The Hidden Burden: Gastrointestinal Involvement in Lysosomal Storage Disorders

Abstract

Background: Lysosomal storage disorders (LSDs) are rare inherited metabolic diseases characterized by defects in lysosomal enzyme function or membrane transport. These defects lead to substrate accumulation and multisystemic manifestations. This review focuses on gastrointestinal (GI) involvement in LSDs, which is a significant but often overlooked aspect of these disorders.

Methods: A comprehensive literature review was conducted to examine the pathophysiology, clinical presentation, diagnosis and management of GI manifestations in several LSDs, including Fabry disease, Gaucher disease, Pompe disease, Niemann-Pick disease type C, mucopolysaccharidoses and Wolman disease.

Results: The pathogenesis of GI involvement in LSDs varies and encompasses substrate accumulation in enterocytes, mesenteric lymphadenopathy, mass effects, smooth muscle dysfunction, vasculopathy, neuropathy, inflammation and alterations to the microbiota. Clinical presentations range from non-specific symptoms, such as abdominal pain, diarrhea and malabsorption, to more severe complications, such as protein-losing enteropathy and inflammatory bowel disease. Diagnosis often requires a high level of suspicion, as GI symptoms may precede the diagnosis of the underlying LSD or be misattributed to more common conditions. Management strategies include disease-specific treatments, such as enzyme replacement therapy or substrate reduction therapy, as well as supportive care and targeted interventions for specific GI complications.

Conclusions: This review highlights the importance of recognizing and properly managing GI manifestations in LSDs to improve patient outcomes and quality of life. It also emphasizes the need for further research to develop more effective treatments for life-threatening GI complications associated with these rare genetic disorders.

Keywords: Fabry disease; Gaucher disease; Niemann–Pick type C; Pompe disease; bowel disease; enteropathy; gastrointestinal involvement; lysosomal acid lipase deficiency; lysosomal storage diseases; mucopolysaccharidoses.

Figure 1

Pathogenic mechanisms of gastrointestinal involvement in Fabry disease.

Figure 2

Pathogenic mechanism of protein-losing enteropathy in GD. Enlarged mesenteric lymph nodes block mesenteric lymphatic outflow, resulting in increased lymphatic pressure and intestinal lymphangiectasia.

Figure 3

More frequent gastrointestinal symptoms reported in patients with IOPD and LOPD.

Figure 4

Pathogenic mechanisms of NPC-associated inflammatory bowel disease. The pathophysiology of NPC-associated IBD involves enhanced STING signaling and impaired NOD2-mediated killing of bacteria. LPS: lipopolysaccharide and MDP: muramyl dipeptide.