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We sincerely thank the editors and reviewers for giving us the opportunity to publish this article. Our response to Professors Ahn and Chung's letter are included below. Previous studies of subclinical hypothyroidism (SHT) mainly focused on the aggravation of SHT to overt hypothyroidism [1,2]. However, the clinical significance of long-term, persistent SHT and clinically reliable prognostic factors for predicting the disease course of SHT, including aggravation, maintenance, and improvement, have not been established. Given our present clinical environment, in which increasing numbers of patients with SHT are consistently increasing, as well as our corresponding need to manage them as clinicians, we aimed to identify factors that influence the natural course of SHT. In line with this purpose, our study primarily focused on initial clues and evidence that enable us to predict whether newly-diagnosed SHT will improve spontaneously to a euthyroid state. In this retrospective study, we compared two groups according to thyroid function at follow-up: an SHT maintenance group and a spontaneous improvement group. The mean follow-up period was 10.1 months for the SHT maintenance group and 9.6 months for the spontaneous improvement group. By comparing initial parameters in patients with newly-diagnosed SHT between the two groups using t tests, this study presents evidence that only initial thyroid stimulating hormone (TSH) level was a definite prognostic factor for SHT, and that thyroid peroxidase antibody (TPO-Ab) titer was also a helpful prognostic factor for SHT in cases with mildly elevated TSH levels. As mentioned in the letter from the reviewers, multivariate Cox regression analysis would be a more concrete method to prove the prognostic value of a specific factor because it can correct for the influence of other confounding variables on prognosis. However, our data were determined to be inappropriate for a Cox regression model by the test of goodness of fit during the analysis. There are several possible reasons for this relating to the characteristics of our patients. The range of TSH levels was too narrow: subjects with TSH levels of 5 to 7 µIU/mL accounted for 59.5% of all subjects. When we also consider the short follow-up period in this study (less than 12.0 months), it was difficult to detect a significant odds ratio for SHT prognosis according to TSH range. Also, with regard to TPO-Ab, a large majority of subjects (79.3%) had TPO-Ab titers of

Background: Patients with subclinical hypothyroidism (SHT) are common in clinical practice. However, the clinical significance of SHT, including prognosis, has not been established. Further clarifying SHT will be critical in devising a management plan and treatment guidelines for SHT patients. Thus, the aim of this study was to investigate the prognostic factors of SHT. Methods: We reviewed the medical records of Korean patients who visited the endocrinology outpatient clinic of Severance Hospital from January 2008 to September 2012. Newly-diagnosed patients with SHT were selected and reviewed retrospectively. We compared two groups: the SHT maintenance group and the spontaneous improvement group. Results: The SHT maintenance group and the spontaneous improvement group had initial thyroid-stimulating hormone (TSH) levels that were significantly different (P=0.035). In subanalysis for subjects with TSH levels between 5 to 10 μIU/mL, the spontaneous improvement group showed significantly lower antithyroid peroxidase antibody (anti-TPO-Ab) titer than the SHT maintenance group (P=0.039). Regarding lipid profiles, only triglyceride level, unlike total cholesterol and low density lipoprotein cholesterol, was related to TSH level, which is correlated with the severity of SHT. Diffuse thyroiditis on ultrasonography only contributed to the severity of SHT, not to the prognosis. High sensitivity C-reactive protein and urine iodine excretion, generally regarded as possible prognostic factors, did not show any significant relation with the prognosis and severity of SHT. Conclusion: Only initial TSH level was a definite prognostic factor of SHT. TPO-Ab titer was also a helpful prognostic factor for SHT in cases with mildly elevated TSH. Other than TSH and TPO-Ab, we were unable to validate biochemical prognostic factors in this retrospective study for Korean SHT patients.

Wonjin Kim1, Jung Ho Kim1, Youngsook Kim1, Ji Hye Huh1, Su Jin Lee1, Mi Sung Park1, Eun Yeong Choe1, Jeong Kyung Park2, Myung Won Lee3, Jae Won Hong, Byung Wan Lee14, Eun Seok Kang14, Bong Soo Cha14, Eun Jig Lee14, Hyun Chul Lee14 Department of Internal Medicine, Yonsei University College of Medicine, Seoul; Institute of Endocrinology, Goodmorning Hospital, Pyeongtaek; Institute of Endocrinology, Gwangmyung Sungae Hospital, Gwangmyeong; Institute of Endocrine Research, Yonsei University College of Medicine, Seoul; Diabetes Center, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea