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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:2021/12/22
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   

スクリーニング:
  1. 幅広い精神医学的および身体的症状を示す初めての精神病患者において、甲状腺機能のスクリーニングが推奨される(推奨度2)
  1. その優れた予後のために、粘液水腫性精神病は常に新たに発症した精神病の鑑別診断と見なされるべきである(推奨度2)
  1. 入院中のCOVID-19患者では、甲状腺機能の定期的な評価が必要である(推奨度2)
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  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)
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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。
※同効薬・小児・妊娠および授乳中の注意事項等は、海外の情報も掲載しており、日本の医療事情に適応しない場合があります。
※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、実際の保険適応の査定において保険適応及び保険適応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応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))[2022年]
監修:平田結喜緒 : 特に申告事項無し[2022年]

改訂のポイント:
  1. 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、人種で異なる可能性がある。
  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. 研究事例の説明: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のより狭い基準値に説得力がある。
  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. 研究事例の説明: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。
 
潜在性甲状腺機能低下症のリスクに関して:
 
  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. 潜在性甲状腺機能低下症は、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. 甲状腺機能障害は認知機能低下に関連しない(認知機能の低下した高齢者における甲状腺機能スクリーニングは支持されない:推奨度3)。
  1. 背景:臨床ガイドラインでは顕性および潜在性の甲状腺機能障害が認知機能低下の原因および治療可能な要因とされているが,多くの調査結果には必ずしも一貫性がない。
  1. 研究事例の説明:1989~2017年に実施されたコホート研究・調査23件(甲状腺機能と認知機能のデータを含む縦断研究15件、認知症と甲状腺機能障害の関連に関するメタ解析6件、米国民保健栄養調査2件)から74,565例のデータを抽出した。個々の参加者データ(IPD)解析により、甲状腺機能障害と認知機能の関連を横断的および縦断的に検討した。甲状腺機能はTSHの統一カットオフ値と各研究のFT4値に基づき、HYPO(0.8%; 577例)またはscHypo(3.4%; 2,557例)、甲状腺機能正常(89.3%)、HYPER(0.9%; 697例)またはscHyper(5.6%; 4,167例)の5群に分類した。ベースラインの年齢中央値は57~93歳で、女性は42,847例(57.5%)であった。主要評価項目は全体的認知機能(主にMMSEで評価)とし、副次評価項目は遂行機能、記憶力、認知症とした。各研究レベルで多変量線形回帰分析と多変量Cox回帰分析を行った上、制限付き最尤法により各研究データを統合した。各研究で使用された尺度の違いを調整するため、結果を標準化平均差に変換し、認知症の新規発症ハザード比を算出した。認知機能に関するデータは21件のコホートにおける計38,144例から得られ、追跡期間は114,267人・年(中央値1.7~11.3年)であった。認知症の新規発症に関するデータは8件のコホート計2,033症例と対照群44,573例から得られ、追跡期間は525,222人・年(中央値3.8~15.3年)であった。解析の結果、甲状腺機能障害と全体的認知機能の間に関連は認められなかった。最も大きな差が認められたのは、HYPO群と甲状腺機能正常群の比較で、横断解析におけるスコアの標準化平均差が−0.06(95%CI -0.20~0.08、P=0.40)、縦断解析における標準化平均差の上昇は0.11/年(同-0.01~0.23/年、P=0.09)であった(M)[13]
  1. 結論:甲状腺機能障害と遂行機能、記憶、認知症リスクとの間に一貫した関連は認められない。
 
  1. 甲状腺機能障害は、甲状腺癌、乳癌、前立腺癌のリスクの増加と関連する。
  1. 目的:HYPERまたはHYPOに関連する部位特異的ながんのリスクを評価する。
  1. 研究事例の説明:MEDLINEおよびCOCHRANEライブラリー(2019年1月28日まで)で、HYPERまたはHYPOとその後の部位特異的癌発生率との関連を報告する観察研究の系統的レビューを実施。癌バイオマーカーとして評価された、または以前の癌診断後に甲状腺機能障害が評価された研究、および妊娠中または重篤な病気の間の一過性の甲状腺機能障害を考慮した研究は除外。バイアスリスクは、修正されたニューカッスル-オタワスケールを使用して評価。5件以上の研究で特定のがん部位のデータが報告された場合、リスク推定値は変量効果モデルを使用してプール。20の研究が含まれ、そのうち15がメタアナリシスに貢献。結果:甲状腺機能正常と比較して、HYPERは、甲状腺(RR:4.49、95%CI:2.84-7.12)、乳房(RR:1.20、95%CI:1.04-1.38)、前立腺(RR:1.35、95%CI:1.05-1.74)のより高いリスクと関連した。気道(RR:1.06、95%CI:0.80-1.42)の癌との関連はなかった。HYPOは、フォローアップの最初の10年以内にのみ甲状腺癌のリスクが高いことに関連した(RR:3.31、95%CI:1.20-9.13)。他の癌部位の甲状腺機能障害に関連するリスクの証拠はないか、限られていた(S)[14]
  1. 結論:甲状腺機能障害は、甲状腺癌、乳癌、前立腺癌のリスクの増加と関連していた。ただし、治療と潜在的な交絡因子に関する情報が頻繁に不足していたため、これらの調査結果が、因果関係を表すかどうかは不明である。
 
  1. 潜在性甲状腺機能低下症は、結腸・直腸癌や甲状腺癌のリスク増加、及び、癌による死亡率の増加と関連している可能性がある。
  1. 背景:甲状腺ホルモンは細胞増殖経路への影響を介して発癌に関与していることが示されている。目的:scHypoと、癌の発症リスクおよび癌死亡率との関連を調べる。
  1. 研究事例の説明: MedlineとPubmedで検索。RCTと、scHypoまたはその治療と偶発的な癌または癌死亡率のリスクを評価する観察研究を特定した。結果:計7つのコホートと2つのケースコントロール研究が選択基準を満たした。全体として、scHypoと乳癌および前立腺癌との間に関連性は見られなかった。ある研究では、未治療のscHypoが結腸直腸癌のリスク増加と関連している可能性があった(調整OR:1.16、95%CI:1.08-1.24)。別の研究では、1.64 mIU/Lを超えるTSHの上昇に関連し、甲状腺癌の発生率のリスクが増加することが示されていた(調整済みOR:3.38、95%CI:2.05-5.59)。 2つの研究では、甲状腺機能正常者と比較して、scHypo患者の癌死亡率が増加していた。一方、ある研究では、scHypoと高齢男性の癌死亡率との間に関連性は見られなかった(S)[15]
  1. 結論:甲状腺機能障害と癌のリスクや死亡率を調べる研究の数は限られている。甲状腺機能障害と癌のリスクおよび死亡率との関連を評価するさらなる研究が必要であり、それはscHypo治療の必要性を明らかにする。
 
  1. 甲状腺疾患は、さまざまな職業上の結果に影響を及ぼす可能性がある。
  1. 背景:甲状腺疾患は、患者の生物学的機能、感情的および社会的生活に影響を与える可能性のある幅広い身体的および精神的症状と関連している。しかし、作業機能への影響はまだ完全には理解されていない。目的:甲状腺疾患が職業上の結果、すなわち、患者の就業率、病欠、労働力、労働所得に影響を与える可能性があるかどうかを評価する。
  1. 研究事例の説明: Pubmed、Scopus、ISI Web of Knowledgeデータベースの系統的レビューを実施。甲状腺癌の生存者の約3分の1が失業している可能性。HYPERおよびHYPOの患者は、病気の重症度に応じて、対照よりも長期の病欠のリスクが高かった。HYPERは、特に複視を伴う眼症を合併した症例において、罹患した患者の約3分の1で作業能力を損なっていた(S)[16]
  1. 結論:甲状腺疾患がさまざまな職業上の結果に影響を及ぼす可能性が明らかになったが、仕事上の問題、経時的な特定の病理学的特徴、職場での危険因子の間の関係を理解するには、さらなる研究が必要である。このような研究の成果は、甲状腺疾患の包括的で学際的な管理をサポートし、患者の個人的、社会的、職業的生活に利益をもたらす可能性がある。
 
  1. 原発性甲状腺機能低下症と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)[17]
  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)[18]
  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. 潜在性甲状腺機能異常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)[19]
  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)。
 
甲状腺機能低下症の周産期リスクに関して:
 
  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)[20]
  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)[21]
  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)[22]
  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)[23]
  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)[24]
  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. 妊娠中の母体の潜在性甲状腺機能低下症は、SGAのリスクが高く、低出生体重に関連するが、孤立性低T4血症は、SGAのリスクが低く、高出生体重に関連する。母体のTSHおよびFT4と出生体重との間には逆の用量反応関係がある。
  1. 背景:母体の甲状腺ホルモンの適切な経胎盤通過は、正常な胎児の成長と発達にとって重要である。母体のHYPOとHYPERは低出生体重症と関連しているが、潜在性甲状腺機能異常が出生体重に及ぼす影響に関し、特に、妊娠の第2三半期後半と第3三半期に重要な知識の欠落が残っている。目的:母体の甲状腺機能と出生時体重との関連を調べる。
  1. 研究事例の説明:前向きコホートについて、MEDLINE(Ovid)、Embase、Web of Science、Cochrane Central Register of Controlled Trials、Google Scholarを、開始から2019年10月15日まで検索。多胎妊娠、体外受精、既存の甲状腺疾患または甲状腺薬の使用、流産、死産のある参加者は除外。評価項目は、小出生体重(SGA)児、巨大児、出生体重。母親の年齢、BMI、民族性、喫煙、出産歴、採血時の在胎週数、胎児の性別、出生時の在胎週数を調整する混合効果回帰モデルを使用して、個人参加者のデータを分析。結果:2526の論文を特定し、そのうち36のコホートが選択基準を満たした。このうち15の研究著者が参加することに同意し、さらに5つの未発表のデータセットが追加され、除外後の母子ペア48,145の研究集団が得られ、そのうち1,275(3.1%)がscHypo(TSHの増加)を、929(2.2%)は孤立性低T4血症(正常TSH)を示した。母体のscHypoは、甲状腺機能正常よりもSGAのリスクが高いこと(11.8%対10.0%; 調整されたリスク差2.43%、95%CI:0.43〜4.81; OR 1.24、1.04〜1.48; p=0.015)およびより低い平均出生体重(平均差-38g、-61〜-15; p=0.0015)に関連し、第1または第2よりも第3三半期で顕著であった。孤立性低T4血症は、HYPERよりもSGAのリスクが低いこと(7.3%対10.0%、調整されたリスク差-2.91、-4.49〜-0.88;または0.70、0.55〜0.91; p=0.0073)およびより高い平均出生体重(平均差45g、18〜73; p=0.0012)に関連していた。母体のTSH濃度が1SD増加するごとに、出生体重が6g低くなり(-10〜-2; p=0.0030)、TPO抗体陽性の女性の方が陰性の女性よりも効果の推定値が高かった(交互作用 = 0.10)。 FT4濃度が1SD増加するごとに、出生体重が21g低くなり(-25〜-17; p<0.0001)、第1または第2よりも第3三半期で顕著であった(S)[25]
  1. 結論:妊娠中の母体のscHypoは、SGAのリスクが高く、低出生体重に関連しているが、孤立性低T4血症は、SGAのリスクが低く、高出生体重に関連している。母体のTSHおよびFT4(正常範囲内であっても)と出生体重との間に逆の用量反応関係が認められた。妊娠中のLT4療法の潜在的なリスクと利点を慎重に検討する必要がある。
 
  1. 妊娠中の女性には、甲状腺機能の定期的な測定とタイムリーな治療を検討する必要がある(推奨度2)
  1. 背景:従来の研究は、母親の甲状腺機能障害と、有害な神経認知転帰および子孫の内臓の発達障害との潜在的な関連を示唆していた。目的:母親の甲状腺機能障害と子孫の有害転帰のリスクとの関連を評価する。
  1. 研究事例の説明:PubMed、EMBASE、コクランライブラリを用いて、母親の甲状腺機能と子供の有害な結果のリスクとの関連を報告した論文を検索した。結果:29の適格な論文を特定した。母体のHYPERと注意欠陥多動性障害(ADHD)(OR:1.18、95%CI:1.04-1.34、I2 = 0%)および、てんかん(OR:1.19、95%CI:子で1.08-1.31、I2 = 0%)との関連を見いだした。また、母体のHYPOとADHD(OR:1.14、95%CI:1.03-1.26、I2 = 25%)、自閉症スペクトラム障害(OR:1.41、95%CI:1.05-1.90、I2 = 63%)、子のてんかん(OR:1.21、95%CI:1.06-1.39、I2 = 0%)のリスク増加との関連を認めた(S)[26]
  1. 結論:妊娠中の女性には、甲状腺機能の定期的な測定とタイムリーな治療を検討する必要がある。
 
  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)[27]
  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)[28]
  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)[29]
  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)[30]
  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)[31]
  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。
病歴・診察のポイント  
  1. 耐寒性低下・発汗減少・便秘・浮腫・体重増加・傾眠傾向など、の本症に特徴的な症状・徴候(下記)のどれか1つでもあてはまる場合は、その他の症状・徴候の有無についても聴取と診察を進める。

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文献 

Thenmalar Vadiveloo, Peter T Donnan, Michael J Murphy, Graham P Leese
Age- and gender-specific TSH reference intervals in people with no obvious thyroid disease in Tayside, Scotland: the Thyroid Epidemiology, Audit, and Research Study (TEARS).
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
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
Reference values for TSH may be inadequate to define hypothyroidism in persons with morbid obesity: Di@bet.es study.
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
Laura Boucai, Joseph G Hollowell, Martin I Surks
An approach for development of age-, gender-, and ethnicity-specific thyrotropin reference limits.
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
Leonard Wartofsky, Richard A Dickey
The evidence for a narrower thyrotropin reference range is compelling.
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
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)
Harmonization of Serum Thyroid-Stimulating Hormone Measurements Paves the Way for the Adoption of a More Uniform Reference Interval.
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
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
Subclinical and overt thyroid dysfunction and risk of all-cause mortality and cardiovascular events: a large population study.
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
Alon Grossman, Avraham Weiss, Nira Koren-Morag, Ilan Shimon, Yichayaou Beloosesky, Joseph Meyerovitch
Subclinical Thyroid Disease and Mortality in the Elderly: A Retrospective Cohort Study.
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
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
Thyroid antibody status, subclinical hypothyroidism, and the risk of coronary heart disease: an individual participant data analysis.
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
Layal Chaker, Christine Baumgartner, M Arfan Ikram, Abbas Dehghan, Marco Medici, W Edward Visser, Albert Hofman, Nicolas Rodondi, Robin P Peeters, Oscar H Franco
Subclinical thyroid dysfunction and the risk of stroke: a systematic review and meta-analysis.
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
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
Subclinical Hypothyroidism and the Risk of Stroke Events and Fatal Stroke: An Individual Participant Data Analysis.
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
Abimbola A Akintola, Steffy W Jansen, David van Bodegom, Jeroen van der Grond, Rudi G Westendorp, Anton J M de Craen, Diana van Heemst
Subclinical hypothyroidism and cognitive function in people over 60 years: a systematic review and meta-analysis.
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
Nicolien A van Vliet, Diana van Heemst, Osvaldo P Almeida, Bjørn O Åsvold, Carole E Aubert, Jong Bin Bae, Linda E Barnes, Douglas C Bauer, Gerard J Blauw, Carol Brayne, Anne R Cappola, Graziano Ceresini, Hannie C Comijs, Jean-Francois Dartigues, Jean-Marie Degryse, Robin P F Dullaart, Marlise E A van Eersel, Wendy P J den Elzen, Luigi Ferrucci, Howard A Fink, Leon Flicker, Hans J Grabe, Ji Won Han, Catherine Helmer, Martijn Huisman, M Arfan Ikram, Misa Imaizumi, Renate T de Jongh, J Wouter Jukema, Ki Woong Kim, Lewis H Kuller, Oscar L Lopez, Simon P Mooijaart, Jae Hoon Moon, Elisavet Moutzouri, Matthias Nauck, Jim Parle, Robin P Peeters, Mary H Samuels, Carsten O Schmidt, Ulf Schminke, P Eline Slagboom, Eystein Stordal, Bert Vaes, Henry Völzke, Rudi G J Westendorp, Michiko Yamada, Bu B Yeap, Nicolas Rodondi, Jacobijn Gussekloo, Stella Trompet, Thyroid Studies Collaboration
Association of Thyroid Dysfunction With Cognitive Function: An Individual Participant Data Analysis.
JAMA Intern Med. 2021 Nov 1;181(11):1440-1450. doi: 10.1001/jamainternmed.2021.5078.
Abstract/Text Importance: In clinical guidelines, overt and subclinical thyroid dysfunction are mentioned as causal and treatable factors for cognitive decline. However, the scientific literature on these associations shows inconsistent findings.
Objective: To assess cross-sectional and longitudinal associations of baseline thyroid dysfunction with cognitive function and dementia.
Design, Setting, and Participants: This multicohort individual participant data analysis assessed 114 267 person-years (median, 1.7-11.3 years) of follow-up for cognitive function and 525 222 person-years (median, 3.8-15.3 years) for dementia between 1989 and 2017. Analyses on cognitive function included 21 cohorts comprising 38 144 participants. Analyses on dementia included eight cohorts with a total of 2033 cases with dementia and 44 573 controls. Data analysis was performed from December 2016 to January 2021.
Exposures: Thyroid function was classified as overt hyperthyroidism, subclinical hyperthyroidism, euthyroidism, subclinical hypothyroidism, and overt hypothyroidism based on uniform thyrotropin cutoff values and study-specific free thyroxine values.
Main Outcomes and Measures: The primary outcome was global cognitive function, mostly measured using the Mini-Mental State Examination. Executive function, memory, and dementia were secondary outcomes. Analyses were first performed at study level using multivariable linear regression and multivariable Cox regression, respectively. The studies were combined with restricted maximum likelihood meta-analysis. To overcome the use of different scales, results were transformed to standardized mean differences. For incident dementia, hazard ratios were calculated.
Results: Among 74 565 total participants, 66 567 (89.3%) participants had normal thyroid function, 577 (0.8%) had overt hyperthyroidism, 2557 (3.4%) had subclinical hyperthyroidism, 4167 (5.6%) had subclinical hypothyroidism, and 697 (0.9%) had overt hypothyroidism. The study-specific median age at baseline varied from 57 to 93 years; 42 847 (57.5%) participants were women. Thyroid dysfunction was not associated with global cognitive function; the largest differences were observed between overt hypothyroidism and euthyroidism-cross-sectionally (-0.06 standardized mean difference in score; 95% CI, -0.20 to 0.08; P = .40) and longitudinally (0.11 standardized mean difference higher decline per year; 95% CI, -0.01 to 0.23; P = .09). No consistent associations were observed between thyroid dysfunction and executive function, memory, or risk of dementia.
Conclusions and Relevance: In this individual participant data analysis of more than 74 000 adults, subclinical hypothyroidism and hyperthyroidism were not associated with cognitive function, cognitive decline, or incident dementia. No rigorous conclusions can be drawn regarding the role of overt thyroid dysfunction in risk of dementia. These findings do not support the practice of screening for subclinical thyroid dysfunction in the context of cognitive decline in older adults as recommended in current guidelines.

PMID 34491268
Thi-Van-Trinh Tran, Cari M Kitahara, Florent de Vathaire, Marie-Christine Boutron-Ruault, Neige Journy
Thyroid dysfunction and cancer incidence: a systematic review and meta-analysis.
Endocr Relat Cancer. 2020 Apr;27(4):245-259. doi: 10.1530/ERC-19-0417.
Abstract/Text In this study, we aimed to evaluate site-specific cancer risks associated with hyperthyroidism or hypothyroidism. We performed a systematic review of observational studies reporting associations between hyperthyroidism or hypothyroidism and subsequent site-specific cancer incidence, in MEDLINE and the COCHRANE library (inception-28/01/2019) (PROSPERO: CRD42019125094). We excluded studies with thyroid dysfunction evaluated as a cancer biomarker or after prior cancer diagnosis and those considering transient thyroid dysfunction during pregnancy or severe illnesses. Risk of bias was assessed using a modified Newcastle-Ottawa scale. Risk estimates were pooled using random-effects models when ≥5 studies reported data for a specific cancer site. Twenty studies were included, of which 15 contributed to the meta-analysis. Compared to euthyroidism, hyperthyroidism was associated with higher risks of thyroid (pooled risk ratio: 4.49, 95%CI: 2.84-7.12), breast (pooled risk ratio: 1.20, 95%CI: 1.04-1.38), and prostate (pooled risk ratio: 1.35, 95%CI: 1.05-1.74), but not respiratory tract (pooled risk ratio: 1.06, 95%CI: 0.80-1.42) cancers. Hypothyroidism was associated with a higher risk of thyroid cancer within the first 10 years of follow-up only (pooled risk ratio: 3.31, 95%CI: 1.20-9.13). There was no or limited evidence of thyroid dysfunction-related risks of other cancer sites. In conclusion, thyroid dysfunction was associated with increased risks of thyroid, breast, and prostate cancers. However, it remains unclear whether these findings represent causal relationships because information on treatments and potential confounders was frequently lacking.

PMID 32045361
Juan Gómez-Izquierdo, Kristian B Filion, Jean-Franҫois Boivin, Laurent Azoulay, Michael Pollak, Oriana Hoi Yun Yu
Subclinical hypothyroidism and the risk of cancer incidence and cancer mortality: a systematic review.
BMC Endocr Disord. 2020 Jun 9;20(1):83. doi: 10.1186/s12902-020-00566-9. Epub 2020 Jun 9.
Abstract/Text BACKGROUND: Thyroid hormone has been shown to be involved in carcinogenesis via its effects on cell proliferation pathways. The objective of this study is to determine the association between subclinical hypothyroidism (SCH) and the risk of incident cancer and cancer mortality via systematic review.
METHODS: A systematic search was performed on Medline and Pubmed to identify relevant studies. Randomized controlled trials, and observational studies assessing SCH or its treatment and the risk of incident cancer or cancer mortality were identified.
RESULTS: A total of 7 cohort and 2 case-control studies met our inclusion criteria. In general, these studies were of medium to good quality. Overall, studies revealed no association between SCH and breast and prostate cancer. One study found that untreated SCH may be associated with an increased risk of colorectal cancer (adjusted odds ratio [OR]: 1.16; 95% confidence interval [CI]: 1.08-1.24). One study showed an increased risk in thyroid cancer incidence (adjusted OR: 3.38; 95% CI: 2.05-5.59) associated with elevation of a thyroid stimulating hormone (TSH) of > 1.64mIU/L. Two studies found an increase in cancer mortality among patients with SCH compared to euthyroid individuals; in contrast one study found no association between subclinical hypothyroidism and cancer mortality among aging men.
CONCLUSION: The number of studies examining thyroid dysfunction and cancer risk and mortality is limited. Future studies assessing the association between thyroid dysfunction and cancer risk and mortality are needed, which will further address the need to treat subclinical hypothyroidism.

PMID 32517676
Veruscka Leso, Ilaria Vetrani, Luigi De Cicco, Alessandro Cardelia, Luca Fontana, Gaetano Buonocore, Ivo Iavicoli
The Impact of Thyroid Diseases on the Working Life of Patients: A Systematic Review.
Int J Environ Res Public Health. 2020 Jun 16;17(12). doi: 10.3390/ijerph17124295. Epub 2020 Jun 16.
Abstract/Text Thyroid diseases are characterized by a wide range of physical and mental symptoms that can affect biological function, emotional and social life of patients. However, their impact on work functioning is not yet fully understood. Therefore, this review aims to address the way in which thyroid diseases can affect occupational outcomes, i.e., the employment rate, sick leave, working capacity and work income of patients. A systematic review of Pubmed, Scopus and ISI Web of Knowledge databases has been performed. Although it is not possible to extrapolate precise data for benign pathologies, about a third of the survivors of thyroid cancer could be unemployed. Hyperthyroid and hypothyroid patients presented a greater risk of long-term sick leave than controls, depending on the severity of the disease. Hyperthyroidism impaired working ability in about a third of affected patients, particularly in cases complicated by orbitopathy with diplopia. A possible influence of thyroid diseases on various occupational outcomes emerged from our review, however further research seems necessary to understand the relationship between work problems, specific pathological characteristics over time and risk factors in the workplace. This may support a comprehensive, interdisciplinary management of thyroid disorders, with benefits for patients' personal, social and professional life.

PMID 32560169
Yi Shen, Xu-Lin Wang, Jin-Ping Xie, Jian-Guo Shao, Yi-Hua Lu, Sheng Zhang, Gang Qin
Thyroid Disturbance in Patients with Chronic Hepatitis C Infection: A Systematic Review and Meta-analysis.
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
Penelope M Sheehan, Alison Nankervis, Edward Araujo Júnior, Fabricio Da Silva Costa
Maternal Thyroid Disease and Preterm Birth: Systematic Review and Meta-Analysis.
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
B J Smit, J H Kok, T Vulsma, J M Briët, K Boer, W M Wiersinga
Neurologic development of the newborn and young child in relation to maternal thyroid function.
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
Tuija Männistö, Pauline Mendola, Jagteshwar Grewal, Yunlong Xie, Zhen Chen, S Katherine Laughon
Thyroid diseases and adverse pregnancy outcomes in a contemporary US cohort.
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
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
Hypothyroxinemia and TPO-antibody positivity are risk factors for premature delivery: the generation R study.
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
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
Maternal subclinical hypothyroidism, thyroid autoimmunity, and the risk of miscarriage: a prospective cohort study.
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
Arash Derakhshan, Robin P Peeters, Peter N Taylor, Sofie Bliddal, David M Carty, Margreet Meems, Bijay Vaidya, Liangmiao Chen, Bridget A Knight, Farkhanda Ghafoor, Polina V Popova, Lorena Mosso, Emily Oken, Eila Suvanto, Aya Hisada, Jun Yoshinaga, Suzanne J Brown, Judit Bassols, Juha Auvinen, Wichor M Bramer, Abel López-Bermejo, Colin M Dayan, Robert French, Laura Boucai, Marina Vafeiadi, Elena N Grineva, Victor J M Pop, Tanja G Vrijkotte, Leda Chatzi, Jordi Sunyer, Ana Jiménez-Zabala, Isolina Riaño, Marisa Rebagliato, Xuemian Lu, Amna Pirzada, Tuija Männistö, Christian Delles, Ulla Feldt-Rasmussen, Erik K Alexander, Scott M Nelson, Layal Chaker, Elizabeth N Pearce, Mònica Guxens, Eric A P Steegers, John P Walsh, Tim I M Korevaar
Association of maternal thyroid function with birthweight: a systematic review and individual-participant data meta-analysis.
Lancet Diabetes Endocrinol. 2020 Jun;8(6):501-510. doi: 10.1016/S2213-8587(20)30061-9.
Abstract/Text BACKGROUND: Adequate transplacental passage of maternal thyroid hormone is important for normal fetal growth and development. Maternal overt hypothyroidism and hyperthyroidism are associated with low birthweight, but important knowledge gaps remain regarding the effect of subclinical thyroid function test abnormalities on birthweight-both in general and during the late second and third trimester of pregnancy. The aim of this study was to examine associations of maternal thyroid function with birthweight.
METHODS: In this systematic review and individual-participant data meta-analysis, we searched MEDLINE (Ovid), Embase, Web of Science, the Cochrane Central Register of Controlled Trials, and Google Scholar from inception to Oct 15, 2019, for prospective cohort studies with data on maternal thyroid function during pregnancy and birthweight, and we issued open invitations to identify study authors to join the Consortium on Thyroid and Pregnancy. We excluded participants with multiple pregnancies, in-vitro fertilisation, pre-existing thyroid disease or thyroid medication usage, miscarriages, and stillbirths. The main outcomes assessed were small for gestational age (SGA) neonates, large for gestational age neonates, and newborn birthweight. We analysed individual-participant data using mixed-effects regression models adjusting for maternal age, BMI, ethnicity, smoking, parity, gestational age at blood sampling, fetal sex, and gestational age at birth. The study protocol was pre-registered at the International Prospective Register of Systematic Reviews, CRD42016043496.
FINDINGS: We identified 2526 published reports, from which 36 cohorts met the inclusion criteria. The study authors for 15 of these cohorts agreed to participate, and five more unpublished datasets were added, giving a study population of 48 145 mother-child pairs after exclusions, of whom 1275 (3·1%) had subclinical hypothyroidism (increased thyroid stimulating hormone [TSH] with normal free thyroxine [FT4]) and 929 (2·2%) had isolated hypothyroxinaemia (decreased FT4 with normal TSH). Maternal subclinical hypothyroidism was associated with a higher risk of SGA than was euthyroidism (11·8% vs 10·0%; adjusted risk difference 2·43%, 95% CI 0·43 to 4·81; odds ratio [OR] 1·24, 1·04 to 1·48; p=0·015) and lower mean birthweight (mean difference -38 g, -61 to -15; p=0·0015), with a higher effect estimate for measurement in the third trimester than in the first or second. Isolated hypothyroxinaemia was associated with a lower risk of SGA than was euthyroidism (7·3% vs 10·0%, adjusted risk difference -2·91, -4·49 to -0·88; OR 0·70, 0·55 to 0·91; p=0·0073) and higher mean birthweight (mean difference 45 g, 18 to 73; p=0·0012). Each 1 SD increase in maternal TSH concentration was associated with a 6 g lower birthweight (-10 to -2; p=0·0030), with higher effect estimates in women who were thyroid peroxidase antibody positive than for women who were negative (pinteraction=0·10). Each 1 SD increase in FT4 concentration was associated with a 21 g lower birthweight (-25 to -17; p<0·0001), with a higher effect estimate for measurement in the third trimester than the first or second.
INTERPRETATION: Maternal subclinical hypothyroidism in pregnancy is associated with a higher risk of SGA and lower birthweight, whereas isolated hypothyroxinaemia is associated with lower risk of SGA and higher birthweight. There was an inverse, dose-response association of maternal TSH and FT4 (even within the normal range) with birthweight. These results advance our understanding of the complex relationships between maternal thyroid function and fetal outcomes, and they should prompt careful consideration of potential risks and benefits of levothyroxine therapy during pregnancy.
FUNDING: Netherlands Organization for Scientific Research (grant 401.16.020).

Copyright © 2020 Elsevier Ltd. All rights reserved.
PMID 32445737
Grace Mengqin Ge, Miriam T Y Leung, Kenneth K C Man, Wing Cheong Leung, Patrick Ip, Gloria H Y Li, Ian C K Wong, Annie W C Kung, Ching-Lung Cheung
Maternal Thyroid Dysfunction During Pregnancy and the Risk of Adverse Outcomes in the Offspring: A Systematic Review and Meta-Analysis.
J Clin Endocrinol Metab. 2020 Dec 1;105(12). doi: 10.1210/clinem/dgaa555.
Abstract/Text CONTEXT: Previous studies suggested a potential link of maternal thyroid dysfunction with adverse neurocognitive outcomes and impaired development of internal organs in offspring.
OBJECTIVE: To review the association between maternal thyroid dysfunction and the risk of adverse outcomes in offspring.
DATA SOURCES: PubMed, EMBASE, and Cochrane Library.
STUDY SELECTIONS: Eligible studies reported the association between maternal thyroid hormone function and the risk of adverse outcomes in their children.
DATA EXTRACTION: Reviewers extracted data on study characteristics and results independently.
DATA SYNTHESIS: Estimates were pooled and reported as odds ratio (OR) with 95% confidence interval (CI). I2 tests were applied to assess the heterogeneity across studies.
RESULTS: We identified 29 eligible articles and found an association between maternal hyperthyroidism and attention deficit hyperactivity disorder (ADHD) (OR: 1.18, 95% CI: 1.04-1.34, I2 = 0%) and epilepsy (OR: 1.19, 95% CI: 1.08-1.31, I2 = 0%) in offspring; as well as an association of maternal hypothyroidism with increased risk of ADHD (OR: 1.14, 95% CI: 1.03-1.26, I2 = 25%), autism spectrum disorder (OR: 1.41, 95% CI: 1.05-1.90, I2 = 63%), and epilepsy (OR: 1.21, 95% CI: 1.06-1.39, I2 = 0%) in offspring.
CONCLUSION: Routine measurement and timely treatment on thyroid function should be considered for pregnant women.

© Endocrine Society 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
PMID 32810262
Xuegang Fan, Lina Wu
The impact of thyroid abnormalities during pregnancy on subsequent neuropsychological development of the offspring: a meta-analysis.
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
Karen A Willoughby, Mary Pat McAndrews, Joanne F Rovet
Effects of maternal hypothyroidism on offspring hippocampus and memory.
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
Akhgar Ghassabian, Hanan El Marroun, Robin P Peeters, Vincent W Jaddoe, Albert Hofman, Frank C Verhulst, Henning Tiemeier, Tonya White
Downstream effects of maternal hypothyroxinemia in early pregnancy: nonverbal IQ and brain morphology in school-age children.
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
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
Subclinical Hypothyroidism and Thyroid Autoimmunity Are Not Associated With Fecundity, Pregnancy Loss, or Live Birth.
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
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
Treatment of Subclinical Hypothyroidism or Hypothyroxinemia in Pregnancy.
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
Giuseppe Pasqualetti, Gennaro Pagano, Giuseppe Rengo, Nicola Ferrara, Fabio Monzani
Subclinical Hypothyroidism and Cognitive Impairment: Systematic Review and Meta-Analysis.
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
Geanina Popoveniuc, Tanu Chandra, Anchal Sud, Meeta Sharma, Marc R Blackman, Kenneth D Burman, Mihriye Mete, Sameer Desale, Leonard Wartofsky
A diagnostic scoring system for myxedema coma.
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
Mouhand F H Mohamed, Mohammed Danjuma, Mohammed Mohammed, Samreen Mohamed, Martin Siepmann, Kristian Barlinn, Salah Suwileh, Lina Abdalla, Dabia Al-Mohanadi, Juan Carlos Silva Godínez, Abdel-Naser Elzouki, Timo Siepmann
Myxedema Psychosis: Systematic Review and Pooled Analysis.
Neuropsychiatr Dis Treat. 2021;17:2713-2728. doi: 10.2147/NDT.S318651. Epub 2021 Aug 18.
Abstract/Text Background and Objective: The term myxedema psychosis (MP) was introduced to describe the occurrence of psychotic symptoms in patients with untreated hypothyroidism, but the optimal assessment and treatment of this condition are unclear. We aimed to synthesize data from the literature to characterize the clinical presentation and management of MP.
Methods: We performed a systematic review according to the PRISMA (preferred reporting items for systematic reviews and meta-analyses) guidelines in PubMed (Medline), Embase, Google Scholar, and Cochrane databases, including observational studies, case series, and case reports published from 1/1/1980 to 31/12/2019 in the English language. Descriptive statistics along with univariate and multivariate analysis were used for data synthesis.
Results: Out of 1583 articles screened, 71 case reports met our inclusion criteria providing data on 75 MP cases. The median age at diagnosis was 42 years [32-56]. About 53% had no prior hypothyroidism diagnosis. Delusions occurred in 91%, with a predominance of persecutory ideas (84%), while hallucinations occurred in 78%. Physical symptoms and signs of hypothyroidism were absent in 37% and 26%, respectively. If symptoms occurred, nonspecific fatigue was seen most frequently (63%). The median thyroid-stimulating hormone value was 93 mIU/L [60-139]. Thyroid peroxidase antibodies were found positive in 75% (23/33) of reported cases. Creatinine kinase was reported abnormal in seven cases. Cranial imaging (CT or MRI) and electroencephalogram were normal in 89%, 75%, and 73% of the cases reported. The majority of patients were treated orally with thyroxine in combination with short-term antipsychotics. More than 90% of them showed complete recovery. Univariate analysis revealed a trend towards a shorter duration of psychosis with IV thyroid hormone therapy (p= 0.0502), but the effect was not consistent in a multivariate analysis.
Conclusion: While we identified a substantial lack of published research on MP, our pooled analysis of case observations suggests that the condition presents a broad spectrum of psychiatric and physical symptoms lending support to the value of screening for thyroid dysfunction in patients with first-ever psychosis.
Prospero Registration Number: CRD42020160310.

© 2021 Mohamed et al.
PMID 34447249
Jana Krüger, Adrian Kraschewski, Maria C Jockers-Scherübl
Myxedema Madness - Systematic literature review of published case reports.
Gen Hosp Psychiatry. 2021 Sep-Oct;72:102-116. doi: 10.1016/j.genhosppsych.2021.08.005. Epub 2021 Aug 14.
Abstract/Text Myxedema Madness is a rare but easily treatable cause of psychosis. Since Myxedema Madness was first described the question of a specific psychopathological symptom complex caused by severe hypothyroidism was raised in the literature. The present review of 52 published cases indicates that there are no specific somatic and psychopathological findings to diagnose a myxedema psychosis. It is diagnosed through the measurement of thyroid stimulating hormone and treated by application of L-thyroxine. Due to its excellent prognosis, myxedema madness should always be considered a differential diagnosis in new onset psychosis.

Copyright © 2021. Published by Elsevier Inc.
PMID 34419786
John P Walsh, Alexandra P Bremner, Peter Feddema, Peter J Leedman, Suzanne J Brown, Peter O'Leary
Thyrotropin and thyroid antibodies as predictors of hypothyroidism: a 13-year, longitudinal study of a community-based cohort using current immunoassay techniques.
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
Ken K Ong, Diana Kuh, Mary Pierce, Jayne A Franklyn, Medical Research Council National Survey of Health and Development Scientific and Data Collection Teams
Childhood weight gain and thyroid autoimmunity at age 60-64 years: the 1946 British birth cohort study.
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
Giorgio Radetti, Mara Maselli, Fabio Buzi, Andrea Corrias, Alessandro Mussa, Paola Cambiaso, Mariacarolina Salerno, Marco Cappa, Michela Baiocchi, Roberto Gastaldi, Luigi Minerba, Sandro Loche
The natural history of the normal/mild elevated TSH serum levels in children and adolescents with Hashimoto's thyroiditis and isolated hyperthyrotropinaemia: a 3-year follow-up.
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
Kristen A Hyland, Alice M Arnold, Jennifer S Lee, Anne R Cappola
Persistent subclinical hypothyroidism and cardiovascular risk in the elderly: the cardiovascular health study.
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
Gary D Rothberger, Sonya Gadhvi, Nickolaos Michelakis, Amit Kumar, Rose Calixte, Lawrence E Shapiro
Usefulness of Serum Triiodothyronine (T3) to Predict Outcomes in Patients Hospitalized With Acute Heart Failure.
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
Yukun Wang, Dejiu Kong, Chaokun Wang, Jing Chen, Jing Li, Zhiwei Liu, Xinyang Li, Ziming Wang, Ge Yao, Xinshuai Wang
A Systematic Review and Meta-Analysis of Immune-Related Adverse Events of Anti-PD-1 Drugs in Randomized Controlled Trials.
Technol Cancer Res Treat. 2020 Jan-Dec;19:1533033820967454. doi: 10.1177/1533033820967454.
Abstract/Text OBJECTIVE: We aimed to evaluate immune-related adverse events occurring in clinical trials of anti-programmed cell death 1 (PD-1) drugs, compared with control treatments, including chemotherapy, targeted drugs, or placebo. Further we compared the occurrence of immune -related events in patients treated with different anti-PD-1 drugs.
DATA SOURCES: Randomized controlled trial (RCT) data were sourced from PubMed, Embase, and the Cochrane Central Register of Controlled Trials combined with https://clinicaltrials.gov.
METHODS: Randomized controlled trial of anti-PD-1 drugs compared with control treatments published between January 1, 1970 and March 1,2019, were searched and data on trial patient characteristics, and adverse events extracted, reviewed, and subjected to meta-analysis.
RESULTS: Eighteen Randomized controlled trials were included in our study. The Randomized controlled trials compared nivolumab (n = 12), pembrolizumab (n = 6), with chemotherapy (n = 13), targeted drugs (n = 2), or placebo (n = 3). Compared with the control group, the risk of any immune-related adverse events in patients treated with anti-PD-1 drugs was increased (RR, 2.65; 95% confidence interval, 1.84-3.83; P < 0.00001). Of the immune-related adverse events, the risk rates of pneumonitis (risk ratio, 2.10; 95% CI, 0.85-5.18), colitis (2.96;1.62-5.38), hypophysitis(4.79;1.54-14.89), hypothyroidism(7.87;5.36-11.57), hyperthyroidism (7.03;4.35-11.34), rash (1.58;0.98-2.54), pruritus (2.28; 1.38-3.76), and hepatitis (9.31;2.18-39.85) were increased by anti-PD-1 drugs. Further, the risk of immune-related adverse events was similar for patients treated with pembrolizumab and nivolumab (P = 0.14).
CONCLUSIONS: In addition to previously reported organ-specific immune-related adverse events, we found that the risk of hyperthyroidism was also increased, in anit-PD-1-treated patients, relative to control treatments. The risk of total immune-related adverse events, was similar for pembrolizumab and nivolumab.

PMID 33084525
Lijun Da, Yuanjun Teng, Na Wang, Karen Zaguirre, Yating Liu, Yali Qi, Feixue Song
Organ-Specific Immune-Related Adverse Events Associated With Immune Checkpoint Inhibitor Monotherapy Versus Combination Therapy in Cancer: A Meta-Analysis of Randomized Controlled Trials.
Front Pharmacol. 2019;10:1671. doi: 10.3389/fphar.2019.01671. Epub 2020 Jan 30.
Abstract/Text Background: Although combination therapy with immune checkpoint inhibitors (ICIs) provides a promising efficacy in multiple cancers, their use is facing challenges for a high incidence of adverse effects. This meta-analysis was conducted to compare the risks of organ-specific immune-related adverse events (IRAEs) associated with ICI monotherapy versus combination therapy among cancer patients.
Methods: Electronic databases were systematically searched to include eligible randomized controlled trials (RCTs). Any-grade and 3-5 grade IRAEs (colitis, pneumonitis, hepatitis, hypothyroidism, hyperthyroidism, and hypophysitis) were extracted for meta-analysis. Two reviewers independently assessed the methodological quality. The RevMan 5.3.5 software was used for meta-analysis.
Results: A total of 10 studies involving 8 RCTs with 2716 patients were included in this study. The most common any-grade adverse event was colitis (14.5%), followed by hypothyroidism (13.8%), hepatitis (10.4%), hypophysitis (10.0%), hyperthyroidism (9.3%), and pneumonitis (4.6%). Meta-analysis showed that ICI combination therapy significantly increased the risks of any-grade IRAEs in colitis [relative risk (RR), 3.56; 95% confidence interval (CI), 1.56-8.12; p < 0.05], pneumonitis (RR, 2.31; 95% CI, 1.54-3.45; p < 0.05), hepatitis (RR, 2.54; 95% CI, 1.65-3.91; p < 0.05), hypothyroidism (RR, 2.17; 95% CI, 1.71-2.76; p < 0.05), hyperthyroidism (RR, 3.13; 95% CI, 2.08-4.70; p < 0.05), and hypophysitis (RR, 3.54; 95% CI, 2.07-6.07; p < 0.05) compared with ICI monotherapy, as well as 3-5 grade IRAEs in colitis (RR, 2.50; 95% CI, 1.62-3.86; p < 0.05), pneumonitis (RR, 1.99; 95% CI, 1.00-3.93; p = 0.05), and hepatitis (RR, 2.70; 95% CI, 1.29-5.63; p < 0.05).
Conclusions: This meta-analysis demonstrated that, compared with ICI monotherapy, patients receiving ICI combination therapy significantly increased organ-specific IRAEs in colitis, hypothyroidism, hepatitis, hypophysitis, hyperthyroidism, and pneumonitis. The incidence and severity of organ-specific IRAEs were drug and dose independent.

Copyright © 2020 Da, Teng, Wang, Zaguirre, Liu, Qi and Song.
PMID 32082164
Jun Shao, Chengdi Wang, Pengwei Ren, Yuting Jiang, Panwen Tian, Weimin Li
Treatment- and immune-related adverse events of immune checkpoint inhibitors in advanced lung cancer.
Biosci Rep. 2020 May 29;40(5). doi: 10.1042/BSR20192347.
Abstract/Text BACKGROUND: Immune checkpoint inhibitors (ICIs) emerged as the preferred therapy in advanced lung cancer, understanding the treatment- and immune-related adverse events of these drugs is of great significance for clinical practice.
MATERIALS AND METHODS: PubMed, Embase, Cochrane library and major conference proceedings were systematically searched for all randomized controlled trials (RCTs) in lung cancer using PD-1/PD-L1/CTLA-4 inhibitors. The outcomes included treatment-related adverse events (TRAEs) and several organ specific immune-related adverse events (IRAEs).
RESULTS: 24 RCTs involving 14,256 patients were included. There was a significant difference for ICI therapy in the incidence of any grade of TRAEs (RR: 0.90; 95%CI: 0.84-0.95; P=0.001) and a lower frequency of grade 3-5 of TRAEs (RR: 0.65; 95%CI: 0.51-0.82; P<0.001). Patients treated with ICI therapy in non-small-cell lung cancer (NSCLC) were less reported TRAEs than in small cell lung cancer (SCLC). A lower risk of TRAEs was favored by anti-PD-1 inhibitors over anti-PD-L1 antibodies and anti-CTLA-4 drugs. The most common organ specific IRAE was hypothyroidism that occurred 8.7%. The incidence of pneumonitis and hepatitis reached 4.5% and 4.0% respectively. Compared with patients treated in control arms, those treated with ICI drugs were at higher risk for each organ specific adverse event including colitis, hepatitis, pneumonitis, hypothyroidism and hypophysitis.
CONCLUSIONS: ICI therapy was safer than chemotherapy, especially ICI monotherapy such as anti-PD-1 antibodies in NSCLC. Compared with standard treatments, ICI drugs increased the risk of organ-specific IRAEs, although the overall incidence remained low.

© 2020 The Author(s).
PMID 32315071
Zhi-Qiang Li, Hai-Cui Yan, Jing-Jing Gu, Yong-Liang Yang, Ming-Kui Zhang, Xin-Jian Fang
Comparative efficacy and safety of PD-1/PD-L1 Inhibitors versus platinum-based chemotherapy for the first-line treatment of advanced non-small cell lung cancer: a meta analysis of randomized controlled trials.
Pharmacol Res. 2020 Oct;160:105194. doi: 10.1016/j.phrs.2020.105194. Epub 2020 Sep 13.
Abstract/Text OBJECTIVE: The main aim of this study was to systematically evaluate the efficacy and safety of inhibitors of programmed cell death receptor 1 (PD-1) and its ligand, programmed cell death ligand-1 (PD-L1), in the treatment of advanced non-small cell lung cancer (NSCLC).
METHODS: Randomized controlled trials assessing the efficacy of PD-1/PD-L1 inhibitors relative to platinum-based chemotherapy for advanced NSCLC in PubMed, EMBASE, and Cochrane libraries from 2015 to 2020 were searched, along with review of studies at American Society of Clinical Oncology (ASCO) and European society for Medical Oncology (ESMO). Pooled hazard ratios (HR) for progression-free survival (PFS) and overall survival (OS) and odds ratios (OR) for adverse events (AE) were calculated using STATA and Revman software.
RESULTS: PD-1/PD-L1 inhibitors alone or combined with chemotherapy significantly improved OS (HR = 0.82, 95% CI:0.74-0.91, P = 0.01 or HR = 0.74, 95% CI:0.67-0.82, P = 0.001). PD-1/PD-L1 inhibitors alone did not benefit PFS (HR = 0.99, 95% CI: 0.89-1.10, P = 0.892), while combination therapy led to prolonged PFS (HR = 0.61, 95% CI: 0.56-0.67, P < 0.001). Subgroup analysis showed that in NSCLC with PD-L1 ≥ 50%, treatment with PD-1/PD-L1 inhibitors alone significantly improved both PFS and OS. In patients subjected to the combined treatment regimen, we observed significant differences in PFS among groups stratified by PD-L1 expression (p < 0.001), immune drug type (p = 0.029), gender (p = 0.014) and liver metastasis (p = 0.035) and OS among groups stratified by immune drug type (p < 0.001), gender (P = 0.001) and smoking status (P = 0.041). Safety analysis showed that combination therapy increased chemotherapy-induced adverse events (AE), while PD-1/PD-L1 inhibitors alone were associated with a lower incidence of any grade of treatment-related AEs (TRAE). A higher incidence of Grade 3-5 TRAEs and hypothyroidism was observed with PD-1 inhibitors than PD-L1 inhibitors.
CONCLUSIONS: First-line treatment of advanced NSCLC with immune monotherapy or immunochemotherapy confers a greater survival benefit than chemotherapy alone. Combination of chemotherapy with PD-1/PD-L1 inhibitors leads to an increase in adverse events, and PD-1 inhibitors offer enhanced survival benefits and fewer adverse events than PD-L1 inhibitors. Remarkably, female patients undergoing combination therapy had longer overall survival than male patients.

Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.
PMID 32937178
Yuan Tian, Ran Li, Yan Liu, Meng Li, Yuxiao Song, Yan Zheng, Aiqin Gao, Qing Wen, Guohai Su, Yuping Sun
The Risk of Immune-Related Thyroid Dysfunction Induced by PD-1/PD-L1 Inhibitors in Cancer Patients: An Updated Systematic Review and Meta-Analysis.
Front Oncol. 2021;11:667650. doi: 10.3389/fonc.2021.667650. Epub 2021 Jul 12.
Abstract/Text Background: Thyroid dysfunction is common for cancer patients receiving PD-1/PD-L1 inhibitor therapies. To clarify the incidence risk of thyroid dysfunction would be important for guiding anti-PD-1 and anti-PD-L1 immunotherapy. Therefore, the updated meta-analysis was conducted to evaluate the incidence risk of thyroid dysfunction caused by PD-1/PD-L1 inhibitors.
Methods: PD-1/PD-L1 inhibitor related clinical trials were collected by a systematic search of the PubMed. Some relevant studies were identified by a manual search. The incidence risk of all grades and grades 3-5 was analyzed and evaluated by random effect model. The Newcastle Ottawa Scale was used for the quality assessment of all clinical trials.
Results: Forty-three clinical trials were collected. Compared with chemotherapy, the risk of hypothyroidism of all grades was significantly higher (OR=7.15, 95%CI:[4.85, 10.55], I2 = 40%, Z=9.91(P <0.00001)) in PD-1/PD-L1 group. Similar results could also be noted, when the control group was placebo or CTLA-4. When PD-1/PD-L1 was combined with other treatments for cancer patients, the risk of hypothyroidism of all grades was also significantly increased. Similar to the analysis results of hypothyroidism, PD-1/PD-L1 inhibitors played the same role in increasing the risk of hyperthyroidism and thyroiditis. Few significant analysis results was noted, when the risk of thyroid dysfunction of grades 3-5 was assessed.
Conclusion: Whether used alone or in combination with other anti-tumor drugs, PD-1/PD-L1 inhibitors increased the risk of thyroid dysfunction, especially for hypothyroidism. Furthermore, PD-1/PD-L1 was better than chemotherapy and CTLA-4 in increasing the risk of thyroid dysfunction.

Copyright © 2021 Tian, Li, Liu, Li, Song, Zheng, Gao, Wen, Su and Sun.
PMID 34322382
Andrea Luciani, Antonio Ghidini, Lorenzo Dottorini, Fausto Petrelli
Safety and Effectiveness of Immune Checkpoint Inhibitors in Older Patients with Cancer: A Systematic Review of 48 Real-World Studies.
Drugs Aging. 2021 Oct 20;. doi: 10.1007/s40266-021-00899-7. Epub 2021 Oct 20.
Abstract/Text BACKGROUND: Over recent years, immune checkpoint inhibitors (ICIs) have changed the clinical management and prognosis for most cancers. However, data on older patients in clinical trials are scarce.
OBJECTIVE: We performed a systematic review and pooled analysis of real-life studies to explore the efficacy and toxicity of ICIs in unselected older individuals in multiple tumor settings treated outside of clinical trials.
PATIENTS AND METHODS: We searched articles, including prospective cohort studies, observational or retrospective series, or expanded access programs, published in English from 2010 to October 2020 in PubMed, MEDLINE, the Cochrane Library, and EMBASE. We excluded hematological malignancies.
RESULTS: Forty-eight studies met the predefined criteria and were eligible for inclusion in the systematic review. We included 5524 patients. The pooled median overall survival was 8.9 (95% CI 7.3-10.5) and 14.3 (95% CI 11.3-17) months for non-small cell lung cancer (NSCLC: n = 17 studies; 95% in pretreated setting) and melanoma, respectively (n = 3). Median progression-free survival was 3.2 (95% CI 2.7-3.8) and 7.9 (95% CI 6.05-9.78) months for NSCLC and melanoma cohorts. Pooled rates of Grade 1-5 hepatitis, pneumonitis, hypothyroidism, and diarrhea were 5.3% (95% CI 3.7-7.6), 6% (95% CI 3.8-9.4), 8.3% (95% CI 5.4-12.5) and 7.6% (95% CI 5.7-10), respectively.
CONCLUSIONS: Our findings suggest that ICIs could be safely administered in older individuals with comparable survival outcomes with respect to younger individuals. Future studies should include some form of geriatric assessment to improve patient stratification.

© 2021. The Author(s), under exclusive licence to Springer Nature Switzerland AG.
PMID 34671933
Shaojun Zhang, Guilong Feng, Fangfang Kang, Yali Guo, Hongyan Ti, Lufang Hao, Peng Gao, Jiangqin Gao
Hypothyroidism and Adverse Endpoints in Diabetic Patients: A Systematic Review and Meta-Analysis.
Front Endocrinol (Lausanne). 2019;10:889. doi: 10.3389/fendo.2019.00889. Epub 2020 Jan 10.
Abstract/Text Background: This study investigated the relationship strength between hypothyroidism and cardiovascular and renal outcomes in diabetic patients. Methods: The electronic databases PubMed, EmBase, and Cochrane library were screened for relevant studies published before November 2018. The outcomes included major cardiovascular events (MACEs), all-cause mortality, cardiac death, stroke, diabetic nephropathy (DN), diabetic retinopathy (DR), and chronic kidney disease (CKD). The pooled results for all outcomes were calculated using random-effects models. Results: A total of eight studies met the inclusion criteria. The summary results indicated that hypothyroidism was not associated with the risk of MACEs (OR:1.21; 95%CI:0.68-2.16; P = 0.514), all-cause mortality (OR:1.27; 95%CI:0.93-1.74; P = 0.136), cardiac death (OR:1.16; 95%CI:0.89-1.52; P = 0.271), stroke (OR:0.96; 95%CI: 0.49-1.88; P = 0.915), and DN (OR:1.71; 95%CI:0.37-7.90; P = 0.490). There was a significant association between hypothyroidism and the risk of DR (OR:1.73; 95%CI:1.08-2.77; P = 0.023) and CKD (OR:1.22; 95%CI:1.10-1.36; P < 0.001). Conclusions: These findings indicate that diabetic patients with hypothyroidism have an increased risk of DR and CKD. Additional large-scale prospective studies should be carried out to verify the prognosis of patients with diabetes and hypothyroidism.

Copyright © 2020 Zhang, Feng, Kang, Guo, Ti, Hao, Gao and Gao.
PMID 31998230
Tou-Yuan Tsai, Yu-Kang Tu, Kashif M Munir, Shu-Man Lin, Rachel Huai-En Chang, Sheng-Lun Kao, Ching-Hui Loh, Carol Chiung-Hui Peng, Huei-Kai Huang
Association of Hypothyroidism and Mortality in the Elderly Population: A Systematic Review and Meta-Analysis.
J Clin Endocrinol Metab. 2020 Jun 1;105(6). doi: 10.1210/clinem/dgz186.
Abstract/Text CONTEXT: The evidence of whether hypothyroidism increases mortality in the elderly population is currently inconsistent and conflicting.
OBJECTIVE: The objective of this meta-analysis is to determine the impact of hypothyroidism on mortality in the elderly population.
DATA SOURCES: PubMed, Embase, Cochrane Library, Scopus, and Web of Science databases were searched from inception until May 10, 2019.
STUDY SELECTION: Studies evaluating the association between hypothyroidism and all-cause and/or cardiovascular mortality in the elderly population (ages ≥ 60 years) were eligible.
DATA EXTRACTION: Two reviewers independently extracted data and assessed the quality of the studies. Relative risk (RR) was retrieved for synthesis. A random-effects model for meta-analyses was used.
DATA SYNTHESIS: A total of 27 cohort studies with 1 114 638 participants met the inclusion criteria. Overall, patients with hypothyroidism experienced a higher risk of all-cause mortality than those with euthyroidism (pooled RR = 1.26, 95% CI: 1.15-1.37); meanwhile, no significant difference in cardiovascular mortality was found between patients with hypothyroidism and those with euthyroidism (pooled RR = 1.10, 95% CI: 0.84-1.43). Subgroup analyses revealed that overt hypothyroidism (pooled RR = 1.10, 95% CI: 1.01-1.20) rather than subclinical hypothyroidism (pooled RR = 1.14, 95% CI: 0.92-1.41) was associated with increased all-cause mortality. The heterogeneity primarily originated from different study designs (prospective and retrospective) and geographic locations (Europe, North America, Asia, and Oceania).
CONCLUSIONS: Based on the current evidence, hypothyroidism is significantly associated with increased all-cause mortality instead of cardiovascular mortality among the elderly. We observed considerable heterogeneity, so caution is needed when interpreting the results. Further prospective, large-scale, high-quality studies are warranted to confirm these findings.

© Endocrine Society 2019. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
PMID 31829418
Arjola Bano, Layal Chaker, Taulant Muka, Francesco U S Mattace-Raso, Lia Bally, Oscar H Franco, Robin P Peeters, Salman Razvi
Thyroid Function and the Risk of Fibrosis of the Liver, Heart, and Lung in Humans: A Systematic Review and Meta-Analysis.
Thyroid. 2020 Jun;30(6):806-820. doi: 10.1089/thy.2019.0572. Epub 2020 Feb 13.
Abstract/Text Background: Fibrotic diseases have an unclear etiology and poor prognosis. Fluctuations in thyroid function may play a role in the development of fibrosis, but evidence is fragmented and inconclusive. This systematic review and meta-analysis aimed to investigate the association of thyroid function with fibrotic diseases of the liver, heart, and lung in humans. Methods: We searched PubMed, Medline Ovid, Embase Ovid, and Web-of-Science for studies published from inception to 14 June 2019, to identify observational studies that investigated the association of thyroid function with fibrosis of the liver, heart, and lung in humans. Study quality was evaluated by the Newcastle-Ottawa Scale. The Mantel-Haenszel method was used to pool the odds ratios (ORs) of studies investigating the association of hypothyroidism with liver fibrosis. Results: Of the 2196 identified articles, 18 studies were included in the systematic review, of which 11 studies reported on liver fibrosis, 4 on myocardial fibrosis, and 3 on pulmonary fibrosis. The population sample size ranged from 36 to 7259 subjects, with median mean age 51 years (range, 36-69) and median percentage of women 53 (range, 17-100). The risk of bias of studies was low to moderate to high. Higher serum thyrotropin and lower thyroid hormone levels were generally associated with higher likelihood of fibrosis. Compared with euthyroidism, overt and subclinical hypothyroidism was associated with a higher likelihood of fibrosis in the liver (six of seven studies), heart (three of three studies), and lung (three of three studies). Based on the results of the seven studies included in the meta-analysis, overt and subclinical hypothyroidism was associated with an increased risk of liver fibrosis (pooled OR, 2.81; 95% confidence interval [CI], 1.74-4.53; heterogeneity, I2 31.4%; pooled OR, 2.12; CI, 1.45-3.12; heterogeneity, I2 0%; respectively), without evidence of publication bias. Conclusions: This study suggests that low thyroid function is associated with increased likelihood of chronic fibrotic diseases of the liver, heart, and lung. However, the evidence is mainly based on cross-sectional data. Prospective studies and randomized clinical trials are needed to investigate the potential efficacy of thyroid hormone and its analogs on the occurrence and progression of fibrosis.

PMID 31910097
Juliana Muñoz-Ortiz, Maria Camila Sierra-Cote, Estefanía Zapata-Bravo, Laura Valenzuela-Vallejo, Maria Alejandra Marin-Noriega, Pilar Uribe-Reina, Juan Pablo Terreros-Dorado, Marcela Gómez-Suarez, Karla Arteaga-Rivera, Alejandra de-la-Torre
Prevalence of hyperthyroidism, hypothyroidism, and euthyroidism in thyroid eye disease: a systematic review of the literature.
Syst Rev. 2020 Sep 1;9(1):201. doi: 10.1186/s13643-020-01459-7. Epub 2020 Sep 1.
Abstract/Text BACKGROUND: Thyroid eye disease is an autoimmune disorder of the orbital retrobulbar tissue commonly associated with dysthyroid status. The most frequent condition is hyperthyroidism, although it is also present in hypothyroid and euthyroid patients. The prevalence of thyroid conditions in patients with thyroid eye disease had been previously evaluated; however, there is no consensus on a global prevalence. The study aims to estimate the prevalence of hyperthyroidism, hypothyroidism, and euthyroidism in patients with TED, through a systematic review of literature.
METHODS: We conducted a systematic review of the literature following the PRISMA guidelines, in MEDLINE, COCHRANE, EMBASE, Science Direct, and LILACS databases. Inclusion criteria were primary studies of patients with a diagnosis of thyroid eye disease made by an ophthalmologist or with diagnosis criteria, with measurement of thyroid function (TSH, T3, and free T4), and diagnosis of the primary thyroid condition. A quality assessment was made through the Joanna Briggs Institute Quality tools. Finally, we extracted relevant details about the design, the results, and the prevalence of thyroid disorders in thyroid eye disease.
RESULTS: The initial search revealed 916 studies, of which finally thirteen met inclusion criteria. Six studies were performed in Europe (Germany, Wales, and Spain), five in Asia (Iran, South Korea, Japan, and Singapore), one in North America (USA), and one in Africa (Ghana). The global prevalence, in patients of thyroid eye disease, was 10.36% for hypothyroidism, 7.9% for euthyroidism, and 86.2% for hyperthyroidism.
CONCLUSIONS: Professionals should be aware that thyroid eye disease can be present in patients with a normal thyroid function. The assessment for these patients is based on orbital images; serum TSH, T3, and free T4; antibody levels as thyrotropin receptor antibodies; and thyroperoxidase levels. Additionally, we want to encourage research in this field in other regions of the world such as Latin America.
SYSTEMATIC REVIEW REGISTRATION: PROSPERO ID CRD42020107167.

PMID 32873324
Freddy J K Toloza, Yuanjie Mao, Lakshmi Menon, Gemy George, Madhura Borikar, Soumya Thumma, Hooman Motahari, Patricia Erwin, Richard Owen, Spyridoula Maraka
Association of Thyroid Function with Suicidal Behavior: A Systematic Review and Meta-Analysis.
Medicina (Kaunas). 2021 Jul 15;57(7). doi: 10.3390/medicina57070714. Epub 2021 Jul 15.
Abstract/Text Thyroid disease is a very common condition that influences the entire human body, including cognitive function and mental health. As a result, thyroid disease has been associated with multiple neuropsychiatric conditions. However, the relationship between thyroid dysfunction and suicide is still controversial. We conducted a systematic review and meta-analysis to describe the association of thyroid function with suicidal behavior in adults. We searched four data bases (MEDLINE, EMBASE, PsycINFO, and Scopus) from their inception to 20 July 2018. Studies that reported mean values and standard deviation (SD) of thyroid hormone levels [Thyroid-stimulating hormone (TSH), free thyroxine (FT4), free triiodothyronine (FT3), total thyroxine (TT4), and total triiodothyronine (TT3)] in patients with suicidal behavior compared with controls were included in this meta-analysis. The abstracts and papers retrieved with our search strategies were reviewed independently and in duplicate by four reviewers for assessment of inclusion criteria and data extraction, as well as for evaluation of risk of bias. Random-effects models were used in this meta-analysis to establish the mean difference on thyroid function tests between groups. Overall, 2278 articles were identified, and 13 studies met the inclusion criteria. These studies involved 2807 participants, including 826 participants identified with suicidal behavior. We found that patients with suicide behavior had lower levels of FT3 (-0.20 pg/mL; p = 0.02) and TT4 (-0.23 µg/dL; p = 0.045) compared to controls. We found no differences in either TSH, FT4, or TT3 levels among groups. With our search strategy, we did not identify studies with a comparison of overt/subclinical thyroid disease prevalence between patients with and without suicide behavior. The studies included in this meta-analysis had a low-to-moderate risk of bias. In the available literature, the evidence regarding the association of thyroid disorders and suicidal behavior is limited. We found that patients with suicidal behavior have significantly lower mean FT3 and TT4 levels when compared to patients without suicidal behavior. The clinical implications and pathophysiologic mechanisms of these differences remain unknown and further research is needed.

PMID 34356995
Jahanzeb Malik, Syed Muhammad Jawad Zaidi, Ali Umer Waqar, Hashir Khawaja, Asmara Malik, Uzma Ishaq, Abdul Sattar Rana, Ali Haider Awan
Association of hypothyroidism with acute COVID-19: a systematic review.
Expert Rev Endocrinol Metab. 2021 Sep;16(5):251-257. doi: 10.1080/17446651.2021.1968830. Epub 2021 Aug 23.
Abstract/Text OBJECTIVE: There is an increasing body of literature on the impact of COVID-19 on the pituitary-thyroid axis. Therefore, we conducted a systematic review to assess the prevalence of hypothyroidism in patients with COVID-19.
METHODS: A literature review was conducted using LitCOVID for study selection in PubMed and MEDLINE till May 2021. All relevant original articles evaluating thyroid dysfunction were included and information regarding the prevalence of hypothyroid disease in COVID-19 was retrieved from the eligible articles.
RESULTS: Out of 32 articles, six articles qualified for the final analysis which included 1160 patients. There was significant heterogeneity among the included articles. Most of the patients had lower mean triiodothyronine (T3) and normal or low thyroid-stimulating hormone (TSH). Increased TSH ranged from 5.1% to 8% while low T3 was present in up to 28% of the patients. In these studies, the prevalence of altered thyroid hormones was significantly more in COVID-19 patients as compared to control groups. A positive correlation between low mean T3 and clinical severity of COVID-19 was reported.
CONCLUSION: This systematic review reveals a significant proportion of hypothyroidism associated with COVID-19. Therefore, routine assessment of thyroid function is warranted in hospitalized COVID-19 patients.

PMID 34424110
Henry Bode, Beatrice Ivens, Tom Bschor, Guido Schwarzer, Jonathan Henssler, Christopher Baethge
Association of Hypothyroidism and Clinical Depression: A Systematic Review and Meta-analysis.
JAMA Psychiatry. 2021 Sep 15;. doi: 10.1001/jamapsychiatry.2021.2506. Epub 2021 Sep 15.
Abstract/Text Importance: Hypothyroidism is considered a cause of or a strong risk factor for depression, but recent studies provide conflicting evidence regarding the existence and the extent of the association. It is also unclear whether the link is largely due to subsyndromal depression or holds true for clinical depression.
Objective: To estimate the association of hypothyroidism and clinical depression in the general population.
Data Sources: PubMed, PsycINFO, and Embase databases were searched from inception until May 2020 for studies on the association of hypothyroidism and clinical depression.
Study Selection: Two reviewers independently selected epidemiologic and population-based studies that provided laboratory or International Statistical Classification of Diseases and Related Health Problems diagnoses of hypothyroidism and diagnoses of depression according to operationalized criteria (eg, Diagnostic and Statistical Manual of Mental Disorders or International Statistical Classification of Diseases and Related Health Problems) or cutoffs in established rating scales.
Data Extraction and Synthesis: Two reviewers independently extracted data and evaluated studies based on the Newcastle-Ottawa Scale. Summary odds ratios (OR) were calculated in random-effects meta-analyses.
Main Outcomes and Measures: Prespecified coprimary outcomes were the association of clinical depression with either hypothyroidism or autoimmunity.
Results: Of 4350 articles screened, 25 studies were selected for meta-analysis, including 348 014 participants. Hypothyroidism and clinical depression were associated (OR, 1.30 [95% CI, 1.08-1.57]), while the OR for autoimmunity was inconclusive (1.24 [95% CI, 0.89-1.74]). Subgroup analyses revealed a stronger association with overt than with subclinical hypothyroidism, with ORs of 1.77 (95% CI, 1.13-2.77) and 1.13 (95% CI, 1.01-1.28), respectively. Sensitivity analyses resulted in more conservative estimates. In a post hoc analysis, the association was confirmed in female individuals (OR, 1.48 [95% CI, 1.18-1.85]) but not in male individuals (OR, 0.71 [95% CI, 0.40-1.25]).
Conclusions and Relevance: In this systematic review and meta-analysis, the effect size for the association between hypothyroidism and clinical depression was considerably lower than previously assumed, and the modest association was possibly restricted to overt hypothyroidism and female individuals. Autoimmunity alone may not be the driving factor in this comorbidity.

PMID 34524390
Nykola L Kent, Sophia L Young, Lisa K Akison, James S M Cuffe
Is the link between elevated TSH and gestational diabetes mellitus dependant on diagnostic criteria and thyroid antibody status: a systematic review and meta-analysis.
Endocrine. 2021 Oct;74(1):38-49. doi: 10.1007/s12020-021-02733-x. Epub 2021 May 15.
Abstract/Text PURPOSE: Clinical studies have investigated the prevalence of gestational diabetes mellitus (GDM) in women with subclinical hypothyroidism (SCH). While some studies demonstrate a clear association, others do not. It is possible this may be due to varied diagnostic criteria for SCH and the presence of thyroid antibodies (TA). We conducted a meta-analysis, separating patients diagnosed with SCH using a diagnostic cut-off <4.0 mIU/L from those diagnosed using a cut-off >4.0 mIU/L and determined the association with GDM and factored TA status into our analysis.
METHODS: A computerised search of five databases including PubMed, Embase, Cochrane Library, Web of Science and CINAHL returned 787 records. Two independent reviewers assessed abstracts and full texts against pre-specified inclusion and exclusion criteria. Ten cohort studies were included in the final analysis. The diagnostic criteria for SCH and incidence of GDM were extracted from each study. Study quality and risk of bias was assessed by two reviewers.
RESULTS: TSH levels <4.0 mIU/L for SCH diagnosis was not associated with GDM unless patients were TA positive. Studies that used a diagnostic cut-off >4.0 mIU/L saw a significant increase in the odds of GDM, regardless of TA status (OR = 1.60, 95% CI 1.33-1.93).
CONCLUSIONS: Women with TSH levels >4.0 mIU/L have an increased odds of GDM regardless of TA status but at TSH levels <4.0 mIU/L, GDM is dependent on TA status. The use of TSH levels to identify pregnancies at risk of GDM is a novel concept that warrants exploration.

© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.
PMID 33991314
Paulina Belén Sepulveda Figueroa, Ana Flávia Fernandes Ferreira, Luiz Roberto Britto, Arlette Patricia Doussoulin, Andréa da Silva Torrão
Association between thyroid function and Alzheimer's disease: A systematic review.
Metab Brain Dis. 2021 Oct;36(7):1523-1543. doi: 10.1007/s11011-021-00760-1. Epub 2021 Jun 19.
Abstract/Text Alterations in metabolic parameters have been associated with an increased risk of dementia, among which thyroid function has gained great importance in Alzheimer's disease (AD) pathology in recent years. However, it remains unclear whether thyroid dysfunctions could influence and contribute to the beginning and/or progression of AD or if it results from AD. This systematic review was conducted to examine the association between thyroid hormone (TH) levels and AD. Medline, ISI Web of Science, EMBASE, Cochrane library, Scopus, Scielo, and LILACS were searched, from January 2010 to March 2020. A total of 17 articles were selected. The studies reported alterations in TH and circadian rhythm in AD patients. Behavior, cognition, cerebral blood flow, and glucose consumption were correlated with TH deficits in AD patients. Whether thyroid dysfunctions and AD have a cause-effect relationship was inconclusive, however, the literature was able to provide enough data to corroborate a relationship between TH and AD. Although further studies are needed in this field, the current systematic review provides information that could help future investigations.

© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.
PMID 34146214
Chun-Yu Chang, Yung-Jiun Chien, Po-Chen Lin, Chien-Sheng Chen, Meng-Yu Wu
Nonthyroidal Illness Syndrome and Hypothyroidism in Ischemic Heart Disease Population: A Systematic Review and Meta-Analysis.
J Clin Endocrinol Metab. 2020 Aug 1;105(8). doi: 10.1210/clinem/dgaa310.
Abstract/Text CONTEXT: The association of non-thyroidal illness syndrome (NTIS) and hypothyroidism with the prognosis in ischemic heart disease (IHD) population is inconclusive.
OBJECTIVE: We aimed to evaluate the influence of NTIS and hypothyroidism on all-cause mortality and major adverse cardiac events (MACE) in IHD population.
DATA SOURCES: We searched PubMed, EMBASE, Scopus, Web of Science, and Cochrane Library from inception through February 17, 2020.
STUDY SELECTION: Original articles enrolling IHD patients, comparing all-cause mortality and MACE of NTIS and hypothyroidism with those of euthyroidism, and providing sufficient information for meta-analysis were considered eligible.
DATA EXTRACTION: Relevant information and numerical data were extracted for methodological assessment and meta-analysis.
DATA SYNTHESIS: Twenty-three studies were included. The IHD population with NTIS was associated with higher risk of all-cause mortality (hazard ratio [HR] = 2.61; 95% confidence interval [CI] = 1.89-3.59) and MACE (HR = 2.22; 95% CI = 1.71-2.89) than that without. In addition, the IHD population with hypothyroidism was also associated with higher risk of all-cause mortality (HR = 1.47; 95% CI = 1.10-1.97) and MACE (HR = 1.53; 95% CI = 1.19-1.97) than that without. In the subgroup analysis, the acute coronary syndrome (ACS) subpopulation with NTIS was associated with higher risk of all-cause mortality (HR = 3.30; 95% CI = 2.43-4.48) and MACE (HR = 2.19; 95% CI = 1.45-3.30). The ACS subpopulation with hypothyroidism was also associated with higher risk of all-cause mortality (HR = 1.67; 95% CI = 1.17-2.39).
CONCLUSIONS: The IHD population with concomitant NTIS or hypothyroidism was associated with higher risk of all-cause mortality and MACE. Future research is required to provide evidence of the causal relationship and to elucidate whether normalizing thyroid function parameters can improve prognosis.

© Endocrine Society 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
PMID 32459357
M A Pollock, A Sturrock, K Marshall, K M Davidson, C J Kelly, A D McMahon, E H McLaren
Thyroxine treatment in patients with symptoms of hypothyroidism but thyroid function tests within the reference range: randomised double blind placebo controlled crossover trial.
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
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
Association of Thyroid Hormone Therapy With Quality of Life and Thyroid-Related Symptoms in Patients With Subclinical Hypothyroidism: A Systematic Review and Meta-analysis.
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
Wilmar M Wiersinga, Leonidas Duntas, Valentin Fadeyev, Birte Nygaard, Mark P J Vanderpump
2012 ETA Guidelines: The Use of L-T4 + L-T3 in the Treatment of Hypothyroidism.
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
Laura Paone, Abby F Fleisch, Henry A Feldman, Rosalind S Brown, Ari J Wassner
Liothyronine Improves Biochemical Control of Congenital Hypothyroidism in Patients with Central Resistance to Thyroid Hormone.
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
Hakan Cinemre, Cemil Bilir, Feyzi Gokosmanoglu, Talat Bahcebasi
Hematologic effects of levothyroxine in iron-deficient subclinical hypothyroid patients: a randomized, double-blind, controlled study.
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
Camila Luhm Silva Perez, Fernanda Sumire Araki, Hans Graf, Gisah Amaral de Carvalho
Serum thyrotropin levels following levothyroxine administration at breakfast.
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
Xiao Pang, Tao Pu, Li Xu, Ru Sun
Effect of l-thyroxine administration before breakfast vs at bedtime on hypothyroidism: A meta-analysis.
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
H Kececi, Y Degirmenci
Hormone replacement therapy in hypothyroidism and nerve conduction study.
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
Todd D Nebesio, Matthew D Wise, Susan M Perkins, Erica A Eugster
Does clinical management impact height potential in children with severe acquired hypothyroidism?
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
Thomas Reinehr
Thyroid function in the nutritionally obese child and adolescent.
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
J Parle, L Roberts, S Wilson, H Pattison, A Roalfe, M S Haque, C Heath, M Sheppard, J Franklyn, F D R Hobbs
A randomized controlled trial of the effect of thyroxine replacement on cognitive function in community-living elderly subjects with subclinical hypothyroidism: the Birmingham Elderly Thyroid study.
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
Salman Razvi, Jolanta U Weaver, Timothy J Butler, Simon H S Pearce
Levothyroxine treatment of subclinical hypothyroidism, fatal and nonfatal cardiovascular events, and mortality.
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
Mette Nygaard Andersen, Anne-Marie Schjerning Olsen, Jesper Clausager Madsen, Jens Faber, Christian Torp-Pedersen, Gunnar Hilmar Gislason, Christian Selmer
Levothyroxine Substitution in Patients with Subclinical Hypothyroidism and the Risk of Myocardial Infarction and Mortality.
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
Mette Nygaard Andersen, Anne-Marie Schjerning Olsen, Jesper Clausager Madsen, Søren Lund Kristensen, Jens Faber, Christian Torp-Pedersen, Gunnar H Gislason, Christian Selmer
Long-Term Outcome in Levothyroxine Treated Patients With Subclinical Hypothyroidism and Concomitant Heart Disease.
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
Lea Wildisen, Cinzia Del Giovane, Elisavet Moutzouri, Shanthi Beglinger, Lamprini Syrogiannouli, Tinh-Hai Collet, Anne R Cappola, Bjørn O Åsvold, Stephan J L Bakker, Bu B Yeap, Osvaldo P Almeida, Graziano Ceresini, Robin P F Dullaart, Luigi Ferrucci, Hans Grabe, J Wouter Jukema, Matthias Nauck, Stella Trompet, Henry Völzke, Rudi Westendorp, Jacobijn Gussekloo, Stefan Klöppel, Drahomir Aujesky, Douglas Bauer, Robin Peeters, Martin Feller, Nicolas Rodondi
An individual participant data analysis of prospective cohort studies on the association between subclinical thyroid dysfunction and depressive symptoms.
Sci Rep. 2020 Nov 5;10(1):19111. doi: 10.1038/s41598-020-75776-1. Epub 2020 Nov 5.
Abstract/Text In subclinical hypothyroidism, the presence of depressive symptoms is often a reason for starting levothyroxine treatment. However, data are conflicting on the association between subclinical thyroid dysfunction and depressive symptoms. We aimed to examine the association between subclinical thyroid dysfunction and depressive symptoms in all prospective cohorts with relevant data available. We performed a systematic review of the literature from Medline, Embase, Cumulative Index to Nursing and Allied Health Literature, and the Cochrane Library from inception to 10th May 2019. We included prospective cohorts with data on thyroid status at baseline and depressive symptoms during follow-up. The primary outcome was depressive symptoms measured at first available follow-up, expressed on the Beck's Depression Inventory (BDI) scale (range 0-63, higher values indicate more depressive symptoms, minimal clinically important difference: 5 points). We performed a two-stage individual participant data (IPD) analysis comparing participants with subclinical hypo- or hyperthyroidism versus euthyroidism, adjusting for depressive symptoms at baseline, age, sex, education, and income (PROSPERO CRD42018091627). Six cohorts met the inclusion criteria, with IPD on 23,038 participants. Their mean age was 60 years, 65% were female, 21,025 were euthyroid, 1342 had subclinical hypothyroidism and 671 subclinical hyperthyroidism. At first available follow-up [mean 8.2 (± 4.3) years], BDI scores did not differ between participants with subclinical hypothyroidism (mean difference = 0.29, 95% confidence interval =  - 0.17 to 0.76, I2 = 15.6) or subclinical hyperthyroidism (- 0.10, 95% confidence interval =  - 0.67 to 0.48, I2 = 3.2) compared to euthyroidism. This systematic review and IPD analysis of six prospective cohort studies found no clinically relevant association between subclinical thyroid dysfunction at baseline and depressive symptoms during follow-up. The results were robust in all sensitivity and subgroup analyses. Our results are in contrast with the traditional notion that subclinical thyroid dysfunction, and subclinical hypothyroidism in particular, is associated with depressive symptoms. Consequently, our results do not support the practice of prescribing levothyroxine in patients with subclinical hypothyroidism to reduce the risk of developing depressive symptoms.

PMID 33154486
Yan Chen, Hai-Yan Tai
Levothyroxine in the treatment of overt or subclinical hypothyroidism: a systematic review and meta-analysis.
Endocr J. 2020 Jul 28;67(7):719-732. doi: 10.1507/endocrj.EJ19-0583. Epub 2020 Mar 31.
Abstract/Text The goal of this study was to review relevant randomized controlled trials in order to determine the clinical efficacy of levothyroxine in the treatment of overt or subclinical hypothyroidism. Using appropriate keywords, we identified relevant studies using PubMed, the Cochrane library, and Embase. Key pertinent sources in the literature were also reviewed, and all articles published through December 2019 were considered for inclusion. For each study, we assessed odds ratios (ORs), mean difference (MD), and 95% confidence interval (95%CI) to assess and synthesize outcomes. We included 25 studies with totally 1,735 patients in the meta-analysis. In the patients with hypothyroidism, compared with L-T4, L-T4 plus L-T3 significantly decreased TSH levels and increased FT3 levels. Compared with placebo, L-T4 significantly increased FT4 levels and decreased TSH levels. In patients with subclinical hypothyroidism, compared with placebo, L-T4 significantly decreased SBP, TSH, T3 and TC and increased FT3 and FT4.

PMID 32238664
Dragos Nemescu, Ingrid Andrada Tanasa, Dana Liana Stoian, Dan Bogdan Navolan, Angela Elena Vinturache
Conservative in utero treatment of fetal dyshormonogenetic goiter with levothyroxine, a systematic literature review.
Exp Ther Med. 2020 Sep;20(3):2434-2438. doi: 10.3892/etm.2020.8794. Epub 2020 May 26.
Abstract/Text Fetal goitrous hypothyroidism is a rare condition associated with important obstetrical, neonatal complications, and neurodevelopmental impairments. Prenatal treatment remains controversial, and the risk to benefit ratio must be accurately assessed and considered for individualized management. The objective of this review was to evaluate the feasibility, safety, and effectiveness of the conservative in utero treatment of fetal goitrous hypothyroidism. In total, 25 reports that met our inclusion criteria were selected and the management of 38 cases was analyzed. Prenatal diagnosis consisted mainly of ultrasonographic findings. Fetal thyroid status was assessed by cordocentesis. Prenatal treatment varied widely in terms of levothyroxine (LT4) route of administration, dosage, number of injections, and frequency. Although different regimens and routes of administration were proposed, they seem to have similar results regarding fetal goiter reduction and thyroid status at birth. At birth, most babies had hypothyroidism, but the long-term follow-up indicated a normal psycho-neuromotor development. Our data confirm the feasibility of conservative treatment with LT4 for fetal goitrous hypothyroidism. Further studies are needed to determine the optimal management of this disorder.

Copyright: © Nemescu et al.
PMID 32765729
Anna-Maria Papadopoulou, Nikolaos Bakogiannis, Ioanna Skrapari, Dimitrios Moris, Chris Bakoyiannis
Thyroid Dysfunction and Atherosclerosis: A Systematic Review.
In Vivo. 2020 Nov-Dec;34(6):3127-3136. doi: 10.21873/invivo.12147.
Abstract/Text BACKGROUND/AIM: Thyroid dysfunction, both hypo- and hyperthyroidism, has been associated with cardiovascular disease. The aim of this study was to evaluate the association between thyroid dysfunction and atherosclerosis measured mostly by carotid intima-media thickness, as well as discuss whether L-T4 replacement is able to reverse or slow down the progression of atherosclerosis.
MATERIALS AND METHODS: The review was conducted according the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. We performed on PubMed a literature search from May 2004 to January 2020, using the search terms 'subclinical hypothyroidism' or 'thyroid disorders' and 'carotid artery', 'carotid intima-media thickness (IMT)', 'levothyroxine', and 'atherosclerosis'.
RESULTS: Twenty-six studies were eligible and included in the analysis. Overall, the studies encompassed a total of 36.434 patients included in this review. Most studies indicated a proportional correlation between IMT and thyroid dysfunction. Levothyroxine (L-T4) replacement led to significant decrease of IMT after 1 year in most studies.
CONCLUSION: Most studies have concluded that thyroid dysfunction is associated with arterial wall remodeling and, thus, with increased cardiovascular risk. However, the exact mechanistic background of pathological structural changes in the arterial wall is still unsettled. Large randomized controlled studies are required to definitively address the extent to which T4 replacement therapy might benefit patients with subclinical thyroid disorders.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
PMID 33144416
Anupam Kotwal, Tiffany Cortes, Natalia Genere, Oksana Hamidi, Sina Jasim, Connie B Newman, Larry J Prokop, M Hassan Murad, Fares Alahdab
Treatment of Thyroid Dysfunction and Serum Lipids: A Systematic Review and Meta-analysis.
J Clin Endocrinol Metab. 2020 Dec 1;105(12). doi: 10.1210/clinem/dgaa672.
Abstract/Text CONTEXT: Hyperthyroidism is associated with low levels of cholesterol and triglycerides, and hypothyroidism is associated with hypercholesterolemia and hypertriglyceridemia.
OBJECTIVE: The aim of this systematic review was to investigate the impact of therapy for overt and subclinical hyper- and hypothyroidism on serum lipids.
DATA SOURCES: We searched MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, the Cochrane Database of Systematic Reviews, and Scopus from 1970 through April 5, 2018.
STUDY SELECTION: Pairs of independent reviewers selected randomized and observational studies evaluating lipid parameters in patients undergoing treatment for hyper- or hypothyroidism.
DATA EXTRACTION: Pairs of independent reviewers extracted data and appraised studies.
DATA SYNTHESIS: Treatment of overt hyperthyroidism showed a significant increase in total cholesterol (TC) by 44.50 mg/dL (95% confidence interval [CI]: 37.99, 51.02), low-density lipoprotein cholesterol (LDL-C) by 31.13 mg/dL (95% CI: 24.33, 37.93), high-density lipoprotein cholesterol (HDL-C) by 5.52 mg/dL (95% CI: 1.48, 9.56), apolipoprotein A (Apo A) by 15.6 mg/dL (95% CI: 10.38, 20.81), apolipoprotein B (apo B) by 26.12 mg/dL (95% CI: 22.67, 29.57), and lipoprotein (Lp[a]) by 4.18 mg/dL (95% CI: 1.65, 6.71). There was no significant change in triglyceride (TG) levels. Treatment of subclinical hyperthyroidism did not change any lipid parameters significantly. Levothyroxine therapy in overt hypothyroidism showed a statistically significant decrease in TC by -58.4 mg/dL (95% CI: -64.70, -52.09), LDL-C by -41.11 mg/dL (95% CI: -46.53, -35.69), HDL-C by -4.14 mg/dL (95% CI: -5.67, -2.61), TGs by -7.25 mg/dL (95% CI: -36.63, 17.87), apo A by -12.59 mg/dL (95% CI: -17.98, -7.19), apo B by -33.96 mg/dL (95% CI: 41.14, -26.77), and Lp(a) by -5.6 mg/dL (95% CI: -9.06, -2.14). Levothyroxine therapy in subclinical hypothyroidism showed similar changes but with a smaller magnitude. The studies contained varied population characteristics, severity of thyroid dysfunction, and follow-up duration.
CONCLUSIONS: Treatment of overt but not subclinical hyperthyroidism is associated with worsening of the lipid profile. Levothyroxine therapy in both overt and subclinical hypothyroidism leads to improvement in the lipid profile, with a smaller magnitude of improvement in subclinical hypothyroidism.

© The Author(s) 2020. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
PMID 32954428
Carol Chiung-Hui Peng, Huei-Kai Huang, Brian Bo-Chang Wu, Rachel Huai-En Chang, Yu-Kang Tu, Kashif M Munir
Association of Thyroid Hormone Therapy with Mortality in Subclinical Hypothyroidism: A Systematic Review and Meta-Analysis.
J Clin Endocrinol Metab. 2021 Jan 1;106(1):292-303. doi: 10.1210/clinem/dgaa777.
Abstract/Text CONTEXT: Benefits of thyroid hormone therapy on mortality in adults with subclinical hypothyroidism remain undetermined.
OBJECTIVE: To summarize the impact of thyroid hormone therapy on mortality in adults with subclinical hypothyroidism.
DATA SOURCES: PubMed, Embase, Scopus, Web of Science, and Clinicaltrials.gov from inception until April 25, 2020.
STUDY SELECTION: Studies comparing the effect of thyroid hormone therapy with that of placebo or no therapy in adults with subclinical hypothyroidism on all-cause and/or cardiovascular mortality.
DATA EXTRACTION: Two reviewers independently extracted data and performed quality assessments. Random-effects models for meta-analyses were used.
DATA SYNTHESIS: Five observational studies and 2 randomized controlled trials with 21 055 adults were included. Overall, thyroid hormone therapy was not significantly associated with all-cause (pooled relative risk [RR] = 0.95, 95% confidence interval [CI]: 0.75-1.22, P = .704) or cardiovascular (pooled RR = 0.99, 95% CI: 0.82-1.20, P = .946) mortality. Subgroup analyses revealed that in younger adults (aged <65-70 years), thyroid hormone therapy was significantly associated with a lower all-cause (pooled RR = 0.50, 95% CI: 0.29-0.85, P = .011) and cardiovascular (pooled RR = 0.54, 95% CI: 0.37-0.80, P = .002) mortality. However, no significant association between thyroid hormone therapy and mortality was observed in older adults (aged ≥65-70 years).
CONCLUSIONS: Use of thyroid hormone therapy does not provide protective effects on mortality in older adults with subclinical hypothyroidism. However, thyroid hormone therapy for subclinical hypothyroidism may show benefits on morality in adults aged <65 to 70 years.

© The Author(s) 2020. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
PMID 33107557
Magnus Bein, Oriana Hoi Yun Yu, Sonia Marzia Grandi, Francesca Y E Frati, Ihab Kandil, Kristian B Filion
Levothyroxine and the risk of adverse pregnancy outcomes in women with subclinical hypothyroidism: a systematic review and meta-analysis.
BMC Endocr Disord. 2021 Feb 27;21(1):34. doi: 10.1186/s12902-021-00699-5. Epub 2021 Feb 27.
Abstract/Text BACKGROUND: Levothyroxine replacement therapy may decrease the risk of adverse pregnancy outcomes among women with subclinical hypothyroidism (SCH). The aim of this study is to conduct a systematic review and meta-analysis to examine the risk of adverse pregnancy, perinatal, and early childhood outcomes among women with SCH treated with levothyroxine.
METHODS: A systematic literature search was conducted using Ovid-Medline, Ovid-EMBASE, Pubmed (non-Medline), Ebsco-CINAHL Plus with full text and Cochrane Library databases. Randomized controlled studies (RCTs) and observational studies examining the association between treatment of SCH during pregnancy and our outcomes of interest were included. Studies that compared levothyroxine treatment versus no treatment were eligible for inclusion. Data from included studies were extracted and quality assessment was performed by two independent reviewers.
RESULTS: Seven RCTs and six observational studies met our inclusion criteria. A total of 7342 individuals were included in these studies. RCTs demonstrated several sources of bias, with lack of blinding of the participants or research personnel; only one study was fully blinded. In the observational studies, there was moderate to serious risk of bias due to lack of adjustment for certain confounding variables, participant selection, and selective reporting of results. Pooled analyses showed decreased risk of pregnancy loss (RR: 0.79; 95% CI: 0.67 to 0.93) and neonatal death (RR: 0.35; 95% CI: 0.17 to 0.72) associated with levothyroxine treatment during pregnancy among women with SCH. There were no associations between levothyroxine treatment and outcomes during labour and delivery, or cognitive status in children at 3 or 5 years of age.
CONCLUSION: Treatment of SCH with levothyroxine during pregnancy is associated with decreased risks of pregnancy loss and neonatal death. Given the paucity of available data and heterogeneity of included studies, additional studies are needed to address the benefits of levothyroxine use among pregnant women with SCH.

PMID 33639909
Revathi Myneni, Harsh V Chawla, Amit S Grewal, Govinathan Vivekanandan, Andrew Ndakotsu, Ansha P Abubacker, Aimen Iqbal, Safeera Khan
Thyroxine Replacement for Subfertile Females With Subclinical Hypothyroidism and Autoimmune Thyroiditis: A Systematic Review.
Cureus. 2021 Aug;13(8):e16872. doi: 10.7759/cureus.16872. Epub 2021 Aug 4.
Abstract/Text The second most prevalent endocrine condition affecting women of reproductive age is thyroid disease. The difference between an increased thyroid-stimulating hormone (TSH) concentration and a normal free thyroxine hormone level is used to identify subclinical hypothyroidism. Thyroid autoantibodies, independent of thyroid hormone levels, are used to diagnose autoimmune thyroid disease (ATD). Thyroxine can help infertile women with these two types of thyroid illnesses have better birth outcomes during fertility treatment. We performed a systematic review using PubMed (Medline) as a major database and some other sources EMBASE, the Cochrane Library, Web of Science, Scopus, and Science Direct. We concentrated on four studies, including 806 patients. Our goal is to investigate the efficacy and risks of levothyroxine therapy in infertile women who are receiving fertility treatments and have subclinical hypothyroidism or adequate thyroid function as well as thyroid autoimmunity (euthyroid autoimmune thyroid disorder). Thyroid activity in hypothyroid women should be tracked at pregnancy confirmation and closely monitored during the pregnancy. Early in pregnancy, the dosage of levothyroxine (LT4) can be raised. To ensure optimum TSH levels during breastfeeding, we recommend that patients who are followed in the primary sector have their LT4 dose increased by their general practitioner before their first referral to an endocrinological outpatient clinic. It's important to pay more attention to and track pregnant women with hypothyroidism, who consider pregnancy, to get the best results. LT4 therapy can help subfertile women with subclinical hypothyroidism who are having in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) since it improves embryo growth, implantation rate, and live birth rate.

Copyright © 2021, Myneni et al.
PMID 34513447
Lorraine Lau, Jamie L Benham, Patricia Lemieux, Jennifer Yamamoto, Lois E Donovan
Impact of levothyroxine in women with positive thyroid antibodies on pregnancy outcomes: a systematic review and meta-analysis of randomised controlled trials.
BMJ Open. 2021 Feb 23;11(2):e043751. doi: 10.1136/bmjopen-2020-043751. Epub 2021 Feb 23.
Abstract/Text OBJECTIVE: To evaluate the effect of levothyroxine therapy on pregnancy outcomes compared with placebo or no treatment in women without overt hypothyroidism with presence of thyroid peroxidase antibodies (TPOAb) and/or thyroglobulin antibodies (TgAb).
DESIGN: Systematic review and meta-analysis of randomised controlled trials STUDY ELIGIBILITY CRITERIA: Prespecified criteria for inclusion were: randomised trials of levothyroxine versus control (placebo or no treatment) among women with positive TPOAb or TgAb who were pregnant or considering conception.
DATA SOURCES: Ovid MEDLINE, EMBASE, CINAHL, Cochrane Database of Systematic Reviews and Cochrane Central Register of Controlled Trials were searched from 1980 to 5 November 2020.
OUTCOME MEASURES: Prespecified data elements were extracted and where appropriate, meta-analyses were conducted. Main outcomes include pregnancy achieved, miscarriage, preterm delivery and live birth.
RISK OF BIAS ASSESSMENT: Cochrane Risk of Bias Tool for Quality Assessment of Randomised Controlled Trials.
RESULTS: From 3023 citations, 79 citations were identified for full-text review. Of these, six trials (total of 2263 women) were included for qualitative and quantitative analyses. Risk of bias was deemed low for only one trial. There was no significant difference in the relative risk (RR) of pregnancy achieved (RR 1.03; 95% CI 0.93 to 1.13), miscarriage (RR 0.93; 95% CI 0.76 to 1.14), preterm delivery (RR 0.66; 95% CI 0.39 to 1.10) or live births (RR 1.01; 95% CI 0.89 to 1.16) in thyroid autoimmune women treated with levothyroxine compared with controls. Sensitivity analyses of preterm birth identified study quality and timing of levothyroxine initiation as sources of heterogeneity.
CONCLUSIONS: Among pregnant women or women planning conception, with thyroid autoimmunity, there is a lack of evidence of benefit for levothyroxine use (moderate to high Grading of Recommendations, Assessment, Development and Evaluations). Recommendations to use levothyroxine in this setting need to be reconsidered.
PROSPERO REGISTRATION NUMBER: CRD42019130459.

© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.
PMID 33622947
Juan Manuel Millan-Alanis, José Gerardo González-González, Andrea Flores-Rodríguez, Naykky Singh Ospina, Spyridoula Maraka, Pablo J Moreno-Peña, Juan P Brito, Camilo González-Velázquez, René Rodríguez-Gutiérrez
Benefits and Harms of Levothyroxine/L-Triiodothyronine Versus Levothyroxine Monotherapy for Adult Patients with Hypothyroidism: Systematic Review and Meta-Analysis.
Thyroid. 2021 Nov;31(11):1613-1625. doi: 10.1089/thy.2021.0270. Epub 2021 Sep 28.
Abstract/Text Background: Combined therapy with levothyroxine (LT4)/L-triiodothyronine (LT3) has garnered attention among clinicians and patients as a potential treatment alternative to LT4 monotherapy. The objective of this study was to compare the benefits and harms of LT4/LT3 combined therapy and LT4 monotherapy for patients with hypothyroidism. Methods: A systematic search in MEDLINE, Scopus, EMBASE, Web of Science, and Cochrane Central Register of Controlled Trials was performed by a librarian from inception date until September 2020. Randomized clinical trials and quasiexperimental studies comparing combined therapy (LT4/LT3) versus monotherapy (LT4) for adult patients with hypothyroidism were considered for inclusion. Independent data extraction was performed by paired reviewers. A meta-analysis comparing standardized mean differences of the effect of each therapy was performed on clinical outcomes and patient preferences. Proportions of adverse events and reactions were assessed narratively. Results: A total of 1398 references were retrieved, from which 18 fulfilled the inclusion criteria. Results supported by evidence at low-to-moderate certainty evidence did not display a difference in treatment effect between therapies on clinical status, quality of life, psychological distress, depressive symptoms, and fatigue; all measured with standardized questionnaires. Furthermore, meta-analysis of patient preferences revealed higher proportions of choice for combined therapy (43%) when compared with monotherapy (23%) or having no preference (30%). When evaluating treatment adverse events or adverse reactions, similar proportions were observed between treatment groups; meta-analysis was not possible. Conclusions: The available evidence at low-to-moderate certainty demonstrates that there is no difference in clinical outcomes between LT4/LT3 combined therapy and LT4 monotherapy for treating hypothyroidism in adults, except for a higher proportion of patient preferring combined therapy. Adverse events and reactions appear to be similar across both groups, however, this observation is only narrative. These results could inform shared decision-making conversations between patients with hypothyroidism and their clinicians. PROSPERO Registration ID: CRD42020202658.

PMID 34340589
Avais Jabbar, Lorna Ingoe, Shahid Junejo, Peter Carey, Caroline Addison, Honey Thomas, Jehill D Parikh, David Austin, Kieren G Hollingsworth, Deborah D Stocken, Simon H S Pearce, John P Greenwood, Azfar Zaman, Salman Razvi
Effect of Levothyroxine on Left Ventricular Ejection Fraction in Patients With Subclinical Hypothyroidism and Acute Myocardial Infarction: A Randomized Clinical Trial.
JAMA. 2020 Jul 21;324(3):249-258. doi: 10.1001/jama.2020.9389.
Abstract/Text Importance: Thyroid hormones play a key role in modulating myocardial contractility. Subclinical hypothyroidism in patients with acute myocardial infarction is associated with poor prognosis.
Objective: To evaluate the effect of levothyroxine treatment on left ventricular function in patients with acute myocardial infarction and subclinical hypothyroidism.
Design, Setting, and Participants: A double-blind, randomized clinical trial conducted in 6 hospitals in the United Kingdom. Patients with acute myocardial infarction including ST-segment elevation and non-ST-segment elevation were recruited between February 2015 and December 2016, with the last participant being followed up in December 2017.
Interventions: Levothyroxine treatment (n = 46) commencing at 25 µg titrated to aim for serum thyrotropin levels between 0.4 and 2.5 mU/L or identical placebo (n = 49), both provided in capsule form, once daily for 52 weeks.
Main Outcomes and Measures: The primary outcome measure was left ventricular ejection fraction at 52 weeks, assessed by magnetic resonance imaging, adjusted for age, sex, type of acute myocardial infarction, affected coronary artery territory, and baseline left ventricular ejection fraction. Secondary measures were left ventricular volumes, infarct size (assessed in a subgroup [n = 60]), adverse events, and patient-reported outcome measures of health status, health-related quality of life, and depression.
Results: Among the 95 participants randomized, the mean (SD) age was 63.5 (9.5) years, 72 (76.6%) were men, and 65 (69.1%) had ST-segment elevation myocardial infarction. The median serum thyrotropin level was 5.7 mU/L (interquartile range, 4.8-7.3 mU/L) and the mean (SD) free thyroxine level was 1.14 (0.16) ng/dL. The primary outcome measurements at 52 weeks were available in 85 patients (89.5%). The mean left ventricular ejection fraction at baseline and at 52 weeks was 51.3% and 53.8%, respectively, in the levothyroxine group compared with 54.0% and 56.1%, respectively, in the placebo group (adjusted difference in groups, 0.76% [95% CI, -0.93% to 2.46%]; P = .37). None of the 6 secondary outcomes showed a significant difference between the levothyroxine and placebo treatment groups. There were 15 (33.3%) and 18 (36.7%) cardiovascular adverse events in the levothyroxine and placebo groups, respectively.
Conclusions and Relevance: In this preliminary study involving patients with subclinical hypothyroidism and acute myocardial infarction, treatment with levothyroxine, compared with placebo, did not significantly improve left ventricular ejection fraction after 52 weeks. These findings do not support treatment of subclinical hypothyroidism in patients with acute myocardial infarction.
Trial Registration: isrctn.org Identifier: http://www.isrctn.com/ISRCTN52505169.

PMID 32692386
Lea Wildisen, Martin Feller, Cinzia Del Giovane, Elisavet Moutzouri, Robert S Du Puy, Simon P Mooijaart, Tinh-Hai Collet, Rosalinde K E Poortvliet, Patricia Kearney, Terence J Quinn, Stefan Klöppel, Douglas C Bauer, Robin P Peeters, Rudi Westendorp, Drahomir Aujesky, Jacobijn Gussekloo, Nicolas Rodondi
Effect of Levothyroxine Therapy on the Development of Depressive Symptoms in Older Adults With Subclinical Hypothyroidism: An Ancillary Study of a Randomized Clinical Trial.
JAMA Netw Open. 2021 Feb 1;4(2):e2036645. doi: 10.1001/jamanetworkopen.2020.36645. Epub 2021 Feb 1.
Abstract/Text Importance: Previous trials on the effect of levothyroxine on depressive symptom scores in patients with subclinical hypothyroidism were limited by small sample sizes (N = 57 to 94) and potential biases.
Objective: To assess the effect of levothyroxine on the development of depressive symptoms in older adults with subclinical hypothyroidism in the largest trial on this subject and to update a previous meta-analysis including the results from this study.
Design, Setting, and Participants: This predefined ancillary study analyzed data from participants in the Thyroid Hormone Replacement for Untreated Older Adults with Subclinical Hypothyroidism (TRUST) trial, a double-blind, randomized, placebo-controlled, parallel-group clinical trial conducted from April 2013 to October 31, 2016. The TRUST trial included adults aged 65 years or older diagnosed with subclinical hypothyroidism, defined as the presence of persistently elevated thyroid-stimulating hormone (TSH) levels (4.6-19.9 mIU/L) with free thyroxine (T4) within the reference range. Participants were identified from clinical and general practitioner laboratory databases and recruited from the community in Switzerland, the Netherlands, Ireland, and the UK. This ancillary study included a subgroup of 472 participants from the Netherlands and Switzerland; after exclusions, a total of 427 participants (211 randomized to levothyroxine and 216 to placebo) were analyzed. This analysis was conducted from December 1, 2019, to September 1, 2020.
Interventions: Randomization to either levothyroxine or placebo.
Main Outcomes and Measures: Depressive symptom scores after 12 months measured with the Geriatric Depression Scale (GDS-15), with higher scores indicating more depressive symptoms (minimal clinically important difference = 2).
Results: A total of 427 participants with subclinical hypothyroidism (mean [SD] age, 74.52 [6.29] years; 239 women [56%]) were included in this analysis. The mean (SD) TSH level was 6.57 (2.22) mIU/L at baseline and decreased after 12 months to 3.83 (2.29) mIU/L in the levothyroxine group; in the placebo group, it decreased from 6.55 (2.04) mIU/L to 5.91 (2.66) mIU/L. At baseline, the mean (SD) GDS-15 score was 1.26 (1.85) in the levothyroxine group and 0.96 (1.58) in the placebo group. The mean (SD) GDS-15 score at 12 months was 1.39 (2.13) in the levothyroxine and 1.07 (1.67) in the placebo group with an adjusted between-group difference of 0.15 for levothyroxine vs placebo (95% CI, -0.15 to 0.46; P = .33). In a subgroup analysis including participants with a GDS-15 of at least 2, the adjusted between-group difference was 0.61 (95% CI, -0.32 to 1.53; P = .20). Results did not differ according to age, sex, or TSH levels. A previous meta-analysis (N = 278) on the association of levothyroxine with depressive symptoms was updated to include these findings, resulting in an overall standardized mean difference of 0.09 (95% CI, -0.05 to 0.22).
Conclusions and Relevance: This ancillary study of a randomized clinical trial found that depressive symptoms did not differ after levothyroxine therapy compared with placebo after 12 months; thus, these results do not provide evidence in favor of levothyroxine therapy in older persons with subclinical hypothyroidism to reduce the risk of developing depressive symptoms.
Trial Registration: ClinicalTrials.gov Identifier: NCT01853579.

PMID 33566107
Mirah J Stuber, Elisavet Moutzouri, Martin Feller, Cinzia Del Giovane, Douglas C Bauer, Manuel R Blum, Tinh-Hai Collet, Jacobijn Gussekloo, Simon P Mooijaart, Vera J C McCarthy, Drahomir Aujesky, Rudi Westendorp, David J Stott, Nancy W Glynn, Patricia M Kearney, Nicolas Rodondi
Effect of Thyroid Hormone Therapy on Fatigability in Older Adults With Subclinical Hypothyroidism: A Nested Study Within a Randomized Placebo-Controlled Trial.
J Gerontol A Biol Sci Med Sci. 2020 Sep 16;75(9):e89-e94. doi: 10.1093/gerona/glaa123.
Abstract/Text BACKGROUND: Fatigue often triggers screening for and treatment of subclinical hypothyroidism. However, data on the impact of levothyroxine on fatigue is limited and previous studies might not have captured all aspects of fatigue.
METHOD: This study is nested within the randomized, placebo-controlled, multicenter TRUST trial, including community-dwelling participants aged ≥65 and older, with persistent subclinical hypothyroidism (TSH 4.60-19.99 mIU/L, normal free thyroxine levels) from Switzerland and Ireland. Interventions consisted of daily levothyroxine starting with 50 μg (25 μg if weight <50 kg or known coronary heart diseases) together with dose adjustments to achieve a normal TSH and mock titration in the placebo group. Main outcome was the change in physical and mental fatigability using the Pittsburgh Fatigability Scale over 1 year, assessed through multivariable linear regression with adjustment for country, sex, and levothyroxine starting dose.
RESULTS: Among 230 participants, the mean ± standard deviation (SD) TSH was 6.2 ± 1.9 mIU/L at baseline and decreased to 3.1 ± 1.3 with LT4 (n = 119) versus 5.3 ± 2.3 with placebo (n = 111, p < .001) after 1 year. After adjustment we found no between-group difference at 1 year on perceived physical (0.2; 95% CI -1.8 to 2.1; p = .88), or mental fatigability (-1.0; 95% CI -2.8 to 0.8; p = .26). In participants with higher fatigability at baseline (≥15 points for the physical score [n = 88] or ≥13 points for the mental score [n = 41]), the adjusted between-group differences at 1 year were 0.4 (95% CI -3.6 to 2.8, p = .79) and -2.2 (95% CI -8.8 to 4.5, p = .51).
CONCLUSIONS: Levothyroxine in older adults with mild subclinical hypothyroidism provides no change in physical or mental fatigability.

© The Author(s) 2020. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
PMID 32577745
Maria de Montmollin, Martin Feller, Shanthi Beglinger, Alex McConnachie, Drahomir Aujesky, Tinh-Hai Collet, Ian Ford, Jacobijn Gussekloo, Patricia M Kearney, Vera J C McCarthy, Simon Mooijaart, Rosalinde K E Poortvliet, Terence Quinn, David J Stott, Torquil Watt, Rudi Westendorp, Nicolas Rodondi, Douglas C Bauer
L-Thyroxine Therapy for Older Adults With Subclinical Hypothyroidism and Hypothyroid Symptoms: Secondary Analysis of a Randomized Trial.
Ann Intern Med. 2020 Jun 2;172(11):709-716. doi: 10.7326/M19-3193. Epub 2020 May 5.
Abstract/Text BACKGROUND: L-thyroxine does not improve hypothyroid symptoms among adults with subclinical hypothyroidism (SCH). However, those with greater symptom burden before treatment may still benefit.
OBJECTIVE: To determine whether L-thyroxine improves hypothyroid symptoms and tiredness among older adults with SCH and greater symptom burden.
DESIGN: Secondary analysis of the randomized, placebo-controlled trial TRUST (Thyroid Hormone Replacement for Untreated Older Adults with Subclinical Hypothyroidism Trial). (ClinicalTrials.gov: NCT01660126).
SETTING: Switzerland, Ireland, the Netherlands, and Scotland.
PARTICIPANTS: 638 persons aged 65 years or older with persistent SCH (thyroid-stimulating hormone level of 4.60 to 19.9 mIU/L for >3 months and normal free thyroxine level) and complete outcome data.
INTERVENTION: L-thyroxine or matching placebo with mock dose titration.
MEASUREMENTS: 1-year change in Hypothyroid Symptoms and Tiredness scores (range, 0 to 100; higher scores indicate more symptoms) on the Thyroid-Related Quality-of-Life Patient-Reported Outcome Questionnaire among participants with high symptom burden (baseline Hypothyroid Symptoms score >30 or Tiredness score >40) versus lower symptom burden.
RESULTS: 132 participants had Hypothyroid Symptoms scores greater than 30, and 133 had Tiredness scores greater than 40. Among the group with high symptom burden, the Hypothyroid Symptoms score improved similarly between those receiving L-thyroxine (mean within-group change, -12.3 [95% CI, -16.6 to -8.0]) and those receiving placebo (mean within-group change, -10.4 [CI, -15.3 to -5.4]) at 1 year; the adjusted between-group difference was -2.0 (CI, -5.5 to 1.5; P = 0.27). Improvements in Tiredness scores were also similar between those receiving L-thyroxine (mean within-group change, -8.9 [CI, -14.5 to -3.3]) and those receiving placebo (mean within-group change, -10.9 [CI, -16.0 to -5.8]); the adjusted between-group difference was 0.0 (CI, -4.1 to 4.0; P = 0.99). There was no evidence that baseline Hypothyroid Symptoms score or Tiredness score modified the effects of L-thyroxine versus placebo (P for interaction = 0.20 and 0.82, respectively).
LIMITATION: Post hoc analysis, small sample size, and examination of only patients with 1-year outcome data.
CONCLUSION: In older adults with SCH and high symptom burden at baseline, L-thyroxine did not improve hypothyroid symptoms or tiredness compared with placebo.
PRIMARY FUNDING SOURCE: European Union FP7.

PMID 32365355
Baris Gencer, Elisavet Moutzouri, Manuel R Blum, Martin Feller, Tinh-Hai Collet, Cinzia Delgiovane, Bruno R da Costa, Eric Buffle, Pierre Monney, Vincent Gabus, Hajo Müller, Gerasimos P Sykiotis, Patricia Kearney, Jacobijn Gussekloo, Rudi Westendorp, David J Stott, Douglas C Bauer, Nicolas Rodondi
The Impact of Levothyroxine on Cardiac Function in Older Adults With Mild Subclinical Hypothyroidism: A Randomized Clinical Trial.
Am J Med. 2020 Jul;133(7):848-856.e5. doi: 10.1016/j.amjmed.2020.01.018. Epub 2020 Mar 12.
Abstract/Text BACKGROUND: Subclinical hypothyroidism has been associated with heart failure, but only small trials assessed whether treatment with levothyroxine has an impact on cardiac function.
METHODS: In a randomized, double-blind, placebo-controlled, trial nested within the TRUST trial, Swiss participants ages ≥65 years with subclinical hypothyroidism (thyroid-stimulating hormone [TSH] 4.60-19.99 mIU/L; free thyroxine level within reference range) were randomized to levothyroxine (starting dose of 50 µg daily) to achieve TSH normalization or placebo. The primary outcomes were the left ventricular ejection fraction for systolic function and the ratio between mitral peak velocity of early filling to early diastolic mitral annular velocity (E/e' ratio) for diastolic function. Secondary outcomes included e' lateral/septal, left atrial volume index, and systolic pulmonary artery pressure.
RESULTS: A total of 185 participants (mean age 74.1 years, 47% women) underwent echocardiography at the end of the trial. After a median treatment duration of 18.4 months, the mean TSH decreased from 6.35 mIU/L to 3.55 mIU/L with levothyroxine (n = 96), and it remained elevated at 5.29 mIU/L with placebo (n = 89). The adjusted between-group difference was not significant for the mean left ventricular ejection fraction (62.7% vs 62.5%, difference = 0.4%, 95% confidence interval -1.8% to 2.5%, P = 0.72) and the E/e' ratio (10.6 vs 10.1, difference 0.4, 95% confidence interval -0.7 to 1.4, P = 0.47). No differences were found for the secondary diastolic function parameters or for interaction according to sex, baseline TSH, preexisting heart failure, and treatment duration (P value >0.05).
CONCLUSION: Systolic and diastolic heart function did not differ after treatment with levothyroxine compared with placebo in older adults with mild subclinical hypothyroidism.

Copyright © 2020 Elsevier Inc. All rights reserved.
PMID 32171774
Elena Gonzalez Rodriguez, Mirah Stuber, Cinzia Del Giovane, Martin Feller, Tinh-Hai Collet, Axel L Löwe, Manuel R Blum, Nicolien A van Vliet, Diana van Heemst, Patricia M Kearney, Jacobijn Gussekloo, Simon Mooijaart, Rudi G J Westendorp, David J Stott, Daniel Aeberli, Douglas C Bauer, Didier Hans, Nicolas Rodondi
Skeletal Effects of Levothyroxine for Subclinical Hypothyroidism in Older Adults: A TRUST Randomized Trial Nested Study.
J Clin Endocrinol Metab. 2020 Jan 1;105(1). doi: 10.1210/clinem/dgz058.
Abstract/Text CONTEXT: Both thyroid dysfunction and levothyroxine (LT4) therapy have been associated with bone loss, but studies on the effect of LT4 for subclinical hypothyroidism (SHypo) on bone yielded conflicting results.
OBJECTIVE: To assess the effect of LT4 treatment on bone mineral density (BMD), Trabecular Bone Score (TBS), and bone turnover markers (BTMs) in older adults with SHypo.
DESIGN AND INTERVENTION: Planned nested substudy of the double-blind placebo-controlled TRUST trial. Participants with SHypo were randomized to LT4 with dose titration versus placebo with computerized mock titration.
SETTING AND PARTICIPANTS: 196 community-dwelling adults over 65 years enrolled at the Swiss TRUST sites had baseline and 1-year follow-up bone examinations; 4 participants withdrew due to adverse events not related to treatment.
MAIN OUTCOME MEASURES: One-year percentage changes of BMD, TBS, and 2 serum BTMs (serum CTX-1 [sCTX] and procollagen type 1 N-terminal polypeptide [P1NP]). Student's t-test for unadjusted analyses and linear regression adjusted for clinical center and sex were performed.
RESULTS: Mean age was 74.3 years ± 5.7, 45.4% were women, and 19.6% were osteoporotic. The unadjusted 1-year change in lumbar spine BMD was similar between LT4 (+0.8%) and placebo-treated groups (-0.6%; between-groups difference +1.4%: 95% confidence interval [CI] -0.1 to 2.9, P = .059). Likewise, there were no between-group differences in 1-year change in TBS (-1.3%: 95% CI -3.1 to 0.6, P = .19), total hip BMD (-0.2%: 95% CI -1.1 to 0.1, P = .61), or BTMs levels (sCTX +24.1%: 95% CI -7.9 to 56.2, P = .14), or after adjustment for clinical centers and sex.
CONCLUSIONS: Over 1-year levothyroxine had no effect on bone health in older adults with SHypo.
REGISTRATION: ClinicalTrial.gov NCT01660126 and NCT02491008.

© Endocrine Society 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
PMID 31702015
Maged M Costantine, Karen Smith, Elizabeth A Thom, Brian M Casey, Alan M Peaceman, Michael W Varner, Yoram Sorokin, Uma M Reddy, Ronald J Wapner, Kim Boggess, Alan T N Tita, Dwight J Rouse, Baha Sibai, Jay D Iams, Brian M Mercer, Jorge E Tolosa, Steve N Caritis, J Peter VanDorsten, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Maternal-Fetal Medicine Units (MFMU) Network, Bethesda, MD
Effect of Thyroxine Therapy on Depressive Symptoms Among Women With Subclinical Hypothyroidism.
Obstet Gynecol. 2020 Apr;135(4):812-820. doi: 10.1097/AOG.0000000000003724.
Abstract/Text OBJECTIVE: To estimate the effect of antenatal treatment of subclinical hypothyroidism on maternal depressive symptoms.
METHODS: We conducted an ancillary study to a multicenter trial in women with singleton pregnancies diagnosed with subclinical hypothyroidism randomized to antenatal thyroxine therapy or placebo. Treatment was discontinued at the end of pregnancy. Women with overt thyroid disease, diabetes, autoimmune disease, and those diagnosed with depression were excluded. Participants were assessed for depressive symptoms using the Center for Epidemiological Studies-Depression scale (CES-D) before starting the study drug (between 11 and 20 weeks of gestation), between 32 and 38 weeks of gestation, and at 1 year postpartum. The primary outcome was maternal depressive symptoms score as assessed using the CES-D. Secondary outcome was the percentage of women who scored 16 or higher on the CES-D, as such a score is considered screen-positive for depression.
RESULTS: Two hundred forty-five (36.2% of parent trial) women with subclinical hypothyroidism were allocated to thyroxine (n=124) or placebo (n=121). Median CES-D scores and the proportion of participants with positive scores were similar at baseline between the two groups. Treatment with thyroxine was not associated with differences in CES-D scores (10 [5-15] vs 10 [5-17]; P=.46) or in odds of screening positive in the third trimester compared with placebo, even after adjusting for baseline scores (24.3% vs 30.1%, adjusted odds ratio 0.63, 95% CI 0.31-1.28, P=.20). At 1 year postpartum, CES-D scores were not different (6 [3-11] vs 6 [3-12]; P=.79), nor was the frequency of screen-positive CES-D scores in the treated compared with the placebo group (9.7% vs 15.8%; P=.19). Treatment with thyroxine during pregnancy was also not associated with differences in odds of screening positive at the postpartum visit compared with placebo even after adjusting for baseline scores. Sensitivity analysis including women who were diagnosed with depression by the postpartum visit did not change the results.
CONCLUSIONS: This study did not achieve its planned sample size, thus our conclusions may be limited, but in this cohort of pregnant women with subclinical hypothyroidism, antenatal thyroxine replacement did not improve maternal depressive symptoms.

PMID 32168208
Agnieszka Wiesner, Danuta Gajewska, Paweł Paśko
Levothyroxine Interactions with Food and Dietary Supplements-A Systematic Review.
Pharmaceuticals (Basel). 2021 Mar 2;14(3). doi: 10.3390/ph14030206. Epub 2021 Mar 2.
Abstract/Text Levothyroxine (l-thyroxine, l-T4) is a drug of choice for treating congenital and primary hypothyroidism. Although clinically significant interactions between l-T4 and food can alter the safety and efficacy of the treatment, they still seem to be generally underestimated by patients, physicians and pharmacists. This review aimed to investigate the effects of meals, beverages, and dietary supplements consumption on l-T4 pharmacokinetics and pharmacodynamics, to identify the most evident interactions, and to perform the recommendations for safe co-administering of l-T4 and food. A total of 121 studies were identified following a systematic literature search adhering to PRISMA guidelines. After full-text evaluation, 63 studies were included. The results proved that l-T4 ingestion in the morning and at bedtime are equally effective, and also that the co-administration of l-T4 with food depends on the drug formulation. We found limited evidence for l-T4 interactions with coffee, soy products, fiber, calcium or iron supplements, and enteral nutrition but interestingly they all resulted in decreased l-T4 absorption. The altered l-T4 efficacy when ingested with milk, juices, papaya, aluminium-containing preparations, and chromium supplements, as well as observed enhancement effect of vitamin C on l-T4 absorption, shall be further investigated in larger, well-designed studies. Novel formulations are likely to solve the problem of coffee, calcium and iron induced malabsorption of l-T4. Maintaining a proper time interval between l-T4 and food intake, especially for coffee and calcium, or iron supplements, provides another effective method of eliminating such interactions.

PMID 33801406
Allan C Dong, Mary D Stephenson, Alex Stewart Stagnaro-Green
The Need for Dynamic Clinical Guidelines: A Systematic Review of New Research Published After Release of the 2017 ATA Guidelines on Thyroid Disease During Pregnancy and the Postpartum.
Front Endocrinol (Lausanne). 2020;11:193. doi: 10.3389/fendo.2020.00193. Epub 2020 Apr 7.
Abstract/Text Background: The American Thyroid Association Guidelines on Thyroid Disease During Pregnancy and the Postpartum (ATA Guidelines) were published in 2017, with an update not expected for another 5 years. Since release of the 2017 ATA Guidelines, greater than 500 articles have been published in the field. Furthermore, there are presently 14 prospective, interventional trials in progress registered at Clinicaltrials.gov Static guidelines updated every 5-7 years fail to provide timely evidence-based guidance to practicing clinicians. Consequently, guideline development should move toward the creation of dynamic documents. The present article reviews the literature published since the 2017 ATA Guidelines, both to benefit clinicians in practice and to make the case for Dynamic ATA Guidelines. Methods: Using the search terms "thyroid" and "pregnancy," a systematic review of literature published in Pubmed from 3/1/2017 to 12/31/2018 was conducted. The titles and/or abstracts of all articles were reviewed. All articles were classified by subject headings used in the 2017 ATA Guidelines. English-text articles classified under "hypothyroidism" or "thyroid autoimmunity" were examined in full-text. Using the questions and recommendations put forth by the previous ATA Guidelines, relevant articles were selected for discussion in this review. Results: At the time of the search, 659 unique articles on "thyroid and pregnancy" were identified, including 66 original studies on hypothyroidism and 26 on thyroid autoimmunity. Of these, 26 studies on hypothyroidism and 18 studies on thyroid autoimmunity were selected for inclusion in this review based on specific questions in the 2017 ATA Guidelines. Based on these 44 articles, we propose two specific changes to the 2017 ATA Guidelines. Conclusion: Based on new research, we recommend the 2017 ATA Guidelines be updated to recommend against treating thyroid antibody-negative women diagnosed with subclinical hypothyroidism in the second trimester or later; to reflect new, moderate-quality evidence supporting the treatment of thyroid peroxidase antibody-negative women with elevated thyroid stimulating hormone levels in the first trimester or earlier; and to recommend against treatment of euthyroid, thyroid peroxidase antibody-positive women undergoing assisted reproductive technology. Transitioning to a Dynamic ATA Guidelines would allow for these and future recommendations to be implemented in real time.

Copyright © 2020 Dong, Stephenson and Stagnaro-Green.
PMID 32318026
Allan C Dong, Jessica Morgan, Monica Kane, Alex Stagnaro-Green, Mary D Stephenson
Subclinical hypothyroidism and thyroid autoimmunity in recurrent pregnancy loss: a systematic review and meta-analysis.
Fertil Steril. 2020 Mar;113(3):587-600.e1. doi: 10.1016/j.fertnstert.2019.11.003.
Abstract/Text OBJECTIVE: To determine whether overt/subclinical hypothyroidism and/or thyroid autoimmunity is associated with recurrent pregnancy loss (RPL) and whether treatment improves outcomes.
DESIGN: Systematic review and meta-analysis.
SETTING: University obstetrics and gynecology departments.
PATIENT(S): Women with RPL and overt/subclinical hypothyroidism, and/or thyroid autoimmunity.
INTERVENTION(S): None.
MAIN OUTCOME MEASURE(S): Associations between RPL and overt/subclinical hypothyroidism and/or thyroid autoimmunity and any effects of treatment.
RESULT(S): After our review of articles from PubMed, EMBASE, Web of Science, and CENTRAL, we found two interventional studies in which levothyroxine did not improve the subsequent live-birth rate in women with subclinical hypothyroidism with or without thyroid antibodies. A meta-analysis of five studies revealed the prevalence of subclinical hypothyroidism in RPL to be 12.9% (95% confidence interval [CI], 0%-35.2%). A meta-analysis of 17 studies revealed a statistically significant association between RPL and thyroid autoimmunity (odds ratio 1.94; 95% CI, 1.43-2.64). However, a randomized study suggested that levothyroxine does not benefit euthyroid women with thyroid autoimmunity.
CONCLUSION(S): Based on the limited observational studies available, no association exists between RPL and subclinical hypothyroidism, nor does levothyroxine improve subsequent pregnancy outcomes. An association exists between RPL and thyroid autoimmunity, but levothyroxine does not improve subsequent pregnancy outcomes. Women with RPL should be screened/treated for overt thyroid disease but not thyroid autoimmunity. Thyroid antibody screening is not supported by the published studies, and further randomized studies are needed. No recommendation regarding the treatment of subclinical hypothyroidism can be made at this time; prospective and randomized studies are urgently needed.

Copyright © 2019 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.
PMID 32192591
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
Subclinical Hypothyroidism in Pregnancy: A Systematic Review and Meta-Analysis.
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
Waka Yoshioka, Nobuyuki Amino, Akane Ide, Shino Kang, Takumi Kudo, Eijun Nishihara, Mitsuru Ito, Hirotoshi Nakamura, Akira Miyauchi
Thyroxine treatment may be useful for subclinical hypothyroidism in patients with female infertility.
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
M Ahsan Akhtar, Rina Agrawal, Julie Brown, Yasmin Sajjad, Laurentiu Craciunas
Thyroxine replacement for subfertile women with euthyroid autoimmune thyroid disease or subclinical hypothyroidism.
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
Olympia Koulouri, Mohammed A Auldin, Ravi Agarwal, Veronica Kieffer, Carole Robertson, James Falconer Smith, Miles J Levy, Trevor A Howlett
Diagnosis and treatment of hypothyroidism in TSH deficiency compared to primary thyroid disease: pituitary patients are at risk of under-replacement with levothyroxine.
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

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