Chronic diarrhea

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Omodamola Aje B.Sc, M.D. [2]

Chronic diarrhea is a common symptom of many conditions and has an estimated prevalence of 5%. Although chronic diarrhea has multiple definitions, a current working definition is the production of loose stools for longer than 4 weeks. Frequent defecation with normal consistency is termed psuedodiarrhea. There are 3 basic categories of chronic diarrhea: watery, fatty (malabsorption), and inflammatory (with blood and pus). The fundamental pathophysiology of all diarrhea is altered intestinal water and electrolyte transport caused by several factors majorly dependent on the socioeconomic status of the population. If left untreated, patients with chronic diarrhea may progress to develop symptoms of altered sensorium due to electrolyte imbalance, dehydration, and malnutrition. Common complications of chronic diarrhea include confusion, perforated bowels, sepsis, and death. Prognosis is generally good when the underlying cause is identified and treated early. The laboratory findings in chronic diarrhea include complete blood count to evaluate for anemia and abnormal white blood cell count, electrolytes, thyroid function tests, serology testing for celiac disease, and stool analysis for fecal leukocytes, fecal lactoferrin, and fecal occult blood. Treatment is targeted at treating the underlying cause of the diarrhea.

The word “diarrhea” was coined by Hippocrates. Diarrhea is derived from the Greek term “to flow through.” Diarrhea is a common manifestation of gastrointestinal disease.

Chronic diarrhea may be classified into 3 basic categories: watery, fatty (malabsorption), and inflammatory (with blood and pus). It is important to note that not all chronic diarrhea falls into one category alone. Classifying a patient’s chronic diarrhea into a subcategory helps to direct the diagnostic workup.

The fundamental pathophysiology of all diarrhea is incomplete absorption of water from the lumen because of either a reduced rate of net water absorption or osmotic retention of water intraluminally. The causes of chronic diarrhea include inflammatory, osmotic, secretory, iatrogenic, motility, and functional diseases. Osmotic chronic diarrhea involves an unabsorbed substance that draws water from the plasma into the intestinal lumen along osmotic gradients. If excessive amounts of unabsorbed substance are retained in the intestinal lumen, water will not be absorbed and diarrhea will result. Secretory chronic diarrhea on the other hand, results from disordered electrolyte transport and, despite the term, is more commonly caused by decreased absorption rather than net secretion. A disruption of the normal colonic epithelial barrier by microorganisms is mainly responsible for inflammatory chronic diarrhea. This disruption can lead to exudative, secretory, or malabsorptive components of inflammatory chronic diarrhea. Both rapid transit time and slow transit time are associated with motility disorders causing chronic diarrhea. Some iatrogenic causes of chronic diarrhea are seen after abdominal surgeries such as cholecystectomy, where about 5%–10% of patients develop chronic diarrhea. In general, the causes of chronic diarrhea are multifactorial.

Depending on the socioeconomic status of the population, chronic diarrhea can be caused by several factors. In a developing nation, the most likely causes of chronic diarrhea are mycobacterial and parasitic infections, while functional disorders such as malabsorption and inflammatory bowel diseases are less likely causes. In a developed nation, however, the most likely causes of diarrhea are irritable bowel syndrome (IBS), inflammatory bowel disease, malabsorption syndromes (such as lactose intolerance and celiac disease), and chronic infections (particularly in patients who are immunocompromised).

The differential diagnosis for chronic diarrhea is enormous, with a large number of diagnostic tests available that can be used to evaluate these patients. Classifying a patient’s chronic diarrhea into a subcategory such as watery, fatty, and inflammatory helps to direct the diagnostic workup. Some watery causes of chronic diarrhea which should be differentiated from one another include Crohn’s disease, hyperthyroidism, VIPoma, lactose intolerance, celiac disease, and irritable bowel syndrome (IBS). The causes of fatty diarrhea that should be differentiated from one another include celiac sprue, pancreatic insufficiency, bacterial overgrowth, and maldigestion problems which results from pancreatic exocrine insufficiencyy. Finally, the inflammatory causes of chronic diarrhea such as diverticulitis, ulcerative colitis, and entamoeba histolytica must also be differentiated.

In developed countries, the prevalence of chronic diarrhea is estimated to be about 300-500 per 100,000 persons. In any given year, about 3–5% of the population has diarrhea lasting more than 1 month.

The risk factors of chronic diarrhea can be assessed based on epidemiological associations and the patient‘s characteristics. Some of these factors can be classified based on travel history, epidemics and outbreaks, patients with acquired immune deficiency syndrome, and whether the patients are institutionalized or hospitalized.

If left untreated, patients with chronic diarrhea may progress to develop symptoms of altered sensorium due to electrolyte imbalance, dehydration, and malnutrition. Common complications of chronic diarrhea include confusion, perforated bowels, sepsis, and death. Prognosis is generally good when the underlying cause is identified and treated early.

There are no criteria for the diagnosis of chronic diarrhea. However, in order to make an accurate diagnosis, it is important to take a detailed history and a physical exam from an expert’s opinion and from experience in individual clinical centers. The use of these methods is subject to bias; however, a specific diagnosis can be achieved in more than 90% of patients.

Obtaining the history of a patient is the most important aspect of making a diagnosis of chronic diarrhea. Specific histories about the symptoms (duration, onset, progression), associated symptoms, and drug usage have to be obtained. The hallmark of chronic diarrhea is loose stools lasting for 4 weeks or more. A positive history of foul smelling stools that are difficult to flush, bloody loose bowel movements, and cramping abdominal pain are suggestive of chronic diarrhea. The most common symptoms of chronic diarrhea include cramping abdominal pain, elevation in body temperature, and increased frequency of bowel movements.

Some of the physical findings of chronic diarrhea are orthostatic hypotension, dehydration, neuropathy, muscle wasting, edema, malnutrition, urticaria pigmentosa, dermatographism, pinch purpura, macroglossia, hyperpigmentation, Addison’s disease, and migratory necrotizing erythema.

The laboratory findings in chronic diarrhea include complete blood count to evaluate for anemia and abnormal white blood cell count, electrolytes, thyroid function tests, serology testing for celiac disease, and stool analysis for fecal leukocytes, fecal lactoferrin, and fecal occult blood. Some other diagnostic studies that have been adopted in the diagnosis of chronic diarrhea include flexible sigmoidoscopy, colonoscopy, esophagogastroduodenoscopy, and capsule endoscopy.

There are no electrocardiogram findings associated with chronic diarrhea.

There are no chest x-ray findings associated with chronic diarrhea.

There are no CT findings associated with chronic diarrhea.

There are no additional imaging findings for chronic diarrhea.

Medications are the mainstay of treatment; the treatment of chronic diarrhea is targeted at treating the underlying cause. Antidiarrheal drugs, which act by improving stool consistency, reducing stool frequency, or reducing stool weight, are mainly employed for symptomatic treatment.

Surgery is not the first-line treatment option for patients with chronic diarrhea. Surgical intervention is usually reserved for patients who have failed all medical therapy and when malignancy is suspected on biopsy as the cause of the chronic diarrhea.

The primary and secondary prevention methods of chronic diarrhea are the same.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Omodamola Aje B.Sc, M.D. [2]

The word “diarrhea” was coined by Hippocrates. Diarrhea is derived from the Greek term “to flow through.” Diarrhea is a common manifestation of gastrointestinal disease.

The word “diarrhea” was coined by Hippocrates. Diarrhea is derived from the Greek term “to flow through.” Diarrhea is a common manifestation of gastrointestinal disease.^[1]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Omodamola Aje B.Sc, M.D. [2]

Chronic diarrhea may be classified into 3 basic categories: watery, fatty (malabsorption), and inflammatory (with blood and pus). It is important to note that not all chronic diarrhea falls into one category alone. Classifying a patient’s chronic diarrhea into a subcategory helps to direct the diagnostic workup.

Chronic diarrhea may be classified into:^[1][2][3][4]

• Inflammatory diarrhea
• Watery diarrhea
• Fatty diarrhea

Diarrhea may be classified as inflammatory, when stool analysis tools, such as stool cultures and interventions, such as flexible sigmoidoscopy or colonoscopy with biopsies show evidence of the presence of fecal leukocytes. Causes of inflammatory diarrhea include:

• Idiopathic inflammatory bowel disease, such as Crohn’s disease or ulcerative colitis
• Infectious diseases such as:
  • Cytomegalovirus
  • Herpes simplex
  • Tuberculosis
  • Strongyloidiasis
  • Aeromonas
  • Plesiomonas
• Ischemic colitis
• Radiation colitis
• Neoplasia

Watery diarrhea can be classified as:

• Osmotic diarrhea (stools with high osmotic gap >100 mosm/kg). Causes of osmotic diarrhea include:
  • Celiac sprue
  • Chronic pancreatitis
  • Lactase deficiency
  • Lactulose
  • Laxative use/abuse
  • Whipple’s disease

• Secretory diarrhea (stools with low osmotic gap <50 mosm/kg). Causes of secretory diarrhea include:
  • Cholera
  • Enterotoxigenic strains of E. coli
  • Medullary thyroid carcinoma
  • Factitious diarrhea from laxative abuse^[5]
  • Villous adenoma
  • Aeromonas
  • Plesiomonas
  • Microsporidia
  • Giardia
  • Coccidia
  • Cryptosporidium

• Structural and endocrine diseases should also be considered. These diseases include the following:
  • Diabetes
  • Hyperthyroidism
  • Addison’s disease
  • Peptide secreting endocrine tumors

A normal gap is between 50 and 100 mosm/kg.^[6]

Fatty diarrhea can be either due to malabsorption or maldigestion problems:

• The most common causes of malabsorption are:
  • Celiac sprue
  • Pancreatic insufficiency
  • Bacterial overgrowth
• Maldigestion results from pancreatic exocrine insufficiency

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Omodamola Aje B.Sc, M.D. [2]

The fundamental pathophysiology of all diarrhea is incomplete absorption of water from the lumen because of either a reduced rate of net water absorption or osmotic retention of water intraluminally. The causes of chronic diarrhea include inflammatory, osmotic, secretory, iatrogenic, motility, and functional diseases. Osmotic chronic diarrhea involves an unabsorbed substance that draws water from the plasma into the intestinal lumen along osmotic gradients. If excessive amounts of unabsorbed substance are retained in the intestinal lumen, water will not be absorbed and diarrhea will result. Secretory chronic diarrhea on the other hand, results from disordered electrolyte transport and, despite the term, is more commonly caused by decreased absorption rather than net secretion. A disruption of the normal colonic epithelial barrier by microorganisms is mainly responsible for inflammatory chronic diarrhea. This disruption can lead to exudative, secretory, or malabsorptive components of inflammatory chronic diarrhea. Both rapid transit time and slow transit time are associated with motility disorders causing chronic diarrhea. Some iatrogenic causes of chronic diarrhea are seen after abdominal surgeries such as cholecystectomy, where about 5%–10% of patients develop chronic diarrhea. In general, the causes of chronic diarrhea are multifactorial.

Diarrhea is a condition of altered intestinal water and electrolyte transport. The physiological mechanisms of diarrhea include osmotic, secretory, inflammatory, altered motility, and iatrogenic mechanisms.^[1]

Osmotic chronic diarrhea involves an unabsorbed substance that draws water from the plasma into the intestinal lumen along osmotic gradients. If excessive amounts of unabsorbed substance are retained in the intestinal lumen, water will not be absorbed and diarrhea will result.

• Chronic diarrhea due to an osmotic cause includes osmotic laxatives such as lactose intolerance antacids, fructose, lactulose, laxatives magnesium, phosphate, and sorbitol.^[2]
• Maldigestion syndromes such as disaccharidase deficiency and pancreatic exocrine insufficiency can also result in osmotic chronic diarrhea.
• Osmotic diarrheas might result in steatorrhea and azotorrhea (passage of fat and nitrogenous substances into the stool), but they typically do not cause any rectal bleeding.^[3]

Secretory chronic diarrhea results from disordered electrolyte transport and, despite the term, is more commonly caused by decreased absorption rather than net secretion.

• Secretory diarrheas include congenital abnormalities such as congenital chloridorrhea, in which an abnormality in the genetic control of chloride-bicarbonate exchange in the ileum results in the loss of chloride into the stool.
• Another example is the loss of α2-adrenergic function in enterocytes of patients with autonomic neuropathy caused by diabetes mellitus.
• The typical features of secretory diarrhea include the persistence of the diarrhea with fasting and the absence of steatorrhea, azotorrhea, or blood per rectum.
• Secretory diarrheas caused by neuroendocrine tumors have been identified by measurement of plasma levels of the hormone or its metabolite in the urine.
• Investigations include measurements of VIP, gastrin, or calcitonin in plasma or 24-hour collections of urine for 5-hydroxyindoleacetic acid.^[4]

Disruption of the normal colonic epithelial barrier by microorganisms is mainly responsible for inflammatory chronic diarrhea. This disruption can lead to exudative, secretory, or malabsorptive components of inflammatory chronic diarrhea.

• Inflammatory causes of chronic diarrhea might present with features that suggest malabsorption or rectal bleeding.
• The nature of the malabsorption depends on the regions affected (e.g., proximal vs. distal small bowel), and rectal bleeding is usually a manifestation of colonic or rectal ulcerations.
• Anti-inflammatory agents, including bismuth subsalicylate or other, more potent anti-inflammatory medications, appear to benefit patients with microscopic or collagenous colitis.^[5]

Both rapid transit time and slow transit time are associated with motility disorders causing chronic diarrhea.

• Rapid transit time delivers fluid secreted during digestion to the distal small bowel or colon. This prevents reabsorption of normally secreted fluid in the small bowel, overwhelming the re-absorptive capacity of the colon.
• Slow transit time results in bacterial overgrowth with bile acid deconjugation, poor micelle formation, and steatorrhea.
• The clinical manifestations of chronic diarrhea caused by motility disorders include steatorrhea, usually up to 14 g per day.
• Osmotic laxatives result in acceleration of transit through the bowel, which is associated with up to 14 g of fat in the stool.
• Presence of more than 14 g per day of fat in the stool suggests the presence of bacterial overgrowth or associated disease such as celiac disease.^[6]

After abdominal surgeries such as cholecystectomy, about 5%–10% of patients develop chronic diarrhea.

• Most of these cases resolve completely or significantly improve within a couple of months.
• Iatrogenic diarrhea is related to excessive bile acids being delivered into the intestine.^[7][8]
• After a cholecystectomy, bile is delivered directly into the small bowel, overcoming the terminal ileum‘s ability to reabsorb adequately, leading to cholerheic diarrhea.
• Some other iatrogenic causes of chronic diarrhea might result from vagal injury and ileal resection.

For the details of the genetics, associated conditions, gross and microscopic pathology of the following causes of chronic diarrhea, click the links below.

• Ulcerative colitis
• Crohn’s disease
• Lactose intolerance
• Celiac disease
• Chronic pancreatitis
• Cholera
• Microsporidiosis
• Giardiasis
• Cryptosporidiosis
• Hyperthyroidism

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Omodamola Aje B.Sc, M.D. [2] Anum Ijaz M.B.B.S., M.D.[3]

Depending on the socioeconomic status of the population, chronic diarrhea can be caused by several factors. In a developing nation, the most likely causes of chronic diarrhea are mycobacterial and parasitic infections, while functional disorders such as malabsorption and inflammatory bowel diseases are less likely causes. In a developed nation, however, the most likely causes of diarrhea are irritable bowel syndrome (IBS), inflammatory bowel disease, malabsorption syndromes (such as lactose intolerance and celiac disease), and chronic infections (particularly in patients who are immunocompromised).

There are no life-threatening causes of chronic diarrhea; however, complications resulting from untreated chronic diarrhea are common.

In patients presenting with chronic diarrhea, the most frequent noninfectious causes include a mix of functional and organic disorders. Together, Functional diarrhea and Irritable Bowel Syndrome with Diarrhea (IBS-D) account for approximately 35% of cases.Other significant contributors include Lactase deficiency: 35% ^[1], Bile acid diarrhea: 25%–33%,^[2], Celiac disease: 12% ^[3].

There following are some of the common causes of chronic diarrhea:^{[4][5][6][7][8]}

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To review the differential diagnosis of diarrhea, click here.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sadaf Sharfaei M.D.[2], Seyedmahdi Pahlavani, M.D. [3]

The differential diagnosis for chronic diarrhea is enormous, with a large number of diagnostic tests available that can be used to evaluate these patients. Classifying a patient’s chronic diarrhea into a subcategory such as watery, fatty and inflammatory helps to direct the diagnostic work-up. Some watery causes of chronic diarrhea which should be differentiated from one another include crohn’s disease, hyperthyroidism, VIPoma, lactose intolerance, celiac disease and irritable bowel syndrome (IBS). The causes of fatty diarrhea that should be differentiated from one another include celiac sprue, pancreatic insufficiency, bacterial overgrowth and maldigestion problems which results from pancreatic exocrine insufficiency. Finally, the inflammatory causes of chronic diarrhea such as ulcerative colitis and entamoeba histolytica must also be differentiated.

The following table outlines the major differential diagnoses of chronic diarrhea.^{[1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30]}

Abbreviations: GI: Gastrointestinal, CBC: Complete blood count, WBC: White blood cell, RBC: Red blood cell, Plt: Platelet, Hgb: Hemoglobin, ESR: Erythrocyte sedimentation rate, CRP: C–reactive protein, IgE: Immunoglobulin E, IgA: Immunoglobulin A, ETEC: Escherichia coli enteritis, EPEC: Enteropathogenic Escherichia coli, EIEC: Enteroinvasive Escherichia coli, EHEC: Enterohemorrhagic Escherichia coli, EAEC: Enteroaggregative Escherichia coli, Nl: Normal, ASCA: Anti saccharomyces cerevisiae antibodies, ANCA: Anti–neutrophil cytoplasmic antibody, DNA: Deoxyribonucleic acid, CFTR: Cystic fibrosis transmembrane conductance regulator, SLC10A2: Solute carrier family 10 member 2, SeHCAT: Selenium homocholic acid taurine or tauroselcholic acid, IEL: Intraepithelial lymphocytes, MRCP: Magnetic resonance cholangiopancreatography, ANA: Antinuclear antibodies, AMA: Anti-mitochondrial antibody, LDH: Lactate dehydrogenase, CPK: Creatine phosphokinase, PCR: Polymerase chain reaction, ELISA: Enzyme–linked immunosorbent assay, LT: Heat–labile enterotoxin, ST: Heat–stable enterotoxin, RT-PCR: Reverse–transcriptase polymerase chain reaction, CD4: Cluster of differentiation 4, HIV: Human immunodeficiency virus, RUQ: Right-upper quadrant, VIP: Vasoactive intestinal peptide, GI: Gastrointestinal, FAP: Familial adenomatous polyposis, HNPCC: Hereditary nonpolyposis colorectal cancer, MTP: Microsomal triglyceride transfer protein, Scl‑70: Anti–topoisomerase I, TSH: Thyroid-stimulating hormone, T4: Thyroxine, T3: Triiodothyronine, DTR: Deep tendon reflex, RNA: Ribonucleic acid

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Omodamola Aje B.Sc, M.D. [2]

The prevalence of chronic diarrhea is estimated to be about 300-500 per 100,000 persons. In any given year, about 3–5% of the population has diarrhea lasting more than 1 month.

In developed countries, the prevalence of chronic diarrhea is estimated to be about 300-500 per 100,000 persons.^[1][2][3]

For details about prevalence, incidence, age, and sex distribution of some of the causes of chronic diarrhea, click the links below:

• Ulcerative colitis
• Crohn’s disease
• Lactose intolerance
• Endocrine disorders such as hyperthyroidism
• Neuroendocrine tumors such as VIPoma
• Celiac disease
• Irritable bowel syndrome
• Giardiasis
• Tropical sprue
• Diverticulitis
• Clostridium difficile infection
• Ulcerating viral infections such as cytomegalovirus infection
• Invasive bacterial infections such as tuberculosis
• Neoplasias such as colorectal carcinoma

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Omodamola Aje B.Sc, M.D. [2]

The risk factors of chronic diarrhea can be assessed based on the epidemiologic associations and the patient’s characteristics. Some of these factors can be classified based on travel history, epidemics and outbreaks, diabetic patients, patients with acquired immune deficiency syndrome and whether the patients are institutionalized or hospitalized.

The risk factors for chronic diarrhea include^[1]

• Travel^[2]
  • Bacterial infection (mostly acute)
  • Protozoal infections (eg, amebiasis, giardiasis)
  • Tropical sprue
• Genetics
  • Mutations in certain genes are associated with chronic diarrhea in inflammatory bowel diseases.

• Epidemics and outbreaks
  • Bacterial infection
  • Epidemic idiopathic secretory diarrhea (eg, Brainerd diarrhea)
  • Protozoal infection (eg, cryptosporidiosis)
  • Viral infection (eg, rotavirus)
• Diabetic patients
  • Altered motility (increased or decreased)
  • Pancreatic exocrine insufficiency
  • Small Intestinal Bowel Obstruction
  • Drugs (especially acarbose, metformin)
• Patients with acquired immunodeficiency syndrome
  • Drug side effects
  • Lymphoma
  • Opportunistic infections (eg, cryptosporidiosis, cytomegalovirus, herpesvirus, Mycobacterium avium complex)
• Institutionalized and hospitalized patients
  • Clostridium difficile infection
  • Fecal impaction with overflow diarrhea
  • Ischemic colitis
  • Parenteral nutrition

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Omodamola Aje B.Sc, M.D. [2]

According to the USPSTF, screening for chronic diarrhea is not recommended.

According to the USPSTF, screening for chronic diarrhea is not recommended.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Omodamola Aje B.Sc, M.D. [2]

If left untreated, patients with chronic diarrhea may progress to develop symptoms of altered consciousness due to electrolyte imbalance, dehydration, and malnutrition. Common complications of chronic diarrhea include confusion, perforated bowels, sepsis, and death. Prognosis is generally good when the underlying cause is identified and treated early.

Without treatment, the patient will develop symptoms of dehydration, malnutrition, altered mental status, sepsis, and eventually coma or death.

Complications that can develop as a result of chronic diarrhea are:

• Dehydration
• Malnutrition
• Electrolyte disturbance

The prognosis of chronic diarrhea is good especially when the underlying cause is identified early and treated. The presence of these features in a patient complaining of diarrhea for over 4 weeks may indicate poor prognosis:^{[1][2][3][4][5]}

• Dietary causes of diarrhea
• Rectal bleeding
• Weight loss
• Age > 50 years
• Pain
• Associated psychological factors
• Somatization

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