Reference Work Entry

Encyclopedia of Molecular Mechanisms of Disease

pp 528-530

Diarrhea

  • Michael FrommAffiliated withClinical Physiology, Campus Benjamin Franklin, Charité
  • , Jörg-Dieter SchulzkeAffiliated withGastroenterology, Infectiology and Rheumatology, Campus Benjamin Franklin, Charité

Synonyms

Diarrhoea

Definition and Characteristics

The normal consistency of stool and frequency of bowel movements varies in a wide range due to diet composition (e.g. rate of vegetables) and individual factors. Diarrhea is characterized by alterations away from normal behavior and is defined, alone or together, by increases of:
  1. 1.

    Water content >80%, making feces more fluid than usual

     
  2. 2.

    Number of bowel movements per day, e.g. from usually 1 to >3 or from usually 2 to >5

     
  3. 3.

    Feces weight per day, e.g. from 100 g/d to >200 g/d or from 200 g/d to >400 g/d [1,2]

     
Acute diarrhea (<2–4 weeks) is usually caused by bacterial, viral, or parasitic infection. In children, infection with rotavirus is the most common cause of acute diarrhea.

Chronic diarrhea (>4 weeks) is usually related to either organic disorders like the inflammatory bowel diseases (IBD) ulcerative colitis and Crohn’s disease or celiac disease or to functional disorders like the irritable bowel syndrome (IBS) [3].

Usually acute diarrhea in adults is mild and self-limiting so that it deserves no diagnostic or therapeutic efforts. In contrast, in newborns and small children severe diarrhea, even if lasting only 1 or 2 days, can lead to critical dehydration. Diarrhea is one of the major causes of infant morbidity and mortality worldwide. At any age, cholera induces a severe life-threatening diarrhea which must be treated.

Prevalence

Acute diarrheal episodes are very common. Diarrheal illnesses account for >10,000 deaths per day in children in Asia, Africa, and Latin America. The causes of diarrhea include a wide array of viruses, bacteria, and parasites.

Compared to this, several genetically determined forms of chronic diarrhea e.g. congenital lactase deficiency, congenital chloridorrhea, and glucose/galactose malabsorption are very rare. As an exception, celiac disease is relatively common, affecting 1 of every 100–300 persons.

Molecular and Systemic Pathophysiology

In general, all types of diarrhea are driven by osmotic forces inasmuch as an inappropriate amount of solutes remains in the gut lumen which is accompanied by an equivalent volume of fluid. An additional osmotic effect can occur by brake up of non-absorbable large molecules to small ones due to bacterial overgrowth. Often diarrhea is caused by more than one mechanism alone.

There are numerous classifications of diarrhea, most of them based on clinical criteria. However, from a functional viewpoint the situation is clear. Diarrhea is caused by quantitatively altered transepithelial net transport, i.e. impaired absorption and/or increased secretion, of solutes plus osmotically equivalent amounts of water. These alterations can be created through five different general mechanisms (Table 1).
Diarrhea. Table 1

Classification of diarrheal diseases according to pathophysiological criteria. Note that osmotic diarrhea as defined here may differ from clinical usage, where malabsorptive diarrhea is included into the term osmotic diarrhea

Type

Mechanism

Typical causes

 

Altered absorption

 

Osmotic diarrhea

Presence of non-absorbable solutes

Mannitol, sweeteners, SO4, PO4, citrate, antacids, non-digested macromolecules, lactase deficiency

 

Malabsorptive diarrhea

Defective absorptive transporters

Congenital chloridorrhea, glucose/galactose malabsorption

 

Reduced absorptive epithelial area

Celiac disease, bacterial overgrowth

 

Motility-driven diarrhea

Insufficient absorptive contact time

Hyperthyreosis, laxatives

 

Altered secretion

 

Secretory diarrhea

Increased chloride secretion

Cholera toxin, E. coli toxins

 

Leak flux diarrhea

Back leak across tight junctions into the lumen

Ulcerative colitis, Crohn’s disease, cholera-ZOT, Clostridium perfringens

 
Osmotic diarrhea as defined here results from the presence of solutes in the intestinal lumen, for which no epithelial transport mechanism exists. The mechanism of this type of diarrhea is identically to that renal osmotic diuresis caused by non-absorbable solutes. Osmotic diarrhea can be caused by
  1. 1.

    Non-absorbable laxatives, e.g. lactulose, mannitol, Glauber’s salt (Na2SO4)

     
  2. 2.

    Nutrients, which were not digested into an absorbable form, e.g. lactose in lactase deficiency (congenital form: OMIM # 223000)

     
  3. 3.

    Low-calorie sweeteners, e.g. cyclamate, saccharin, aspartame

     
  4. 4.

    Mg2+-based antacids

     
  5. 5.

    Contrast agents containing sulfate, phosphate or citrate

     
Malabsorptive diarrhea is caused by impaired absorption of solutes for which under normal circumstances transport pathways exist. This may have two reasons:
  1. 1.

    Transport proteins can be defective congenitally, like SGLT1 (SLC5A1) in glucose/galactose malabsorption (OMIM #606824) or DRA (SLC26A3) in congenital chloridorrhea (OMIM #214700).

     
  2. 2.

    The number of transport proteins can be insufficient due to a reduced area of absorptive epithelium. This can be caused e.g. by celiac disease (celiac sprue, gluten-sensitive enteropathy; OMIM #212750), tropical sprue, bacterial overgrowth, short bowel syndrome, and Crohn’s disease.

     
Motility-driven diarrhea is caused by accelerated transit time leaving a too short time for proper absorption although the absorptive mechanisms are working properly. The rectum then is overspilled by solutes and an osmotically equivalent amount of water. Typical reasons are hyperthyreosis or abuse of laxatives.

Secretory diarrhea is mainly driven by excessive chloride secretion plus some inhibition of NaCl absorption. Normally, in the intestine absorptive processes exceed the secretory ones, so that the net effect is absorption. Secretion is driven by the apical channel CFTR, in conjunction with SLC26 anion exchangers, which mediate electrogenic Cl and HCO3 secretion. If, however, secretagogues cause opening of CFTR, large net secretion of chloride occurs which is followed by water. Numerous regulatory endocrine, paracrine, and neural compounds stimulate active Cl secretion and at the same time inhibit active absorption in villus cells. Typical secretory diarrheas are:

Traveler’s diarrhea is caused by food, contaminated with enterotoxins, mostly of E. coli.

Cholera leads to a life-threatening diarrhea which is mediated by two toxins: Cholera toxin stimulates Cl secretion (and inhibits NaCl absorption) via cAMP. Zonula occludens toxin causes a disruption of the tight junction, leading to a leak flux diarrhea [4].

As listed in Table 2, numerous other microbiota and parasites cause secretory diarrhea and/or leak flux diarrhea.
Diarrhea. Table 2

Most prominent microbiota and parasites causing secretory diarrhea and/or leak flux diarrhea

Bacteria

Viruses

Parasites

 

Enterotoxigenic Escherichia coli

Adenovirus

Cryptosporidium parvum

 

Campylobacter jejuni

Human immunodeficiency virus (HIV)

Entamoeba histolytica

 

Clostridium difficile

Norovirus

Giardia lamblia

 

Listeria monocytogenes

Rotavirus

Strongyloides stercoralis

 

Salmonella

   

Shigella

   

Staphylococcus aureus

   

Vibrio cholerae

   

Leak flux diarrhea is the result of impaired epithelial barrier function, caused either by opening of tight junctions or by significant loss of epithelial cells [1,5], the latter also named exudative diarrhea (synonym: exudative diarrhea).

Colon and rectum are tight epithelia with well developed tight junctions. However, numerous intestinal diseases which cause mucosal inflammation, ulceration or increased apoptotic rate (e.g. ulcerative colitis [3], Crohn’s disease, cholera-ZOT [4], Clostridium perfringens) induce a break-down of the epithelial barrier, allowing for a back leak of osmotically relevant amounts of solutes and water from the interstitium into the lumen across tight junctions or the defective cell layer.

Diagnostic Principles

Osmotic diarrhea as well as malabsorptive diarrhea cease after leaving out the suspected substances from the meal. This improvement after fasting is typical for a type of diarrhea due to insufficient absorption, as a result of which this can be used for differential diagnosis. Secretory diarrhea and leak flux diarrhea cannot be terminated by fasting.

Therapeutic Principles

Acute diarrhea mostly ceases without specific therapy. However, severe acute diarrhea requires proper fluid and electrolyte replacement to avoid dehydration and acidosis. In infants dehydratation can occur within a few hours, therefore it is essential to start rehydration immediately.

If infusion therapy is not available, secretory diarrhea (e.g. cholera, traveler’s diarrhea) can be effectively treated by oral rehydration solution (ORS). The essential components of ORS are glucose, NaCl, and NaHCO3. This simple therapy takes advantage of the fact that in secretory diarrhea the intestinal sodium-glucose symporter SGLT1 (SLC5A1) is not affected. Although chloride (and bicarbonate) secretion may continue, osmotically driven water loss is prevented due to the counterbalancing effect of increased sodium-glucose absorption.

Chronic diarrhea due to osmotic effects of non-absorbable or malabsorbed solute [5] can be treated by avoiding the respective solutes.

Enteritis

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