Endocrinology and Metabolism

Original Articles

Thyroid
In Vitro Investigation of HIF-1α as a Therapeutic Target for Thyroid-Associated Ophthalmopathy: Jeongmin Lee, Jinsoo Lee, Hansang Baek, Dong-Jun Lim, Seong-Beom Lee, Jung-Min Lee, Sang-Ah Jang, Moo Il Kang, Suk-Woo Yang, Min-Hee Kim; Endocrinol Metab. 2024;39(5):767-776. Published online October 16, 2024; DOI: https://doi.org/10.3803/EnM.2024.1952

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Abstract PDF Supplementary Material PubReader ePub: Background
Thyroid-associated ophthalmopathy (TAO) involves tissue expansion and inflammation, potentially causing a hypoxic microenvironment. Hypoxia-inducible factor (HIF)-1α is crucial in fibrosis and adipogenesis, which are observed in TAO progression. We investigated the effects of hypoxia on orbital fibroblasts (OFs) in TAO, focusing on the role of HIF-1α in TAO progression.
Methods
OFs were isolated from TAO and non-TAO patients (as controls). In addition to HIF-1α, adipogenic differentiation markers including peroxisome proliferator-activated receptor γ (PPARγ) and CCAAT/enhancer binding protein (CEBP) were measured by Western blot, and phenotype changes were evaluated by Oil Red O staining under both normoxia and hypoxia. To elucidate the effect of HIF-1α inhibition, protein expression changes after HIF-1α inhibitor treatment were evaluated under normoxia and hypoxia.
Results
TAO OFs exhibited significantly higher HIF-1α expression than non-TAO OFs, and the difference was more distinct under hypoxia than under normoxia. Oil Red O staining showed that adipogenic differentiation of TAO OFs was prominent under hypoxia. Hypoxic conditions increased the expression of adipogenic markers, namely PPARγ and CEBP, as well as HIF-1α in TAO OFs. Interleukin 6 levels also increased in response to hypoxia. The effect of hypoxia on adipogenesis was reduced at the protein level after HIF-1α inhibitor treatment, and this inhibitory effect was sustained even with IGF-1 stimulation in addition to hypoxia.
Conclusion
Hypoxia induces tissue remodeling in TAO by stimulating adipogenesis through HIF-1α activation. These data could provide insights into new treatment strategies and the mechanisms of adipose tissue remodeling in TAO.

Thyroid
Phospholipase C-γ as a Potential Therapeutic Target for Graves’ Orbitopathy: Tae Hoon Roh, Min Kyung Chae, Jae Sang Ko, Don O. Kikkawa, Sun Young Jang, Jin Sook Yoon; Endocrinol Metab. 2023;38(6):739-749. Published online November 21, 2023; DOI: https://doi.org/10.3803/EnM.2023.1780

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Abstract PDF Supplementary Material PubReader ePub

Background
Phospholipase C-γ (PLC-γ) plays a crucial role in immune responses and is related to the pathogenesis of various inflammatory disorders. In this study, we investigated the role of PLC-γ and the therapeutic effect of the PLC-specific inhibitor U73122 using orbital fibroblasts from patients with Graves’ orbitopathy (GO).
Methods
The expression of phospholipase C gamma 1 (PLCG1) and phospholipase C gamma 2 (PLCG2) was evaluated using polymerase chain reaction in GO and normal orbital tissues/fibroblasts. The primary cultures of orbital fibroblasts were treated with non-toxic concentrations of U73122 with or without interleukin (IL)-1β to determine its therapeutic efficacy. The proinflammatory cytokine levels and activation of downstream signaling molecules were determined using Western blotting.
Results
PLCG1 and PLCG2 mRNA expression was significantly higher in GO orbital tissues than in controls (P<0.05). PLCG1 and PLCG2 mRNA expression was significantly increased (P<0.05) in IL-1β, tumor necrosis factor-α, and a cluster of differentiation 40 ligand-stimulated GO fibroblasts. U73122 significantly inhibited the IL-1β-induced expression of proinflammatory molecules, including IL-6, IL-8, monocyte chemoattractant protein-1, cyclooxygenase-2, and intercellular adhesion molecule-1 (ICAM-1), and phosphorylated protein kinase B (p-Akt) and p38 (p-p38) kinase in GO fibroblasts, whereas it inhibited IL-6, IL-8, and ICAM-1, and p-Akt and c-Jun N-terminal kinase (p-JNK) in normal fibroblasts (P<0.05).
Conclusion
PLC-γ-inhibiting U73122 suppressed the production of proinflammatory cytokines and the phosphorylation of Akt and p38 kinase in GO fibroblasts. This study indicates the implications of PLC-γ in GO pathogenesis and its potential as a therapeutic target for GO.

Citations

Citations to this article as recorded by

Structure and Roles of Phospholipase C (PLC), Phosphatidylinositol 4,5-bisphosphate (PIP2), and Inositol 1,4,5-trisphosphate (IP3) in Metabolism and Disease: A Systematic Review
Jasper Hoi Chun Luong, Io Hong Cheong, Xue Feng Zhang, Zisis Kozlakidis, Hui Wang
Innovations in Digital Health, Diagnostics, and Biomarkers.2025; 5(2025): 1. CrossRef
Aryl Hydrocarbon Receptor Deficiency Upregulates Intercellular Adhesion Molecule 1 in Retinal Pigment Epithelial Cells and Contributes to Retinal Inflammation
Tsung-Min Yang, Te-Chao Fang, Yu-Cheng Lee, Chen-Chen Lee, Yen-Ju Chan, Ida Fitriana, Yu-Wen Cheng, Ching-Hao Li
Laboratory Investigation.2025; 105(9): 104197. CrossRef
Mammalian PI-Phospholipase C Isozymes: Structural and Functional Insights and Roles in Health and Disease
May Hamdi, Mohammed Al-Matwi, Nour Elghoul, Hissa Al-Kuwari, Tahseen S. Sayed, Emna Riguene, Michail Nomikos
Medicina.2025; 61(6): 1054. CrossRef
Dynamic transition of Tregs to cytotoxic phenotype amid systemic inflammation in Graves’ ophthalmopathy
Zhong Liu, Shu-Rui Ke, Zhuo-Xing Shi, Ming Zhou, Li Sun, Qi-Hang Sun, Bing Xiao, Dong-Liang Wang, Yan-Jin Huang, Jin-Shan Lin, Hui-Shi Wang, Qi-Kai Zhang, Cai-Neng Pan, Xuan-Wei Liang, Rong-Xin Chen, Zhen Mao, Xian-Chai Lin
JCI Insight.2024;[Epub] CrossRef

Case Reports

Ophthalmopathy Induced by Bilateral Carotid Cavernous Fistula in a Patient with Graves' Disease.: Jong Kun Ha, Ji Hye Suk, A Ra Jo, Chan Woo Jung, Bong Jae Kim, Seong Oh Park, Sang Su Kim, Mi Kyung Kim; Endocrinol Metab. 2011;26(4):335-339. Published online December 1, 2011; DOI: https://doi.org/10.3803/EnM.2011.26.4.335

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Abstract PDF: Graves' disease (GD) can lead to specific eye afflictions including proptosis, periorbital swelling, conjunctival injection, chemosis, and opthalmoplegia, which then become a condition called Graves' ophthalmopathy or thyroid-associated ophthalmopathy (TAO). A carotid cavernous fistula (CCF) is an abnormal vascular communication between the carotid artery and the cavernous sinus. The clinical signs of CCF are very similar to TAO and should be considered as a differential diagnosis of TAO. We would like to present an interesting case of a bilateral ophthalmopathy induced by CCF in a GD patient. A 54-year-old man with a 6-year history of GD presented with bilateral exophthalmos and conjunctival injection for two months. The orbital CT scan findings were consistent with CCF, and an angiography revealed bilateral CCF. He received a bilateral coil embolization for the CCF and his ophthalmic signs were immediately improved. We recommend orbital imaging to exclude other coexisting diseases in patients who are suspected of TAO, especially when the diagnosis is uncertain or when determining whether medical or surgical intervention is appropriate.

A Case of Unilateral Exophthalmos Caused by a Dural Arteriovenous Malformation in Thyroid-Associated Ophthalmopathy.: Sun Ryoung Choi, Seong Jin Lee, Hae Ri Lee, Jun Goo Kang, Ohk Hyun Ryu, Chul Sik Kim, Byung Wan Lee, Eun Gyung Hong, Hyeon Kyu Kim, Doo Man Kim, Jae Myung Yoo, Sung Hee Ihm, Moon Gi Choi, Hyung Joon Yoo; J Korean Endocr Soc. 2008;23(1):51-55. Published online February 1, 2008; DOI: https://doi.org/10.3803/jkes.2008.23.1.51

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Abstract PDF

Thyroid-associated ophthalmopathy is associated with thyroid dysfunction, particularly Graves' disease, and is manifested as eye signs, including proptosis. In cases of unilateral exophthalmos with thyroid-associated ophthalmopathy, other causes such as orbital neoplasm, carotid-cavernous fistula, cavernous sinus thrombosis, and dural arteriovenous malformation (AVM) should be excluded. Dural AVM, an abnormal dural arteriovenous connection, is a rare neurovascular entity that mimics thyroid-associated ophthalmopathy. When eye involvement is unilateral or asymmetric, dural AVM can be considered in the differential diagnosis of thyroid-associated ophthalmopathy. A twenty-six year-old woman presented with unilateral exophthalmos in Graves' disease. By orbital magnetic resonance imaging and cerebral angiography, thyroid-associated ophthalmopathy and dural AVM were diagnosed. The unilateral exophthalmos improved after coil embolization of the dural AVM. In summary, we report the first case of a dural AVM with Graves' disease and thyroid-associated ophthalmopathy.

Citations

Citations to this article as recorded by

Proptosis as a Primary Symptom of Brain Arteriovenous Malformation
Jong Eun Lee, Jin Sook Yoon, Keun Young Park
Ophthalmic Plastic & Reconstructive Surgery.2020; 36(2): e53. CrossRef
Ophthalmopathy Induced by Bilateral Carotid Cavernous Fistula in a Patient with Graves' Disease
Jong Kun Ha, Ji Hye Suk, A Ra Jo, Chan Woo Jung, Bong Jae Kim, Seong Oh Park, Sang Su Kim, Mi Kyung Kim
Endocrinology and Metabolism.2011; 26(4): 335. CrossRef

Original Article

Lanreotide Therapy in Graves' Ophthalmopathy.: Il Seong Nam-Goong, Eun Ju Lee, Jung Hwoon Kim, Jong Chul Won, Woo jae Lee, Jung Hee Han, sung Jin Lee, Sang Wook Kim, Moo Kon Son, Ho Hye Lee, Il Min Ahn; J Korean Endocr Soc. 2001;16(1):18-25. Published online February 1, 2001

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Abstract PDF: BACKGROUND
Graves' ophthalmopathy (GO) is an autoimmune process that affects the orbital tissues. Patients with GO are usually treated with high doses of corticosteroids, retrobulbar irradiation, or by surgical decompression, however, those have some adverse effect. Recently, a synthetic somatostatin analogue has been reported for the treatment of GO. This study was performed prospectively to evaluate the therapeutic effects of lanreotide, a potent long acting synthetic somatostatin analogue, in patients that have GO. METHODS: Eight patients with moderate to severe GO (M:F=1:7, age 39.0+/-11.8 years) were included. Patients who had been treated with other modalities than GO, or had a systemic illness such as diabetes were excluded. Eight patients were given lanreotide, 40mg IM every 2 weeks over a period of 8 weeks. Their therapeutic responses were evaluated using an orbital CT or MRI and by ophthalmologic examinations. RESULTS: After 8 weeks' of lanreotide treatment, 4 patients showed decreased scores in the NOSPECS classification (p=0.059) as well as 5 patients in their clinical activity scores(p=0.109). All of the 8 patients showed improvements according to clinical evaluation criteria (p=0.008). Significant changes in the thickness of both the lateral rectus and superior rectus muscles were observed (p<0.05). No patient showed serious adverse effects related to lanreotide therapy during the follow-up periods. CONCLUSION: We conclude that lanreotide therapy has clinical benefits and show radiologic improvements in GO. Considering the minimal side-effects of lanreotide compared to those of corticosteroid, lanreotide therapy should be considered for use in selected patients that have Graves' ophthalmopathy

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