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10th Asia and Oceania Thyroid Association Congress October 24, 2012 Discovery Kartika Plaza Hotel, Bali, Indonesia Practical Approaches to Regional Needs in Thyroidology Symposium 9: Subclinical thyroid dysfunction Subclinical hypothyroidism ○Koshi Hashimoto, Masanobu Yamada and Masatomo Mori Department of Medicine and Molecular Science Gunma University Graduate School of Medicine Maebashi, Gunma, Japan normal Subclinical hypothyroidism low Serum TSH high Subclinical hypothyroidism Subclinical thyrotoxicosis low normal Free T4 high Dyslipidemia in subclinical hypothyroidism is controversial Lancet. 2012 379:1142-1154. J Clin Endocrinol Metab. 2012 97:326-333 J Clin Endocrinol Metab. 2012 97:326-333 In consistent findings regarding lipid metabolism in SCH could be due to… 1) Lack of large-scale clinical studies 2) Inconsistent exclusion criteria that may include patients treated with medications for dyslipidemia 3) Variation in blood drawing time Background of the current study 7494 participants in a complete medical check-up in Gunma prefecture, Japan including 4756 males and 2738 females Exclusion criteria We have excluded … 242 males, 92 females under medication for dyslipidemia 38 males, 59 females under medication for thyroid disease 32 males, 21 males administered glucocorticoid, and those who have a past history of thyroid disorders, liver cirrhosis or collagen disease. The mean age of the participants was 48 years old in both male and female 4756 males (6939) Mean age (48±9 years-old) male female 2738 female (4290) Mean age (48±9 years-old) Age Q What percent of the participants have SCH? 7 (0.09 %) normal 0 4 (0.05 %) 6979 (94.2 % ) 2 (0.02 %) low Serum TSH high Thyroid status of 7403 participants (4726 males, 2677 females) 0 94 (1.2 %) 19 (0.2 %) low normal high Free T4 normal 4 (0.15 %) 2 (0.07 %) low Serum TSH high Thyroid status of 2677 females 0 low 6% of females 156 have SCH ! 0 (5.8 %) 2476 (92.5 % ) 28 (1.0 %) normal Free T4 0 10 (0.04 %) high Prevalence of SCH in each decade of life 20 18 About 20% of females over 16 14 70 years old have SCH ! 12 10 Male Female 男性 女性 8 6 4 2 0 21-30 31-40 41-50 51-60 61-70 71- Age About 15% of males over 74 years old have SCH in the US Q Is SCH more prevalent with age due to a decrease in thyroid hormone levels? Serum TSH levels increase after the age of 30 TSH Male Age TSH Female Age Free T4 levels decrease with age freeT4 Male 男性 freeT4 Female 女性 The elevation in serum TSH levels with age is attributed to the concurrent decrease in T4 levels Age Age Q Do patients with SCH have elevated serum LDL-C levels? LDL-C levels are comparable between euthyroid participants and SCH patients LDL-C (mg/dl) 121.4 122.6 Normal:121.4. ± 0.5 mg/dl (mean ± SE)(n=4236) SCH: 122.6 ± 2.8 mg/dl (n=123) Not significant LDL-C levels are significantly elevated in SCH females LDL-C (mg/dl) 111.5 mg/dl 125.0 normal:111.5 ± 0.6 mg/dl (mean ± SE)(n = 2286) SCH: 125.0 ± 2.7 mg/dl (n = 133) p<0.0001 LDL-C levels and age are significantly correlated, especially in females (mg/dl) (mg/dl) Male p<0.05 Female p<0.001 Age-adjusted LDL-C levels in SCH females are significantly elevated LDL-C (mg/dl) Mean SCH 111.9 ± 0.6 mg/dl normal 119.6 ± 2.5 mg/dl Age Q What happens to serum triglyceride levels in patients with SCH? SCH is a risk factor for increased Triglyceride and LDL-C Q Are the patients with SCH susceptible to metabolic syndrome(MetS) ? Criteria for metabolic syndrome in Japan Abdominal obesity, given as waist circumference Male >=85cm Female >=90cm Plus any 2 of the following 1)Plasma triglycerides ≥150 mg/dL HDL cholesterol <40 mg/dL 2) High blood pressure (≥140 mm Hg systolic or ≥90 mm Hg diastolic) 3) Fasting glucose levels >=110 mg/dL Prevalence of metabolic syndrome (MetS) in each decade of life 25 Prevalence of MetS is 20 increased with age in 15females! male 女性 female 男性 10 5 0 21-30 31-40 41-50 51-60 61-70 71- age Comparison of SCH and MetS prevalence in each decade of life SCH and MetS are 20 18 age in increased with SCH 16 females! 14 MetS 25 20 12 (%) (%) 15 10 8 10 6 5 4 2 0 0 21-30 31-40 41-50 51-60 Male 61-70 71- 21-30 31-40 41-50 51-60 Female 61-70 71- SCH is significantly correlated to MetS in females Summary (1) 1. The prevalence of SCH is about 6 % in middle aged Japanese women and it increases with age. 2. This increase may be due to lowered thyroid hormone levels with age. 3. SCH increases not only serum LDL-c levels but also TG levels particularly in women and may be involved with metabolic syndrome. Subclinical primary hypothyroidism TRH + TSH Thyroid gland is - SCH. impaired in + - + T4 T3 Central hypothyroidism + TRH + - or TSH - + T4 T3 ‘Subclinical Central hypothyroidism(SCCH)’ In SCCH, hypothalamus and/or TRHpituitary should be impaired + - + TSH - + T4 T3 Profile of pituitary tumors No. of subject s Average age (years, mean ± SD) No. of males (% male) No. of microadenomas Acromegaly 150 47.7± 13.9 70 (46.7%) 53 (37.1%) Non Functioning 95 52.6 ± 12.8 49(51.6%) 5 (5.3%) Cushing’s 28 51.9 ± 15.6 4(14.3%) 21 (75.0%) Prolactinomas 18 37.9 ± 12.9 7(38.9%) 6 (33.3%) Rathke's cleft cyst 9 45.6 ± 16.2 3 (33.3%) 2 (22.2%) total 300 133(44. 3%) 87(29%) Thyroid status of patients with pituitary tumors Free T4 Normal Normal Group 3 36 12.0 % Group 1 207 69.0 % Low Group 4 11 3.7 % Group 2 46 15.3 % 47 15.7 % 253 84.3 % TSH Low Total Serum TSH Group 2: Normal T4, Low TSH Free T4 TSH 2 1.8 1.8 1.6 1.6 1.4 1.4 1.2 1.2 1 1 0.8 0.8 0.6 0.6 0.4 0.4 0.2 0 Free T4 0.2 1 Before After 2 0 1 2 手術前 Before 後 After 0.14 ± 0.04 ng/dl P = 0.009 normal Subclinical hypothyroidism Subclinical thyrotoxicosis Subclinical central Hypothyroidism (SCCH) low Serum TSH high Some patients with pituitary tumors demonstrate SCCH low normal Free T4 high Thyroid status of patients with pituitary tumors Free T4 Normal Normal Group 3 36 12.0 % Group 1 207 69.0 % Low Group 4 11 3.7 % Group 2 46 15.3 % 47 15.7 % 253 84.3 % TSH Low Total Serum TSH Group1 : Normal T4 and normal TSH Free T4 Free T4 TSH 1.6 increased within Free T4 levels are 1.4 normal range after the surgery ! 6 5 1.2 4 1 3 0.8 0.6 2 0.4 1 0.2 0 0 1 Before After 2 1 Before 2 After TRH knockout mouse Serum T4 TSH biological activity is impaired in TRH knockout mouse ! TRH V A L E Y Q V V T I TRH-R S R N Y Y S P I Y L M D F G V F Y V V P M I L A T V L Y G F I S F L S S P N F V Q E N W F V V L T R Y P L L F C R I C MW L I Y L N N L A F S A I N L I V V V A L P V I A M Y K R N T L I T V S S R K Q V M L S S F N Q L F C R N S T N V N L N T K N F N P T F C Q R I H A P T S D P K E N S K T W K N D S A F R K E T P K Q K C N C L D D L E T S F H D S E K I V S Y N L A V S Y N A P K I K K A R S S Intracellular I T V T D T Y L S A T K V S F D D T C L A S E V S F S Q S TR TSH Extracellular V A R P Q L Q T Q N L E S V T E N E M V I S C G Y K I I G S W V Y G A Y Y D I V K S G Y D C T T S L I I C L L V N L D L N P L I T Y L I I C G A A V L Q Y L L F F W G L G G I N L MC L V M I V G N L D A V A S S C Y L S T I M V A L S S I T F A W V L V V A F T V F I I V L Y M C I R E N R T T Y K P I H M R T A I C H P I K A Q F L T3 T3 T3 Α chain Β chain conjugation secretion T3 TSH Hypothesis for SCCH with pituitary tumors TRH TSH biological activity could be impaired by the pituitary tumors ! TRH Receptor Pituitary tumors Extracellular V A R P Q L Q T Q N L E S V T E N E M V A V I SC G Y K I S R N L I Y E G S WV Y G A Y Y Y Y D S Q I V K P S G V Y I V D C S F L S S P T Y T T N F S L L I V Q I I C M E N W F L L V N L D L V V L T N P L D F G V I T Y L I I C F Y V R Y P L Q Y L L F F W L L F C G A AV G L G G I N R I C L MC V PM MW L L VM A S S C I VG N L D A V Y L S T I Y L N I L A L A F I M V S A I N A L S S I T F A W T V L L I V V L V V A F T V F I I Y G F I V V A L P V I V L Y A M Y I M C I K N K R R E N T L R K T I V S S R K Q T V T Y M K A L P S S I R F H M R T N Q A S L S F C R N S T N V N L N T K N I F N P C F T Q H P I K AQ F L C R I H A P S D P K E N S K TW K N D S T A F R K E T P K Q K C N C L D D L E T S F H D S E K I V S Y N L A V S Y N A P K Intracellular I T V T D T Y L S A T K V S F D D T C L A S E V S F S Q S CoA NcoR TR T3 T3 X Glycosylation TSH TSH TSH TSH T3 T3 T3 TSH βchain αchain conjugation Secretion T3 T3 T3 T3 normal Subclinical hypothyroidism Subclinical thyrotoxicosis low Serum TSH high “Subclinical central hypothyroidism (SCCH)” low normal high Free T4 10~15 % of the general population have pituitary adenomas Summary (2) 1) Subclinical central hypothyroidism (SCCH) was found in about 15% of patients with pituitary tumors. 2) After the removal of pituitary tumors, free T4 levels of the patients were significantly improved. 3) SCCH in patients with pituitary tumors could be related to impairment of TRH secretion and potential biological activity . Acknowledgment Gunma University Department of Medicine and Molecular Science Tetsurou Satoh Nobuyuki Shibusawa Atsushi Ozawa Sumiyasu Ishii Takuya Tomaru Yasuyo Nakajima Satoshi Yoshino Emi Ishida Ryo Taguchi Akiko Katano-Toki Takashi Okamura Department of Neurosurgery Masahiko Tosaka Department of Pathology Jyunko Hirato Gunma Tokyo Toranomon Hospital Syozo Yamada National Institute of Genetics Yumiko Saga National Institute of Health Kazuhiko Horiguchi