THYROID PROFILE AND LIPID PEROXIDATION IN DOWN SYNDROME: A REVIEW
Main Article Content
Keywords
Down syndrome, thyroid dysfunction, oxidative stress, lipid peroxidation, mitochondrial dysfunction
Abstract
Trisomy 21 causes Down Syndrome(DS), a chromosome condition characterized by numerous systemic dysfunctions, of which oxidative stress and thyroid abnormalities are particularly evident. These interconnected disorders have a major role in early-onset neurodegeneration, metabolic impairment, and neurodevelopmental abnormalities. To summarize the current understanding of the relationship between thyroid dysfunction and oxidative stress in people with Down syndrome, this review will focus on common molecular pathways, clinical implications, diagnostic biomarkers, and new treatment approaches. Data on thyroid hormone modulation, oxidative damage biomarkers, and their interaction in DS were analysed by a thorough assessment of peer-reviewed literature. Molecular processes, diagnostic approaches, and translational limitations in clinical applicability were highlighted. Hypothyroidism, which is commonly asymptomatic and underdiagnosed, is a common feature of thyroid dysfunction in DS. At the same time, overexpression of genes like Superoxide Dismutase 1(SOD1) and Regulator of Calcineurin 1 (RCAN1) makes mitochondrial dysfunction and the buildup of reactive oxygen species (ROS) worse. Malondialdehyde (MDA) and 4-Hydroxynonenal (4-HNE) are examples of lipid peroxidation products that not only indicate systemic oxidative stress but also reduce the activity of thyroid enzymes, especially thyroid peroxidase (TPO). Both oxidative damage and endocrine disruption are exacerbated by this reciprocal interplay. Treatment strategies are still dispersed, and hormonal and oxidative indicators are not sufficiently integrated into the current diagnosis. The oxidative stress and thyroid dysfunction both affect DS, which highlights the need for individualized treatment plans and integrated diagnostic methods. For precision medicine in DS, future research should give priority to multi-omics profiling, AI-enhanced biomarker analysis, and longitudinal cohort studies.
References
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28. Muchova, L., Wong, R. J., Hsu, M., Morioka, I., Vitek, L., Zelenka, J., ... & Stevenson, D. K. (2007). Statin treatment increases formation of carbon monoxide and bilirubin in mice: a novel mechanism of in vivo antioxidant protection. Canadian journal of physiology and pharmacology, 85(8), 800-810.
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30. Nakanishi, T. (2015). A meta‐analysis of extensive reading research. Tesol Quarterly, 49(1), 6-37.
31. Ndakotsu, A., Dwumah-Agyen, M., & Patel, M. (2024). The Bidirectional Relationship Between Obstructive Sleep Apnea and Atrial Fibrillation: Pathophysiology, Diagnostic Challenges, and Strategies-A Narrative Review. Current Problems in Cardiology, 102873.
32. Ortiga‐Carvalho, T. M., Chiamolera, M. I., Pazos‐Moura, C. C., & Wondisford, F. E. (2011). Hypothalamus‐pituitary‐thyroid axis. Comprehensive physiology, 6(3), 1387-1428.
33. Pepe, G., Corica, D., De Sanctis, L., Salerno, M., Faienza, M. F., Tessaris, D., ... & Wasniewska, M. (2020). Prospective evaluation of autoimmune and non-autoimmune subclinical hypothyroidism in Down Syndromechildren. European Journal of Endocrinology, 182(4), 385-392.
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39. Rueda Revilla, N., & Martínez-Cué, C. (2020). Antioxidants in down syndrome: From preclinical studies to clinical trials. Antioxidants, 9(8), 692.
40. Sarici, D., Akin, M. A., Kurtoglu, S., Gunes, T., Ozturk, M. A., & Akcakus, M. (2012). Thyroid functions of neonates with Down syndrome. Italian journal of pediatrics, 38, 1-3.
41. Shaikh, M. A., Al-Rawashdeh, H. S., & Sait, A. R. W. (2025). A Review of Artificial Intelligence-Based Down SyndromeDetection Techniques. Life, 15(3), 390.
42. Singh, A., Kukreti, R., Saso, L., & Kukreti, S. (2019). Oxidative stress: a key modulator in neurodegenerative diseases. Molecules, 24(8), 1583.
43. Smedinga, M., Tromp, K., Schermer, M. H., & Richard, E. (2018). Ethical arguments concerning the use of Alzheimer’s disease biomarkers in individuals with no or mild cognitive impairment: A systematic review and framework for discussion. Journal of Alzheimer’s disease, 66(4), 1309-1322.
44. Spickett, C. M. (2013). The lipid peroxidation product 4-hydroxy-2-nonenal: advances in chemistry and analysis. Redox biology, 1(1), 145-152.
45. Sheiham, A., Williams, D. M., Weyant, R. J., Glick, M., Naidoo, S., Eisele, J. L., & Selikowitz, H. S. (2015). Billions with oral disease: a global health crisis—a call to action. The Journal of the American Dental Association, 146(12), 861-864.
46. Santoro, J. D., Patel, L., Kammeyer, R., Filipink, R. A., Gombolay, G. Y., Cardinale, K. M., ... & Rafii, M. S. (2022). Assessment and diagnosis of Down Syndromeregression disorder: international expert consensus. Frontiers in neurology, 13, 940175.
47. Tiano, L., Padella, L., Carnevali, P., Gabrielli, O., Bruge, F., Principi, F., & Littarru, G. P. (2008). Coenzyme Q10 and oxidative imbalance in Down syndrome: biochemical and clinical aspects. Biofactors, 32(1‐4), 161-167.
48. Tolun, A. A., Scarbrough, P. M., Zhang, H., McKillop, J. A., Wang, F., Kishnani, P. S., ... & Il’yasova, D. (2012). Systemic oxidative stress, as measured by urinary allantoin and F2-isoprostanes, is not increased in Down syndrome. Annals of epidemiology, 22(12), 892-894.
49. Tiano, L., & Busciglio, J. (2011). Mitochondrial dysfunction and Down's syndrome: Is there a role for coenzyme Q10?. Biofactors, 37(5), 386-392.
50. Uddin, M., Wang, Y., & Woodbury-Smith, M. (2019). Artificial intelligence for precision medicine in neurodevelopmental disorders. NPJ digital medicine, 2(1), 112.
51. Villanueva, I., Alva-Sánchez, C., & Pacheco-Rosado, J. (2013). The role of thyroid hormones as inductors of oxidative stress and neurodegeneration. Oxidative medicine and cellular longevity, 2013(1), 218145.
52. Vissenberg, R., Manders, V. D., Mastenbroek, S., Fliers, E., Afink, G. B., Ris-Stalpers, C., ... & Bisschop, P. H. (2015). Pathophysiological aspects of thyroid hormone disorders/thyroid peroxidase autoantibodies and reproduction. Human reproduction update, 21(3), 378-387.
53. van Trotsenburg, A. P., Heymans, H. S., Tijssen, J. G., de Vijlder, J. J., & Vulsma, T. (2006). Comorbidity, hospitalization, and medication use and their influence on mental and motor development of young infants with Down syndrome. Pediatrics, 118(4), 1633-1639.
54. Zhong, H., & Yin, H. (2015). Role of lipid peroxidation derived 4-hydroxynonenal (4-HNE) in cancer: focusing on mitochondria. Redox Biol 4: 193–199.
55. Žitňanová, I., Korytár, P., Sobotová, H., Horáková, L. U., Šustrová, M., Pueschel, S., & Ďuračková, Z. (2006). Markers of oxidative stress in children with Down syndrome. Clinical Chemistry and Laboratory Medicine (CCLM), 44(3), 306-310.
56. Zis, P., & Strydom, A. (2018). Clinical aspects and biomarkers of Alzheimer's disease in Down syndrome. Free Radical Biology and Medicine, 114, 3-9.
2. Alexandrov, P. N., Percy, M. E., & Lukiw, W. J. (2018). Chromosome 21-encoded microRNAs (mRNAs): impact on Down’s Syndromeand trisomy-21 linked disease. Cellular and molecular neurobiology, 38, 769-774.
3. Alldred, M. J., Martini, A. C., Patterson, D., Hendrix, J., & Granholm, A. C. (2021). Aging with Down syndrome—where are we now and where are we going?. Journal of clinical medicine, 10(20), 4687.
4. Aversa, T., Lombardo, F., Valenzise, M., Messina, M. F., Sferlazzas, C., Salzano, G., ... & Wasniewska, M. (2015). Peculiarities of autoimmune thyroid diseases in children with Turner or Down syndrome: an overview. Italian journal of paediatrics, 41, 1-5.
5. Bartley, M. G., Marquardt, K., Kirchhof, D., Wilkins, H. M., Patterson, D., & Linseman, D. A. (2012). Overexpression of amyloid-β protein precursor induces mitochondrial oxidative stress and activates the intrinsic apoptotic cascade. Journal of Alzheimer’s Disease, 28(4), 855-868.
6. Campos, C., Guzmán, R., López-Fernández, E., & Casado, Á. (2011). Evaluation of urinary biomarkers of oxidative/nitrosative stress in children with Down syndrome. Life sciences, 89(17-18), 655-661.
7. Chow, J., Rahman, J., Achermann, J. C., Dattani, M. T., & Rahman, S. (2017). Mitochondrial disease and endocrine dysfunction. Nature Reviews Endocrinology, 13(2), 92-104.
8. Colvin, K. L., & Yeager, M. E. (2017). What people with Down Syndromecan teach us about cardiopulmonary disease. European Respiratory Review, 26(143).
9. Convertini, P., Menga, A., Andria, G., Scala, I., Santarsiero, A., Castiglione Morelli, M. A., ... & Infantino, V. (2016). The contribution of the citrate pathway to oxidative stress in Down syndrome. Immunology, 149(4), 423-431.
10. Ferrari, M., & Stagi, S. (2021). Oxidative stress in Down and Williams-Beuren syndromes: an overview. Molecules, 26(11), 3139.
11. Ganguly, G., Chakrabarti, S., Chatterjee, U., & Saso, L. (2017). Proteinopathy, oxidative stress and mitochondrial dysfunction: cross talk in Alzheimer’s disease and Parkinson’s disease. Drug design, development and therapy, 797-810.
12. Garlet, T. R., Parisotto, E. B., de Medeiros, G. D. S., Pereira, L. C. R., Dalmarco, E. M., Dalmarco, J. B., & Wilhelm Filho, D. (2013). Systemic oxidative stress in children and teenagers with Down syndrome. Life sciences, 93(16), 558-563.
13. Gillenwater, L. A., Galbraith, M. D., Rachubinski, A. L., Eduthan, N. P., Sullivan, K. D., Espinosa, J. M., & Costello, J. C. (2024). Integrated analysis of immunometabolic interactions in Down syndrome. Science Advances, 10(50), eadq3073.
14. Hamlett, E. D., Ledreux, A., Potter, H., Chial, H. J., Patterson, D., Espinosa, J. M., ... & Granholm, A. C. (2018). Exosomal biomarkers in Down Syndromeand Alzheimer's disease. Free Radical Biology and Medicine, 114, 110-121.
15. Helguera, P., Seiglie, J., Rodriguez, J., Hanna, M., Helguera, G., & Busciglio, J. (2013). Adaptive downregulation of mitochondrial function in down syndrome. Cell metabolism, 17(1), 132-140.
16. Ioannidis, J. P., & Bossuyt, P. M. (2017). Waste, leaks, and failures in the biomarker pipeline. Clinical chemistry, 63(5), 963-972.
17. Ishihara, K., & Akiba, S. (2017). A comprehensive diverse ‘-omics’ approach to better understanding the molecular pathomechanisms of down syndrome. Brain Sciences, 7(4), 44.
18. Iughetti, L., Predieri, B., Bruzzi, P., Predieri, F., Vellani, G., Madeo, S. F., ... & Bozzola, M. (2014). Ten-year longitudinal study of thyroid function in children with Down's syndrome. Hormone research in paediatrics, 82(2), 113-121.
19. Izzo, A., Mollo, N., Nitti, M., Paladino, S., Calì, G., Genesio, R., ... & Nitsch, L. (2018). Mitochondrial dysfunction in down syndrome: molecular mechanisms and therapeutic targets. Molecular Medicine, 24, 1-8.
20. Koul, A. M., Ahmad, F., Bhat, A., Aein, Q. U., Ahmad, A., Reshi, A. A., & Kaul, R. U. R. (2023). Unraveling Down syndrome: from genetic anomaly to artificial intelligence-enhanced diagnosis. Biomedicines, 11(12), 3284.
21. Lanzillotta, C., & Di Domenico, F. (2021). Stress responses in down Syndromeneurodegeneration: state of the art and therapeutic molecules. Biomolecules, 11(2), 266.
22. Lee, N. C., Chien, Y. H., & Hwu, W. L. (2017). A review of biomarkers for Alzheimer’s disease in Down syndrome. Neurology and Therapy, 6, 69-81.
23. Ma, X., Li, W., Ma, J., Han, Z., Deng, S., & Wang, S. (2024). Autophagy is a promising process for linking inflammation and redox homeostasis in Down syndrome. Frontiers in Pharmacology, 15, 1491563.
24. McPartland, J. C. (2016). Considerations in biomarker development for neurodevelopmental disorders. Current opinion in neurology, 29(2), 118-122.
25. Mégarbané, A., Ravel, A., Mircher, C., Sturtz, F., Grattau, Y., Rethoré, M. O., ... & Mobley, W. C. (2009). The 50th anniversary of the discovery of trisomy 21: the past, present, and future of research and treatment of Down syndrome. Genetics in medicine, 11(9), 611-616.
26. Miranda, S., Opazo, C., Larrondo, L. F., Muñoz, F. J., Ruiz, F., Leighton, F., & Inestrosa, N. C. (2000). The role of oxidative stress in the toxicity induced by amyloid β-peptide in Alzheimer’s disease. Progress in neurobiology, 62(6), 633-648.
27. Molinari, S., Fossati, C., Nicolosi, M. L., Di Marco, S., Faraguna, M. C., Limido, F., ... & Cattoni, A. (2024). Endocrine, auxological and metabolic profile in children and adolescents with Down syndrome: from infancy to the first steps into adult life. Frontiers in Endocrinology, 15, 1348397.
28. Muchova, L., Wong, R. J., Hsu, M., Morioka, I., Vitek, L., Zelenka, J., ... & Stevenson, D. K. (2007). Statin treatment increases formation of carbon monoxide and bilirubin in mice: a novel mechanism of in vivo antioxidant protection. Canadian journal of physiology and pharmacology, 85(8), 800-810.
29. Niedzielska, E., Smaga, I., Gawlik, M., Moniczewski, A., Stankowicz, P., Pera, J., & Filip, M. (2016). Oxidative stress in neurodegenerative diseases. Molecular neurobiology, 53, 4094-4125.
30. Nakanishi, T. (2015). A meta‐analysis of extensive reading research. Tesol Quarterly, 49(1), 6-37.
31. Ndakotsu, A., Dwumah-Agyen, M., & Patel, M. (2024). The Bidirectional Relationship Between Obstructive Sleep Apnea and Atrial Fibrillation: Pathophysiology, Diagnostic Challenges, and Strategies-A Narrative Review. Current Problems in Cardiology, 102873.
32. Ortiga‐Carvalho, T. M., Chiamolera, M. I., Pazos‐Moura, C. C., & Wondisford, F. E. (2011). Hypothalamus‐pituitary‐thyroid axis. Comprehensive physiology, 6(3), 1387-1428.
33. Pepe, G., Corica, D., De Sanctis, L., Salerno, M., Faienza, M. F., Tessaris, D., ... & Wasniewska, M. (2020). Prospective evaluation of autoimmune and non-autoimmune subclinical hypothyroidism in Down Syndromechildren. European Journal of Endocrinology, 182(4), 385-392.
34. Pinter, J. (2018). Does central bank financial strength really matter for inflation? The key role of the fiscal support. Open Economies Review, 29(5), 911-952.
35. Pierce, M. J., LaFranchi, S. H., & Pinter, J. D. (2017). Characterization of thyroid abnormalities in a large cohort of children with Down syndrome. Hormone research in paediatrics, 87(3), 170-178.
36. Parisotto, E., Ba, J. L., & Salakhutdinov, R. (2015). Actor-mimic: Deep multitask and transfer reinforcement learning. arXiv preprint arXiv:1511.06342.
37. Porteri, C., Albanese, E., Scerri, C., Carrillo, M. C., Snyder, H. M., Martensson, B., ... & for the Roadmap, G. T. F. (2017). The biomarker-based diagnosis of Alzheimer's disease. 1—ethical and societal issues. Neurobiology of aging, 52, 132-140.
38. Rodríguez-Sureda, V., Vilches, Á., Sánchez, O., Audí, L., & Domínguez, C. (2015). Intracellular oxidant activity, antioxidant enzyme defense system, and cell senescence in fibroblasts with trisomy 21. Oxidative Medicine and Cellular Longevity, 2015(1), 509241.
39. Rueda Revilla, N., & Martínez-Cué, C. (2020). Antioxidants in down syndrome: From preclinical studies to clinical trials. Antioxidants, 9(8), 692.
40. Sarici, D., Akin, M. A., Kurtoglu, S., Gunes, T., Ozturk, M. A., & Akcakus, M. (2012). Thyroid functions of neonates with Down syndrome. Italian journal of pediatrics, 38, 1-3.
41. Shaikh, M. A., Al-Rawashdeh, H. S., & Sait, A. R. W. (2025). A Review of Artificial Intelligence-Based Down SyndromeDetection Techniques. Life, 15(3), 390.
42. Singh, A., Kukreti, R., Saso, L., & Kukreti, S. (2019). Oxidative stress: a key modulator in neurodegenerative diseases. Molecules, 24(8), 1583.
43. Smedinga, M., Tromp, K., Schermer, M. H., & Richard, E. (2018). Ethical arguments concerning the use of Alzheimer’s disease biomarkers in individuals with no or mild cognitive impairment: A systematic review and framework for discussion. Journal of Alzheimer’s disease, 66(4), 1309-1322.
44. Spickett, C. M. (2013). The lipid peroxidation product 4-hydroxy-2-nonenal: advances in chemistry and analysis. Redox biology, 1(1), 145-152.
45. Sheiham, A., Williams, D. M., Weyant, R. J., Glick, M., Naidoo, S., Eisele, J. L., & Selikowitz, H. S. (2015). Billions with oral disease: a global health crisis—a call to action. The Journal of the American Dental Association, 146(12), 861-864.
46. Santoro, J. D., Patel, L., Kammeyer, R., Filipink, R. A., Gombolay, G. Y., Cardinale, K. M., ... & Rafii, M. S. (2022). Assessment and diagnosis of Down Syndromeregression disorder: international expert consensus. Frontiers in neurology, 13, 940175.
47. Tiano, L., Padella, L., Carnevali, P., Gabrielli, O., Bruge, F., Principi, F., & Littarru, G. P. (2008). Coenzyme Q10 and oxidative imbalance in Down syndrome: biochemical and clinical aspects. Biofactors, 32(1‐4), 161-167.
48. Tolun, A. A., Scarbrough, P. M., Zhang, H., McKillop, J. A., Wang, F., Kishnani, P. S., ... & Il’yasova, D. (2012). Systemic oxidative stress, as measured by urinary allantoin and F2-isoprostanes, is not increased in Down syndrome. Annals of epidemiology, 22(12), 892-894.
49. Tiano, L., & Busciglio, J. (2011). Mitochondrial dysfunction and Down's syndrome: Is there a role for coenzyme Q10?. Biofactors, 37(5), 386-392.
50. Uddin, M., Wang, Y., & Woodbury-Smith, M. (2019). Artificial intelligence for precision medicine in neurodevelopmental disorders. NPJ digital medicine, 2(1), 112.
51. Villanueva, I., Alva-Sánchez, C., & Pacheco-Rosado, J. (2013). The role of thyroid hormones as inductors of oxidative stress and neurodegeneration. Oxidative medicine and cellular longevity, 2013(1), 218145.
52. Vissenberg, R., Manders, V. D., Mastenbroek, S., Fliers, E., Afink, G. B., Ris-Stalpers, C., ... & Bisschop, P. H. (2015). Pathophysiological aspects of thyroid hormone disorders/thyroid peroxidase autoantibodies and reproduction. Human reproduction update, 21(3), 378-387.
53. van Trotsenburg, A. P., Heymans, H. S., Tijssen, J. G., de Vijlder, J. J., & Vulsma, T. (2006). Comorbidity, hospitalization, and medication use and their influence on mental and motor development of young infants with Down syndrome. Pediatrics, 118(4), 1633-1639.
54. Zhong, H., & Yin, H. (2015). Role of lipid peroxidation derived 4-hydroxynonenal (4-HNE) in cancer: focusing on mitochondria. Redox Biol 4: 193–199.
55. Žitňanová, I., Korytár, P., Sobotová, H., Horáková, L. U., Šustrová, M., Pueschel, S., & Ďuračková, Z. (2006). Markers of oxidative stress in children with Down syndrome. Clinical Chemistry and Laboratory Medicine (CCLM), 44(3), 306-310.
56. Zis, P., & Strydom, A. (2018). Clinical aspects and biomarkers of Alzheimer's disease in Down syndrome. Free Radical Biology and Medicine, 114, 3-9.
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Jun 29, 2025
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Dr. Gangadharan Jaikrishan. (2025). THYROID PROFILE AND LIPID PEROXIDATION IN DOWN SYNDROME: A REVIEW. Journal of Population Therapeutics and Clinical Pharmacology, 32(6), 421-437. https://doi.org/10.53555/ka8nx583
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Author Biography
Dr. Gangadharan Jaikrishan
MBBS MD, Department of Biochemistry Azeezia Institute of Medical Science and Research, Meeyannoor P.O, Kollam 691 537 Kerala
How to Cite
Dr. Gangadharan Jaikrishan. (2025). THYROID PROFILE AND LIPID PEROXIDATION IN DOWN SYNDROME: A REVIEW. Journal of Population Therapeutics and Clinical Pharmacology, 32(6), 421-437. https://doi.org/10.53555/ka8nx583