Studies of Thyroid Function in Health and Disease

自身免疫性甲状腺疾病如Graves病可能与甲状腺外表现相关-眼眶病、皮肤病和肢端痛（骨膜改变和手指和脚趾的杵状突起）。严重形式的格雷夫斯皮肤病，如结节性皮肤病或疣状象皮病，可导致显着的发病率。Graves皮肤病的病理生理机制知之甚少。多种因素的结合可能有助于其发展，包括免疫因素，如T和B淋巴细胞的浸润、细胞因子的产生、血清促甲状腺激素受体抗体（TRAb）与皮肤组织中促甲状腺激素和胰岛素样生长因子I受体之间的相互作用;细胞因素，如成纤维细胞产生的糖胺聚糖;以及其他因素，如吸烟、局部创伤和依赖性水肿。许多药物已被用于治疗这种疾病，包括糖皮质激素，沙利度胺，环磷酰胺，静脉注射免疫球蛋白，英夫利昔单抗，喷替福林，利妥昔单抗和利妥昔单抗加血浆置换的单药治疗，但都产生了有限和可变的反应。联合免疫抑制治疗Graves皮肤病的疗效尚不清楚。 我们已经成功地使用联合免疫抑制疗法来治疗严重的难治性Graves皮肤病患者。 病例报告：我们为一名55岁男性提供护理，他患有20多年来逐渐发展的严重致残性皮肤病、肢端痛和象皮病。我们开始了利妥昔单抗、地塞米松和口服环磷酰胺单疗程的联合免疫抑制治疗。12个月时，体格检查发现上肢Graves皮肤病消退，下肢外观和功能明显改善，包括患者穿鞋的能力。MRI扫描记录了患者四肢软组织肿胀的大幅减少。他的生活质量评分（通过简表-36问卷测量）从425.8分增加到582.5分（最高可达到的评分为800分;一般人群的平均评分为584分）。血清自身抗体水平（TRAB）从大于40 IU/L降至1.12 IU/L（正常，0至1.75 IU/L），如免疫测定和荧光素酶免疫沉淀系统测定所记录。联合免疫抑制治疗似乎是一个安全和有效的选择严重的格雷夫斯皮肤病的管理。 我们还进行了一项初步研究，使用质谱分析在两个三级转诊中心因SARS-CoV-2住院的患者的类固醇和甲状腺激素谱。肾上腺皮质类固醇孕酮、皮质酮、17-羟孕酮、11-脱氧皮质醇、皮质醇、可的松、脱氢表雄酮（DHEA）、雄烯二酮、睾酮、总甲状腺素（TT 4）、总三碘甲状腺原氨酸（TT 3）、反三碘甲状腺原氨酸（rT 3）的液相色谱质谱分析，促肾上腺皮质激素（ACTH）、促甲状腺激素（TSH）、促黄体生成激素、促卵泡激素和醛固酮。我们发现约17.7%的TSH值偏低，高达52.8%的TT 4和69.4%的TT 3值偏低，而52.8%的rT 3值升高。这种低TT 4和TT 3、rT 3升高和低至正常TSH的生化模式提示通常与COVID 19相关的非甲状腺系统性疾病综合征。

Autoimmune thyroid disorders such as Graves disease might be associated with extrathyroidal manifestations - orbitopathy, dermopathy, and acropachy (periosteal changes and clubbing of fingers and toes). Severe forms of Graves dermopathy, such as nodular dermopathy or elephantiasis nostras verrucosa, can cause significant morbidity. The pathophysiology of Graves dermopathy is poorly understood. A combination of factors may contribute to its development, including immunologic factors, such as infiltration of T and B lymphocytes, cytokine production, interactions between serum thyroid-stimulating hormone receptor antibodies (TRAbs) and thyroid-stimulating hormone and insulin-like growth factor I receptors in dermal tissues; cellular factors, such as glycosaminoglycan production from fibroblasts; and other factors, such as smoking, local trauma, and dependent edema. Many agents have been used to treat this condition, including monotherapy with glucocorticoids, thalidomide, cyclophosphamide, intravenous immunoglobulins, infliximab, pentoxifylline, rituximab, and rituximab plus plasmapheresis, but all have produced limited and variable responses. The efficacy of combined immunosuppressive therapy for Graves dermopathy is unknown. We have successfully used combined immunosuppressive therapy to treat a patient with severe, refractory Graves dermopathy. Case Report: We provided care for a 55-year-old man with severe, disabling dermopathy, acropachy, and elephantiasis that developed gradually over 20 years. We started combined immunosuppressive therapy with a single course of rituximab, dexamethasone, and oral cyclophosphamide At 12 months, the physical examination found resolution of Graves dermopathy of the upper extremities and marked improvement in the appearance and function of the lower extremities, including the ability of the patient to wear shoes. An MRI scan documented a substantial reduction in soft tissue swelling of the patient's extremities. His quality-of-life score, as measured by the Short Form-36 questionnaire, increased from 425.8 to 582.5 points (maximum achievable score, 800; mean score in the general population, 584). Serum autoantibodies levels (TRABs) decreased from greater than 40 to 1.12 IU/L (normal, 0 to 1.75 IU/L), as documented by immunoassay and by the luciferase immunoprecipitation system assay. Combined immunosuppressive therapy appears to be a safe and effective option for the management of severe Graves dermopathy. We also performed a pilot study, using mass spectrometry analysis of steroid and thyroid hormone profiles in patients hospitalized with SARS-CoV-2 at two tertiary referral centers. Liquid chromatography mass spectrometry analysis of adrenocortical steroids progesterone, corticosterone, 17-hydroxyprogesterone, 11-deoxycortisol, cortisol, cortisone, dehydroepiandrosterone (DHEA), androstenedione, testosterone, total thyroxine (TT4), total triiodothyronine (TT3), reverse triiodothyronine (rT3), and immunoassay analysis of adrenocorticotropic hormone (ACTH), thyroid stimulating hormone (TSH), luteinizing and follicle-stimulating hormones, and aldosterone were performed. We found about 17.7% of TSH values being low, up to 52.8% of TT4 and 69.4% of TT3 values being low, while 52.8% of rT3 values were elevated. This biochemical pattern of low TT4 and TT3, elevated rT3, and low to normal TSH is suggestive of non-thyroidal systemic illness syndrome commonly associated with COVID19.