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Pathogenesis of diarrhea in the adult: diagnostic challenges and life-threatening conditions

Payne, Claire M.a d; Fass, Ronnieb d e; Bernstein, Harrisa d; Giron, Jorgec; Bernstein, Carola; Dvorak, Katerinaa d; Garewal, Harinderb d f

European Journal of Gastroenterology & Hepatology: October 2006 - Volume 18 - Issue 10 - p 1047-1051
doi: 10.1097/01.meg.0000231748.60889.be
Leading Articles
  • The mechanisms that regulate ionic balance, fluid absorption and secretion in the gastrointestinal tract are complex.
  • Disturbance of this homeostatic state by bile acids, bacterial enterotoxins and neoplasm-derived secretagogues, for example, can lead to diarrhea.
  • Determining the causes of chronic diarrhea in individual patients may, therefore, represent a diagnostic challenge.

The mechanisms that regulate ionic balance, fluid absorption and secretion in the gastrointestinal tract are complex.Disturbance of this homeostatic state by bile acids, bacterial enterotoxins and neoplasm-derived secretagogues, for example, can lead to diarrhea.Determining the causes of chronic diarrhea in individual patients may, therefore, represent a diagnostic challenge. The gastrointestinal tract has finely tuned mechanisms to maintain ionic balance, fluid absorption and secretion. To achieve this homeostasis, various ionic transport proteins/complexes are targeted to the apical, basal or basolateral membranes of epithelial cells. Na+, K+ and Cl ion transport proteins are regulated by endogenous activators (e.g. cAMP, PGE2, Ca2+), dietary-related factors (e.g. bile acids) and through post-translational modifications (e.g. phosphorylation). In certain pathophysiologic states, this homeostatic ionic/fluid exchange becomes dysfunctional as a result of failure of compensatory pro-absorptive/anti-secretory mechanisms. The excessive secretion of Na+ and Cl ions followed by the release of a large amount of H2O into the colonic lumen results in diarrhea, which may be acute or chronic, and can be life-threatening if not ameliorated. Diverse infectious organisms (e.g. bacteria, protozoa, viruses) utilize different mechanisms to cause intestinal disease and diarrhea. These pathophysiologic mechanisms include alterations in ion transport, disruption of tight junctions and elicitation of inflammatory responses. Studies of patients infected with certain pathogens, those with ulcerative colitis and those harboring extra-colonic or colonic neoplasms have elucidated some of these pathophysiologic mechanisms of diarrhea. Determining the etiology of chronic diarrhea in specific cases may be a diagnostic challenge for both gastroenterologists and primary care physicians.

Departments of aCell Biology and Anatomy

bInternal Medicine

cMicrobiology and Immunology, College of Medicine

dArizona Cancer Center, University of Arizona

Sections of eGastroenterology

fHematology/Oncology Southern Arizona Veterans Affairs Health Care System, Tucson, Arizona, USA

Correspondence and requests for reprints to Claire M. Payne, PhD, Department of Cell Biology and Anatomy, College of Medicine, University of Arizona, Tucson, AZ 85724-5044, USA

Tel: +1 520 626 2870; fax: +1 520 626 2097; e-mail: cpayne@email.arizona.edu

Sponsorship: This work was supported in part by NIH grant no. 5R21CA111513-2 and Biomedical Diagnostics & Research Inc., Tucson, Arizona, USA.

This leading article refers to: Lepur D, Klinar I, Himbele J, Vranjican Z, Barsic B. McKittrick–Wheelock syndrome: a rare cause of diarrhea. Eur J Gastroenterol Hepatol 2006; 18:557–559.

All co-authors contributed equally toward the completion of this article, which included a literature review, writing specific sections, providing clinical relevance or mechanistic insights.

Received 4 May 2006 Accepted 6 May 2006

In the gastrointestinal tract, ionic balance, fluid absorption and secretion are crucial to maintain homeostasis allowing for the maintenance of a membrane potential, adequate nutrient intake, normal gut motility, protection against toxins and microbes, and epithelial cell viability. This homeostatic state is dependent upon the normal physiological function of the small intestinal and colonic cells and a complex array of hormonal mechanisms that control gut motility and entry and exit of fluid into the lumen of the gastrointestinal tract [1–4]. Hormones and peptides derived from the pituitary gland (e.g. antisecretory factor), the gut enteric system and cells of the diffuse neuroendocrine system (e.g. 5-hydroxytryptamine), vasoactive intestinal peptide, kinins (e.g. substance P), cholecystokinin, galanin and guanylin/uroguanylin all have a role. As enterochromaffin cells (i.e. gut epithelial cells that secrete hormones/peptides) are interspersed throughout the entire gastrointestinal mucosa, the gut is classified as the largest endocrine organ of the body.

The surface area of the human colon is ∼2000 cm2 and is responsible for the absorption of Na+, Cl, and water and the secretion of K+ and HCO 3. One of the major functions of the human colonic epithelium is fluid transport, with ∼1.5–2 l of water being reabsorbed from the lumenal contents within a 24-h period. Net water absorption is directly proportional to net Na+ and Cl absorption and is driven by osmotic gradients. Water molecules are small enough (the distance between the two hydrogen atoms of water is <2 Å) to cross membrane channels, or the intermolecular spaces between hydrophobic chains. Water can also move into the intercellular spaces between enterocytes via transcellular and paracellular (e.g. between adjacent epithelial junctional complexes that provide a protective barrier) routes in response to an osmotic gradient that exists between the lumen and the epithelial cell, and between the epithelial cells and the extracellular space. Net water intake into the enterocyte also occurs through nutrient uptake. For example, every glucose molecule in solution is surrounded by water molecules that are carried into the cell during membrane translocation. Electroneutral NaCl cotransport occurs throughout the colon, mediated by Na+/H+ and Cl/HCO 3 exchangers operating in parallel at the surface epithelium. By contrast, electrogenic Na+ transport (three Na+ ions leave the cell for every two K+ ions that enter) occurs mainly in the descending colon, sigmoid colon and rectum. Na+ ions move passively into the surface colonocyte by the apical Na+ channel and are then extruded at the basolateral side of the cell by the Na+/K+-ATPase. Colonic Cl secretion occurs through several ion transport mechanisms. These include (i) the lumenal cystic fibrosis transmembrane conductance regulator (CFTR)-type Cl channel, which is activated by cAMP, (ii) the basolateral Na+/K+/2Cl cotransport system, (iii) the basolateral K+ channels, which recycle K+ and provide the membrane voltage as the driving force for the exit of Cl ions, and (iv) the Na+/K+-ATPase, which energizes Cl transport. Molecular evidence in recent years indicates that some of these ionic transport protein complexes are regulated at several levels including protein expression (i.e. transcription, translation, proteasomal degradation), membrane targeting in lipid rafts and endocytosis, alterations in regulatory proteins (e.g. the Na+/H+ exchange regulatory factor), binding proteins (e.g. ezrin) and post-translational modifications. One important post-translational mechanism is phosphorylation, which may be regulated through either cAMP or cGMP [resulting in the activation of protein kinase (PK)A, PKC or PKG] or calcium/calmodulin-related kinases.

Although the contribution of paracellular Cl absorption might be limited by the paracellular shunt resistance, which is approximately 20 times larger than the transepithelial resistance, the paracellular shunt is not strictly ion selective and allows for paracellular movement of Cl. Tight junctions (consisting of occludin, claudin and paracellin) found at the apical border of the epithelium are actively regulated, and can control the secretion of Cl ions into the lumen.

In certain pathophysiologic states, this finely tuned ionic/fluid exchange becomes dysfunctional as a result of the failure of compensatory pro-absorptive/anti-secretory mechanisms. The excessive secretion of Na+ and Cl ions followed by the release of a large amount of H2O into the colonic lumen (usually >2–3 l daily) results in acute and chronic diarrhea [1–4]. In extreme cases, secretory diarrhea can lead to liters of fluid being secreted per hour. If not treated, excessive diarrhea can lead to severe fluid and electrolyte depletion, resulting in renal failure and death.

Infectious agents (e.g. bacteria, microsporidia, Cryptosporidia, viruses) can be an important cause of acute diarrhea [5]. Infectious outbreaks of diarrhea involving large numbers of people are generally linked to contaminated drinking water or recreational water. In 1993, for example, an outbreak of cryptosporidium in Milwaukee, Wisconsin, was estimated to involve over 400 000 people. A variety of molecular and cellular techniques [5] (e.g. stool culture, polymerase chain reaction, enzyme-linked immunosorbent assay, bright-field microscopy, special stains, DNA microarrays and transmission electron microscopy [6]) are used in specific diagnostic situations. Although the occurrence of viral gastroenteritis is prominent among the pediatric population [7], outbreaks among adults caused by Norwalk agent (e.g. cruise ships, nursing homes) and rotavirus (e.g. an epidemic in the Truk islands in 1964 involving 3439 people) have been reported.

Studies of how certain microbes can induce diarrhea at the molecular level has contributed greatly to our understanding of the mechanisms of ion transport and fluid exchange in the gut. We will briefly discuss some of the mechanisms of acute diarrhea caused by several bacterial strains as these mechanisms are enlightening with regard to perturbation of ion transport processes. A variety of bacterial pathogens can induce secretory diarrhea and inflammatory diarrhea. For example, enterotoxigenic Escherichia and Vibrio cholerae induce secretory diarrhea owing to the activity of potent cytotoxins. Other pathogens such as Shigella flexneri and Salmonella enterica serotype Typhimurium cause an inflammatory diarrhea owing to activation of proinflammatory molecules. It is clear that diverse pathogens utilize different mechanisms to cause intestinal disease, which include alteration in ion transport, disruption of tight junctions, and acute inflammatory responses. In the case of enterotoxigenic Escherichia coli and V. cholerae, these alterations result in a large amount of fluid secreted into the lumen leading to diarrhea.

The heat-labile and cholera enterotoxins produced by E. coli and V. cholerae, respectively, increase the level of intracellular second messengers (e.g. cAMP and cGMP), which then activate the lumenal CFTR, resulting in the overstimulation of the secretory pathway. At the same time, the enterotoxins inhibit electroneutral absorption by Na+/H+ exchangers and electrogenic absorption by epithelial Na+ channels. Cholera toxin and heat-labile E. coli toxin increase cAMP by irreversible activation of adenylate cyclase. Heat-stable E. coli toxin can also activate cAMP indirectly by increasing cGMP-deactivation of phosphodiesterase, leading to enhanced cAMP levels. Increased levels of cGMP can also activate protein kinase GII and Cl secretion in crypts and apical membranes of the colon. Guanylin, the regulatory peptide secreted by goblet cells, is the natural ligand for heat-stable toxin receptors. The release of guanylin into the lumen is probably triggered by cholinergic stimulation. Binding of guanylin to heat-stable toxin receptors then results in an increase in levels of cGMP. The toxin-induced increases in second messengers then lead to hyperactivation of the CFTR protein on the apical membrane. This mechanism has been confirmed in CFTR-deficient mice, in which bacterial toxins fail to elicit secretory diarrhea. These in-vitro and in-vivo findings provide an explanation for a genetic advantage of patients who are heterozygotes for CFTR mutations, in that they are naturally protected from secretory diarrhea caused by bacterial and viral pathogens.

Cholera toxin and several other toxins produced by V. cholerae increase the permeability of tight junctions and stimulate Ca2+-dependent secretion. Aside from cholera toxin, two putative toxins namely, the accessory cholera toxin and the zonula occludens toxin were reported, but these proteins were later demonstrated to be part of a filamentous bacteriophage. Several in-vitro studies have shown that V. cholerae secretes other cytotoxic factors such as the hemagglutinin/protease, hemolysin and repeats-in-toxin (RTX). Hemagglutinin/protease affects paracellular barrier function in epithelial cells by degrading occludin in tight junctions and hydrolyzing mucin leading to enhancement of detachment of V. cholerae from cultured epithelial cells. Hemolysin causes necrosis of intestinal epithelial cells and vacuolation of cells. Lastly, RTX induces cell rounding and increased permeability through paracellular tight junctions owing to cross-linking of actin monomers leading to depolymerization of actin stress fibers. It was proposed that these cytotoxic factors might cause tissue damage that in turn could contribute to proinflammatory responses. Only RTX mutants of V. cholerae, however, have been demonstrated in a murine pulmonary cholera model to show less severe pathology and decreased serum levels of proinflammatory interleukin (IL)-6 and murine macrophage inflammatory protein-2, suggesting that RTX participates in the severity of acute inflammatory responses.

Several pathogens are known to cause chronic diarrhea. These include bacterial species (e.g. Clostridium difficile, Mycobacterium tuberculosis), parasites (e.g. Giardia lamblia, Entamoeba histolytica) and yeast (e.g. Candida albicans). C. difficile, for example, produces clostridial toxin that increases intracellular Ca2+ levels and modulates small GTP-binding proteins. Small GTP-binding proteins are responsible for maintaining cytoskeletal architecture and the integrity of tight junctions. In addition to clostridial toxin itself, two other large clostridial toxins have been reported to modulate small GTP-binding proteins. Mucosal IL-8 and neutrophil recruitment are, however, central to the pathogenesis of C. difficile toxin-induced diarrhea [8]. A common polymorphism in the IL-8 gene promoter (−251A/A allele) was recently found to be associated with increased mean fecal IL-8 levels and increased susceptibility to C. difficile toxin-induced diarrhea [8].

Studies of patients with ulcerative colitis have elucidated some of the pathophysiologic mechanisms of diarrhea. Diarrhea is the most common and debilitating symptom of ulcerative colitis [9]. It appears that impaired absorption of Na+ (accompanied by impaired absorption of Cl and H2O) is the critical ion defect in ulcerative colitis. The inflamed mucosa of patients with ulcerative colitis is very leaky to all monovalent ions because mucosal inflammation (i) down-regulates expression of the Cl/HCO 3 exchanger, (ii) impairs the Na+/H+ exchanger, (iii) is associated with pro-inflammatory-mediated (e.g. tumor necrosis factor-α, interferon-γ) decreases in expression of Na+ channel β-subunit and γ-subunit at the transcriptional level, (iv) causes decreased expression of Na+/K+-ATPase and Na+/K+/2Cl proteins at the translational level mediated by tumor necrosis factor-α via the prostaglandin, PGE2 [10], (v) causes abnormal trafficking of a Na+/K+-ATPase isoform to the basolateral membrane and (vi) significantly decreases the number of the most abundant intermediate conductance calcium-activated K+ channel, KCNN4. Decreased epithelial resistance in ulcerative colitis results from impairment of tight junction integrity and the presence of apoptotic foci. The resultant increase in intercellular permeability also contributes to the chronic diarrhea associated with this disease. As a result of the multifactorial components responsible for the abnormal fluid exchange, the treatment of inflammation and associated diarrhea in patients with ulcerative colitis can be very challenging for the gastroenterologist.

Of particular interest to the field of inflammatory bowel disease is the ability of bile acids to interact with the colonic epithelial cells to cause secretory diarrhea. As many of the secretagogues increased in inflammatory bowel disease by bile acids (e.g. cAMP, cGMP, nitric oxide, PGE2) are also implicated in signal-transduction pathways associated with colon carcinogenesis, a greater understanding of their role in carcinogenesis is needed. Taurodeoxycholic acid, TDOC (a conjugated bile acid) and deoxycholic acid (DOC) are both secondary bile acids that result from the action of bacterial 7-α-dehydroxylase on primary bile acids in the colon. The removal of the 7-α-OH group results in an increase in hydrophobicity, which increases the membrane-perturbing effects of these bile acids.

TDOC increases electrogenic Cl secretion into the proximal colonic lumen [11]. This stimulus for secretion is believed to occur via an increase in intracellular Ca2+ concentration. TDOC induces Ca2+ influx, which activates the Ca2+-dependent basolateral K+ channels. The basolateral K+ channels maintain a hyperpolarized membrane voltage and the electrical driving force for apical Cl secretion and Na+ absorption, in part, through basolateral Na+/K+/2Cl co-transporter activation. DOC also induces an increase in intracellular Ca2+ concentrations, which may also activate the Ca2+-dependent basolateral K+ pathway, resulting in basolateral Na+/K+/2Cl co-transporter activation. DOC also acts at more than one target in the cell and can reduce transepithelial Na+ absorption by inhibition of amiloride-sensitive Na+ channels, and increased secretion of Na+, K+ and Cl ions in the distal colon [12]. Bile acids can also disturb epithelial permeability through a disturbance of tight junction integrity. In a novel model of DOC-induced colitis developed in our laboratory [13], we found that the inclusion of DOC in the diet (∼1 mmol/l concentration in the lumen) caused a decrease in JAM-3, one of the junctional adhesion molecules. This effect on tight junctions could contribute to the diarrhea associated with the malabsorption of bile acids in ileal resections.

The etiology of chronic diarrhea needs to be methodically ascertained, and may represent a diagnostic challenge for both gastroenterologists and primary care physicians. The causes of diarrhea can be organic or functional in nature. A general approach to determine the causes of chronic diarrhea should include obtaining a history of (i) excessive consumption of dietary-related substances [e.g. excess non-absorbable fiber (e.g. soy fiber, gum arabic)], (ii) excess phytohemagglutinins (present in red kidney beans and jackbeans), (iii) the excessive use of laxatives, (iv) whether the patient has undergone extensive ileal resection resulting in the malabsorption of bile acids that increase diarrhea (e.g. TDOC in the proximal colon and DOC in the distal colon), (v) the presence of irritable bowel syndrome and (vi) the presence of long-standing insulin-dependent diabetes. In the case of long-standing diabetes, affected individuals may have poor diabetic control and develop peripheral neuropathy, a condition that is secondary to degeneration of adrenergic nerves. Adequate adrenergic nerve stimulation is antisecretory and/or pro-absorptive in intestinal fluid homeostasis. Advanced diabetes can result in autonomic neuropathy that can affect the enteric nervous system, resulting in decreased intestinal motility. The latter can lead to bacterial overgrowth, with the production of bacterial toxins and their perturbation of mucosal integrity and ion transport mechanisms.

An extremely important, although rarer, cause of chronic diarrhea is the presence of extra-colonic and colonic-associated neoplasms. Neoplasms of enterochromaffin cells that produce hormones or peptides that affect the intestine or colon can cause secretory diarrhea. Carcinoids, for example, secrete hormones such as vasoactive intestinal peptide, 5-hydroxytryptamine, substance P, bradykinin and prostaglandins, which all have a pro-secretory effect. Vasoactive intestinal peptide is pro-secretory by causing an increase in cAMP levels. Kinins (e.g. bradykinin, substance P) act at the basolateral membrane Na+/K+-ATPase and the CFTR chloride channels to increase lumenal concentrations of Na+ and Cl. Secretory gastrointestinal hormones, in general, appear to increase intracellular Ca2+ levels in the colon more than in the small intestine. The elevated Ca2+ levels then increase the conductance of basolateral K+ channels accompanied by the release of Cl ions into the lumen. Profuse diarrhea develops in 30% of patients with medullary carcinoma of the thyroid because of secretion of calcitonin, another hormone that acts as a stimulus for secretory diarrhea in the intestine.

Secretory villous adenomas of the rectum characterized by a severe electrolyte and fluid depletion syndrome were first described in 1954 by McKittrick and Wheelock [14]. Secretory villous adenomas of the colon/rectum are characterized by dehydration, prerenal azotemia, hyponatremia, hypokalemia, metabolic acidosis and obtundation [15]. The presence of secretory diarrhea can exist over several years, which can be compensated by increased oral fluid intake and renal mechanisms. Both cAMP and PGE2 have been implicated as the secretagogues responsible for the pathogenesis of this disorder. The prostaglandin inhibitor, indomethacin, has been used in some patients to control the excess fluid that characterizes this severe diarrhea. As the physiologic compensation mechanisms are exhausted, a life-threatening condition develops in association with prerenal failure. Therefore, the presence of the triad of prerenal failure, electrolyte disorder and chronic diarrhea may signal the existence of a villous adenoma. Rectal exam followed by colonoscopy should then be performed. Surgical resection of the villous adenoma before malignant transformation will lead to adequate gut homeostasis and cure. An untreated secretory villous adenoma, however, can cause death through extensive fluid loss and disturbances in electrolyte balance.

The article published in a previous issue of the European Journal of Gastroenterology & Hepatology by Lepur et al. [16] described in detail the clinical course, diagnostic work-up and treatment of a patient with a previously undescribed rectal adenocarcinoma as a rare cause of the McKittrick–Wheelock syndrome. As a result of the multiple causes of chronic diarrhea, the work-up of a patient with severe fluid depletion can be very challenging, and if untreated is life-threatening.

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Conflict of interest

None declared.

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Keywords:

bile acids; diarrhea; infectious organisms; mechanisms; neoplasms

© 2006 Lippincott Williams & Wilkins, Inc.