| 概要 |
Background/Aims : Ursodeoxycholic acid (UDCA) is currently the only available pharmacological treatment for asymptomatic primary biliary cirrhosis (aPBC). Fibrates may be useful for treating aPBC pati...ents who exhibit incomplete responses to UDCA. The mechanism of action of such fibrates involves the regulation of the expression of various kinds of lipids and proteins through the activation of peroxisome proliferator-activated receptor-α (PPAR-α), which increases the phospholipid output into the bile and reduces the cytotoxicity of hydrophobic bile acids. Among these fibrates, the binding activity of fenofibrate to PPAR-α is stronger than that of bezafibrate. Because the majority of PBC patients exhibit a slow progression of their disease, and since the administration of UDCA plus fibrate may further delay the liver deterioration, cardiovascular risk factors, such as dyslipidemia may thus have a bigger impact on the long-term survival of PBC patients. The aim of this study was to evaluate the effects of fenofibrate in patients with aPBC who are refractory to UDCA and to simultaneously compare the effectiveness of fenofibrate with that of bezafibrate. Methods : This study included 14 patients with aPBC treated with fenofibrate (80 mg/day) plus UDCA (fenofibrate group) for 48 weeks and seven patients with aPBC treated with bezafibrate (400 mg/day) plus UDCA (bezafibrate group) for 48 weeks. The data for the aPBC patients in both groups were analyzed to compare the effects of fenofibrate and bezafibrate. Results : In the patients in the fenofibrate group, the serum alkaline phosphatase (ALP), γ-glutamyl transpeptitase (γGTP) and serum IgM levels decreased from 522.5 ±181.4 to 236.8 ±47.8 IU/l, 197.1 ± 98.4 to 47.2 ± 37.5 IU/l and 337.6 ± 160.6 to 174.5 ± 101.1 mg/dl (p < 0.0001), respectively. In the patients in the bezafibrate group, the serum levels of ALP, γGTP and IgM decreased from 595.9 ± 247.8 to 238.0 ± 80.4 IU/l, 188.3 ± 85.6 to 46.3 ±31.9 IU/l and 304.7 ±165.2 to 155.1 ±45.4 mg/dl (p < 0.0001), respectively. The serum levels of triglycerides (TG) and low-density lipoprotein cholesterol (LDL) significantly decreased in both groups and the LDL levels significantly decreased in the patients in the fenofibrate group compared to those in the bezafibrate group (p = 0.0357). In addition, the serum uric acid levels of the patients in the fenofibrate group decreased significantly (from 4.7 ±1.4 to 3.6 ± 0.9 mg/dl, p < 0.0001), while those in the patients in the bezafibrate group did not change from 4.1 ± 0.6 to 4.1 ± 0.4 mg/dl. Conclusion : Combination therapies with fenofibrate plus UDCA and bezafibrate plus UDCA induce significant biochemical improvements in patients with aPBC. However, the ability of fenofibrate to reduce the LDL and uric acid levels in aPBC patients is superior to that of bezafibrate. As a result, the use of fenofibrate might translate into a decreased risk of developing cardiovascular events and renal failure in patients with aPBC. Limitation : Short follow-up, small number of samples, retrospective and single center study and no evidence of the effect of fibrates on the liver histology.
【背景と目的】ウルソ酸(UDCA)に不応性の無症候性原発性胆汁性肝硬変(aPBC)に対し,ウルソ酸とフィブラート剤の併用療法による有効性はよく知られている. フィブラート剤は核内受容体のひとつであるα型ペルオキシゾーム増殖剤活性化受容体(PPARα)のリガンドであり, PPARαを活性化させることで胆汁酸代謝や炎症の調節を行なっている. フィブラート剤の中でfenofibrate(リピディル®)はbezafibrate(ベザトール®)よりもPPARαに対する特異性が高く, かつ活性が強い. そのためfenofibrateはPPARα選択的アゴニスト(PPARα-selective agonist)と, PPARα. PPARδ, PPARγに対して選択性のないbezafibrateは汎PPARアゴニスト(pan-PPAR agonist)と, それぞれ呼称される.aPBC に対するfenofibrateとbezafibrateとの効果を生化学的諸検査にて比較した. 【方法】14例のaPBC患者に対し,fenofibrate（80mg/日）+ UDCA（600 mg/日）（fenofibrate群）を, 7例のaPBC患者に対し, bezafibrate（400 mg/日）+ UDCA（600 mg/日）（bezafibrate群）をそれぞれ投与し, 48週後に種々の因子を比較した. 【結果】治療開始時の両群間の背景因子に有意差はみられなかった. 治療前と治療48週後の比較において, fenofibrate群ではALP, γGTPならびにIgMは522.5 ± 181.4から236.8 ± 74.8 IU/l,197.1±98.4から47.2±37.5 IU/l,337.6±160.6から174.5 ± 101.1 mg/dlにそれぞれ低下した（p < 0.0001). bezafibrate群においても同様にALP, γGTP, IgMは595.9±247.8から238.0 ± 80.4 IU/l,188.3 ± 85.6から46.3 ±31.9 IU/l, 304.7±165.2から155.1±45.4mg/dlにそれぞれ低下した（p < 0.0001）. TG とLDL は両群において有意に低下したが, LDL の低下度を両群で比較するとfenofibrate群の低下度が有意であった（p=0.0357）. 尿酸値はfenofibrate群では有意に低下したが（4.7±1.4から3.6±0.9mg/dl, p < 0.0001）, bezafibrate群では変化はみられなかった（4.1±0.6から4.1±0.4 mg/dl）. 【考察】UDCAとfenofibrateあるいはbezafibrateの併用療法はいずれもaPBC症例に対し, 生化学的諸検査の値を有意に改善させた. 薬剤に反応性のよいaPBC患者は長期生存が得られることが知られており, UDCAとフィブラート剤の併用療法はaPBC患者の予後を改善すると期待される. aPBC患者の死因として肝不全死に次ぎ, 動脈硬化性疾患の頻度が高いとする報告から, LDL, 尿酸値を有意に低下させるfenofibrateはbezafibrateと比較し, 動脈硬化性疾患を予防し, 長期生存に有益である可能性がある.続きを見る
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