Ingestion of toxin

Ingestion of organisms

Bowel colonization

Toxin elaboration

Toxin binding to enterocyte receptors

Increased concentrations of intracellular mediators

Activation of targets of intracellular mediators

Alteration of transfer proteins and low channels

Infection Diarrhea

Pathophysiology of Infection Diarrhea

PATHOPHYSIOLOGY OF ACUTE INFECTIOUS DIARRHEAL DISEASES

Author: admin Enteropathogens gain access to the intestinal tract via oral contamination and cause diarrhea by disrupting intestinal and colonic mucosa through a variety of mechanisms. Bacteria such as Staphylococcus aureus, Bacillus cereus, and Clostridium botulinum release enterotoxins, which invoke intestinal secretion. Other pathogens, such as Shigella and enteroinvasive Escherichia coli, express invasins, which allow tissue invasion and disruption of mucosa. Many other bacteria elicit cytotoxic mediators that directly damage enteric and colonic mucosa. Enteropathogenic mechanisms of disease, therefore, are the basis for the two common clinical syndromes: inflammatory and non-inflammatory diarrhea. Inflammatory diarrheal syndromes often manifest clinically as dysentery, characterized by fever, tenesmus, abdominal pain, and frequent, small-volume stools that are often bloody. Organisms such as Shigella, Campylobacter jejuni, and enteroinvasive E. coli produce an inflammatory reaction that yields fecal leukocytes and blood on laboratory examination of stool. Patients with an inflammatory acute diarrheal illness can be quite toxic appearing and often require antibiotic treatment. Conversely, non-inflammatory diarrheal syndromes are usually self-limited and more often do not require antimicrobial therapy. Enteropathogens such as Vibrio parahaemolyticus, Cryptosporidium parvum, and Giardia lamblia as well as viral agents and toxin-producing bacteria, such as Staphylococcus aureus, Clostridium difficile, and enterotoxigenic E. coli, typically induce watery, non-bloody diarrhea without fever or significant abdominal pain. Stool examination is notable for the absence of leukocytes and blood. Typically, more than 1 L of watery stool is passed each day, and volume depletion may be profound. *66/348/5* PATHOPHYSIOLOGY OF ACUTE INFECTIOUS DIARRHEAL DISEASESEnteropathogens gain access to the intestinal tract via oral contamination and cause diarrhea by disrupting intestinal and colonic mucosa through a variety of mechanisms. Bacteria such as Staphylococcus aureus, Bacillus cereus, and Clostridium botulinum release enterotoxins, which invoke intestinal secretion. Other pathogens, such as Shigella and enteroinvasive Escherichia coli, express invasins, which allow tissue invasion and disruption of mucosa. Many other bacteria elicit cytotoxic mediators that directly damage enteric and colonic mucosa. Enteropathogenic mechanisms of disease, therefore, are the basis for the two common clinical syndromes: inflammatory and non-inflammatory diarrhea.Inflammatory diarrheal syndromes often manifest clinically as dysentery, characterized by fever, tenesmus, abdominal pain, and frequent, small-volume stools that are often bloody. Organisms such as Shigella, Campylobacter jejuni, and enteroinvasive E. coli produce an inflammatory reaction that yields fecal leukocytes and blood on laboratory examination of stool. Patients with an inflammatory acute diarrheal illness can be quite toxic appearing and often require antibiotic treatment.Conversely, non-inflammatory diarrheal syndromes are usually self-limited and more often do not require antimicrobial therapy. Enteropathogens such as Vibrio parahaemolyticus, Cryptosporidium parvum, and Giardia lamblia as well as viral agents and toxin-producing bacteria, such as Staphylococcus aureus, Clostridium difficile, and enterotoxigenic E. coli, typically induce watery, non-bloody diarrhea without fever or significant abdominal pain. Stool examination is notable for the absence of leukocytes and blood. Typically, more than 1 L of watery stool is passed each day, and volume depletion may be profound.

Pathophysiology
Infectious agents usually cause acute gastroenteritis. These agents cause diarrhea by adherence, mucosal invasion, enterotoxin production, and/or cytotoxin production. These mechanisms result in increased fluid secretion and/or decreased absorption. This produces an increased luminal fluid content that cannot be adequately reabsorbed, leading to dehydration and the loss of electrolytes and nutrients. Diarrheal illnesses may be classified as follows: Osmotic, due to an increase in the osmotic load presented to the intestinal lumen, either through excessive intake or diminished absorption

 Inflammatory (or mucosal), when the mucosal lining of the intestine is inflamed Secretory, when increased secretory activity occurs Motile, caused by intestinal motility disorders The small intestine is the prime absorptive surface. The colon then absorbs additional fluid, transforming a relatively liquid fecal stream in the cecum to well-formed solid stool in the rectosigmoid. Disorders of the small intestine result in increased amounts of diarrheal fluid with a concomitantly greater loss of electrolytes and nutrients. Microorganisms may produce toxins that facilitate infection. Enterotoxins are generated by bacteria (ie, enterotoxigenic Escherichia coli, Vibrio cholera) that act directly on secretory mechanisms and produce typical, copious watery (rice water) diarrhea. No mucosal invasion occurs. The small intestines are primarily affected, and elevation of the adenosine monophosphate (AMP) levels is the common mechanism. Cytotoxin production by bacteria (ie, Shigella dysenteriae, Vibrio parahaemolyticus, Clostridium difficile, enterohemorrhagic E coli) results in mucosal cell destruction that leads to bloody stools with inflammatory cells. A resulting decreased absorptive ability occurs. Enterocyte invasion is the preferred method by which microbes such asShigella and Campylobacter organisms and enteroinvasive E coli cause destruction and inflammatory diarrhea. Similarly, Salmonella and Yersiniaspecies also invade cells but do not cause cell death. Hence, dysentery does not usually occur. However, these bacteria invade the bloodstream across the lamina propria and cause enteric fever such as typhoid. Diarrheal illness occurs when microbial virulence overwhelms normal host defenses. A large inoculum may overwhelm the host capacity to mount an effective defense. Normally, more than 100,000 E coli are required to cause disease, while only 10 Entamoeba or Giardia cysts may suffice to do the same. Some organisms (eg, V cholera, enterotoxigenic E coli) produce proteins that aid their adherence to the intestinal wall, thereby displacing the normal flora and colonizing the intestinal lumen. In addition to the ingestion of pathogenic organisms or toxins, other intrinsic factors can lead to infection. An alteration of normal bowel flora can create a biologic void that is filled by pathogens. This occurs most commonly after antibiotic administration, but infants are also at risk prior to colonization with normal bowel flora. The normally acidic pH of the stomach and colon is an effective antimicrobial defense. In achlorhydric states (ie, caused by antacids, histamine-2 [H2] blockers, gastric surgery, decreased colonic anaerobic flora), this defense is weakened. Hypomotility states may result in colonization by pathogens, especially in the proximal small bowel, where motility is the major mechanism in the removal of organisms. Hypomotility may be induced by antiperistaltic agents (eg, opiates, diphenoxylate and atropine [Lomotil], loperamide) or anomalous anatomy (eg, fistulae, diverticula, antiperistaltic afferent loops) or is inherent in disorders such as diabetes mellitus or scleroderma. The immunocompromised host is more susceptible to infection, as evidenced by the wide spectrum of diarrheal pathogens in patients with AIDS. The exact mechanism of vomiting in acute diarrheal illness is not known, although serotonin release has been postulated as a cause, stimulating visceral afferent input to the chemoreceptor trigger zone in the lower brainstem. Preformed neurotoxins produced by Staphylococcus aureus andBacillus cereus, when ingested, can cause severe vomiting.

Background

Gastroenteritis is a nonspecific term for various pathologic states of the gastrointestinal tract. The primary manifestation is diarrhea, but it may be accompanied by nausea, vomiting, and abdominal pain. A universal definition of diarrhea does not exist, although patients seem to have no difficulty defining their own situation. Although most definitions center on the frequency, consistency, and water content of stools, the author prefers defining diarrhea as stools that take the shape of their container. The severity of illness may vary from mild and inconvenient to severe and life threatening. Appropriate management requires extensive history and assessment and appropriate, general supportive treatment that is often etiology specific. Diarrhea associated with nausea and vomiting is referred to as gastroenteritis. Diarrhea is one of the most common reasons patients seek medical care. In the developed world, it is the most common reason for missing work, while in the developing world, it is a leading cause of death. In developing countries, diarrhea is a seasonal scourge usually worsened by natural phenomena, as evidenced by monsoon floods in Bangladesh in 1998. An estimated 100 million cases of acute diarrhea occur every year in the United States. Of these patients, 90% do not seek medical attention, and 1-2% require admission. Diarrheal diseases can quickly reach epidemic proportions, rapidly overwhelming public health systems in even the most advanced societies.

Background
Acute diarrhea is defined as the abrupt onset of abnormally high fluid content in the stool: more than the normal value of approximately 10 mL/kg/d in the infant and young child, and more than 200 g/d in the teenager and adult. This situation typically implies an increased frequency of bowel movements, which can range from 4-5 to more than 20 times per day. The augmented water content in the stools is due to an imbalance in the physiology of the small and large intestinal processes involved in the absorption of ions, organic substrates, and thus water. A common disorder in its acute form, diarrhea has many causes and may be mild to severe. Childhood acute diarrhea is usually caused by infection; however, numerous disorders may cause this condition, including a malabsorption syndrome and various enteropathies. Acute-onset diarrhea is usually self-limited; however, an acute infection can have a protracted course. By far, the most common complication of acute diarrhea is dehydration. Although the term "acute gastroenteritis" is commonly used synonymously with "acute diarrhea," the former term is a misnomer. The term gastroenteritisimplies inflammation of both the stomach and the small intestine, whereas, in reality, gastric involvement is rarely if ever seen in acute diarrhea (including diarrhea with an infectious origin); enteritis is also not consistently present. Examples of infectious acute diarrhea syndromes that do not cause enteritis include Vibrio cholerae induced diarrhea and Shigella -induced diarrhea. Thus, the term acute diarrhea is preferable to acute gastroenteritis. Diarrheal episodes are classically distinguished into acute and chronic (or persistent) based on their duration. Acute diarrhea is thus defined as an episode that has an acute onset and lasts no longer than 14 days; chronic or persistent diarrhea is defined as an episode that lasts longer than 14 days. The distinction, supported by the World Health Organization (WHO), has implications not only for classification and epidemiological studies but also from a practical standpoint because protracted diarrhea often has a different set of causes, poses different problems of management, and has a different prognosis.

Pathophysiology
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.