Navigating Protein-Losing Enteropathy: A Stepwise Approach for Primary Care Clinicians

Protein-losing enteropathy (PLE) is a rare syndrome characterized by excessive, nonspecific loss of serum proteins through the gastrointestinal tract. More than 60 distinct conditions across organ systems have been associated with PLE. The presentation is often nonspecific-manifesting as edema, diarrhea, or malnutrition-leading to delayed recognition. Protein-losing enteropathy arises through mucosal injury or lymphatic dysfunction. Evaluation requires exclusion of hepatic, renal, and nutritional causes, followed by targeted testing with stool α₁-antitrypsin and upper or lower endoscopy. Early identification enables prompt management of nutritional, immune, and thrombotic complications while also facilitating the detection of secondary causes that may be treatable or reversible. This review provides a practical overview of PLE's pathophysiologic mechanisms, clinical features, diagnostic approach, and indications for subspeciality referral.