Thyroid involvement in lysosomal storage diseases: current evidence and clinical perspectives

Lysosomal storage diseases are inherited multisystem disorders caused by defects in lysosomal enzymes, transporters, or associated proteins, leading to intracellular substrate accumulation and progressive organ dysfunction. The thyroid gland may be particularly vulnerable because hormone release depends on thyroglobulin endocytosis, endosomal trafficking, lysosomal proteolysis, iodide recycling, and cellular proteostasis. This review summarizes current evidence on thyroid involvement in lysosomal storage diseases, with emphasis on clinical manifestations, pathophysiological mechanisms, diagnostic evaluation, and management. A literature search was performed in PubMed/MEDLINE, Scopus, Web of Science, and Google Scholar from database inception through August 31, 2026. Eligible clinical, review, and experimental studies addressing thyroid function, morphology, autoimmunity, treatment effects, or bidirectional thyroid-lysosomal mechanisms were descriptively synthesized. The strongest association is observed in nephropathic cystinosis, in which progressive primary hypothyroidism is frequent and may be delayed by early cysteamine therapy. Thyroid abnormalities have also been reported in Fabry disease, Gaucher disease, Hurler syndrome, and Pompe disease, although evidence is less consistent and often based on small cohorts, isolated reports, or animal models. Proposed mechanisms include direct substrate accumulation, impaired thyroglobulin processing, altered autophagy and proteostasis, oxidative and inflammatory injury, microvascular dysfunction, and indirect effects of chronic systemic disease. Experimental evidence also suggests that thyroid hormones can modulate lysosomal activity, although clinical relevance remains unproven. Routine disease-specific surveillance is best supported in nephropathic cystinosis; in other lysosomal storage diseases, thyroid assessment should be individualized. Prospective multicenter studies and standardized screening protocols are needed to clarify prevalence, natural history, reversibility, and optimal management.