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Pathophysiology of Diarrhea and

2.1. Introduction
Diarrhea may best be defined as doctors Roux and Ryle did in 1924: Diarrhea is the too rapid
evacuation of too fluid stools." Normal stooling varies from three bowel movements per week to
three bowel movements per day. Patients may report diarrhea when their own normal pattern of
bowel movements is altered. Loosening of the stool occurs when daily fecal water output
increases by only 50-60mL. An increase of fecal water excretion of 100mL is sufficient to
increase daily stool weight by 200grams/24 hours, the upper limit of normal.
The major causes of diarrhea, outlined in Table 1 , may be classified into five broad categories
related to their pathophysiology:
1. Osmotic diarrhea,
2. Malabsorption /maldigestion/fatty diarrhea (steatorrhea),
3. Inflammatory diarrhea,
4. Secretory diarrhea, or
5. Altered motility.

This section will review the pathophysiology of some of the more common and important causes
of diarrhea in these categories. It should be remembered, though, that these categories are not
absolute and that in any one individual disease or syndrome one or more pathophysiologic
processes may be the mechanism behind the development of diarrhea. For example, Crohns
disease may cause diarrhea based on an inflammatory, malabsorptive, and secretory
pathophysiology. In addition, some causes of malabsorption or maldigestion may not necessarily
be associated with diarrhea.
Diarrhea may also be divided into acute diarrhea and chronic diarrhea . Acute diarrheal states
(diarrhea lasting less than 4 weeks) are most commonly due to infectious causes. However, many
different medications or ischemia to the intestines can cause acute diarrhea. Chronic diarrhea is
diarrhea which lasts for longer than 4 weeks.
This section will not only discuss the pathophysiology of diarrhea, but also the evaluation and
treatment of patients with diarrhea. This section will NOT focus on inflammatory bowel disease
or infectious diarrhea, as these entities are covered elsewhere.
Table 1. Major Causes of Diarrhea
Osmotic diarrhea :
Osmotic laxative abuse
o Mg(OH)
), MgSO
, Na
, Lactulose, Polyethylene glycol
Carbohydrate malabsorption
o Lactose intolerance
Malabsorption/Maldigestion/Fatty Diarrhea
Malabsorption syndromes
o Mucosal diseases of small intestine (e.g. Celiac sprue)
o Short bowel syndrome (after multiple surgical resections)
o Small bowel bacterial overgrowth
Mesenteric ischemia
o Pancreatic insufficiency (chronic pancreatitis, cystic fibrosis)
o Reduced luminal bile acid
Inflammatory diarrhea
Inflammatory bowel disease
o Ulcerative colitis
o Crohns disease
o Lymphocytic or collagenous colitis
o Ulcerative jejunoileitis (rare complication of celiac sprue)
o Invasive bacterial infection (Clostridium difficile, E.Coli 0157:H7 and others)
o Phenolphthalein, anthraquinones, bisacodyl, senna, aloe, ricinoleic acid (castor
oil), dioctyl sodium sulfosuccinate
Ischemic Colitis
Radiation enterocolitis
Neoplasia: colon carcinoma, lymphoma
Secretory diarrhea
Non-osmotic laxative use
o Phenolphthalein, anthraquinones, bisacodyl, senna, aloe, ricinoleic acid (castor
oil), dioctyl sodium sulfosuccinate
Congential chloridorrhea
Infectious diarrhea: liberation of bacterial toxins
Ileal bile acid malabsorption
Neuroendocrine tumors
o Gastrinoma
o VIPoma
o Somatostatinomas
o Mastocytosis
o Carcinoid syndrome
o Medullary carcinoma of thyroid
Neoplasia: villous adenoma, colon cancer, lymphoma
Idiopathic secretory diarrhea
Disordered motility
Diabetic neuropathy
Addisons disease (adrenal insufficiency)
Irritable bowel syndrome
2.2. Osmotic Diarrhea
Excess amounts of poorly absorbed substances that remain in the intestinal lumen may cause
osmotic diarrhea. Large amounts of these substances (e.g. lactose, lactulose, magnesium) contain
osmotically active solutes which obligate retention of water in the lumen of the intestine by
virtue of their osmotic effects.
Electrolyte absorption (Na
, K
, Cl
) is unaffected by these osmotically-active substances
therefore stool water contains very little unabsorbed sodium and potassium. This is the basis for
the measurement and calculation of the fecal osmotic gap , a diagnostic test in the evaluation of
patients with chronic diarrhea.
The fecal osmotic gap estimates the difference between luminal osmolality and the osmolality of
luminal contents contributed by fecal electrolytes. Luminal osmolality is approximately equal to
body fluid osmolality (290 mosm/kg H
O) since the colon cannot maintain an osmotic gradient
against plasma. Furthermore, fecal osmolality may be measured directly but this measurement
should NOT be used in the calculation of the fecal osmotic gap: fecal osmolality begins to rise
almost immediately as it sits in the collection container. This rise is due to monosaccharide
conversion by bacterial fermentation to several osmotically active organic acids. The osmolality
of luminal contents contributed by fecal electrolytes is calculated by multiplying the sum of the
Na+ and K+ concentrations measured in a stool sample by 2 (to account for the anions that
accompany these cations). Therefore:
Fecal osmotic gap = 290 mosm/kg H
O 2 ([Na
] + [K
]) mmol/L
In patients with pure osmotic diarrhea the fecal osmotic gap should be large (> 125 mosm/kg
O). In patients with secretory diarrhea (see Table 1) the osmotic gap should be small (<50
mosm/kg H
Measurement of the pH of feces may also be helpful in assessing osmotic diarrhea. Carbohydrate
induced diarrhea, such as lactase deficiency, typically has a low pH whereas magnesium induced
diarrhea has a high pH.
The hydrogen breath test (also occasionally utilized in the assessment of bacterial overgrowth
syndrome, discussed below) may be used to detect lactose intolerance. A oral dose of lactose is
administered and, in patients with lactase deficiency, excess H
is produced by colonic bacterial
fermentation of the unabsorbed carbohydrate. H
diffuses into the general circulation and is
liberated in expired air. In general, a rise of over 20 ppm (parts per million) in exhaled hydrogen
at 3-6 hours after ingestion of the substrate is abnormal.
Important examples of osmotic diarrhea include lactose malabsorption and ingestion of excess
magnesium as in magnesium hydroxide. Lactose intolerance is due to congenital or, more
commonly, acquired deficiency in the brush border disaccharidase lactase. This leads to
malabsorption of lactose the sugar contained in dairy products. Lactose remains in the
intestinal lumen and acts as a strong osmotic substance. This leads to symptoms of flatulence,
bloating, and diarrhea. Lactase deficiency is particularly common in Asians, African-Americans,
Native Americans, Jews, Hispanics, Southern Europeans, and Mediterraneans. Over one-half of
the world's population is affected. Lactose intolerance is treated by avoidance of lactose
containing foods and/or supplementing oral intake of dairy products with liquid or tablet form of
the lactase enzyme.
2.3. Malabsorption, Maldigestion, and Fatty Diarrhea
Abnormalities of absorption may have several pathophysiologic mechanisms as outlined below.
Although all three major nutrients (fat, carbohydrate, and protein) may be malabsorbed, clinical
symptoms usually only develop with carbohydrate and fat malabsorption. Some disorders that
cause fat, carbohydrate, and protein malabsorption may not cause diarrhea. The student is
directed to the review section on normal physiology of digestion and absorption prior to studying
this section.
1. Luminal Phase
1. Reduced nutrient availability
1. Cofactor deficiency
2. Nutrient consumption
2. Impaired fat solubilization
1. Reduced bile salt
2. Impaired bile salt secretion
3. Bile salt inactivation
4. Impaired CCK release
5. Increased bile salt losses
3. Defective nutrient hydrolysis
1. Lipase
2. Enzyme deficiency
3. Improper mixing or rapid transit
2. Mucosal Phase
1. Extensive mucosal loss
2. Diffuse mucosal disease
3. Enterocyte defects
1. Microvillous inclusion disease
2. Brush border hydrolase deficiency
3. Transport defects
4. Epithelial processing
3. Transport Phase
1. Vacular
2. Lymphatic
Nutrients may be malabsorbed due to defects in digestion during the luminal phase of nutrient
Intralumenal maldigestion may occur at several levels:
1. Reduced nutrient availability:
1. Patients who lack intrinsic factor, the cofactor necessary for vitamin B

absorption, due to autoimmune atrophic gastritis (atrophic gastritis due to an
autoimmune process where antibodies target the H
-ATPase on parietal cells
causing parietal cell loss; parietal cells produce intrinsic factor in addition to HCl)
leading to pernicious anemia. Patients are unable to absorb B
2. Bacterial overgrowth syndrome (discussed below) leads to nutrient consumption
by bacteria.
2. Impaired fat solubilization
1. Reduced bile salt synthesis due to severe liver disease (cirrhosis) and impaired
bile salt secretion due to chronic cholestasis (intrinsic liver disease which causes
bile duct damage or extrahepatic bile duct obstruction): bile salts are thus not
available to form micelles to aid in fat solubilization for absorption.
2. Bile salts may be inactivated in the intestinal lumen by overgrowth of bacteria in
the small bowel bacterial overgrowth syndrome . The normal concentration of
bacteria in the proximal small intestine is less than 10
cfus/ml (colony forming
units per ml). In patients with conditions that predispose to intestinal stasis either
by anatomic or motility abnormalities (see Predisposing conditions favoring
bacterial overgrowth table below) or in patients with abnormal connections
between loops of proximal and distal bowel, bacteria may overgrow in the
proximal small intestine. These excess bacteria deconjugate bile salts leaving
them unconjugated and unable to participate in micelle formation. This leads to
malabsorption of fat and symptoms of abdominal pain, diarrhea, and bloating. It
may also lead to malabsorption of the fat soluble vitamins A, D, E, K. Clinically,
vitamin K deficiency is detected by measuring the prothrombin time (PT) in
blood. If prolonged this may suggest vitamin K deficiency as several of the
proteins in the coagulation cascade rely on vitamin K for their formation.
Table 2. Predisposing Conditions Favoring Bacterial Overgrowth
Intestinal Stasis
Intestinal strictures (secondary to Crohns disease, radiation, or malignancy, for
Small intestinal diverticulosis (seen in scleroderma
Surgical procedures creating blind loops (end-side entero-enteric anastomoses,
Billroth II anastomoses, jejuno-ileal bypass)
Motility disorders
Diabetes mellitus (diabetic autonomic neuropathy)
Idiopathic intestinal pseudoobrstruction
Abnormal connections between proximal and distal bowel
Resection of ileocecal valve
Fistulas (gastrocolic, jejunocolic due to Crohns, peptic ulcer disease, cancer)
1. Diagnosis of bacterial overgrowth
1. Direct aspiration of luminal contents at the time of endoscopy (not routinely
performed) and cultured
2. Hydrogen breath tests. A substrate (a carbohydrate such as glucose, lactulose,
lactose, or fructose) is administered and then expired air is then analyzed for
hydrogen (H2) content. An early peak (30-60 minutes after ingestion) in the H2
concentration in expired air is detected if the substrate is metabolized by
excessive small intestinal bacteria. A late peak (2-3 hours after ingestion) is
typically seen when malabsorbed substrate reaches the colon and is metabolized
by normally present colonic bacteria.
2. Treatment of bacterial overgrowth:
1. Correction of predisposing factor if possible (i.e., correction of surgical
abnormality or treatment of underlying disease)
2. Correction of nutritional deficiencies
3. Antibiotics
1. Increased bile salt losses
Surgical resection of or extensive inflammatory disease in the terminal ileum (as seen in
Crohns disease) may lead to malabsorption of bile acids. The loss of bile acids in the
stool leads to relative bile salt deficiency resulting in impaired fat solubilization.
1. Defective nutrient hydrolysis
1. Zollinger Ellison syndrome excess HCl (acid) production may inactivate gastric
lipase and proteolytic pancreatic exocrine enzymes.
2. Pancreatic enzyme deficiency due to chronic pancreatitis or a malignancy
obstructing the outflow of pancreatic juices into the duodenum.
3. Improper mixing due to surgical resection such as post-gastrectomy (Billroth I
or Billroth II anastomoses for example)
4. Rapid intestinal transit - diabetic neuropathy or hyperthyroidism (disordered
Malabsorption : Mucosal abnormalities:
Many diseases may interrupt the mucosal integrity and thus the absorptive surface of the
intestine leading to malabsorption. The small bowel mucosa may be damaged due to prior
radiation treatment, vascular insufficiency, or from inflammatory or infectious conditions. As
mentioned above, inflammatory diseases such as Crohns disease disrupt the mucosa leading to
malabsorption. Celiac sprue is a diffuse mucosal disease of the small bowel which leads to
villous atrophy and subsequent nutrient malabsorption.
Celiac sprue or gluten sensitive enteropathy is a chronic disease with a characteristic although
not specific mucosal lesion of the small intestine which impairs nutrient absorption and with
removal of all wheat gliadins (the toxic alcohol-soluble gluten fractions) from the diet there is
resolution of the mucosal abnormality and improvement in nutrient absorption.
Pathology: Small intestinal villous atrophy and increases in lamina propria lymphocytes.
Epidemiology: Whites (highest incidence in Northern Europeans, particularly Ireland)
although celiac sprue has been documented in Asians from India and Pakistan.
Clinical presentation: Varied often depending on extent and degree of villous atrophy.
Classically, crampy abdominal pain, diarrhea, flatulence, bloating, weight loss,
steatorrhea. Also: Iron deficiency anemia, osteoporosis (vitamin D malabsorption),
peripheral neuropathy (B12 deficiency), easy bruising (vitamin K malabsorption), edema
(malabsorption of protein).
Diagnosis :
o Biopsy of small intestine during upper endoscopy for pathologic evaluation
o Serology:
Anti-gliadin antibodies (IgA and IgG)
Anti-endomysial antibodies (IgA) these IgA antibodies are reactive with
the lining of visceral smooth muscle (i.e., the endomysium). Sensitivity
and specificity is very high with these antibodies compared to anti-gliadin
in the detection of celiac sprue. It is unclear if these antibodies play a role
in the pathogenesis of celiac sprue.
It was recently (1997-1998) discovered that tissue transglutaminase is the
antigen recognized by endomysial antibodies. There is now an ELISA that
can be used to measure tissue transglutaminase antibodies with high
specificity and sensitivity.
Treatment :
o The mainstay of treatment for celiac sprue is a gluten free diet. This diet is
incredibly restrictive necessitating the evaluation by a dedicated nutritionist.
Gliadins (the alcohol soluble fraction of gluten the major wheat storage protein)
and prolamins (alcohol soluble fractions of rye, barley, and oat storage proteins)
of rye, barley, and possibly oats are toxic to celiac sprue patients. For more details
on the gluten free diet the Celiac Sprue association website is particularly helpful: .

Other aspects of treatment include nutrient supplementation: iron, B12, calcium,
vitamin D, vitamin K.
Pathogenesis of celiac sprue :
o Genetic factors: >95% of patients carry HLA-DQ2 or DQ8; 10% of first degree
relatives have celiac sprue
o Environmental agent gliadin component of gluten
o Autoimmune response to gliadin and prolamin peptide fragments.
o Diarrhea caused by malabsorbed substances including electrolytes, protein, and
o Presumed pathophysiology: Gliadin is absorbed into the lamina pro Congenital
defects of ion absorptive processes pria and presented to T cells by antigen
presenting cells in conjunction with HLA-DQ2 or DQ8. Tissue transglutaminase
deamidates gliadin peptides which generates acidic, negatively charged residues
which binds the T cell receptor more strongly. This leads to a more pronounced T
cell response. These activated lymphocytes generate a cytokine response (TNF-,
interleukin-4, interferon-), which lead to damaged villi and inflammation.
o See illustration in N Engl J Med 2002; 346: 180-188
Celiac Sprue : associated diseases: Dermatitis herpetiformis, pruritic blistering skin
eruption associated with IgA deposits in skin
o Small intestinal lymphoma (increased risk of lymphoma in patients with celiac
sprue: risk may be lessened with adherence to gluten free diet)
Post-absorptive/Transport Phase Abnormalities Resulting in Malabsorption
Defective chylomicron synthesis in a-beta lipoproteinemia
Submucosal infiltration in the intestinal wall due to lymphoma or amyloidosis
Lymphatic obstruction in intestinal lymphangiectasia
2.4. Inflammatory Diarrhea
Diarrheal diseases that fit into this category are discussed in detail in the section on inflammatory
bowel diseases and in the infectious disease section on infectious diarrhea. Briefly, in addition to
mucosal disruption resulting in enterocyte damage and abnormal absorption of nutrients and
electrolytes, inflammatory processes may result in discharge of mucus, proteins, and blood into
the intestinal lumen.
2.5. Secretory Diarrhea
Secretory diarrhea is caused by abnormal ion transport in intestinal epithelial cells usually
resulting in decreased absorption of electrolytes. The major solutes in the intestinal lumen of
patients with secretory diarrhea are Na
, K
, Cl
, and HCO
therefore electrolytes account for
most of the luminal osmolality. Consequently, the fecal osmotic gap {290 2([Na
] + [K
])} is
small, usually less than 50 mosm/kg H
O. In addition, because this type of diarrhea is due to
abnormalities in ion transport, the diarrhea usually persists despite fasting. However, reliance on
this clinical history point (i.e., diarrhea which continues despite fasting) can be troublesome:
most patients with secretory diarrhea (defined as a small fecal osmotic gap) still absorb most of
the 9-10L of fluid entering the jejunum each day they just do not absorb almost all of it as in
normal circumstances. Therefore, one may argue that the term secretory diarrhea is a misnomer
and should really be called non-osmotic diarrhea.

There are four main categories of disease resulting in secretory diarrhea:
1. Congenital defects of ion absorptive processes
1. Congenital chloridorrhea results from defective or absent Cl
exchanger in
the ileum and colon. This results in excess Cl- loss in the stool and metabolic
2. Congenitally defective or absent Na
exchanger leads to excess Na
in the
stool and metabolic acidosis
2. Intestinal resection
1. Decreased absorptive surface for not only nutrients but also electrolytes and fluid
2. Combined malabsorption and secretory component
3. Diffuse mucosal disease with destruction of enterocytes or reduction in enterocyte
1. Similar pathophysiology to intestinal resection also may cause nutrient
malabsorption in addition to electrolyte malabsorption (defective ion transport)
4. Abnormal mediators: result in changes in intracellular signaling pathways
1. Changes in cAMP (cyclic adenosine monophosphate), cGMP (cyclic guanosine
monophosphate), calcium, and/or protein kinases. These changes lead to a
decrease in Na+ absorption or an increase in Cl- secretion.
2. Mediators
3. Other mediators: bacterial toxins
4. Other mediators: non-osmotic laxatives (see Table 1)
5. More mediators: fatty acids byproducts of fat malabsorption which reach colon
and stimulate colonic secretion.
6. More mediators: bile acids bile acids not absorbed in ileum due to ileal resection
or severe ileal disease (such as in Crohns disease) can also act as a cathartic in
the colon and stimulate secretion of fluid and electrolytes.
7. Final mediators: circulating agents released by neuroendocrine tumors (rare). (See
Table 3)
Table 3. Neuroendocrine Tumors and Secretory Diarrhea
Condition Mediator Mechanism of Diarrhea Other Manifestations
Zollinger-Ellison syndrome Gastrin Acid inactivation of
pancreatic enzymes and
bile salts
Intestinal fluid and
Severe peptic ulcer
Erosive esophagitis
electrolyte secretion
Acid-induced damage to
intestinal mucosa
Increased motility
Tumor in pancreas or
Carcinoid syndrome Serotonin,
substance P,
Increased motility
Intestinal fluid and
electrolyte secretion
Right-sides heart
Medullary Carcinoma of the
Intestinal fluid and
electrolyte secretion
Increased motility
Thyroid module or
Pancreatic Cholera VIP
Intestinal fluid and
electrolyte secretion
Glucagonoma Glucagon Intestinal fluid and
electrolyte secretion
Necrolytic erythema
migrans (rash)
Tumor in pancreas
Somatostatinoma Somatostatin Decreased intestinal
nutrient absorption
Steaorrhea due to
decrease pancreatic
Pancreatic tumor
Systemic Mastocytosis Histamine Intestinal fluid and Flushing
electrolyte secretion
Gastric hypersecretion
Villous atrophy
Abdominal pain
2.6. Disordered Motility
Conditions which cause altered gastric, small intestinal, or colonic motor activity may cause
diarrhea by limiting the time for the normal digestive and absorptive processes to take place.
That is, food boluses are propelled rapidly through the intestinal lumen decreasing the contact
time at absorptive epithelial cells.
Patients with autonomic diabetic neuropathy or hyperthyroidism may have altered intestinal
motility leading to diarrhea. Patients who have had a vagotomy and/or partial gastrectomy are
also prone to altered motility. Abnormal motility also likely contributes to diarrhea in patients
with the irritable bowel syndrome.
Irritable bowel syndrome (IBS), one of the most common syndromes identified in
gastroenterology clinics, is felt to be due to heightened visceral sensation and altered intestinal
motility. Typically, symptoms include intermittent, non-localizing abdominal pain with an
altered bowel pattern. That is, patients alternate from being constipated to having diarrhea. This
is often associated with a sensation of incomplete evacuation after bowel movements or the
passage of mucus in the stool. IBS does not cause blood in the stool, fevers, nocturnal symptoms
of diarrhea, or weight loss. There are set criteria for the diagnosis of IBS based on the clinical
history alone and most gastroenterologists may suspect and can diagnose IBS without diagnostic
testing, but endoscopic procedures, blood work, or gastrointestinal x-rays are often performed to
rule out other diseases. Treatment is usually symptomatic (anti-diarrheals, anti-spasmodics, fiber
supplementation, avoidance of laxatives).
Slow motility may also result in diarrhea: Slow intestinal transit may result in intestinal stasis
leading to bacterial overgrowth (discussed above).
Diarrhea is the reversal of the normal net absorptive status of water and electrolyte absorption to
secretion. Such a derangement can be the result of either an osmotic force that acts in the lumen
to drive water into the gut or the result of an active secretory state induced in the enterocytes. In
the former case, diarrhea is osmolar in nature, as is observed after the ingestion of nonabsorbable
sugars such as lactulose or lactose in lactose malabsorbers. Instead, in the typical active secretory
state, enhanced anion secretion (mostly by the crypt cell compartment) is best exemplified by
enterotoxin-induced diarrhea.
In osmotic diarrhea, stool output is proportional to the intake of the unabsorbable substrate and is
usually not massive; diarrheal stools promptly regress with discontinuation of the offending
nutrient, and the stool ion gap is high, exceeding 100 mOsm/kg. In fact, the fecal osmolality in
this circumstance is accounted for not only by the electrolytes but also by the unabsorbed
nutrient(s) and their degradation products. The ion gap is obtained by subtracting the
concentration of the electrolytes from total osmolality (assumed to be 290 mOsm/kg), according
to the formula: ion gap = 290 [(Na + K) 2].
In secretory diarrhea, the epithelial cells ion transport processes are turned into a state of active
secretion. The most common cause of acute-onset secretory diarrhea is a bacterial infection of
the gut. Several mechanisms may be at work. After colonization, enteric pathogens may adhere
to or invade the epithelium; they may produce enterotoxins (exotoxins that elicit secretion by
increasing an intracellular second messenger) or cytotoxins. They may also trigger release of
cytokines attracting inflammatory cells, which, in turn, contribute to the activated secretion by
inducing the release of agents such as prostaglandins or platelet-activating factor. Features of
secretory diarrhea include a high purging rate, a lack of response to fasting, and a normal stool
ion gap (ie, 100 mOsm/kg or less), indicating that nutrient absorption is intact.
Pathophysiology of Diarrhea

Diarrhea is an increase in the volume of stool or frequency of defecation. It is one of the
most common clinical signs of gastrointestinal disease, but also can reflect primary
disorders outside of the digestive system. Certainly, disorders affecting either the small
or large bowel can lead to diarrhea.
For many people, diarrhea represents an occasional inconvenience or annoyance, yet at
least 2 million people in the world, mostly children, die from the consequences of
diarrhea each year.
There are numerous causes of diarrhea, but in almost all cases, this disorder is a
manifestation of one of the four basic mechanisms described below. It is also common
for more than one of the four mechanisms to be involved in the pathogenesis of a given
Osmotic Diarrhea
Absorption of water in the intestines is dependent on
adequate absorption of solutes. If excessive amounts of
solutes are retained in the intestinal lumen, water will
not be absorbed and diarrhea will result. Osmotic diarrhea typically results from one of
two situations:
Ingestion of a poorly absorbed substrate: The offending molecule is usually a
carbohydrate or divalent ion. Common examples include mannitol or sorbitol, epson
salt (MgSO
) and some antacids (MgOH
Malabsorption: Inability to absorb certain carbohydrates is the most common deficit in
this category of diarrhea, but it can result virtually any type of malabsorption. A
common example of malabsorption, afflicting many adults humans and pets is lactose
intolerance resulting from a deficiency in the brush border enzyme lactase. In such
cases, a moderate quantity of lactose is consumed (usually as milk), but the intestinal
epithelium is deficient in lactase, and lactose cannot be effectively hydrolyzed into
glucose and galactose for absorption. The osmotically-active lactose is retained in the
intestinal lumen, where it "holds" water. To add insult to injury, the unabsorbed
lactose passes into the large intestine where it is fermented by colonic bacteria,
resulting in production of excessive gas.
A distinguishing feature of osmotic diarrhea is that it stops after the patient is fasted or
stops consuming the poorly absorbed solute.
Secretory Diarrhea
Large volumes of water are normally secreted into the
small intestinal lumen, but a large majority of this water
is efficienty absorbed before reaching the large intestine.
Diarrhea occurs when secretion of water into the
intestinal lumen exceeds absorption.
Many millions of people have died of the secretory diarrhea associated with cholera.
The responsible organism, Vibrio cholerae, produces cholera toxin, which strongly
activates adenylyl cyclase, causing a prolonged increase in intracellular concentration of
cyclic AMP within crypt enterocytes. This change results in prolonged opening of the
chloride channels that are instrumental in secretion of water from the crypts, allowing
uncontrolled secretion of water. Additionally, cholera toxin affects the enteric nervous
system, resulting in an independent stimulus of secretion.
Exposure to toxins from several other types of bacteria (e.g. E. coli heat-labile toxin)
induce the same series of steps and massive secretory diarrhea that is often lethal unless
the person or animal is aggressively treated to maintain hydration.
In addition to bacterial toxins, a large number of other agents can induce secretory
diarrhea by turning on the intestinal secretory machinery, including:
some laxatives
hormones secreted by certain types of tumors (e.g. vasoactive intestinal peptide)
a broad range of drugs (e.g. some types of asthma medications, antidepressants,
cardiac drugs)
certain metals, organic toxins, and plant products (e.g. arsenic, insecticides, mushroom
toxins, caffeine)
In most cases, secretory diarrheas will not resolve during a 2-3 day fast.
Inflammatory and Infectious Diarrhea
The epithelium of the digestive tube is protected from
insult by a number of mechanisms constituting the
gastrointestinal barrier, but like many barriers, it can be
breached. Disruption of the epithelium of the intestine
due to microbial or viral pathogens is a very common
cause of diarrhea in all species. Destruction of the
epithelium results not only in exudation of serum and blood into the lumen but often is
associated with widespread destruction of absorptive epithelium. In such cases,
absorption of water occurs very inefficiently and diarrhea results. Examples of
pathogens frequently associated with infectious diarrhea include:
Bacteria: Salmonella, E. coli, Campylobacter
Viruses: rotaviruses, coronaviruses, parvoviruses (canine and feline), norovirus
Protozoa: coccidia species, Cryptosporium, Giardia
The immune response to inflammatory conditions in the bowel contributes
substantively to development of diarrhea. Activation of white blood cells leads them to
secrete inflammatory mediators and cytokines which can stimulate secretion, in effect
imposing a secretory component on top of an inflammatory diarrhea. Reactive oxygen
species from leukocytes can damage or kill intestinal epithelial cells, which are replaced
with immature cells that typically are deficient in the brush border enyzmes and
transporters necessary for absorption of nutrients and water. In this way, components of
an osmotic (malabsorption) diarrhea are added to the problem.
Diarrhea Associated with Deranged Motility
In order for nutrients and water to be efficiently
absorbed, the intestinal contents must be adequately
exposed to the mucosal epithelium and retained long
enough to allow absorption. Disorders in motility than
accelerate transit time could decrease absorption,
resulting in diarrhea even if the absorptive process per
se was proceeding properly.
Alterations in intestinal motility (usually increased propulsion) are observed in many
types of diarrhea. What is not usally clear, and very difficult to demonstrate, is whether
primary alterations in motility are actually the cause of diarrhea or simply an effect.