that cause chronic diarrhea are osmotic, secretory and
exudative factors, and abnormal intestinal transit (Table
11).
If the diarrhea ceases when fasting, or if there is a
significant osmotic gap in the stool water, then an osmotic cause for the
diarrhea is suspect. Examples include diarrhea after ingesting milk (a
result of lactase deficiency) or drugs such as laxatives and antacids, or
the excessive use of artificial sweeteners such as sorbitol and mannitol,
which contain polycyclic alcohols.
If the patient's diarrhea persists when fasting (such
as may occur at nighttime when the diarrhea awakens the person from
sleep), a secretory diarrhea is likely. Secretory
diarrhea usually arises from infection or inflammation associated with
toxigenic and invasive bacteria. Secretory diarrhea may also result from
the spillage of excess bile acids into the colon (choleretic enteropathy)
or from the cathartic effect of hydroxy fatty acids arising from the
colonic bacterial action on malabsorbed fat. Very rarely, secretory
diarrhea can arise from a tumor producing an intestinal secretagogue
(e.g., pancreatic islet cell tumor producing vasoactive intestinal peptide
or gastrin).
Exudative diarrhea results from mucosal damage to the
small or large bowel, which interferes with absorption of salt and water,
and may be associated with the exudation of serum proteins, blood, and
mucus and sloughed cells. This mechanism is seen in infectious,
inflammatory and neoplastic disorders.
Disorders of intestinal transit may give rise to diarrhea secondary to
abnormal intestinal motility in hyperthyroidism or diabetic neuropathy.
Scleroderma leads to bacterial overgrowth and steatorrhea (as can the
rapid transit in hyperthyroidism). The mechanism of diarrhea in these
conditions relates to a combination of bacterial overgrowth, bile salt
wastage and disorders of motility (slow or rapid intestinal transit). Retention of solute molecules within the bowel lumen
generates osmotic forces that retard the normal absorption of water (Table
12). Practical examples include poorly absorbed carbohydrates
or a divalent ion. Poorly absorbed divalent ions (e.g., phosphate, sulfate
and magnesium) are the laxative constituents of several common antacids
and saline purges. Since the "pores" through which ions are
absorbed are highly charged, these polyvalent ions tend to be absorbed
slowly. Thus, they accumulate within the intestinal lumen, raise the
osmolality, and so retard the normal absorption of water or even act to
draw water from the circulation into the intestinal lumen. TABLE 12. Causes of osmotic diarrhea Carbohydrates Divalent ions Carbohydrates
constitute the other major group of osmotic agents. Some are poorly
absorbed by everybody; lactulose, for example, was developed to be a
nonhydrolyzable, nonabsorbable disaccharide that would act as a cathartic.
The action of lactulose mimics the effects of primary lactase
deficiency. This condition normally develops after weaning in the
majority of African-, Caribbean- or Asian-Canadians and occurs in 30% of
persons with southern European ancestry. The unabsorbed lactose acts
osmotically to retain water in the small intestine. In fact, any disease
that interferes with carbohydrate absorption (e.g., impaired intraluminal
digestion due to pancreatic disease, primary disaccharidase deficiencies,
and secondary disaccharidase deficiencies due to small bowel disease) will
lead to osmotic diarrhea. Since carbohydrates are not inert in the colon,
their metabolism leads to further osmotic forces. Once carbohydrate
reaches the fecal flora, anaerobic fermentation occurs (Figure
12). Intermediary products are ethanol and formic, succinic
and lactic acids. These products are further consumed to varying degrees.
CO2 and H2 are rapidly absorbed, and CO2
rises in exhaled air. (Exhaled H2 is the basis for the hydrogen
breath test described earlier.) Excess gas production causes borborygmi
and flatus rich in H2. Short-chain fatty acids (SCFAs) are also
produced (acetic acid, propionic acid and butyric acid) and account for
the acidic stool pH noted in diarrhea of carbohydrate malabsorption. The
caloric loss due to carbohydrate malabsorption is diminished to the extent
that short-chain fatty acids can be absorbed from the colon (where they
may be used as nutrients by the colonocytes), thus "salvaging"
some of the malabsorbed carbohydrates that enter the colon.
The consequences of malabsorption are as follows: With
minor impairment of sugar absorption, colonic fermentation is complete and
only small amounts of excess solute are present in stool water. Stool
volume and stool pH do not initially change much, and up to three-quarters
of the glucose energy is returned to the body in the form of short-chain
fatty acids (colonic "salvage"). As the extent of carbohydrate
malabsorption increases, more short-chain fatty acids are formed than can
be reabsorbed. This results in diarrhea due to the presence of osmotically
active short-chain fatty acids. The stool pH consequently begins to fall,
which further decreases colonic salvage.
Clinically, osmotic diarrhea should stop when the
patient stops ingesting the poorly absorbed solute. Stool analysis should
not reveal fat, RBC or WBC. There should be a positive osmotic gap - that
is, stool osmolality minus stool Na+ plus stool K+
times 2 (multiplied by 2 to account for anions) is greater than 50, the
size of the osmotic gap being approximately equivalent to the
concentration of poorly absorbed solutes in fecal water. The basal electrical rhythm
of the small intestine alters the excitability of the muscle cells. The
motility patterns of the small intestine consist of three essential
patterns: (1) migrating motor complex (MMC), periodic bursts of
contractile activity lasting at least 5 minutes that are succeeded by
periods of quiescence and appear to migrate down the small intestine at a
slow rate of less than 5 cm/min; (2) minute rhythm, regular groups of
between 3 and 10 contractions that occur at intervals of 1 to 2 minutes,
separated by periods of quiescence, and appear to migrate down the small
intestine at a rapid rate of 60-120 cm/min; (3) migrating action potential
complex, a single ring contraction or single burst of spike potentials
that migrates down the intestine at a rate exceeding 90 cm/min.
These forms of small intestinal motility control the
rate at which material travels along the intestine and hence arrives at
the anus. Gastrointestinal motor activity also determines the time and
thus the degree of contact between gut contents, the digestive enzymes and
the absorptive epithelium. Accelerated transit of material through the gut
produces diarrhea by limiting digestion and absorption.
Understanding of motility-associated diarrhea remains
limited, and only rudimentary measures of intestinal myoelectrical
activity exist for humans. The oral-anal transit times of radiolabeled
markers, radiopaque tubing, or nonabsorbable carbohydrate markers provide
the only clinical assessments. Even small intestinal motility, unlike
esophageal motility, remains a research tool.
The ileocecal valve is important to gut function. The
ileocecal sphincter extends over a 4 cm length of distal small intestine
and produces a high- pressure zone of about 20 mm Hg. Distention of the
ileum results in a decrease in the ileocecal sphincter pressure, whereas
distention of the colon results in an increased pressure in this area. The
ileocecal valve slows down intestinal transit and prevents backwash from
the colon. By this mechanism the ileocecal valve is important in
regulating intestinal transit. Removal of the ileocecal valve during
surgery will result in marked intestinal hurry as well as the potential
for bacterial overgrowth from fecal "backwash." Disorders that
impair peristalsis in the small gut allow bacterial overgrowth, resulting
in diarrhea. Lastly, premature evacuation of the colon because of an
abnormality of its contents or because of intrinsic colonic
"irritability" or inflammation results in a reduced contact
between luminal contents and colonic mucosa and, therefore, in more
frequent, liquid stools. The small intestine
normally secretes as well as absorbs fluid and electrolytes; the secretion
rate is lower than the absorption rate. Therefore, the net effect of small
bowel transport is absorption of fluid. This is an important concept,
because it means that a pathophysiologic event may reduce the absorption
rate in either of two ways: by stimulating secretion or inhibiting
absorption. Either or both can result in what is clinically recognized as
secretory diarrhea. It is usually difficult, if not impossible, to
ascertain which of the two events is predominant. For clinical purposes,
it seems best to consider inhibition of ion absorption and stimulation of
ion secretion together.
The prototype of secretory diarrhea is Vibrio cholerae;
its clinical description first aroused interest in the secretory process
as a mechanism for diarrhea (Table
13). TABLE 13. Causes of secretory
diarrhea Pathophysiologic mechanisms Clinical syndromes Bacterial secretagogues
fall into two major classes. The first class comprises large (MW 84,000),
heat-labile proteins, of which cholera enterotoxin is the prototype. These
toxins appear to stimulate secretion by activating mucosal adenylate
cyclase and thus increasing cyclic AMP levels in the mucosa. The
intracellular "messenger" for secretion is less well defined;
cyclic AMP is considered important, though there are additional steps that
might also involve intracellular levels of Ca++ and the calcium
regulatory protein, calmodulin. A second class of secretagogues comprises
smaller proteins that are heat-stable. The best studied is the ST
(heat-stable toxin) of E. coli, which stimulates secretion by activating
mucosal guanylate cyclase, leading to higher levels of cyclic GMP in the
mucosa.
Bacterial toxins, however, are only part of the story.
Secretion is also stimulated experimentally by hormones, peptides acting
locally (paracrine hormones), luminal factors (e.g., dihydroxy bile acids
and fatty acids), neurotransmitters, prostaglandins and physical factors
(e.g., distention). Bile acids and fatty acids not absorbed in the small
intestine evoke secretion of electrolytes and water by the colon. The
exact mechanism(s) for this are uncertain. Both groups have multiple
effects on the bowel, including stimulation of secretion, increased
intestinal permeability and transient alterations in morphology.
One or more humoral stimuli can elicit a massive
secretion of water and electrolytes from the small bowel. The colon is
usually not involved directly, but it may be unable to adequately reabsorb
the fluid load imposed on it. A key question, difficult to answer, is
"What is the responsible hormone?" Putative secretagogues
include vasoactive intestinal peptides in the pancreatic cholera syndrome,
calcitonin in medullary carcinoma of the thyroid, gastrin in the Zollinger-Ellison
syndrome, serotonin in the malignant carcinoid syndrome, and glucagon in
glucagonomas. Prostaglandins are also potent stimulators of intestinal
secretion. Diarrhea secondary to prostaglandin-stimulated intestinal
secretion is a common side effect.
The intestinal distention that occurs with obstruction
or ileus also produces a local secretory state proximal to the
obstruction. The mechanism is not entirely clear and may be related to
changes in permeability (as tight junctions are stretched and broken) as
well as to direct, perhaps neural, stimulation of secretory mechanisms.
Secretory diarrhea is recognized clinically by four
features: (1) the stools are large-volume, watery and often >1 L/day;
(2) the diarrhea persists during fasting; (3) there is a measured stool
osmolar gap of < 50 mOsm/L; and (4) patients with secretory diarrhea do
not have excessive fat, blood or pus in their stools, but often develop
depletion in fluid, Na+ and K+.
Therapeutically, the offending agent must be removed. A
variety of empirical therapies that influence the secretory process (e.g.,
somatostatin, prostaglandin inhibitors, phenothiazines, calcium channel
blockers, a2-adrenergic agonists and lithium)
may be effective but should be reserved for use in a research center. Oral
glucose-saline replacement therapy is useful for maintenance of hydration.
For bile acid-induced diarrhea, cholestyramine works well unless there has
been a greater than 100 cm resection of the terminal ileum. Exudation is a far simpler
concept. Structural disruption of the intestinal wall by diffuse
ulceration, inflammation, infiltrations and tumors will add cellular
debris, mucus, serum proteins and blood to the lumen. The effects on stool
volume will be most pronounced when the lesions also involve the colon,
since there will be little opportunity for normal mechanisms of colonic
fluid and electrolyte absorption to compensate for the increased volume of
chyme. The possibility that the
diarrhea is self-induced must be considered when a patient complains of
chronic diarrhea and when the routine investigations are negative. In
general, abusing laxatives, diuretics and sometimes thyroid hormones will
induce diarrhea. Often the diarrhea is sufficiently severe to cause
electrolyte disturbances, acid-based problems and dehydration. The
diagnosis can be extremely difficult since the history is often misleading
or not obtained. The usual investigations (including sigmoidoscopy and
radiographs) will be negative, unless the patient is taking a drug that
can cause melanosis coli (brown-black pigmentation of the colonic mucosa),
such as the anthracene laxatives senna or aloe. Stool analysis for Mg++,
sennas or phenolphthalein may reveal the culprit. Finding packages of
laxatives and other drugs in room searches is often the only method that
permits the diagnosis; this approach has been criticized because of
ethical considerations, but may be the only way to uncover the problem.
Ethical issues and respect for the patient's privacy must be carefully
considered before embarking on a room or locker search. For a patient with chronic
diarrhea, a careful history and physical examination can help define the
site in the intestinal tract responsible (Table
14). TABLE 14. Anatomic approach to the
causes of chronic diarrhea Gastric Small intestine Large bowel Drugs Metabolic *Common This may avoid the expense
and frustration of the unproductive "shotgun" approach. One
possible diagnostic approach appears in Figure
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