Saturday, 2 November 2013

DIARRHEA AND CONSTIPATION

Diarrhea and constipation are exceedingly common and together exact an enormous toll in terms of morbidity, loss of work productivity, and consumption of medical resources. Worldwide, more than 1 billion people suffer one or more episodes of acute diarrhea each year. Among the 100 million persons affected annually by acute diarrhea in the United States, nearly half must restrict activities, 10% consult physicians, 250,000 require hospitalization, and roughly 3000 die (primarily the elderly). The annual economic burden to society is estimated at >$20 billion. Because of poor sanitation and more limited access to health care, acute infectious diarrhea remains one of the most common causes of mortality in developing countries, particularly among children, accounting for 5 to 8 million deaths per year. Population statistics on chronic diarrhea and constipation are more uncertain, perhaps due to variable definitions and reporting, but the frequency of these conditions is also high. Based on United States population surveys, prevalence rates for chronic diarrhea range from 2 to 7% and for chronic constipation from 3 to 17%. Diarrhea and constipation are among the most common patient complaints faced by internists and primary care physicians, and they account for nearly 50% of referrals to gastroenterologists.
Although diarrhea and constipation may present as mere nuisance symptoms at one extreme, they can be severe or life-threatening at the other. Even mild symptoms may signal a serious underlying gastrointestinal lesion, such as colorectal cancer, or systemic disorder, such as thyroid disease. Given the heterogeneous causes and potential severity of these common complaints, it is imperative for clinicians to appreciate the pathophysiology, etiologic classification, diagnostic strategies, and therapeutic principles of diarrhea and constipation so that rational and cost-effective care can be delivered.

NORMAL PHYSIOLOGY

The human small intestine and colon perform important functions including the secretion and absorption of water and electrolytes, the storage and subsequent transport of intraluminal contents aborally, and the salvage of some nutrients after bacterial metabolism of carbohydrate that are not absorbed in the small intestine. The main motor functions are summarized in Table 1. Alterations in fluid and electrolyte handling contribute significantly to diarrhea. Alterations in motor and sensory functions of the human colon result in highly prevalent syndromes such as irritable bowel syndrome, chronic diarrhea, and chronic constipation.
TABLE 1 Normal Gastrointestinal Motility:
Functions at Different Anatomic Levels
Stomach and small bowel
  Synchronized MMCs in fasting
  Accommodation, trituration, mixing, transit
    Stomach, ~3 h
    Small bowel, ~3 h
  Ileal reservoir empties boluses
Colon: Irregular mixing, absorption, transit
  Ascending, transverse: reservoirs
  Descending: conduit
  Sigmoid/rectum: volitional reservoir
Note: MMC, migrating motor complex.
NEURAL CONTROL
The small intestine and colon have intrinsic and extrinsic innervation. The intrinsic innervation, also called the enteric nervous system, comprises myenteric, submucosal, and mucosal neuronal layers. The function of these layers is modulated by interneurons through the actions of neurotransmitter amines or peptides, including acetylcholine, opioids, norepinephrine, serotonin, ATP, and nitric oxide. The myenteric plexus regulates smooth-muscle function, and the submucosal plexus affects secretion and absorption.
The extrinsic innervations of the small intestine and colon are part of the autonomic nervous system and also modulate both motor and secretory functions. The parasympathetic nerve supply conveys both visceral sensory as well as excitatory pathways to the motor components of the colon. Parasympathetic fibers via the vagus nerve reach the small intestine and proximal colon along the branches of the superior mesenteric artery. The distal colon is supplied by sacral parasympathetic nerves (S2–4) via the pelvic plexus; these fibers course through the wall of the colon as ascending intracolonic fibers as far as, and in some instances including, the proximal colon. The chief excitatory neurotransmitters controlling motor function are acetylcholine and the tachykinins, such as substance P. The sympathetic nerve supply modulates motor functions and reaches the small intestine and colon alongside the arterial arcades of the superior and inferior mesenteric vessels. Sympathetic input to the gut is generally excitatory to sphincters and inhibitory to nonsphincteric muscle. Visceral afferents convey sensation from the gut to the central nervous system; initially, they course along sympathetic fibers, but as they approach the spinal cord they separate, have cell bodies in the dorsal root ganglion, and enter the dorsal horn of the spinal cord. Afferent signals are conveyed to the brain along the lateral spinothalamic tract and the nociceptive dorsal column pathway and are then perceived. Other afferent fibers synapse in the prevertebral ganglia and reflexly modulate intestinal motility.

INTESTINAL FLUID ABSORPTION AND SECRETION

On an average day, 9 L of fluid enters the gastrointestinal tract; approximately 1 L of residual fluid reaches the colon; the stool excretion of fluid constitutes about 0.2 L/d. The colon has a large capacitance and functional reserve and may recover up to four times its usual volume of 0.8 L/d, provided the rate of flow permits reabsorption to occur. Thus, the colon can partially compensate for intestinal absorptive or secretory disorders.
In the colon, sodium absorption is predominantly electrogenic, and uptake takes place at the apical membrane; it is compensated for by the export functions of the basolateral sodium pump. A variety of neural and non-neural mediators regulate colonic fluid and electrolyte balance, including cholinergic, adrenergic, and serotonergic mediators. Angiotensin and aldosterone also influence colonic absorption, reflecting the common embryologic development of the distal colonic epithelium and the renal tubules.

SMALL INTESTINAL MOTILITY

During fasting, the motility of the small intestine is characterized by a cyclical event called the migrating motor complex (MMC), which serves to clear nondigestible residue from the small intestine. This organized, propagated series of contractions lasts on average 4 min, occurs every 60 to 90 min, and usually involves the entire small intestine. After food ingestion, the small intestine produces irregular, mixing contractions of relatively low amplitude, except in the distal ileum where more powerful contractions occur intermittently and empty the ileum by bolus transfers.

ILEOCOLONIC STORAGE AND SALVAGE

The distal ileum acts as a reservoir, emptying intermittently by bolus movements. This action allows time for salvage of fluids, electrolytes, and nutrients. Segmentation by haustra compartmentalizes the colon and facilitates mixing, retention of residue, and formation of solid stools. In health, the ascending and transverse regions of colon function as reservoirs (average transit, 15 h), and the descending colon acts as a conduit (average transit, 3 h). The colon is efficient at conserving sodium and water, a function that is particularly important in sodium-depleted patients in whom the small intestine alone is unable to maintain sodium balance. Diarrhea or constipation may result from alteration in the reservoir function of the proximal colon or the propulsive function of the left colon. Constipation may also result from disturbances of the rectal or sigmoid reservoir, typically as a result of dysfunction of the pelvic floor or the coordination of defecation.

COLONIC MOTILITY AND TONE

The small intestinal MMC only rarely continues into the colon. However, short duration or phasic contractions mix colonic contents, and high-amplitude propagated contractions (HAPCs) are sometimes associated with mass movements through the colon and occur approximately five times per day, usually on awakening in the morning and postprandially. Increased frequency of HAPCs may result in diarrhea. The predominant phasic contractions are irregular and nonpropagated and serve as a “mixing” function.
Colonic tone refers to the background contractility upon which phasic contractile activity (typically contractions lasting <15 s) is superimposed. It is an important cofactor in the colon's capacitance (volume accommodation) and sensation.

COLONIC MOTILITY AFTER MEAL INGESTION

After meal ingestion, colonic phasic and tonic contractility increase for a period of approximately 2 h. The initial phase (about 10 min) is mediated by the vagus nerve in response to mechanical distention of the stomach. The subsequent response of the colon requires caloric stimulation and is at least in part mediated by hormones, e.g., gastrin and serotonin.

DEFECATION

FIGURE 1 Mechanisms involved in continence and defecation. Note the importance of pelvic floor and anal sphincter functions. Continence requires: contraction of puborectalis, maintenance of anorectal angle, normal rectal sensation, and contraction of sphincter. Defecation requires: relaxation of puborectalis, straightening of anorectal angle, and relaxation of sphincter.
Tonic contraction of the puborectalis muscle, which forms a sling around the rectoanal junction, is important to maintain continence; during defecation, sacral parasympathetic nerves relax this muscle, facilitating the straightening of the rectoanal angle (Fig. 1). Distention of the rectum results in transient relaxation of the internal anal sphincter via intrinsic and reflex sympathetic innervation. As sigmoid and rectal contractions increase the pressure within the rectum, the rectosigmoid angle opens by >15°. Voluntary relaxation of the external anal sphincter (striated muscle innervated by the pudendal nerve) permits the evacuation of feces; this evacuation process can be augmented by an increase in intraabdominal pressure created by the Valsalva maneuver.
DIARRHEA
DEFINITION
Diarrhea is loosely defined as passage of abnormally liquid or unformed stools at an increased frequency. For adults on a typical Western diet, stool weight >200 g/d can generally be considered diarrheal. Because of the fundamental importance of duration to diagnostic considerations, diarrhea may be further defined as acute if <2 weeks, persistent if 2 to 4 weeks, and chronic if >4 weeks in duration.
Two common conditions, usually associated with the passage of stool totaling <200 g/d, must be distinguished from diarrhea, as diagnostic and therapeutic algorithms differ. Pseudodiarrhea, or the frequent passage of small volumes of stool, is often associated with rectal urgency and accompanies the irritable bowel syndrome or anorectal disorders such as proctitis. Fecal incontinence is the involuntary discharge of rectal contents and is most often caused by neuromuscular disorders or structural anorectal problems. Diarrhea and urgency, especially if severe, may aggravate or cause incontinence. Pseudodiarrhea and fecal incontinence occur at prevalence rates comparable to or higher than that of chronic diarrhea and should always be considered in patients complaining of “diarrhea.” A careful history and physical examination generally allow these conditions to be discriminated from true diarrhea.

ACUTE DIARRHEA

More than 90% of cases of acute diarrhea are caused by infectious agents; these cases are often accompanied by vomiting, fever, and abdominal pain. The remaining 10% or so are caused by medications, toxic ingestions, ischemia, and other conditions.

Infectious Agents

Most infectious diarrheas are acquired by fecal-oral transmission via direct personal contact or, more commonly, via ingestion of food or water contaminated with pathogens from human or animal feces. In the immunologically competent person, the resident fecal microflora, containing >500 taxonomically distinct species, are rarely the source of diarrhea and may actually play a role in suppressing the growth of ingested pathogens. Acute infection or injury occurs when the ingested agent overwhelms the host's mucosal immune and nonimmune (gastric acid, digestive enzymes, mucus secretion, peristalsis, and suppressive resident flora) defenses. Established clinical associations with specific enteropathogens may offer diagnostic clues.
In the United States, high risk groups are recognized:
1.   Travelers. Nearly 40% of tourists to endemic regions of Latin America, Africa, and Asia develop so-called traveler's diarrhea, most commonly due to enterotoxigenic Escherichia coli as well as to Campylobacter, Shigella, and Salmonella. Visitors to Russia (especially St. Petersburg) may have increased risk of Giardia-associated diarrhea; visitors to Nepal may acquire Cyclospora. Campers, backpackers, and swimmers in wilderness areas may become infected with Giardia.
2.   Consumers of certain foods. Diarrhea closely following food consumption at a picnic, banquet, or restaurant may suggest infection with Salmonella, Campylobacter, or Shigella from chicken; enterohemorrhagic E. coli (O157:H7) from undercooked hamburger; Bacillus aureus from fried rice; Staphylococcus aureus or Salmonella from mayonnaise or creams; Salmonella from eggs; and Vibrio species, Salmonella, or acute hepatitis A or B from seafood, especially if raw.
3.   Immunodeficient persons. Individuals at risk for diarrhea include those with either primary immunodeficiency (e.g., IgA deficiency, common variable hypogammaglobulinemia, chronic granulomatous disease) or the much more common secondary immunodeficiency states (e.g., AIDS, senescence, pharmacologic suppression). Common enteropathogens often cause a more severe and protracted diarrheal illness, and, particularly in persons with AIDS, opportunistic infections, such as by Mycobacterium species, certain viruses (cytomegalovirus, adenovirus, and herpes simplex), and protozoa (Cryptosporidium, Isospora belli, Microsporidia, and Blastocystis hominis) may also play a role. In patients with AIDS, agents transmitted venereally per rectum (e.g., Neisseria gonorrhoeae, Treponema pallidum, Chlamydia) may contribute to proctocolitis.
4.   Daycare participants and their family members. Infections with Shigella, Giardia, Cryptosporidium, rotavirus, and other agents are very common and should be considered.
5.   Institutionalized persons. Infectious diarrhea is one of the most frequent categories of nosocomial infections in many hospitals and long-term care facilities; the causes are a variety of microorganisms but most commonly Clostridium difficile.
TABLE 2 Association between Pathobiology of Causative
Agents and Clinical Features in Acute Infectious Diarrhea

Pathobiology/Agents

Incubation Period

Vomiting

Abdominal Pain
Fever
Diarrhea

Toxin producers






Preformed toxin





Bacillus cereus, Staphylococcus aureus, Clostridium perfringens
1–8 h
8–24 h
3–4+
1–2+
0–1+
3–4+, watery
Enterotoxin





Vibrio cholerae, enterotoxigenic Escherichia coli, Klebsiella pneumoniae, Aeromonas species
8–72 h
2–4+
1–2+
0–1+
3–4+, watery
Enteroadherent





Enteropathogenic and enteroadherent, E. coli, Giardia organisms, cryptosporidiosis, helminths
1–8 d
0–1+
1–3+
1–2+
1–2+, watery
Cytotoxin-producers





 Clostridium difficile
1–3 d
0–1+
3–4+
1–2+
1–3+, usually watery, occasionally bloody
  Hemorrhagic E. coli
12–72 h
0–1+
3–4+
1–2+
1–3+, initially watery, quickly bloody
Invasive organisms





Minimal inflammation





    Rotavirus and Norwalk agent
1–3 d
1–2+
2–3+
3–4+
1–3+, watery
Variable inflammation





Salmonella, Campylobacter, and Aeromonas species, Vibrio parahaemo­lyticus, Yersinia
12 h–11 d
0–3+
2–4+
3–4+
1–4+, watery or bloody
 Severe inflammation





    Shigella species, enteroinvasive E. coli, Entamoeba histolytica
12 h–8 d
0–1+
3–4+
3–4+
1–2+, bloody
The pathophysiology underlying acute diarrhea by infectious agents produces specific clinical features that may also be helpful in diagnosis (Table 2). Profuse watery diarrhea secondary to small bowel hypersecre­tion occurs with ingestion of preformed bacterial toxins, enterotoxin-producing bacteria, and enteroadherent pathogens. Diarrhea associated with marked vomiting and minimal or no fever may occur abruptly within a few hours after ingestion of the former two types; vomiting is usually less, and abdominal cramping or bloating is greater; fever is higher with the latter. Cytotoxin-producing and invasive microorganisms all cause high fever and abdominal pain. Invasive bacteria and Entamoeba histolytica often cause bloody diarrhea (referred to as dysentery). Yersinia invades the terminal ileal and proximal colon mucosa and may cause especially severe abdominal pain with tenderness mimicking acute appendicitis.
Finally, infectious diarrhea may be associated with systemic manifestations. Reiter's syndrome (arthritis, urethritis, and conjunctivitis) may accompany or follow infections by Salmonella, Campylobacter, Shigella, and Yersinia. Yersiniosis may also lead to an autoimmune-type thyroiditis, pericarditis, and glomerulonephritis. Both enterohemorrhagic E. coli (O157:H7) and Shigella can lead to the hemolytic-uremic syndrome with an attendant high mortality rate. Acute diarrhea can also be a major symptom of several systemic infections including viral hepatitis, listeriosis, legionellosis, and toxic shock syndrome.

Other Causes

Side effects from medications are probably the most common noninfectious cause of acute diarrhea, and etiology may be suggested by a temporal association between use and symptom onset. Although innumerable medications may produce diarrhea, some of the more frequently incriminated include antibiotics, cardiac antidysrhythmics, antihypertensives, nonsteroidal anti-inflammatory drugs (NSAIDs), certain antidepressants, chemotherapeutic agents, bronchodilators, antacids, and laxatives. Occlusive or nonocclusive ischemic colitis typically occurs in persons >50 years, often presents as acute lower abdominal pain preceding watery, then bloody diarrhea, and generally results in acute inflammatory changes in the sigmoid or left colon while sparing the rectum. Acute diarrhea may accompany colonic diverticulitis and graft-versus-host disease. Acute diarrhea, often associated with systemic compromise, can follow ingestion of toxins including organophosphate insecticides, amanita and other mushrooms, arsenic, and preformed environmental toxins in seafoods, such as ciguatera and scombroid. The conditions causing chronic diarrhea can also be confused with acute diarrhea early in their course. This confusion may occur with inflammatory bowel disease and some of the other inflammatory chronic diarrheas that may have an abrupt rather than insidious onset and exhibit features that mimic infection.

APPROACH TO THE PATIENT

The decision to evaluate acute diarrhea depends on its severity and duration and on various host factors (Fig. 2). Most episodes of acute diarrhea are mild and self-limited and do not justify the cost and potential morbidity of diagnostic or pharmacologic interventions. Indications for evaluation include profuse diarrhea with dehydration, grossly bloody stools, fever ≥38.5° C, duration >48 h without improvement, new community outbreaks, associated severe abdominal pain in patients >50 years, and elderly (≥70 years) or immunocompromised patients. In some cases of moderately severe febrile diarrhea associated with fecal leukocytes (or increased fecal levels of the leukocyte proteins) or with gross blood, a diagnostic evaluation might be avoided in favor of an empirical antibiotic trial (see below).
The cornerstone of diagnosis in those suspected of severe acute infectious diarrhea is microbiologic analysis of the stool. Workup includes cultures for bacterial and viral pathogens, direct inspection for ova and parasites, and immunoassays for certain bacterial toxins (C. difficile), viral
FIGURE 2. Algorithm for the management of acute diarrhea. Consider empirical Rx before evaluation with (*) metronidazole and (†) with quinolone.
antigens (rotavirus), and protozoal antigens (Giardia, E. histolytica). The aforementioned clinical and epidemiologic associations may assist in focusing the evaluation. If a particular pathogen or set of possible pathogens is so implicated, then either the whole panel of routine studies may not be necessary or, in some instances, special cultures may be appropriate as for enterohemorrhagic and other types of E. coli, Vibrio species, and Yersinia. Molecular diagnosis of pathogens in stool can be made by identification of unique DNA sequences; and evolving microarray technologies could lead to a more rapid, sensitive, specific, and cost-effective diagnostic approach in the future.
Persistent diarrhea is commonly due to Giardia, but additional causative organisms that should be considered include C. difficile (especially if antibiotics had been administered), E. histolytica, Cryptosporidium, Campylobacter, and others. If stool studies are unrevealing, then flexible sigmoidoscopy with biopsies and upper endoscopy with duodenal aspirates and biopsies may be indicated.
Structural examination by sigmoidoscopy, colonoscopy, or abdominal computed tomographic scanning (or other imaging approaches) may be appropriate in patients with uncharacterized persistent diarrhea to exclude inflammatory bowel disease, or as an initial approach in patients with suspected noninfectious acute diarrhea such as might be caused by ischemic colitis, diverticulitis, or partial bowel obstruction.

TREATMENT

Fluid and electrolyte replacement are of central importance to all forms of acute diarrhea. Fluid replacement alone may suffice for mild cases. Oral sugar-electrolyte solutions (sport drinks or designed formulations) should be instituted promptly with severe diarrhea to limit dehydration, which is the major cause of death. Profoundly dehydrated patients, especially infants and the elderly, require intravenous rehydration.
In moderately severe nonfebrile and nonbloody diarrhea, antimotility antisecretory agents such as loperamide can be useful adjuncts to control symptoms. Such agents should be avoided with febrile dysentery, which may be exacerbated or prolonged by them. Bismuth subsalicylate may reduce symptoms of vomiting and diarrhea but should not be used to treat immunocompromised patients because of the risk of bismuth encephalopathy.
Judicious use of antibiotics is appropriate in selected instances of acute diarrhea and may reduce its severity and duration (Fig. 2). Many physicians treat moderately to severely ill patients with febrile dysentery empirically without diagnostic evaluation using a quinolone, such as ciprofloxacin (500 mg bid for 3 to 5 d). Empirical treatment can also be considered for suspected giardiasis with metronidazole (250 mg qid for 7 d). Selection of antibiotics and dosage regimens are otherwise dictated by specific pathogens and conditions found. Antibiotic coverage is indicated whether or not a causative organism is discovered in patients who are immunocompromised, have mechanical heart valves or recent vascular grafts, or are elderly. Antibiotic prophylaxis is indicated for certain patients traveling to high-risk countries in whom the likelihood or seriousness of acquired diarrhea would be especially high, including those with immunocompromise, inflammatory bowel disease, or gastric achlorhydria. Use of trimethoprim/sulfamethoxazole or ciprofloxacin may reduce bacterial diarrhea in such travelers by 90%.

CHRONIC DIARRHEA

Diarrhea lasting >4 weeks warrants evaluation to exclude serious underlying pathology. In contrast to acute diarrhea, most of the many causes of chronic diarrhea are noninfectious. The classification of chronic diarrhea by pathophysiologic mechanism facilitates a rational approach to management (Table 3).
TABLE 3 Major Causes of Chronic Diarrhea According to Predominant Pathophysiologic Mechanism
Secretory causes
  Exogenous stimulant laxatives
  Chronic ethanol ingestion
  Other drugs and toxins
  Endogenous laxatives (dihydroxy bile acids)
  Idiopathic secretory diarrhea
  Certain bacterial infections
  Bowel resection, disease, or fistula (↓ absorption)
  Partial bowel obstruction or fecal impaction
  Hormone-producing tumors (carcinoid, VIPoma, medullary cancer of thyroid, mastocytosis, gastrinoma, colorectal villous adenoma)
  Addison's disease
  Congenital electrolyte absorption defects
Osmotic causes
  Osmotic laxatives (Mg2+, PO43-, SO42-)
  Lactase and other disaccharide deficiencies
  Nonabsorbable carbohydrates (sorbitol, lactulose, polyethylene glycol)
Steatorrheal causes
  Intraluminal maldigestion (pancreatic exocrine insufficiency, bacterial overgrowth, liver disease)
  Mucosal malabsorption (celiac sprue, Whipple's disease, infections, abetalipoproteinemia, ischemia)
  Postmucosal obstruction (1° or 2° lymphatic obstruction)
Inflammatory causes
  Idiopathic inflammatory bowel disease (Crohn's chronic ulcerative colitis)
  Microscopic and collagenous colitis
  Immune-related mucosal disease (1° or 2° immunodeficiencies, food allergy, eosinophilic gastroenteritis, graft-vs-host disease)
Infections (invasive bacteria, viruses, and parasites)
Radiation injury
Gastrointestinal malignancies
Dysmotile causes
  Visceral neuromyopathies
  Hyperthyroidism
  Drugs (prokinetic agents)
Factitial causes
  Munchausen
  Bulimia
Secretory Causes
Secretory diarrheas are due to derangements in fluid and electrolyte transport across the enterocolic mucosa. They are characterized clinically by watery, large-volume fecal outputs that are typically painless and persist with fasting. Because there is no malabsorbed solute, stool osmolality is accounted for by normal endogenous electrolytes with no fecal osmotic gap.

MEDICATIONS

Side effects from regular ingestion of drugs and toxins are the most common secretory causes of chronic diarrhea. Hundreds of prescription and over-the-counter medications (see “Other Causes of Acute Diarrhea,” above) may produce unwanted diarrhea. Surreptitious or habitual use of stimulant laxatives [e.g., senna, cascara, bisacodyl, ricinoleic acid (castor oil)] must also be considered. Chronic ethanol consumption may cause a secretory-type diarrhea due to enterocyte injury with impaired sodium and water absorption as well as to rapid transit and other alterations. Inadver­tent ingestion of certain environmental toxins (e.g., arsenic) may lead to chronic rather than acute forms of diarrhea. Certain bacterial infections may occasionally persist and be associated with a secretory-type diarrhea.

HORMONES

Although uncommon, the classic examples of secretory diarrhea are those mediated by hormones. Metastatic gastrointestinal carcinoid tumors or, rarely, primary bronchial carcinoids may produce watery diarrhea alone or as part of the carcinoid syndrome that comprises episodic flushing, wheezing, dyspnea, and right-sided valvular heart disease. Diarrhea is due to the release into the circulation of potent intestinal secretagogues including serotonin, histamine, prostaglandins, and various kinins. Pellagra-like skin lesions may rarely occur as the result of serotonin overproduction with niacin depletion. Gastrinoma, one of the most common neuroendocrine tumors, most typically presents with refractory peptic ulcers, but diarrhea occurs in up to one-third of cases and may be the only clinical manifestation in 10%. While various secretagogues released with gastrin may play a role, the diarrhea most often results from fat maldigestion owing to pancreatic enzyme inactivation by low intraduodenal pH. The watery diarrhea hypokalemia achlorhydria syndrome, also called pancreatic cholera, is due to a non-β cell pancreatic adenoma, referred to as a VIPoma, that secretes vasoactive intestinal peptide (VIP) and a host of other peptide hormones including pancreatic polypeptide, secretin, gastrin, gastrin-inhibitory polypeptide, neurotensin, calcitonin, and prostaglandins. The secretory diarrhea is often massive with stool volumes >3 L/d; daily volumes as high as 20 L have been reported. Life-threatening dehydration; neuromuscular dysfunction from associated hypokalemia, hypomagnesemia, or hypercalcemia; flushing; and hyperglycemia may accompany a VIPoma. Medullary carcinoma of the thyroid may present with watery diarrhea caused by calcitonin, other secretory peptides, or prostaglandins. This tumor occurs sporadically or, in 25 to 50% of cases, as a feature of multiple endocrine neoplasia type IIa with pheochromocytomas and hyperparathyroidism. Prominent diarrhea is often associated with metastatic disease and poor prognosis. Systemic mastocytosis, which may be associated with the skin lesion urticaria pigmentosa, may cause diarrhea that is either secretory and mediated by histamine or inflammatory and due to intestinal filtration by mast cells. Large colorectal villous adenomas may rarely be associated with a secretory diarrhea that may cause hypokalemia, can be inhibited by NSAIDs, and is apparently mediated by prostaglandins.

CONGENITAL DEFECTS IN ION ABSORPTION

Rarely, these defects cause watery diarrhea from birth and include defective Cl-/HCO3- exchange (congenital chloridorrhea) with alkalosis and defective Na+/H+ exchange with acidosis. Some hormone deficiencies may be associated with watery diarrhea, such as occurs with adrenocortical insufficiency (Addison's disease) that may be accompanied by hyperpigmentation.

Osmotic Causes

Osmotic diarrhea occurs when ingested, poorly absorbable, osmotically active solutes draw enough fluid lumenward to exceed the resorptive capacity of the colon. Fecal water output increases in proportion to such a solute load. Osmotic diarrhea characteristically ceases with fasting or with discontinued oral intake of the offending agent.

OSMOTIC LAXATIVES

Ingestion of magnesium-containing antacids, health supplements, or laxatives may induce osmotic diarrhea typified by a stool osmotic gap: 2([Na] + [K]) <290 mosm/kg. Anionic laxatives containing sulfates or phosphates produce osmotic diarrhea without an osmotic gap, as sodium accompanies the anionic solutes; direct measurement of stool sulfates and phosphates may be necessary to confirm the cause of diarrhea.

CARBOHYDRATE MALABSORPTION

Carbohydrate malabsorption due to acquired or congenital defects in brush-border disaccharidases and other enzymes leads to osmotic diarrhea with a low pH. One of the most common causes of chronic diarrhea in adults is lactase deficiency, which affects three-fourths of non-Caucasians worldwide and 5 to 30% of persons in the United States; most learn to avoid milk products without an intervention. Some sugars, such as sorbitol, are universally malabsorbed, and diarrhea ensues with ingestion of ample medications, gum, or candies sweetened with these nonabsorbable sugars. Lactulose, used to acidify stools in patients with hepatic failure, also causes diarrhea on this basis.

Steatorrheal Causes

Fat malabsorption may lead to greasy, foul-smelling, difficult-to-flush diarrhea often associated with weight loss and nutritional deficiencies due to concomitant malabsorption of amino acids and vitamins. Increased fecal output is caused by the osmotic effects of fatty acids, especially after bacterial hydroxylation, and, to a lesser extent, by the burden of neutral fat. Quantitatively, steatorrhea is defined as stool fat exceeding the normal 7 g/d; daily fecal fat averages 15 to 25 g with small intestinal diseases and is often >40 g with pancreatic exocrine insufficiency. Intraluminal maldigestion, mucosal malabsorption, or lymphatic obstruction may produce steatorrhea.

INTRALUMINAL MALDIGESTION

This condition most commonly results from pancreatic exocrine insufficiency, which occurs when >90% of pancreatic secretory function is lost. Chronic pancreatitis, usually a sequela of ethanol abuse, most frequently causes pancreatic insufficiency. Other causes include cystic fibrosis, pancreatic duct obstruction, and rarely, somatostatinoma. Bacterial overgrowth in the small intestine may deconjugate bile acids and alter micelle formation that impairs fat digestion; it occurs with stasis from a blind-loop, small bowel diverticulum or dysmotility and is especially likely in the elderly. Finally, cirrhosis or biliary obstruction may lead to mild steatorrhea due to deficient intraluminal bile acid concentration.

MUCOSAL MALABSORPTION

Mucosal malabsorption occurs from a variety of enteropathies but most prototypically and perhaps most commonly from celiac sprue. This gluten-sensitive enteropathy characterized by villous atrophy and crypt hyperplasia in the proximal small bowel often presents with fatty diarrhea associated with multiple nutritional deficiencies of varying severity and affects all ages. Tropical sprue may produce a similar histologic and clinical syndrome but occurs in residents of or travelers to tropical climates; its often abrupt onset and response to antibiotics suggest an infectious etiology. Whipple's disease, due to the actinomycete Treponema whippleii and histiocytic infiltration of the small bowel mucosa, is a less common cause of steatorrhea that most typically occurs in young or middle-aged men; it is frequently associated with arthralgias, fever, lymphadenopathy, and extreme fatigue and may affect the central nervous system and endocardium. A similar clinical and histologic picture results from Mycobacterium avium-intracellulare infection in patients with AIDS. Abetalipoproteinemia is a rare defect of chylomicron formation and fat malabsorption in children associated with acanthocytic erythrocytes, ataxia, and retinitis pigmentosa. Several other conditions may cause mucosal malabsorption including infections, especially with protozoa such as Giardia, numerous medications (e.g., colchicine, cholestyramine, neomycin), and chronic ischemia.

POSTMUCOSAL LYMPHATIC OBSTRUCTION

The pathophysiology of this condition, which is due to the rare congenital intestinal lymphangiectasia or to acquired lymphatic obstruction secondary to trauma, tumor, or infection, leads to the unique constellation of fat malabsorption with enteric losses of protein (often causing edema) and lymphocytes (with resultant lymphocytopenia) that enter the portal circulation directly. Carbohydrate and amino acid absorption are preserved.

Inflammatory Causes

Inflammatory diarrheas are generally accompanied by pain, fever, bleeding, or other manifestations of inflammation. The mechanism of diarrhea may not only be exudation but, depending on lesion site, may include fat malabsorption, disrupted fluid/electrolyte absorption, and hypersecretion or hypermotility from release of cytokines and other inflammatory mediators. The unifying feature on stool analysis is the presence of leukocytes or leukocyte-derived proteins such as calprotectin. With severe inflammation, exudative protein loss can lead to anasarca (generalized edema). Any middle-aged or older person with chronic inflammatory-type diarrhea, especially with blood, should be carefully evaluated to exclude a colorectal or large enteric tumor.

IDIOPATHIC INFLAMMATORY BOWEL DISEASE

The illnesses in this category, which include Crohn's disease and chronic ulcerative colitis, are among the most common organic causes of chronic diarrhea in adults and range in severity from mild to fulminant and life-threatening. They may be associated with uveitis, polyarthralgias, cholestatic liver disease (primary sclerosing cholangitis), and various skin lesions (erythema nodosum, pyoderma gangrenosum). Microscopic colitis, including collagenous colitis, is an increasingly recognized cause of chronic watery diarrhea; biopsy of a normal appearing colorectum is required for histologic diagnosis.

PRIMARY OR SECONDARY FORMS OF IMMUNODEFICIENCY

Immunodeficiency may lead to prolonged infectious diarrhea. With common, variable hypogammaglobulinemia, diarrhea is particularly prevalent and often the result of giardiasis.

EOSINOPHILIC GASTROENTERITIS

Eosinophil infiltration of the mucosa, muscularis, or serosa at any level of the gastrointestinal tract may cause diarrhea, pain, vomiting, or ascites. Affected patients often have an atopic history, Charcot-Leyden crystals due to extruded eosinophil contents may be seen on microscopic inspection of stool, and peripheral eosinophilia is present in 50 to 75% of patients. While hypersensitivity to certain foods occurs in adults, true food allergy causing chronic diarrhea is rare.

OTHER CAUSES

Chronic inflammatory diarrhea may be caused by radiation enterocolitis, chronic graft-versus-host disease, Behçet's syndrome, and Cronkite-Canada syndrome, among others.

Dysmotile Causes

Rapid transit may accompany many diarrheas as a secondary or contributing phenomenon, but primary dysmotility is an unusual etiology of true diarrhea. Stool features often suggest a secretory diarrhea, but mild steatorrhea of up to 14 g of fat per day can be produced by maldigestion from rapid transit alone. Hyperthyroidism, carcinoid syndrome, and certain drugs (e.g., prostaglandins, prokinetic agents) may produce hypermotility with resultant diarrhea. Primary visceral neuromyopathies or idiopathic acquired intestinal pseudo-obstruction may lead to stasis with secondary bacterial overgrowth causing diarrhea. Diabetic diarrhea, often accompanied by peripheral and generalized autonomic neuropathies, may occur in part because of intestinal dysmotility.
The exceedingly common irritable bowel syndrome (10% point prevalence, 1 to 2% per year incidence) is characterized by disturbed intestinal and colonic motor and sensory responses to various stimuli. Symptoms of stool frequency typically cease at night, alternate with periods of constipation, are accompanied by abdominal pain relieved with defecation, and rarely result in weight loss or true diarrhea.

Factitial Causes

Factitial diarrhea accounts for up to 15% of unexplained diarrheas referred to tertiary care centers. Either as a form of Munchausen syndrome (deception or self-injury for secondary gain) or bulimia, some patients covertly self-administer laxatives alone or in combination with other medications (e.g., diuretics) or surreptitously add water or urine to stool sent for analysis. Such patients are typically women, often with histories of psychiatric illness, and disproportionately from careers in health care. Hypotension and hypokalemia are common co-presenting features. Such patients often deny this possibility when confronted, but they do benefit from psychiatric counseling when they acknowledge their behavior.

APPROACH TO THE PATIENT

The laboratory tools available to evaluate the very common problem of chronic diarrhea are extensive, and many are costly and invasive. As such, the diagnostic evaluation must be rationally directed by a careful history and physical examination, and simple triage tests are often warranted before complex investigations are launched (Fig. 3). The history, physical examination, and routine blood studies should attempt to characterize the mechanism of diarrhea, identify diagnostically helpful associations, and assess the patient's fluid/electrolyte and nutritional status. Patients should be questioned about the onset, duration, pattern, aggravating (especially diet) and relieving factors, and stool characteristics of their diarrhea. The presence or absence of fecal incontinence, fever, weight loss, pain, certain exposures (travel, medications, contacts with diarrhea), and common extraintestinal manifestations (skin changes, arthralgias, oral aphtha) should be noted. Physical findings may offer clues such as a thyroid mass, wheezing, heart murmurs, edema, hepatomegaly, abdominal masses, lymphadenopathy, mucocutaneous abnormalities, perianal fistulae, or anal sphincter laxity. Peripheral blood counts may reveal leukocytosis that suggests inflammation; anemia that reflects blood loss or nutritional deficiencies; or eosinophilia that may occur with parasitoses, neoplasia, collagen-vascular disease, allergy, or eosinophilic gastroenteritis. Blood chemistries may demonstrate electrolyte, hepatic, or other metabolic disturbances.
A therapeutic trial is often appropriate, definitive, and highly cost effective when a specific diagnosis is suggested on the initial physician encounter. For example, chronic watery diarrhea, which ceases with fasting in an otherwise healthy young adult, may justify a trial of a lactose-restricted diet; bloating and diarrhea persisting since a mountain backpacking trip may warrant a trial of metronidazole for likely giardiasis; and postprandial diarrhea persisting since an ileal resection might be due to bile acid malabsorption and be treated with cholestyramine before further evaluation. Persistent symptoms require additional investigation.
FIGURE 3 Algorithm for the management of chronic diarrhea.* Dysmotility presents variable stool profile.
Certain diagnoses may be suggested on the initial encounter, e.g., idiopathic inflammatory bowel disease; however, additional focused evaluations may be necessary to confirm the diagnosis and characterize the severity or extent of disease so that treatment can be best guided. Patients suspected of having irritable bowel syndrome should be initially evaluated with proctosigmoidoscopy and mucosal biopsies; those with normal findings might be reassured and, as indicated, treated empirically with antispasmodics, antidiarrheals, bulk agents, anxiolytics, or antidepressants. Any patient who presents with chronic diarrhea and hematochezia should be evaluated with stool microbiologic studies and colonoscopy.
In an estimated two-thirds of cases, the cause for chronic diarrhea remains unclear after the initial encounter, and further testing is required. Quantitative stool collection and analyses can yield important objective data that may establish a diagnosis or characterize the type of diarrhea as a triage for focused additional studies (Fig. 3). If stool weight is >200 g/d, additional stool analyses should be performed that might include electrolyte concentration, pH, occult blood testing, leukocyte inspection (or leukocyte protein assay), fat quantitation, and laxative screens.
For secretory diarrheas (watery, normal osmotic gap), possible medication-related side effects or surreptitious laxative use should be reconsidered. Microbiologic studies should be done including fecal bacterial cultures (including media for Aeromonas and Pleisiomonas), inspection for ova and parasites, and Giardia antigen assay (the most sensitive test for giardiasis). Small bowel bacterial overgrowth can be excluded by intestinal aspirates with quantitative cultures or with glucose or xylose breath tests involving measurement of breath hydrogen or other metabolite (e.g., 14CO2). However, interpretation of these breath tests may be confounded by disturbances of intestinal transit. When suggested by history or other findings, screens for peptide hormones should be pursued (e.g., serum gastrin, VIP, calcitonin, and thyroid hormone/thyroid stimulating hormone, or urinary 5-hydroxyindolacetic acid and histamine). Upper endoscopy and colonoscopy with biopsies and small-bowel barium x-rays are helpful to rule out structural or occult inflammatory disease.
Further evaluation of osmotic diarrhea should include tests for lactose intolerance and magnesium ingestion, the two most common causes. Low fecal pH suggests carbohydrate malabsorption; lactose malabsorption can be confirmed by lactose breath testing or by a therapeutic trial with lactose exclusion and observation of the effect of lactose challenge (e.g., a quart of milk). Lactase determination on small-bowel biopsy is generally not available. If fecal Mg2+ or laxative levels are elevated, then inadvertent or surreptitious ingestion should be considered and psychiatric help should be sought.
For those with proven fatty diarrhea, endoscopy with small-bowel biopsy (including aspiration for Giardia and quantitative cultures) should be performed; if this procedure is unrevealing, a small-bowel radiograph is often an appropriate next step. If small-bowel studies are negative or if pancreatic disease is suspected, pancreatic exocrine insufficiency should be excluded with direct tests, such as the secretin-cholecystokinin stimulation test, or by indirect tests, such as assay of fecal chymotrypsin activity or a bentiromide test.
Chronic inflammatory-type diarrheas should be suspected by the presence of blood or leukocytes in the stool. Such findings warrant stool cultures, inspection for ova and parasites, C. difficile toxin assay, colonoscopy with biopsies, and, if indicated, small-bowel oral contrast studies.

TREATMENT

Treatment of chronic diarrhea depends on the specific etiology and may be curative, suppressive, or empirical. If the cause can be eradicated, treatment is curative as with resection of a colorectal cancer, antibiotic administration for Whipple's disease, or discontinuation of an offending drug. For many chronic conditions, diarrhea can be controlled by suppression of the underlying mechanism. Examples include elimination of dietary lactose for lactase deficiency or gluten for celiac sprue, use of glucocorticoids or other anti-inflammatory agents for idiopathic inflammatory bowel diseases, adsorptive agents such as cholestyramine for ileal bile acid malabsorption, proton pump inhibitors such as omeprazole for the gastric hypersecretion of gastrinomas, somatostatin analogues such as octreotide for malignant carcinoid, prostaglandin inhibitors such as indomethacin for medullary carcinoma of the thyroid, and pancreatic enzyme replacement for pancreatic insufficiency. When the specific cause or mechanism of chronic diarrhea evades diagnosis, empirical therapy may be beneficial. Mild opiates such as diphenoxylate or loperamide are often helpful in mild or moderate watery diarrhea. For those with more severe diarrhea, codeine or tincture of opium may be beneficial. Such antimotility agents should be avoided with inflammatory bowel disease, as toxic megacolon may be precipitated. Clonidine, an α2-adrenergic agonist, may allow control of diabetic diarrhea. For all patients with chronic diarrhea, fluid and electrolyte repletion is an important component of management (see “Acute Diarrhea,” above). Replacement of fat-soluble vitamins may also be necessary in patients with chronic steatorrhea.

CONSTIPATION

DEFINITION
Constipation is a common complaint in clinical practice and usually refers to persistent, difficult, infrequent, or seemingly incomplete defecation. Because of the wide range of normal bowel habits, constipation is difficult to define precisely. Most persons have at least three bowel movements per week; however, stool frequency alone is not a sufficient criterion for the diagnosis of constipation because many constipated patients describe a normal frequency of defecation but subjective complaints of excessive straining, hard stools, lower abdominal fullness, and a sense of incomplete evacuation. The individual patient's symptoms must be analyzed in detail to ascertain what is meant by “constipation” or “difficulty” with defecation.
Stool form and consistency are well correlated with the time elapsed from the preceding defecation. Hard, pellety stools occur with slow transit, while loose watery stools are associated with rapid transit. Small, pellety stools are more difficult to expel than large ones.

CAUSES

TABLE 4 Causes of Constipation in Adults
Types of Constipation and Causes

Examples

Recent onset

  Colonic obstruction
Neoplasm: stricture: ischemic, diverticular, inflammatory

  Anal sphincter spasm

Anal fissure, painful hemorrhoids
  Medications

Chronic

  Irritable bowel syndrome
Constipation–predominant, alternating
  Medications
Ca2+ blockers, antidepressants
  Colonic pseudo-obstruction
Slow transit constipation, megacolon (rare Hirschsprung's, Chagas)
  Disorders of rectal evacuation
Pelvic floor dysfunction, anismus, descending perineum syndrome, rectal mucosal prolapse, rectocele
  Endocrinopathies
Hypothyroidism, hypercalcemia, pregnancy
  Psychiatric disorders
Depression, eating disorders, drugs
  Neurologic disease
Parkinsonism, multiple sclerosis, spinal cord injury
  Generalized muscle disease
Progressive systemic sclerosis
The perception of hard stools or excessive straining is more difficult to assess objectively, and the need for enemas or digital disimpaction is a clinically useful way to corroborate the patient's perceptions of difficult defecation.
Psychosocial factors may also be important. A person whose parents attached great importance to daily defecation will become greatly concerned when he or she misses a daily bowel movement; some children withhold stool to gain attention; and some adults are simply too busy or too embarrassed to interrupt their work when the call to have a bowel movement is sensed.
Pathophysiologically, chronic constipation generally results from inadequate fiber intake or from disordered colonic transit or anorectal function as a result of a neurogastroenterologic disturbance, certain drugs, or in association with a large number of systemic diseases that affect the gastroinestinal tract (Table 4). Constipation of recent onset may be a symptom of significant organic disease such as tumor or stricture. In idiopathic constipation, a subset of patients exhibit delayed emptying of the ascending and transverse colon with prolongation of transit (often in the proximal colon) and a reduced frequency of propulsive colonic contractions (HAPCs). Outlet obstruction to defecation (also called evacuation disorders) may cause delayed colonic transit, which is usually corrected by biofeedback retraining of the disordered defecation. Constipation of any cause may be exacerbated by chronic illnesses that lead to physical or mental impairment and result in inactivity or physical immobility.

APPROACH TO THE PATIENT
A careful history should explore the patient's symptoms and confirm whether he or she is indeed constipated based on frequency (e.g., fewer than three bowel movements per week), consistency (lumpy/hard), excessive straining, prolonged defecation time, or need to support the perineum or digitate the anorectum. In the vast majority of cases (probably >90%), there is no underlying cause (e.g., cancer, depression, or hypothyroidism), and constipation responds to ample hydration, exercise, and supplementation of dietary fiber (15 to 25 g/d). A good diet and medication history and attention to psychosocial issues are key. Physical examination and, particularly, a rectal examination should exclude most of the important diseases that present with constipation and possibly indicate features suggesting an evacuation disorder (e.g., high anal sphincter tone).
There is broad consensus on the selection of patients for further investigation. The presence of weight loss, rectal bleeding, or anemia with constipation mandates either sigmoidoscopy plus barium enema or colonoscopy alone, particularly in patients >40 years, to exclude structural diseases such as cancer or strictures. Colonoscopy alone is most cost effective in this setting since it provides an opportunity to biopsy mucosal lesions, perform polypectomy, or dilate strictures. Barium enema has advantages over colonoscopy in the patient with isolated constipation, since it is less costly and identifies colonic dilatation and all significant mucosal lesions or strictures that are likely to present with constipation. Melanosis coli, or pigmentation of the colon mucosa, indicates the use of anthraquinone laxatives such as cascara or senna; however, this is usually apparent from a careful history. An unexpected disorder such as megacolon or cathartic colon may also be detected by colonic radiographs. Measurement of serum calcium and thyroid stimulating hormone levels will identify rare patients with metabolic disorders.
FIGURE 4 Algorithm for the management of constipation.










Patients with more troublesome constipation may not respond to fiber alone and may be helped by a bowel training regimen: taking an osmotic laxative and evacuating with enema or glycerine suppository as needed. After breakfast, a distraction-free 15 to 20 min on the toilet without straining is encouraged. Excessive straining may lead to development of hemorrhoids, and, if there is weakness of the pelvic floor or injury to the pudendal nerve, may result in obstructed defecation from descending perineum syndrome several years later. Those few who do not benefit from the simple measures delineated above or require long-term treatment with stimulant laxatives with the attendant risk of developing laxative abuse syndrome are assumed to have severe or intractable constipation and should have further investigation (Fig. 4).

INVESTIGATION OF SEVERE CONSTIPATION

A small minority (probably <5%) of all patients with constipation have cases that are considered severe or “intractable”; these are the patients most likely to be seen by gastroenterologists or in referral centers. Further observation of the patient may occasionally reveal a previously unrecognized cause, such as an evacuation disorder, laxative abuse, malingering, or psychiatric disorder. In these patients, recent studies suggest that evaluations of the physiologic function of the colon and pelvic floor and of psychological status aid in the rational choice of treatment. Even among these highly selected patients with severe constipation, a cause can be identified in only about 30% (see below).

Measurement of Colonic Transit

Radiopaque marker transit tests are easy, repeatable, generally safe, inexpensive, reliable, and highly applicable in evaluating constipated patients in clinical practice. There are several validated methods that are very simple. For example, radiopaque markers are ingested, and an abdominal flat film taken 5 d later should indicate passage of 80% of the markers out of the colon. This test does not provide useful information about the transit profile of the stomach and small bowel, and avoidance of laxatives or enemas during the testing period is essential.
Radioscintigraphy with a delayed-release capsule containing radiolabeled particles has been used to noninvasively characterize normal, accelerated, or delayed colonic function over 24 to 48 h with low radiation exposure. This approach simultaneously assesses gastric, small-bowel, and colonic transit. The disadvantages are the greater cost and the need for specific materials prepared in a nuclear medicine laboratory.
Anorectal and Pelvic Floor Tests
Pelvic floor dysfunction is suggested by the inability to evacuate the rectum, a feeling of persistent rectal fullness, rectal pain, the need to extract stool from the rectum digitally, application of pressure on the posterior wall of the vagina, support of the perineum during straining, and excessive straining. These significant symptoms should be contrasted with the sense of incomplete rectal evacuation, which is common in irritable bowel syndrome.
Patients with clinically suspected obstruction of defecation should also be evaluated by a psychologist to identify eating disorders or a “need to control,” to provide stress management or relaxation training, and to identify depression.
A simple clinical test in the office to document a nonrelaxing puborectalis muscle is to have the patient strain to expel the index finger during a digital rectal examination. Motion of the puborectalis posteriorly during straining indicates proper coordination of the pelvic floor muscles.
Measurement of perineal descent is relatively easy to gauge clinically by placing the patient in the left decubitus position and watching the perineum to assess either paucity or lack of descent (<1.5 cm, a sign of pelvic floor dysfunction) or perineal ballooning during straining relative to bony landmarks (>4 cm, suggesting excessive perineal descent).
A useful overall test of evacuation is the balloon expulsion test. A urinary catheter is placed in the rectum, the balloon is inflated to 50 mL with water, and a determination is made about whether the patient can expel it while seated on a toilet or in the left lateral decubitus position. In the lateral position, the weight needed to facilitate expulsion of the balloon (normal, 0 to 200 g) is determined.
Anorectal manometry is not often contributory in the evaluation of patients presenting with severe constipation, except when an excessively high resting or squeeze anal sphincter tone suggests anismus (anal sphincter spasm). This test also identifies rare syndromes, such as adult Hirschsprung's disease, by the absence of the rectoanal inhibitory reflex or the presence of occult incontinence.
Defecography (a dynamic barium enema including lateral views obtained during barium expulsion) reveals “soft abnormalities” in many patients; the most relevant findings are the measured changes in rectoanal angle, anatomic defects of the rectum, and enteroceles or rectoceles. In a very small proportion of patients, significant anatomic defects associated with intractable constipation respond best to surgical treatment. These defects include severe intussusception with complete outlet obstruction due to funnel-shaped plugging at the anal canal or an extremely large rectocele that is preferentially filled during attempts at defecation instead of expulsion of the barium through the anus. In summary, defecography requires an interested and experienced radiologist, and abnormalities are not pathognomonic for pelvic floor dysfunction. More commonly, outlet obstruction results from a nonrelaxing puborectalis muscle, which impedes rectal emptying, rather than from defects identified by defecography.
Dynamic imaging studies such as proctography during defecation or scintigraphic expulsion of artificial stool help measure perineal descent and the rectoanal angle during rest, squeezing, and straining, and scintigraphic expulsion quantitates the amount of “artificial stool” emptied. Failure of the rectoanal angle to increase significantly (~15°) during straining confirms pelvic floor dysfunction.
Neurologic testing (electromyography) is more helpful in the evaluation of patients with incontinence than of those with symptoms suggesting obstructed defecation. The absence of neurologic signs in the lower extremities suggests that any documented denervation of the puborectalis results from pelvic (e.g., obstetric) injury or from stretching of the pudendal nerve by chronic, long-standing straining.
Ultrasonography identifies sphincter or rectal wall defects and may help select patients for surgical correction. Spinal-evoked responses during electrical rectal stimulation or stimulation of external anal sphincter contraction by applying magnetic stimulation over the lumbosacral cord identify patients with limited sacral neuropathies with sufficient residual nerve conduction to attempt biofeedback training.
In summary, a balloon expulsion test is an important screening test for anorectal dysfunction. If positive, an anatomic evaluation of the rectum or anal sphincters and an assessment of pelvic floor relaxation are the tools for evaluating patients in whom obstructed defecation is suspected.

TREATMENT

After the cause of constipation is characterized, a treatment decision can be made. Slow transit constipation requires aggressive medical or surgical treatment; anismus or pelvic floor dysfunction usually responds to biofeedback management (Fig. 4). However, only about 30% of patients with severe constipation are found to have such a physiologic disorder.
Patients with slow transit constipation are treated with bulk, osmotic, and stimulant laxatives, including fiber, psyllium, milk of magnesia, lactulose, polyethylene glycol (colonic lavage solution), and bisacodyl. If a 2- to 3-month trial of medical therapy fails and patients continue to have documented slow transit constipation unassociated with obstructed defecation, colectomy with ileorectostomy is indicated. The decision to resort to surgery is facilitated in the presence of megacolon and megarectum. The complications after surgery include small-bowel obstruction (11%) and fecal soiling, particularly at night during the first postoperative year.

Patients who have a combined disorder should pursue pelvic floor retraining (biofeedback and muscle relaxation), psychological counseling, and dietetic advice first, followed by colectomy and ileorectosomy if colonic transit studies do not normalize with biofeedback alone. In patients with pelvic floor dysfunction alone, biofeedback training has a 70 to 80% success rate, measured by the acquisition of comfortable stool habits. Attempts to manage pelvic floor dysfunction with operations (internal anal sphincter or puborectalis muscle division) have achieved only mediocre success and have been largely abandoned.Diarrhea and constipation are exceedingly common and together exact an enormous toll in terms of morbidity, loss of work productivity, and consumption of medical resources. Worldwide, more than 1 billion people suffer one or more episodes of acute diarrhea each year. Among the 100 million persons affected annually by acute diarrhea in the United States, nearly half must restrict activities, 10% consult physicians, 250,000 require hospitalization, and roughly 3000 die (primarily the elderly). The annual economic burden to society is estimated at >$20 billion. Because of poor sanitation and more limited access to health care, acute infectious diarrhea remains one of the most common causes of mortality in developing countries, particularly among children, accounting for 5 to 8 million deaths per year. Population statistics on chronic diarrhea and constipation are more uncertain, perhaps due to variable definitions and reporting, but the frequency of these conditions is also high. Based on United States population surveys, prevalence rates for chronic diarrhea range from 2 to 7% and for chronic constipation from 3 to 17%. Diarrhea and constipation are among the most common patient complaints faced by internists and primary care physicians, and they account for nearly 50% of referrals to gastroenterologists.
Although diarrhea and constipation may present as mere nuisance symptoms at one extreme, they can be severe or life-threatening at the other. Even mild symptoms may signal a serious underlying gastrointestinal lesion, such as colorectal cancer, or systemic disorder, such as thyroid disease. Given the heterogeneous causes and potential severity of these common complaints, it is imperative for clinicians to appreciate the pathophysiology, etiologic classification, diagnostic strategies, and therapeutic principles of diarrhea and constipation so that rational and cost-effective care can be delivered.

NORMAL PHYSIOLOGY

The human small intestine and colon perform important functions including the secretion and absorption of water and electrolytes, the storage and subsequent transport of intraluminal contents aborally, and the salvage of some nutrients after bacterial metabolism of carbohydrate that are not absorbed in the small intestine. The main motor functions are summarized in Table 1. Alterations in fluid and electrolyte handling contribute significantly to diarrhea. Alterations in motor and sensory functions of the human colon result in highly prevalent syndromes such as irritable bowel syndrome, chronic diarrhea, and chronic constipation.
TABLE 1 Normal Gastrointestinal Motility:
Functions at Different Anatomic Levels
Stomach and small bowel
  Synchronized MMCs in fasting
  Accommodation, trituration, mixing, transit
    Stomach, ~3 h
    Small bowel, ~3 h
  Ileal reservoir empties boluses
Colon: Irregular mixing, absorption, transit
  Ascending, transverse: reservoirs
  Descending: conduit
  Sigmoid/rectum: volitional reservoir
Note: MMC, migrating motor complex.
NEURAL CONTROL
The small intestine and colon have intrinsic and extrinsic innervation. The intrinsic innervation, also called the enteric nervous system, comprises myenteric, submucosal, and mucosal neuronal layers. The function of these layers is modulated by interneurons through the actions of neurotransmitter amines or peptides, including acetylcholine, opioids, norepinephrine, serotonin, ATP, and nitric oxide. The myenteric plexus regulates smooth-muscle function, and the submucosal plexus affects secretion and absorption.
The extrinsic innervations of the small intestine and colon are part of the autonomic nervous system and also modulate both motor and secretory functions. The parasympathetic nerve supply conveys both visceral sensory as well as excitatory pathways to the motor components of the colon. Parasympathetic fibers via the vagus nerve reach the small intestine and proximal colon along the branches of the superior mesenteric artery. The distal colon is supplied by sacral parasympathetic nerves (S2–4) via the pelvic plexus; these fibers course through the wall of the colon as ascending intracolonic fibers as far as, and in some instances including, the proximal colon. The chief excitatory neurotransmitters controlling motor function are acetylcholine and the tachykinins, such as substance P. The sympathetic nerve supply modulates motor functions and reaches the small intestine and colon alongside the arterial arcades of the superior and inferior mesenteric vessels. Sympathetic input to the gut is generally excitatory to sphincters and inhibitory to nonsphincteric muscle. Visceral afferents convey sensation from the gut to the central nervous system; initially, they course along sympathetic fibers, but as they approach the spinal cord they separate, have cell bodies in the dorsal root ganglion, and enter the dorsal horn of the spinal cord. Afferent signals are conveyed to the brain along the lateral spinothalamic tract and the nociceptive dorsal column pathway and are then perceived. Other afferent fibers synapse in the prevertebral ganglia and reflexly modulate intestinal motility.

INTESTINAL FLUID ABSORPTION AND SECRETION

On an average day, 9 L of fluid enters the gastrointestinal tract; approximately 1 L of residual fluid reaches the colon; the stool excretion of fluid constitutes about 0.2 L/d. The colon has a large capacitance and functional reserve and may recover up to four times its usual volume of 0.8 L/d, provided the rate of flow permits reabsorption to occur. Thus, the colon can partially compensate for intestinal absorptive or secretory disorders.
In the colon, sodium absorption is predominantly electrogenic, and uptake takes place at the apical membrane; it is compensated for by the export functions of the basolateral sodium pump. A variety of neural and non-neural mediators regulate colonic fluid and electrolyte balance, including cholinergic, adrenergic, and serotonergic mediators. Angiotensin and aldosterone also influence colonic absorption, reflecting the common embryologic development of the distal colonic epithelium and the renal tubules.

SMALL INTESTINAL MOTILITY

During fasting, the motility of the small intestine is characterized by a cyclical event called the migrating motor complex (MMC), which serves to clear nondigestible residue from the small intestine. This organized, propagated series of contractions lasts on average 4 min, occurs every 60 to 90 min, and usually involves the entire small intestine. After food ingestion, the small intestine produces irregular, mixing contractions of relatively low amplitude, except in the distal ileum where more powerful contractions occur intermittently and empty the ileum by bolus transfers.

ILEOCOLONIC STORAGE AND SALVAGE

The distal ileum acts as a reservoir, emptying intermittently by bolus movements. This action allows time for salvage of fluids, electrolytes, and nutrients. Segmentation by haustra compartmentalizes the colon and facilitates mixing, retention of residue, and formation of solid stools. In health, the ascending and transverse regions of colon function as reservoirs (average transit, 15 h), and the descending colon acts as a conduit (average transit, 3 h). The colon is efficient at conserving sodium and water, a function that is particularly important in sodium-depleted patients in whom the small intestine alone is unable to maintain sodium balance. Diarrhea or constipation may result from alteration in the reservoir function of the proximal colon or the propulsive function of the left colon. Constipation may also result from disturbances of the rectal or sigmoid reservoir, typically as a result of dysfunction of the pelvic floor or the coordination of defecation.

COLONIC MOTILITY AND TONE

The small intestinal MMC only rarely continues into the colon. However, short duration or phasic contractions mix colonic contents, and high-amplitude propagated contractions (HAPCs) are sometimes associated with mass movements through the colon and occur approximately five times per day, usually on awakening in the morning and postprandially. Increased frequency of HAPCs may result in diarrhea. The predominant phasic contractions are irregular and nonpropagated and serve as a “mixing” function.
Colonic tone refers to the background contractility upon which phasic contractile activity (typically contractions lasting <15 s) is superimposed. It is an important cofactor in the colon's capacitance (volume accommodation) and sensation.

COLONIC MOTILITY AFTER MEAL INGESTION

After meal ingestion, colonic phasic and tonic contractility increase for a period of approximately 2 h. The initial phase (about 10 min) is mediated by the vagus nerve in response to mechanical distention of the stomach. The subsequent response of the colon requires caloric stimulation and is at least in part mediated by hormones, e.g., gastrin and serotonin.

DEFECATION

FIGURE 1 Mechanisms involved in continence and defecation. Note the importance of pelvic floor and anal sphincter functions. Continence requires: contraction of puborectalis, maintenance of anorectal angle, normal rectal sensation, and contraction of sphincter. Defecation requires: relaxation of puborectalis, straightening of anorectal angle, and relaxation of sphincter.
Tonic contraction of the puborectalis muscle, which forms a sling around the rectoanal junction, is important to maintain continence; during defecation, sacral parasympathetic nerves relax this muscle, facilitating the straightening of the rectoanal angle (Fig. 1). Distention of the rectum results in transient relaxation of the internal anal sphincter via intrinsic and reflex sympathetic innervation. As sigmoid and rectal contractions increase the pressure within the rectum, the rectosigmoid angle opens by >15°. Voluntary relaxation of the external anal sphincter (striated muscle innervated by the pudendal nerve) permits the evacuation of feces; this evacuation process can be augmented by an increase in intraabdominal pressure created by the Valsalva maneuver.
DIARRHEA
DEFINITION
Diarrhea is loosely defined as passage of abnormally liquid or unformed stools at an increased frequency. For adults on a typical Western diet, stool weight >200 g/d can generally be considered diarrheal. Because of the fundamental importance of duration to diagnostic considerations, diarrhea may be further defined as acute if <2 weeks, persistent if 2 to 4 weeks, and chronic if >4 weeks in duration.
Two common conditions, usually associated with the passage of stool totaling <200 g/d, must be distinguished from diarrhea, as diagnostic and therapeutic algorithms differ. Pseudodiarrhea, or the frequent passage of small volumes of stool, is often associated with rectal urgency and accompanies the irritable bowel syndrome or anorectal disorders such as proctitis. Fecal incontinence is the involuntary discharge of rectal contents and is most often caused by neuromuscular disorders or structural anorectal problems. Diarrhea and urgency, especially if severe, may aggravate or cause incontinence. Pseudodiarrhea and fecal incontinence occur at prevalence rates comparable to or higher than that of chronic diarrhea and should always be considered in patients complaining of “diarrhea.” A careful history and physical examination generally allow these conditions to be discriminated from true diarrhea.

ACUTE DIARRHEA

More than 90% of cases of acute diarrhea are caused by infectious agents; these cases are often accompanied by vomiting, fever, and abdominal pain. The remaining 10% or so are caused by medications, toxic ingestions, ischemia, and other conditions.

Infectious Agents

Most infectious diarrheas are acquired by fecal-oral transmission via direct personal contact or, more commonly, via ingestion of food or water contaminated with pathogens from human or animal feces. In the immunologically competent person, the resident fecal microflora, containing >500 taxonomically distinct species, are rarely the source of diarrhea and may actually play a role in suppressing the growth of ingested pathogens. Acute infection or injury occurs when the ingested agent overwhelms the host's mucosal immune and nonimmune (gastric acid, digestive enzymes, mucus secretion, peristalsis, and suppressive resident flora) defenses. Established clinical associations with specific enteropathogens may offer diagnostic clues.
In the United States, high risk groups are recognized:
1.   Travelers. Nearly 40% of tourists to endemic regions of Latin America, Africa, and Asia develop so-called traveler's diarrhea, most commonly due to enterotoxigenic Escherichia coli as well as to Campylobacter, Shigella, and Salmonella. Visitors to Russia (especially St. Petersburg) may have increased risk of Giardia-associated diarrhea; visitors to Nepal may acquire Cyclospora. Campers, backpackers, and swimmers in wilderness areas may become infected with Giardia.
2.   Consumers of certain foods. Diarrhea closely following food consumption at a picnic, banquet, or restaurant may suggest infection with Salmonella, Campylobacter, or Shigella from chicken; enterohemorrhagic E. coli (O157:H7) from undercooked hamburger; Bacillus aureus from fried rice; Staphylococcus aureus or Salmonella from mayonnaise or creams; Salmonella from eggs; and Vibrio species, Salmonella, or acute hepatitis A or B from seafood, especially if raw.
3.   Immunodeficient persons. Individuals at risk for diarrhea include those with either primary immunodeficiency (e.g., IgA deficiency, common variable hypogammaglobulinemia, chronic granulomatous disease) or the much more common secondary immunodeficiency states (e.g., AIDS, senescence, pharmacologic suppression). Common enteropathogens often cause a more severe and protracted diarrheal illness, and, particularly in persons with AIDS, opportunistic infections, such as by Mycobacterium species, certain viruses (cytomegalovirus, adenovirus, and herpes simplex), and protozoa (Cryptosporidium, Isospora belli, Microsporidia, and Blastocystis hominis) may also play a role. In patients with AIDS, agents transmitted venereally per rectum (e.g., Neisseria gonorrhoeae, Treponema pallidum, Chlamydia) may contribute to proctocolitis.
4.   Daycare participants and their family members. Infections with Shigella, Giardia, Cryptosporidium, rotavirus, and other agents are very common and should be considered.
5.   Institutionalized persons. Infectious diarrhea is one of the most frequent categories of nosocomial infections in many hospitals and long-term care facilities; the causes are a variety of microorganisms but most commonly Clostridium difficile.
TABLE 2 Association between Pathobiology of Causative
Agents and Clinical Features in Acute Infectious Diarrhea

Pathobiology/Agents

Incubation Period

Vomiting

Abdominal Pain
Fever
Diarrhea

Toxin producers






Preformed toxin





Bacillus cereus, Staphylococcus aureus, Clostridium perfringens
1–8 h
8–24 h
3–4+
1–2+
0–1+
3–4+, watery
Enterotoxin





Vibrio cholerae, enterotoxigenic Escherichia coli, Klebsiella pneumoniae, Aeromonas species
8–72 h
2–4+
1–2+
0–1+
3–4+, watery
Enteroadherent





Enteropathogenic and enteroadherent, E. coli, Giardia organisms, cryptosporidiosis, helminths
1–8 d
0–1+
1–3+
1–2+
1–2+, watery
Cytotoxin-producers





 Clostridium difficile
1–3 d
0–1+
3–4+
1–2+
1–3+, usually watery, occasionally bloody
  Hemorrhagic E. coli
12–72 h
0–1+
3–4+
1–2+
1–3+, initially watery, quickly bloody
Invasive organisms





Minimal inflammation





    Rotavirus and Norwalk agent
1–3 d
1–2+
2–3+
3–4+
1–3+, watery
Variable inflammation





Salmonella, Campylobacter, and Aeromonas species, Vibrio parahaemo­lyticus, Yersinia
12 h–11 d
0–3+
2–4+
3–4+
1–4+, watery or bloody
 Severe inflammation





    Shigella species, enteroinvasive E. coli, Entamoeba histolytica
12 h–8 d
0–1+
3–4+
3–4+
1–2+, bloody
The pathophysiology underlying acute diarrhea by infectious agents produces specific clinical features that may also be helpful in diagnosis (Table 2). Profuse watery diarrhea secondary to small bowel hypersecre­tion occurs with ingestion of preformed bacterial toxins, enterotoxin-producing bacteria, and enteroadherent pathogens. Diarrhea associated with marked vomiting and minimal or no fever may occur abruptly within a few hours after ingestion of the former two types; vomiting is usually less, and abdominal cramping or bloating is greater; fever is higher with the latter. Cytotoxin-producing and invasive microorganisms all cause high fever and abdominal pain. Invasive bacteria and Entamoeba histolytica often cause bloody diarrhea (referred to as dysentery). Yersinia invades the terminal ileal and proximal colon mucosa and may cause especially severe abdominal pain with tenderness mimicking acute appendicitis.
Finally, infectious diarrhea may be associated with systemic manifestations. Reiter's syndrome (arthritis, urethritis, and conjunctivitis) may accompany or follow infections by Salmonella, Campylobacter, Shigella, and Yersinia. Yersiniosis may also lead to an autoimmune-type thyroiditis, pericarditis, and glomerulonephritis. Both enterohemorrhagic E. coli (O157:H7) and Shigella can lead to the hemolytic-uremic syndrome with an attendant high mortality rate. Acute diarrhea can also be a major symptom of several systemic infections including viral hepatitis, listeriosis, legionellosis, and toxic shock syndrome.

Other Causes

Side effects from medications are probably the most common noninfectious cause of acute diarrhea, and etiology may be suggested by a temporal association between use and symptom onset. Although innumerable medications may produce diarrhea, some of the more frequently incriminated include antibiotics, cardiac antidysrhythmics, antihypertensives, nonsteroidal anti-inflammatory drugs (NSAIDs), certain antidepressants, chemotherapeutic agents, bronchodilators, antacids, and laxatives. Occlusive or nonocclusive ischemic colitis typically occurs in persons >50 years, often presents as acute lower abdominal pain preceding watery, then bloody diarrhea, and generally results in acute inflammatory changes in the sigmoid or left colon while sparing the rectum. Acute diarrhea may accompany colonic diverticulitis and graft-versus-host disease. Acute diarrhea, often associated with systemic compromise, can follow ingestion of toxins including organophosphate insecticides, amanita and other mushrooms, arsenic, and preformed environmental toxins in seafoods, such as ciguatera and scombroid. The conditions causing chronic diarrhea can also be confused with acute diarrhea early in their course. This confusion may occur with inflammatory bowel disease and some of the other inflammatory chronic diarrheas that may have an abrupt rather than insidious onset and exhibit features that mimic infection.

APPROACH TO THE PATIENT

The decision to evaluate acute diarrhea depends on its severity and duration and on various host factors (Fig. 2). Most episodes of acute diarrhea are mild and self-limited and do not justify the cost and potential morbidity of diagnostic or pharmacologic interventions. Indications for evaluation include profuse diarrhea with dehydration, grossly bloody stools, fever ≥38.5° C, duration >48 h without improvement, new community outbreaks, associated severe abdominal pain in patients >50 years, and elderly (≥70 years) or immunocompromised patients. In some cases of moderately severe febrile diarrhea associated with fecal leukocytes (or increased fecal levels of the leukocyte proteins) or with gross blood, a diagnostic evaluation might be avoided in favor of an empirical antibiotic trial (see below).
The cornerstone of diagnosis in those suspected of severe acute infectious diarrhea is microbiologic analysis of the stool. Workup includes cultures for bacterial and viral pathogens, direct inspection for ova and parasites, and immunoassays for certain bacterial toxins (C. difficile), viral
FIGURE 2. Algorithm for the management of acute diarrhea. Consider empirical Rx before evaluation with (*) metronidazole and (†) with quinolone.
antigens (rotavirus), and protozoal antigens (Giardia, E. histolytica). The aforementioned clinical and epidemiologic associations may assist in focusing the evaluation. If a particular pathogen or set of possible pathogens is so implicated, then either the whole panel of routine studies may not be necessary or, in some instances, special cultures may be appropriate as for enterohemorrhagic and other types of E. coli, Vibrio species, and Yersinia. Molecular diagnosis of pathogens in stool can be made by identification of unique DNA sequences; and evolving microarray technologies could lead to a more rapid, sensitive, specific, and cost-effective diagnostic approach in the future.
Persistent diarrhea is commonly due to Giardia, but additional causative organisms that should be considered include C. difficile (especially if antibiotics had been administered), E. histolytica, Cryptosporidium, Campylobacter, and others. If stool studies are unrevealing, then flexible sigmoidoscopy with biopsies and upper endoscopy with duodenal aspirates and biopsies may be indicated.
Structural examination by sigmoidoscopy, colonoscopy, or abdominal computed tomographic scanning (or other imaging approaches) may be appropriate in patients with uncharacterized persistent diarrhea to exclude inflammatory bowel disease, or as an initial approach in patients with suspected noninfectious acute diarrhea such as might be caused by ischemic colitis, diverticulitis, or partial bowel obstruction.

TREATMENT

Fluid and electrolyte replacement are of central importance to all forms of acute diarrhea. Fluid replacement alone may suffice for mild cases. Oral sugar-electrolyte solutions (sport drinks or designed formulations) should be instituted promptly with severe diarrhea to limit dehydration, which is the major cause of death. Profoundly dehydrated patients, especially infants and the elderly, require intravenous rehydration.
In moderately severe nonfebrile and nonbloody diarrhea, antimotility antisecretory agents such as loperamide can be useful adjuncts to control symptoms. Such agents should be avoided with febrile dysentery, which may be exacerbated or prolonged by them. Bismuth subsalicylate may reduce symptoms of vomiting and diarrhea but should not be used to treat immunocompromised patients because of the risk of bismuth encephalopathy.
Judicious use of antibiotics is appropriate in selected instances of acute diarrhea and may reduce its severity and duration (Fig. 2). Many physicians treat moderately to severely ill patients with febrile dysentery empirically without diagnostic evaluation using a quinolone, such as ciprofloxacin (500 mg bid for 3 to 5 d). Empirical treatment can also be considered for suspected giardiasis with metronidazole (250 mg qid for 7 d). Selection of antibiotics and dosage regimens are otherwise dictated by specific pathogens and conditions found. Antibiotic coverage is indicated whether or not a causative organism is discovered in patients who are immunocompromised, have mechanical heart valves or recent vascular grafts, or are elderly. Antibiotic prophylaxis is indicated for certain patients traveling to high-risk countries in whom the likelihood or seriousness of acquired diarrhea would be especially high, including those with immunocompromise, inflammatory bowel disease, or gastric achlorhydria. Use of trimethoprim/sulfamethoxazole or ciprofloxacin may reduce bacterial diarrhea in such travelers by 90%.

CHRONIC DIARRHEA

Diarrhea lasting >4 weeks warrants evaluation to exclude serious underlying pathology. In contrast to acute diarrhea, most of the many causes of chronic diarrhea are noninfectious. The classification of chronic diarrhea by pathophysiologic mechanism facilitates a rational approach to management (Table 3).
TABLE 3 Major Causes of Chronic Diarrhea According to Predominant Pathophysiologic Mechanism
Secretory causes
  Exogenous stimulant laxatives
  Chronic ethanol ingestion
  Other drugs and toxins
  Endogenous laxatives (dihydroxy bile acids)
  Idiopathic secretory diarrhea
  Certain bacterial infections
  Bowel resection, disease, or fistula (↓ absorption)
  Partial bowel obstruction or fecal impaction
  Hormone-producing tumors (carcinoid, VIPoma, medullary cancer of thyroid, mastocytosis, gastrinoma, colorectal villous adenoma)
  Addison's disease
  Congenital electrolyte absorption defects
Osmotic causes
  Osmotic laxatives (Mg2+, PO43-, SO42-)
  Lactase and other disaccharide deficiencies
  Nonabsorbable carbohydrates (sorbitol, lactulose, polyethylene glycol)
Steatorrheal causes
  Intraluminal maldigestion (pancreatic exocrine insufficiency, bacterial overgrowth, liver disease)
  Mucosal malabsorption (celiac sprue, Whipple's disease, infections, abetalipoproteinemia, ischemia)
  Postmucosal obstruction (1° or 2° lymphatic obstruction)
Inflammatory causes
  Idiopathic inflammatory bowel disease (Crohn's chronic ulcerative colitis)
  Microscopic and collagenous colitis
  Immune-related mucosal disease (1° or 2° immunodeficiencies, food allergy, eosinophilic gastroenteritis, graft-vs-host disease)
Infections (invasive bacteria, viruses, and parasites)
Radiation injury
Gastrointestinal malignancies
Dysmotile causes
  Visceral neuromyopathies
  Hyperthyroidism
  Drugs (prokinetic agents)
Factitial causes
  Munchausen
  Bulimia
Secretory Causes
Secretory diarrheas are due to derangements in fluid and electrolyte transport across the enterocolic mucosa. They are characterized clinically by watery, large-volume fecal outputs that are typically painless and persist with fasting. Because there is no malabsorbed solute, stool osmolality is accounted for by normal endogenous electrolytes with no fecal osmotic gap.

MEDICATIONS

Side effects from regular ingestion of drugs and toxins are the most common secretory causes of chronic diarrhea. Hundreds of prescription and over-the-counter medications (see “Other Causes of Acute Diarrhea,” above) may produce unwanted diarrhea. Surreptitious or habitual use of stimulant laxatives [e.g., senna, cascara, bisacodyl, ricinoleic acid (castor oil)] must also be considered. Chronic ethanol consumption may cause a secretory-type diarrhea due to enterocyte injury with impaired sodium and water absorption as well as to rapid transit and other alterations. Inadver­tent ingestion of certain environmental toxins (e.g., arsenic) may lead to chronic rather than acute forms of diarrhea. Certain bacterial infections may occasionally persist and be associated with a secretory-type diarrhea.

HORMONES

Although uncommon, the classic examples of secretory diarrhea are those mediated by hormones. Metastatic gastrointestinal carcinoid tumors or, rarely, primary bronchial carcinoids may produce watery diarrhea alone or as part of the carcinoid syndrome that comprises episodic flushing, wheezing, dyspnea, and right-sided valvular heart disease. Diarrhea is due to the release into the circulation of potent intestinal secretagogues including serotonin, histamine, prostaglandins, and various kinins. Pellagra-like skin lesions may rarely occur as the result of serotonin overproduction with niacin depletion. Gastrinoma, one of the most common neuroendocrine tumors, most typically presents with refractory peptic ulcers, but diarrhea occurs in up to one-third of cases and may be the only clinical manifestation in 10%. While various secretagogues released with gastrin may play a role, the diarrhea most often results from fat maldigestion owing to pancreatic enzyme inactivation by low intraduodenal pH. The watery diarrhea hypokalemia achlorhydria syndrome, also called pancreatic cholera, is due to a non-β cell pancreatic adenoma, referred to as a VIPoma, that secretes vasoactive intestinal peptide (VIP) and a host of other peptide hormones including pancreatic polypeptide, secretin, gastrin, gastrin-inhibitory polypeptide, neurotensin, calcitonin, and prostaglandins. The secretory diarrhea is often massive with stool volumes >3 L/d; daily volumes as high as 20 L have been reported. Life-threatening dehydration; neuromuscular dysfunction from associated hypokalemia, hypomagnesemia, or hypercalcemia; flushing; and hyperglycemia may accompany a VIPoma. Medullary carcinoma of the thyroid may present with watery diarrhea caused by calcitonin, other secretory peptides, or prostaglandins. This tumor occurs sporadically or, in 25 to 50% of cases, as a feature of multiple endocrine neoplasia type IIa with pheochromocytomas and hyperparathyroidism. Prominent diarrhea is often associated with metastatic disease and poor prognosis. Systemic mastocytosis, which may be associated with the skin lesion urticaria pigmentosa, may cause diarrhea that is either secretory and mediated by histamine or inflammatory and due to intestinal filtration by mast cells. Large colorectal villous adenomas may rarely be associated with a secretory diarrhea that may cause hypokalemia, can be inhibited by NSAIDs, and is apparently mediated by prostaglandins.

CONGENITAL DEFECTS IN ION ABSORPTION

Rarely, these defects cause watery diarrhea from birth and include defective Cl-/HCO3- exchange (congenital chloridorrhea) with alkalosis and defective Na+/H+ exchange with acidosis. Some hormone deficiencies may be associated with watery diarrhea, such as occurs with adrenocortical insufficiency (Addison's disease) that may be accompanied by hyperpigmentation.

Osmotic Causes

Osmotic diarrhea occurs when ingested, poorly absorbable, osmotically active solutes draw enough fluid lumenward to exceed the resorptive capacity of the colon. Fecal water output increases in proportion to such a solute load. Osmotic diarrhea characteristically ceases with fasting or with discontinued oral intake of the offending agent.

OSMOTIC LAXATIVES

Ingestion of magnesium-containing antacids, health supplements, or laxatives may induce osmotic diarrhea typified by a stool osmotic gap: 2([Na] + [K]) <290 mosm/kg. Anionic laxatives containing sulfates or phosphates produce osmotic diarrhea without an osmotic gap, as sodium accompanies the anionic solutes; direct measurement of stool sulfates and phosphates may be necessary to confirm the cause of diarrhea.

CARBOHYDRATE MALABSORPTION

Carbohydrate malabsorption due to acquired or congenital defects in brush-border disaccharidases and other enzymes leads to osmotic diarrhea with a low pH. One of the most common causes of chronic diarrhea in adults is lactase deficiency, which affects three-fourths of non-Caucasians worldwide and 5 to 30% of persons in the United States; most learn to avoid milk products without an intervention. Some sugars, such as sorbitol, are universally malabsorbed, and diarrhea ensues with ingestion of ample medications, gum, or candies sweetened with these nonabsorbable sugars. Lactulose, used to acidify stools in patients with hepatic failure, also causes diarrhea on this basis.

Steatorrheal Causes

Fat malabsorption may lead to greasy, foul-smelling, difficult-to-flush diarrhea often associated with weight loss and nutritional deficiencies due to concomitant malabsorption of amino acids and vitamins. Increased fecal output is caused by the osmotic effects of fatty acids, especially after bacterial hydroxylation, and, to a lesser extent, by the burden of neutral fat. Quantitatively, steatorrhea is defined as stool fat exceeding the normal 7 g/d; daily fecal fat averages 15 to 25 g with small intestinal diseases and is often >40 g with pancreatic exocrine insufficiency. Intraluminal maldigestion, mucosal malabsorption, or lymphatic obstruction may produce steatorrhea.

INTRALUMINAL MALDIGESTION

This condition most commonly results from pancreatic exocrine insufficiency, which occurs when >90% of pancreatic secretory function is lost. Chronic pancreatitis, usually a sequela of ethanol abuse, most frequently causes pancreatic insufficiency. Other causes include cystic fibrosis, pancreatic duct obstruction, and rarely, somatostatinoma. Bacterial overgrowth in the small intestine may deconjugate bile acids and alter micelle formation that impairs fat digestion; it occurs with stasis from a blind-loop, small bowel diverticulum or dysmotility and is especially likely in the elderly. Finally, cirrhosis or biliary obstruction may lead to mild steatorrhea due to deficient intraluminal bile acid concentration.

MUCOSAL MALABSORPTION

Mucosal malabsorption occurs from a variety of enteropathies but most prototypically and perhaps most commonly from celiac sprue. This gluten-sensitive enteropathy characterized by villous atrophy and crypt hyperplasia in the proximal small bowel often presents with fatty diarrhea associated with multiple nutritional deficiencies of varying severity and affects all ages. Tropical sprue may produce a similar histologic and clinical syndrome but occurs in residents of or travelers to tropical climates; its often abrupt onset and response to antibiotics suggest an infectious etiology. Whipple's disease, due to the actinomycete Treponema whippleii and histiocytic infiltration of the small bowel mucosa, is a less common cause of steatorrhea that most typically occurs in young or middle-aged men; it is frequently associated with arthralgias, fever, lymphadenopathy, and extreme fatigue and may affect the central nervous system and endocardium. A similar clinical and histologic picture results from Mycobacterium avium-intracellulare infection in patients with AIDS. Abetalipoproteinemia is a rare defect of chylomicron formation and fat malabsorption in children associated with acanthocytic erythrocytes, ataxia, and retinitis pigmentosa. Several other conditions may cause mucosal malabsorption including infections, especially with protozoa such as Giardia, numerous medications (e.g., colchicine, cholestyramine, neomycin), and chronic ischemia.

POSTMUCOSAL LYMPHATIC OBSTRUCTION

The pathophysiology of this condition, which is due to the rare congenital intestinal lymphangiectasia or to acquired lymphatic obstruction secondary to trauma, tumor, or infection, leads to the unique constellation of fat malabsorption with enteric losses of protein (often causing edema) and lymphocytes (with resultant lymphocytopenia) that enter the portal circulation directly. Carbohydrate and amino acid absorption are preserved.

Inflammatory Causes

Inflammatory diarrheas are generally accompanied by pain, fever, bleeding, or other manifestations of inflammation. The mechanism of diarrhea may not only be exudation but, depending on lesion site, may include fat malabsorption, disrupted fluid/electrolyte absorption, and hypersecretion or hypermotility from release of cytokines and other inflammatory mediators. The unifying feature on stool analysis is the presence of leukocytes or leukocyte-derived proteins such as calprotectin. With severe inflammation, exudative protein loss can lead to anasarca (generalized edema). Any middle-aged or older person with chronic inflammatory-type diarrhea, especially with blood, should be carefully evaluated to exclude a colorectal or large enteric tumor.

IDIOPATHIC INFLAMMATORY BOWEL DISEASE

The illnesses in this category, which include Crohn's disease and chronic ulcerative colitis, are among the most common organic causes of chronic diarrhea in adults and range in severity from mild to fulminant and life-threatening. They may be associated with uveitis, polyarthralgias, cholestatic liver disease (primary sclerosing cholangitis), and various skin lesions (erythema nodosum, pyoderma gangrenosum). Microscopic colitis, including collagenous colitis, is an increasingly recognized cause of chronic watery diarrhea; biopsy of a normal appearing colorectum is required for histologic diagnosis.

PRIMARY OR SECONDARY FORMS OF IMMUNODEFICIENCY

Immunodeficiency may lead to prolonged infectious diarrhea. With common, variable hypogammaglobulinemia, diarrhea is particularly prevalent and often the result of giardiasis.

EOSINOPHILIC GASTROENTERITIS

Eosinophil infiltration of the mucosa, muscularis, or serosa at any level of the gastrointestinal tract may cause diarrhea, pain, vomiting, or ascites. Affected patients often have an atopic history, Charcot-Leyden crystals due to extruded eosinophil contents may be seen on microscopic inspection of stool, and peripheral eosinophilia is present in 50 to 75% of patients. While hypersensitivity to certain foods occurs in adults, true food allergy causing chronic diarrhea is rare.

OTHER CAUSES

Chronic inflammatory diarrhea may be caused by radiation enterocolitis, chronic graft-versus-host disease, Behçet's syndrome, and Cronkite-Canada syndrome, among others.

Dysmotile Causes

Rapid transit may accompany many diarrheas as a secondary or contributing phenomenon, but primary dysmotility is an unusual etiology of true diarrhea. Stool features often suggest a secretory diarrhea, but mild steatorrhea of up to 14 g of fat per day can be produced by maldigestion from rapid transit alone. Hyperthyroidism, carcinoid syndrome, and certain drugs (e.g., prostaglandins, prokinetic agents) may produce hypermotility with resultant diarrhea. Primary visceral neuromyopathies or idiopathic acquired intestinal pseudo-obstruction may lead to stasis with secondary bacterial overgrowth causing diarrhea. Diabetic diarrhea, often accompanied by peripheral and generalized autonomic neuropathies, may occur in part because of intestinal dysmotility.
The exceedingly common irritable bowel syndrome (10% point prevalence, 1 to 2% per year incidence) is characterized by disturbed intestinal and colonic motor and sensory responses to various stimuli. Symptoms of stool frequency typically cease at night, alternate with periods of constipation, are accompanied by abdominal pain relieved with defecation, and rarely result in weight loss or true diarrhea.

Factitial Causes

Factitial diarrhea accounts for up to 15% of unexplained diarrheas referred to tertiary care centers. Either as a form of Munchausen syndrome (deception or self-injury for secondary gain) or bulimia, some patients covertly self-administer laxatives alone or in combination with other medications (e.g., diuretics) or surreptitously add water or urine to stool sent for analysis. Such patients are typically women, often with histories of psychiatric illness, and disproportionately from careers in health care. Hypotension and hypokalemia are common co-presenting features. Such patients often deny this possibility when confronted, but they do benefit from psychiatric counseling when they acknowledge their behavior.

APPROACH TO THE PATIENT

The laboratory tools available to evaluate the very common problem of chronic diarrhea are extensive, and many are costly and invasive. As such, the diagnostic evaluation must be rationally directed by a careful history and physical examination, and simple triage tests are often warranted before complex investigations are launched (Fig. 3). The history, physical examination, and routine blood studies should attempt to characterize the mechanism of diarrhea, identify diagnostically helpful associations, and assess the patient's fluid/electrolyte and nutritional status. Patients should be questioned about the onset, duration, pattern, aggravating (especially diet) and relieving factors, and stool characteristics of their diarrhea. The presence or absence of fecal incontinence, fever, weight loss, pain, certain exposures (travel, medications, contacts with diarrhea), and common extraintestinal manifestations (skin changes, arthralgias, oral aphtha) should be noted. Physical findings may offer clues such as a thyroid mass, wheezing, heart murmurs, edema, hepatomegaly, abdominal masses, lymphadenopathy, mucocutaneous abnormalities, perianal fistulae, or anal sphincter laxity. Peripheral blood counts may reveal leukocytosis that suggests inflammation; anemia that reflects blood loss or nutritional deficiencies; or eosinophilia that may occur with parasitoses, neoplasia, collagen-vascular disease, allergy, or eosinophilic gastroenteritis. Blood chemistries may demonstrate electrolyte, hepatic, or other metabolic disturbances.
A therapeutic trial is often appropriate, definitive, and highly cost effective when a specific diagnosis is suggested on the initial physician encounter. For example, chronic watery diarrhea, which ceases with fasting in an otherwise healthy young adult, may justify a trial of a lactose-restricted diet; bloating and diarrhea persisting since a mountain backpacking trip may warrant a trial of metronidazole for likely giardiasis; and postprandial diarrhea persisting since an ileal resection might be due to bile acid malabsorption and be treated with cholestyramine before further evaluation. Persistent symptoms require additional investigation.
FIGURE 3 Algorithm for the management of chronic diarrhea.* Dysmotility presents variable stool profile.
Certain diagnoses may be suggested on the initial encounter, e.g., idiopathic inflammatory bowel disease; however, additional focused evaluations may be necessary to confirm the diagnosis and characterize the severity or extent of disease so that treatment can be best guided. Patients suspected of having irritable bowel syndrome should be initially evaluated with proctosigmoidoscopy and mucosal biopsies; those with normal findings might be reassured and, as indicated, treated empirically with antispasmodics, antidiarrheals, bulk agents, anxiolytics, or antidepressants. Any patient who presents with chronic diarrhea and hematochezia should be evaluated with stool microbiologic studies and colonoscopy.
In an estimated two-thirds of cases, the cause for chronic diarrhea remains unclear after the initial encounter, and further testing is required. Quantitative stool collection and analyses can yield important objective data that may establish a diagnosis or characterize the type of diarrhea as a triage for focused additional studies (Fig. 3). If stool weight is >200 g/d, additional stool analyses should be performed that might include electrolyte concentration, pH, occult blood testing, leukocyte inspection (or leukocyte protein assay), fat quantitation, and laxative screens.
For secretory diarrheas (watery, normal osmotic gap), possible medication-related side effects or surreptitious laxative use should be reconsidered. Microbiologic studies should be done including fecal bacterial cultures (including media for Aeromonas and Pleisiomonas), inspection for ova and parasites, and Giardia antigen assay (the most sensitive test for giardiasis). Small bowel bacterial overgrowth can be excluded by intestinal aspirates with quantitative cultures or with glucose or xylose breath tests involving measurement of breath hydrogen or other metabolite (e.g., 14CO2). However, interpretation of these breath tests may be confounded by disturbances of intestinal transit. When suggested by history or other findings, screens for peptide hormones should be pursued (e.g., serum gastrin, VIP, calcitonin, and thyroid hormone/thyroid stimulating hormone, or urinary 5-hydroxyindolacetic acid and histamine). Upper endoscopy and colonoscopy with biopsies and small-bowel barium x-rays are helpful to rule out structural or occult inflammatory disease.
Further evaluation of osmotic diarrhea should include tests for lactose intolerance and magnesium ingestion, the two most common causes. Low fecal pH suggests carbohydrate malabsorption; lactose malabsorption can be confirmed by lactose breath testing or by a therapeutic trial with lactose exclusion and observation of the effect of lactose challenge (e.g., a quart of milk). Lactase determination on small-bowel biopsy is generally not available. If fecal Mg2+ or laxative levels are elevated, then inadvertent or surreptitious ingestion should be considered and psychiatric help should be sought.
For those with proven fatty diarrhea, endoscopy with small-bowel biopsy (including aspiration for Giardia and quantitative cultures) should be performed; if this procedure is unrevealing, a small-bowel radiograph is often an appropriate next step. If small-bowel studies are negative or if pancreatic disease is suspected, pancreatic exocrine insufficiency should be excluded with direct tests, such as the secretin-cholecystokinin stimulation test, or by indirect tests, such as assay of fecal chymotrypsin activity or a bentiromide test.
Chronic inflammatory-type diarrheas should be suspected by the presence of blood or leukocytes in the stool. Such findings warrant stool cultures, inspection for ova and parasites, C. difficile toxin assay, colonoscopy with biopsies, and, if indicated, small-bowel oral contrast studies.

TREATMENT

Treatment of chronic diarrhea depends on the specific etiology and may be curative, suppressive, or empirical. If the cause can be eradicated, treatment is curative as with resection of a colorectal cancer, antibiotic administration for Whipple's disease, or discontinuation of an offending drug. For many chronic conditions, diarrhea can be controlled by suppression of the underlying mechanism. Examples include elimination of dietary lactose for lactase deficiency or gluten for celiac sprue, use of glucocorticoids or other anti-inflammatory agents for idiopathic inflammatory bowel diseases, adsorptive agents such as cholestyramine for ileal bile acid malabsorption, proton pump inhibitors such as omeprazole for the gastric hypersecretion of gastrinomas, somatostatin analogues such as octreotide for malignant carcinoid, prostaglandin inhibitors such as indomethacin for medullary carcinoma of the thyroid, and pancreatic enzyme replacement for pancreatic insufficiency. When the specific cause or mechanism of chronic diarrhea evades diagnosis, empirical therapy may be beneficial. Mild opiates such as diphenoxylate or loperamide are often helpful in mild or moderate watery diarrhea. For those with more severe diarrhea, codeine or tincture of opium may be beneficial. Such antimotility agents should be avoided with inflammatory bowel disease, as toxic megacolon may be precipitated. Clonidine, an α2-adrenergic agonist, may allow control of diabetic diarrhea. For all patients with chronic diarrhea, fluid and electrolyte repletion is an important component of management (see “Acute Diarrhea,” above). Replacement of fat-soluble vitamins may also be necessary in patients with chronic steatorrhea.

CONSTIPATION

DEFINITION
Constipation is a common complaint in clinical practice and usually refers to persistent, difficult, infrequent, or seemingly incomplete defecation. Because of the wide range of normal bowel habits, constipation is difficult to define precisely. Most persons have at least three bowel movements per week; however, stool frequency alone is not a sufficient criterion for the diagnosis of constipation because many constipated patients describe a normal frequency of defecation but subjective complaints of excessive straining, hard stools, lower abdominal fullness, and a sense of incomplete evacuation. The individual patient's symptoms must be analyzed in detail to ascertain what is meant by “constipation” or “difficulty” with defecation.
Stool form and consistency are well correlated with the time elapsed from the preceding defecation. Hard, pellety stools occur with slow transit, while loose watery stools are associated with rapid transit. Small, pellety stools are more difficult to expel than large ones.

CAUSES

TABLE 4 Causes of Constipation in Adults
Types of Constipation and Causes

Examples

Recent onset

  Colonic obstruction
Neoplasm: stricture: ischemic, diverticular, inflammatory

  Anal sphincter spasm

Anal fissure, painful hemorrhoids
  Medications

Chronic

  Irritable bowel syndrome
Constipation–predominant, alternating
  Medications
Ca2+ blockers, antidepressants
  Colonic pseudo-obstruction
Slow transit constipation, megacolon (rare Hirschsprung's, Chagas)
  Disorders of rectal evacuation
Pelvic floor dysfunction, anismus, descending perineum syndrome, rectal mucosal prolapse, rectocele
  Endocrinopathies
Hypothyroidism, hypercalcemia, pregnancy
  Psychiatric disorders
Depression, eating disorders, drugs
  Neurologic disease
Parkinsonism, multiple sclerosis, spinal cord injury
  Generalized muscle disease
Progressive systemic sclerosis
The perception of hard stools or excessive straining is more difficult to assess objectively, and the need for enemas or digital disimpaction is a clinically useful way to corroborate the patient's perceptions of difficult defecation.
Psychosocial factors may also be important. A person whose parents attached great importance to daily defecation will become greatly concerned when he or she misses a daily bowel movement; some children withhold stool to gain attention; and some adults are simply too busy or too embarrassed to interrupt their work when the call to have a bowel movement is sensed.
Pathophysiologically, chronic constipation generally results from inadequate fiber intake or from disordered colonic transit or anorectal function as a result of a neurogastroenterologic disturbance, certain drugs, or in association with a large number of systemic diseases that affect the gastroinestinal tract (Table 4). Constipation of recent onset may be a symptom of significant organic disease such as tumor or stricture. In idiopathic constipation, a subset of patients exhibit delayed emptying of the ascending and transverse colon with prolongation of transit (often in the proximal colon) and a reduced frequency of propulsive colonic contractions (HAPCs). Outlet obstruction to defecation (also called evacuation disorders) may cause delayed colonic transit, which is usually corrected by biofeedback retraining of the disordered defecation. Constipation of any cause may be exacerbated by chronic illnesses that lead to physical or mental impairment and result in inactivity or physical immobility.

APPROACH TO THE PATIENT
A careful history should explore the patient's symptoms and confirm whether he or she is indeed constipated based on frequency (e.g., fewer than three bowel movements per week), consistency (lumpy/hard), excessive straining, prolonged defecation time, or need to support the perineum or digitate the anorectum. In the vast majority of cases (probably >90%), there is no underlying cause (e.g., cancer, depression, or hypothyroidism), and constipation responds to ample hydration, exercise, and supplementation of dietary fiber (15 to 25 g/d). A good diet and medication history and attention to psychosocial issues are key. Physical examination and, particularly, a rectal examination should exclude most of the important diseases that present with constipation and possibly indicate features suggesting an evacuation disorder (e.g., high anal sphincter tone).
There is broad consensus on the selection of patients for further investigation. The presence of weight loss, rectal bleeding, or anemia with constipation mandates either sigmoidoscopy plus barium enema or colonoscopy alone, particularly in patients >40 years, to exclude structural diseases such as cancer or strictures. Colonoscopy alone is most cost effective in this setting since it provides an opportunity to biopsy mucosal lesions, perform polypectomy, or dilate strictures. Barium enema has advantages over colonoscopy in the patient with isolated constipation, since it is less costly and identifies colonic dilatation and all significant mucosal lesions or strictures that are likely to present with constipation. Melanosis coli, or pigmentation of the colon mucosa, indicates the use of anthraquinone laxatives such as cascara or senna; however, this is usually apparent from a careful history. An unexpected disorder such as megacolon or cathartic colon may also be detected by colonic radiographs. Measurement of serum calcium and thyroid stimulating hormone levels will identify rare patients with metabolic disorders.
FIGURE 4 Algorithm for the management of constipation.










Patients with more troublesome constipation may not respond to fiber alone and may be helped by a bowel training regimen: taking an osmotic laxative and evacuating with enema or glycerine suppository as needed. After breakfast, a distraction-free 15 to 20 min on the toilet without straining is encouraged. Excessive straining may lead to development of hemorrhoids, and, if there is weakness of the pelvic floor or injury to the pudendal nerve, may result in obstructed defecation from descending perineum syndrome several years later. Those few who do not benefit from the simple measures delineated above or require long-term treatment with stimulant laxatives with the attendant risk of developing laxative abuse syndrome are assumed to have severe or intractable constipation and should have further investigation (Fig. 4).

INVESTIGATION OF SEVERE CONSTIPATION

A small minority (probably <5%) of all patients with constipation have cases that are considered severe or “intractable”; these are the patients most likely to be seen by gastroenterologists or in referral centers. Further observation of the patient may occasionally reveal a previously unrecognized cause, such as an evacuation disorder, laxative abuse, malingering, or psychiatric disorder. In these patients, recent studies suggest that evaluations of the physiologic function of the colon and pelvic floor and of psychological status aid in the rational choice of treatment. Even among these highly selected patients with severe constipation, a cause can be identified in only about 30% (see below).

Measurement of Colonic Transit

Radiopaque marker transit tests are easy, repeatable, generally safe, inexpensive, reliable, and highly applicable in evaluating constipated patients in clinical practice. There are several validated methods that are very simple. For example, radiopaque markers are ingested, and an abdominal flat film taken 5 d later should indicate passage of 80% of the markers out of the colon. This test does not provide useful information about the transit profile of the stomach and small bowel, and avoidance of laxatives or enemas during the testing period is essential.
Radioscintigraphy with a delayed-release capsule containing radiolabeled particles has been used to noninvasively characterize normal, accelerated, or delayed colonic function over 24 to 48 h with low radiation exposure. This approach simultaneously assesses gastric, small-bowel, and colonic transit. The disadvantages are the greater cost and the need for specific materials prepared in a nuclear medicine laboratory.
Anorectal and Pelvic Floor Tests
Pelvic floor dysfunction is suggested by the inability to evacuate the rectum, a feeling of persistent rectal fullness, rectal pain, the need to extract stool from the rectum digitally, application of pressure on the posterior wall of the vagina, support of the perineum during straining, and excessive straining. These significant symptoms should be contrasted with the sense of incomplete rectal evacuation, which is common in irritable bowel syndrome.
Patients with clinically suspected obstruction of defecation should also be evaluated by a psychologist to identify eating disorders or a “need to control,” to provide stress management or relaxation training, and to identify depression.
A simple clinical test in the office to document a nonrelaxing puborectalis muscle is to have the patient strain to expel the index finger during a digital rectal examination. Motion of the puborectalis posteriorly during straining indicates proper coordination of the pelvic floor muscles.
Measurement of perineal descent is relatively easy to gauge clinically by placing the patient in the left decubitus position and watching the perineum to assess either paucity or lack of descent (<1.5 cm, a sign of pelvic floor dysfunction) or perineal ballooning during straining relative to bony landmarks (>4 cm, suggesting excessive perineal descent).
A useful overall test of evacuation is the balloon expulsion test. A urinary catheter is placed in the rectum, the balloon is inflated to 50 mL with water, and a determination is made about whether the patient can expel it while seated on a toilet or in the left lateral decubitus position. In the lateral position, the weight needed to facilitate expulsion of the balloon (normal, 0 to 200 g) is determined.
Anorectal manometry is not often contributory in the evaluation of patients presenting with severe constipation, except when an excessively high resting or squeeze anal sphincter tone suggests anismus (anal sphincter spasm). This test also identifies rare syndromes, such as adult Hirschsprung's disease, by the absence of the rectoanal inhibitory reflex or the presence of occult incontinence.
Defecography (a dynamic barium enema including lateral views obtained during barium expulsion) reveals “soft abnormalities” in many patients; the most relevant findings are the measured changes in rectoanal angle, anatomic defects of the rectum, and enteroceles or rectoceles. In a very small proportion of patients, significant anatomic defects associated with intractable constipation respond best to surgical treatment. These defects include severe intussusception with complete outlet obstruction due to funnel-shaped plugging at the anal canal or an extremely large rectocele that is preferentially filled during attempts at defecation instead of expulsion of the barium through the anus. In summary, defecography requires an interested and experienced radiologist, and abnormalities are not pathognomonic for pelvic floor dysfunction. More commonly, outlet obstruction results from a nonrelaxing puborectalis muscle, which impedes rectal emptying, rather than from defects identified by defecography.
Dynamic imaging studies such as proctography during defecation or scintigraphic expulsion of artificial stool help measure perineal descent and the rectoanal angle during rest, squeezing, and straining, and scintigraphic expulsion quantitates the amount of “artificial stool” emptied. Failure of the rectoanal angle to increase significantly (~15°) during straining confirms pelvic floor dysfunction.
Neurologic testing (electromyography) is more helpful in the evaluation of patients with incontinence than of those with symptoms suggesting obstructed defecation. The absence of neurologic signs in the lower extremities suggests that any documented denervation of the puborectalis results from pelvic (e.g., obstetric) injury or from stretching of the pudendal nerve by chronic, long-standing straining.
Ultrasonography identifies sphincter or rectal wall defects and may help select patients for surgical correction. Spinal-evoked responses during electrical rectal stimulation or stimulation of external anal sphincter contraction by applying magnetic stimulation over the lumbosacral cord identify patients with limited sacral neuropathies with sufficient residual nerve conduction to attempt biofeedback training.
In summary, a balloon expulsion test is an important screening test for anorectal dysfunction. If positive, an anatomic evaluation of the rectum or anal sphincters and an assessment of pelvic floor relaxation are the tools for evaluating patients in whom obstructed defecation is suspected.

TREATMENT

After the cause of constipation is characterized, a treatment decision can be made. Slow transit constipation requires aggressive medical or surgical treatment; anismus or pelvic floor dysfunction usually responds to biofeedback management (Fig. 4). However, only about 30% of patients with severe constipation are found to have such a physiologic disorder.
Patients with slow transit constipation are treated with bulk, osmotic, and stimulant laxatives, including fiber, psyllium, milk of magnesia, lactulose, polyethylene glycol (colonic lavage solution), and bisacodyl. If a 2- to 3-month trial of medical therapy fails and patients continue to have documented slow transit constipation unassociated with obstructed defecation, colectomy with ileorectostomy is indicated. The decision to resort to surgery is facilitated in the presence of megacolon and megarectum. The complications after surgery include small-bowel obstruction (11%) and fecal soiling, particularly at night during the first postoperative year.
Patients who have a combined disorder should pursue pelvic floor retraining (biofeedback and muscle relaxation), psychological counseling, and dietetic advice first, followed by colectomy and ileorectosomy if colonic transit studies do not normalize with biofeedback alone. In patients with pelvic floor dysfunction alone, biofeedback training has a 70 to 80% success rate, measured by the acquisition of comfortable stool habits. Attempts to manage pelvic floor dysfunction with operations (internal anal sphincter or puborectalis muscle division) have achieved only mediocre success and have been largely abandoned.

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