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A systematic review of multimodal clinical biomarkers in the management of thyroid eye disease

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Abstract

Thyroid Eye Disease (TED) is an autoimmune disease that affects the extraocular muscles and periorbital fat. It most commonly occurs with Graves’ Disease (GD) as an extrathyroidal manifestation, hence, it is also sometimes used interchangeably with Graves’ Ophthalmopathy (GO). Well-known autoimmune markers for GD include thyroid stimulating hormone (TSH) receptor antibodies (TSH-R-Ab) which contribute to hyperthyroidism and ocular signs. Currently, apart from radiological investigations, detection of TED is based on clinical signs and symptoms which is largely subjective, with no established biomarkers which could differentiate TED from merely GD. We evaluated a total of 28 studies on potential biomarkers for diagnosis of TED. Articles included were published in English, which investigated clinical markers in tear fluid, orbital adipose-connective tissues, orbital fibroblasts and extraocular muscles, serum, thyroid tissue, as well as imaging biomarkers. Results demonstrated that biomarkers with reported diagnostic power have high sensitivity and specificity for TED, including those using a combination of biomarkers to differentiate between TED and GD, as well as the use of magnetic resonance imaging (MRI). Other biomarkers which were upregulated include cytokines, proinflammatory markers, and acute phase reactants in subjects with TED, which are however, deemed less specific to TED. Further clinical investigations for these biomarkers, scrutinising their specificity and sensitivity on a larger sample of patients, may point towards selection of suitable biomarkers for aiding detection and prognosis of TED in the future.

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Abbreviations

ADAMTS14:

ADAM metallopeptidase with thrombospondin type 1 motif 14

ADH1B:

Alcohol dehydrogenase 1B

ALDH2:

Aldehyde dehydrogenase 2

AS:

Ankylosing spondylitis

AOC3:

Metalloproteinase semicarbazide-sensitive amine oxidase 3

ApoE:

Apolipoprotein E

AUC:

Area under curve

AZGP1:

Zinc-alpha-2 glycoprotein

C3:

Complement 3

C4A:

Complement 4A

CA-1:

Carbonic anhydrase 1

CA-2:

Carbonic anhydrase 2

CALR:

Calreticulin

CAS:

Clinical activity score

CDCA5:

Cell division cycle associated 5

COL2A1:

Collagen type II alpha I

COL11A2:

Collagen type XI alpha 2

CSRP3:

Cysteine and glycine rich protein 3

CYR61:

Cysteine-rich angiogenic inducer 61

ECM:

Extracellular matrix

ELISA:

Enzyme-linked immunosorbent assay

EOM:

Extraocular muscles

ER:

Endoplasmic reticulum

EUGOGO:

European Group on Graves’ Orbitopathy

FCN1:

Ficolin 1

G proteins:

Guanine nucleotide-binding proteins

GC:

Glucocorticoid

GD:

Graves’ disease

GO:

Graves’ ophthalmopathy

GPDH:

Glycerol-3-phosphate dehydrogenase

GR \(\alpha\) :

Glucocorticoid receptor alpha

GSK-3 \(\beta\) :

Glycogen synthase kinase 3 beta

HIF-1 \(\alpha\) :

Hypoxia-induced factor 1\(\alpha\) 

HMGB1:

High-mobility group box 1

HSP 60:

Heat shock protein 60

IDH:

Isocitrate dehydrogenase

IFN-\(\gamma\) :

Interferon gamma

IGF-1:

Insulin-like growth factor-1

IgKC:

Immunoglobulin kappa chain C region

IHC:

Immunohistochemistry

IL:

Interleukin

IMP:

Inosine monophosphate

KIF:

Kinesin family member

LACRT:

Lacritin

LCN1:

Lipocalin 1

LDLR:

Low-density lipoprotein receptor

LGH:

Lacrimal gland herniation

LYZ:

Lysozyme C

MCP-1:

Monocyte chemoattractant protein-1

MHC:

Major histocompatibility complex

MKI67:

Marker of proliferation Ki-67

MMP:

Matrix metalloproteinase

mTOR:

Mammalian target of rapamycin

MRI:

Magnetic resonance imaging

MYH:

Myosin heavy chain

NADPH:

Micotinamide adenine dinucleotide phosphate

NCAPRP:

Nasopharyngeal carcinoma-associated proline-rich protein 4

NLR:

Neutrophil-to-lymphocyte ratio

NPV:

Negative predictive value

P4HB:

Protein disulphide-isomerase

PCR:

Polymerase chain reaction

PCSK9:

Proprotein convertase subtilisin/kexin type 9

PDIA3:

Protein disulfide-isomerase A3

PI3k:

Phosphatidylinositol-3-kinase

PIP:

Prolactin induced protein

POCT:

Point-of-care testing

POTEI:

POTE ankyrin domain family member 1

PPAR:

Peroxisome proliferator-activated receptors

PPV:

Positive predictive value

PRC1:

Protein regulator of cytokinesis 1

PROL1:

Proline-rich protein 1

PROL4:

Proline-rich protein 4

PRP4:

Proline-rich protein 4

PTX3:

Pentraxin 3

RAGE:

Receptor for advanced glycation end product

RAI:

Radioactive iodine

RT-PCR:

Reverse transcriptase polymerase chain reaction

ROC:

Receiver operator characteristic

ROS:

Reactive oxygen species

S100A4:

S100 calcium binding protein A4

S100A8:

Calgranulin A

S100A8/A9:

Calprotectin

SIR:

Signal intensity ratio

SLE:

Systemic lupus erythematosus

SMC3:

Structural maintenance of chromosomes protein 3

SMCA4:

Transcription-activator BRG1

SOD:

Superoxide dismutase

SRR:

Specimen-to-reference ratio

TAO:

Thyroid-associated orbitopathy

TBII:

Thyroid stimulating hormone receptor binding inhibitory immunoglobulin

TED:

Thyroid eye disease

TER ATPase:

Transitional endoplasmic reticulum ATPase

TIRTCS :

T1 relaxation time cold spot

TLR:

Toll-like receptor

TNF-\(\alpha\) :

Tumour necrosis factor alpha

TNF AIP6:

Tumour necrosis factor alpha-induced protein 6

TPX2:

Targeting protein for the Xenopuskinesinxklp2

TRAb:

Thyroid stimulating hormone receptor antibodies

TSH:

Thyroid stimulating hormone

TSHR:

Thyroid stimulating hormone receptor

TSH-R-Ab:

Thyroid stimulating hormone receptor antibody

TSI:

Thyroid stimulating hormone receptor stimulating immunoglobulin

TWEAK:

Tumour necrosis factor-like weak inducer of apoptosis

UBR1:

Ubiquitin-protein ligase E3 component N-recognin 1

VCAN:

Versican

WBC:

White blood cell

ZNF263:

Zinc finger protein 263

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  1. Department of Ophthalmology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, 301B Cyberport 4, 100 Cyberport Road, Pokfulam, Hong Kong SAR

    Stephanie Hiu Ling Poon, Kendrick Co Shih & Yau Kei Chan

  2. C-MER Dennis Lam & Partners Eye Centre, Central, Hong Kong SAR

    Janice Jing-Chee Cheung

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Poon, S.H.L., Cheung, J.JC., Shih, K.C. et al. A systematic review of multimodal clinical biomarkers in the management of thyroid eye disease. Rev Endocr Metab Disord 23, 541–567 (2022). https://doi.org/10.1007/s11154-021-09702-9

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