Chronic diarrhea differential diagnosis

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Case #1

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

Overview

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 the patient with chronic diarrhea into a subcategory helps to direct the diagnostic work-up.

Differential diagnosis

It is important to differentiate chronic diarrhea based on the kind of diarrhea that is produced. Chronic diarrhea can be subdivided into three major types; watery, fatty, inflammatory. Watery chronic diarrhea can then further be sub-divided into osmotic or secretory diarrhea. Below is a list of differential diagnosis of chronic diarrhea by stool characteristics.

• The stool osmotic gap is a calculation performed to distinguish among different causes of diarrhea.
• 290 − 2 * (stool Na + stool K)
• A low stool osmolic gap can imply secretory diarrhea, while a high gap can imply osmotic diarrhea.

Adults with chronic diarrhea (> 4 weeks)

Characterize the symptoms: ❑ Onset (congenital, abrupt or gradual) ❑ Pattern (continuous or intermittent) ❑ Duration ❑ Stool characteristics (watery, bloody or fatty) ❑ Fever ❑ Abdominal pain ❑ Weight loss ❑ Fecal incontinence Obtain a detailed history: ❑ Aggravating factors (diet or stress) ❑ Over-the-counter drugs or use of prescription ❑ Previous evaluations (objective records, radiograms or biopsy specimens) ❑ Radiation therapy or surgery ❑ Factitious diarrhea (eating disorders, laxative ingestion, secondary gain or malingering) ❑ Systemic disease (cancer, diabetes, HIV, hyperthyroidism) Elicit the epidemiological factors: ❑ Travel before the onset of illness ❑ Exposure to contaminated food or water ❑ Illness in other family members

Examine the patient: Assess the volume status: ❑ General condition ❑ Thirst ❑ Pulse ❑ Blood pressure ❑ Eyes ❑ Mucosa Perform a general physical exam: ❑ Skin (flushing, rashes or dermatographism) ❑ Oral cavity (ulcers) ❑ Cardiovascular system (murmur) ❑ Respiratory system (wheezing) ❑ Thyroid (mass) ❑ Abdomen (ascites, hepatomegaly, mass or tenderness) ❑ Anorectal (Abscess, blood, fistula or sphincter competence) ❑ Extremities (edema)

Order routine laboratory tests: ❑ CBC and differential ❑ ESR ❑ Serum electrolytes ❑ Total serum protein and albumin ❑ Thyroid function tests ❑ Urinalysis

Start altered diet: ❑ Stop lactose products ❑ Avoid alcohol and high osmolar supplements ❑ Drink 8-10 large glasses of clear fluids (fruit juices, soft drinks etc) ❑ Eat frequent small meals (rice, potato, banana, pastas etc) ❑ Start oral rehydration therapy or intravenous fluids depending on the hydration status

Any specific obvious diagnosis through history and examination?

Yes

No

Chronic infection (outbreaks or endemic areas) ❑ Trial of oral metronidazole 500 mg TID for 5 days for protozoal diarrhea ❑ Oral ciprofloxacin 500 mg BD X 3 days for enteric bacterial diarrhea Medication induced: ❑ Discontinuation of the drug Irritable bowel syndrome (chronic abdominal pain and altered bowel habits in the absence of any organic disorder) ❑ Trial of antispasmodic agents (oral dicyclomine 20 mg QID),OR ❑ TCA's(amitriptyline 10-25 mg OD), OR ❑ SSRI (fluoxetine 20-40 mg OD), OR ❑ Rifaximin

No resolution of the diarrhea

Order stool analysis: ❑ Stool weight ❑ Stool electrolytes and fecal osmotic gap ❑ Stool pH ❑ Fecal occult blood testing ❑ Stool WBC's ❑ Stool fat: Quantitative / Sudan stain ❑ Laxative screen

This management is as per the American Gastroenterological Association guidelines for the evaluation and management of chronic diarrhea.

Additional Management

❑ Classify diarrhea by the results of the stool analysis:

Stool osmotic gap >50 mOsm/kg

Stool osmotic gap <50 mOsm/kg

Fecal occult blood (+), WBC (+), lactoferrin (+), calprotectin(+)

Fecal fat (+)

Osmotic diarrhea

Secretory diarrhea

Inflammatory diarrhea

Fatty diarrhea

❑ Check the pH of the stool

Low pH ❑ Evaluate for carbohydrate malabsorption

High pH ❑ Evaluate for ingestion of magnesium or antacids ❑ Evaluate for laxative abuse

1. Exclude infection by any/combination of the following tests: ❑ Stool culture ❑ Microscopic evaluation for ova and parasites ❑ Stool antigen test for Giardia ❑ Small bowel aspirate or breath H2 test to rule out bacterial overgrowth

1. Exclude structural disease by any/combination of the following tests: ❑ Small bowel radiographs ❑ Sigmoidoscopy or colonoscopy with biopsy ❑ CT abdomen ❑ UGI scopy and small bowel biopsy

1. Exclude structural disease by any/combination of the following tests ❑ Small bowel radiographs ❑ CT abdomen ❑ Small bowel biopsy and aspirate for quantitative culture

❑ Take a careful dietary history ❑ Order breath H2 test (lactose), OR ❑ Order lactase measurement in a mucosal biopsy

❑ Order stool alkanization test ❑ Order chromatographic and chemical tests

2. Exclude structural disease by any/combination of the following tests: ❑ Small bowel radiographs ❑ Sigmoidoscopy or colonoscopy with biopsy ❑ CT abdomen ❑ Biopsy of the proximal small bowel mucosa

2. Exclude infection by any/combination of the following tests: ❑ Stool culture: Standard Aeromonas, Plesiomonas, Tuberculosis etc ❑ Stool for ova and parasites ❑ Clostridium toxin assay ❑ Other specific test (Serology, ELISA, immunofluorescence to rule out virus and parasites)

2. Exclude exocrine pancreatic insufficieny by any/combination of the following tests: ❑ Secretin test ❑ Stool chymotrypsin activity ❑ Bentiromide test ❑ Others (D-xylose absorption tests / Schilling test)

3. Order selective testing: ❑ Cholestyramine test for bile acid diarrhea ❑ Plasma peptides (Gastrin, calcitonin, vasoactive intestinal polypeptide or somatostatin) ❑ Urine (5-hydroxyindole acetic acid, metanephrine or histamine) ❑ Others (TSH, ACTH stimulation test, serum protein electrophoresis or serum immunoglobulins)

Confirmatory diagnosis

Yes

No

Specific treatment per results and symptomatic treatment

No response

Administer empirical therapy ❑ Adequate hydration ❑ Opiates or octreotide

Watery

• Secretory (often nocturnal; unrelated to food intake; fecal osmotic gap < 50 mOsm per kg*)
  • Alcoholism
  • Bacterial enterotoxins (e.g., cholera)
  • Bile acid malabsorption
  • Brainerd diarrhea (epidemic secretory diarrhea)
  • Congenital syndromes
  • Crohn disease (early ileocolitis)
  • Endocrine disorders e.g., hyperthyroidism
  • Medications (see causes section)
  • Microscopic colitis (lymphocytic and collagenous subtypes)
  • Neuroendocrine tumors (e.g., gastrinoma, vipoma, carcinoid tumors, mastocytosis)
  • Nonosmotic laxatives (e.g., senna, docusate sodium)
  • Postsurgical (e.g., cholecystectomy, gastrectomy, vagotomy, intestinal resection)
  • Vasculitis
• Osmotic (fecal osmotic gap > 50 mOsm per kg*)
  • Carbohydrate malabsorption syndromes (e.g., lactose, fructose)
  • Celiac disease
  • Osmotic laxatives and antacids (e.g., magnesium, phosphate, sulfate)
  • Sugar alcohols (e.g., mannitol, sorbitol, xylitol)
• Functional (distinguished from secretory types by hypermotility, smaller volumes, and improvement at night and with fasting)
  • Irritable bowel syndrome

Table showing watery causes of chronic diarrhea (Table 1)

Cause			Osmotic gap		History	Physical exam	Gold standard	Treatment
			< 50 mOsm per kg	> 50 mOsm per kg*
Watery	Secretory	Crohns	+	-	Abdominal pain followed by diarrhea	Abdominal tenderness when palpated in severe disease Blood seen on rectal exam Fever Tachycardia Hypotension	Colonoscopy with biopsy	Topical mucosamine and corticosteroids are prefferd Mesalamine and sulfasalazine are used for remission
		Hyperthyroidism	+	-	Excessive sweating Heat intolerance Increased bowel movements	Lump in the neck Proptosis Tremors Increased DTR	TSH with T3 and T4	Carbimazole and methimazole Beta blockers like propylthiouracil Iodine-131
		VIPoma	+	-	Watery diarrhea Dehydration (thirst, dry skin, dry mouth, tiredness, headaches, and dizziness) Lethargy, muscle weakness Nausea, vomiting Crampy abdominal pain Weight loss Flushing	Tachycardia Rash Facial flushing Abdominal distention Abdominal tenderness in the right upper abdominal quadrant	Elevated VIP levels Followed by imaging	Sandostatin or chemotherapy for malignant tumors Surgical removal of the tumor
	Osmotic	Lactose intolerance	-	+	Abdominal pain Bloating Diarrhea Flatulence	Abdominal tenderness	Intestinal biopsy	Avoidance of dietary lactose Substitution to maintain nutrient intake Regulation of calcium intake Use of enzyme lactase
		Celiac disease	-	+	May be asymptomatic Vague abdominal pain Diarrhea Weight loss Malabsorption / steatorrhea Bloatedness	Abdominal pain and cramping Abdominal distention Tetany Mouth ulcers Dermatitis herpetiformis Signs of the fat-soluble vitamins A, D, E, and K deficiency	IgA tissue transglutaminase Ab	Gluten-free diet
	Functional	Irritable bowel syndrome	-	-	Abdominal pain or discomfort recurring at least 3 days per month in the past 3 months and associated with 2 or more of the following: Improves with defecation Onset associated with change in frequency of stool Onset associated with change in appearance of stool 25% of bowel movements are loose stools History of straining is also common	Abdominal tenderness Hard stool in the rectal vault	Clinical diagnosis ROME III criteria Pharmacologic studies based criteria	High dietary fiber Osmotic laxatives such as polyethylene glycol, sorbitol, and lactulose Antispasmodic drugs (e.g. anticholinergics such as hyoscyamine or dicyclomine)

Fatty (bloating and steatorrhea in many, but not all cases)

• Malabsorption syndrome (damage to or loss of absorptive ability)
  • Amyloidosis
  • Carbohydrate malabsorption (e.g., lactose intolerance)
  • Celiac sprue (gluten enteropathy)–various clinical presentations
  • Gastric bypass
  • Lymphatic damage (e.g., congestive heart failure, some lymphomas)
  • Medications (e.g., orlistat Xenical; inhibits fat absorption, acarbose Precose; inhibits carbohydrate absorption])
  • Mesenteric ischemia
  • Noninvasive small bowel parasite (e.g., Giardia)
  • Post-resection diarrhea
  • Short bowel syndrome
  • Small bowel bacterial overgrowth (> 105 bacteria per mL)
  • Tropical sprue
  • Whipple disease (Tropheryma whippelii infection)
• Maldigestion (loss of digestive function)
  • Hepato-biliary disorders
  • Inadequate luminal bile acid
  • Loss of regulated gastric emptying
  • Pancreatic exocrine insufficiency

Table showing fatty causes of chronic diarrhea ( Table 2)

Cause	Osmotic gap		History	Physical exam	Gold standard	Treatment
	< 50 mOsm per kg	> 50 mOsm per kg*
lactose intolerance	-	+	Bloating, Flatulence Abdominal pain, and/or chronic diarrhea after ingestion of lactose	Abdominal tenderness when palpated in severe disease Fever Hypotension Tachycardia Nausea and vomitting	Lactose breath hydrogen test	Restriction of lactose and maintain calcium and vitamin D intake.
Celiac sprue	-	+	Diarrhea with bulky, foul-smelling stools Growth failure in children, Weight loss, Anemia, Neurologic disorders Osteopenia	Neuropsychiatric disease Dermatitis herpetiformis Arthritis Iron deficiency Metabolic bone disease Hyposplenism Kidney disease Idiopathic pulmonary hemosiderosis	Immunoglobulin A (IgA) anti-tissue transglutaminase (TTG) antibody followed by upper ebdoscopy with biopsy.	Dietary counseling, elimination of gluten in the diet.
Whipple disease	-	+	Arthralgias Weight loss Diarrhea Abdominal pain	Leukocytopenia Thrombocytopenia Skin hyperpigmentation	Upper endoscopy with biopsies of the small intestine for T. whipplei testing (histology with PAS staining, polymerase chain reaction [PCR] testing, and immunohistochemistry)	Doxycycline and hydroxychloroquine was bactericidal

Inflammatory or exudative (elevated white blood cell count, occult or frank blood or pus)

• Inflammatory bowel disease Crohn disease (ileal or early Crohn disease may be secretory)
  • Diverticulitis
  • Ulcerative colitis
  • Ulcerative jejunoileitis
• Invasive infectious diseases
  • Clostridium difficile (pseudomembranous) colitis–antibiotic history
  • Invasive bacterial infections (e.g., tuberculosis, yersiniosis)
  • Invasive parasitic infections (e.g., Entamoeba)–travel history
  • Ulcerating viral infections (e.g., cytomegalovirus, herpes simplex virus)
• Neoplasia
  • Colon carcinoma
  • Lymphoma
  • Villous adenocarcinoma
• Radiation colitis

Table showing inflammatory causes of chronic diarrhea ( Table 3)

Cause	History	Laboratory findings	Diagnosis	Treatment
Diverticulitis	Bloody diarrhea Left lower quadrant abdominal pain Abdominal tenderness on physical examination Low grade fever	Leukocytosis Elevated serum amylase and lipase Sterile pyuria on urinalysis	Abdominal CT scan with oral and intravenous (IV) contrast	bowel rest, IV fluid resuscitation, and broad-spectrum antimicrobial therapy which covers anaerobic bacteria and gram-negative rods
Ulcerative colitis	Diarrhea mixed with blood and mucus, of gradual onset. Signs of weight loss Rectal urgency Tenesmus Blood is often noticed on underwear Different degrees of abdominal pain	Anemia Thrombocytosis A high platelet count Elvated ESR (>30mm/hr) Low albumin	Endoscopy	Induction of remission with mesalamine and corticosteroids followed by the administration of sulfasalazine and 6-Mercaptopurine depending on the severity of the disease. See ...
Entamoeba histolytica	Abdominal cramps Diarrhea Passage of 3 - 8 semiformed stools per day Passage of soft stools with mucus and occasional blood Fatigue Intestinal gas (excessive flatus) Rectal pain while having a bowel movement (tenesmus) Unintentional weight loss	cysts shed with the stool	detects ameba DNA in feces	Amebic dysentery ; Metronidazole 500-750mg three times a day for 5-10 days Tinidazole 2g once a day for 3 days is an alternative to metronidazole Luminal amebicides for E. histolytica in the colon: Paromomycin 500mg three times a day for 10 days Diloxanide furoate 500mg three times a day for 10 days Iodoquinol 650mg three times a day for 20 days For amebic liver abscess: Metronidazole 400mg three times a day for 10 days Tinidazole 2g once a day for 6 days is an alternative to metronidazole Diloxanide furoate 500mg three times a day for 10 days must always be given afterwards.

References

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