Correspondence Response to Letter Regarding Article, “Digital Clubbing” I appreciate the comments about the article on digital clubbing.1 The authors correctly point out that thyroid, and parathyroid, disease have been associated with clubbing. Danforth and Humphrey described the association of Graves’ disease, pretibial myxedema (thyroid dermopathy), and exophthalmos in 1958.2 What we now describe as autoimmune thyroid disease has these associations that tend to occur together. Interestingly, increased levels of vascular endothelial growth factor have been seen in untreated Graves’ disease and goitrous Hashimoto thyroiditis and have been associated with increased tissue vascularity and gland size.3 In cultures of human thyrocytes, increased transcription and protein expression of vascular endothelial growth factor, and its receptors, have been detected in goiter tissue and the highest levels seen in Graves disease.4 So, as in other conditions described with digital clubbing, release of signal proteins such as vascular endothelial growth factor and stimulation of angiogenesis are probably contributory. More importantly, increased expression of vascular endothelial growth factor and its receptors is seen in thyroid cancer5 and is 1 of the targets for cancer therapy.6 In the descriptive clinical vignette, the patient was euthyroid, without a goiter or evidence of thyroid dermopathy or ophthalmopathy.

Sources of Funding Dr Rutherford is supported by the Jonsson-Rogers Chair in Cardiology.

Disclosures None. John D. Rutherford, MB ChB, FRACP Division of Cardiology, Department of Internal Medicine UT Southwestern Medical Center Dallas, TX

References 1 . Rutherford JD. Digital clubbing. Circulation. 2013;127:1997–1999. 2. Danforth WH, Humphrey HA. Hypertrophic osteoarthropathy and pretibial myxedema associated with Graves’ disease. J Clin Endocrinol Metab. 1958;18:1302–1307. 3. Iitaka M, Miura S, Yamanaka K, Kawasaki S, Kitahama S, Kawakami Y, Kakinuma S, Oosuga I, Wada S, Katayama S. Increased serum vascular endothelial growth factor levels and intrathyroidal vascular area in patients with Graves’ disease and Hashimoto’s thyroiditis. J Clin Endocrinol Metab. 1998;83:3908–3912. 4. Malkomes P, Oppermann E, Bechstein WO, Holzer K. Vascular endothelial growth factor: marker for proliferation in thyroid diseases? Exp Clin Endocrinol Diabetes. 2013;121:6–13. 5. Capp C, Wajner SM, Siqueira DR, Brasil BA, Meurer L, Maia AL. Increased expression of vascular endothelial growth factor and its receptors, VEGFR-1 and VEGFR-2, in medullary thyroid carcinoma. Thyroid. 2010;20:863–871. 6. Perez CA, Santos ES, Arango BA, Raez LE, Cohen EE. Novel molecular targeted therapies for refractory thyroid cancer. Head Neck. 2012;34:736–745.

(Circulation. 2013;128:e449.) © 2013 American Heart Association, Inc. Circulation is available at http://circ.ahajournals.org

DOI: 10.1161/CIRCULATIONAHA.113.005707

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Response to Letter Regarding Article, ''Digital Clubbing'' John D. Rutherford Circulation. 2013;128:e449 doi: 10.1161/CIRCULATIONAHA.113.005707 Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Copyright © 2013 American Heart Association, Inc. All rights reserved. Print ISSN: 0009-7322. Online ISSN: 1524-4539

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