Diarrhea

Diarrhea can be defined as an increase in the fluidity, frequency, and volume of daily stool output. The daily stool weight is usually increased over the normal average of 200 g due to an increase in the stool water above the normal content of 60% to 75%. There may also be a change in the stool solids.

Normal intestinal fluid balance

During fasting, the intestine contains very little fluid. On a normal diet of three meals a day, about 9 L of fluid is delivered to the small intestine. Oral intake accounts for 2000 mL, and the remainder is secreted from various parts of the gastrointestinal tract into the lumen. Of this, 90% is absorbed in the small intestine. One to two liters is presented to the colon, and approximately 90% is absorbed. The colon has the capacity to absorb all of the fluid presented to it, but the presence of unabsorbed osmotically active solutes from the diet (e.g., some carbohydrates) and from bacterial action prevents complete fluid absorption and desiccation of the fecal material. This results in 100 to 200 mL of fluid in the stool. Thus, approximately 98% of the fluid presented to the intestine each day is absorbed by the small and large intestines.

Feces on the average contain 100 mL of water, 40 mEq/L of sodium (Na⁺), 90 MEq/ liter of potassium (K⁺), 16 mEq/ liter of chloride (Cl^–), and 30-mEq/liter of bicarbonate (HCO₃^–). The remaining anions are organic and result from bacterial fermentation of unabsorbed carbohydrates. The gastrointestinal tract does not have diluting mechanisms; thus, the osmolality of the fecal fluid is never less than the osmolality of plasma. In fact, osmolality of fecal fluid is usually greater than that of plasma due to continuing bacterial fermentation of unabsorbed carbohydrates into osmotically active particles after defecation.

Water transport across the intestinal epithelium is passive. It is secondary to osmotic gradients generated by active transport of electrolytes such as Na⁺ and Cl^– or other solutes, such as sugars and amino acids. Intestinal ion absorption occurs mainly across epithelial cells that reside at the tips of the villi. Crypt cells are involved in ion secretion: Na⁺ is the major ion actively absorbed, and Cl^– is the major ion secreted.

Na⁺ is actively absorbed throughout the intestinal tract empowered by the Na⁺ pump in the form of Na⁺ -K^– -ATPase located in the basolateral plasma membrane of intestinal epithelial cells. Thus water is absorbed along with Na⁺.

Active intraluminal secretion in the intestine is accomplished by active secretion of Cl^–. This process is also powered by Na⁺ -K^– -ATPase located in basolateral membranes of the crypt cells. Cl^– secretion is also followed by water secretion into the intestinal lumen.

Any process that either impairs absorption of Na⁺ and water or causes Cl^– and water to be secreted into the intestinal lumen can result in diarrhea.

Pathophysiology of diarrhea

There are four major mechanisms of diarrhea.

• Osmotic diarrhea, in which there is increased amounts of poorly absorbable, osmotically active solutes in the gut lumen.
• Secretory diarrhea, in which there is, increased Cl^– and water secretion with or without inhibition of normal active Na⁺ and water absorption.
• Exudation of mucus, blood, and protein from sites of active inflammation into the bowel lumen.
• Abnormal intestinal motility, with increased or decreased contact between luminal contents and mucosal surface.

Osmotic diarrhea

Causes.

Osmotic diarrhea is caused by ingestion of a poorly absorbable solute, usually a carbohydrate or a divalent ion (e.g., magnesium [Mg²⁺] or sulfate [SO₄^2-]). The higher osmolality of the luminal contents causes water influx into the intestinal lumen across the duodenal and jejunal epithelium to dilute the solute, in an attempt to make the chyme isotonic. Due to the leakiness of this epithelium, Na⁺ follows the influx of water from the plasma to the gut lumen due to the difference in the Na⁺ concentration gradient. This Na⁺ influx causes further influx of water even after the osmolality of the luminal contents and plasma is identical.

In contrast, the epithelium of the ileum and colon has a low permeability to Na⁺ and to the solute. It also has an efficient active ion transport mechanism that allows it to reabsorb Na⁺ and water even against a steep electrochemical gradient. Thus, water is absorbed as it traverses the ileum and colon, and the severity of the osmotic diarrhea is reduced. This has been called «colon salvage». Since the fluid volume entering the colon still exceeds the ability of the colon to absorb, diarrhea results.

In lactase deficiency, lactose from the diet cannot be absorbed in the small intestine, remains in the lumen, and reaches the colon, where it is broken down by the endogenous bacteria into additional osmotically active solute particles, which increase the osmotic load and cause diarrhea.

Clinically, osmotic diarrhea stops when the patient fasts. The stool osmolality ([Na⁺]+[K⁺]) x 2 (to account for anions) is less than the osmolality of the stool fluid measured by freezing point depression. This osmotic anion gap accounts for the presence of the poorly absorbable solutes in fecal fluid. Anion gaps greater than 50 are considered clinically significant. Determination of the stool pH may be helpful in the diagnosis of osmotic diarrhea. Carbohydrates in stool yield an acid pH; milk of magnesia, an alkaline pH; and poorly absorbable salts containing Mg²⁺ or SO₄²⁺, a neutral pH.

Secretory diarrhea

Causes.

Diarrhea of 1 L or more per day results from secretion of fluid across the intestinal mucosa. In most cases, a pathophysiologic event causes small intestinal secretion by simultaneously stimulating active secretion and partial inhibition of intestinal absorption. Often, the intestinal mucosa is intact and has normal histologic findings.

Clinically, there are five features that characterize secretory diarrhea.

• Stool volume is usually large (>1 L per day).
• Stools are watery in consistency.
• Stools do not contain pus or blood.

Diarrhea typically continues while the patient fasts for 24 to 48 hours. However, secretory diarrhea from fatty acid malabsorption or from laxative abuse will stop when these agents are not ingested.

The osmolality of the stool is close to the osmolality of plasma, and there is no anion gap.

Exudative diarrhea.

If the intestinal mucosa is inflamed and ulcerated, mucus, blood, and pus leak into the lumen and are discharged as stool. This may also create an increased osmotic load. If a large surface area of the bowel lumen is involved, absorption of ions, solutes, and water will also be impaired, and patients may have large-volume diarrhea. Inflammation may generate prostaglandins, which stimulate secretion and may increase bowel motility, thus compounding the diarrhea. The severity of the diarrhea and the systemic signs and symptoms depends on the extent of bowel involvement.

Inflammatory states may be

• Idiopathic (e.g., Crohn’s disease, ulcerative colitis).
• Infectious (e.g., from invasive organisms or cytotoxins: Shigella, Salmonella, Campylobacter, Yersinia, tuberculosis, amebae, Clostridium difficile).
• Ischemic.
• Vasculitic.
• Due to radiation injury.
• Caused by abscess formation (e.g., diverticulitis, infected carcinoma).
• Motility disturbances. Both reduced and increased motility of the intestine may result in diarrhea.

Increased motility of the small intestine results in decreased contact time of chyme with absorptive surfaces. Large amounts of fluid delivered to the colon may overwhelm its absorptive capacity and result in diarrhea. The reduced contact time in the small intestine may interfere with absorption of fatty acids and bile salts, allowing them to reach the colon, where they induce a secretory diarrhea. Diarrhea associated with hyperthyroidism, carcinoid, and postgastrectomy dumping syndrome are examples.

Decreased motility of the small intestine may allow colonization of the small intestine with colonic-type bacteria. The digestion and absorption of fats, carbohydrates, and bile salts may be affected, resulting in osmotic or secretory diarrhea. This mechanism is involved in the diarrhea seen with diabetes, hypothyroidism, scleroderma, amyloidosis, and postvagotomy states.

Increased colonic motility with premature emptying of colonic contents is the major cause of diarrhea in the irritable bowel syndrome.

Anal sphincter dysfunction caused by neuromuscular disease, inflammation, scarring, and postsurgical states may result in fecal incontinence, which may be interpreted by the patient as diarrhea.

Clinical approach

Diagnosis of Diarrhea

Treatment

Acute diarrhea with fluid and electrolyte depletion is a major cause of mortality, especially in children in developing countries of the world. Fluid repletion by intravenous or oral routes can prevent death. Oral rehydration therapy can be accomplished with a simply prepared oral rehydration solution. Physiologically water absorption follows the absorption of glucose-coupled sodium transport in the small intestine, which remains intact even in the severest of diarrheal illnesses.

Oral rehydration solution can be prepared by adding 3.5 g of sodium chloride (or three fourths of a teaspoon or 3.5 g of table salt), 2.5 g of sodium bicarbonate (or 2.9 g of sodium citrate or 1 teaspoon of baking soda), 1.5 g of  potassium chloride (or one cup of orange juice or two bananas), and 20 g of glucose (or 40 g of sucrose or 4 tablespoons of sugar) to a liter (1.05 qt) of clean water. This makes a solution of approximately 90 mmol of sodium, 20 mmol of potassium, 80 mmol of chloride, 30 mmol of bicarbonate, and 111 mmol of glucose per liter. Not only is this solution lifesaving in severe diarrhea, but also it is less painful, safer, less costly, and superior to intravenous fluids, because the patient’s thirst protects against overhydration.

It should therefore be the preferred route of rehydration in conscious adult and pediatric patients in tertiary and intensive care units. Furthermore, the output of stool can be reduced with food-based oral rehydration therapy. With the additional sodium-coupled absorption of neutral amino acids and glutamine (a key mucosal nutrient in the small bowel, analogous to short-chain fatty acids in the colon), oral rehydration therapy can also be used to speed recovery from small-bowel injury.

The composition of cereal-based oral rehydration solution is like that of standard oral rehydration solution (3.5 g of sodium chloride, 2.5 g of sodium bicarbonate, and 1.5 g of potassium chloride), except that the 20 g of glucose is replaced by 50 to 60 g of cereal flour (rice, maize, millet, wheat, or sorghum) or 200 g of mashed, boiled potato; stirred into 1.1 L of water; and brought to a boil. Not only can oral rehydration therapy (especially with cereal and continued feeding) reverse the loss of fluid, but also it can prevent the fatal hypoglycemia seen with failure of gluconeogenesis, a major cause of death in children with diarrhea in developing areas. Furthermore, simple oral rehydration therapy can be started early in the home and can prevent most complications of dehydration and malnutrition.

Attention should also be directed at reduction of the patient’s symptoms and discomfort to reduce absenteeism from work or school as well as to improve the sense of well-being of the patient. Available drugs can be divided into groups based on their mechanisms of action: absorbents, antisecretory agents, opiate derivatives, anticholinergic agents, and antimicrobial agents.

Absorbents (e.g., Kaopectate, aluminum hydroxide) do not influence the course of the disease but help to produce solid stools. This effect may allow the patient to alter the timing of stooling and permit a more voluntary control of defecation.

Antisecretory agents

In most cases of diarrhea, regardless of etiology, invasive or noninvasive, intestinal secretion contributes greatly to the stool volume. Antisecretory drugs, including prostaglandin synthesis inhibitors, have been used to diminish bowel secretion.

Bismuth subsalicylate (Pepto-Bismol) has been shown to block the secretory effects of V. cholerae, enterotoxigenic E. coli, and Shigella as well as to prevent intestinal infection by these agents if given prophylactically. The usual therapeutic dosage of Pepto-Bismol is 30 mL every 30 minutes for eight doses. The prophylactic dosage is 60 mL or two tablets four times daily (q.i.d.) for the duration of the prophylaxis (e.g., for travelers). Pepto-Bismol tablets are as effective as the liquid preparation.

Opiate derivatives are widely used in both acute and chronic diarrhea. By diminishing peristalsis, they delay gut transit of fluid and allow more time for fluid absorption. They may be used in patients with moderate symptoms (3-5 stools per day) but should not be used in patients with fever, systemic toxicity, or bloody diarrhea. Their use should be discontinued in patients who have not shown improvement or whose condition has worsened on therapy.

Opiate derivatives include paregoric (tincture of opium), diphenoxylate with atropine (Lomotil), and loperamide (Imodium). Imodium has two advantages over Lomotil in that it does not contain atropine and it has fewer central opiate effects.

Anticholinergic agents do not appear to be useful in the treatment of most diarrheal disorders. Some patients with irritable bowel syndrome may benefit from use of dicyclomine hydrochloride (Bentyl).

Antimicrobial agents

When the diarrhea is severe and the patient has systemic signs of toxicity, stool cultures should be performed to identify the pathogenic organism. The most effective antimicrobial agent for the particular pathogen should be used. In selected cases of severe diarrhea, if a laboratory is not available, empiric antibiotics with activity against both Shigella and Campylobacter strains may be administered (e.g., ciprofloxacin or trimethoprim/ sulfamethoxazole or erythromycin).

Treatment of E. coli 0157:H7 with an antimicrobial agent is controversial since there is some inconclusive data that suggests complications with hemolytic uremic syndrome may be higher with antimicrobial therapy. However, in patients with severe diarrhea, antimicrobial therapy (e.g., ciprofloxacin hydrochloride 500 mg twice daily, by mouth) may be used with caution.

Chemoprophylaxis of traveler’s diarrhea

Bismuth subsalicylate, doxycycline, and trimethoprim/sulfamethoxazole, norfloxacin, and ciprofloxacin hydrochloride have been shown to be effective in preventing most causes of traveler’s diarrhea. Doxycycline resistance among enteric bacterial pathogens does occur in some regions. Starting on the first day of travel, the dosage of each drug is as follows: bismuth subsalicylate, 60 mL q.i.d.; doxycycline, 100 mg daily; trimethoprim/sulfamethoxazole, 160/800 mg daily; ciprofloxacin hydrochloride, 500 mg daily; norfloxacin, 400 mg daily. Aztreonam, 100 mg daily, has also been shown to be effective. Each drug should be continued for 1 to 2 days after returning home. No drug should be taken for more than 3 weeks.

The use of antimicrobial chemoprophylaxis should be discouraged for most travelers. Each drug has its side and adverse effects and will confer antimicrobial resistance to the gut flora of the individual. This may present a therapeutic problem if another infection (e.g., a urinary tract infection) develops. Antimicrobial chemoprophylaxis should be restricted to 2 to 5 days in persons who are on a special «business» trip and who accept the risks of side and adverse effects.

Chronic or recurrent diarrhea

The therapy of chronic and recurrent diarrhea should be based on the etiology and pathophysiology of the disease process. Occasionally, when a diagnosis cannot be made, an empiric trial of diet restriction (e.g., lactose, gluten, long-chain fatty acids), pancreatic enzyme supplements along with histamine-2 (H₂) blockers, cholestyramine, clonidine, and antimicrobial (e.g., metronidazole) therapy may be use. When all fails, the judicious use of antidiarrheal opiate derivatives may result in symptom relief.

Imodium

Attapulgite

Bismuth subsalicylate

Calcium polycarbophil

Jennifer Bowles

Jennifer is a clinical pharmacologist. She helps doctors of all medical specialties choose medications. Jennifer consults about drug dosage, interactions, and side effects.