| 11. Chronic Diarrhea |
page 233 |
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.
TABLE 11.
Pathophysiologic mechanisms of chronic diarrhea
|
| Major disturbance |
Probable mechanisms |
Examples/Associated
conditions |
|
|
| Osmotic* |
Ingestion |
Antacids, laxatives |
|
Maldigestion |
Pancreatic insufficiency,
disaccharidase deficiency |
|
Malabsorption |
Carbohydrate malabsorption,
congenital chloridorrhea |
| Disorders of intestinal transit |
Slow transit ("blind loop
syndrome") - excessive contact time |
Fistulas, strictures (such as in
the patient with Crohn's disease), diabetic neuropathy |
|
Rapid transit - insufficient
contact time |
Intestinal resection,
hyperthyroidism, irritable bowel |
| Secretory** |
Bacterial enterotoxins |
Vibrio cholerae, enterotoxigenic
E. coli |
|
Secretagogues |
Bile acids, fatty acids, ethanol,
prostaglandins, phenolphthalein, dioctyl sodium sulfosuccinate, VIP, gastrin, calcitonin |
| Exudative |
Increased passage of body fluids
into lumen |
Ulcerative colitis, Crohn's
disease |
|
| *See Table 12. **See Table 13. |
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).
| 11.1.1 OSMOTIC DIARRHEA |
page 235 |
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
Specific disaccharidase deficiencies
Glucose-galactose malassimilation
Fructose malassimilation
Mannitol, sorbitol ingestion ("chewing gum diarrhea")
Lactulose therapy
Divalent ions
Magnesium sulfate (Epsom salts)
Sodium sulfate
Sodium phosphate
Sodium citrate
Magnesium-containing antacids
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.
| 11.1.2 INTESTINAL
TRANSIT AND DIARRHEA |
page
236 |
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.
| 11.1.3 SECRETORY DIARRHEA |
page
237 |
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
Enterotoxins
Circulating secretagogues (VIP, calcitonin, prostaglandins, serotonin)
Increased hydrostatic pressure and tissue pressure
Gastric hypersecretion (Zollinger-Ellison syndrome)
Pancreatic hypersecretion
Laxatives (ricinoleic acid, bisacodyl, phenolphthalein, oxyphenisatin, dioctyl sodium
sulfosuccinate, aloe, senna, danthron)
Bile salts
Fatty acids
Clinical syndromes
Acute secretory diarrhea
Chronic secretory diarrhea
- Surreptitious laxative ingestion
- Pancreatic cholera syndrome (VIP)
- Medullary carcinoma of the thyroid (calcitonin)
- Ganglioneuroma, ganglioneuroblastoma, neurofibroma
- Zollinger-Ellison syndrome (gastrin)
- Malignant carcinoid syndrome (serotonin)
- Idiopathic secretory diarrhea
- Congenital chloridorrhea (some cases)
- Secreting villous adenoma
- Total villous atrophy of small bowel mucosa
- Niacin deficiency
- Intestinal lymphoma
Miscellaneous
- Intestinal obstruction
- Intestinal distention/ileus
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.
| 11.1.4 EXUDATIVE DIARRHEA |
page
239 |
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.
| 11.1.5 SELF-INDUCED
DIARRHEA |
|
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.
| 11.2 Investigation of
the Patient with Chronic Diarrhea |
page
240 |
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
Excessive use of antacids*
Hypergastrinemia/Zollinger-Ellison syndrome
Postoperative unmasked celiac disease, lactase deficiency or pancreatic insufficiency
Postoperative dumping syndrome*
Small intestine
Crohn's disease*
Celiac disease*
Lymphoma
Whipple's disease
Bacterial, viral or parasitic infection*
Abnormal intestinal integrity: scleroderma, amyloidosis, diabetes
Large bowel
Colon neoplasia*
Irritable bowel syndrome*
Inflammatory bowel disease: ulcerative colitis, Crohn's disease*
Drugs
Antacids*
Antibiotics*
Alcohol*
Antimetabolites
Laxatives
Digitalis
Colchicine
Metabolic
Hyperthyroidism
Hypoparathyroidism
Addison's disease
Diabetes*
Carcinoid syndrome
VIPoma syndrome
*Common
This may avoid the expense and frustration
of the unproductive "shotgun" approach. One possible diagnostic approach appears
in Figure 15. |
