Table 2.

The list of 16 untargeted studies related to the cometabolites in TC

	Title of article	First author	Year	Country	Sample size	Type of study	Metabolite measurement techniques	Significant different metabolites
1.	Development of data independent acquisition workflows for metabolomic analysis on a quadrupole-orbitrap platform49	Juntuo Zhou	2017	China	n: 30 TC n: 27 HI	Case/control	LC-DIA-MS	Carnitine Trimethylamine N-oxide Some amino acids
2.	Analysis on the metabolite composition of serum samples from patients with papillary thyroid carcinoma using NMR50	Wen-Xin Zhao	2015	China	n: 20 PTC n: 20 BTN n: 20 HI	Case/control	NOEPR-CPMG NMR	A list of metabolites involves glucose metabolism, lipids, amino acids, and nucleic acid
3.	Detection of metastatic breast and TC in lymph nodes by desorption electrospray ionization mass spectrometry imaging51	Jialing Zhang	2017	USA	n: 18 NLN n: 8 LNMP n: 16 LNMBC	Case/control	DESI-MS	Ceramides Glycerophosphoinositol
4.	Serum metabolic profiling and features of papillary thyroid carcinoma and nodular goiter52	Zhenzhen Yao	2011	China	n: 30 PTC n: 80 MNG n: 30 HI	Case/control	Liquid chromatography-LTQ Orbitrap MS	3-Hydroxybutyric acid
5.	Distinct metabolomic profiles of papillary thyroid carcinoma and benign thyroid adenoma53	Yanan Xu	2015	China	n: 57 PTC n: 48 BTA	Case/control	GC-TOFMS UPLC–Q-TOF-MS	Purine and pyrimidine metabolites Taurine Hypotaurine
6.	Serum and urine 1H NMR-based metabolomics in the diagnosis of selected thyroid diseases54	Wojciech Wojtowicz	2017	Poland	n: 20 NN n: 13 FA n: 17 TC n: 17 HI	Case/control	NMR	Amino acids: alanine, creatine, glutamine, tyrosine, valine Carboxylic acids: acetate, citrate, formate, lactate Monosaccharides: glucose Alcohols: glycerol Imidazolinones: creatinine
7.	Metabolic alteration of urinary steroids in premenopausal and postmenopausal women and men with papillary thyroid carcinoma55	Man Ho Choi	2011	Korea	n: 21 premenopausal female n: 19 postmenopausal female n: 16 male PTC	Case/control	GC-MS	Androgens Androstenedione Androstenediol 16α-hydroxy DHEA Corticoid
9.	Metabolomics approach to thyroid nodules: a high-resolution magic-angle spinning NMR-based study31	Paolo Miccoli	2012	Italy, France, Brazil	n: 28 PTC n: 40 FA n: 4 BN	Case/control	HRMAS HRMAS-NMR	Lactate Taurine Phosphocholine Myo-inositol Scyllo-inositol
10.	Metabolomic analysis of percutaneous fine-needle aspiration specimens of thyroid nodules: potential application for thepreoperative diagnosis of TC57	Inseon Ryoo	2016	Korea	n: 35 PTC n: 69 BN	Case/control	NMR	Lactate Glycine Citrate Glutamine Glutamate Choline O-phosphocholine
11.	A distinct serum metabolic signature of distant metastatic papillary thyroid carcinoma58	Chen-Tian Shen	2017	China	n: 37 distant metastatic PTC n: 40 ablation group	Case/control	GC-TOF-MS	Phthalimide, cyclohexanamine, aminooxyacetic acid, 3-hydroxypyruvate, carbamate, canavanine, creatine, asparagine, uridine, 4-deoxypyridoxine, 2-hydroxypyridine, γ-aminobutyric acid, myo-inositol, pyroglutamic acid, stearic acid, palmitic acid, fructose, heptadecanoic acid, phenyl acetate, glycerol-3-phosphate, lactose, arachidic acid, uric acid, valine, palmitoleic acid, γ-linoleic acid, parabanic acid, picolinic acid, oxalic acid, uracil, d-altrose
12.	Toward the reliable diagnosis of indeterminate thyroid lesions: a HRMAS NMR-based metabolomics case of study59	Liborio Torregrossa	2012	Italy, France, Brazil	n: 72 PTC	Case series	HRMAS	↑ PHE, taurine, and lactate ↓ Choline and choline derivatives ↓ myo- and scyllo-inositol
13.	Exhaled breath volatile biomarker analysis for TC60	Lei Guo	2015	China	n: 39 PTC n: 25 MNG	Case/control	GC/MS	Sulfurous acid, cyclohexylmethyl hexyl ester, isolongifolene-5-ol, 3,5-Decadien-7-yne, 6-t-butyl-2,2,9,9-tetramethyl, cyclohexanone, 4-hydroxybutyric acid, phenol, 2,2-dimethyldecane, ethylhexanol, ethylene glycol mono vinyl ester, cyclopropane, 1-bromo-1-(3-methyl-1-pentenylidene)–2,2,3,3-tetramethyl, (3-Methyl-oxiran-2-yl)-methanol, cyclopentane, 1,1,3-trimethyl-3-(2-methyl-2-propenyl), trans-2-dodecen-1-ol
14.	Association of PBDEs and hydroxylated metabolites (OH-PBDEs) serum levels with thyroid function in TC patients61	Sisi Lui	2017	China	n: 33 PTC	Case series	Chemiluminescence enzyme immunoassay	Diphenylethers (PBDEs) Hydroxylated metabolites (OH-PBDEs)
15.	Noninvasive diagnosis of papillary thyroid microcarcinoma: a NMR-based metabolomics approach62	Jinghui Lu	2016	China, Italy	n: 35 PTC	Case series	HRMAS H-NMR	Lysine Glutamate Tyrosine Catecholamines (dopamine, norepinephrine, and epinephrine)
16.	Follicular adenomas exhibit a unique metabolic profile. 1H NMR studies of thyroid lesions63	StanisławDeja	2013	Poland	n: 45 TC n: 19 HI	Cohort	H-NMR	Isoleucine, valine, alanine, NACs, methionine, citrate, creatine, choline, GPC, scyllo-inositol, taurine, glycine, myo-inositol, lactate, histidine, tyrosine, phenylalanine

Abbreviations: BN, benign nodule; BTA, benign thyroid adenoma; BTN, benign thyroid nodule; DESI-MS, desorption electrospray ionization mass spectrometry; DHEA, dehydroepiandrosterone; FA, follicular adenoma; GC-TOF-MS, gas chromatography–time-of-flight mass spectrometry; GC-MS, gas chromatography–mass spectrometry; HI, healthy individual; HRMAS, high-resolution magic angle spinning; LC-DIA-MS, liquid chromatography–data independent-mass spectrometry; LNMBC, lymph node with metastatic breast cancer; LNMP, lymph node with metastatic NAC, N-acetyl-cysteine; PHE, phenylalanine; PTC; MNG, multinodular goiter; NAT, normal adjacent tissue; NOEPR, nuclear over Hauser effect spectroscopy with P re-saturation; CPMG, Carr-Pure-Me boom-Gill sequence; NLN, normal lymph node; NMR, nuclear magnetic resonance; NN, non-neoplastic nodule; OH-PBDE, hydroxylated polybrominated diphenylether; PBDE, polybrominated diphenylether; PTC, papillary thyroid carcinoma; TC, thyroid cancer; UPCL-Q-TOF-MS, The ultra-high performance liquid chromatography-quadrupole time-of-flight mass spectrometry.