Tropical sprue differential diagnosis

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Associate Editor(s)-in-Chief: Aravind Kuchkuntla, M.B.B.S[2] Akshun Kalia M.B.B.S.[3]

Overview

Tropical sprue should be differentiated from diseases causing chronic diarrhea and malabsorption such as celiac disease, osmotic diarrhea and secretory diarrhea.

Differentiating Tropical Sprue from other Diseases

Tropical sprue is a diagnosis of exclusion therefore it must be be differentiated from other diseases causing malabsorption such as:

• Infectious causes
• Celiac disease
• Pancreatic insufficiency
• Osmotic diarrhea
• Secretory diarrhea

Approach to a Patient with Chronic Diarrhea

The following is an algorithm describing the approch to a patient with chronic diarrhea:

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

Specific treatment per results and symptomatic treatment

Suspect Tropical sprue and initiate antibiotic therapy and folate supplementation

Differentiating Tropical Sprue from Other causes of Fat Malabsorption

Tropical sprue must also be differentiated from other causes of fat malabsorption such as Whipple's disease, celiac disease, pancreatic disorders and other less common conditions.

Abbreviations: RUQ= Right upper quadrant of the abdomen, LUQ= Left upper quadrant, LLQ= Left lower quadrant, RLQ= Right lower quadrant, LFT= Liver function test, SIRS= Systemic inflammatory response syndrome, ERCP= Endoscopic retrograde cholangiopancreatography, IV= Intravenous, N= Normal, AMA= Anti mitochondrial antibodies, LDH= Lactate dehydrogenase, GI= Gastrointestinal, CXR= Chest X ray, IgA= Immunoglobulin A, IgG= Immunoglobulin G, IgM= Immunoglobulin M, CT= Computed tomography, PMN= Polymorphonuclear cells, ESR= Erythrocyte sedimentation rate, CRP= C-reactive protein, TS= Transferrin saturation, SF= Serum Ferritin, SMA= Superior mesenteric artery, SMV= Superior mesenteric vein, ECG= Electrocardiogram, US = Ultrasound

Disease Clinical manifestations Diagnosis Comments Symptoms Signs Abdominal Pain Fever Nausea or vomiting Jaundice Constipation Diarrhea Weight loss GI bleeding Hypo- tension Guarding Rebound Tenderness Bowel sounds Lab Findings Imaging Tropical sprue Diffuse + − − − + + − − − − N Fat soluble vitamin deficiency Hypoalbuminemia Fecal stool test Barium studies: Dilation and edema of mucosal folds Steatorrhea- 10-40 g/day (Normal=5 g/day) Whipple's disease Diffuse ± − ± − + + − ± − − N Thrombocytopenia Hypoalbuminemia Small intestinal biopsy for Tropheryma whipplei Endoscopy is used to confirm diagnosis. Images used to find complications Chest and joint x-ray CT MRI Echocardiography Extra intestinal findings: Uveitis Endocarditis Encephalitis Dementia Hepatosplenomegaly Arthritis Ascites Celiac disease Diffuse − − − − + + − − − − Hyperactive IgA endomysial antibody IgA tissue transglutaminase antibody Anti-gliadin antibody Small bowel biopsy US: Bull’s eye or target pattern Pseudokidney sign Gluten allergy Acute pancreatitis Epigastric + + ± − − + − ± − − N Increased amylase / lipase Ultrasound shows evidence of inflammation CT scan shows severity of pancreatitis Pain radiation to back Disease Abdominal Pain Fever Nausea or vomiting Jaundice Constipation Diarrhea Weight loss GI bleeding Hypo- tension Guarding Rebound Tenderness Bowel sounds Lab Findings Imaging Comments Chronic pancreatitis Epigastric − ± ± − + + − − − − N Increased amylase / lipase Increased stool fat content Pancreatic function test CT scan Calcification Pseudocyst Dilation of main pancreatic duct Predisposes to pancreatic cancer Pancreatic carcinoma Epigastric − + + − + + − − − − N ↑ Alkaline phosphatase ↑ serum bilirubin ↑ gamma-glutamyl transpeptidase ↑ CA 19-9  MDCT with  PET/CT MRI Skin manifestations may include: Bullous pemphigoid Cicatricial pemphigoid Migratory superficial thrombophlebitis (classic Trousseau's syndrome) Pancreatic panniculitis Dumping syndrome Lower and then diffuse − + − − + + − + − − Hyperactive Glucose challenge test Hydrogen breath test Upper GI series Gastric emptying study Postgastrectomy Acute diverticulitis LLQ + + − + ± − + Positive in perforated diverticulitis + + Hypoactive Leukocytosis CT scan Ultrasound History of constipation Inflammatory bowel disease Diffuse ± − ± − + + + − − − Normal or hyperactive Anti-neutrophil cytoplasmic antibody (P-ANCA) in Ulcerative colitis Anti saccharomyces cerevisiae antibodies (ASCA) in Crohn's disease String sign on abdominal x-ray in Crohn's disease Extra intestinal findings: Uveitis Arthritis Disease Abdominal Pain Fever Nausea or vomiting Jaundice Constipation Diarrhea Weight loss GI bleeding Hypo- tension Guarding Rebound Tenderness Bowel sounds Lab Findings Imaging Comments Irritable bowel syndrome Diffuse − − − ± ± - − − − − N Normal Normal Symptomatic treatment High dietary fiber Osmotic laxatives Antispasmodic drugs Infective colitis Diffuse + ± − − + − + Positive in fulminant colitis ± ± Hyperactive Stool culture and studies Shiga toxin in bloody diarrhea PCR CT scan Bowel wall thickening Edema Colon carcinoma Diffuse/ RLQ/LLQ − − − ± ± + + ± − − Normal or hyperactive if obstruction present CBC Carcinoembryonic antigen (CEA) Colonoscopy Flexible sigmoidoscopy Barium enema CT colonography  PILLCAM 2: A colon capsule for CRC screening may be used in patients with an incomplete colonoscopy who lacks obstruction Viral hepatitis RUQ + + + − Positive in Hep A and E + − Positive in fulminant hepatitis Positive in acute + N Abnormal LFTs Viral serology US Hep A and E have fecal-oral route of transmission Hep B and C transmits via blood transfusion and sexual contact. Liver abscess RUQ + + + − ± + − + + ± Normal or hypoactive CBC Blood cultures Abnormal liver function tests US CT Cirrhosis RUQ − − + − − + + + − − N Hypoalbuminemia Prolonged PT Abnormal LFTs Hyponatremia Thrombocytopenia US Nodular, shrunken liver Ascites Stigmata of liver disease Cruveilhier- Baumgarten murmur

Differentiating Tropical Sprue from Other causes of Fat Malabsorption in Immunocompromised Patients

Tropical sprue must be differentiated from other diseases that may cause chronic diarrhea, weight loss, and abdominal pain especially in immunocompromised patients. These conditions include chronic giardiasis, cryptosporidiosis, Cystoisosporiasis (isosporiasis)

Disease Clinical manifestations Diagnosis Comments Symptoms Signs Abdominal Pain Fever Nausea or vomiting Jaundice Constipation Diarrhea Weight loss GI bleeding Hypo- tension Guarding Rebound Tenderness Bowel sounds Lab Findings Imaging Tropical sprue Diffuse + − − − + + − − − − N Fat soluble vitamin deficiency Hypoalbuminemia Fecal stool test Barium studies: Dilation and edema of mucosal folds Steatorrhea- 10-40 g/day (Normal=5 g/day) Giardiasis Diffuse ± + - - + + - ± - - N Hypoalbuminaemia Vitamin B12 and folate deficiencies (as the organism inhabits the duodenum) EGD with small bowel tissue biopsy Reserved for patients with high suspicion of giardiasis and undiagnosed by other methods Microscopic identification of the organism in the stool Cryptosporiadisis Diffuse + + - - + + - + - - N PCR: Most specific and sensitive diagnostic tool. PCR is expensive and used in limited cases. Normal Stool examination: Oocysts appear red on staining with modified acid fast staining Cystoisosporiasis (isosporiasis) Diffuse + + - - + + - + - - N Peripheral eosinophilia Stool test is positive for immature oocyst that contains a spherical mass of protoplasm Upper GI series depicts minimal or irregular thickening of mucosal folds AIDS defining condition