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甲状腺機能低下症

著者: 田上哲也 国立病院機構京都医療センター 内分泌・代謝内科

監修: 平田結喜緒 公益財団法人 兵庫県予防医学協会 健康ライフプラザ

著者校正/監修レビュー済:2020/11/06
参考ガイドライン:
  1. BMJ: Thyroid hormones treatment for subclinical hypothyroidism – a clinical practice guideline (2019)
  1. 米国甲状腺協会(ATA)/米国臨床内分泌学会(AACE):Clinical practice guidelines for hypothyroidism in adults: cosponsored by the AACE and the ATA(2012)
  1. ATA: Guidelines for the diagnosis and management of thyroid disease during pregnancy and the postpartum (2017)
  1. 米国内分泌学会(ES): Management of thyroid dysfunction during pregnancy and postpartum: an Endocrine Society clinical practice guideline(2012)
  1. ATA: Guidelines for the treatment of hypothyroidism: prepared by the ATA task force on thyroid hormone replacement (2014)
  1. 欧州甲状腺学会(ETA): Guidelines on the management of thyroid dysfunction following immune reconstitution therapy (2019)
  1. ETA: Guidelines for the management of amiodarone-associated thyroid dysfunction (2018)
  1. ETA: Guidelines on the diagnosis and management of central hypothyroidism (2018)
  1. ETA: Guidelines for the management of subclinical hypothyroidism in pregnancy and in children (2014)
  1. ETA: Guideline for the management of subclinical hypothyroidism (2013)
  1. 欧州小児内分泌学会(ESPE): Consensus guidelines on screening, diagnosis, and management of congenital hypothyroidism (2014)
  1. 日本小児内分泌学会(JSPE): Guidelines for mass screening of congenital hypothyroidism, revision (2014)
患者向け説明資料

概要・推奨   

  1. レボチロキシン(LT4)は、甲状腺機能低下症様の症状はあるが、甲状腺機能が正常の患者に投与をしても効果がないため、投与をしないことが勧められる(推奨度3)
  1. TSHの厳密な管理が必要な患者では、LT4朝食前の服用が望ましい(推奨度2)。
  1. 顕性甲状腺機能低下症の治療において、T3併用療法や甲状腺末の使用がLT4単独療法より優れるというエビデンスはなく、現時点では、LT4とリオチロニン(LT3)の併用療法は勧められない(推奨度3)
  1. LT4+LT3併用療法は、先天性顕性甲状腺機能低下症と甲状腺ホルモン不応症のTSHとT4の正常化を促進する(推奨度2)。
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  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が
  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となりま
  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要と
  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要
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  1. 妊娠8~20週の妊婦の潜在性甲状腺機能低下症または低T4血症にLT4補充療法を行っても、児の5歳までの認知アウトカム(IQ)は改善しない(推奨度3)。
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薬剤監修について:
オーダー内の薬剤用量は日本医科大学付属病院 薬剤部 部長 伊勢雄也 以下、林太祐、渡邉裕次、井ノ口岳洋、梅田将光による疑義照会のプロセスを実施、疑義照会の対象については著者の方による再確認を実施しております。
※薬剤中分類、用法、同効薬、診療報酬は、エルゼビアが独自に作成した薬剤情報であり、
著者により作成された情報ではありません。
尚、用法は添付文書より、同効薬は、薬剤師監修のもとで作成しております。
※薬剤情報の(適外/適内/⽤量内/⽤量外/㊜)等の表記は、エルゼビアジャパン編集部によって記載日時にレセプトチェックソフトなどで確認し作成しております。ただし、これらの記載は、実際の保険適用の査定において保険適用及び保険適用外と判断されることを保証するものではありません。また、検査薬、輸液、血液製剤、全身麻酔薬、抗癌剤等の薬剤は保険適用の記載の一部を割愛させていただいています。
(詳細はこちらを参照)
著者のCOI(Conflicts of Interest)開示:
田上哲也 : 研究費・助成金など(ヤマサ醤油(株))[2021年]
監修:平田結喜緒 : 特に申告事項無し[2021年]

改訂のポイント:
  1. 新規策定または更新されたガイドラインの追加と、最近発表されたシステマティックレビューやメタアナリシスを中心に追加を行った。

病態・疫学・診察

疾患情報(疫学・病態)  
  1. 甲状腺機能低下症では、甲状腺ホルモンの産生・分泌が低下し、耐寒性低下・発汗減少・便秘・浮腫・体重増加・傾眠傾向などの症状を来す疾患である。
  1. 本症の病態・予後・治療は、原発性か中枢性かによって大きく異なり、妊娠/出産との関係も重要である。最も多い原因は橋本病(慢性甲状腺炎)による原発性のものであり、その経過は多様である。また薬剤性機能障害が増加している。
  1. 診断には遊離サイロキシン(FT4)・甲状腺刺激ホルモン(TSH)測定が必須であるが、測定に至るまでに特徴的症状・徴候や一般検査異常から本症を疑うことが重要である(図アルゴリズム)。
  1. FT4↓・TSH↑のみで原発性機能低下があるといえるが(一過性の場合がある点に注意)、特徴的所見や原因が特定できれば確定的である。なおFT4→・TSH↑の状態(潜在性機能低下症)でも動脈硬化や虚血性心疾患の一因になることが指摘されている。
  1. 中枢性(FT4↓TSH→~↓)では下垂体機能評価や画像検索が重要である。なおこのパターンは低トリヨードサイロニン(T3)(/T4)症候群の際にもみられることに留意する。
  1. 妊娠中は甲状腺ホルモンの需要が高くなること、出産後には甲状腺機能が変動しやすいことに留意する。
  1. 的確に診断し補充療法を続けていれば問題のない疾患だが、未発見・治療中断が長期~重症化すると粘液水腫性昏睡という致死的状態になり得る。
  1. 甲状腺機能低下症を生じる疾患の一部である甲状腺刺激ホルモン分泌低下症と甲状腺ホルモン不応症は指定難病であり、重症度分類で重症の場合などでは申請し認定されると、保険料の自己負担分の一部が公費負担として助成される。(平成27年1月施行)
  1. 難病法に基づく医療費助成制度
 
TSHの基準値に関して:
 
  1. 不要な治療を避けるために、70歳以上のTSHの基準値の上限の設定には再考の余地がある。
  1. 背景:健常人でのTSHレベルは、年齢、性、糖尿病の有無別に異なる可能性がある。
  1. 研究事例の説明:15万人の年齢、性別、糖尿病の有無で健常人のTSHレベルを評価した。TSHの中央値は年齢とともに上昇した (1.58 mU/L:31~40歳、1.86 mU/L: 90歳以上、P<0.001)。97.5th centile TSHは年齢とともに上昇し(3.98~5.94 mU/L)、2.5th centile TSHは低下した(0.51~0.31 mU/L)。糖尿病患者のTSHは有意に高かった(1.80 vs. 1.70 mU/L、P<0.001)(O)[1]
  1. 結論:不要な治療を避けるために、70歳以上のTSHの基準値の上限の設定には再考の余地がある。
 
  1. 肥満者のTSHは非肥満者のそれと異なる可能性がある。
  1. 研究事例の説明:スペインで、甲状腺疾患(既往含む)や甲状腺機能に影響する薬剤使用がなく、TSH<10 mIU/L、TPOAb<50 IU/mLの3,928例の成人のTSHを評価した。TSHの基準範囲(p2.5-97.5)は、BMI<20 kg/m2で0.6〜4.8 IU/L、BMI 20-24.9 kg/m2で0.6〜5.5 mIU/L、BMI 25-29.9 kg/m2で0.6〜5.5 mIU/L、BMI 30-39.9 kg/m2で0.5〜5.9 mIU/L、BMI ≥40 kg/m2で0.7〜7.5 mIU/Lであった。正常体重の基準値を用いると高度肥満者における高TSH血症の頻度は3倍に上昇した(P<0.01)(O)[2]
  1. 結論:高度肥満者では、非肥満者のTSH基準値が適用されない可能性がある。
 
  1. TSHは年齢性別人種なる可能性がある。
  1. 背景年齢、性別、人種ごとにTSHの基準値を設定することで、誤った甲状腺機能異常の診断を減らすことができる。
  1. 研究事例説明NHANESIIIのデータベースを用いて、甲状腺疾患フリーの15,277例を対照(甲状腺自己抗体陰性でTSHが0.1〜10 mIU/L)13,344例と比較した。人種(白人、黒人、およびメキシコ系アメリカ人)、年齢、性別、体重、尿中ヨウ素排泄でTSH(p2.5-97.5)を評価した。黒人では自己抗体の有無は基準値に影響を及ぼさなかった。甲状腺疾患フリーの白人およびメキシコ系アメリカ人の基準値上限は1.0 mIU/L高かった。基準値は年齢とともに上昇した。下限値と中央値は女性が男性より低かった(O)[3]
  1. 結論年齢、性別、人種ごとに設定したTSH基準値は甲状腺自己抗体の有無が不明な対象に有用である。
 
  1. TSHのより基準値説得力がある。
  1. 背景従来設定されたTSHの基準値は、アッセイがより高感度になったことと対照に甲状腺疾患が潜在していた可能性があることから不正確である。
  1. 研究事例説明National Academy of Clinical Biochemistryは健常人の95%以上のTSHは2.5 mU/Lとしている。それ以上の数値を示すほとんどにTSHが高値となる橋本病や他の原因が潜在しているようである。特に橋本病の頻度が非常に低いアフリカ系アメリカ人の平均TSHが1.18 mU/Lであることは基準値が現状より狭いことを支持する(O)[4]
  1. 結論より正確なTSH基準値の設定が甲状腺疾患、特に潜在性甲状腺疾患のスクリーニングや治療に重要である。
 
  1. 最近、甲状腺刺激ホルモン(TSH)値のハーモナイゼーションについて、日本臨床検査医学会標準化委員会から以下のように発表された。詳細は日本甲状腺学会のHPにアップされている[http://www.japanthyroid.jp/common/20200130_tsh.pdf]。
  1. 日本人基準範囲(RI):日本人成人(20~60歳)の基準範囲(RI)はAPTM-10の2.5%タイル下限と97.5%タイル上限とし、0.61~4.23 mIU/L とする。
  1. この数値は、米国人のRI 0.56~4.27 mIU/L[5]とほぼ一致する。
 
  1. 心不全は顕性甲状腺機能亢進症と潜在性甲状腺機能亢進症の両方において心血管死増加の主因である。TSH 5~10 mIU/Lの潜在性甲状腺機能低下症(scHypo)は全死因死亡率の低リスクと関係する。
  1. 背景:甲状腺機能異常は全死亡および心血管死の増加と相関するが、軽度異常の場合原因別死亡率との関係は明らかではない。
  1. 研究事例の説明:2000~2009年にデンマークの総合診療医を受診した甲状腺疾患の既往ない患者で甲状腺機能検査を施行した563,700人(平均年齢48.6歳、39%が男性)のうち47,327人(8.4%)が死亡し、全死因死亡率、原因別イベントおよび主要有害心血管系イベント(Major adverse cardiovascular events、MACE)を調べた。全死因死亡率は正常甲状腺機能(Euthyroidism、Eu)(年齢調整罹患率:12/1,000人・年)と比較して顕性甲状腺機能亢進症(Overt Hyperthyroidism、HYPER)(16/1,000)と潜在性甲状腺機能亢進症(Subclinical Hyperthyroidism、scHyper)(15/1,000)において有意に高かった。罹患率比(IRR)はそれぞれ 1.25(CI 1.15-1.36)、1.23(CI 1.16-1.30)であった。MACEのリスクはHYPERでIRR 1.16 (CI 1.05-1.27)、scHyperで1.09(CI 1.02-1.16)であり、心不全で顕著であった(HYPERでIRR 1.14[CI 0.99-1.32]、scHyperで1.20 [CI 1.10-1.31])。全死因死亡率の低下がTSH of 5~10 mIU/LのscHypoでみられた(IRR 0.92、CI 0.86-0.98)(O)[6]
  1. 結論:心不全はHYPOとscHypoの両方において心血管死増加の主因である。TSH 5~10 mIU/LのscHypoは全死因死亡率の低リスクと関係する。
 
  1. 高齢者の潜在性甲状腺機能低下症や潜在性甲状腺機能亢進症は死亡率を増加させる。
  1. 背景:高齢者でのscHypoや潜在性甲状腺機能亢進症(Subclinical Hyperthyroidism、scHyper)と死亡率との関係は明らかではない。高齢者でのscHypoやscHyperと死亡率との関係および死亡率と関連するTSH値を明らかにする。
  1. 研究事例の説明:2002~2012年のデータベースから65歳以上でFT4が正常である17,440人を、正常甲状腺機能(Euthyroidism、Eu)(14,946人[85.7%]、平均年齢83歳、女性10,289人)、scHypo(TSH>4.2 mIU/L、538人[3.1%])、scHyper(TSH<0.35 mIU/L、1,956人[11.2%])に分け、10年間追跡して全死亡率を比較した。結果、HRはscHypo 1.75(CI 1.63-1.88)、scHyper 2.33(CI、2.08-2.63)であった。多変量解析でもscHypo 1.68(CI 1.56-1.8、scHyper 1.93(CI 1.7-2.17)と全死亡率は有意に高かった。粗死亡率は1、2、5年で高かったが、年数とともに低下した(1年次が最大)。多変量調整後HR はscHypoのTSH>6.38 mIU/Lで1.71(CI 1.38-2.12)と最も高かった。scHyperのTSHに閾値はなかった(O)[7]
  1. 結論:高齢者のscHypoやscHyperは死亡率を増加させる。TSHの閾値はscHypoで>6.35 mIU/L、scHyperではなかった。
 
  1. 潜在性甲状腺機能低下症関連のCHDリスクはTPOAbの有無と無関係であり、自己免疫性甲状腺炎の存在は予測因子とならない。
  1. 背景:TSH 10.0 mIU/L以上のscHypoはCHDリスクを増加させる。甲状腺自己抗体の測定はHYPOの予測因子となるが、CHDリスクに影響するかどうかは不明である。scHypoのCHDリスクをTPOAbの有無別に検討した。
  1. 研究事例の説明:1950年から2011年までの、CHD 死亡を研究した6つの前向き観察研究から38,274人(460,333人・年)、CHDイベントを研究した4つの前向き観察研究から33,394人について検討した。38,274人(年齢中央値は55歳で63%が女性)のうち、1,691人(4.4%)がscHypoであり、そのうち775人(45.8%)でTPOAbが陽性であった。1,436人がCHDで死亡、3,285人がCHDイベントを発症した。年齢・性別を合わせたEuと比較して、scHypoのCHD死亡のHRはTPOAb陽性で1.15(CI 0.87-1.53)、陰性で1.26(CI 1.01-1.58、P = 0.62)、CHDイベントのHRはそれぞれ1.16(CI 0.87-1.56)と1.26(CI 1.02-1.56、P = 0.65)であった。CHD死亡とイベントのリスクはTSHが高いほど増えたが、いずれもその分散の範囲内であり、TPOAbの有無で差はなかった(S)[8]
  1. 結論:scHypo関連のCHDリスクはTPOAbの有無と無関係であり、自己免疫性甲状腺炎の存在は予測因子とならない。
  1. scHypoは、特にCVDリスクの高い患者において、CVDリスクと全死因死亡を増加させる
  1. 背景:scHypoのCVDリスクと全死因死亡に対する影響を検証する。
  1. 研究事例の説明:PubMedとEmbaseを用い、scHypoと全死因死亡について検索した。CVD のRRと全死因死亡をMantel-Haenszel法を用いてプール解析した。サブ解析としてCVD のハイリスク(冠血管、脳血管、末梢血管障害の既往、拡張型心筋症、心不全、心房細動、静脈血栓塞栓症、糖尿病、CKD)患者についても検討した。35文献(555,530例)が採用条件を満たした。scHypo はCVD (RR=1.33 [CI 1.14-1.54]) と全死因死亡(RR=1.20 [CI 1.07-1.34])のリスク上昇と関連した。しかし、65歳以上では関連はなかった。サブ解析で、CVDリスクの高いscHypo患者のCVDイベント (RR=2.20 [CI 1.28-3.77])と全死因死亡(RR=1.66 [CI 1.41-1.94])は上昇したが、低リスク患者ではリスクの上昇を認めなかった。CVDリスクの高いscHypo患者(平均年齢65歳以上)の6文献を用いた別のサブ解析では全死因死亡(RR=1.41 [CI 1.08-1.85]; I2=0%)のリスク上昇を認めた(S)[9]
  1. 結論:CVDリスクの高い患者ではscHypoはCVDリスクと全死因死亡増加と関連する。
 
  1. 現時点では潜在性甲状腺機能異常は脳卒中に影響しないといわざるをえないが、さらなる研究が必要である。
  1. 背景:scHypoはCHDとの関連が指摘されているが、脳卒中との関連は不明である。
  1. 研究事例の説明:6つの前向き観察研究(11,309人)から665件の脳卒中イベントを見いだした。4つの研究に6,029人のscHyperと、5つの研究に10,118人のscHypoが含まれていた。Euに対するHRはscHypoで1.08(CI 0.87-1.34)、scHyperで1.17(CI 0.54-2.56)であった(S)[10]
  1. 結論:現時点では潜在性甲状腺機能異常は脳卒中に影響しないといわざるをえないが、さらなる研究が必要である。
 
  1. 65歳未満とTSH高値で潜在性甲状腺機能低下症による脳卒中のリスク上昇がみられる。
  1. 研究事例の説明:17の観察研究の47,573人のうち、3451人のscHypo(TSH:4.5-19.9 mIU/L)と脳卒中についてレビューした(489,192人・年)。ハザードレシオ(HR)は脳卒中イベントで1.05、致死的脳卒中で1.07であった。年齢別では、HRは18~49歳の脳卒中イベントで3.32、致死的脳卒中の18~49歳では4.22、50~64歳では2.86であった。65~79歳と80歳以上ではリスクの上昇はみられなかった。致死的脳卒中はTSHが高いほど多い傾向があった(S)[11]
  1. 結論:全体としてはscHypoにより脳卒中のリスク上昇はみられなかったが、65歳未満とTSH高値でリスク上昇がみられた。
 
  1. 高齢者の潜在性甲状腺機能低下症は認知機能に影響しない
  1. 背景:高齢者ではscHypoと認知障害はどちらも頻度が高い。Hypoと認知障害の関係はよく知られているが、scHypoとの関係は一定しない。
  1. 研究事例の説明:PubMed、EMBASE、Web of Science、COCHRANE、CINAHL、PsycINFO、およびAcademic Search Premierを用い、60歳以上のSCHと認知機能について文献検索を行った(1966年1月〜2015年4月1日まで)。 270文献のうち、15文献が採用条件を満たした。scHypo 1,199例を含む19,944例についてプール解析を行った。Mini-Mental State Examination(MMSE)を用いた全般的認知機能、実行機能、記憶について変量効果モデルに基づき評価した。その結果、比較的健康な高齢者においてscHypoと認知障害との間に有意な関係は見出せなかった。また、4つの前向き研究において、scHypoは認知機能の低下速度を速める証拠はなかった(S)[12]
  1. 結論:scHypoは認知機能に影響しない。
 
  1. 原発性甲状腺機能低下症NAFLDは関連する
  1. 背景:原発性甲状腺機能低下症とNAFLDとの関連は不明である。
  1. 研究事例の説明:PubMed、Web of Science and Scopusを用い、NAFLD(画像か生検で診断)について、観察横断、症例対照、および縦断研究を文献検索した(2000年1月〜2018年3月まで)。12の横断研究と3つの縦断研究から44,140例について変量効果モデルを用いて解析した。Hypo(治療中か機能検査で判定)では年齢、性別、BMIおよびその他のメタボリックリスク因子と独立してNAFLDの有病率が有意に高かった(12研究;変量効果OR 1.42 [CI 1.15-1.77]; I2=51.2%)。リスクの大きさは病理学的に判定したNAFLDの重症度と関連し(3研究;変量効果OR 2.73 [CI 1.90-3.93]; I2=0%)、甲状腺機能低下症の程度と相関した。3つの縦断研究のメタ解析では、scHypoは中央値5年以上の超音波診断によるNAFLDの発症リスクと関連しなかった(S)[13]
  1. 結論:HypoとNAFLDとは関連するが、因果関係は明らかではない。
 
  1. HCV感染自体が甲状腺機能異常と関連する
  1. 背景:IFN-α治療前の慢性のHCV感染と自己免疫性甲状腺疾患や甲状腺機能異常との関連は不明である。
  1. 研究事例の説明:IFN-α治療前の慢性のHCV感染と自己免疫性甲状腺疾患や甲状腺機能異常について、観察研究を文献検索した(~2015年8月まで)。12の研究から1,735例のHCV感染患者と1,868例の非 HCV感染患者について変量効果および固定効果モデルでメタ解析した。甲状腺自己抗体の保有率はHCV感染患者で高い傾向にあった。 HCV感染患者におけるTGAb、TPOAbおよびマクロゾーム抗体の陽性率は対照のそれぞれ2.40倍、1.96倍、1.86倍であった。Hypoの有病率は対照の3.10倍(95%CI: 2.19-4.40)であった。一方、Hyperの有病率に差はなかった(S)[14]
  1. 結論:慢性のHCV感染は甲状腺機能異常の独立したリスク因子である。IFN-α治療の有無にかかわらず、甲状腺自己抗体と甲状腺機能をモニターすることが推奨される。
 
  1. 潜在性甲状腺機能亢進症と脆弱性骨折は関連する
  1. 背景:潜在性甲状腺機能異常症と骨折または低骨密度との関連は不明である。
  1. 研究事例の説明:Medline(via PubMed)、EMBASE、Cochrane Library、Web of Science、CENTRALおよびSinoMedを用い、骨折または骨密度について文献検索した(~2016年7月31日まで)。19のコホート研究(参加者79,368例)における骨折のRRは、scHypoで大腿骨頚部骨折1.34(95% CI 1.14, 1.58; I2=32%)、全骨折1.27(95% CI 1.02, 1.58; I2=51.9%)、前腕部骨折1.25(95% CI 1.04, 1.50)、scHyperで椎体骨折1.71(95% CI 1.06, 2.76; I2=0.0%)、非椎体骨折1.20(95% CI 1.03, 1.39; I2=0.0%)、大腿骨頚部骨折1.44(95% CI 1.21, 1.71; I2=0.0%)、全骨折1.38(95% CI 1.21, 1.58; I2=0.0%)であった。LT4またはATD使用の有無によるサブ解析では結果に差はなかった。正常甲状腺機能に対しscHyperのBMDは転子部で加重平均の差(WMD)=-0.060, 95% CI -0.116, -0.004; I2=0.0%、大腿骨頚部でWMD=-0.046, 95% CI -0.077, -0.015; I2=0.0%と有意に減少した。scHypoで差は認めなかった(S)[15]
  1. 結論:scHyper およびscHypoは骨折リスクと関連した。scHyperは低骨密度と関連したが、scHypoとの関連性は得られなかった(ただし、コホートの質は全体として低かった)。
 
  1. 顕性甲状腺機能低下症および顕性甲状腺機能亢進症では小さいが有意に早産のリスクが上昇する。
  1. 研究事例の説明:scHypo、HYPO、HYPER、低T4血症と早産の関係についてレビューした。14の観察研究と1つの症例対照研究から2,532,704人を解析した。オッズレシオ(OR)はHYPOで1.19(CI、1.12-1.26、P<0.00001)、HYPERで1.24(CI 1.17-1.31、P<0.00001)であった。scHypoと低T4血症ではリスク上昇はみられなかった(S)[16]
  1. 結論:HYPOおよびHYPERでは小さいが有意に早産のリスクが上昇する。
 
  1. 母親の妊娠前半における潜在性甲状腺機能低下症は、1歳児の平均精神発達指標スコアの低下と関連する。
  1. 背景:妊娠初期の甲状腺機能異常が幼児の神経発達に及ぼす影響について一定した見解が得られていない。
  1. 研究事例の説明:20人の妊婦で、母親の甲状腺機能に基づいて分けたscHypo 7人、Eu 6人、潜在性を含む顕性甲状腺機能亢進症(Hyperthyroidism、HYPER)7人について、児の神経学的発達状態について検討した。6カ月と12カ月齢における平均の精神発達指標(MDI)スコアはscHypoはEuより16ポイントずつ低かった(P = 0.03と0.02)。24カ月齢の平均MDIスコアは6ポイント低かったが、有意差はなかった。神経生理学的および神経学的評価に差はなかった(O)[17]
  1. 結論:母親の妊娠前半におけるscHypoは、1歳児の平均MDIスコアの低下と関連する。
 
  1. 甲状腺疾患は産科的、陣痛・分娩時合併症と関連する。
  1. 背景:甲状腺疾患と妊娠合併症の関係は一定しない。
  1. 研究事例の説明:米国人223,512人(2002~2008年)の電子カルテを調べた。HYPOは子癇前症(OR:1.47、CI 1.20-1.81)、重積子癇前症(OR: 2.25、CI 1.53-3.29)、妊娠糖尿病(OR: 1.57、CI 1.33-1.86)、早産(OR: 1.34、CI 1.17-1.53)、陣痛誘発(OR: 1.15、CI 1.04-1.28)、帝王切開 (陣痛前、OR: 1.31、CI 1.11-1.54; 陣痛後 OR: 1.38、CI 1.14-1.66)、ICU入室 (OR: 2.08、CI 1.04-4.15)を増加させた。医原性HYPOは胎盤早期剝離(OR: 2.89、CI 1.14-7.36)、骨盤位(OR: 2.09、CI 1.07-4.07)、陣痛後帝王切開(OR: 2.05、CI 1.01-4.16)。Hyperは子癇前症(OR: 1.78、CI 1.08-2.94)、重積子癇前症(OR: 3.64、CI 1.82-7.29)、早産(OR: 1.81、CI 1.32-2.49)、陣痛誘発(OR: 1.40、CI 1.06-1.86)、ICU入室 (OR: 3.70、CI 1.16-11.80)と関連していた(O)[18]
  1. 結論:甲状腺疾患は産科的、陣痛・分娩時合併症と関連する。
 
  1. 低T4血症とTPOAb陽性は早産のリスクを増加させる。TPOAb陽性のリスク上昇は甲状腺機能に依存しない。
  1. 背景:早産は児の死亡や生涯にわたる精神・代謝・心血管疾患の重要なリスク因子である。多くの場合、早産の原因は不明である。現時点では、母体の甲状腺機能異常が早産のリスクになるかどうかは明らかではない。
  1. 研究事例の説明:5,971人の妊婦において妊娠初期の甲状腺機能とTPOAbを測定した。5.0%が早産、(<37 週)、4.4%が自然早産、1.4%が超早期産 (<34週)であった。TSH高値とscHypoは早産と相関したが、自然早産とはしなかった。母体の低T4血症は早産のリスクを2.5倍、自然早産を3.4倍、超早期産を3.6倍に増加させた(すべてP<0.01)。TPOAb陽性は早産を1.7倍(P=0.01)、自然早産を2.1倍(P=0.02)、超早期産を2.5倍(P=0.04)に増加させた(TSHとFT4で補正しても同じ)(O)[19]
  1. 結論:低T4血症とTPOAb陽性は早産のリスクを増加させる。TPOAb陽性のリスク上昇は甲状腺機能に依存しない。
 
  1. 潜在性甲状腺機能低下症と自己免疫性甲状腺疾患を併せ持つ妊婦では、妊娠初期の流産の確率が高い。
  1. 背景:scHypoと自己免疫性甲状腺疾患は妊娠・出産の有害事象と関連する証拠が蓄積されつつあるが、妊娠初期の甲状腺異常と流産についての研究は少ない。
  1. 研究事例の説明:3,315人の4~8週妊婦を前向きに観察し、20週までの流産率を検討した。scHypoのTSH値は2.5≤TSH<5.22 mIU/L(scHypo1)と5.22 ≤ TSH<10 mIU/L(scHypo2)の2群に分けた。結果、Euに対し、scHypo 2群で7.1%(P = 0.002)、甲状腺自己抗体陽性群(Eu)で5.7%(P = 0.003)、scHypo1+抗体陽性群で10.0%(P = 0.000)、scHypo2+抗体陽性群で15.2%(P = 0.000)であった(O)[20]
  1. 結論:scHypoと自己免疫性甲状腺疾患を併せ持つ妊婦では、妊娠初期の流産の確率が高い。
 
  1. 妊娠中の甲状腺異常は児の神経心理学的発達に影響する。
  1. 研究事例の説明:PubMed、Embase and Web of Scienceを用い、妊娠中の甲状腺機能正常の甲状腺障害について症例対照研究とコホート研究を検索した。転帰として児の知能指数と運動指数を調べた。固定効果モデルと変量効果モデルを用いたプール解析を行った。6件研究(4,449例)を解析した。母親がなんらかの甲状腺障害を有すると、健常妊婦と比較して、児の平均知能指数は6.27点、平均運動指数は5.99点低かった。サブ解析では低T4血症、scHypo、TPOAb陽性では、それぞれ、平均知能指数が5.69点、8.76点、10.55点、平均運動指数が4.19点、9.98点、9.03点低かった(S)[21]
  1. 結論:妊娠中の低T4血症、scHypo、TPOAb陽性は児の神経心理学的発達に影響する。
 
  1. 妊婦の顕性甲状腺機能低下症は児の海馬発達と記憶力に影響する。
  1. 背景:先天性HYPOの児では海馬の発達障害を認める。海馬の発達は妊娠初期に始まることから、HYPOの妊婦から生まれた児では、海馬の発達障害や記憶力障害をきたす可能性がある。
  1. 研究事例の説明:9~12歳の54人の小児(妊娠前または妊娠中にHYPOと診断されLT4治療を受けた24人と30人の対照の子)について、記憶力テストとMRI検査を行った。HYPOで有意な海馬容積の減少を認めた。HYPOにおける海馬容積は妊娠第3期のTSHと負に、FT4と正に相関した。記憶力もHYPOで有意に低く、海馬容積と相関した(C)[22]
  1. 結論:妊婦のHYPOは児の海馬発達と記憶力に影響する。
 
  1. 母親の低T4血症は学齢期小児の非言語IQに多大な影響を及ぼすが、脳の形態異常は認めない。
  1. 背景:母親の低T4血症は児の神経発達に影響を及ぼす可能性がある。
  1. 研究事例の説明:3,727組の母児について、妊娠18週までの甲状腺機能と6歳児のIQを評価した。652児については8歳時にMRIを施行した。母親の低T4血症はFT4が5%(10.99 ng/dL)未満でTSHが正常であるものとした。結果、妊娠初期に低T4血症であった母親の児では4.3ポイントIQが低かった。しかし、脳の形態に差は認めなかった(O)[23]
  1. 結論:母親の低T4血症は学齢期小児の非言語IQに多大な影響を及ぼすが、脳の形態異常は認めない。
 
  1. 流産の既往のある肥沃な健康女性では、TSH ≥ 2.5 mIU/Lまたは甲状腺自己抗体の存在は妊孕性・流産・生産に影響しない。
  1. 背景:scHypo・甲状腺自己抗体と妊娠出産の転帰に関するこれまでの研究では、妊娠までの期間(TTP)との関係は不明である。
  1. 研究事例の説明:出産歴や流産の既往のある妊娠前のTSH値・甲状腺自己抗体とTTP・流産・生産について調べた。対象は挙児希望で1~2回の流産歴があり、不妊でない18~40歳の健康女性。年齢とBMI補正後で、TSH<2.5 mIU/L群と比較して、TSH≥2.5 mIU/L群で、流産の増加(RR: 1.07、CI 0.81-1.41)、生産の減少(RR: 0.97、CI 0.88-1.07)、TTP(OR: 1.09、CI 0.90-1.31)。自己抗体の有無についても同様の結果であった(O)[24]
  1. 結論:流産の既往のある肥沃な健康女性では、TSH ≥ 2.5 mIU/Lまたは甲状腺自己抗体の存在は妊孕性・流産・生産に影響しない。
 
  1. 妊娠8~20週の妊婦の潜在性甲状腺機能低下症または低T4血症にレボチロキシン補充療法を行っても、児の5歳までの認知アウトカム(IQ)は改善しない(推奨度3)
  1. 研究背景:妊娠中の潜在性甲状腺疾患は児のIQが正常値より低いなどの有害なアウトカムに関連する可能性が指摘されている。
  1. 研究事例の説明:約1,200例の妊娠8~20週の単胎妊婦を対象として、児のIQに及ぼす妊娠中のscHypo(FT4正常、TSH≧4.00 mIU/L)と低T4血症(TSH正常、FT4<0.86ng/dL)のスクリーニングおよびLT4補充療法の有用性を疾患別の2つのRCT(scHypo 677例と低T4血症526例;各LT4投与群とプラセボ群)で評価した。児に対し発達および行動評価を年1回、5年間行った。主要評価項目は5歳時のIQスコアまたは3歳未満での死亡。結果、妊婦および新生児の有害事象の頻度は低く、2つの試験とも2群間に差はなかった。scHypo試験では児のIQ中央値はLT4群97、プラセボ群94、低T4血症試験ではLT4群94、プラセボ群91と、いずれのRCTでも2群間に有意差はなかった。12、24カ月時のBayley乳幼児発達検査IIIの認知、運動、言語などの副次評価項目においても差はなかった(R)[25]
  1. 結論:妊娠8~20週の妊婦のscHypoまたは低T4血症にLT4補充療法を行っても、児の5歳までの認知アウトカム(IQ)は改善しない。
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文献 

著者: Thenmalar Vadiveloo, Peter T Donnan, Michael J Murphy, Graham P Leese
雑誌名: J Clin Endocrinol Metab. 2013 Mar;98(3):1147-53. doi: 10.1210/jc.2012-3191. Epub 2013 Jan 23.
Abstract/Text OBJECTIVE: The aim of the study was to examine the association of tested TSH with age, gender, and diabetes in a large population-based cohort without evidence of thyroid disease.
DESIGN: Record-linkage technology was used retrospectively to identify people without evidence of thyroid disease in the general population of Tayside, Scotland, from July 1, 2003, to December 31, 2009.
COHORT: All Tayside residents who had thyroid function tests performed were identified. Using a unique patient identifier, data linkage enabled a cohort without thyroid disease to be identified by excluding anyone with thyroid or antithyroid prescription, thyroid-related admission or surgery, treatment with radioactive iodine and/or positive thyroid antibodies. Cases below 18 years of age were also excluded.
OUTCOME MEASURES: We measured TSH distribution among different age groups and by gender.
RESULTS: We identified the latest TSH measurements in 153127 people from the reference population after applying the exclusion criteria. There was a significant increase in median TSH (1.58 mU/L at 31-40 y to 1.86 mU/L at >90 y; P < .001) and 97.5th centile TSH (3.98 to 5.94 mU/L, respectively) with increasing age. The 2.5th centile decreased with age (0.51 to 0.31 mU/L). Patients with diabetes had marginally higher TSH concentration (1.80 vs 1.70 mU/L; P < .001).
CONCLUSION: The use of these age-specific reference intervals for TSH, especially in those over 70 years old, would result in the reclassification of many TSH results from "abnormal" to "normal" (within the 95th centile reference interval) and avoid unnecessary treatment.

PMID 23345094  J Clin Endocrinol Metab. 2013 Mar;98(3):1147-53. doi: 1・・・
著者: Sergio Valdés, Cristina Maldonado-Araque, Ana Lago-Sampedro, Juan Antonio Lillo-Muñoz, Eduardo Garcia-Fuentes, Vidal Perez-Valero, Carolina Gutiérrez-Repiso, Eva Garcia-Escobar, Albert Goday, Inés Urrutia, Laura Peláez, Alfonso Calle-Pascual, Elena Bordiú, Luis Castaño, Conxa Castell, Elias Delgado, Edelmiro Menéndez, Josep Franch-Nadal, Sonia Gaztambide, Joan Girbés, Emilio Ortega, Joan Vendrell, Matilde R Chacón, F Javier Chaves, Federico Soriguer, Gemma Rojo-Martínez
雑誌名: Obesity (Silver Spring). 2017 Apr;25(4):788-793. doi: 10.1002/oby.21796. Epub 2017 Mar 9.
Abstract/Text OBJECTIVE: To analyze the reference range of thyroid-stimulating hormone (TSH) in different BMI categories and its impact on the classification of hypothyroidism.
METHODS: The study included 3,928 individuals free of thyroid disease (without previous thyroid disease, no interfering medications, TSH <10 µUI/mL and thyroid peroxidase antibodies [TPO Abs] <50 IU/mL) who participated in a national, cross-sectional, population-based study and were representative of the adult population of Spain. Data gathered included clinical and demographic characteristics, physical examination, and blood and urine sampling. TSH, free thyroxine, free triiodothyronine, and TPO Ab were analyzed by electrochemiluminescence (E170, Roche Diagnostics, Basel, Switzerland).
RESULTS: The reference range (p2.5-97.5) for TSH was estimated as 0.6 to 4.8 µUI/mL in the underweight category (BMI<20 kg/m2 ), 0.6 to 5.5 µUI/mL in the normal-weight category (BMI 20-24.9 kg/m2 ), 0.6 to 5.5 µUI/mL in the overweight category (BMI 25-29.9 kg/m2 ), 0.5 to 5.9 µUI/mL in the obesity category (BMI 30-39.9 kg/m2 ), and 0.7 to 7.5 µUI/mL in the morbid obesity category (BMI ≥40). By using the reference criteria for the normal-weight population, the prevalence of high TSH levels increased threefold in the morbid obesity category (P < 0.01).
CONCLUSIONS: Persons with morbid obesity might be inappropriately classified if the standard ranges of normality of TSH for the normal-weight population are applied to them.

© 2017 The Obesity Society.
PMID 28276648  Obesity (Silver Spring). 2017 Apr;25(4):788-793. doi: 1・・・
著者: Laura Boucai, Joseph G Hollowell, Martin I Surks
雑誌名: Thyroid. 2011 Jan;21(1):5-11. doi: 10.1089/thy.2010.0092. Epub 2010 Nov 8.
Abstract/Text BACKGROUND: The use of age- and ethnicity-specific thyrotropin (TSH) reference limits decreases misclassification of patients with thyroid dysfunction. Developing such limits requires TSH measurements in different subpopulations.
METHODS: We determined, in the National Health and Nutrition Examination Survey III, the TSH median, 2.5th and 97.5th centiles as a function of age, and anti-thyroid antibodies (ABs) in specific racial/ethnic groups (REGs) designated as non-Hispanic Whites, non-Hispanic Blacks, and Mexican Americans, as classified by the U.S. Office of Management and Budget (OMB) Directive 15. We compared TSH limits of a thyroid disease-free population (n = 15,277) to a reference population (n = 13,344) formed by exclusion of AB+ subjects and TSH >10 mIU/L or <0.1 mIU/L. With quantile regression, we examined the effect of age, REG, gender, body weight, and urinary iodine concentration on TSH reference limits in the AB- population.
RESULTS: AB status did not affect the 2.5th centile and median TSH in any REG or the 97.5th centile in Blacks. The average 97.5th centile of the disease-free Whites and Mexican Americans was 1.0 mIU/L higher than the reference population group. The TSH 2.5th, 50th, and 97.5th centiles increased with age and were lower in Blacks than in Whites or Mexican Americans. Women had lower 2.5th and 50th centiles than males. From these data, we developed equations to predict subpopulation-specific TSH reference limits.
CONCLUSIONS: Our study provides a method to determine TSH limits in individual patients of different ages, gender, and REG criteria whose AB status is uncertain and it will enable clinicians to better classify patients within their subpopulation-specific TSH reference range.

PMID 21058882  Thyroid. 2011 Jan;21(1):5-11. doi: 10.1089/thy.2010.009・・・
著者: Leonard Wartofsky, Richard A Dickey
雑誌名: J Clin Endocrinol Metab. 2005 Sep;90(9):5483-8. doi: 10.1210/jc.2005-0455.
Abstract/Text Debate and controversy currently surround the recommendations of a recent consensus conference that considered issues related to the management of early, mild, or so-called subclinical hypothyroidism and hyperthyroidism. Intimately related to the controversy is the definition of the normal reference range for TSH. It has become clear that previously accepted reference ranges are no longer valid as a result of both the development of more highly sensitive TSH assays and the appreciation that reference populations previously considered normal were contaminated with individuals with various degrees of thyroid dysfunction that served to increase mean TSH levels for the group. Recent laboratory guidelines from the National Academy of Clinical Biochemistry indicate that more than 95% of normal individuals have TSH levels below 2.5 mU/liter. The remainder with higher values are outliers, most of whom are likely to have underlying Hashimoto thyroiditis or other causes of elevated TSH. Importantly, data indicating that African-Americans with very low incidence of Hashimoto thyroiditis have a mean TSH level of 1.18 mU/liter strongly suggest that this value is the true normal mean for a normal population. Recognition and establishment of a more precise and true normal range for TSH have important implications for both screening and treatment of thyroid disease in general and subclinical thyroid disease in particular.

PMID 16148345  J Clin Endocrinol Metab. 2005 Sep;90(9):5483-8. doi: 10・・・
著者: Linda M Thienpont, Katleen Van Uytfanghe, Linde A C De Grande, Dries Reynders, Barnali Das, James D Faix, Finlay MacKenzie, Brigitte Decallonne, Akira Hishinuma, Bruno Lapauw, Paul Taelman, Paul Van Crombrugge, Annick Van den Bruel, Brigitte Velkeniers, Paul Williams, IFCC Committee for Standardization of Thyroid Function Tests (C-STFT)
雑誌名: Clin Chem. 2017 Jul;63(7):1248-1260. doi: 10.1373/clinchem.2016.269456. Epub 2017 May 18.
Abstract/Text BACKGROUND: The IFCC Committee for Standardization of Thyroid Function Tests developed a global harmonization approach for thyroid-stimulating hormone measurements. It is based on a multiassay method comparison study with clinical serum samples and target setting with a robust factor analysis method. Here we describe the Phase IV method comparison and reference interval (RI) studies conducted with the objective to recalibrate the participating assays and demonstrate the proof-of-concept.
METHODS: Fourteen manufacturers measured the harmonization and RI panel; 4 of them quantified the harmonization and first follow-up panel in parallel. All recalibrated their assays to the statistically inferred targets. For validation, we used desirable specifications from the biological variation for the bias and total error (TE). The RI measurements were done with the assays' current calibrators, but data were also reported after transformation to the new calibration status. We estimated the pre- and postrecalibration RIs with a nonparametric bootstrap procedure.
RESULTS: After recalibration, 14 of 15 assays met the bias specification with 95% confidence; 8 assays complied with the TE specification. The CV of the assay means for the harmonization panel was reduced from 9.5% to 4.2%. The RI study showed improved uniformity after recalibration: the ranges (i.e., maximum differences) exhibited by the assay-specific 2.5th, 50th, and 97.5th percentile estimates were reduced from 0.27, 0.89, and 2.13 mIU/L to 0.12, 0.29, and 0.77 mIU/L.
CONCLUSIONS: We showed that harmonization increased the agreement of results from the participating immunoassays, and may allow them to adopt a more uniform RI in the future.

© 2017 American Association for Clinical Chemistry.
PMID 28522444  Clin Chem. 2017 Jul;63(7):1248-1260. doi: 10.1373/clinc・・・
著者: Christian Selmer, Jonas Bjerring Olesen, Morten Lock Hansen, Lene Mia von Kappelgaard, Jesper Clausager Madsen, Peter Riis Hansen, Ole Dyg Pedersen, Jens Faber, Christian Torp-Pedersen, Gunnar Hilmar Gislason
雑誌名: J Clin Endocrinol Metab. 2014 Jul;99(7):2372-82. doi: 10.1210/jc.2013-4184. Epub 2014 Mar 21.
Abstract/Text CONTEXT: Thyroid dysfunction has been associated with both increased all-cause and cardiovascular mortality, but limited data are available on mild thyroid dysfunction and cause-specific mortality.
OBJECTIVE: The objective of the study was to examine the risk of all-cause mortality, major adverse cardiovascular events (MACEs), and cause-specific events in subjects with overt and subclinical thyroid dysfunction.
DESIGN: This was a retrospective cohort study.
SETTING AND PARTICIPANTS: Participants in the study were subjects who underwent thyroid blood tests, without prior thyroid disease, consulting their general practitioner in 2000-2009 in Copenhagen, Denmark.
MAIN OUTCOME MEASURE: All-cause mortality, MACEs, and cause-specific events identified in nationwide registries were measured.
RESULTS: A total of 47 327 (8.4%) deaths occurred among 563 700 included subjects [mean age 48.6 (SD ± 18.2) y; 39% males]. All-cause mortality was increased in overt and subclinical hyperthyroidism [age adjusted incidence rates of 16 and 15 per 1000 person-years, respectively; incidence rate ratios (IRRs) 1.25 [95% confidence interval (CI) 1.15-1.36] and 1.23 (95% CI 1.16-1.30)] compared with euthyroid (incidence rate of 12 per 1000 person-years). Risk of MACEs was elevated in overt and subclinical hyperthyroidism [IRRs 1.16 (95% CI 1.05-1.27) and 1.09 (95% CI 1.02-1.16)] driven by heart failure [IRRs 1.14 (95% CI 0.99-1.32) and 1.20 (95% CI 1.10-1.31)]. A reduction of all-cause mortality was observed in subclinical hypothyroidism with TSH of 5-10 mIU/L [IRR 0.92 (95% CI 0.86-0.98)].
CONCLUSIONS: Heart failure is the leading cause of an increased cardiovascular mortality in both overt and subclinical hyperthyroidism. Subclinical hypothyroidism with TSH 5-10 mIU/L might be associated with a lower risk of all-cause mortality.

PMID 24654753  J Clin Endocrinol Metab. 2014 Jul;99(7):2372-82. doi: 1・・・
著者: Alon Grossman, Avraham Weiss, Nira Koren-Morag, Ilan Shimon, Yichayaou Beloosesky, Joseph Meyerovitch
雑誌名: Am J Med. 2016 Apr;129(4):423-30. doi: 10.1016/j.amjmed.2015.11.027. Epub 2015 Dec 20.
Abstract/Text OBJECTIVE: The association between subclinical hypothyroidism and hyperthyroidism and mortality in the elderly is poorly defined. This study was designed to evaluate the association between subclinical hypothyroidism and subclinical hyperthyroidism and mortality in the elderly and to define the thyroid-stimulating hormone values associated with excess mortality in the elderly.
METHODS: We performed a retrospective cohort study with a review of a computerized database of a large health care organization. Patients aged more than 65 years evaluated in the years 2002 to 2012 with documented normal free T4 values were included in the analysis. All cases of known thyroid disease or cases in which thyroid medications were dispensed were excluded. Analysis was performed only on individuals who were not treated for hyperthyroidism or hypothyroidism during the follow-up period. Subjects were divided into 3 groups based on thyroid-stimulating hormone values: normal (normal thyroid-stimulating hormone), subclinical hypothyroidism (thyroid-stimulating hormone >4.2 mIU/L), and subclinical hyperthyroidism (thyroid-stimulating hormone <0.35 mIU/L). All-cause mortality hazard ratio (HR) was compared among the 3 groups, and a subanalysis according to thyroid-stimulating hormone values was performed in those with subclinical hypothyroidism and subclinical hyperthyroidism.
RESULTS: A final analysis was performed on 17,440 individuals with subclinical thyroid disease (538 with subclinical hyperthyroidism [3.1%], 1956 with subclinical hypothyroidism [11.2%], 14,946 normal cases [85.7%], average age of 83 years, 10,289 were women) who were followed up for 10 years. Both subclinical hypothyroidism (HR, 1.75; confidence interval [CI], 1.63-1.88) and subclinical hyperthyroidism (HR, 2.33; CI, 2.08-2.63) were associated with significantly increased mortality, and this association persisted on multivariate analysis (subclinical hypothyroidism HR, 1.68; CI, 1.56-1.8, subclinical hyperthyroidism HR, 1.93; CI, 1.7-2.17). Crude mortality was elevated at 1, 2, and 5 years, but this association seemed to decrease as time from initial analysis increased (most significant association at 1 year). Thyroid-stimulating hormone values greater than 6.38 mIU/L were associated with the highest mortality in those with subclinical hypothyroidism after multivariate adjustment (HR, 1.708; CI, 1.38-2.12), whereas in subclinical hyperthyroidism, no threshold for increased mortality was identified. Mortality was higher.
CONCLUSIONS: Both subclinical hypothyroidism and subclinical hyperthyroidism are associated with increased mortality in the elderly. A threshold thyroid-stimulating hormone value (>6.35 mIU/L) exists for increased mortality in subclinical hypothyroidism, but not in subclinical hyperthyroidism.

Copyright © 2016 Elsevier Inc. All rights reserved.
PMID 26714213  Am J Med. 2016 Apr;129(4):423-30. doi: 10.1016/j.amjmed・・・
著者: Tinh-Hai Collet, Douglas C Bauer, Anne R Cappola, Bjørn O Asvold, Stefan Weiler, Eric Vittinghoff, Jacobijn Gussekloo, Alexandra Bremner, Wendy P J den Elzen, Rui M B Maciel, Mark P J Vanderpump, Jacques Cornuz, Marcus Dörr, Henri Wallaschofski, Anne B Newman, José A Sgarbi, Salman Razvi, Henry Völzke, John P Walsh, Drahomir Aujesky, Nicolas Rodondi, Thyroid Studies Collaboration
雑誌名: J Clin Endocrinol Metab. 2014 Sep;99(9):3353-62. doi: 10.1210/jc.2014-1250. Epub 2014 Jun 10.
Abstract/Text CONTEXT: Subclinical hypothyroidism has been associated with increased risk of coronary heart disease (CHD), particularly with thyrotropin levels of 10.0 mIU/L or greater. The measurement of thyroid antibodies helps predict the progression to overt hypothyroidism, but it is unclear whether thyroid autoimmunity independently affects CHD risk.
OBJECTIVE: The objective of the study was to compare the CHD risk of subclinical hypothyroidism with and without thyroid peroxidase antibodies (TPOAbs).
DATA SOURCES AND STUDY SELECTION: A MEDLINE and EMBASE search from 1950 to 2011 was conducted for prospective cohorts, reporting baseline thyroid function, antibodies, and CHD outcomes.
DATA EXTRACTION: Individual data of 38 274 participants from six cohorts for CHD mortality followed up for 460 333 person-years and 33 394 participants from four cohorts for CHD events.
DATA SYNTHESIS: Among 38 274 adults (median age 55 y, 63% women), 1691 (4.4%) had subclinical hypothyroidism, of whom 775 (45.8%) had positive TPOAbs. During follow-up, 1436 participants died of CHD and 3285 had CHD events. Compared with euthyroid individuals, age- and gender-adjusted risks of CHD mortality in subclinical hypothyroidism were similar among individuals with and without TPOAbs [hazard ratio (HR) 1.15, 95% confidence interval (CI) 0.87-1.53 vs HR 1.26, CI 1.01-1.58, P for interaction = .62], as were risks of CHD events (HR 1.16, CI 0.87-1.56 vs HR 1.26, CI 1.02-1.56, P for interaction = .65). Risks of CHD mortality and events increased with higher thyrotropin, but within each stratum, risks did not differ by TPOAb status.
CONCLUSIONS: CHD risk associated with subclinical hypothyroidism did not differ by TPOAb status, suggesting that biomarkers of thyroid autoimmunity do not add independent prognostic information for CHD outcomes.

PMID 24915118  J Clin Endocrinol Metab. 2014 Sep;99(9):3353-62. doi: 1・・・
著者: Layal Chaker, Christine Baumgartner, M Arfan Ikram, Abbas Dehghan, Marco Medici, W Edward Visser, Albert Hofman, Nicolas Rodondi, Robin P Peeters, Oscar H Franco
雑誌名: Eur J Epidemiol. 2014 Nov;29(11):791-800. doi: 10.1007/s10654-014-9946-8. Epub 2014 Sep 2.
Abstract/Text Subclinical thyroid dysfunction has been associated with coronary heart disease, but the risk of stroke is unclear. Our aim is to combine the evidence on the association between subclinical thyroid dysfunction and the risk of stroke in prospective cohort studies. We searched Medline (OvidSP), Embase, Web-of-Science, Pubmed Publisher, Cochrane and Google Scholar from inception to November 2013 using a cohort filter, but without language restriction or other limitations. Reference lists of articles were searched. Two independent reviewers screened articles according to pre-specified criteria and selected prospective cohort studies with baseline thyroid function measurements and assessment of stroke outcomes. Data were derived using a standardized data extraction form. Quality was assessed according to previously defined quality indicators by two independent reviewers. We pooled the outcomes using a random-effects model. Of 2,274 articles screened, six cohort studies, including 11,309 participants with 665 stroke events, met the criteria. Four of six studies provided information on subclinical hyperthyroidism including a total of 6,029 participants and five on subclinical hypothyroidism (n = 10,118). The pooled hazard ratio (HR) was 1.08 (95 % CI 0.87-1.34) for subclinical hypothyroidism (I (2) of 0 %) and 1.17 (95 % CI 0.54-2.56) for subclinical hyperthyroidism (I (2) of 67 %) compared to euthyroidism. Subgroup analyses yielded similar results. Our systematic review provides no evidence supporting an increased risk for stroke associated with subclinical thyroid dysfunction. However, the available literature is insufficient and larger datasets are needed to perform extended analyses. Also, there were insufficient events to exclude clinically significant risk from subclinical hyperthyroidism, and more data are required for subgroup analyses.

PMID 25179793  Eur J Epidemiol. 2014 Nov;29(11):791-800. doi: 10.1007/・・・
著者: Layal Chaker, Christine Baumgartner, Wendy P J den Elzen, M Arfan Ikram, Manuel R Blum, Tinh-Hai Collet, Stephan J L Bakker, Abbas Dehghan, Christiane Drechsler, Robert N Luben, Albert Hofman, Marileen L P Portegies, Marco Medici, Giorgio Iervasi, David J Stott, Ian Ford, Alexandra Bremner, Christoph Wanner, Luigi Ferrucci, Anne B Newman, Robin P Dullaart, José A Sgarbi, Graziano Ceresini, Rui M B Maciel, Rudi G Westendorp, J Wouter Jukema, Misa Imaizumi, Jayne A Franklyn, Douglas C Bauer, John P Walsh, Salman Razvi, Kay-Tee Khaw, Anne R Cappola, Henry Völzke, Oscar H Franco, Jacobijn Gussekloo, Nicolas Rodondi, Robin P Peeters, Thyroid Studies Collaboration
雑誌名: J Clin Endocrinol Metab. 2015 Jun;100(6):2181-91. doi: 10.1210/jc.2015-1438. Epub 2015 Apr 9.
Abstract/Text OBJECTIVE: The objective was to determine the risk of stroke associated with subclinical hypothyroidism.
DATA SOURCES AND STUDY SELECTION: Published prospective cohort studies were identified through a systematic search through November 2013 without restrictions in several databases. Unpublished studies were identified through the Thyroid Studies Collaboration. We collected individual participant data on thyroid function and stroke outcome. Euthyroidism was defined as TSH levels of 0.45-4.49 mIU/L, and subclinical hypothyroidism was defined as TSH levels of 4.5-19.9 mIU/L with normal T4 levels.
DATA EXTRACTION AND SYNTHESIS: We collected individual participant data on 47 573 adults (3451 subclinical hypothyroidism) from 17 cohorts and followed up from 1972-2014 (489 192 person-years). Age- and sex-adjusted pooled hazard ratios (HRs) for participants with subclinical hypothyroidism compared to euthyroidism were 1.05 (95% confidence interval [CI], 0.91-1.21) for stroke events (combined fatal and nonfatal stroke) and 1.07 (95% CI, 0.80-1.42) for fatal stroke. Stratified by age, the HR for stroke events was 3.32 (95% CI, 1.25-8.80) for individuals aged 18-49 years. There was an increased risk of fatal stroke in the age groups 18-49 and 50-64 years, with a HR of 4.22 (95% CI, 1.08-16.55) and 2.86 (95% CI, 1.31-6.26), respectively (p trend 0.04). We found no increased risk for those 65-79 years old (HR, 1.00; 95% CI, 0.86-1.18) or ≥ 80 years old (HR, 1.31; 95% CI, 0.79-2.18). There was a pattern of increased risk of fatal stroke with higher TSH concentrations.
CONCLUSIONS: Although no overall effect of subclinical hypothyroidism on stroke could be demonstrated, an increased risk in subjects younger than 65 years and those with higher TSH concentrations was observed.

PMID 25856213  J Clin Endocrinol Metab. 2015 Jun;100(6):2181-91. doi: ・・・
著者: Abimbola A Akintola, Steffy W Jansen, David van Bodegom, Jeroen van der Grond, Rudi G Westendorp, Anton J M de Craen, Diana van Heemst
雑誌名: Front Aging Neurosci. 2015;7:150. doi: 10.3389/fnagi.2015.00150. Epub 2015 Aug 11.
Abstract/Text Subclinical hypothyroidism (SCH), defined as elevated thyroid stimulating hormone (TSH) and normal thyroid hormone levels, and cognitive impairment are both common in older people. While the relation between overt hypothyroidism and cognitive impairment is well established, data on the association between SCH and cognitive impairment are conflicting. This systematic review and meta-analysis was performed to assess available evidence on the association of SCH with cognition in community dwelling, relatively healthy older adults. PubMed, EMBASE, Web of Science, COCHRANE, CINAHL, PsycINFO, and Academic Search Premier (January 1966 to April 1, 2015) were searched without language restrictions, as were references of key articles, for studies on the association between SCH and cognition in older adults (>60 years). These studies were reviewed by two independent reviewers according to predefined criteria for eligibility and methodological quality, and data were extracted using standardized forms. Of the 844 reports initially identified, 270 remained after exclusion of duplicates. Of the 270, 15 studies comprising 19,944 subjects, of whom 1,199 had subclinical hypothyroidism were included. Data from the 15 studies was pooled, and meta-analyzed cross-sectionally for global cognition [assessed by Mini-Mental State Examination (MMSE)], executive function, and memory, using random effects models. Pooled effect size (ES) for MMSE was -0.01 (95% CI -0.09, 0.08), with heterogeneity (I (2)) of 55.1%. Pooled ES was < 0.001 (95% CI -0.10, 0.09) for executive function (I (2) = 13.5%), and 0.01 (95% CI -0.12, 0.14) for memory (I (2) = 46.9%). In addition, prospective analysis including four studies showed pooled ES of 0.033 (95% CI -0.001 - 0.067) for MMSE (I (2) < 0.001%), indicating that subclinical hypothyroidism was not significantly associated with accelerated cognitive decline. This systematic review and meta-analysis provides no evidence that supports an association between SCH and cognitive impairment in relatively healthy older adults.

PMID 26321946  Front Aging Neurosci. 2015;7:150. doi: 10.3389/fnagi.20・・・
著者: Yi Shen, Xu-Lin Wang, Jin-Ping Xie, Jian-Guo Shao, Yi-Hua Lu, Sheng Zhang, Gang Qin
雑誌名: J Gastrointestin Liver Dis. 2016 Jun;25(2):227-34. doi: 10.15403/jgld.2014.1121.252.chc.
Abstract/Text BACKGROUND AND AIMS: The involvement of thyroid autoimmunity and dysfunction in patients with chronic hepatitis C virus (HCV) infection before interferon-α (IFN-α) therapy remains controversial. We performed this meta-analysis to evaluate the association of HCV infection with the presence of anti-thyroid antibodies and dysthyroidism.
METHODS: A literature search was carried out to collect articles dated up to August 2015 to identify observational studies which compared the prevalence of anti-thyroid antibodies and thyroid dysfunction in IFN-α naïve chronic HCV-infected subjects with non-HCV infected controls. Random-effect or fixed-effect meta-analyses were applied and results reported as odds ratios (ORs) with 95% confidence intervals (CIs).
RESULTS: Twelve studies were included, involving 1,735 HCV-infected and 1,868 non-HCV infected subjects. Pooled anti-thyroid antibody prevalence tended to be higher in HCV-infected subjects. The prevalence of anti-thyroglobulin antibody (TGAb), anti-thyroid peroxidase antibody (TPOAb), anti-thyroid microsomal antibody (ATMA) were 2.40-fold, 1.96-fold and 1.86-fold higher in HCV-infected subjects than in controls, respectively. The prevalence of hypothyroidism also differed by HCV infection status, with a pooled risk of 3.10 (95%CI: 2.19-4.40) in HCV-infected subjects. However, the results did not show a significant difference in the prevalence of hyperthyroidism between the two groups.
CONCLUSION: Chronic HCV infection may be an independent risk factor for thyroid disturbance. It is advisable for the clinicians to monitor both thyroid antibodies and function in the course of chronic HCV infection, independent of IFN-α treatment.

PMID 27308655  J Gastrointestin Liver Dis. 2016 Jun;25(2):227-34. doi:・・・
著者: Penelope M Sheehan, Alison Nankervis, Edward Araujo Júnior, Fabricio Da Silva Costa
雑誌名: J Clin Endocrinol Metab. 2015 Nov;100(11):4325-31. doi: 10.1210/jc.2015-3074. Epub 2015 Sep 18.
Abstract/Text CONTEXT: Thyroid disease in pregnancy is increasing with rising average maternal ages in developed countries. The evidence for an association between preterm birth and thyroid disease has been confounded by small studies with varying outcomes and methodology.
OBJECTIVE: The aim of this meta-analysis is to review the literature regarding thyroid disease including subclinical and overt hypothyroidism, hyperthyroidism, and isolated hypothyroxinemia and the specific outcome of preterm birth.
DATA SOURCES: A search of PubMed and Embase databases was performed in May 2015. A fixed-effects model was used to calculate the overall combined odds ratio (OR) with its corresponding 95% confidence interval (95% CI) to evaluate the relationship between thyroid disease and preterm delivery.
STUDY SELECTION: Studies were considered eligible if they met the following criteria: prospective cohort study or a case control study; the exposure of interest was maternal thyroid disease, including subclinical hypothyroidism, overt hypothyroidism, hyperthyroidism, or isolated hypothyroxinemia; the outcome of interest was preterm delivery; and data regarding numbers of preterm births in each cohort were reported.
DATA EXTRACTION: Data were recorded in a database evidence table including any incidence data for maternal thyroid disease and preterm birth compared to a reference group.
DATA SYNTHESIS: Fourteen cohort studies and one case control study involving 2 532 704 participants were included. The combined OR of preterm delivery for pregnant women with overt hypothyroidism compared with the reference group was 1.19 (95% CI, 1.12-1.26; P < .00001). There was also a significant risk of preterm birth in women with hyperthyroidism (OR, 1.24 [95%, CI 1.17-1.31]; P < .00001). Subclinical hypothyroidism and isolated hypothyroxinemia showed no significant increase in OR. Sensitivity analysis made no change to these results.
CONCLUSION: Both overt hypothyroidism and hyperthyroidism are associated with a small but statistically significant increase in OR for preterm birth not seen in subclinical hypothyroidism or isolated hypothyroxinemia.

PMID 26383905  J Clin Endocrinol Metab. 2015 Nov;100(11):4325-31. doi:・・・
著者: B J Smit, J H Kok, T Vulsma, J M Briët, K Boer, W M Wiersinga
雑誌名: Acta Paediatr. 2000 Mar;89(3):291-5.
Abstract/Text A prospective observational study was performed in pregnant women with known thyroid disease. We studied the effect of maternal thyroid function in the first half of pregnancy on the neurologic development of the infant in the first 2 y of life. Clinical and thyroid function data were collected from 20 pregnant women with known thyroid disease and their newborn children. Infants were divided into three groups according to their maternal thyroid function within the first half of pregnancy: Group A (n = 7): maternal subclinical hypothyroidism, Group B (n = 6): maternal euthyroidism, and Group C (n = 7): maternal hyperthyroidism or subclinical hyperthyroidism. Neurophysiologic, i.e. motor nerve conduction velocity and somatosensory evoked potentials and neurologic and developmental (Bayley scales) assessments were done. One infant, born to a mother with Graves' disease, developed transient hyperthyroidism. At the age of 6 and 12 mo, the mean mental developmental index (MDI) score was 16 points lower for infants in Group A than for those in Group B (p = 0.03 and 0.02, respectively). At the age of 24 mo, the mean MDI score was 6 points lower, which was not statistically significant. Neurophysiologic and neurologic assessments and the mean Psychomotor Developmental scores did not differ among the three groups. In conclusion, maternal subclinical hypothyroidism in the first half of pregnancy was associated with a lower mean MDI score in their infants during the first year of life.

PMID 10772276  Acta Paediatr. 2000 Mar;89(3):291-5.
著者: Tuija Männistö, Pauline Mendola, Jagteshwar Grewal, Yunlong Xie, Zhen Chen, S Katherine Laughon
雑誌名: J Clin Endocrinol Metab. 2013 Jul;98(7):2725-33. doi: 10.1210/jc.2012-4233. Epub 2013 Jun 6.
Abstract/Text CONTEXT: Thyroid diseases are inconsistently reported to increase risk for pregnancy complications.
OBJECTIVE: The objective of this study was to study pregnancy complications associated with common and uncommon thyroid diseases.
DESIGN, SETTING, AND PARTICIPANTS: We analyzed singleton pregnancies (N = 223 512) from a retrospective US cohort, the Consortium on Safe Labor (2002-2008). Thyroid diseases and outcomes were derived from electronic medical records. Multivariable logistic regression with generalized estimating equations estimated adjusted odds ratios (ORs) with 99% confidence intervals (99% CI).
MAIN OUTCOME MEASURES: Hypertensive diseases, diabetes, preterm birth, cesarean sections, inductions, and intensive care unit (ICU) admissions were analyzed.
RESULTS: Primary hypothyroidism was associated with increased odds of preeclampsia (OR = 1.47, 99% CI = 1.20-1.81), superimposed preeclampsia (OR = 2.25, 99% CI = 1.53-3.29), gestational diabetes (OR = 1.57, 99% CI = 1.33-1.86), preterm birth (OR = 1.34, 99% CI = 1.17-1.53), induction (OR = 1.15, 99% CI = 1.04-1.28), cesarean section (prelabor, OR = 1.31, 99% CI = 1.11-1.54; after spontaneous labor OR = 1.38, 99% CI = 1.14-1.66), and ICU admission (OR = 2.08, 99% CI = 1.04-4.15). Iatrogenic hypothyroidism was associated with increased odds of placental abruption (OR = 2.89, 99% CI = 1.14-7.36), breech presentation (OR = 2.09, 99% CI = 1.07-4.07), and cesarean section after spontaneous labor (OR = 2.05, 99% CI = 1.01-4.16). Hyperthyroidism was associated with increased odds of preeclampsia (OR = 1.78, 99% CI = 1.08-2.94), superimposed preeclampsia (OR = 3.64, 99% CI = 1.82-7.29), preterm birth (OR = 1.81, 99% CI = 1.32-2.49), induction (OR = 1.40, 99% CI = 1.06-1.86), and ICU admission (OR = 3.70, 99% CI = 1.16-11.80).
CONCLUSIONS: Thyroid diseases were associated with obstetrical, labor, and delivery complications. Although we lacked information on treatment during pregnancy, these nationwide data suggest either that there is a need for better thyroid disease management during pregnancy or that there may be an intrinsic aspect of thyroid disease that causes poor pregnancy outcomes.

PMID 23744409  J Clin Endocrinol Metab. 2013 Jul;98(7):2725-33. doi: 1・・・
著者: Tim I M Korevaar, Sarah Schalekamp-Timmermans, Yolanda B de Rijke, W Edward Visser, Willy Visser, Sabine M P F de Muinck Keizer-Schrama, Albert Hofman, H Alec Ross, Herbert Hooijkaas, Henning Tiemeier, Jacoba J Bongers-Schokking, Vincent W V Jaddoe, Theo J Visser, Eric A P Steegers, Marco Medici, Robin P Peeters
雑誌名: J Clin Endocrinol Metab. 2013 Nov;98(11):4382-90. doi: 10.1210/jc.2013-2855. Epub 2013 Sep 13.
Abstract/Text CONTEXT: Premature delivery is an important risk factor for child mortality and psychiatric, metabolic, and cardiovascular disease later in life. In the majority of cases, the cause of prematurity cannot be identified. Currently, it remains controversial whether abnormal maternal thyroid function during pregnancy increases the risk of premature delivery. Therefore, we investigated the relation between maternal serum thyroid parameters and the risk of premature delivery in a large prospective population-based study.
DESIGN: Serum TSH, free T4 (FT4), T4, and TPO antibodies (TPOAbs) were determined during early pregnancy in 5971 pregnant women from the Generation R study. Data were available on maternal age, parity, smoking, socioeconomic status, ethnicity, maternal anthropometrics, and urinary iodine levels.
RESULTS: Of all women, 5.0% had a premature delivery (<37 weeks), 4.4% had a spontaneous premature delivery, and 1.4% had a very premature delivery (<34 weeks). High TSH levels and subclinical hypothyroidism were associated with premature delivery but not with spontaneous premature delivery. Maternal hypothyroxinemia was associated with a 2.5-fold increased risk of premature delivery, a 3.4-fold increased risk of spontaneous premature delivery, and a 3.6-fold increased risk of very premature delivery (all P < .01). TPOAb positivity was associated with a 1.7-fold increased risk of premature delivery (P = .01), a 2.1-fold increased risk of spontaneous premature delivery (P = .02), and a 2.5-fold increased risk of very premature delivery (P = .04). These effects remained similar after correction for TSH and FT4 levels.
CONCLUSIONS: Hypothyroxinemia and TPOAb positivity are associated with an increased risk of premature delivery. The increased risk in TPOAb-positive women seems to be independent of thyroid function.

PMID 24037884  J Clin Endocrinol Metab. 2013 Nov;98(11):4382-90. doi: ・・・
著者: Haixia Liu, Zhongyan Shan, Chenyan Li, Jinyuan Mao, Xiaochen Xie, Weiwei Wang, Chenling Fan, Hong Wang, Hongmei Zhang, Cheng Han, Xinyi Wang, Xin Liu, Yuxin Fan, Suqing Bao, Weiping Teng
雑誌名: Thyroid. 2014 Nov;24(11):1642-9. doi: 10.1089/thy.2014.0029. Epub 2014 Sep 17.
Abstract/Text BACKGROUND: Increasing data suggest that subclinical hypothyroidism (SCH) and thyroid autoimmunity (TAI) are associated with adverse pregnancy outcomes, but there are limited data on the association of these conditions in early pregnancy with subsequent miscarriage.
METHODS: In this prospective cohort study, we screened 3315 women at low risk for thyroid dysfunction at four to eight weeks' gestation from iodine-sufficient areas of China between January 2012 and September 2012. Thyrotropin (TSH), free thyroxine (fT4), and the autoantibodies thyroid-peroxidase antibody (TPOAb) and thyroglobulin antibody (TgAb) were measured. Based on these results, women were divided into four groups for comparison: euthyroidism (ET), isolated SCH, isolated TAI (positive TPOAb or/and TgAb), and SCH with TAI (SCH+TAI). The SCH group was stratified into two subgroups (SCH 1 and SCH 2) on the basis of the level of TSH (2.5 ≤ TSH < 5.22 or 5.22 ≤ TSH < 10 respectively). Accordingly, the SCH+TAI group was also stratified into two subgroups (SCH+TAI 1 and SCH+TAI 2). The outcome of interest was miscarriage, defined as spontaneous pregnancy loss prior to 20 weeks.
RESULTS: Compared to women with ET, the risk of miscarriage was significantly higher among women with SCH 2 (7.1% vs. 2.2%, aOR 3.40 [CI 1.62-7.15]; p = 0.002), isolated TAI (5.7% vs. 2.2%, aOR 2.71 [CI 1.43-5.12]; p = 0.003), SCH+TAI 1 (10.0% vs. 2.2%, aOR 4.96 [CI 2.76-8.90]; p = 0.000), and SCH+TAI 2 (15.2% vs. 2.2%, aOR 9.56 [CI 3.76-24.28]; p = 0.000). The gestational ages of 110 women at miscarriage were lower among women with subclinical thyroid abnormalities compared to ET (11.13 ± 3.21 weeks with subclinical thyroid abnormalities vs. 9.33 ± 1.71 weeks with ET; p = 0.024). In parallel with the higher TSH levels, there were earlier gestation ages at miscarriage between subgroups of SCH and SCH+TAI (SCH 1 vs. SCH 2: 10.79 ± 1.77 vs. 9.70 ± 1.47 weeks, p = 0.039; SCH+TAI 1 vs. SCH+TAI 2: 9.59 ± 1.97 vs. 8.88 ± 1.24 weeks, p = 0.031).
CONCLUSIONS: Women with SCH and TAI are at an increased risk of miscarriage between four and eight gestational weeks. Women with a combination of SCH and TAI were found to have the highest risk and earlier gestational ages of miscarriage.

PMID 25087688  Thyroid. 2014 Nov;24(11):1642-9. doi: 10.1089/thy.2014.・・・
著者: Xuegang Fan, Lina Wu
雑誌名: J Matern Fetal Neonatal Med. 2016 Dec;29(24):3971-6. doi: 10.3109/14767058.2016.1152248. Epub 2016 Mar 18.
Abstract/Text OBJECTIVE: To investigate the relationship between specific thyroid abnormalities in women during pregnancy and the subsequent neuropsychological development of their offspring.
METHODS: A systematic literature search of PubMed, Embase and Web of Science was conducted. Eligible studies were case-control or cohort study that explored this association with euthyroid thyroid abnormalities during pregnancy. The outcomes included intelligence scores and motor scores. Weighted mean differences (WMDs) and 95% confidence intervals (CIs) were calculated and heterogeneity was assessed with Cochrane Q chi-square test and I(2) statistics. A fixed-effects or random-effects model was used to pool the estimates according to the heterogeneity among the included studies.
RESULTS: Six studies, involving 4449 participants, were included. Children of women with thyroid abnormalities had mean intelligence score of 6.27 points and motor score of 5.99 points lower than that of children of euthyroid women. Subgroup analysis suggested that, children of women with hypothyroxinaemia, subclinical hypothyroidism and positive TPOAb had mean intelligence scores of 5.69 points, 8.76 points and 10.55 points, and mean motor scores of 4.19 points, 9.98 points and 9.03 points lower than those of the controls, respectively.
CONCLUSIONS: The thyroid abnormalities in pregnant women may adversely affect neuropsychological development of their offspring.

PMID 26988121  J Matern Fetal Neonatal Med. 2016 Dec;29(24):3971-6. do・・・
著者: Karen A Willoughby, Mary Pat McAndrews, Joanne F Rovet
雑誌名: Thyroid. 2014 Mar;24(3):576-84. doi: 10.1089/thy.2013.0215. Epub 2013 Nov 13.
Abstract/Text BACKGROUND: Rodents with gestational thyroid-hormone (TH) deficiencies and children with congenital hypothyroidism show abnormal hippocampal development. Given that the human hippocampus starts to develop early in gestation, we asked if children born to women with hypothyroidism during pregnancy also show hippocampal abnormalities and if this is related to the severity of maternal TH insufficiency and current memory functioning. We additionally sought to determine whether effects were more prominent in anterior or posterior hippocampal subsections given these support different memory functions and have different developmental trajectories. We hypothesized that these children would have smaller than normal hippocampal volumes than controls and show memory deficits on both standardized tests and indices of "everyday" memory functioning.
METHODS: We studied 54 children aged 9 to 12 years: 30 controls and 24 HYPO cases-offspring from women diagnosed with hypothyroidism prior to or during pregnancy and treated with l-thyroxine. All children received a thorough assessment of memory functions and an MRI scan. For each child, right and left hippocampi were manually traced, and volumes of right and left hippocampi and anterior and posterior segments were determined.
RESULTS: HYPO cases showed significantly smaller right and left hippocampal volumes than controls, particularly in right posterior and left anterior segments. In HYPO children, hippocampal volumes were negatively correlated with maternal third-trimester TSH levels and positively correlated with third-trimester fT4. HYPO cases scored significantly below controls on one objective and several subjective memory indices, and these were correlated with hippocampal volumes.
CONCLUSION: Early TH insufficiency from maternal hypothyroidism affects offspring hippocampal development and memory.

PMID 24015847  Thyroid. 2014 Mar;24(3):576-84. doi: 10.1089/thy.2013.0・・・
著者: Akhgar Ghassabian, Hanan El Marroun, Robin P Peeters, Vincent W Jaddoe, Albert Hofman, Frank C Verhulst, Henning Tiemeier, Tonya White
雑誌名: J Clin Endocrinol Metab. 2014 Jul;99(7):2383-90. doi: 10.1210/jc.2013-4281. Epub 2014 Mar 31.
Abstract/Text CONTEXT: Although maternal hypothyroxinemia is suggested to be related to various adverse consequences in a child's neurodevelopment, the underlying neurobiology is largely unknown.
OBJECTIVE: The objective of the study was to examine the relationship between maternal hypothyroxinemia in early pregnancy and children's nonverbal intelligence quotient (IQ). Furthermore, we explored whether global brain volumes, cortical thickness, and brain surface area differed between children exposed prenatally to hypothyroxinemia and healthy controls.
DESIGN AND SETTING: The study included a large population-based prospective birth cohort in The Netherlands.
PARTICIPANTS: A total of 3727 mother-child pairs with data on prenatal thyroid function at less than 18 weeks of gestation and nonverbal IQ at 6 years participated in the study. In 652 children, brain imaging was performed at 8 years of age.
MAIN MEASURES: Maternal hypothyroxinemia was defined as free T4 in the lowest 5% of the sample, whereas TSH was in the normal range. At 6 years, children's IQ was assessed using a Dutch test battery. Global brain volumetric measures, cortical thickness, and surface area were assessed using high-resolution structural magnetic resonance imaging.
RESULTS: The children of mothers with hypothyroxinemia in early pregnancy scored 4.3 points IQ lower than the children of mothers with normal thyroid status (95% confidence interval -6.68, -1.81; P = .001). After adjustment for multiple testing, we did not find any differences in brain volumetric measures, cortical thickness, and surface area between children exposed prenatally to hypothyroxinemia and controls.
CONCLUSIONS: Our findings confirm a large adverse effect of maternal hypothyroxinemia on children's nonverbal IQ at school age. However, we found no evidence that maternal hypothyroxinemia is associated with differences in brain morphology in school-age children.

PMID 24684462  J Clin Endocrinol Metab. 2014 Jul;99(7):2383-90. doi: 1・・・
著者: Torie C Plowden, Enrique F Schisterman, Lindsey A Sjaarda, Shvetha M Zarek, Neil J Perkins, Robert Silver, Noya Galai, Alan H DeCherney, Sunni L Mumford
雑誌名: J Clin Endocrinol Metab. 2016 Jun;101(6):2358-65. doi: 10.1210/jc.2016-1049. Epub 2016 Mar 29.
Abstract/Text CONTEXT: Prior studies examining associations between subclinical hypothyroidism and antithyroid antibodies with early pregnancy loss and live birth suggest mixed results and time to pregnancy (TTP) has not been studied in this patient population.
OBJECTIVE: This study sought to examine associations of prepregnancy TSH concentrations and thyroid autoimmunity with TTP, pregnancy loss, and live birth among women with proven fecundity and a history of pregnancy loss.
DESIGN AND SETTING: This was a prospective cohort study from a large, randomized controlled trial that took place at four medical centers in the United States.
PATIENTS OR OTHER PARTICIPANTS: Healthy women, ages 18-40 y, who were actively attempting to conceive and had one or two prior pregnancy losses and no history of infertility were eligible for the study.
INTERVENTION: There were no interventions.
MAIN OUTCOME MEASURE: TTP, pregnancy loss, and live birth.
RESULTS: Women with TSH ≥ 2.5 mIU/L did not have an increased risk of pregnancy loss (risk ratio, 1.07; 95% confidence interval [CI], 0.81-1.41) or a decrease in live birth rate (risk ratio, 0.97; 95% CI, 0.88-1.07) or TTP (fecundability odds ratio, 1.09; 95% CI, 0.90-1.31) compared with women with TSH <2.5 mIU/L after adjustment for age and body mass index. Similar findings were observed for women with thyroid autoimmunity and after additional adjustment for treatment assignment.
CONCLUSIONS: Among healthy fecund women with a history pregnancy loss, TSH levels ≥ 2.5 mIU/L or the presence of antithyroid antibodies were not associated with fecundity, pregnancy loss, or live birth. Thus, women with subclinical hypothyroidism or thyroid autoimmunity can be reassured that their chances of conceiving and achieving a live birth are likely unaffected by marginal thyroid dysfunction.

PMID 27023447  J Clin Endocrinol Metab. 2016 Jun;101(6):2358-65. doi: ・・・
著者: Brian M Casey, Elizabeth A Thom, Alan M Peaceman, Michael W Varner, Yoram Sorokin, Deborah G Hirtz, Uma M Reddy, Ronald J Wapner, John M Thorp, George Saade, Alan T N Tita, Dwight J Rouse, Baha Sibai, Jay D Iams, Brian M Mercer, Jorge Tolosa, Steve N Caritis, J Peter VanDorsten, Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal–Fetal Medicine Units Network
雑誌名: N Engl J Med. 2017 Mar 2;376(9):815-825. doi: 10.1056/NEJMoa1606205.
Abstract/Text Background Subclinical thyroid disease during pregnancy may be associated with adverse outcomes, including a lower-than-normal IQ in offspring. It is unknown whether levothyroxine treatment of women who are identified as having subclinical hypothyroidism or hypothyroxinemia during pregnancy improves cognitive function in their children. Methods We screened women with a singleton pregnancy before 20 weeks of gestation for subclinical hypothyroidism, defined as a thyrotropin level of 4.00 mU or more per liter and a normal free thyroxine (T4) level (0.86 to 1.90 ng per deciliter [11 to 24 pmol per liter]), and for hypothyroxinemia, defined as a normal thyrotropin level (0.08 to 3.99 mU per liter) and a low free T4 level (<0.86 ng per deciliter). In separate trials for the two conditions, women were randomly assigned to receive levothyroxine or placebo. Thyroid function was assessed monthly, and the levothyroxine dose was adjusted to attain a normal thyrotropin or free T4 level (depending on the trial), with sham adjustments for placebo. Children underwent annual developmental and behavioral testing for 5 years. The primary outcome was the IQ score at 5 years of age (or at 3 years of age if the 5-year examination was missing) or death at an age of less than 3 years. Results A total of 677 women with subclinical hypothyroidism underwent randomization at a mean of 16.7 weeks of gestation, and 526 with hypothyroxinemia at a mean of 17.8 weeks of gestation. In the subclinical hypothyroidism trial, the median IQ score of the children was 97 (95% confidence interval [CI], 94 to 99) in the levothyroxine group and 94 (95% CI, 92 to 96) in the placebo group (P=0.71). In the hypothyroxinemia trial, the median IQ score was 94 (95% CI, 91 to 95) in the levothyroxine group and 91 (95% CI, 89 to 93) in the placebo group (P=0.30). In each trial, IQ scores were missing for 4% of the children. There were no significant between-group differences in either trial in any other neurocognitive or pregnancy outcomes or in the incidence of adverse events, which was low in both groups. Conclusions Treatment for subclinical hypothyroidism or hypothyroxinemia beginning between 8 and 20 weeks of gestation did not result in significantly better cognitive outcomes in children through 5 years of age than no treatment for those conditions. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Institute of Neurological Disorders and Stroke; ClinicalTrials.gov number, NCT00388297 .).

PMID 28249134  N Engl J Med. 2017 Mar 2;376(9):815-825. doi: 10.1056/N・・・
著者: Giuseppe Pasqualetti, Gennaro Pagano, Giuseppe Rengo, Nicola Ferrara, Fabio Monzani
雑誌名: J Clin Endocrinol Metab. 2015 Nov;100(11):4240-8. doi: 10.1210/jc.2015-2046. Epub 2015 Aug 25.
Abstract/Text BACKGROUND: The association between subclinical hypothyroidism (sHT) and cognitive impairment or risk of dementia is not well-defined, especially in the elderly, where the assessment of central nervous system function is challenging. The aim of this systematic review and meta-analysis was to evaluate the possible effect of sHT on cognitive decline and the risk of dementia.
METHODS: Cognitive function was the primary outcome, evaluated as composite endpoint of incidence or prevalence of dementia or difference of Mini Mental State Examination, Wechsler Adult Intelligence Scale, and Wechsler Memory Scale-Revised scores.
RESULTS: Thirteen studies were included in the meta-analysis. A significant risk of cognitive alteration was observed only in sHT individuals younger than age 75 years: composite endpoint odds ratio (OR) 1.56 (95% confidence interval [CI] 1.07-2.27, P = .02, I(2) = 82.5%), risk of dementia OR 1.81 (95% CI 1.43-2.28, P < .01, I(2) = 35%). Mean serum thyroid-stimulating hormone (TSH) levels and the OR of composite endpoint were positively correlated. No significant effect of sHT was found when considering all the studies as a whole: composite endpoint OR 1.26 (95% CI 0.96-1.66, P = .09, I(2) = 87.2%), risk of dementia OR 1.42 (95% CI, 0.97-2.07, P = .07, I(2) = 66.8%), Mini Mental State Examination mean difference -0.059 (95% CI -0.464 to 0.346 P = .78, I(2) = 51.8%).
CONCLUSIONS: This meta-analysis demonstrates a relationship between sHT and cognitive impairment only in individuals younger than 75 years of age and those with higher TSH concentrations. No correlation was found while considering all the studies as a whole. The lack of utilization of age-related serum TSH reference ranges and consequent potential misdiagnosis of sHT in older people may account for this.

PMID 26305618  J Clin Endocrinol Metab. 2015 Nov;100(11):4240-8. doi: ・・・
著者: Geanina Popoveniuc, Tanu Chandra, Anchal Sud, Meeta Sharma, Marc R Blackman, Kenneth D Burman, Mihriye Mete, Sameer Desale, Leonard Wartofsky
雑誌名: Endocr Pract. 2014 Aug;20(8):808-17. doi: 10.4158/EP13460.OR.
Abstract/Text OBJECTIVE: To develop diagnostic criteria for myxedema coma (MC), a decompensated state of extreme hypothyroidism with a high mortality rate if untreated, in order to facilitate its early recognition and treatment.
METHODS: The frequencies of characteristics associated with MC were assessed retrospectively in patients from our institutions in order to derive a semiquantitative diagnostic point scale that was further applied on selected patients whose data were retrieved from the literature. Logistic regression analysis was used to test the predictive power of the score. Receiver operating characteristic (ROC) curve analysis was performed to test the discriminative power of the score.
RESULTS: Of the 21 patients examined, 7 were reclassified as not having MC (non-MC), and they were used as controls. The scoring system included a composite of alterations of thermoregulatory, central nervous, cardiovascular, gastrointestinal, and metabolic systems, and presence or absence of a precipitating event. All 14 of our MC patients had a score of ≥60, whereas 6 of 7 non-MC patients had scores of 25 to 50. A total of 16 of 22 MC patients whose data were retrieved from the literature had a score ≥60, and 6 of 22 of these patients scored between 45 and 55. The odds ratio per each score unit increase as a continuum was 1.09 (95% confidence interval [CI], 1.01 to 1.16; P = .019); a score of 60 identified coma, with an odds ratio of 1.22. The area under the ROC curve was 0.88 (95% CI, 0.65 to 1.00), and the score of 60 had 100% sensitivity and 85.71% specificity.
CONCLUSION: A score ≥60 in the proposed scoring system is potentially diagnostic for MC, whereas scores between 45 and 59 could classify patients at risk for MC.

PMID 24518183  Endocr Pract. 2014 Aug;20(8):808-17. doi: 10.4158/EP134・・・
著者: John P Walsh, Alexandra P Bremner, Peter Feddema, Peter J Leedman, Suzanne J Brown, Peter O'Leary
雑誌名: J Clin Endocrinol Metab. 2010 Mar;95(3):1095-104. doi: 10.1210/jc.2009-1977. Epub 2010 Jan 22.
Abstract/Text CONTEXT: Longitudinal studies of risk factors for hypothyroidism are required to inform debate regarding the TSH reference range. There are limited longitudinal data on the predictive value of thyroid antibodies measured by automated immunoassay (as opposed to semiquantitative methods).
METHODS: We measured TSH, free T(4), thyroid peroxidase antibodies (TPOAbs), and thyroglobulin antibodies (TgAbs) using the Immulite platform on sera from 1184 participants in the 1981 and 1994 Busselton Health Surveys. Outcome measures at follow-up were hypothyroidism, defined as TSH greater than 4.0 mU/liter or on thyroxine treatment; and overt hypothyroidism, defined as TSH above 10.0 mU/liter or on thyroxine treatment. Receiver-operator characteristic analysis was used to determine optimal cutoffs for baseline TSH, TPOAbs, and TgAbs as predictors of hypothyroidism.
RESULTS: At 13 yr follow-up, 110 subjects (84 women) had hypothyroidism, of whom 42 (38 women) had overt hypothyroidism. Optimal cutoffs for predicting hypothyroidism were baseline TSH above 2.5 mU/liter, TPOAbs above 29 kIU/liter, and TgAbs above 22 kIU/liter, compared with reference range upper limits of 4.0 mU/liter, 35 kIU/liter, and 55 kIU/liter, respectively. In women with positive thyroid antibodies (TPOAbs or TgAbs), the prevalence of hypothyroidism at follow-up (with 95% confidence intervals) was 12.0% (3.0-21.0%) when baseline TSH was 2.5 mU/liter or less, 55.2% (37.1-73.3%) for TSH between 2.5 and 4.0 mU/liter, and 85.7% (74.1-97.3%) for TSH above 4.0 mU/liter.
CONCLUSIONS: The use of TSH cutoffs of 2.5 and 4.0 mU/liter, combined with thyroid antibodies, provides a clinically useful estimate of the long-term risk of hypothyroidism.

PMID 20097710  J Clin Endocrinol Metab. 2010 Mar;95(3):1095-104. doi: ・・・
著者: Ken K Ong, Diana Kuh, Mary Pierce, Jayne A Franklyn, Medical Research Council National Survey of Health and Development Scientific and Data Collection Teams
雑誌名: J Clin Endocrinol Metab. 2013 Apr;98(4):1435-42. doi: 10.1210/jc.2012-3761. Epub 2013 Feb 22.
Abstract/Text BACKGROUND: Complex bidirectional relationships have been described between body weight, thyroid function, and risk of thyroid disorders, including thyroid autoimmunity. We used a life-course approach to examine the potential association of childhood or adult body weight with the risk of thyroid autoimmunity and other thyroid disorders at age 60-64 years in a large population-based birth cohort study.
METHODS: In the UK Medical Research Council 1946 British Birth Cohort study, at age 60-64 years, 1277 women and 1185 men (78% of the target sample) responded to a postal questionnaire, which included questions on thyroid disease and thyroid medication. Circulating antithyroid peroxidase antibodies, free T4, and TSH concentrations were measured in 1057 women and 997 men at a subsequent clinic visit. Birth weight was recorded, and height and weight were measured at ages 2, 4, 6, 7, 11, 15 years and also repeatedly in adulthood.
RESULTS: At age 60-64 years, 10.9% of women (139 of 1277) and 2.3% of men (27 of 1185) reported they were taking T4, and 11.5% of women (122 of 1057) and 3.3% of men (33 of 997) had positive anti-TPO antibodies (>100 IU/mL), consistent with thyroid autoimmunity. Among women, both T4 use and positive anti-TPO antibodies at age 60-64 years were positively associated with childhood body weight, childhood overweight, and adult body mass index. Childhood weight gain between 0 and 14 years of age was positively associated with later T4 use (odds ratio 1.21, 95% confidence interval 1.03-1.42) and positive anti-TPO antibodies (1.21, 1.00-1.47). Women who were overweight or obese at age 14 years (127 of 972) had a higher risk of later positive anti-TPO antibodies (2.05, 1.12-3.76). In men and women without any thyroid disorders, serum free T4 concentrations were inversely associated with concurrent body mass index (P = .002).
CONCLUSIONS: Childhood weight gain and childhood overweight conferred an increased susceptibility to later hypothyroidism and thyroid autoimmunity, particularly in women.

PMID 23436917  J Clin Endocrinol Metab. 2013 Apr;98(4):1435-42. doi: 1・・・
著者: Giorgio Radetti, Mara Maselli, Fabio Buzi, Andrea Corrias, Alessandro Mussa, Paola Cambiaso, Mariacarolina Salerno, Marco Cappa, Michela Baiocchi, Roberto Gastaldi, Luigi Minerba, Sandro Loche
雑誌名: Clin Endocrinol (Oxf). 2012 Mar;76(3):394-8. doi: 10.1111/j.1365-2265.2011.04251.x.
Abstract/Text OBJECTIVE:   The natural history of Hashimoto's thyroiditis (HT) and isolated hyperthyrotropinaemia (IH) is not well defined. We therefore studied the natural course of patients with HT and IH and looked for possible prognostic factors.
DESIGN:   This is retrospective cross-sectional study.
PATIENTS:   Three hundred and twenty-three patients with HT (88 boys and 235 girls) and 59 with IH (30 boys and 29 girls), mean age 9·9 ± 3·8 years were included in the study. When first examined, 236 of the children with HT had a normal TSH (G0) and in 87, it was elevated but <100% of the upper limit (G1). All IH subjects had elevated TSH. Potential risk factors for thyroid failure were evaluated after 3 years and included the presence or familiarity for endocrine/autoimmune diseases, premature birth, signs and symptoms of hypothyroidism, TSH levels, antithyroid antibodies and thyroid volume.
RESULTS:   HT: Of those with HT, 170 G0 patients remained stable, 31 moved to G1 and 35 to G2 (hypothyroidism). Thirty-six G1 children moved to G0, 17 remained stable and 34 moved to G2. Of patients with IH: 23 normalized, 28 remained stable and eight became overtly hypothyroid. In patients with HT, the presence of coeliac disease, elevated TSH and thyroid peroxidase antibodies (TPOAb) increased the risk of developing hypothyroidism by 4·0-, 3·4- and 3·5-fold, respectively. The increase in TSH levels during follow-up was strongly predictive of the development of hypothyroidism. In patients with IH, no predictive factor could be identified.
CONCLUSIONS:   Coeliac disease, elevated TSH and TPOAb at presentation and a progressive increase in TSH are predictive factors for thyroid failure in HT patients.

© 2012 Blackwell Publishing Ltd.
PMID 21981142  Clin Endocrinol (Oxf). 2012 Mar;76(3):394-8. doi: 10.11・・・
著者: Kristen A Hyland, Alice M Arnold, Jennifer S Lee, Anne R Cappola
雑誌名: J Clin Endocrinol Metab. 2013 Feb;98(2):533-40. doi: 10.1210/jc.2012-2180. Epub 2012 Nov 16.
Abstract/Text CONTEXT: Use of a single set of thyroid function tests to define subclinical hypothyroidism may lead to misclassification over time and could influence findings from longitudinal studies.
OBJECTIVE: We assessed the risks of coronary heart disease (CHD), heart failure (HF), and cardiovascular (CV) death in older adults with persistent subclinical hypothyroidism.
DESIGN, SETTING, AND PARTICIPANTS: The study included 679 subclinically hypothyroid and 4184 euthyroid U.S. individuals at least 65 yr old enrolled in the Cardiovascular Health Study and not taking thyroid preparations.
MAIN OUTCOME MEASURE: We measured the 10-yr risk of incident CHD, HF, and CV death from persistent subclinical hypothyroidism, overall and stratified by degree of TSH elevation (4.5-6.9, 7.0-9.9, and 10.0-19.9 mU/liter).
RESULTS: There was no association between persistent subclinical hypothyroidism and incident CHD [hazard ratio (HR), 1.12; 95% confidence interval (CI), 0.93-1.36], HF (HR, 1.05; 95% CI, 0.97-1.27), or CV death (HR, 1.07; 95% CI, 0.87-1.31) in adjusted analyses in which subclinical hypothyroidism was modeled as a time-varying exposure using up to four serial thyroid function tests. When subclinical hypothyroidism was stratified by degree of TSH elevation, no significant associations were found in any stratum. Findings were similar in fixed exposure analyses in which only participants with testing 2 yr apart were considered, with no association between persistent or transient subclinical hypothyroidism and incident CHD, HF, or CV death.
CONCLUSIONS: Our data do not support increased risk of CHD, HF, or CV death in older adults with persistent subclinical hypothyroidism.

PMID 23162099  J Clin Endocrinol Metab. 2013 Feb;98(2):533-40. doi: 10・・・
著者: Gary D Rothberger, Sonya Gadhvi, Nickolaos Michelakis, Amit Kumar, Rose Calixte, Lawrence E Shapiro
雑誌名: Am J Cardiol. 2017 Feb 15;119(4):599-603. doi: 10.1016/j.amjcard.2016.10.045. Epub 2016 Nov 16.
Abstract/Text Thyroid hormone plays an important role in cardiac function. Low levels of serum triiodothyronine (T3) due to nonthyroidal illness syndrome may have adverse effects in heart failure (HF). This study was designed to assess the ability of T3 to predict in-hospital outcomes in patients with acute HF. In total, 137 patients without thyroid disease or treatment with drugs which affect TH levels, who were hospitalized with acute HF were prospectively enrolled and studied. TH levels were tested upon hospital admission, and outcomes were compared between patients with low (<2.3 pg/ml) and normal (≥2.3 pg/ml) free T3 levels as well as between those with low (<0.6 ng/ml) and normal (≥0.6 ng/ml) total T3 levels. Low free T3 correlated with an increased length of stay in the hospital (median 11 vs 7 days, p <0.001) and higher rates of intensive care unit admission (31.8% vs 16.9%, p = 0.047), with a trend toward increased need for invasive mechanical ventilation (9.0% vs 1.4%, p = 0.056). Low total T3 correlated with an increased length of stay in the hospital (median 11 vs 7 days, p <0.001) and increased need for invasive mechanical ventilation (9.8% vs 1.3%, p = 0.045). In conclusion, low T3 predicts worse hospital outcomes in patients with acute HF and can be useful in the risk stratification of these patients.

Copyright © 2016 Elsevier Inc. All rights reserved.
PMID 28017303  Am J Cardiol. 2017 Feb 15;119(4):599-603. doi: 10.1016/・・・
著者: M A Pollock, A Sturrock, K Marshall, K M Davidson, C J Kelly, A D McMahon, E H McLaren
雑誌名: BMJ. 2001 Oct 20;323(7318):891-5.
Abstract/Text OBJECTIVES: To determine whether thyroxine treatment is effective in patients with symptoms of hypothyroidism but with thyroid function tests within the reference range, and to investigate the effect of thyroxine treatment on psychological and physical wellbeing in healthy participants.
DESIGN: Randomised double blind placebo controlled crossover trial.
SETTING: Outpatient clinic in a general hospital. Participants: 25 patients with symptoms of hypothyroidism who had thyroid function tests within the reference range, and 19 controls. Methods: Participants were given thyroxine 100 microgram or placebo to take once a day for 12 weeks. Washout period was six weeks. They were then given the other to take once a day for 12 weeks. All participants were assessed physiologically and psychologically at baseline and on completion of each phase.
MAIN OUTCOME MEASURES: Thyroid function tests, measures of cognitive function and of psychological and physical wellbeing.
RESULTS: 22 patients and 19 healthy controls completed the study. At baseline, patients' scores on 9 out of 15 psychological measures were impaired when compared with controls. Patients showed a significantly greater response to placebo than controls in 3 out of 15 psychological measures. Healthy participants had significantly lower scores for vitality when taking thyroxine compared to placebo (mean (SD) 60 (17) v 73 (16), P<0.01). However, patients' scores from psychological tests when taking thyroxine were no different from those when taking placebo except for a poorer performance on one visual reproduction test when taking thyroxine. Serum concentrations of free thyroxine increased and those of thyroid stimulating hormone decreased in patients and controls while they were taking thyroxine, confirming compliance with treatment. Although serum concentrations of free triiodothyronine increased in patients and controls taking thyroxine, the difference between the response to placebo and to thyroxine was significant only in the controls.
CONCLUSIONS: Thyroxine was no more effective than placebo in improving cognitive function and psychological wellbeing in patients with symptoms of hypothyroidism but thyroid function tests within the reference range. Thyroxine did not improve cognitive function and psychological wellbeing in healthy participants.

PMID 11668132  BMJ. 2001 Oct 20;323(7318):891-5.
著者: Martin Feller, Marieke Snel, Elisavet Moutzouri, Douglas C Bauer, Maria de Montmollin, Drahomir Aujesky, Ian Ford, Jacobijn Gussekloo, Patricia M Kearney, Simon Mooijaart, Terry Quinn, David Stott, Rudi Westendorp, Nicolas Rodondi, Olaf M Dekkers
雑誌名: JAMA. 2018 Oct 2;320(13):1349-1359. doi: 10.1001/jama.2018.13770.
Abstract/Text Importance: The benefit of thyroid hormone therapy for subclinical hypothyroidism is uncertain. New evidence from recent large randomized clinical trials warrants an update of previous meta-analyses.
Objective: To conduct a meta-analysis of the association of thyroid hormone therapy with quality of life and thyroid-related symptoms in adults with subclinical hypothyroidism.
Data Sources: PubMed, EMBASE, ClinicalTrials.gov, Web of Science, Cochrane Library, CENTRAL, Emcare, and Academic Search Premier from inception until July 4, 2018.
Study Selection: Randomized clinical trials that compared thyroid hormone therapy with placebo or no therapy in nonpregnant adults with subclinical hypothyroidism were eligible. Two reviewers independently evaluated eligibility based on titles and abstracts of all retrieved studies. Studies not excluded in this first step were independently assessed for inclusion after full-text evaluation by 2 reviewers.
Data Extraction and Synthesis: Two independent reviewers extracted data, assessed risk of bias (Cochrane risk-of-bias tool), and evaluated the quality of evidence (GRADE tool). For synthesis, differences in clinical scores were transformed (eg, quality of life) into standardized mean differences (SMDs; positive values indicate benefit of thyroid hormone therapy; 0.2, 0.5, and 0.8 correspond to small, moderate, and large effects, respectively). Random-effects models for meta-analyses were applied.
Main Outcomes and Measures: General quality of life and thyroid-related symptoms after a minimum follow-up of 3 months.
Results: Overall, 21 of 3088 initially identified publications met the inclusion criteria, with 2192 adults randomized. After treatment (range, 3-18 months), thyroid hormone therapy was associated with lowering the mean thyrotropin value into the normal reference range compared with placebo (range, 0.5-3.7 mIU/L vs 4.6 to 14.7 mIU/L) but was not associated with benefit regarding general quality of life (n = 796; SMD, -0.11; 95% CI, -0.25 to 0.03; I2=66.7%) or thyroid-related symptoms (n = 858; SMD, 0.01; 95% CI, -0.12 to 0.14; I2=0.0%). Overall, risk of bias was low and the quality of evidence assessed with the GRADE tool was judged moderate to high.
Conclusions and Relevance: Among nonpregnant adults with subclinical hypothyroidism, the use of thyroid hormone therapy was not associated with improvements in general quality of life or thyroid-related symptoms. These findings do not support the routine use of thyroid hormone therapy in adults with subclinical hypothyroidism.

PMID 30285179  JAMA. 2018 Oct 2;320(13):1349-1359. doi: 10.1001/jama.2・・・
著者: Wilmar M Wiersinga, Leonidas Duntas, Valentin Fadeyev, Birte Nygaard, Mark P J Vanderpump
雑誌名: Eur Thyroid J. 2012 Jul;1(2):55-71. doi: 10.1159/000339444. Epub 2012 Jun 13.
Abstract/Text BACKGROUND: Data suggest symptoms of hypothyroidism persist in 5-10% of levothyroxine (L-T4)-treated hypothyroid patients with normal serum thyrotrophin (TSH). The use of L-T4 + liothyronine (L-T3) combination therapy in such patients is controversial. The ETA nominated a task force to review the topic and formulate guidelines in this area.
METHODS: Task force members developed a list of relevant topics. Recommendations on each topic are based on a systematic literature search, discussions within the task force, and comments from the European Thyroid Association (ETA) membership at large.
RESULTS: SUGGESTED EXPLANATIONS FOR PERSISTING SYMPTOMS INCLUDE: awareness of a chronic disease, presence of associated autoimmune diseases, thyroid autoimmunity per se, and inadequacy of L-T4 treatment to restore physiological thyroxine (T4) and triiodothyronine (T3) concentrations in serum and tissues. There is insufficient evidence that L-T4 + L-T3 combination therapy is better than L-T4 monotherapy, and it is recommended that L-T4 monotherapy remains the standard treatment of hypothyroidism. L-T4 + L-T3 combination therapy might be considered as an experimental approach in compliant L-T4-treated hypothyroid patients who have persistent complaints despite serum TSH values within the reference range, provided they have previously received support to deal with the chronic nature of their disease, and associated autoimmune diseases have been excluded. Treatment should only be instituted by accredited internists/endocrinologists, and discontinued if no improvement is experienced after 3 months. It is suggested to start combination therapy in an L-T4/L-T3 dose ratio between 13:1 and 20:1 by weight (L-T4 once daily, and the daily L-T3 dose in two doses). Currently available combined preparations all have an L-T4/L-T3 dose ratio of less than 13:1, and are not recommended. Close monitoring is indicated, aiming not only to normalize serum TSH and free T4 but also normal serum free T4/free T3 ratios. Suggestions are made for further research.
CONCLUSION: L-T4 + L-T3 combination therapy should be considered solely as an experimental treatment modality. The present guidelines are offered to enhance its safety and to counter its indiscriminate use.

PMID 24782999  Eur Thyroid J. 2012 Jul;1(2):55-71. doi: 10.1159/000339・・・
著者: Laura Paone, Abby F Fleisch, Henry A Feldman, Rosalind S Brown, Ari J Wassner
雑誌名: J Pediatr. 2016 Aug;175:167-172.e1. doi: 10.1016/j.jpeds.2016.04.022. Epub 2016 May 11.
Abstract/Text OBJECTIVE: To assess whether adding liothyronine (LT3) to levothyroxine (LT4) monotherapy normalizes serum thyrotropin (TSH) and thyroxine (T4) concentrations in children with congenital hypothyroidism and central resistance to thyroid hormone.
STUDY DESIGN: We retrospectively studied 12 patients with congenital hypothyroidism and central resistance to thyroid hormone (6 treated with LT3+LT4 combined therapy and 6 treated with LT4 monotherapy). In patients receiving combined therapy, we compared serum concentrations of TSH, T4, and triiodothyronine before and after addition of LT3. We used repeated measures analysis to compare thyroid function in participants receiving combined therapy vs monotherapy, while accounting for age and intrasubject correlation.
RESULTS: In patients receiving combined therapy, the addition of LT3 was associated with normalization of mean TSH (9.2 vs 4.5 mIU/L, P = .002), a lower proportion of TSH values greater than 10 mIU/L (35% vs 8%, P = .03), and a decrease in mean serum T4 by 23 ± 9% (P < .001). Compared with patients receiving LT4 monotherapy, patients receiving combined therapy had lower mean TSH (8.5 ± 0.9 vs 4.3 ± 0.4, P < .001), lower odds of TSH elevation greater than 10 mIU/L (OR 0.20, 95% CI 0.10-0.41, P < .001), and lower odds of T4 elevation (OR 0.21, 95% CI 0.04-1.09, P = .06). LT3 treatment did not increase serum T3 levels significantly.
CONCLUSION: The addition of LT3 to LT4 monotherapy facilitates normalization of both serum TSH and T4 in patients with congenital hypothyroidism and central resistance to thyroid hormone. Larger prospective studies are needed to confirm these findings and to determine the effect of combined therapy on neurodevelopmental outcomes.

Copyright © 2016 Elsevier Inc. All rights reserved.
PMID 27178621  J Pediatr. 2016 Aug;175:167-172.e1. doi: 10.1016/j.jped・・・
著者: Hakan Cinemre, Cemil Bilir, Feyzi Gokosmanoglu, Talat Bahcebasi
雑誌名: J Clin Endocrinol Metab. 2009 Jan;94(1):151-6. doi: 10.1210/jc.2008-1440. Epub 2008 Nov 4.
Abstract/Text CONTEXT: In patients with coexisting iron-deficiency anemia and subclinical hypothyroidism, anemia does not adequately respond to oral iron therapy.
OBJECTIVE: We studied whether iron-deficiency anemia might indicate treatment of subclinical hypothyroidism.
DESIGN: PATIENTS were assigned to a control or experimental group: 240 mg/d oral iron alone (iron group) or 240 mg/d oral iron plus 75 microg/d levothyroxine (iron/levothyroxine group). Levels of hemoglobin, hematocrit, red blood cell count, serum iron levels, ferritin, total iron-binding capacity, TSH, and free T(4) were measured before and after treatment.
SETTING: The study was conducted at a university hospital outpatient clinic.
PATIENTS: Fifty-one patients with coexisting iron-deficiency anemia and subclinical hypothyroidism participated in the study.
INTERVENTION: PATIENTS were treated as described above in either the iron group or the iron/levothyroxine group.
MAIN OUTCOME MEASURE: A clinically satisfactory increase in hemoglobin was regarded as successful.
RESULTS: Mean hemoglobin levels increased by 0.4 g/dl in the iron group [95% confidence interval (CI) 0.2-0.7, P = 0.001], whereas it increased by a mean of 1.9 g/dl in the iron/levothyroxine group (95% CI 1.5-2.3, P < 0.0001). The increase in serum iron was greater in the iron/levothyroxine group by a mean of 47.6 microg/dl (95% CI 34.5-60.6, P < 0.0001). Increases in hemoglobin, red blood cells, hematocrit, and serum ferritin levels after treatment were statistically significantly greater in the iron/levothyroxine group (P < 0.0001). Starting hemoglobin and increase in hemoglobin were negatively correlated in the iron/levothyroxine group (r = -0.531, P = 0.006).
CONCLUSIONS: Subclinical hypothyroidism should be treated in iron-deficiency anemia patients when both conditions coexist. This would provide a desired therapeutic response to oral iron replacement and prevent ineffective iron therapy.

PMID 18984662  J Clin Endocrinol Metab. 2009 Jan;94(1):151-6. doi: 10.・・・
著者: Camila Luhm Silva Perez, Fernanda Sumire Araki, Hans Graf, Gisah Amaral de Carvalho
雑誌名: Thyroid. 2013 Jul;23(7):779-84. doi: 10.1089/thy.2012.0435. Epub 2013 Jun 21.
Abstract/Text BACKGROUND: Hypothyroidism is treated with oral levothyroxine. Some patients fail to attain adequate control because of poor compliance. Delaying breakfast to take levothyroxine on an empty stomach can decrease adherence to hypothyroidism treatment. The objective of this study was to evaluate whether administering levothyroxine with breakfast can maintain thyrotropin (TSH) levels in the therapeutic range, without major clinical changes.
METHODS: A prospective, randomized, open-label, crossover study was conducted to compare usual levothyroxine administration while in a fasting state with administration during breakfast. From September 2008 to April 2009, 45 patients with primary hypothyroidism who received levothyroxine were recruited. The patients completed 180 days of the protocol and were randomized to 90 days of each levothyroxine administration regimen (while fasting or with breakfast). Clinical and biochemical analyses were performed at baseline and on days 45, 90, 135, and 180. The primary outcome was TSH level.
RESULTS: Forty-two patients completed the protocol. The TSH level was higher for levothyroxine administration with breakfast than while fasting (2.89 vs. 1.9 mIU/L, p=0.028). Uncontrolled hypothyroidism (TSH ≥3.5 mIU/L) occurred regardless of the type of levothyroxine administration (p=0.26). No risk factors were identified for TSH elevation.
CONCLUSIONS: Levothyroxine administration with breakfast could be an alternative regimen for patients who have adherence difficulties due to the need for delaying intake, and is more likely to cause variability in the TSH level, meaning the patient should be followed more closely. For patients in whom a specific serum TSH goal is important, taking levothyroxine while fasting is recommended.

PMID 23363386  Thyroid. 2013 Jul;23(7):779-84. doi: 10.1089/thy.2012.0・・・
著者: Xiao Pang, Tao Pu, Li Xu, Ru Sun
雑誌名: Clin Endocrinol (Oxf). 2020 Feb 5;. doi: 10.1111/cen.14172. Epub 2020 Feb 5.
Abstract/Text PURPOSE: To compare the effects of l-thyroxine (L-T4) administration before breakfast and administration at bedtime on hypothyroidism.
METHODS: The PubMed, EMBASE, Cochrane Library, Web of Science, China National Knowledge Infrastructure (CNKI) and Wanfang databases were searched to identify relevant articles. All prospective or randomized controlled studies (RCTs) comparing L-T4 administration before breakfast to the administration at bedtime in patients with hypothyroidism were included in the analysis.
RESULTS: Initially, 2884 articles were retrieved from the databases, and 10 articles were included in the quantitative analysis. The effect of L-T4 administration before breakfast compared with administration at bedtime had no statistically significant association with hormone thyrotropin (TSH) (Standardized mean differences [SMD] = 0.09, 95% confidence intervals (CI): -0.12, 0.30; P = .39), or free triiodothyronine (FT3) (SMD=-0.19, 95% CI: -0.53, 0.15; P = .28) in patients with hypothyroidism. However, the result of FT4 level was favourable for L-T4 bedtime administration group (SMD=-0.27, 95% CI: -0.52, -0.02; P = .03).
CONCLUSION: Our meta-analysis revealed that L-T4 administration at bedtime is as effective as administration before breakfast for patients with hypothyroidism. Taking L-T4 at bedtime may be an attractive option for patients with hypothyroidism.

© 2020 John Wiley & Sons Ltd.
PMID 32022947  Clin Endocrinol (Oxf). 2020 Feb 5;. doi: 10.1111/cen.14・・・
著者: H Kececi, Y Degirmenci
雑誌名: Neurophysiol Clin. 2006 Mar-Apr;36(2):79-83. doi: 10.1016/j.neucli.2006.04.001. Epub 2006 Apr 25.
Abstract/Text OBJECTIVES: To evaluate the electrodiagnostic evidence of peripheral nerve dysfunction in patients with hypothyroidism before and after hormone replacement treatment.
MATERIALS AND METHODS: Forty patients aged above 18 years diagnosed with hypothyroidism were included in our study. Patients with FT4 levels below 11.6 pmol/l and TSH levels above 4.2 IU/ml were accepted as hypothyroidic. Electrodiagnostic evaluation was performed at the onset of the study and after 3 months. Electrodiagnostic evaluation included motor and sensory nerve conduction studies, and F wave.
RESULTS: The differences between pre- and post-treatment FT4, FT3 and TSH values were found to be statistically significant. At the onset, electrophysiological evaluation revealed carpal tunnel syndrome in 15 patients and polyneuropathy in seven patients; whereas 18 patients were found normal in these respects. After treatment, the electrodiagnostic evaluation revealed that 35 patients were normal, while only two patients had carpal tunnel syndrome and three patients had polyneuropathy. The differences between before and after treatment values of median motor distal latency and amplitude, median sensorial nerve conduction velocity, tibial motor nerve conduction velocity and sural sensory nerve conduction velocity were found to be statistically significant.
CONCLUSION: The results of the control evaluation after treatment demonstrated that the findings related to entrapment neuropathy and polyneuropathy in hypothyroid patients can be reversible in a period of 3 months if appropriate hormone replacement treatment can be obtained. Especially in the treatment of entrapment neuropathy in hypothyroidism, the chance of medical treatment must be given to patients before considering surgical treatment.

PMID 16844546  Neurophysiol Clin. 2006 Mar-Apr;36(2):79-83. doi: 10.10・・・
著者: Todd D Nebesio, Matthew D Wise, Susan M Perkins, Erica A Eugster
雑誌名: J Pediatr Endocrinol Metab. 2011;24(11-12):893-6.
Abstract/Text BACKGROUND: Severe acquired hypothyroidism often results in significant height deficit due to rapid bone age advancement following treatment. Whether gradual correction of hypothyroidism and/or adjunctive growth-promoting therapies (GPTs) augment final adult height (FAH) is controversial.
OBJECTIVE: To investigate time to euthyroidism, pace of bone age advancement (deltaBA/deltaCA), and impact of GPTs on FAH.
METHODS AND PATIENTS: Retrospective review of 21 children (10.1 +/- 3.0 years) with profound hypothyroidism.
RESULTS: Baseline bone age standard deviation score (SDS) was -4.1 +/- 1.8, whereas height SDS was -3.0 +/- 1.1. Average time to euthyroidism was 9.7 months (2.3-33.7 months). Average deltaBA/deltaCA was 2.3 +/- 0.9. Six of 13 patients at FAH received GPTs. No correlation was found between time to euthyroidism and rate of skeletal maturation. No difference in height outcome was seen between those who received GPTs and those who did not.
CONCLUSIONS: Neither time to euthyroidism nor use of GPTs significantly affected height potential in our patients.

PMID 22308838  J Pediatr Endocrinol Metab. 2011;24(11-12):893-6.
著者: Thomas Reinehr
雑誌名: Curr Opin Pediatr. 2011 Aug;23(4):415-20. doi: 10.1097/MOP.0b013e328344c393.
Abstract/Text PURPOSE OF REVIEW: In recent years, there has been an increasing focus on thyroid function in obese children. There is controversy concerning whether the changes in the levels of thyroid hormones and thyroid-stimulating hormone (thyrotropin - TSH) in obesity are causes or consequences of weight status and whether these subtle differences merit treatment with thyroxine. This review aimed to study the prevalence of disturbed thyroid hormone and TSH values in childhood obesity and the underlying pathophysiologic mechanisms linking obesity to thyroid function.
RECENT FINDINGS: In the past 18 months, four studies demonstrated moderate elevation of TSH concentrations in 10-23% of obese children, which was associated with normal or slightly elevated thyroxine and triiodothyronine values. Two studies reported ultrasonographic hypoechogenicity of the thyroid in obese children with hyperthyrotropinemia, which was not caused by autoimmune thyroiditis; therefore, the authors hypothesized a link to chronic inflammation in obesity. Weight loss led to a normalization of elevated TSH levels in two studies. The adipokine leptin is the most promising link between obesity and hyperthyrotropinemia since leptin stimulates the hypothalamic-pituitary-thyroid.
SUMMARY: The elevated TSH levels in obesity seem a consequence rather than a cause of obesity. Therefore, treatment of hyperthyrotropinemia with thyroxine seems unnecessary in obese children.

PMID 21430532  Curr Opin Pediatr. 2011 Aug;23(4):415-20. doi: 10.1097/・・・
著者: J Parle, L Roberts, S Wilson, H Pattison, A Roalfe, M S Haque, C Heath, M Sheppard, J Franklyn, F D R Hobbs
雑誌名: J Clin Endocrinol Metab. 2010 Aug;95(8):3623-32. doi: 10.1210/jc.2009-2571. Epub 2010 May 25.
Abstract/Text CONTEXT: Subclinical hypothyroidism (SCH) and cognitive dysfunction are both common in the elderly and have been linked. It is important to determine whether T4 replacement therapy in SCH confers cognitive benefit.
OBJECTIVE: Our objective was to determine whether administration of T4 replacement to achieve biochemical euthyroidism in subjects with SCH improves cognitive function.
DESIGN AND SETTING: We conducted a double-blind placebo-controlled randomized controlled trial in the context of United Kingdom primary care.
PATIENTS: Ninety-four subjects aged 65 yr and over (57 females, 37 males) with SCH were recruited from a population of 147 identified by screening.
INTERVENTION: T4 or placebo was given at an initial dosage of one tablet of either placebo or 25 microg T4 per day for 12 months. Thyroid function tests were performed at 8-weekly intervals with dosage adjusted in one-tablet increments to achieve TSH within the reference range for subjects in treatment arm. Fifty-two subjects received T4 (31 females, 21 males; mean age 73.5 yr, range 65-94 yr); 42 subjects received placebo (26 females, 16 males; mean age 74.2 yr, 66-84 yr).
MAIN OUTCOME MEASURES: Mini-Mental State Examination, Middlesex Elderly Assessment of Mental State (covering orientation, learning, memory, numeracy, perception, attention, and language skills), and Trail-Making A and B were administered.
RESULTS: Eighty-two percent and 84% in the T4 group achieved euthyroidism at 6- and 12-month intervals, respectively. Cognitive function scores at baseline and 6 and 12 months were as follows: Mini-Mental State Examination T4 group, 28.26, 28.9, and 28.28, and placebo group, 28.17, 27.82, and 28.25 [not significant (NS)]; Middlesex Elderly Assessment of Mental State T4 group, 11.72, 11.67, and 11.78, and placebo group, 11.21, 11.47, and 11.44 (NS); Trail-Making A T4 group, 45.72, 47.65, and 44.52, and placebo group, 50.29, 49.00, and 46.97 (NS); and Trail-Making B T4 group, 110.57, 106.61, and 96.67, and placebo group, 131.46, 119.13, and 108.38 (NS). Linear mixed-model analysis demonstrated no significant changes in any of the measures of cognitive function over time and no between-group difference in cognitive scores at 6 and 12 months.
CONCLUSIONS: This RCT provides no evidence for treating elderly subjects with SCH with T4 replacement therapy to improve cognitive function.

PMID 20501682  J Clin Endocrinol Metab. 2010 Aug;95(8):3623-32. doi: 1・・・
著者: Salman Razvi, Jolanta U Weaver, Timothy J Butler, Simon H S Pearce
雑誌名: Arch Intern Med. 2012 May 28;172(10):811-7. doi: 10.1001/archinternmed.2012.1159.
Abstract/Text BACKGROUND Subclinical hypothyroidism (SCH) has been associated with ischemic heart disease (IHD); however, it is unknown whether treatment of SCH with levothyroxine sodium will reduce the risk of IHD. The aim of this study was to investigate the association between levothyroxine treatment of SCH with IHD morbidity and mortality. METHODS We used the United Kingdom General Practitioner Research Database to identify individuals with new SCH (serum thyrotropin levels of 5.01-10.0 mIU/L and normal free thyroxine levels) recorded during 2001 with outcomes analyzed until March 2009. All analyses were performed separately for younger (40-70 years) and older (>70 years) individuals. Hazard ratios (HRs) for IHD events (fatal and nonfatal) were calculated after adjustment for conventional IHD risk factors, baseline serum thyrotropin levels, and initiation of levothyroxine treatment as a time-dependent covariate. RESULTS Subclinical hypothyroidism was identified in 3093 younger and 1642 older individuals. For a median follow-up period of 7.6 years, 52.8% and 49.9% of younger and older patients with SCH were treated with levothyroxine, respectively. There were 68 incident IHD events in 1634 younger patients treated with levothyroxine (4.2%) vs 97 IHD events in 1459 untreated individuals (6.6%) (multivariate-adjusted HR, 0.61; 95% CI, 0.39-0.95). In contrast, in the older group there were 104 events in 819 treated patients (12.7%) vs 88 events in 823 untreated individuals (10.7%) (HR, 0.99; 95% CI, 0.59-1.33). CONCLUSIONS Treatment of SCH with levothyroxine was associated with fewer IHD events in younger individuals, but this was not evident in older people. An appropriately powered randomized controlled trial of levothyroxine in SCH examining vascular outcomes is now warranted.

PMID 22529180  Arch Intern Med. 2012 May 28;172(10):811-7. doi: 10.100・・・
著者: Mette Nygaard Andersen, Anne-Marie Schjerning Olsen, Jesper Clausager Madsen, Jens Faber, Christian Torp-Pedersen, Gunnar Hilmar Gislason, Christian Selmer
雑誌名: PLoS One. 2015;10(6):e0129793. doi: 10.1371/journal.pone.0129793. Epub 2015 Jun 12.
Abstract/Text BACKGROUND: Subclinical hypothyroidism is associated with a number of cardiovascular risk factors, yet only limited data exist on long-term outcome of levothyroxine treatment of this condition with respect to hard end-points. The aim of this retrospective cohort study was to determine effects of levothyroxine treatment on myocardial infarction (MI), cardiovascular death and all-cause mortality, in patients with subclinical hypothyroidism.
METHODS AND RESULTS: Primary care patients aged 18 years and older that underwent thyroid function tests between 2000 and 2009 were enrolled. Participants were identified by individual-level linkage of nationwide registers. Patients with subclinical hypothyroidism at baseline were included in the study. Exclusion criteria included a history of thyroid disease, related medication or medication affecting thyroid function. The total cohort comprised 628,953 patients of which 12,212 (1.9%) had subclinical hypothyroidism (mean age 55.2 [SD ± 18.8] years; 79.8% female). Within the first six months 2,483 (20.3%) patients claimed a prescription for levothyroxine. During a median follow-up of 5.0 (IQR: 5.2) years, 358 MI's and 1,566 (12.8%) deaths were observed. Out of these, 766 of the deaths were cardiovascular related. No beneficial effects were found in levothyroxine treated patients on MI (IRR 1.08 [95% CI: 0.81 to 1.44]), cardiovascular death (IRR 1.02 [95% CI: 0.83 to 1.25]) or all-cause mortality (IRR 1.03 [95% CI: 0.90 to 1.19]), except in patients under the age of 65 years (IRR 0.63 [95% CI: 0.40 to 0.99]).
CONCLUSION: Levothyroxine substitution in subclinical hypothyroid patients does not indicate an association with lower mortality or decreased risk of MI.

PMID 26069971  PLoS One. 2015;10(6):e0129793. doi: 10.1371/journal.pon・・・
著者: Mette Nygaard Andersen, Anne-Marie Schjerning Olsen, Jesper Clausager Madsen, Søren Lund Kristensen, Jens Faber, Christian Torp-Pedersen, Gunnar H Gislason, Christian Selmer
雑誌名: J Clin Endocrinol Metab. 2016 Nov;101(11):4170-4177. doi: 10.1210/jc.2016-2226. Epub 2016 Aug 29.
Abstract/Text CONTEXT: Subclinical hypothyroidism is a common condition that may lead to impaired cardiac function.
OBJECTIVE: This study sought to examine the effects of levothyroxine treatment in patients with subclinical hypothyroidism and heart disease.
DESIGN: This was a register-based historical cohort study.
SETTING AND PARTICIPANTS: The study was composed of Danish primary care patients and hospital outpatients age 18 years and older with established heart disease who were diagnosed with subclinical hypothyroidism in 1997-2011. Patients were stratified according to whether they claimed a subsequent prescription of levothyroxine. Event rates and incidence rate ratios (IRR) were calculated by use of time-dependent multivariable Poisson regression models.
MAIN OUTCOME MEASURES: Measures included all-cause mortality and major adverse cardiac events (MACEs), defined as cardiovascular death, fatal or nonfatal myocardial infaction and stroke, and all-cause hospital admissions.
RESULTS: Of 61 611 patients with a diagnosis of cardiac disease having their first time thyroid function testing, 1192 patients with subclinical hypothyroidism (mean age 73.6 [SD ± 13.3] y, 63.8% female) were included, of whom 136 (11.4%) were treated with levothyroxine. During a median follow-up time of 5.6 y (interquartile range, 6.5 y), 694 (58.2%) patients died. Patients treated with levothyroxine displayed no significantly increased risk of all-cause mortality (adjusted IRR, 1.17; 95% confidence interval [CI], 0.90-1.52), MACE (adjusted IRR, 1.08; 95% CI, 0.80-1.45), or hospital admission (adjusted IRR, 0.94; 95% CI, 0.71-1.24), when compared with patients not treated with levothyroxine.
CONCLUSION: Levothyroxine treatment in patients with subclinical hypothyroidism and heart disease was not associated with a significant benefit nor risk of all-cause mortality, MACE, or hospital admission in this large real-world cohort study.

PMID 27571183  J Clin Endocrinol Metab. 2016 Nov;101(11):4170-4177. do・・・
著者: Spyridoula Maraka, Naykky M Singh Ospina, Derek T O'Keeffe, Ana E Espinosa De Ycaza, Michael R Gionfriddo, Patricia J Erwin, Charles C Coddington, Marius N Stan, M Hassan Murad, Victor M Montori
雑誌名: Thyroid. 2016 Apr;26(4):580-90. doi: 10.1089/thy.2015.0418. Epub 2016 Mar 3.
Abstract/Text BACKGROUND: The impact of subclinical hypothyroidism (SCH) and of levothyroxine replacement in pregnant women with SCH is unclear. The aims of this study were to assess (i) the impact of SCH during pregnancy on maternal and neonatal outcomes, and (ii) the effect of levothyroxine replacement therapy in these patients.
METHODS: Ovid MEDLINE In-Process & Other Non-Indexed Citations, Ovid MEDLINE, the Cochrane Controlled Trials Register, Ovid EMBASE, Web of Science, and Scopus were searched from inception to January 2015. Randomized trials and cohort studies of pregnant women with SCH that examined adverse pregnancy and neonatal outcomes were included. Reviewers extracted data and assessed methodological quality in duplicate. Eighteen cohort studies at low-to-moderate risk of bias were included. Compared with euthyroid pregnant women, pregnant women with SCH were at higher risk for pregnancy loss (relative risk [RR] 2.01 [confidence interval (CI) 1.66-2.44]), placental abruption (RR 2.14 [CI 1.23-3.70]), premature rupture of membranes (RR 1.43 [CI 1.04-1.95]), and neonatal death (RR 2.58 [CI 1.41-4.73]). One study at high risk of bias compared pregnant women with SCH who received levothyroxine to those who did not and found no significant decrease in the rate of pregnancy loss, preterm delivery, gestational hypertension, low birth weight, or low Apgar score.
CONCLUSIONS: SCH during pregnancy is associated with multiple adverse maternal and neonatal outcomes. The value of levothyroxine therapy in preventing these adverse outcomes remains uncertain.

PMID 26837268  Thyroid. 2016 Apr;26(4):580-90. doi: 10.1089/thy.2015.0・・・
著者: Waka Yoshioka, Nobuyuki Amino, Akane Ide, Shino Kang, Takumi Kudo, Eijun Nishihara, Mitsuru Ito, Hirotoshi Nakamura, Akira Miyauchi
雑誌名: Endocr J. 2015;62(1):87-92. doi: 10.1507/endocrj.EJ14-0300. Epub 2014 Oct 10.
Abstract/Text Infertile women sometimes associated with subclinical hypothyroidism (SCH). The guidelines of the American Endocrine Society, and American Association of Clinical Endocrinologists and American Thyroid Association recommend treatment with thyroxine (T4) for patients with SCH who want to have children. We examined 69 female infertile patients with SCH and the effects of levothyroxine (l-T4) therapy on pregnancy rates and pregnancy outcomes were observed. Fifty-eight (84.1%) patients successfully conceived during the T4 treatment period (Group A), although 17 patients (29.3%) had miscarriage afterward. The remaining 11 patients continued to be infertile (Group B). The median TSH value in Group A before the T4 treatment was 5.46 μIU/mL (range 3.1-13.3) and this significantly decreased to 1.25 μIU/mL (range 0.02-3.75) during the treatment (p<0.001). The estimated duration of infertility before the T4 treatment was 2.8±1.7 years and the duration until pregnancy after the treatment was significantly shorter at 0.9±0.9 years (p<0.001). Shortening of the infertile period after the T4 therapy was observed not only in patients who were treated with assisted reproductive technology (ART) but also in patients who conceived spontaneously in Group A. Administered T4 dose was 54.3±14.2 μg before pregnancy and 68.5±22.8 μg during pregnancy (p<0.001). Anti-thyroid autoantibodies were identified in 42.0% of all patients and no significant difference was observed in positivity between Group A and Group B. High successful pregnancy rate and shorter duration of infertility until pregnancy after T4 treatment strongly suggest that T4 enhanced fertility in infertile patients with SCH.

PMID 25312747  Endocr J. 2015;62(1):87-92. doi: 10.1507/endocrj.EJ14-0・・・
著者: M Ahsan Akhtar, Rina Agrawal, Julie Brown, Yasmin Sajjad, Laurentiu Craciunas
雑誌名: Cochrane Database Syst Rev. 2019 Jun 25;6:CD011009. doi: 10.1002/14651858.CD011009.pub2. Epub 2019 Jun 25.
Abstract/Text BACKGROUND: Thyroid disease is the second most common endocrine disorder affecting women of reproductive age. Subclinical hypothyroidism is diagnosed by an elevated thyroid-stimulating hormone concentration with a normal concentration of free thyroxine hormone. Autoimmune thyroid disease (ATD) is diagnosed by the presence of thyroid autoantibodies, regardless of thyroid hormone levels. Thyroxine may be a useful treatment for subfertile women with these two specific types of thyroid disease for improving pregnancy outcomes during assisted reproduction.
OBJECTIVES: To evaluate the efficacy and harms of levothyroxine replacement in subfertile women with subclinical hypothyroidism or with normal thyroid function and thyroid autoimmunity (euthyroid autoimmune thyroid disease, or euthyroid ATD) undergoing assisted reproduction.
SEARCH METHODS: We searched the Cochrane Gynaecology and Fertility (CGF) Group specialised register, CENTRAL, MEDLINE, Embase, PsycINFO, CINAHL and two trials registers together with reference checking and contact with study authors and experts in the field to identify studies. We searched for all published and unpublished randomised controlled trials (RCTs) comparing thyroxine with no treatment or placebo, without language restrictions, from inception to 8 April 2019, and in consultation with the Cochrane CGF Information Specialist.
SELECTION CRITERIA: We included women undergoing assisted reproduction treatment, meaning both in vitro fertilisation and intracytoplasmic sperm injection, with a history of subfertility and with subclinical hypothyroidism or with euthyroid ATD. We excluded women with a previously known clinical hypothyroidism or already taking thyroxine or tri-iodothyronine. RCTs compared thyroxine (levothyroxine) with either placebo or no treatment.
DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. Our primary review outcomes were live birth and adverse events of thyroxine; our secondary outcomes were clinical pregnancy, multiple pregnancy and miscarriage.
MAIN RESULTS: The review included four studies with 820 women. The included studies were of overall low risk of bias. Using GRADE methodology, we assessed the quality of evidence for the primary outcomes of this review to be very low- to low-quality evidence. Evidence was downgraded for imprecision as it was based on single, small trials with wide confidence intervals (CI). We were able to include data from three of the four included studies.In one study of women with both subclinical hypothyroidism and positive or negative anti-TPO antibodies (autoimmune disease), the evidence suggested that thyroxine replacement may have improved live birth rate (RR 2.13, 95% CI 1.07 to 4.21; 1 RCT, n = 64; low-quality evidence) and it may have led to similar miscarriage rates (RR 0.11, 95% CI 0.01 to 1.98; 1 RCT, n = 64; low-quality evidence). The evidence suggested that women with both subclinical hypothyroidism and positive or negative anti-TPO antibodies would have a 25% chance of a live birth with placebo or no treatment, and that the chance of a live birth in these women using thyroxine would be between 27% and 100%.In women with normal thyroid function and thyroid autoimmunity (euthyroid ATD), treatment with thyroxine replacement compared with placebo or no treatment may have led to similar live birth rates (risk ratio (RR) 1.04, 95% CI 0.83 to 1.29; 2 RCTs, number of participants (n) = 686; I2 = 46%; low-quality evidence) and miscarriage rates (RR 0.83, 95% CI 0.47 to 1.46, 2 RCTs, n = 686, I2 = 0%; low-quality evidence). The evidence suggested that women with normal thyroid function and thyroid autoimmunity would have a 31% chance of a live birth with placebo or no treatment, and that the chance of a live birth in these women using thyroxine would be between 26% and 40%.Adverse events were rarely reported. One RCT reported 0/32 in the thyroxine replacement group and 1/32 preterm births in the control group in women diagnosed with subclinical hypothyroidism and positive or negative anti-TPO antibodies. One RCT reported 21/300 preterm births in the thyroxine replacement group and 19/300 preterm births in the control group in women diagnosed with positive anti-TPO antibodies. None of the RCTs reported on other maternal pregnancy complications, foetal complications or adverse effects of thyroxine.
AUTHORS' CONCLUSIONS: We could draw no clear conclusions in this systematic review due to the very low to low quality of the evidence reported.

PMID 31236916  Cochrane Database Syst Rev. 2019 Jun 25;6:CD011009. doi・・・
著者: Olympia Koulouri, Mohammed A Auldin, Ravi Agarwal, Veronica Kieffer, Carole Robertson, James Falconer Smith, Miles J Levy, Trevor A Howlett
雑誌名: Clin Endocrinol (Oxf). 2011 Jun;74(6):744-9. doi: 10.1111/j.1365-2265.2011.03984.x.
Abstract/Text OBJECTIVE: Achieving optimal thyroid hormone replacement is more difficult in TSH deficiency compared to primary hypothyroidism because of the inability to be guided by serum TSH levels. A combination of clinical symptoms and free thyroxine levels (fT4) are typically used to make a diagnosis and monitor replacement. We investigated the diagnosis of TSH deficiency in patients with pituitary disease and the adequacy of levothyroxine replacement compared with primary thyroid disease.
DESIGN: Using our department's clinical information system, we identified all patients with a diagnosis of any type of pituitary tumour who had been seen in clinic over a 2-year period. We divided the patients into those at high risk and low risk of TSH deficiency based on the presence of macroadenoma and/or intervention by surgery or radiotherapy. We compared fT4 values in these patients with values in patients with primary thyroid disease in our thyrotoxicosis shared-care scheme (TSC) and hypothyroid register within the same timescale, assessing only those samples considered euthyroid in which TSH was in the normal range.
RESULTS: A database query identified 525 patients with a pituitary tumour of whom 344 were considered at high risk of TSH deficiency. A free T4 (fT4) value was found for 514 patients (97·9%). TSC and thyroid register databases revealed fT4 values for comparison with simultaneous normal TSH in patients on no treatment (n = 3777 samples) or on levothyroxine alone (n = 11,805). fT4 levels overall were lower in pituitary patients than in equivalent controls. Of the high risk group not taking levothyroxine 17% had a free T4 ≤ 11 pmol/l compared to only 8·4% of untreated controls. Furthermore, 38·9% of patients on levothyroxine had a free T4 ≤ 13 pmol/l compared to 9·5% of controls on levothyroxine with previous thyrotoxicosis and 13·4% of controls with primary hypothyroidism. Median fT4 in controls on levothyroxine was 16 pmol/l and 20-80th centile range was 14-19 pmol/l.
CONCLUSION: Levothyroxine doses were generally under-replaced in pituitary patients compared to primary thyroid disease and the data imply that some untreated patients were actually TSH deficient. The distribution of fT4 in patients with primary thyroid disease on levothyroxine may guide optimum replacement levels in pituitary disease.

© 2011 Blackwell Publishing Ltd.
PMID 21521256  Clin Endocrinol (Oxf). 2011 Jun;74(6):744-9. doi: 10.11・・・

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