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Metallothionein immunohistochemistry has high sensitivity and specificity for detection of Wilson disease

ABSTRACT: Diagnosis of Wilson disease (WD) can be difficult because of its protean clinical presentation, but early diagnosis is important because effective treatment is available and can prevent disease progression. Using quantitative proteomics, we characterized proteins that are differentially expressed in WD compared to normal liver. Further the expression of MT1M and COX17 were validated using immunohistochemistry. We found diffuse MT immunoreactivity in all liver specimens from patients with WD (n=20), the intensity of the staining was moderate to strong. This staining pattern was distinct from that seen in specimens from the control groups which included diseases that may be in the clinical or histologic differential of WD (steatohepatitis (n=51), chronic viral hepatitis (n=40), autoimmune hepatitis (n=50), chronic biliary tract disease (n=42), and normal liver (n=20)). COX17 immunostain showed no significant difference in expression between the WD and control groups. MT had higher sensitivity than rhodanine for diagnosis of WD. While the quantitative liver copper assays also had high sensitivity, they require more tissue, have a higher cost, have longer turnaround time, and are less widely available than an immunohistochemical stain. We conclude that MT IHC is a sensitive immunohistochemical stain for the diagnosis of Wilson disease that could be widely deployed as a screening tool for liver biopsies in which Wilson disease is in the clinical or histologic differential diagnosis.

INSTRUMENT(S): Orbitrap Eclipse

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Liver

DISEASE(S): Wilson Disease

SUBMITTER: Akhilesh Pandey

LAB HEAD: Akhilesh Pandey

PROVIDER: PXD029069 | Pride | 2023-04-18

REPOSITORIES: Pride

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Metallothionein immunohistochemistry has high sensitivity and specificity for detection of Wilson disease.

Rowan Daniel J DJ Mangalaparthi Kiran K KK Singh Smrita S Moreira Roger K RK Mounajjed Taofic T Lamps Laura L Westerhoff Maria M Cheng Jerome J Bellizzi Andrew M AM Allende Daniela S DS Pandey Akhilesh A Graham Rondell P RP

Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 20211221 7

Diagnosis of Wilson disease (WD) can be difficult because of its protean clinical presentations, but early diagnosis is important because effective treatment is available and can prevent disease progression. Similarly, diagnosis of WD on liver biopsy specimens is difficult due to the wide range of histologic appearances. A stain that could help identify WD patients would be of great value. The goal of this study was to use mass spectrometry-based proteomics to identify potential proteins that ar ...[more]

PMID: 34934154

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Project description:Wilson disease (WD) is an autosomal recessive disease caused by mutations in ATP7B encoding a copper transporter. Consequent copper accumulation results in a variable WD clinical phenotype involving hepatic, neurologic, and psychiatric symptoms, without clear genotype-phenotype correlations. The goal of this study was to analyze alterations in DNA methylation at the whole-genome level in liver and blood from patients with WD to investigate epigenomic alterations associated with WD diagnosis and phenotype. We used whole-genome bisulfite sequencing (WGBS) to examine distinct cohorts of WD subjects to determine whether DNA methylation could differentiate patients from healthy subjects and subjects with other liver diseases and distinguish between different WD phenotypes. WGBS analyses in liver identified 969 hypermethylated and 871 hypomethylated differentially methylated regions (DMRs) specifically identifying patients with WD, including 18 regions with genome-wide significance. WD-specific liver DMRs were associated with genes enriched for functions in folate and lipid metabolism and acute inflammatory response and could differentiate early from advanced fibrosis in WD patients. Functional annotation revealed that WD-hypermethylated liver DMRs were enriched in liver-specific enhancers, flanking active liver promoters, and binding sites of liver developmental transcription factors, including Hepatocyte Nuclear Factor 4 alpha (HNF4A), Retinoid X Receptor alpha (RXRA), Forkhead Box A1 (FOXA1), and FOXA2. DMRs associated with WD progression were also identified, including 15 with genome-wide significance. However, WD DMRs in liver were not related to large-scale changes in proportions of liver cell types. DMRs detected in blood differentiated WD patients from healthy and disease control subjects, and distinguished between patients with hepatic and neurologic WD manifestations. WD phenotype DMRs corresponded to genes enriched for functions in mental deterioration, abnormal B cell physiology, and as members of the polycomb repressive complex 1 (PRC1). 44 DMRs associated with WD phenotype tested in a small validation cohort had a predictive value of 0.9. We identified a disease-mechanism relevant epigenomic signature of WD that reveals new insights into potential biomarkers and treatments for this complex monogenic disease.

Dataset Information

Metallothionein immunohistochemistry has high sensitivity and specificity for detection of Wilson disease

Publications

Metallothionein immunohistochemistry has high sensitivity and specificity for detection of Wilson disease.

Similar Datasets

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