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Myxedema
Clinical Picture
Myxedema Yue Cao, Hui Juan Zhu, He Yi Zheng, Jun Li Lancet Diabetes Endocrinol 2014; 2: 600 Published Online June 13, 2014 http://dx.doi.org/10.1016/ S2213-8587(14)70063-4 Department of General Surgery (Y Cao MD); Department of Endocrinology (H J Zhu MD); and Department of Dermatology (H Y Zheng MD, J Li MD), Peking Union Medical College Hospital, Beijing, China Correspondence to: Dr Jun Li, Department of Dermatology, Peking Union Medical College Hospital, No 1 Shuaifuyuan Wangfujing Dongcheng District, Beijing 100730, China [email protected]
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A 61-year-old man presented with bilateral, asymptomatic, indurated non-pitting verrucous plaques and nodules on his extremities and buttocks. He was diagnosed with Graves’ disease 20 years ago. The patient developed hypothyroidism secondary to radioactive iodine ablation of the thyroid 4 years prior to presenting to us and received levothyroxine replacement therapy, after which he attained a sustained euthyroid state. However, he developed an asymptomatic rash over his extremities and buttock, which worsened gradually. On physical examination, several plaques that were leathery in texture and nodules were observed on his extremities and buttock (figure A–D). The results of thyroid-function tests were normal (free triiodothyronine [T3] 3·83 pg/mL, local reference 1·80–4·10; free thyroxine [T4] 1·23 ng/dL, local reference 0·81–1·89) except for a thyroid-stimulating hormone concentration of 0·094 μIU/mL (local reference 0·38–4·34) and thyrotrophin receptor antibody concentration of 280·51 IU/L (local reference <13). Results of liver and kidney function tests were normal, and concentrations of calcium, 1,25-dihydroxyvitamin D3, 25-hydroxyvitamin D3, parathyroid hormone, urinary calcium, and urine phosphorus were within normal limits. On histological examination of skin lesion biopsy specimens stained with haematoxylin and eosin and alcian blue, abundant deposition of mucin was seen in the dermis (figure E, F). The final diagnosis according to the pathology report was myxedema. Despite application of potent topical corticosteroids, occlusive or compressive therapy, and
multipoint subcutaneous injection of long-acting glucocorticoid, the skin lesions showed no obvious signs of remission after 6 months of treatment. Myxedema results from the accumulation in the dermis of glycosaminoglycan secreted by fibroblasts. The pathogenesis of the extrathyroidal manifestations of myxedema involves fibroblast activation and increased glycosaminoglycan production. Some studies postulate that the destruction of the thyroid gland by therapeutic drugs (especially iodine-131) results in the release of an antigen from thyroid cells that then stimulates the production of the thyrotrophin receptor antibody. The fibroblast in the orbital area and pretibial dermis share antigenic sites that underlie the autoimmune process that causes Graves’ disease. Thereby crossreaction contributes to the development of myxedema occurring long after euthyroid status is achieved through treatment. Although myxedema does not seem to be related to the concentrations of T3 and T4, only four cases of euthyroid patients being diagnosed with myxedema have been reported in the literature. Contributors HJZ was the clinician responsible for care of the patient. YC and HYZ were the initial clinicians and did the literature search. HJZ and JL devised most of the protocol for management and follow-up of the patient. HJZ gave expert opinion on endocrinology, and YC gave expert opinion on surgery. YC prepared the preliminary draft of the report, which was then revised by JL and HYZ. All authors contributed equally to the report. Written consent to publish was obtained from the patient. Declaration of interests We declare no competing interests.
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Figure: Plaques and nodules and punch biopsy samples Plaques and nodules on the dorsal side of the patient’s hands (A), his left buttock (B), his pretibial areas (C), and dorsal side of his feet (D). Histopathology of the lesion: (E) Large quantities of mucin are deposited in the reticular dermis, causing collagen bundles to separate and the dermis to thicken. A grenz zone of normal collagen is also observed as well as orthohyperkeratosis, follicular plugging, and acanthosis (haematoxylin and eosin stain, original magnification ×20); (F) Same findings with alcian blue staining of the same samples (original magnification ×20).
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www.thelancet.com/diabetes-endocrinology Vol 2 July 2014
Myxedema Yue Cao, Hui Juan Zhu, He Yi Zheng, Jun Li Lancet Diabetes Endocrinol 2014; 2: 600 Published Online June 13, 2014 http://dx.doi.org/10.1016/ S2213-8587(14)70063-4 Department of General Surgery (Y Cao MD); Department of Endocrinology (H J Zhu MD); and Department of Dermatology (H Y Zheng MD, J Li MD), Peking Union Medical College Hospital, Beijing, China Correspondence to: Dr Jun Li, Department of Dermatology, Peking Union Medical College Hospital, No 1 Shuaifuyuan Wangfujing Dongcheng District, Beijing 100730, China [email protected]
A
D
A 61-year-old man presented with bilateral, asymptomatic, indurated non-pitting verrucous plaques and nodules on his extremities and buttocks. He was diagnosed with Graves’ disease 20 years ago. The patient developed hypothyroidism secondary to radioactive iodine ablation of the thyroid 4 years prior to presenting to us and received levothyroxine replacement therapy, after which he attained a sustained euthyroid state. However, he developed an asymptomatic rash over his extremities and buttock, which worsened gradually. On physical examination, several plaques that were leathery in texture and nodules were observed on his extremities and buttock (figure A–D). The results of thyroid-function tests were normal (free triiodothyronine [T3] 3·83 pg/mL, local reference 1·80–4·10; free thyroxine [T4] 1·23 ng/dL, local reference 0·81–1·89) except for a thyroid-stimulating hormone concentration of 0·094 μIU/mL (local reference 0·38–4·34) and thyrotrophin receptor antibody concentration of 280·51 IU/L (local reference <13). Results of liver and kidney function tests were normal, and concentrations of calcium, 1,25-dihydroxyvitamin D3, 25-hydroxyvitamin D3, parathyroid hormone, urinary calcium, and urine phosphorus were within normal limits. On histological examination of skin lesion biopsy specimens stained with haematoxylin and eosin and alcian blue, abundant deposition of mucin was seen in the dermis (figure E, F). The final diagnosis according to the pathology report was myxedema. Despite application of potent topical corticosteroids, occlusive or compressive therapy, and
multipoint subcutaneous injection of long-acting glucocorticoid, the skin lesions showed no obvious signs of remission after 6 months of treatment. Myxedema results from the accumulation in the dermis of glycosaminoglycan secreted by fibroblasts. The pathogenesis of the extrathyroidal manifestations of myxedema involves fibroblast activation and increased glycosaminoglycan production. Some studies postulate that the destruction of the thyroid gland by therapeutic drugs (especially iodine-131) results in the release of an antigen from thyroid cells that then stimulates the production of the thyrotrophin receptor antibody. The fibroblast in the orbital area and pretibial dermis share antigenic sites that underlie the autoimmune process that causes Graves’ disease. Thereby crossreaction contributes to the development of myxedema occurring long after euthyroid status is achieved through treatment. Although myxedema does not seem to be related to the concentrations of T3 and T4, only four cases of euthyroid patients being diagnosed with myxedema have been reported in the literature. Contributors HJZ was the clinician responsible for care of the patient. YC and HYZ were the initial clinicians and did the literature search. HJZ and JL devised most of the protocol for management and follow-up of the patient. HJZ gave expert opinion on endocrinology, and YC gave expert opinion on surgery. YC prepared the preliminary draft of the report, which was then revised by JL and HYZ. All authors contributed equally to the report. Written consent to publish was obtained from the patient. Declaration of interests We declare no competing interests.
B
C
E
F
3 mm
3 mm
Figure: Plaques and nodules and punch biopsy samples Plaques and nodules on the dorsal side of the patient’s hands (A), his left buttock (B), his pretibial areas (C), and dorsal side of his feet (D). Histopathology of the lesion: (E) Large quantities of mucin are deposited in the reticular dermis, causing collagen bundles to separate and the dermis to thicken. A grenz zone of normal collagen is also observed as well as orthohyperkeratosis, follicular plugging, and acanthosis (haematoxylin and eosin stain, original magnification ×20); (F) Same findings with alcian blue staining of the same samples (original magnification ×20).
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www.thelancet.com/diabetes-endocrinology Vol 2 July 2014