Biomarker Discovery in Wilson's Disease-A Path Toward Improved Diagnosis and Management: A Comprehensive Review

Abstract

Wilson's disease (WD) is a rare autosomal recessive disorder characterized by defective copper metabolism, which leads to hepatic and neurological damage. The clinical presentation of WD varies significantly, often resulting in delayed diagnosis and an increased risk of irreversible complications. Current diagnostic tools, including biochemical assays, imaging techniques, and genetic testing, lack sufficient specificity and sensitivity, highlighting the need for novel biomarkers for early diagnosis and treatment monitoring. This review explores emerging biomarkers for both hepatic and neurological manifestations of WD, including blood-based molecular markers such as cytokines, proteases, oxidative stress indicators, inflammasomes, and gut microbiota signatures. Recent studies have identified neurofilament light chain (NfL), pentraxin 3 (PTX3), caspase-3/XIAP, and NLRP3 inflammasome activation as promising indicators of neurological impairment. Additionally, markers like soluble CD163 (sCD163) and apoptosis antigen 1 (APO-1) show potential for assessing hepatic dysfunction. Metabolomic and proteomic analyses further suggest distinct molecular profiles associated with different WD subtypes, while microRNA-based biomarkers offer novel insights into disease progression. Identifying and validating these biomarkers could enhance early diagnosis, predict neurological deterioration, and optimize treatment strategies, ultimately improving patient outcomes. Further research is needed to integrate these biomarkers into clinical practice and establish standardized protocols for their use in WD management.

Keywords: Early diagnosis; Neurological impairment; Novel biomarkers; Treatment monitoring; Wilson’s disease.

Fig. 1

Article selection flowchart. The figure schematically depicts the article selection process, from the literature search, through the screening, up to the final assessment of eligibility

Fig. 2

Pathomechanisms related to copper toxicity involved in neurodegeneration, hepatotoxicity, and immune system damage. A Elevated intracellular copper levels induce a conformational modification in XIAP, promoting its proteasomal degradation and attenuating its capacity to inhibit caspase-3 activation. This dysregulation of XIAP function consequently lowers the apoptotic threshold, rendering cells more susceptible to apoptotic stimuli and ultimately leading to increased cell death. B Excess Cu leads to reduced CREB activation which in turn, decreases BDNF gene transcription, impairing neuronal survival and plasticity. Cu toxicity leads to TrkB downregulation or desensitization, reducing BDNF-mediated neuroprotection. Bcl-2 level, which is downregulated under Cu-induced stress, promotes mitochondrial outer membrane permeabilization triggering apoptosis. C Excess Cu can activate the NLRP3 inflammasome by increasing ROS production and cellular stress. Overactivation of the NLRP3 inflammasome results in the excessive release of proinflammatory interleukins. Abbreviations: BDNF, brain-derived neurotrophic factor; IL-10, interleukin-10; IL-8, interleukin-8; IL-23, interleukin-23; TNFα, TNF receptor-associated factor; XIAP, X-linked inhibitors of apoptosis protein; CTR1, copper transporter 1; CREB, cAMP response element-binding protein; Bcl-2, B cell lymphoma 2; Cu, Copper; TrkB, tropomyosin receptor kinase B; ATP7B, copper-transporting P-type ATPase; ROS, reactive oxygen species; NLRP3, NOD-, LRR-, and Pyrin domain-containing protein 3

Fig. 3

Networks presenting the specific biomarkers and non-coding RNA associated with specific manifestation of WD, either hepatic or neurological

Fig. 4

Networks presenting the specific biomarkers associated with WD regardless of the manifestation