Whipple's disease differential diagnosis

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

Overview

Whipple's disease must be differentiated from other diseases that cause malabsorption, chronic diarrhea, multi system involvement, such as Celiac disease, systemic infections, and inflamatory bowel disease.

Differentiating Whipple's disease from other Diseases

Whipple's disease must be differentiated from other diseases that cause malabsorption, chronic diarrhea, joins involvement, and neurologic symptoms.

• Malabsorption with small intestine involvement (celiac disease, sarcoidosis, and lymphoma)
• Infections such as tuberculosis, endemic fungi (eg, Histoplasma spp), Rhodococcus and HIV infection
• Inflammatory bowel diseases
• Connective tissue diseases
• Neurologic disease
• Addison's disease

The following diseases have presentations similar to that of Whipple's disease.

The table below summarizes the findings that differentiate malabsorption

				History
Cause	Peak age of onset	Diarrhea						Physical exam	Lab findings	Additional finding	Cause/Pathogenesis	Gold standard dignosis
		Watery	Fatty	Fever	Weight loss	Abdominal pain	Arthralgia
Whipple disease	50th	+/-	+	-	+	+		Arthralgias of the large joints Hematochezia	Leukocytopenia Thrombocytopenia	Skin hyperpigmentation Arthralgias	Tropheryma whipplei	Upper endoscopy with biopsies of the small intestine for T. whipplei testing
Celiac disease	Childhood Adult	+/-	+/-	+	+	+		Abdominal distention Tetany Mouth ulcers Dermatitis herpetiformis	IgA endomysial antibody (IgA EMA) IgA tissue transglutaminase antibody (IgA tTG) IgG tissue transglutaminase antibody (IgG tTG) IgA deamidated gliadin peptide (IgA DGP) IgG deamidated gliadin peptide (IgG DGP)	Gluten-free diet Signs of the fat-soluble vitamins A, D, E, and K deficiency	HLA-DQ2 and/or DQ8 gene mutation Innate responses to wheat proteins	Immunoglobulin A (IgA) anti-tissue transglutaminase (TTG) antibody
Grain allergy	Childhood	+	-	+	+	+		Vomiting Abdominal distention	Elevated IgE levels	Atopic dermatitis (eczema) Dysphagia	Abnormal immune response to wheat antigens	Measurement of grain-specific immunoglobulin E (IgE)
Cystic fibrosis	Infancy and childhood	-	+	+	+	+		Digital clubbing Respiratory rale, wheeze, and crackle Abdominal pain Cyanosis	Positive DNA analysis for CFTR multimutation method Evaluated nasal transepithelial potential difference (NPD)	Disease manifestations in multiple organ systems: Diabetes Recurrent upper and lower respiratory tract infections Infertility	Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) protein	Elevated sweat chloride ≥60 mmol/L
Lactose intolerance	Adult	+	-	-	-	+		Abdominal tenderness	Stool osmotic gap of >125 mOsm/kg  Stool pH <6	Avoidance of dietary lactose Maintenance of nutrient intake Regulation of calcium intake Use of enzyme lactase	Acquired primary lactase deficiency Adult-type hypolactasia Inability to produce persistentLactase	Lactose breath hydrogen test
Crohns disease	Young adults (20th)	+	-	+/-	+	+		Abdominal tenderness when palpated in severe disease Tachycardia Hypotension	Anemia Iron deficiency Elevated white blood cell count Vitamin B12 deficiency Elevated erythrocyte sedimentation rate Elevated CRP	Blood seen on rectal exam Fever	Abnormal immune response to self antigens	Colonoscopy with biopsy
Laxative overuse	After childhood	+	-	-	+/-	+/-		Enhanced gastrointestinal motility and gastrointestinal sound Mild abdominal tenderness Abdominal bloating	Hypokalemia  Metabolic alkalosis Hypermagnesemia(in case of magnesium laxative usage)	-	Laxative drug abuse	Laxative screening on a stool for: Diphenolic laxatives (eg, bisacodyl) Polyethylene glycol-containing laxatives
Hyperthyroidism	Any age	+	-	-	+	+/-		Lump in the neck Proptosis Tremors Increased DTR	Elevated T4 Elevated T3 Decreased level of TSH	Lid lag Sweating Hyperpigmentation	Graves' disease Hashimoto thyroiditis Toxic adenoma	TSH
Irritable bowel syndrome	Between 30 and 50	+	-	-	-	+		Abdominal tenderness Hard stool in the rectal vault	-	Bloating Flatulence	Postinfectious Inflammatory	Clinical diagnosis ROME III criteria Pharmacologic studies based criteria
VIPoma	Between 30 and 50	+	-	+/-	+	+/-		Tachycardia Rash Facial flushing Abdominal distention Abdominal tenderness in the right upper abdominal quadrant	Hypokalemia Hypochlorhydria or achlorhydria Low osmotic gap (<50 mOsm/kg)	Dehydration Lethargy, muscle weakness Nausea, vomiting Flushing	Primary secretory tumor	Elevated VIP levels Followed by imaging
Gastrinoma (Zollinger-Ellison syndrome)	Between the ages of 20 and 50	+	-	+/-	+	+		Mild to moderate upper abdominal tenderness	Positive secretin stimulation test Elevated serum chromogranin A	Heartburn	Gastrin producing tumor mainly in duodenum	Elevated basal or stimulated serum gastrin more than 1000 pg/mL
Lactose intolerance	Any age	-	+	-	+	+/-		Abdominal tenderness when palpated in severe disease Fever Hypotension Tachycardia Nausea and vomiting	Lactose breath hydrogen test	Bloating Flatulence Symptoms begin mainly after ingestion of lactose	Reduction of lactase enzyme activity or in ability to produce persistent lactase Congenital lactase deficiency	Lactase activity assay
Allergic enteropathy/Food protein-induced enterocolitis syndrome (FPIES)	Infancy	+	-	+/-	+/-	+		Nausea Vomiting Abdominal distention	Stool examination: Blood-tinged and mucusy Polymorphonuclear leukocytes presence	Triggered by cow milk protein Profuse, repetitive vomiting	Autoimmune/allergic response to food antigens	Oral food challenge (OFC)
Eosinophilic gastroenteritis	30th	+	-	+/-	+/-	+		Nausea Vomiting Abdominal distention	Elevated serum IgE levels Abnormal D-xylose test	One-half of patients have other allergic diseases Associated with an identifiable dietary antigen	Autoimmune/allergic response to food antigens	Eosinophilic infiltration of the gastrointestinal tract on biopsy
Primary bile acid malabsorption	Childhood Adolescents	+	+/-	+	+	+/-		-	Low vitamins A, D, E, and K Anemia	Disease hetergenicity lead to varying presentation from chronic diarrhea without significant fat malabsorption to severe watery diarrhea and steatorrhea with malnutrition	Genetic defects in SLC10A2 (solute carrier family 10 member 2 gene)	Total and specific bile acids from stool Gamma emitter selenium-75-homocholic acid taurine (SeHCAT)
Abetalipoproteinemia	Infancy	-	+	+	+	+		Abdominal distention Impaired visual acuity and visual field defects Dysarthria	Low triglyceride Low total cholesterol levels  Acanthocytes Low vitamin E levels	Clumsiness Vision impairment Ataxia	Autosomal recessive disorder caused by mutations encoding the microsomal triglyceride transfer protein (MTP)	Clinical findings and low triglyceride and cholesterol level
Microscopic colitis	60th	+	-	-	+	+		Abdominal tenderness	Elevatedautoantibodies include: RF ANA AMA ANCA	Fecal urgency Incontinence May be associated with extraintestinal symptoms, such as: Arthralgia Arthritis Uveitis	Mucosal immune responses to luminal factors in a genetically predisposed individual	A 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
Congenital chloride diarrhea	Neonate	+	-	+	+	-		-	Hyponatremia Hypochloremia Metabolic alkalosis	History of polyhydramnios	Mutations in the SLC26A3 gene Encodes for an epithelial anion exchanger	Excessive fecal secretion of chloride
Congenital sodium diarrhea	Neonate	+	-	+	+	-		-	Stool examination: Alkaline Fecal sodium concentrations Serum: Metabolic acidosis Hyponatremia	May be associated with choanal or anal atresia	Mutations in the SPINT2 gene	Clinical
Glucose-galactose malabsorption	Infancy	+	-	+/-	+	+		Abdominal tenderness	Stool examination: Acidic	Severe life-threatening diarrhea Dehydration Symptomatic as long as the diet includes lactose or its hydrolysis products, glucose and galactose	Mutations in solute carrier family 5, member 1 gene (SLC5A1, also known as SGLT1) Lead to deficiency in the intestinal sodium/glucose transporter	Positive glucose breath hydrogen test + normal intestinal biopsy

Celiac 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:

Cause	Osmotic gap		History	Physical exam	Gold standard for diagnosis
	< 50 mOsm per kg	> 50 mOsm per kg*
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