Diarrhea

Overview

Definition

Diarrhea is the passage of ≥ 3 watery or loose stools in 24 hours.

Classification

Diarrhea can be classified by the duration of symptoms:

• Acute diarrhea: ≤ 2 weeks 
• Persistent diarrhea: > 2 weeks but < 4 weeks
• Chronic diarrhea: ≥ 4 weeks

Additionally, diarrhea may be classified based on the underlying etiology and pathophysiology:

• Infectious diarrhea:
  • Inflammatory (invasion by an infectious organism)
  • Noninflammatory (no invasion of the mucosa by the organism)
• Noninfectious diarrhea:
  • Secretory (efflux of electrolytes and water)
  • Osmotic (water is drawn into the intestinal lumen)
  • Malabsorption (impaired nutrient absorption)
  • Inflammatory (inflammatory process causing mucosal damage)
  • Altered motility (rapid intestinal transit)

Etiology

Infectious diarrhea

Inflammatory/invasive:

• Bacterial: 
  • Shigella
  • Salmonella
  • Campylobacter jejuni
  • Yersinia enterocolitica
  • Escherichia coli (enterohemorrhagic and enteroinvasive)
  • Clostridioides difficile
  • Listeria monocytogenes
  • Vibrio parahaemolyticus
• Protozoal:
  • Entameoba histolytica
  • Strongyloides

Noninflammatory/noninvasive:

• Bacterial: 
  • Staphylococcus aureus
  • Clostridium perfringens
  • Bacillus cereus
  • E. coli (enterotoxigenic and enteroaggregative)
  • Vibrio cholerae
• Protozoal:
  • Giardia lamblia
  • Cryptosporidium
• Viral:
  • Rotavirus
  • Norovirus
  • Adenovirus
  • Cytomegalovirus

Risk factors:

• Contaminated food products:
  • Seafood
  • Poultry
  • Turkey
  • Eggs
  • Beef
• Contaminated water
• Animal exposure
• High-risk environments for transmission:
  • Daycare
  • Nursing home
  • Hospital

Noninfectious diarrhea

Secretory:

• Laxatives:
  • Senna
  • Docusate
• Hormone-producing tumors: 
  • Carcinoid
  • Vasoactive intestinal peptide-secreting tumor (VIPoma)
  • Gastrinoma
• Bile acid malabsorption
• Endocrine disease:
  • Addison’s disease
  • Diabetes
• Medications:
  • Quinine
  • Colchicine
  • Antibiotics
  • Digoxin
  • Misoprostol

Osmotic:

• Osmotic laxatives:
  • Magnesium sulfate or magnesium hydroxide
  • Polyethylene glycol
• Lactase deficiency (lactose intolerance)
• Nonabsorbable carbohydrates:
  • Sorbitol
  • Lactulose
  • Xylitol

Malabsorption:

• Intraluminal maldigestion:
  • Pancreatic exocrine insufficiency (e.g., chronic pancreatitis)
  • Bacterial overgrowth
  • Bariatric surgery
• Mucosal malabsorption: 
  • Celiac disease
  • Whipple disease
  • Mesenteric ischemia
• Medications:
  • Orlistat
  • Acarbose

Inflammatory/exudative:

• Inflammatory bowel disease:
  • Crohn’s disease
  • Ulcerative colitis
• Microscopic colitis
• Immune-related mucosal disease:
  • Immunodeficiency
  • Food allergy
  • Eosinophilic gastroenteritis
• Infections
• Radiation injury
• GI malignancies:
  • Lymphoma
  • Colon cancer

Altered motility:

• Irritable bowel syndrome (IBS)
• Hyperthyroidism
• Dumping syndrome
• Medications
  • Magnesium-containing medications
  • Cholinesterase inhibitors
  • Selective serotonin reuptake inhibitors

Pathophysiology

Infectious diarrhea

Inflammatory/invasive:

• Invasion of the mucosa by an infectious organism  → inflammatory response and damage to the epithelium → ↓ absorption and exudation of serum and blood into the lumen
• Mucus, blood, and leukocytes can be detected in the stool.

Noninflammatory/noninvasive:

• Pathogens do not invade the mucosa.
• Most often associated with bacterial enterotoxins → alter ion transport → efflux of ions and water into the bowel lumen
• The mucosa remains normal or is only minimally altered.
• Stools are watery and lack fecal leukocytes and blood.

Noninfectious diarrhea

Secretory:

• Active secretion of water into the intestinal lumen due to activated ion transport systems
• Diarrhea occurs throughout the day and night.

Osmotic:

• Water is drawn into the intestinal lumen by poorly absorbed substances.
• Stool output is consistent with the amount of unabsorbable substance that is ingested.
• Occurs during the day only, and stools ↓ with discontinuation of the offending substance
• ↑ Osmolar gap will be seen.

Malabsorption:

• Impaired nutrient absorption or digestion
• Often results in fatty stools (steatorrhea)

Inflammatory/exudative:

• Inflammation → intestinal mucosa damage → impaired absorption
• Mucus, blood, and leukocytes are present in the stool.

Altered motility: rapid intestinal passage → ↓ time for fluid absorption

Clinical Presentation

• Determine duration:
  • Acute
  • Chronic
• Characterize the diarrhea type:
  • Watery (may be secretory or osmotic)
  • Steatorrhea (likely from malabsorption)
  • Bloody (likely inflammatory)
  • Mucoid (likely inflammatory)
• Associated symptoms:
  • Fever
  • Abdominal pain and cramping
  • Flatulence and bloating
  • Nausea and vomiting (especially due to an infectious or toxin-mediated etiology)
  • Tenesmus
• Signs of dehydration:
  • Dry skin and mucous membranes
  • Poor skin turgor
  • Fatigue
  • Tachycardia
  • Rapid breathing

Diagnosis

Acute diarrhea

The majority of cases are infectious in etiology.

Most patients will have self-limiting symptoms and do not require testing.

Indications for stool studies:

• Severe dehydration
• Bloody stools
• > 6 unformed stools in 24 hours
• Fever ≥ 38.5°C (≥ 101°F)
• Duration > 48 hours without improvement
• Recent antibiotic use
• Severe abdominal pain
• High-risk population (elderly, immunocompromised patients, those with known inflammatory bowel disease)

Stool analysis:

• Fecal leukocytes
• Ova and parasites
• Stool culture and polymerase chain reaction (PCR)
• Occult blood
• Lactoferrin
• C. difficile toxin immunoassay (particularly if there is recent antibiotic use)

Supporting laboratory evaluation:

• Generally done only in patients with severe disease and evidence of dehydration
• CBC:
  • Leukocytosis
  • Eosinophilia → may indicate a parasitic infection
  • Significant bandemia → common in C. difficile 
• Basic metabolic panel:
  • Electrolyte abnormalities (hypokalemia)
  • ↑ Creatinine → acute kidney injury from dehydration
  • Non–anion gap metabolic acidosis

Chronic diarrhea

The differential diagnosis of chronic diarrhea is lengthy, and the evaluation will be guided by clinical suspicion from the history and physical exam. Consultation with a gastroenterologist may be needed.

Laboratory studies:

• Used to narrow the differential diagnosis
• CBC → evaluate for anemia (malabsorption, malignancy)
• Basic metabolic panel → evaluate for dehydration and electrolyte disturbances
• Thyroid-stimulating hormone → screen for hyperthyroidism
• ESR and CRP:
  • Nonspecific
  • May be elevated owing to inflammatory etiologies
• Celiac serologies
• Breath test → bacterial overgrowth
• Stool studies:
  • Stool electrolytes → calculate stool osmolar gap
    • Normal stool osmolality = 290 mmol/L (same as serum)
    • The osmotic gap = 290 – 2 × (stool sodium + stool potassium)
    • Osmotic diarrhea: > 125 mmol/L
    • Secretory diarrhea: < 50 mmol/L
  • Occult blood → seen in inflammatory bowel disease, malignancy, and chronic infection
  • Fecal calprotectin or lactoferrin → inflammatory causes
  • Evaluation for infection (especially if persistent diarrhea after travel)
    • Stool culture
    • Ova and parasites
    • C. difficile toxin immunoassay (if history of antibiotic use)
  • Fecal fat → malabsorption of fats
  • Fecal chymotrypsin and elastase → potential pancreatic insufficiency
  • Laxative screen
• Tests for malabsorption:
  • Folate
  • Iron studies
  • Vitamin B₁₂
  • Albumin
  • 25-Hydroxyvitamin D

Imaging and procedures:

• Use of these methods is guided by the patient’s history, symptoms, presence of worrisome features, and clinical suspicion.
• Endoscopy and/or colonoscopy:
  • Should be performed promptly in patients with alarming features: 
    • Symptom onset after the age of 50 years
    • Melena or hematochezia
    • Nocturnal symptoms
    • Progressive abdominal pain
    • Weight loss
    • Systemic symptoms
    • Evidence of malabsorption
    • History of malignancy or inflammatory bowel disease
  • Visualization and mucosal biopsy can help diagnose:
    • Inflammatory bowel disease
    • Celiac disease
    • Microscopic colitis
    • Malignancy
• CT or MRI:
  • Includes specialized testing, such as enterography and cholangiopancreatography
  • Should be considered in patients with: 
    • Significant abdominal pain
    • Fever
    • Weight loss
  • Helpful in detecting:
    • Malignancy
    • Pancreas pathology
    • Crohn’s disease

Management

Acute diarrhea

Supportive care:

• Most patients will require only oral rehydration therapy.
• IV fluid hydration should be used in severe disease.
• Oral and IV solutions should contain replacement electrolytes.
• If possible, withdraw any potentially offending medications.

Antidiarrheal agents:

• Options: loperamide, bismuth subsalicylate
• Reduce the duration of diarrhea
• Be aware that treatment can delay the extraction of pathogens and toxins.
• Contraindications:
  • Diarrhea with fever
  • Bloody or mucoid stool
  • Diarrhea caused by C. difficile and Shigella

Antibiotic therapy:

• Not routinely required
• Empiric therapy may be considered for:
  • Bloody stools
  • Fever
  • Severe symptoms requiring hospitalization
  • High-risk patients (e.g., infants, elderly, immunocompromised)
  • Suspected C. difficile infection
• Frequently used antibiotics:
  • Fluoroquinolones
  • Azithromycin
  • Trimethoprim–sulfamethoxazole
  • 3rd-generation cephalosporins

Chronic diarrhea

The treatment of chronic diarrhea hinges on diagnosing and treating the underlying etiology.

Symptomatic therapy:

• Indicated:
  • For patients who cannot tolerate definitive therapy
  • When no definitive diagnosis has been found
  • For temporary relief during workup
• Options:
  • Loperamide
  • Anticholinergics
  • Bismuth
  • Fiber
  • Clays

Empiric therapy:

• May be used in patients in whom the diagnosis is highly suspected but who cannot tolerate testing
• Lactose restriction → suspected lactose intolerance
• Cholestyramine:
  • Recent ileal resection
  • Abdominal radiation therapy
  • After cholecystectomy
• Antibiotics → for suspected bacterial overgrowth

Special Subtypes

Traveler’s diarrhea

• Diarrhea that develops after individuals from resource-rich settings return from travel to resource-limited regions:
  • Occurs in 40%–60% of travelers to resource-limited areas
  • May be inflammatory or secretory
• Etiology (list is not exhaustive): 
  • Enterotoxigenic E. coli is the most common cause.
  • Campylobacter jejuni
  • Shigella
  • Salmonella
  • Giardia lamblia
  • Norovirus
• Transmission:
  • Foodborne
  • Waterborne
• Clinical presentation:
  • Symptoms begin 12–72 hours after ingestion of contaminated food or water.
  • Abdominal cramps
  • Nausea and vomiting
  • Low-grade fever
  • Typically rice-colored stools
  • Hyperactive bowel sounds
• Most cases are mild and do not require diagnostic evaluation.
• Management:
  • Fluid replacement
  • Antidiarrheal medications
  • Antibiotics
    • Not necessary
    • May be considered in moderate or severe disease
    • Options: fluoroquinolones or azithromycin

Factitious diarrhea and laxative abuse

• Demographics:
  • Factitious diarrhea:
    • > 90% of cases are in women.
    • Significant proportion have worked in healthcare
    • Many patients will have a history of frequent hospital admissions.
  • Laxative abuse:
    • Elderly patients who continue taking laxatives after resolution of constipation
    • Patients with anorexia nervosa or bulimia nervosa
• Etiology: surreptitious or inadvertent overuse of laxatives
• Clinical presentation:
  • Watery diarrhea:
    • Large volume
    • May alternate with constipation
  • Crampy abdominal pain
  • Generalized weakness
  • Dehydration
  • Weight loss
• Diagnosis:
  • Electrolyte imbalances:
    • Hyponatremia
    • Hypokalemia
    • Hyperuricemia
    • Metabolic alkalosis (with chronic use)
    • Hypermagnesemia (with magnesium-containing laxatives)
  • Screening tests for laxatives may help determine the cause.
  • Colonoscopy: 
    • Dark-brown pigmentation (melanosis coli)
    • Pale patches
    • Biopsy shows lipofuscin-laden macrophages.
  • Barium enema: 
    • “Cathartic colon” (large bowel dilation with ↓ or absent haustrations)
    • Most likely seen in the right colon
• Management:
  • Correct dehydration and electrolyte abnormalities.
  • Discontinue laxatives.
  • Treat underlying psychologic issues.