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 Electrolytes Electrolytes are mineral salts that dissolve in water and dissociate into charged particles called ions, which can be either be positively (cations) or negatively (anions) charged. Electrolytes are distributed in the extracellular and intracellular compartments in different concentrations. Electrolytes are essential for various basic life-sustaining functions. Electrolytes and water)
  • Osmotic (water is drawn into the intestinal lumen)
  • Malabsorption Malabsorption Malabsorption involves many disorders in which there is an inability of the gut to absorb nutrients from dietary intake, potentially including water and/or electrolytes. A closely related term, maldigestion is the inability to break down large molecules of food into their smaller constituents. Malabsorption and maldigestion can affect macronutrients (fats, proteins, and carbohydrates), micronutrients (vitamins and minerals), or both. Malabsorption and Maldigestion (impaired nutrient absorption Absorption Absorption involves the uptake of nutrient molecules and their transfer from the lumen of the GI tract across the enterocytes and into the interstitial space, where they can be taken up in the venous or lymphatic circulation. Digestion and Absorption)
  • Inflammatory (inflammatory process causing mucosal damage)
  • Altered motility (rapid intestinal transit)

Etiology

Infectious diarrhea

Inflammatory/invasive:

• Bacterial: 
  • Shigella Shigella Shigella is a genus of gram-negative, non-lactose-fermenting facultative intracellular bacilli. Infection spreads most commonly via person-to-person contact or through contaminated food and water. Humans are the only known reservoir. Shigella
  • Salmonella Salmonella Salmonellae are gram-negative bacilli of the family Enterobacteriaceae. Salmonellae are flagellated, non-lactose-fermenting, and hydrogen sulfide-producing microbes. Salmonella enterica, the most common disease-causing species in humans, is further classified based on serotype as typhoidal (S. typhi and paratyphi) and nontyphoidal (S. enteritidis and typhimurium). Salmonella
  • Campylobacter Campylobacter Campylobacter ("curved bacteria") is a genus of thermophilic, S-shaped, gram-negative bacilli. There are many species of Campylobacter, with C. jejuni and C. coli most commonly implicated in human disease. Campylobacter jejuni
  • Yersinia Yersinia Yersinia is a genus of bacteria characterized as gram-negative bacilli that are facultative anaerobic with bipolar staining. There are 2 enteropathogenic species that cause yersiniosis, Y. enterocolitica and Y. pseudotuberculosis. Infections are manifested as pseudoappendicitis or mesenteric lymphadenitis, and enterocolitis. Enterobacteriaceae: Yersinia spp./Yersiniosis enterocolitica
  • Escherichia coli Escherichia coli The gram-negative bacterium Escherichia coli is a key component of the human gut microbiota. Most strains of E. coli are avirulent, but occasionally they escape the GI tract, infecting the urinary tract and other sites. Less common strains of E. coli are able to cause disease within the GI tract, most commonly presenting as abdominal pain and diarrhea. Escherichia coli (enterohemorrhagic and enteroinvasive)
  • Clostridioides difficile
  • Listeria Listeria Listeria spp. are motile, flagellated, gram-positive, facultative intracellular bacilli. The major pathogenic species is Listeria monocytogenes. Listeria are part of the normal gastrointestinal flora of domestic mammals and poultry and are transmitted to humans through the ingestion of contaminated food, especially unpasteurized dairy products. Listeria Monocytogenes Infections monocytogenes
  • Vibrio Vibrio Vibrio is a genus of comma-shaped, gram-negative bacilli. It is halophilic, acid labile, and commonly isolated on thiosulfate-citrate-bile-sucrose (TCBS) agar. There are 3 clinically relevant species: Vibrio cholerae (V. cholerae), Vibrio vulnificus (V. vulnificus), and Vibrio parahaemolyticus (V. parahaemolyticus). Vibrio parahaemolyticus
• Protozoal:
  • Entameoba histolytica
  • Strongyloides

Noninflammatory/noninvasive:

• Bacterial: 
  • Staphylococcus Staphylococcus Staphylococcus is a medically important genera of Gram-positive, aerobic cocci. These bacteria form clusters resembling grapes on culture plates. Staphylococci are ubiquitous for humans, and many strains compose the normal skin flora. Staphylococcus aureus
  • Clostridium perfringens
  • Bacillus Bacillus Bacillus are aerobic, spore-forming, gram-positive bacilli. Two pathogenic species are Bacillus anthracis (B. anthracis) and B. cereus. Bacillus cereus
  • E. coli (enterotoxigenic and enteroaggregative)
  • Vibrio Vibrio Vibrio is a genus of comma-shaped, gram-negative bacilli. It is halophilic, acid labile, and commonly isolated on thiosulfate-citrate-bile-sucrose (TCBS) agar. There are 3 clinically relevant species: Vibrio cholerae (V. cholerae), Vibrio vulnificus (V. vulnificus), and Vibrio parahaemolyticus (V. parahaemolyticus). Vibrio cholerae
• Protozoal:
  • Giardia lamblia Giardia lamblia Giardiasis is caused by Giardia lamblia (G. lamblia), a flagellated protozoan that can infect the intestinal tract. Giardia transmission occurs most commonly through consumption of cysts in contaminated water or through the fecal-oral route. Excystation occurs in the gastrointestinal (GI) tract, and trophozoites attach to the intestinal wall villi and cause malabsorption. Giardia/Giardiasis
  • Cryptosporidium
• Viral:
  • Rotavirus Rotavirus Rotavirus belongs to the Reoviridae family and is a non-enveloped, double-stranded RNA virus. Transmission occurs through the fecal-oral route. Rotavirus is a common cause of severe gastroenteritis in children. Severe infections can result in dehydration and death. Reoviridae: Rotavirus
  • Norovirus Norovirus Norovirus is a nonenveloped, single-stranded, positive-sense RNA virus belonging to the Caliciviridae family. Norovirus infections are transmitted via the fecal-oral route or by aerosols from vomiting. The virus is one of the most common causes of nonbacterial gastroenteritis epidemic worldwide. Symptoms include watery and nonbloody diarrhea, nausea, vomiting, and low-grade fever. Norovirus
  • Adenovirus Adenovirus Adenovirus (member of the family Adenoviridae) is a nonenveloped, double-stranded DNA virus. Adenovirus is transmitted in a variety of ways, and it can have various presentations based on the site of entry. Presentation can include febrile pharyngitis, conjunctivitis, acute respiratory disease, atypical pneumonia, and gastroenteritis. Adenovirus
  • Cytomegalovirus Cytomegalovirus CMV is a ubiquitous double-stranded DNA virus belonging to the Herpesviridae family. CMV infections can be transmitted in bodily fluids, such as blood, saliva, urine, semen, and breast milk. The initial infection is usually asymptomatic in the immunocompetent host, or it can present with symptoms of mononucleosis. 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 Laxatives Laxatives are medications used to promote defecation. Most often, laxatives are used to treat constipation or for bowel preparation for certain procedures. There are 4 main classes of laxatives: bulk-forming, stimulant, osmotic, and emollient. Laxatives:
  • Senna
  • Docusate
• Hormone-producing tumors: 
  • Carcinoid
  • Vasoactive intestinal peptide-secreting tumor ( VIPoma VIPoma A VIPoma is a rare neuroendocrine tumor arising primarily in the pancreas that releases large amounts of vasoactive intestinal polypeptide (VIP). This process leads to chronic watery diarrhea with concomitant hypokalemia and dehydration, as well as wheezing and flushing (known as Verner-Morrison or WDHA syndrome). VIPoma)
  • Gastrinoma Gastrinoma A gastrinoma is a tumor that secretes excessive levels of the hormone gastrin and is responsible for Zollinger-Ellison syndrome (ZES). Gastrinomas are frequently associated with multiple endocrine neoplasia 1 (MEN 1) and can arise from the pancreas, stomach, duodenum, jejunum, and/or even from the lymph nodes. Gastrinoma
• Bile acid malabsorption
• Endocrine disease:
  • Addison’s disease Addison’s Disease Adrenal insufficiency (AI) is the inadequate production of adrenocortical hormones: glucocorticoids, mineralocorticoids, and adrenal androgens. Primary AI, also called Addison’s disease, is caused by autoimmune disease, infections, and malignancy, among others. Adrenal Insufficiency and Addison’s Disease
  • Diabetes
• Medications:
  • Quinine
  • Colchicine
  • Antibiotics
  • Digoxin
  • Misoprostol

Osmotic:

• Osmotic laxatives:
  • Magnesium sulfate or magnesium hydroxide
  • Polyethylene glycol
• Lactase deficiency ( lactose intolerance Lactose intolerance Lactose intolerance (LI) describes a constellation of symptoms due to lactase deficiency (LD), the enzyme located in the brush border of the absorptive cells in the small intestine. Lactose is the disaccharide present in milk and requires hydrolysis by lactase to break it down into its 2 absorbable constituents, glucose and galactose. Lactose intolerance typically presents with bloating, abdominal cramping, diarrhea, and flatulence. Lactose Intolerance)
• Nonabsorbable carbohydrates Carbohydrates Carbohydrates are one of the 3 macronutrients, along with fats and proteins, serving as a source of energy to the body. These biomolecules store energy in the form of glycogen and starch, and play a role in defining the cellular structure (e.g., cellulose). Basics of Carbohydrates:
  • Sorbitol
  • Lactulose
  • Xylitol

Malabsorption Malabsorption Malabsorption involves many disorders in which there is an inability of the gut to absorb nutrients from dietary intake, potentially including water and/or electrolytes. A closely related term, maldigestion is the inability to break down large molecules of food into their smaller constituents. Malabsorption and maldigestion can affect macronutrients (fats, proteins, and carbohydrates), micronutrients (vitamins and minerals), or both. Malabsorption and Maldigestion:

• Intraluminal maldigestion Maldigestion Malabsorption involves many disorders in which there is an inability of the gut to absorb nutrients from dietary intake, potentially including water and/or electrolytes. A closely related term, maldigestion is the inability to break down large molecules of food into their smaller constituents. Malabsorption and maldigestion can affect macronutrients (fats, proteins, and carbohydrates), micronutrients (vitamins and minerals), or both. Malabsorption and Maldigestion:
  • Pancreatic exocrine insufficiency (e.g., chronic pancreatitis Chronic pancreatitis Chronic pancreatitis is due to persistent inflammation, fibrosis, and irreversible cell damage to the pancreas, resulting in a loss of endocrine and exocrine gland function. The most common etiologies are alcohol abuse and pancreatic duct obstruction. Patients often present with recurrent epigastric abdominal pain, nausea, and features of malabsorption syndrome (diarrhea, steatorrhea, and weight loss). Chronic Pancreatitis)
  • Bacterial overgrowth
  • Bariatric surgery Bariatric surgery Bariatric surgery refers to a group of invasive procedures used to surgically reduce the size of the stomach to produce early satiety, decrease food intake (restrictive type) and/or alter digestion, and artificially induce malabsorption of nutrients (malabsorptive type). The ultimate goal of bariatric surgery is drastic weight loss. Bariatric Surgery
• Mucosal malabsorption: 
  • Celiac disease Celiac disease Celiac disease (also known as celiac sprue or gluten enteropathy) is an autoimmune reaction to gliadin, which is a component of gluten. Celiac disease is closely associated with HLA-DQ2 and HLA-DQ8. The immune response is localized to the proximal small intestine and causes the characteristic histologic findings of villous atrophy, crypt hyperplasia, and intraepithelial lymphocytosis. Celiac Disease
  • Whipple disease
  • Mesenteric ischemia Mesenteric Ischemia Mesenteric ischemia is a rare, life-threatening condition caused by inadequate blood flow through the mesenteric vessels, which results in ischemia and necrosis of the intestinal wall. Mesenteric ischemia can be either acute or chronic. Mesenteric Ischemia
• Medications:
  • Orlistat
  • Acarbose

Inflammatory/exudative:

• Inflammatory bowel disease:
  • Crohn’s disease
  • Ulcerative colitis Ulcerative colitis Ulcerative colitis (UC) is an idiopathic inflammatory condition that involves the mucosal surface of the colon. It is a type of inflammatory bowel disease (IBD), along with Crohn's disease (CD). The rectum is always involved, and inflammation may extend proximally through the colon. Ulcerative Colitis
• Microscopic colitis
• Immune-related mucosal disease:
  • Immunodeficiency
  • Food allergy
  • Eosinophilic gastroenteritis Gastroenteritis Gastroenteritis is inflammation of the stomach and intestines, commonly caused by infections from bacteria, viruses, or parasites. Transmission may be foodborne, fecal-oral, or through animal contact. Common clinical features include abdominal pain, diarrhea, vomiting, fever, and dehydration. Gastroenteritis
• Infections
• Radiation injury
• GI malignancies:
  • Lymphoma
  • Colon cancer

Altered motility:

• Irritable bowel syndrome Irritable bowel syndrome Irritable bowel syndrome (IBS) is a functional bowel disease characterized by chronic abdominal pain and altered bowel habits without an identifiable organic cause. The etiology and pathophysiology of this disease are not well understood, and there are many factors that may contribute. Irritable Bowel Syndrome ( IBS IBS Irritable bowel syndrome (IBS) is a functional bowel disease characterized by chronic abdominal pain and altered bowel habits without an identifiable organic cause. The etiology and pathophysiology of this disease are not well understood, and there are many factors that may contribute. Irritable Bowel Syndrome)
• Hyperthyroidism Hyperthyroidism Thyrotoxicosis refers to the classic physiologic manifestations of excess thyroid hormones and is not synonymous with hyperthyroidism, which is caused by sustained overproduction and release of T3 and/or T4. Graves' disease is the most common cause of primary hyperthyroidism, followed by toxic multinodular goiter and toxic adenoma. Thyrotoxicosis and Hyperthyroidism
• Dumping syndrome
• Medications
  • Magnesium-containing medications
  • Cholinesterase inhibitors
  • Selective serotonin reuptake inhibitors Serotonin Reuptake Inhibitors Antidepressants encompass several drug classes and are used to treat individuals with depression, anxiety, and psychiatric conditions, as well as those with chronic pain and symptoms of menopause. Antidepressants include selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), and many other drugs in a class of their own. Serotonin Reuptake Inhibitors and Similar Antidepressant Medications

Pathophysiology

Infectious diarrhea

Inflammatory/invasive:

• Invasion of the mucosa by an infectious organism  → inflammatory response and damage to the epithelium Epithelium The epithelium is a complex of specialized cellular organizations arranged into sheets and lining cavities and covering the surfaces of the body. The cells exhibit polarity, having an apical and a basal pole. Structures important for the epithelial integrity and function involve the basement membrane, the semipermeable sheet on which the cells rest, and interdigitations, as well as cellular junctions. Surface Epithelium → ↓ absorption Absorption Absorption involves the uptake of nutrient molecules and their transfer from the lumen of the GI tract across the enterocytes and into the interstitial space, where they can be taken up in the venous or lymphatic circulation. Digestion and 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 Malabsorption Malabsorption involves many disorders in which there is an inability of the gut to absorb nutrients from dietary intake, potentially including water and/or electrolytes. A closely related term, maldigestion is the inability to break down large molecules of food into their smaller constituents. Malabsorption and maldigestion can affect macronutrients (fats, proteins, and carbohydrates), micronutrients (vitamins and minerals), or both. Malabsorption and Maldigestion:

• Impaired nutrient absorption Absorption Absorption involves the uptake of nutrient molecules and their transfer from the lumen of the GI tract across the enterocytes and into the interstitial space, where they can be taken up in the venous or lymphatic circulation. Digestion and Absorption or digestion Digestion Digestion refers to the process of the mechanical and chemical breakdown of food into smaller particles, which can then be absorbed and utilized by the body. Digestion and Absorption
• Often results in fatty stools (steatorrhea)

Inflammatory/exudative:

• Inflammation → intestinal mucosa damage → impaired absorption Absorption Absorption involves the uptake of nutrient molecules and their transfer from the lumen of the GI tract across the enterocytes and into the interstitial space, where they can be taken up in the venous or lymphatic circulation. Digestion and Absorption
• Mucus, blood, and leukocytes are present in the stool.

Altered motility: rapid intestinal passage → ↓ time for fluid absorption Absorption Absorption involves the uptake of nutrient molecules and their transfer from the lumen of the GI tract across the enterocytes and into the interstitial space, where they can be taken up in the venous or lymphatic circulation. Digestion and 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 Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain and cramping
  • Flatulence and bloating
  • Nausea and vomiting (especially due to an infectious or toxin-mediated etiology)
  • Tenesmus
• Signs of dehydration Dehydration Volume status is a balance between water and solutes, the majority of which is Na. Volume depletion refers to a loss of both water and Na, whereas dehydration refers only to a loss of water. Dehydration is primarily caused by decreased water intake and presents with increased thirst and can progress to altered mental status and low blood pressure if severe. Volume Depletion and Dehydration:
  • Dry skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin and mucous membranes
  • Poor skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the 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 Dehydration Volume status is a balance between water and solutes, the majority of which is Na. Volume depletion refers to a loss of both water and Na, whereas dehydration refers only to a loss of water. Dehydration is primarily caused by decreased water intake and presents with increased thirst and can progress to altered mental status and low blood pressure if severe. Volume Depletion and 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 Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of 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 Polymerase chain reaction Polymerase chain reaction (PCR) is a technique that amplifies DNA fragments exponentially for analysis. The process is highly specific, allowing for the targeting of specific genomic sequences, even with minuscule sample amounts. The PCR cycles multiple times through 3 phases: denaturation of the template DNA, annealing of a specific primer to the individual DNA strands, and synthesis/elongation of new DNA molecules. Polymerase Chain Reaction (PCR) ( PCR PCR Polymerase chain reaction (PCR) is a technique that amplifies DNA fragments exponentially for analysis. The process is highly specific, allowing for the targeting of specific genomic sequences, even with minuscule sample amounts. The PCR cycles multiple times through 3 phases: denaturation of the template DNA, annealing of a specific primer to the individual DNA strands, and synthesis/elongation of new DNA molecules. 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 Dehydration Volume status is a balance between water and solutes, the majority of which is Na. Volume depletion refers to a loss of both water and Na, whereas dehydration refers only to a loss of water. Dehydration is primarily caused by decreased water intake and presents with increased thirst and can progress to altered mental status and low blood pressure if severe. Volume Depletion and Dehydration
• CBC:
  • Leukocytosis
  • Eosinophilia → may indicate a parasitic infection
  • Significant bandemia → common in C. difficile 
• Basic metabolic panel:
  • Electrolyte abnormalities ( hypokalemia Hypokalemia Hypokalemia is defined as plasma potassium (K+) concentration < 3.5 mEq/L. Homeostatic mechanisms maintain plasma concentration between 3.5-5.2 mEq/L despite marked variation in dietary intake. Hypokalemia can be due to renal losses, GI losses, transcellular shifts, or poor dietary intake. Hypokalemia)
  • ↑ Creatinine → acute kidney injury Acute Kidney Injury Acute kidney injury refers to sudden and often reversible loss of renal function, which develops over days or weeks. Azotemia refers to elevated levels of nitrogen-containing substances in the blood that accompany AKI, which include BUN and creatinine. Acute Kidney Injury from dehydration Dehydration Volume status is a balance between water and solutes, the majority of which is Na. Volume depletion refers to a loss of both water and Na, whereas dehydration refers only to a loss of water. Dehydration is primarily caused by decreased water intake and presents with increased thirst and can progress to altered mental status and low blood pressure if severe. Volume Depletion and Dehydration
  • Non–anion gap metabolic acidosis Metabolic acidosis The renal system is responsible for eliminating the daily load of non-volatile acids, which is approximately 70 millimoles per day. Metabolic acidosis occurs when there is an increase in the levels of new non-volatile acids (e.g., lactic acid), renal loss of HCO3-, or ingestion of toxic alcohols. 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 Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview (malabsorption, malignancy)
• Basic metabolic panel → evaluate for dehydration Dehydration Volume status is a balance between water and solutes, the majority of which is Na. Volume depletion refers to a loss of both water and Na, whereas dehydration refers only to a loss of water. Dehydration is primarily caused by decreased water intake and presents with increased thirst and can progress to altered mental status and low blood pressure if severe. Volume Depletion and 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 Electrolytes Electrolytes are mineral salts that dissolve in water and dissociate into charged particles called ions, which can be either be positively (cations) or negatively (anions) charged. Electrolytes are distributed in the extracellular and intracellular compartments in different concentrations. Electrolytes are essential for various basic life-sustaining functions. 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 Chymotrypsin A serine endopeptidase secreted by the pancreas as its zymogen, chymotrypsinogen and carried in the pancreatic juice to the duodenum where it is activated by trypsin. It selectively cleaves aromatic amino acids on the carboxyl side. Pancreatic Parameters and elastase → potential pancreatic insufficiency
  • Laxative screen
• Tests for malabsorption:
  • Folate Folate Folate and vitamin B12 are 2 of the most clinically important water-soluble vitamins. Deficiencies can present with megaloblastic anemia, GI symptoms, neuropsychiatric symptoms, and adverse pregnancy complications, including neural tube defects. Folate and Vitamin B12
  • 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 Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of 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 Celiac disease Celiac disease (also known as celiac sprue or gluten enteropathy) is an autoimmune reaction to gliadin, which is a component of gluten. Celiac disease is closely associated with HLA-DQ2 and HLA-DQ8. The immune response is localized to the proximal small intestine and causes the characteristic histologic findings of villous atrophy, crypt hyperplasia, and intraepithelial lymphocytosis. 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 Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of 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 Electrolytes Electrolytes are mineral salts that dissolve in water and dissociate into charged particles called ions, which can be either be positively (cations) or negatively (anions) charged. Electrolytes are distributed in the extracellular and intracellular compartments in different concentrations. Electrolytes are essential for various basic life-sustaining functions. Electrolytes.
• If possible, withdraw any potentially offending medications.

Antidiarrheal agents Antidiarrheal agents Antidiarrheal agents include several drug classes, including opioid agonists, somatostatin analogues, adsorbents, and bile acid sequestrants. These medications mainly work through antimotility and/or antisecretory effects. 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 Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever
  • Bloody or mucoid stool
  • Diarrhea caused by C. difficile and Shigella Shigella Shigella is a genus of gram-negative, non-lactose-fermenting facultative intracellular bacilli. Infection spreads most commonly via person-to-person contact or through contaminated food and water. Humans are the only known reservoir. 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 Fluoroquinolones Fluoroquinolones are a group of broad-spectrum, bactericidal antibiotics inhibiting bacterial DNA replication. Fluoroquinolones cover gram-negative, anaerobic, and atypical organisms, as well as some gram-positive and multidrug-resistant (MDR) organisms. Fluoroquinolones
  • Azithromycin
  • Trimethoprim Trimethoprim The sulfonamides are a class of antimicrobial drugs inhibiting folic acid synthesize in pathogens. The prototypical drug in the class is sulfamethoxazole. Although not technically sulfonamides, trimethoprim, dapsone, and pyrimethamine are also important antimicrobial agents inhibiting folic acid synthesis. The agents are often combined with sulfonamides, resulting in a synergistic effect. Sulfonamides and Trimethoprim–sulfamethoxazole
  • 3rd-generation cephalosporins Cephalosporins Cephalosporins are a group of bactericidal beta-lactam antibiotics (similar to penicillins) that exert their effects by preventing bacteria from producing their cell walls, ultimately leading to cell death. Cephalosporins are categorized by generation and all drug names begin with "cef-" or "ceph-." 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 Lactose intolerance Lactose intolerance (LI) describes a constellation of symptoms due to lactase deficiency (LD), the enzyme located in the brush border of the absorptive cells in the small intestine. Lactose is the disaccharide present in milk and requires hydrolysis by lactase to break it down into its 2 absorbable constituents, glucose and galactose. Lactose intolerance typically presents with bloating, abdominal cramping, diarrhea, and flatulence. Lactose Intolerance
• Cholestyramine:
  • Recent ileal resection
  • Abdominal radiation therapy
  • After cholecystectomy Cholecystectomy Cholecystectomy is a surgical procedure performed with the goal of resecting and extracting the gallbladder. It is one of the most common abdominal surgeries performed in the Western world. Cholecystectomy is performed for symptomatic cholelithiasis, cholecystitis, gallbladder polyps > 0.5 cm, porcelain gallbladder, choledocholithiasis and gallstone pancreatitis, and rarely, for gallbladder cancer. Cholecystectomy: Approaches and Technique
• 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 Campylobacter Campylobacter ("curved bacteria") is a genus of thermophilic, S-shaped, gram-negative bacilli. There are many species of Campylobacter, with C. jejuni and C. coli most commonly implicated in human disease. Campylobacter jejuni
  • Shigella Shigella Shigella is a genus of gram-negative, non-lactose-fermenting facultative intracellular bacilli. Infection spreads most commonly via person-to-person contact or through contaminated food and water. Humans are the only known reservoir. Shigella
  • Salmonella Salmonella Salmonellae are gram-negative bacilli of the family Enterobacteriaceae. Salmonellae are flagellated, non-lactose-fermenting, and hydrogen sulfide-producing microbes. Salmonella enterica, the most common disease-causing species in humans, is further classified based on serotype as typhoidal (S. typhi and paratyphi) and nontyphoidal (S. enteritidis and typhimurium). Salmonella
  • Giardia lamblia Giardia lamblia Giardiasis is caused by Giardia lamblia (G. lamblia), a flagellated protozoan that can infect the intestinal tract. Giardia transmission occurs most commonly through consumption of cysts in contaminated water or through the fecal-oral route. Excystation occurs in the gastrointestinal (GI) tract, and trophozoites attach to the intestinal wall villi and cause malabsorption. Giardia/Giardiasis
  • Norovirus Norovirus Norovirus is a nonenveloped, single-stranded, positive-sense RNA virus belonging to the Caliciviridae family. Norovirus infections are transmitted via the fecal-oral route or by aerosols from vomiting. The virus is one of the most common causes of nonbacterial gastroenteritis epidemic worldwide. Symptoms include watery and nonbloody diarrhea, nausea, vomiting, and low-grade fever. 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 Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever
  • Typically rice-colored stools
  • Hyperactive bowel sounds
• Most cases are mild and do not require diagnostic evaluation.
• Management:
  • Fluid replacement
  • Antidiarrheal Antidiarrheal Antidiarrheal agents include several drug classes, including opioid agonists, somatostatin analogues, adsorbents, and bile acid sequestrants. These medications mainly work through antimotility and/or antisecretory effects. Antidiarrheal Agents 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 Constipation Constipation is common and may be due to a variety of causes. Constipation is generally defined as bowel movement frequency < 3 times per week. Patients who are constipated often strain to pass hard stools. The condition is classified as primary (also known as idiopathic or functional constipation) or secondary, and as acute or chronic. Constipation
    • Patients with anorexia nervosa Anorexia Nervosa Anorexia nervosa is an eating disorder marked by self-imposed starvation and inappropriate dietary habits due to a morbid fear of weight gain and disturbed perception of body shape and weight. Patients have strikingly low BMI and diverse physiological and psychological complications. Anorexia Nervosa or bulimia nervosa Bulimia nervosa Bulimia nervosa is an eating disorder marked by recurrent episodes of binge eating accompanied by inappropriate compensatory behaviors (laxatives or diuretics use, self-induced vomiting, fasting, or excessive exercise) to counteract the effects of binge eating and prevent weight gain. Bulimia Nervosa
• Etiology: surreptitious or inadvertent overuse of laxatives
• Clinical presentation:
  • Watery diarrhea:
    • Large volume
    • May alternate with constipation Constipation Constipation is common and may be due to a variety of causes. Constipation is generally defined as bowel movement frequency < 3 times per week. Patients who are constipated often strain to pass hard stools. The condition is classified as primary (also known as idiopathic or functional constipation) or secondary, and as acute or chronic. Constipation
  • Crampy abdominal pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain
  • Generalized weakness
  • Dehydration
  • Weight loss
• Diagnosis:
  • Electrolyte imbalances:
    • Hyponatremia Hyponatremia Hyponatremia is defined as a decreased serum sodium (sNa+) concentration less than 135 mmol/L. Serum sodium is the greatest contributor to plasma osmolality, which is very tightly controlled via antidiuretic hormone (ADH) release from the hypothalamus and by the thirst mechanism. Hyponatremia
    • Hypokalemia
    • Hyperuricemia
    • Metabolic alkalosis Metabolic alkalosis The renal system is responsible for eliminating the daily load of non-volatile acids, which is approximately 70 millimoles per day. Metabolic alkalosis also occurs when there is an increased loss of acid, either renally or through the upper GI tract (e.g., vomiting), increased intake of HCO3-, or a reduced ability to secrete HCO3- when needed. 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 Colon The large intestines constitute the last portion of the digestive system. The large intestine consists of the cecum, appendix, colon (with ascending, transverse, descending, and sigmoid segments), rectum, and anal canal. The primary function of the colon is to remove water and compact the stool prior to expulsion from the body via the rectum and anal canal. Colon, Cecum, and Appendix” (large bowel dilation with ↓ or absent haustrations)
    • Most likely seen in the right colon Colon The large intestines constitute the last portion of the digestive system. The large intestine consists of the cecum, appendix, colon (with ascending, transverse, descending, and sigmoid segments), rectum, and anal canal. The primary function of the colon is to remove water and compact the stool prior to expulsion from the body via the rectum and anal canal. Colon, Cecum, and Appendix
• Management:
  • Correct dehydration Dehydration Volume status is a balance between water and solutes, the majority of which is Na. Volume depletion refers to a loss of both water and Na, whereas dehydration refers only to a loss of water. Dehydration is primarily caused by decreased water intake and presents with increased thirst and can progress to altered mental status and low blood pressure if severe. Volume Depletion and Dehydration and electrolyte abnormalities.
  • Discontinue laxatives.
  • Treat underlying psychologic issues.