Diagnostic clues in patients with clinical malabsorption and pathological small intestinal villous atrophy: Immune-mediated type and beyond

Small intestinal villi are essential for nutrient absorption, and their impairment can lead to malabsorption. Small intestinal villous atrophy (VA) encompasses a heterogeneous group of disorders, including immune-mediated conditions (e.g. , celiac disease, autoimmune enteropathy, inborn errors of immunity), lymphoproliferative disorders (e.g. , enteropathy-associated T-cell lymphoma), infectious causes (e.g. , tropical sprue, Whipple’s disease), iatrogenic factors (e.g. , Olmesartan-associated enteropathy, graft-vs -host disease), as well as inflammatory and idiopathic types. These disorders are often rare and challenging to distinguish due to overlapping clinical, serological, endoscopic, and histopathological features. Through a systematic literature search using keywords such as small intestinal VA, malabsorption, and specific enteropathies, this review provides a comprehensive overview of diagnostic clues for VA and malabsorption. We systematically summarize the pathological characteristics of each condition to assist pathologists and clinicians in accurately identifying the underlying etiologies. Current studies still have many limitations and lack broader and deeper investigations into these diseases. Therefore, future research should focus on the development of novel diagnostic tools, predictive models, therapeutic targets, and mechanistic molecular studies to refine both diagnosis and management strategies.