Crohn's disease differential diagnosis

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Overview

Crohn's disease should be differentiated from other causes of diarrhea. It is very important to differentiate it from ulcerative colitis as the management of both conditions is different though the initial presentation may be confused for any of these disorders.^[1]^[2]

Differentiating Crohn's Disease from other Diseases

Differentiating Crohn's Disease from ulcerative colitis

The most common disease that mimics the symptoms of Crohn's disease is ulcerative colitis, as both are inflammatory bowel diseases that can affect the colon with similar symptoms. It is important to differentiate these diseases, since the course of the diseases and treatments may be different. In some cases, however, it may not be possible to tell the difference, in which case the disease is classified as indeterminate colitis.^[1]^[2]^[3]^[4]^[5]^[6]

**Comparisons of various factors in Crohn's disease and ulcerative colitis**
	Crohn's disease	Ulcerative colitis
Terminal ileum involvement	Commonly	Seldom
Colon involvement	Usually	Always
Rectum involvement	Seldom	Usually^[7]
Involvement around the anus	Common^[8]	Seldom
Bile duct involvement	No increase in rate of primary sclerosing cholangitis	Higher rate^[9]
Distribution of Disease	Patchy areas of inflammation (Skip lesions)	Continuous area of inflammation^[7]
Endoscopy	Deep geographic and serpiginous (snake-like) ulcers	Continuous ulcer
Depth of inflammation	May be transmural, deep into tissues^[8]	Shallow, mucosal
Fistulae	Common^[8]	Seldom
Stenosis	Common	Seldom
Autoimmune disease	Widely regarded as an autoimmune disease	No consensus
Cytokine response	Associated with T_h1	Vaguely associated with T_h2
Granulomas on biopsy	Can have granulomas^[8]	Granulomas uncommon^[7]
Surgical cure	Often returns following removal of affected part	Usually cured by removal of colon
Smoking	Higher risk for smokers	Lower risk for smokers^[7]
Risk of Cancer	Lower than UC	Higher

Differentiating Crohn's from other causes of Gastroenteritis

Organism			Age predilection	Travel History	Incubation Size (cell)	Incubation Time	History and Symptoms			Diarrhea type∞				Food source	Specific consideration
Organism			Age predilection	Travel History	Incubation Size (cell)	Incubation Time	Fever	N/V	Cramping Abd Pain	Small Bowel	Large Bowel	Inflammatory	Non-inflammatory	Food source	Specific consideration
Viral	Rotavirus		<2 y	-	<10²	<48 h	+	+	-	+			+	-	Mostly in day cares, most common in winter.
	Norovirus		Any age	-	10 -10³	24-48 h	+	+	+	+			+	-	Most common cause of gastroenteritis, abdominal tenderness,
	Adenovirus		<2 y	-	10⁵ -10⁶	8-10 d	+	+	+	+			+	-	No seasonality
	Astrovirus		<5 y	-		72-96 h	+	+	+	+			+	Seafood	Mostly during winter
Bacterial	Escherichia coli	ETEC	Any age	+	10⁸ -10¹⁰	24 h	-	+	+	+			+	-	Causes travelers diarrhea, contains heat-labile toxins (LT) and heat-stable toxins (ST)
		EPEC	<1 y	-	10^†	6-12 h	-	+	+	+			+	Raw beef and chicken	-
		EIEC	Any ages	-	10^†	24 h	+	+	+		+		+	Hamburger meat and unpasteurized milk	Similar to shigellosis, can cause bloody diarrhea
		EHEC	Any ages	-	10	3-4 d	-	+	+		+	+		Undercooked or raw hamburger (ground beef)	Known as E. coli O157:H7, can cause HUS/TTP.
		EAEC	Any ages	+	10¹⁰	8-18 h	-	-	+		+		+	-	May cause prolonged or persistent diarrhea in children
	Salmonella sp.		Any ages	+	1	6 to 72 h	+	+	+		+	+		Meats, poultry, eggs, milk and dairy products, fish, shrimp, spices, yeast, coconut, sauces, freshly prepared salad.	Can cause salmonellosis or typhoid fever.
	Shigella sp.		Any ages	-	10 - 200	8-48 h	+	+	+		+	+		Raw foods, for example, lettuce, salads (potato, tuna, shrimp, macaroni, and chicken)	Some strains produce enterotoxin and Shiga toxin similar to those produced by E. coli O157:H7
	Campylobacter sp.		<5 y, 15-29 y	-	10⁴	2-5 d	+	+	+		+	+		Undercooked poultry products, unpasteurized milk and cheeses made from unpasteurized milk, vegetables, seafood and contaminated water.	May cause bacteremia, Guillain-Barré syndrome (GBS), hemolytic uremic syndrome (HUS) and recurrent colitis
	Yersinia enterocolitica		<10 y	-	10⁴ -10⁶	1-11 d	+	+	+		+	+		Meats (pork, beef, lamb, etc.), oysters, fish, crabs, and raw milk.	May cause reactive arthritis; glomerulonephritis; endocarditis; erythema nodosum. can mimic appendicitis and mesenteric lymphadenitis.
	Clostridium perfringens		Any ages		> 10⁶	16 h	-	-	+		+		+	Meats (especially beef and poultry), meat-containing products (e.g., gravies and stews), and Mexican foods.	Can survive high heat,
	Vibrio cholerae		Any ages	-	10⁶-10¹⁰	24-48 h	-	+	+	+			+	Seafoods, including molluscan shellfish (oysters, mussels, and clams), crab, lobster, shrimp, squid, and finfish.	Hypotension, tachycardia, decreased skin turgor. Rice-water stools
Parasites	Protozoa	Giardia lamblia	2-5 y	+	1 cyst	1-2 we	-	-	+	+			+	Contaminated water	May cause malabsorption syndrome and severe weight loss
		Entamoeba histolytica	4-11 y	+	<10 cysts	2-4 we	-	+	+		+	+		Contaminated water and raw foods	May cause intestinal amebiasis and amebic liver abscess
		Cryptosporidium parvum	Any ages	-	10-100 oocysts	7-10 d	+	+	+	+			+	Juices and milk	May cause copious diarrhea and dehydration in patients with AIDS especially with 180 > CD₄
		Cyclospora cayetanensis	Any ages	+	10-100 oocysts	7-10 d	-	+	+	+			+	Fresh produce, such as raspberries, basil, and several varieties of lettuce.	More common in rainy areas
	Helminths	Trichinella spp	Any ages	-	Two viable larvae (male and female)	1-4 we	-	+	+		+		+	Undercooked meats	More common in hunters or people who eat traditionally uncooked meats
		Taenia spp	Any ages	-	1 larva or egg	2-4 m	-	+	+	+			+	Undercooked beef and pork	Neurocysticercosis: Cysts located in the brain may be asymptomatic or seizures, increased intracranial pressure, headache.
		Diphyllobothrium latum	Any ages	-	1 larva	15 d	-	-	-	+			+	Raw or undercooked fish.	May cause vitamin B₁₂ deficiency

∞Small bowel diarrhea: watery, voluminous with less than 5 WBC/high power field

Large bowel diarrhea: Mucousy and/or bloody with less volume and more than 10 WBC/high power field
† It could be as high as 1000 based on patient's immunity system.

Cause			Osmotic gap		History	Physical exam	Gold standard	Treatment
Cause			< 50 mOsm per kg	> 50 mOsm per kg*	History	Physical exam	Gold standard	Treatment
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 preferred 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
	Osmotic	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)

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Differential Diagnosis

Crohn's disease must be differentiated from:^[10]^[11]^[12]^[13]^[14]^[15]^[16]^[17]^[18]

Disease	Cause	Symptoms									Diagnosis	Other findings
		Pain			Nausea & Vomiting	Heartburn	Belching or Bloating	Weight loss	Loss of Appetite	Stools	Endoscopy findings
		Location	Aggravating Factors	Alleviating Factors	Nausea & Vomiting	Heartburn	Belching or Bloating	Weight loss	Loss of Appetite	Stools	Endoscopy findings
Acute gastritis	H. pylori NSAIDS Corticosteroids Alcohol Spicy food Viral infections Crohn's disease Autoimmune diseases Bile reflux Cocaine use Breathing machine or ventilator Ingestion of corrosives	Epigastric pain	Food	Antacids	?	?	?	-	?	Black stools	Pangastritis or antral gastritis Erosive (Superficial, deep, hemorrhagic) Nonerosive (H. pylori)	-
Chronic gastritis	H. pylori Alcohol Medications Autoimmune diseases Chronic stress	Epigastric pain	Food	Antacids	?	?	?	?	?	-	H. pylori gastritis Atrophy Intestinal metaplasia Lymphocytic gastritis Enlarged folds Aphthoid erosions	-
Atrophic gastritis	H. pylori Autoimmune disease	Epigastric pain	-	-	?	-		?	?	-	H. pylori Mucosal atrophy Autoimmune Mucosal atrophy	Iron deficiency anemia Autoimmune gastritis diagnosis include: Antiparietal and anti-IF antibodies Achlorhydria and hypergastrinemia Low serum cobalamine
Crohn's disease	Autoimmune disease	Abdominal pain	-	-	-	-	-	?	?	Chronic diarrhea often bloody with pus or mucus Rectal bleeding	Mucosal nodularity with cobblestoning Multiple aphthous ulcers Linier or serpiginous ulcerations Thickened antral folds Antral narrowing Hypoperistalsis Duodenal strictures	Fever Fatigue Anemia (pernicious anemia)
GERD	Lower esophageal sphincter abnormalities Hiatal hernia Abnormal esophageal contractions Prolonged emptying of stomach Gastrinomas	Epigastric pain	Spicy food Tight fitting clothing	Antacids Head elevation during sleep	? (Suspect delayed gastric emptying)	?	-	-	-	-	Esophagitis Barrette esophagus Strictures	Other symptoms: Dysphagia Regurgitation Nocturnal cough Hoarseness Complications Esophagitis Strictures Barrette esophagus
Peptic ulcer disease	H. pylori Smoking Alcohol Radiation therapy Medications Zollinger-ellison syndrome	Epigastric pain sometimes extending to back Right upper quadrant pain	Duodenal ulcer Pain aggravates with empty stomach Gastric ulcer Pain aggravates with food	Antacids Duodenal ulcer Pain alleviates with food	?	?	-	-	-	Black stools	Gastric ulcers Discrete mucosal lesions with a punched-out smooth ulcer base with whitish fibrinoid base Most ulcers are at the junction of fundus and antrum 0.5-2.5cm Duodenal ulcers Well-demarcated break in the mucosa that may extend into the muscularis propria of the duodenum Found in the first part of duodenum <1cm	Other diagnostic tests Serum gastrin levels Secretin stimulation test Biopsy
Gastrinoma	Associated with MEN type 1	Abdominal pain	-	-	? (suspect gastric outlet obstruction)	?	-	-	-	Black stools	Useful in collecting the tissue for biopsy	May present with symptoms of GERD or peptic ulcer disease Associated with MEN type 1 Diagnostic tests Serum gastrin levels Somatostatin receptor scintigraphy CT and MRI
Gastric Adenocarcinoma	H. pylori infection Smoked and salted food	Abdominal pain	-	-	?	?	?	?	?	Black stools, or blood in stools	Esophagogastroduodenoscopy Multiple biopsies are taken to establish the diagnosis	Other symptoms Dysphagia Early satiety Frequent burping
Primary gastric lymphoma	H. pylori infection	Abdominal pain Chest pain	-	-	-	-	-	?	-	-	Useful in collecting the tissue for biopsy	Other symptoms Painless swollen lymph nodes in neck and armpit Night sweats Fatigue Fever Cough or trouble breathing

Oral Crohn's lesions must be differentiated from other diseases causing oral lesions such as leukoplakia and herpes simplex virus infection.

Disease	Presentation	Risk Factors	Diagnosis	Affected Organ Systems	Important features	Picture
Diseases predominantly affecting the oral cavity
Oral Candidiasis	Dysphagia or odynophagia White patches on the mouth and tongue	Newborn babies Denture users Poorly controlled diabetes As a side effect of medication, most commonly having taken antibiotics. Inhaled corticosteroids for the treatment of lung conditions (e.g, asthma or COPD) may also result in oral candidiasis which may be reduced by regularly rinsing the mouth with water after taking the medication. People with poor nutrition, specifically vitamin A, iron and folate deficiencies. People with an immune deficiency (e.g. as a result of AIDS/HIV or chemotherapy treatment). Women undergoing hormonal changes, like pregnancy or those on birth control pills. Organ transplantation patients	Clinical diagnosis Confirmatory tests rarely needed	Localized candidiasis Oral and esophageal candidasis Candida vulvovaginitis Chronic mucocutaneous candidiasis Invasive candidasis Candidaemia Candida endocarditis Candida osteoarticular disease	Oral candidiaisis is a benign self limiting disease unless accompanied by immunosuppression.	Tongue infected with oral candidiasis - By James Heilman, MD - Own work, CC BY-SA 3.0, httpscommons.wikimedia.orgwindex.phpcurid=11717223.jpg
Herpes simplex oral lesions	Fever Sore throat Painful ulcers	Stress Recent URTI Female sex	Physical examination Viral culture Tzanck smear	Orofacial Infection Anogenital Infection Ocular Infection Herpes Encephalitis Neonatal Herpes Herpetic Whitlow Herpes Gladiatorum	The symptoms of primary HSV infection generally resolve within two weeks	Oral herpes simplex infection - By James Heilman, MD - Own work, CC BY-SA 3.0, httpscommons.wikimedia.orgwindex.phpcurid=19051042.jpg
Aphthous ulcers	Painful, red spot or bump that develops into an open ulcer	Being a female Between the ages of 10-40 Family history of aphthous ulcers	Physical examination Diagnosis of exclusion	Oral cavity	Self-limiting , Pain decreases in 7 to 10 days, with complete healing in 1 to 3 weeks	Apthous ulcer on the lower surface of the tongue - By Ebarruda - Own work, CC BY-SA 3.0, httpscommons.wikimedia.orgwindex.phpcurid=7903358
Squamous cell carcinoma	Non healing ulcer, nodule, indurated plaque or mass May involve skin, lips, inside the mouth, throat or esophagus	Chronic sun or UV exposure Fair skin Elderly age (>45 yrs) Male sex Smoking	Physical exam Biopsy	Oral Cavity Floor of mouth Lateral tongue Throat Esophagus	Malignant Can spread to TMJ Some times associated with leukoplakia	Squamous cell carcinoma - By Luca Pastore, Maria Luisa Fiorella, Raffaele Fiorella, Lorenzo Lo Muzio - http://www.plosmedicine.org/article/showImageLarge.action?uri=info%3Adoi%2F10.1371%2Fjournal.pmed.0050212.g001, CC BY 2.5, https://commons.wikimedia.org/w/index.php?curid=15252632
Leukoplakia	White leathery spots on the mucous membranes of the tongue and inside of the mouth Lateral borders of tongue	Atypical Tobacco use Chronic irritation Immunodeficiency Bloodroot (sanguinaria)	Physical exam Diagnosis of exclusion Biopsy	Vulvar lesions occur independent of oral lesions	Associated with HIV Persistant white spots Benign but can progress to carcinoma after almost 10 years Oral proliferative verrucous leukoplakia is an aggressive sub type with multiple lesions and higher conversion to warts or carcinoma^[19]	Leukoplakia - By Aitor III - Own work, Public Domain, https://commons.wikimedia.org/w/index.php?curid=9873087
Melanoma	A lesion with ABCD Asymmetry Border irregularity Color variation Diameter changes Bleeding from the lesion	UV radiations Genetic predisposition Old age Male gender Family or personal history of melanoma Multiple benign or atypical nevi	ABCD characteristics Bleeding or ulceration may show malignancy Serum LDH may be elevated in case of malignancy Biopsy	Can metastasize All UV radiation or sun exposed areas can be effected independently 1-2 to hundreds of granules	Neural crest cell derivative Development begins with disruption of nevus growth control Progression involves MAPK/ERK pathway N-RAS or BRAF oncogene also involved	Oral melanoma - By Emmanouil K Symvoulakis, Dionysios E Kyrmizakis, Emmanouil I Drivas, Anastassios V Koutsopoulos, Stylianos G Malandrakis, Charalambos E Skoulakis and John G Bizakis - Symvoulakis et al. Head & Face Medicine 2006 2:7 doi:10.1186/1746-160X-2-7 (Open Access), [1], CC BY-SA 2.0, https://commons.wikimedia.org/w/index.php?curid=9839811
Fordyce spots	Rice-like granules or spots Small, painless, raised, pale, red or white 1 to 3 mm in diameter	Greasy skin types Some rheumatic disorders Hereditary nonpolyposis colorectal cancer Lower gingiva (gums) Vestibular mucosa	Physical exam Small keratin-filled pseudocysts May be seen on incidental mucosal biopsy Biopsy not done for them primarily	Oral cavity Vermilion border of the lips Oral mucosa of the upper lip Buccal mucosa in the commissural region often bilaterally Genitals	Benign neoplasms with sebaceous features Visible sebaceous glands No surrounding mucosal change Several adjacent glands may coalesce into a larger cauliflower-like cluster	Fordyce spots - Por Perene - Obra do próprio, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=19772899
Burning mouth syndrome	Burning or tingling on the lips, tongue, or entire mouth	Nutritional deficiencies Chronic anxiety or depression Diabetes type 2 Menopause Oral thrush or dry mouth, or damaged nerves transmitting taste Female gender Menopause	Presentation Physical exam	Oral cavity	Pain typically is low in the morning and builds up over the day Low dosages of benzodiazepines, tricyclic antidepressants or anticonvulsants may be effective
Torus palatinus	Bony growth on midline of the hard palate Nodular mass covered with normal mucosa	Genetic predisposition Autosomal dominant	Physical exam Types Flat tori Spindle tori Nodular tori Lobular tori	Hard palate	More common in Asian and Inuit populations Twice more common in females Repeated trauma can cause bleeding Surgery may be required in symptomatic	Torus palatinus - By Photo taken by dozenist, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=846591
Diseases involving oral cavity and other organ systems
Behcet's disease	Painful mouth sores Acne like skin lesions Headache, fever, poor balance, disorientation Abdominal pain, diarrhea or bleeding Uveitis Joint swelling and joint pain Genital sores wit pain and scaring Aneurysms	Over active immune system	Physical examination	Mouth Genitals GIT Eye Joints Skin Vascular system Brain	Outbreaks of exaggerated inflammation Affects smaller blood vessels	Behcet's disease - By Ahmet Altiner MD, Rajni Mandal MD - http://dermatology.cdlib.org/1611/articles/18_2009-10-20/2.jpg, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=17863021
Crohn's disease	Chronic, episodic diarrhea or constipation Abdominal pain Vomiting Weight loss or weight gain	Smoking Whites and European Jews Hormonal contraception Diets high in microparticles, sweet, fatty or refined foods Industrialized country	Typical history and symptoms Skip lesions on biopsy Anti-Saccharomyces cerevisiae antibodies (ASCA) Anti-neutrophil cytoplasmic antibodies (ANCA)	Eyes Joints Skin	May lead to Obstructions Abscesses Free perforation Hemorrhage
Agranulocytosis	Fever or chills Frequent infections Unusual redness, pain, or swelling around a wound Mouth ulcers Abdominal pain Burning sensation when urinating Sore throat	Medications^[20] Cytotoxic chemotherapy Hematologic malignancies Autoimmune disorders	Neutropenia <100 cells per micro litre Eosinopenia Basopenia	Oral cavity Skin GIT Urinary system Conjunctiva	Immunocompromization Types Drug-induced Malignant Autoimmune
Syphilis^[21]	Chancre Regional lymphadenopathy	Multiple sexual partners Illicit drug use Unprotected sex Men who have sex with men Residence in highly prevalent areas HIV infection Presence of other STIs Previous history of STIs Intravenous drug use	Darkfield microscopy Non treponemal tests like VDRL and RPR test) Treponemal testsFTA-ABS tests, (TP-PA) assay, enzyme immunoassays, and chemiluminescence immunoassays)	Oral cavity Penis Cervix Labia Anal canal Rectum CNS CVS	Primary syphilis Chancre Secondary syphilis Condylomata lata Latent syphilis Asymptomatic Tertiary syphilis Gummas Neurosyphilis	oral syphilis - By CDC/Susan Lindsley - http://phil.cdc.gov/phil_images/20021114/34/PHIL_2385_lores.jpg, Public Domain, https://commons.wikimedia.org/w/index.php?curid=2134349
Coxsackie virus	Fever Sores in the mouth Rash with blisters Aches	Pregnancy immunodeficiency	History and Physical exam Throat swabs Swabs from the lesion Tzanck test	Oral cavity Skin	Symptomatic treatment	Coxsackie virus stomatitis - Adapted from Dermatology Atlas.^[22]
Chicken pox	Conjunctival symptoms Catarrhal symptoms Characteristic spots on the trunk appearing in two or three waves Itching	Pregnancy Premature infants born to susceptible mothers All infants born at less than 28 weeks gestation or who weigh =1000 grams Immunocompromised	History and physical exam PCR to detect VZV in skin lesions (vesicles, scabs, maculopapular lesions)	Oral cavity Skin	Sodium bicarbonate in baths or antihistamines for itching Paracetamol (acetaminophen) for fever Prednisolone is contraindicated	Chickenpox - By James Heilman, MD - Own work, CC BY-SA 4.0, https://commons.wikimedia.org/w/index.php?curid=52872565
Measles	Fever Rash Cough Coryza (runny nose) Conjunctivitis (pink eye) Malaise Koplick spots in mouth	Unvaccinated individuals^[23]^[24] Crowded and/or unsanitary conditions Traveling to less developed and developing countries Immunocompromized Winter and spring seasons Born after 1956 and never fully vaccinated Health care workers	History and examination PCR for Measles-specific IgM antibody PCR for Measles RNA	Oral cavity Skin Respiratory tract Eyes Throat	Caused by Morbillivirus Primary site of infection is the respiratory epithelium of the nasopharynx Transmitted in respiratory secretions, via aerosol droplets containing virus particles	Koplick spots (Measles) - By CDC - http://phil.cdc.gov/PHIL_Images/20040908/4f54ee8f0e5f49f58aaa30c1bc6413ba/6111_lores.jpg, Public Domain, https://commons.wikimedia.org/w/index.php?curid=824483

Crohn's disease must be differentiated from diseases that cause abdominal pain and chronic diarrhea. The table below summarizes the findings that differentiate watery causes of chronic diarrhea:^[25]^[26]^[27]^[28]^[29]

Cause	Osmotic gap		History	Physical exam	Gold standard for diagnosis
Cause	< 50 mOsm per kg	> 50 mOsm per kg*	History	Physical exam	Gold standard for diagnosis
Zollinger-Ellison syndrome	+	-	Abdominal pain and diarrhea Dyspepsia Upper or Lower gastrointestinal bleeding	Abdominal tenderness Hematochezia Hematemesis Tachycardia Hypotension	Gastrin levels
Crohn's disease	+	-	Abdominal pain followed by diarrhea	Abdominal tenderness when palpated in severe disease Blood seen on rectal exam Fever Tachycardia Hypotension	Colonoscopy with biopsy
Hyperthyroidism	+	-	Excessive sweating Heat intolerance Increased bowel movements	Lump in the neck Proptosis Tremors Increased DTR	TSH with T3 and T4
VIPoma	+	-	Watery diarrhea Dehydration (thirst, dry skin, dry mouth, tiredness, headaches, and dizziness) Lethargy, muscle weakness Nausea, vomiting Cramping 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
Lactose intolerance	-	+	Abdominal pain Bloating Diarrhea Flatulence	Abdominal tenderness	Intestinal biopsy
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
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

References

↑ ^1.0 ^1.1 Fattahi MR, Malek-Hosseini SA, Sivandzadeh GR, Safarpour AR, Bagheri Lankarani K, Taghavi AR; et al. (2017). "Clinical Course of Ulcerative Colitis After Liver Transplantation in Patients with Concomitant Primary Sclerosing Cholangitis and Ulcerative Colitis". Inflamm Bowel Dis. doi:10.1097/MIB.0000000000001105. PMID 28520586.
↑ ^2.0 ^2.1 Burisch J, Ungaro R, Vind I, Prosberg MV, Bendtsen F, Colombel JF; et al. (2017). "Proximal disease extension in patients with limited ulcerative colitis: a Danish population-based inception cohort". J Crohns Colitis. doi:10.1093/ecco-jcc/jjx066. PMID 28486626.
↑ Srivastava S, Kedia S, Kumar S, Pratap Mouli V, Dhingra R, Sachdev V; et al. (2015). "Serum human trefoil factor 3 is a biomarker for mucosal healing in ulcerative colitis patients with minimal disease activity". J Crohns Colitis. 9 (7): 575–9. doi:10.1093/ecco-jcc/jjv075. PMID 25964429.
↑ Karolewska-Bochenek K, Dziekiewicz M, Banaszkiewicz A (2017). "Budesonide MMX in pediatric patients with ulcerative colitis". J Crohns Colitis. doi:10.1093/ecco-jcc/jjx069. PMID 28505293.
↑ Silva M, Cardoso H, Macedo G (2017). "Patency Capsule Safety in Crohn's Disease". J Crohns Colitis. doi:10.1093/ecco-jcc/jjx064. PMID 28486597.
↑ Stidham RW, Cross RK (2016). "Endoscopy and cross-sectional imaging for assessing Crohn׳s disease activity". Tech Gastrointest Endosc. 18 (3): 123–130. doi:10.1016/j.tgie.2016.08.001. PMC 5405438. PMID 28458507.
↑ ^7.0 ^7.1 ^7.2 ^7.3 Kornbluth, Asher (2004). "Ulcerative Colitis Practice Guidelines in Adults" (PDF). American Journal of Gastroenterology. 99 (7): 1371–1385. doi:10.1111/j.1572-0241.2004.40036.x. PMID 15233681. Retrieved 2006-11-08. Unknown parameter |month= ignored (help); Unknown parameter |coauthors= ignored (help)
↑ ^8.0 ^8.1 ^8.2 ^8.3 Hanauer, Stephen B. (March 1 2001). "Management of Crohn's Disease in Adults" (PDF). American Journal of Gastroenterology. 96 (3): 635–643. doi:10.1111/j.1572-0241.2001.03671.x. PMID 11280528. Retrieved 2006-11-08. Unknown parameter |coauthors= ignored (help); Check date values in: |date= (help)
↑ Broomé, Ulrika (2006). "Primary sclerosing cholangitis, inflammatory bowel disease, and colon cancer". Seminars in Liver Disease. 26 (1): 31–41. doi:10.1055/s-2006-933561. PMID 16496231. Unknown parameter |coauthors= ignored (help); Unknown parameter |month= ignored (help)
↑ Sugimachi K, Inokuchi K, Kuwano H, Ooiwa T (1984). "Acute gastritis clinically classified in accordance with data from both upper GI series and endoscopy". Scand J Gastroenterol. 19 (1): 31–7. PMID 6710074.
↑ Sipponen P, Maaroos HI (2015). "Chronic gastritis". Scand J Gastroenterol. 50 (6): 657–67. doi:10.3109/00365521.2015.1019918. PMC 4673514. PMID 25901896.
↑ Sartor RB (2006). "Mechanisms of disease: pathogenesis of Crohn's disease and ulcerative colitis". Nat Clin Pract Gastroenterol Hepatol. 3 (7): 390–407. doi:10.1038/ncpgasthep0528. PMID 16819502.
↑ Sipponen P (1989). "Atrophic gastritis as a premalignant condition". Ann Med. 21 (4): 287–90. PMID 2789799.
↑ Badillo R, Francis D (2014). "Diagnosis and treatment of gastroesophageal reflux disease". World J Gastrointest Pharmacol Ther. 5 (3): 105–12. doi:10.4292/wjgpt.v5.i3.105. PMC 4133436. PMID 25133039.
↑ Ramakrishnan K, Salinas RC (2007). "Peptic ulcer disease". Am Fam Physician. 76 (7): 1005–12. PMID 17956071.
↑ Banasch M, Schmitz F (2007). "Diagnosis and treatment of gastrinoma in the era of proton pump inhibitors". Wien Klin Wochenschr. 119 (19–20): 573–8. doi:10.1007/s00508-007-0884-2. PMID 17985090.
↑ Dicken BJ, Bigam DL, Cass C, Mackey JR, Joy AA, Hamilton SM (2005). "Gastric adenocarcinoma: review and considerations for future directions". Ann Surg. 241 (1): 27–39. PMC 1356843. PMID 15621988.
↑ Ghimire P, Wu GY, Zhu L (2011). "Primary gastrointestinal lymphoma". World J Gastroenterol. 17 (6): 697–707. doi:10.3748/wjg.v17.i6.697. PMC 3042647. PMID 21390139.
↑ Ann M. Gillenwater, Nadarajah Vigneswaran, Hanadi Fatani, Pierre Saintigny & Adel K. El-Naggar (2013). "Proliferative verrucous leukoplakia (PVL): a review of an elusive pathologic entity!". Advances in anatomic pathology. 20 (6): 416–423. doi:10.1097/PAP.0b013e3182a92df1. PMID 24113312. Unknown parameter |month= ignored (help)
↑ Andrès E, Zimmer J, Affenberger S, Federici L, Alt M, Maloisel F. (2006). "Idiosyncratic drug-induced agranulocytosis: Update of an old disorder". Eur J Intern Med. 17 (8): 529–35. Text "pmid 17142169" ignored (help)
↑ title="By Internet Archive Book Images [No restrictions], via Wikimedia Commons" href="https://commons.wikimedia.org/wiki/File:A_manual_of_syphilis_and_the_venereal_diseases%2C_(1900)_(14595882378).jpg"
↑ "Dermatology Atlas".
↑ Feikin DR, Lezotte DC, Hamman RF, Salmon DA, Chen RT, Hoffman RE (2000). "Individual and community risks of measles and pertussis associated with personal exemptions to immunization". JAMA. 284 (24): 3145–50. PMID 11135778.
↑ Ratnam S, West R, Gadag V, Williams B, Oates E (1996). "Immunity against measles in school-aged children: implications for measles revaccination strategies". Can J Public Health. 87 (6): 407–10. PMID 9009400.
↑ SCOBIE BA, MCGILL DB, PRIESTLEY JT, ROVELSTAD RA (1964). "EXCLUDED GASTRIC ANTRUM SIMULATING THE ZOLLINGER-ELLISON SYNDROME". Gastroenterology. 47: 184–7. PMID 14201408.
↑ Silverberg MS, Satsangi J, Ahmad T, Arnott ID, Bernstein CN, Brant SR; et al. (2005). "Toward an integrated clinical, molecular and serological classification of inflammatory bowel disease: report of a Working Party of the 2005 Montreal World Congress of Gastroenterology". Can J Gastroenterol. 19 Suppl A: 5A–36A. PMID 16151544.
↑ Sauter GH, Moussavian AC, Meyer G, Steitz HO, Parhofer KG, Jüngst D (2002). "Bowel habits and bile acid malabsorption in the months after cholecystectomy". Am J Gastroenterol. 97 (7): 1732–5. doi:10.1111/j.1572-0241.2002.05779.x. PMID 12135027.
↑ Maiuri L, Raia V, Potter J, Swallow D, Ho MW, Fiocca R; et al. (1991). "Mosaic pattern of lactase expression by villous enterocytes in human adult-type hypolactasia". Gastroenterology. 100 (2): 359–69. PMID 1702075.
↑ RUBIN CE, BRANDBORG LL, PHELPS PC, TAYLOR HC (1960). "Studies of celiac disease. I. The apparent identical and specific nature of the duodenal and proximal jejunal lesion in celiac disease and idiopathic sprue". Gastroenterology. 38: 28–49. PMID 14439871.

[pmid28520586-1] 1.0 ^1.1 Fattahi MR, Malek-Hosseini SA, Sivandzadeh GR, Safarpour AR, Bagheri Lankarani K, Taghavi AR; et al. (2017). "Clinical Course of Ulcerative Colitis After Liver Transplantation in Patients with Concomitant Primary Sclerosing Cholangitis and Ulcerative Colitis". Inflamm Bowel Dis. doi:10.1097/MIB.0000000000001105. PMID 28520586.

[pmid28486626-2] 2.0 ^2.1 Burisch J, Ungaro R, Vind I, Prosberg MV, Bendtsen F, Colombel JF; et al. (2017). "Proximal disease extension in patients with limited ulcerative colitis: a Danish population-based inception cohort". J Crohns Colitis. doi:10.1093/ecco-jcc/jjx066. PMID 28486626.

[pmid25964429-3] Srivastava S, Kedia S, Kumar S, Pratap Mouli V, Dhingra R, Sachdev V; et al. (2015). "Serum human trefoil factor 3 is a biomarker for mucosal healing in ulcerative colitis patients with minimal disease activity". J Crohns Colitis. 9 (7): 575–9. doi:10.1093/ecco-jcc/jjv075. PMID 25964429.

[pmid28505293-4] Karolewska-Bochenek K, Dziekiewicz M, Banaszkiewicz A (2017). "Budesonide MMX in pediatric patients with ulcerative colitis". J Crohns Colitis. doi:10.1093/ecco-jcc/jjx069. PMID 28505293.

[pmid28486597-5] Silva M, Cardoso H, Macedo G (2017). "Patency Capsule Safety in Crohn's Disease". J Crohns Colitis. doi:10.1093/ecco-jcc/jjx064. PMID 28486597.

[pmid28458507-6] Stidham RW, Cross RK (2016). "Endoscopy and cross-sectional imaging for assessing Crohn׳s disease activity". Tech Gastrointest Endosc. 18 (3): 123–130. doi:10.1016/j.tgie.2016.08.001. PMC 5405438. PMID 28458507.

[Kornbluth-Sachar2004-7] 7.0 ^7.1 ^7.2 ^7.3 Kornbluth, Asher (2004). "Ulcerative Colitis Practice Guidelines in Adults" (PDF). American Journal of Gastroenterology. 99 (7): 1371–1385. doi:10.1111/j.1572-0241.2004.40036.x. PMID 15233681. Retrieved 2006-11-08. Unknown parameter |month= ignored (help); Unknown parameter |coauthors= ignored (help)

[HanauerCrohns-8] 8.0 ^8.1 ^8.2 ^8.3 Hanauer, Stephen B. (March 1 2001). "Management of Crohn's Disease in Adults" (PDF). American Journal of Gastroenterology. 96 (3): 635–643. doi:10.1111/j.1572-0241.2001.03671.x. PMID 11280528. Retrieved 2006-11-08. Unknown parameter |coauthors= ignored (help); Check date values in: |date= (help)

[9] Broomé, Ulrika (2006). "Primary sclerosing cholangitis, inflammatory bowel disease, and colon cancer". Seminars in Liver Disease. 26 (1): 31–41. doi:10.1055/s-2006-933561. PMID 16496231. Unknown parameter |coauthors= ignored (help); Unknown parameter |month= ignored (help)

[pmid6710074-10] Sugimachi K, Inokuchi K, Kuwano H, Ooiwa T (1984). "Acute gastritis clinically classified in accordance with data from both upper GI series and endoscopy". Scand J Gastroenterol. 19 (1): 31–7. PMID 6710074.

[pmid25901896-11] Sipponen P, Maaroos HI (2015). "Chronic gastritis". Scand J Gastroenterol. 50 (6): 657–67. doi:10.3109/00365521.2015.1019918. PMC 4673514. PMID 25901896.

[pmid16819502-12] Sartor RB (2006). "Mechanisms of disease: pathogenesis of Crohn's disease and ulcerative colitis". Nat Clin Pract Gastroenterol Hepatol. 3 (7): 390–407. doi:10.1038/ncpgasthep0528. PMID 16819502.

[pmid2789799-13] Sipponen P (1989). "Atrophic gastritis as a premalignant condition". Ann Med. 21 (4): 287–90. PMID 2789799.

[pmid25133039-14] Badillo R, Francis D (2014). "Diagnosis and treatment of gastroesophageal reflux disease". World J Gastrointest Pharmacol Ther. 5 (3): 105–12. doi:10.4292/wjgpt.v5.i3.105. PMC 4133436. PMID 25133039.

[pmid17956071-15] Ramakrishnan K, Salinas RC (2007). "Peptic ulcer disease". Am Fam Physician. 76 (7): 1005–12. PMID 17956071.

[pmid17985090-16] Banasch M, Schmitz F (2007). "Diagnosis and treatment of gastrinoma in the era of proton pump inhibitors". Wien Klin Wochenschr. 119 (19–20): 573–8. doi:10.1007/s00508-007-0884-2. PMID 17985090.

[pmid15621988-17] Dicken BJ, Bigam DL, Cass C, Mackey JR, Joy AA, Hamilton SM (2005). "Gastric adenocarcinoma: review and considerations for future directions". Ann Surg. 241 (1): 27–39. PMC 1356843. PMID 15621988.

[pmid21390139-18] Ghimire P, Wu GY, Zhu L (2011). "Primary gastrointestinal lymphoma". World J Gastroenterol. 17 (6): 697–707. doi:10.3748/wjg.v17.i6.697. PMC 3042647. PMID 21390139.

[19] Ann M. Gillenwater, Nadarajah Vigneswaran, Hanadi Fatani, Pierre Saintigny & Adel K. El-Naggar (2013). "Proliferative verrucous leukoplakia (PVL): a review of an elusive pathologic entity!". Advances in anatomic pathology. 20 (6): 416–423. doi:10.1097/PAP.0b013e3182a92df1. PMID 24113312. Unknown parameter |month= ignored (help)

[PMID17142169-20] Andrès E, Zimmer J, Affenberger S, Federici L, Alt M, Maloisel F. (2006). "Idiosyncratic drug-induced agranulocytosis: Update of an old disorder". Eur J Intern Med. 17 (8): 529–35. Text "pmid 17142169" ignored (help)

[21] title="By Internet Archive Book Images [No restrictions], via Wikimedia Commons" href="https://commons.wikimedia.org/wiki/File:A_manual_of_syphilis_and_the_venereal_diseases%2C_(1900)_(14595882378).jpg"

[Dermatology_Atlas-22] "Dermatology Atlas".

[pmid11135778-23] Feikin DR, Lezotte DC, Hamman RF, Salmon DA, Chen RT, Hoffman RE (2000). "Individual and community risks of measles and pertussis associated with personal exemptions to immunization". JAMA. 284 (24): 3145–50. PMID 11135778.

[pmid9009400-24] Ratnam S, West R, Gadag V, Williams B, Oates E (1996). "Immunity against measles in school-aged children: implications for measles revaccination strategies". Can J Public Health. 87 (6): 407–10. PMID 9009400.

[pmid14201408-25] SCOBIE BA, MCGILL DB, PRIESTLEY JT, ROVELSTAD RA (1964). "EXCLUDED GASTRIC ANTRUM SIMULATING THE ZOLLINGER-ELLISON SYNDROME". Gastroenterology. 47: 184–7. PMID 14201408.

[pmid16151544-26] Silverberg MS, Satsangi J, Ahmad T, Arnott ID, Bernstein CN, Brant SR; et al. (2005). "Toward an integrated clinical, molecular and serological classification of inflammatory bowel disease: report of a Working Party of the 2005 Montreal World Congress of Gastroenterology". Can J Gastroenterol. 19 Suppl A: 5A–36A. PMID 16151544.

[pmid12135027-27] Sauter GH, Moussavian AC, Meyer G, Steitz HO, Parhofer KG, Jüngst D (2002). "Bowel habits and bile acid malabsorption in the months after cholecystectomy". Am J Gastroenterol. 97 (7): 1732–5. doi:10.1111/j.1572-0241.2002.05779.x. PMID 12135027.

[pmid1702075-28] Maiuri L, Raia V, Potter J, Swallow D, Ho MW, Fiocca R; et al. (1991). "Mosaic pattern of lactase expression by villous enterocytes in human adult-type hypolactasia". Gastroenterology. 100 (2): 359–69. PMID 1702075.

[pmid14439871-29] RUBIN CE, BRANDBORG LL, PHELPS PC, TAYLOR HC (1960). "Studies of celiac disease. I. The apparent identical and specific nature of the duodenal and proximal jejunal lesion in celiac disease and idiopathic sprue". Gastroenterology. 38: 28–49. PMID 14439871.

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