Steroid profiling for assessing adrenal hepatic syndrome in canine hepatocellular carcinoma

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Summary in Japanese（和⽂要旨）

Steroid Profiling for assessing Adrenal Hepatic Syndrome in Canine

Hepatocellular Carcinoma

（ステロイドプロファイリングによる肝細胞癌発症メカニズムとしての副腎−

肝臓連関の探索）

この論⽂では、副腎⽪質ホルモンが慢性的に過剰に分泌されることにより、

肝臓に病的な変化が⽣じる状況を副腎肝臓症候群（AHS）と呼ぶ。⽝の副腎⽪

質機能亢進症（HAC）は、副腎⽪質ホルモンの慢性的な過剰産⽣を伴う副腎内

分泌疾患である。HAC の⽝では、肝酵素活性の上昇、ステロイド肝症、肝細胞

のグリコーゲン蓄積などの肝臓の臨床病理学的異常が頻繁に認められる。従っ

て、HAC の⽝では AHS と同様の現象が起こっていると考えられる。肝細胞癌

（HCC）は、⽝の肝腫瘍の 50-70％を占める⼀般的な原発性肝腫瘍である。こ

れまで、HAC は⽝の巨⼤ HCC の最も同時発⽣率の⾼い疾患として知られてい

る。しかし、⽝における HAC と肝発癌の正確なメカニズムはよく分かってい

ない。さらに、空胞性肝症（VH）とステロイドの不均衡を有するスコティッ

シュ・テリアは、HCC を発症するリスクが⾼いことも明らかにされた。したが

って、コルチゾール前駆体や他のホルモンの変化は、肝臓の臨床病理学的変化

に寄与していることが⽰唆される。

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メタボリックシンドロームによる⾮アルコール性脂肪性肝疾患（NAFLD）

は、現在、ヒトの HCC の主要な原因となっている。ステロイドによって引き

起こされる⽝の HAC やスコティッシュテリアの VH の肝病態は、ヒトの

NAFLD による HCC に似ていると考えられる。従って、AHS におけるステロイ

ドプロファイルを評価することは、イヌおよびヒトの肝発癌のメカニズムを理

解する上で有⽤であると思われる。そこで、本研究では、Liquid

chromatography triple quadrupole mass spectrometry (LC/MS/MS) を⽤いて複数の⾎

清ステロイドホルモンを測定することで、AHS が HCC に関与することを明ら

かにすることを⽬的とした。

第 1 章では、⾃動カラムスイッチング LC/MS/MS を⽤いた簡易分析法を開発

し、HAC がステロイドプロファイルに与える影響について検討した。ELISA 法

で測定したコルチゾール濃度は LC/MS/MS よりも⾼かった。2 つの⽅法の⽐較

では、ELISA と LC/MS/MS の間に⽭盾があることがわかった。その結果、HAC

はステロイドプロファイルに影響を与え、ベースライン⾎清ではコルチゾン、

11-デオキシコルチゾール、17α-OH-プロゲステロンが⾼濃度となり、ACTH

刺激後⾎清ではコルチゾール、コルチゾン、11-デオキシコルチゾール、コル

チコステロン、11-デオキシコルチコステロン、17α-OH プロゲステロンが⾼

58

値となることが明らかになった。 コルチゾールに加えて、さらに 5 種類のステ

ロイドが HAC の臨床病態に寄与していることが⽰唆された。

第 2 章では、HCC、HAC、および両疾患を有する⽝における⾎清ステロイド

プロファイルの違いについて検討した。⾎清中の 19 種類のステロイドは、従

来の⾮誘導体化法およびケト誘導体化法で測定可能であった。いずれのステロ

イドも HCC、HAC、両疾患の⽝で有意な差は認められなかった。この結果

は、ステロイド⽣成は HCC の発⽣に関与していない可能性を⽰唆するもので

ある。

本研究では、ステロイドプロファイルの違いにより HCC における AHS を証

明することはできなかったが、HAC と HCC の同時性は明らかである。このこ

とから、HAC と HCC の相互作⽤は他の交絡因⼦の影響を受けている可能性が

あることが⽰唆された。本研究では、⾎清中のステロイドの情報のみであった

ため、今後、肝組織や 24 時間尿中のステロイドならびに代謝物を分析するこ

とで、ステロイドの不均衡と肝発癌の関係を明らかにすることが期待される。

さらに、ステロイドの不均衡と肝発癌のどちらが先⾏するかを明らかにするた

めには、これらの⽝におけるステロイドの追跡測定が有⽤であろう。

59

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