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: Sadaf Sharfaei 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 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.

Differential Diagnosis of Chronic Diarrhea of other diseases

The following table outlines the major differential diagnoses of chronic diarrhea.

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

Cause		Clinical manifestation									Lab findings									Extra intestinal findings	Cause/Pathogenesis	Gold standard diagnosis
		Symptoms								GI signs
		Duration		Diarrhea			Fever	Abdominal pain	Weight loss
											Stool exam					CBC			Other lab findings
		Acute	Chronic	Watery	Bloody	Fatty					WBC	RBC	Ova/Parasite	Osmotic gap	Other	WBC	Hgb	Plt
Crohn's disease		–	+	+	+	+	±	+	+	Abdominal tenderness Oral mucosal lesions	+	+	–	Nl	–	↑	↓	↑	Anti saccharomyces cerevisiae antibodies (ASCA) Vitamin B12 deficiency Elevated ESR Elevated CRP	Uveitis Arthritis Erythema nodosum Pyoderma gangrenosum Amyloidosis Venous and arterial thromboembolism Renal stones Bronchiectasis	Abnormal immune response to self antigens	Colonoscopy with biopsy
Ulcerative colitis		–	+	+	+	+	±	+	+	Abdominal tenderness Blood on rectal examination	+	+	–	Nl	–	↑	↓	↑	Anti–neutrophil cytoplasmic antibody (P–ANCA) Hypoalbuminemia Hypokalemia Hypomagnesemia Elevated ESR Elevated CRP	Skin rash Iritis Uveitis Seronegative arthritis Clubbing Erythema nodosum	Abnormal immune response to self antigens	Colonoscopy with biopsy
Celiac disease		–	+	±	–	±	–	+	+	Abdominal distention Increased bowel sounds Oral mucosal lesions Hepatosplenomegaly Ascites	–	–	–	Nl	Fat droplets on sudan stain	Nl	↓	Nl	IgA endomysial antibody Anti–tissue transglutaminase antibody Anti–gliadin antibody Fat soluble vitamins deficiency	Malabsorption Dementia Dermatitis herpetiformis	HLA–DQ2 HLA–DQ8 Innate responses to wheat proteins	IgA endomysial antibody Anti–tissue transglutaminase antibody
Cystic fibrosis		–	+	–	–	+	±	+	+	Abdominal distention Hepatosplenomegaly Rectal prolapse	–	–	–	Nl	Fat droplets on sudan stain	Nl	↓	Nl	Positive DNA analysis for cystic fibrosis transmembrane conductance regulator (CFTR) Nasal transepithelial potential difference Fat soluble vitamins deficiency	Malabsorption Recurrent respiratory tract infection Bronchiectasis Diabetes mellitus Scoliosis Infertility	Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) protein	Positive genetic testing Elevated sweat chloride ≥60 mmol/L
Chronic pancreatitis		–	+	+	–	+	–	+	+	Abdominal tenderness	–	–	–	Nl	Fat droplets on sudan stain Positive fecal elastase measurement	Nl	Nl	Nl	Slightly elevated amylase and lipase Abnormal pancreatic function test Secretin stimulation test	Malabsorption Diabetes mellitus Pancreatic pseudocyst	Toxins Recurrent acute pancreatitis Genetic predesposition Autoimmune	Magnetic resonance cholangiopancreatography (MRCP)
Bile acid malabsorption		–	+	+	–	+	–	–	+		–	–	–	Nl	Fat droplets on sudan stain	Nl	Nl	Nl	Reduced cholesterol level	Malabsorption Hypotension Tachycardia	Genetic defects in SLC10A2	SeHCAT test
Microscopic colitis		–	+	+	–	–	–	+	+	Abdominal tenderness Fecal incontinence	–	–	–	Nl	–	Nl	↓	Nl	Hypokalemia Elevated CRP Positive autoantibodies include: RF ANA AMA ANCA	Arthritis Uveitis Idiopathic thrombocytopenic purpura Pleuro pericarditis Hypothyroidism Psoriasis	Mucosal immune responses to luminal factors in a genetically predisposed individual Drug–induced	Colonoscopy with mucosal biopsy with mononuclear infiltrates: Collagenous colitis is characterized by a colonic subepithelial collagen band >10 micrometers in diameter Lymphocytic colitis is characterized by ≥20 intraepithelial lymphocytes (IEL) per 100 surface epithelial cells
Infective colitis		–	+	+	+	–	+	+	+	Rebound abdominal tenderness	+	+	+	Nl	Positive stool culture Positive fecal calprotectin Positive fecal lactoferrin	↑	↓	↑	Elevated CRP Elevated ESR	Arthritis Uveitis	Salmonella Shigella Campylobacter E. coli 0157:H7 Clostridium difficile Entamoeba histolytica Adenovirus Cytomegalovirus Herpes simplex virus	Stool culture Blood culture
Ischemic colitis		+	+	+	+	–	+	+	+	Hyperactive then absent bowel sounds Abdominal tenderness	+	+	–	Nl	–	↑	↓	↑	Elevated CRP Elevated ESR Elevated serum lactate Elevated lactate dehydrogenase (LDH)  Elevated creatine phosphokinase (CPK) Elevated amylase Hypoalbuminemia	IgA vasculitis	Hypercoagulability  Nonocclusive colonic ischemia Embolic and thrombotic arterial occlusion Mesenteric vein thrombosis	Abdominal CT scan
Lactose intolerance		+	+	+	–	–	–	+	–	Abdominal tenderness Abdominal distention	–	–	–	↑	–	Nl	Nl	Nl	Lactose tolerance test Genetic testing	Headache Vertigo Memory impairment Lethargy	Reduction of lactase enzyme activity or inability to produce persistent lactase Congenital lactase deficiency Secondary lactose malabsorption	Small bowel biopsy  Lactose breath hydrogen test
Irritable bowel syndrome		–	+	±	–	±	–	±	–	Abdominal tenderness Abdominal distention Normal bowel sounds	–	–	–	Nl	–	Nl	Nl	Nl	Nl	Anxiety Palpitation	Unknown	Diagnosis of exclusion
Whipple's disease		–	+	+	–	+	±	+	+	Hepatosplenomegaly Ascites	–	–	–	Nl	Positive fecal fat	↓	↓	↓/↑	Hypoalbuminemia Fat soluble vitamins deficiency	Malabsorption Abnormal extraocular movement Lymphadenopathy Hyperpigmentation Uveitis Endocarditis Encephalitis Dementia Pleural effusion	Tropheryma whipplei	Small intestine biopsy for Tropheryma whipplei testing PCR testing
Tropical sprue		+	+	+	–	+	+	+	+	Angular stomatitis Oral mucosal lesion	+	–	–	Nl	Positive stool culture	Nl	↓	Nl	Fat soluble vitamins deficiency Vitamin B12 deficiency Folate deficiency Hypokalemia	Myalgia Neuropathy Edema	Escherichia coli Klebsiella pneumoniae Enterobacter cloacae	Diagnosis of exclusion
Small bowel bacterial overgrowth		–	+	+	–	+	–	+	+	Abdominal distention	+	–	–	Nl	Positive stool culture Positive fecal fat	Nl	↓	Nl	Hypoalbuminemia Abnormal hydrogen breath test Lactic acidosis	Malabsorption Rosacea	Excess bacteria in the small intestine Alterations in intestinal anatomy or GI motility	Diagnosis of exclusion
Salmonellosis		+	+	+	+	–	+	+	–	Abdominal distention Diffuse abdominal tenderness Hepatosplenomegaly	+	+	–	Nl	Positive stool culture Positive serologic testing	↑	Nl	↑	Hypokalemia Hypernatremia Hyponatremia Hypercalciuria Hypocitraturia	Post–infectious arthritis Obtundation Bacteremia Pericarditis Pyelonephritis Brain abscess	Salmonella	Stool culture
Escherichia coli enteritis	EPEC	+	+	+	+	–	+	+	+	Diffuse abdominal tenderness	+	+	–	Nl	Positive stool culture	↑	Nl	Nl	–	–	Enteropathogenic E. coli	DNA probe or polymerase chain reaction (PCR) of the EPEC adherence factor Stool culture
	EAEC	+	+	+	+	–	–	+	–	Diffuse abdominal tenderness	+	+	–	Nl	Positive stool culture	↑	↓	↓	–	Chronic infection in immunocompromised patients	Enteroaggregative E. coli	Stool culture
Aeromonas		+	+	+	+	–	+	+	–	Abdominal distention Hyperactive bowel sounds Diffuse abdominal tenderness	+	+	–	Nl	Positive stool culture	↑	Nl	Nl	–	Wound infection Bacteremia Hemolytic uremic syndrome  Meningitis Ocular infection Pneumonia  Urinary tract infection Osteomyelitis Peritonitis Acute cholecystitis Opportunistic infections in immunocompromised patients	Aeromonas virulence factors including endotoxins, hemolysins, enterotoxins, and adherence factors	Blood culture Wound culture
Mycobacterium avium complex		+	+	+	+	–	+	+	–	Abdominal distention Hepatosplenomegaly	+	+	–	Nl	–	↓	↓	Nl	Elevated liver enzymes	Opportunistic infection in immunocompromised patients Pulmonary infection Adenopathy  Night sweats	Mycobacterium avium complex	Blood culture
CMV colitis		+	+	–	+	–	±	+	–	Diffuse abdominal tenderness	+	+	–	Nl	Viral antigen assay	↓	Nl	Nl	Decreased CD4 level Abnormal liver function test	Encephalitis  Guillain–Barré syndrome Pneumonia  Retinitis Pericarditis and myocarditis Atherosclerosis  Venous thrombosis	Cytomegalovirus	Quantitative PCR tests
HIV		–	+	+	–	–	+	+	+	Abdominal distention Diffuse abdominal tenderness	+	–	–	Nl	–	↓	↓	Nl	Decreased CD4 level Electrolyte imbalance	Lymphadenopathy Disseminated infection	HIV	HIV virologic (viral load) test Immunoassay
Entamoeba histolytica		+	+	+	+	–	+	+	–	Abdominal distention Diffuse abdominal tenderness	+	+	+	Nl	–	↑	Nl	Nl	–	Liver abscess Pleuropulmonary infection Cardiac infection Brain abscess Cutaneous infection	Entamoeba histolytica	Antigen testing Serology
Giardia		–	+	+	–	+	–	+	+	Abdominal distention Diffuse abdominal tenderness	–	–	+	Nl	–	Nl	Nl	Nl	–	Malabsorption Urticaria Depression	Giardia lamblia	Antigen detection assays
Cryptosporidium		–	+	+	–	–	–	+	+	Abdominal distention Diffuse abdominal tenderness	–	–	+	Nl	Positive stool microscopy	Nl	Nl	Nl	Elevated alkaline phosphatase	Chronic, life–threatening illness in immunocompromised patients	Cryptosporidium	Polymerase chain reaction
Microsporidia		+	+	+	–	–	+	+	–	Abdominal distention Diffuse abdominal tenderness	–	–	+	Nl	Positive stool microscopy	Nl	Nl	Nl	Decreased CD4 count	Malabsorption Keratitis  Seizure Myositis	Microsporidia	Antigen detection assays
Isospora		+	+	+	–	+	+	+	+	Abdominal distention Diffuse abdominal tenderness	+	+	+	Nl	Positive stool microscopy Positive fecal fat	↑	Nl	Nl	Elevated eosinophils  Hypokalemia Increased creatinine	Chronic illness in immunocompromised patients	Isospora	Detecting oocysts in the feces
Carcinoid tumor		–	+	+	+	–	–	+	+	Abdominal distention	–	+	–	↓	–	Nl	Nl	Nl	Elevated urinary 5–hydroxyindoleacetic acid (5–HIAA) level High chromogranin A	Facial flushing Jaundice Edema Valvular heart disease Right–sided heart failure	Well–differentiated neuroendocrine tumor	Blood chromogranin A level
VIPoma		+	+	+	–	+	–	+	+	Abdominal distention Abdominal RUQ tenderness Nausea Vomiting	–	–	–	↓	–	Nl	Nl	Nl	Elevated VIP level Hypokalemia Hypochlorhydria or achlorhydria Low osmotic gap (<50 mOsm/kg)	Rash Facial flushing Dehydration Lethargy Muscle weakness	Primary secretory tumor	Blood VIP levels Followed by imaging
Zollinger–Ellison syndrome		–	+	+	+	+	–	+	+	Epigastric tenderness	–	–	–	↓	–	Nl	↓	Nl	Positive secretin stimulation test Elevated serum chromogranin A	Jaundice	Gastrin producing tumor mainly in duodenum	Secretin stimulation test
Somatostatinoma		–	+	+	–	–	–	+	+	Epigastric tenderness	–	–	–	↓	–	Nl	Nl	Nl	Elevated fasting plasma somatostatin	Diabetes mellitus Cholelithiasis Jaundice	Neuroendocrine tumors of D–cell origin	Plasma somatostatin level Followed by imaging
Lymphoma		–	+	+	+	–	+	+	+	Diffuse abdominal tenderness Hepatosplenomegaly	–	+	–	Nl	–	Nl	↓	Nl	Paraproteinemia	Malabsorption Lactose intolerance Ascites	Primary tumor of GI tract	Colonoscopy with biopsy
Colorectal cancer		–	+	+	+	+	–	+	+	Diffuse abdominal tenderness	–	+	–	Nl	–	Nl	↓	Nl	Positive carcinoembryonic antigen	Metastasis	FAP gene HNPCC gene	Colonoscopy and biopsy
Medications ACE inhibitors Digoxin Cephalosporins Statins Thiazide diuretics Triptans Lactulose Anti retroviral agents Chemotherapeutic agents Antifungals Magnesium		+	+	+	–	±	±	+	+	Abdominal distention Dehydration	–	–	–	↑/↓	–	↑	Nl	Nl	Elevated plasma level of drug	–	Inflammation Pseudomembranous colitis	Clinical evaluation after discontinuation of the drugs
Factitious diarrhea		+	+	+	–	–	–	+	+	Abdominal distention	–	–	–	↑/↓	–	Nl	Nl	Nl	Hypokalemia  Metabolic alkalosis Hypermagnesemia	Malabsorption Lethargy Generalized weakness Acute renal failure	Medications	Clinical evaluation after discontinuation of the drugs
Heavy metal ingestion		–	+	+	–	–	–	+	+	Abdominal distention	–	–	–	Nl	–	Nl	Nl	Nl	Elevated plasma heavy metal level	Headache Numbness Alopecia Vertigo	Heavy metal ingestion	Plasma level of heavy metal
Organophosphate poisoning		+	+	+	–	–	–	+	–	Salivation Vomiting	–	–	–	Nl	–	Nl	Nl	Nl	Reduced RBC acetylcholinesterase Plasma cholinesterase activity	Autonomic dysfunction Motor deficit Sensory deficit Bronchospasm Urination Miosis Bradycardia Lacrimation Sweating Cardiac arrhythmias Acute renal injury	Neurotoxins bind to acetylcholinesterase (AChE)	Clinical diagnosis
Opium withdrawal		+	+	+	–	–	–	+	–	Hyperactive bowel sounds	–	–	–	Nl	–	Nl	Nl	Nl	Azotemia Hypokalemia Metabolic alkalosis	Dysphoria  Restlessness Sweating Rhinorrhea Lacrimation Myalgia Arthralgia	Opium withdrawal	Clinical diagnosis following opium withdrawal
Short bowel syndrome		+	+	+	–	+	–	–	+	Abdominal distention Abdominal tenderness	–	–	–	Nl	Positive fecal fat	Nl	↓	↑	Hypoalbuminemia High level of acute phase reactant Abnormal liver function tests	Prior intestinal surgery Malabsorption Crohn's disease Malignancy Peripheral edema Muscle atrophy	Surgical bowel resection	Clinical diagnosis following bowel resection
Radiation enteritis		+	+	+	+	+	–	+	+	Abdominal tenderness	+	+	–	Nl	Positive fecal fat	Nl	↓	Nl	Vitamin B12 deficiency Hypoalbuminemia	Prior history of malignancy and radiation therapy Malabsorption Telangiectasias	Radiation	Segmental bowel inflammation on endoscopy or colonoscopy
Dumping syndrome		–	+	+	–	+	–	–	+	Hyperactive bowel sound	–	–	–	Nl	–	Nl	Nl	Nl	Hypoglycemia Hydrogen breath test	Malnutrition Fat soluble vitamin deficiency	Postgastrectomy	Clinical diagnosis following gastrectomy
Abetalipoproteinemia		–	+	+	–	+	–	+	+	Abdominal distension	–	–	–	Nl	–	Nl	Nl	Nl	Low triglyceride Low total cholesterol levels  Acanthocytes Low vitamin E levels	Ataxia Visual field defect Dysarthria	Autosomal recessive disorder caused by mutations encoding the microsomal triglyceride transfer protein (MTP)	Clinical findings and low triglyceride and cholesterol level
Hyperthyroidism		–	+	+	–	–	±	+	+	–	–	–	–	Nl	Positive fecal fat	Nl	Nl	Nl	Elevated T4 Elevated T3 Decreased TSH High serum alkaline phosphatase	Lump in the neck Lid lag Malabsorption Sweating Hyperpigmentation Proptosis Tremor Increased DTR	Graves' disease Hashimoto's thyroiditis Toxic adenoma	TSH
Diabetic neuropathy		–	+	+	–	+	–	+	+	Fecal incontinence	–	–	–	Nl	Positive fecal fat	Nl	↓	Nl	Hyperglycemia Azotemia Hypokalemia	Malabsorption	Unclear Disordered motility Increased intestinal secretion Small intestinal bacterial overgrowth	Clinical diagnosis in a patient with long lasting diabetes mellitus
Systemic sclerosis		–	+	+	±	+	–	+	+	Epigastric tenderness Fecal incontinence	–	+	–	Nl	Positive fecal fat	Nl	↓	Nl	Anti–topoisomerase I (Scl‑70) antibodies Antinuclear antibodies (ANA) Anti–centromere antibodies Anti–RNA polymerase III antibody	Malabsorption Skin changes Raynaud phenomenon Pulmonary hypertension Arthritis Telangiectasia Chronic renal failure	Autoimmune reaction	Clinical diagnosis Followed by serologic tests