Causes of Protein-Losing Enteropathy
Protein-losing enteropathy results from three primary mechanisms: erosive gastrointestinal disorders causing mucosal damage, non-erosive gastrointestinal disorders with increased mucosal permeability, and conditions causing elevated central venous pressure or lymphatic obstruction. 1, 2
Primary Etiologic Categories
Erosive Gastrointestinal Disorders
These conditions cause direct mucosal damage leading to protein leakage:
- Inflammatory bowel disease (Crohn's disease) presents with bloody diarrhea, fever, weight loss, and shows aphthous ulceration, skip lesions, and granulomas on biopsy 3
- Infectious enteritis including tuberculosis (with granulomatous disease, cough, ascites, night sweats), Mycobacterium avium complex, giardiasis, and Whipple's disease (with PAS-positive macrophagic infiltration) 3
- Eosinophilic gastroenteritis characterized by multiple allergies, atopy, and massive eosinophilic infiltration on biopsy 3
Non-Erosive Gastrointestinal Disorders
These cause protein loss through increased mucosal permeability without erosions:
- Primary intestinal lymphangiectasia (Waldmann's disease) represents lymphatic leakage due to increased interstitial pressure 4, 5
- Celiac disease and seronegative enteropathy with villous atrophy—both autoimmune enteropathy (with anti-enterocyte/anti-goblet cell antibodies, absence of Paneth or goblet cells) and tropical sprue (requiring travel to tropical countries, with folate/B12 deficiency) 3, 6
- Common variable immunodeficiency disease presenting with low total IgG, IgA, and IgM levels 3
- Medication-induced enteropathy from olmesartan (causing severe illness that responds rapidly to cessation), other angiotensin receptor blockers, mycophenolate mofetil, methotrexate, and azathioprine 3, 1
- Microscopic colitis as part of the differential for persistent diarrhea 3
Cardiac and Lymphatic Obstruction Disorders
Elevated central venous pressure or lymphatic obstruction causes protein loss:
- Fontan circulation in congenital heart disease—protein-losing enteropathy occurs in patients with elevated Fontan pressures and correlates with poor outcomes 3, 1
- Constrictive pericarditis causing elevated venous pressure requiring surgical pericardiectomy for definitive treatment 1, 7
- Restrictive cardiomyopathy and tricuspid valve disease (stenosis or insufficiency) 7
- Superior or inferior caval venous obstruction—restoration of unobstructed caval flow may be curative 7
Additional Causes
- Radiation enteropathy following pelvic irradiation (>45 Gy), particularly affecting sigmoid and terminal ileum, causing malabsorption, protein loss, diarrhea, and obstruction months to years after treatment 3
- Systemic sclerosis and connective tissue disorders with smooth muscle atrophy and gut wall fibrosis 3
- Amyloidosis (primary type, often with myeloma producing lambda chains) causing both myopathy and neuropathy 3
- HIV enteropathy with decreased CD4+ T lymphocytes 3
- Graft-versus-host disease following bone marrow transplantation, showing crypt cell necrosis and epithelial loss 3
- Small intestinal bacterial overgrowth in patients with anatomical abnormalities or poor motility 3
Critical Diagnostic Pitfall
A common error is diagnosing celiac disease based solely on villous atrophy without performing serologic testing first. 3 Patients with villous atrophy from other causes will not respond to a gluten-free diet. If celiac serology is negative and villous atrophy persists despite gluten-free diet, systematically evaluate for the alternative causes listed above, particularly medication-induced enteropathy, common variable immunodeficiency, autoimmune enteropathy, tropical sprue, infections, and lymphoproliferative disorders 3