BACKGROUND Cystic fibrosis (CF) patients have reduced intestinal absorption of sterols and, despite enhanced endogenous synthesis, low plasma cholesterol. Lumacaftor/ivacaftor CFTR protein modulator therapy is used to improve the clinical outcome of CF patients homozygous for F508del mutation (homo-deltaF508). Aim of the study is to evaluate the cholesterol metabolism and hepatobiliary injury/function in adult homo-deltaF508 patients, before and after lumacaftor/ivacaftor treatment. Baseline parameters in homo-deltaF508 patients were compared to those in CF patients compound heterozygous for F508del mutation and another severe mutation (hetero-deltaF508). METHODS Cholesterol metabolism was evaluated measuring plasma phytosterols and cholestanol, as intestinal absorption markers, and lathosterol, as liver biosynthesis marker. We quantified serum vitamin E, as nutritional marker. We evaluated liver injury by aspartate aminotransferase (AST) and alanine transaminase (ALT), biliary injury by γ-glutamyltransferase (γGT) and AP, and the liver function by bilirubin and albumin. RESULTS Before the treatment, homo-deltaF508 patients (n = 20) had significantly lower cholesterol and vitamin E compared to hetero-deltaF508 (n = 20). Lumacaftor/ivacaftor treatment caused: 1) further reduction of cholesterol; 2) lathosterol reduction, suggesting a normalization of endogenous synthesis; 3) cholestanol and vitamin E increment, indicating an improvement of lipid digestion/absorption. Vitamin E difference (after-before treatment) was positively associated to treatment months. Alkaline phosphatase was also reduced. CONCLUSIONS These data suggest an effect of lumacaftor/ivacaftor on cholesterol metabolism and enterohepatic flux in CF patients. However, lumacaftor/ivacaftor does not promote the increase of cholesterol serum concentration that on the contrary declines. Further studies are needed to research the real mechanism causing this reduction.

中文翻译：

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Lumacaftor/ivacaftor 改善肝脏胆固醇代谢，但不影响囊性纤维化患者的低胆固醇血症

背景囊性纤维化（CF）患者的肠内甾醇吸收减少，尽管内源性合成增加，但血浆胆固醇降低。Lumacaftor/ivacaftor CFTR 蛋白调节剂疗法用于改善 F508del 突变 (homo-deltaF508) 纯合子 CF 患者的临床结果。该研究的目的是评估成人 homo-deltaF508 患者在 lumacaftor/ivacaftor 治疗前后的胆固醇代谢和肝胆损伤/功能。将homo-deltaF508 患者的基线参数与F508del 突变和另一种严重突变（hetero-deltaF508）复合杂合的CF 患者的基线参数进行比较。方法 通过测量血浆植物甾醇和胆固醇（作为肠道吸收标志物）和 lathosterol（作为肝脏生物合成标志物）来评估胆固醇代谢。我们量化了血清维生素 E，作为营养标记。我们评估了天冬氨酸转氨酶 (AST) 和丙氨酸转氨酶 (ALT) 引起的肝损伤、γ-谷氨酰转移酶 (γGT) 和 AP 引起的胆道损伤以及胆红素和白蛋白引起的肝功能。结果 在治疗前，与异源 deltaF508（n = 20）相比，homo-deltaF508 患者（n = 20）的胆固醇和维生素 E 显着降低。Lumacaftor/ivacaftor 治疗导致：1) 胆固醇进一步降低；2) 甾醇减少，表明内源性合成正常化；3) 胆固醇和维生素 E 增加，表明脂质消化/吸收的改善。维生素 E 差异（治疗前后）与治疗月数呈正相关。碱性磷酸酶也降低。结论 这些数据表明 lumacaftor/ivacaftor 对 CF 患者的胆固醇代谢和肝肠流量有影响。然而，lumacaftor/ivacaftor 不促进胆固醇血清浓度的增加，相反会下降。需要进一步的研究来研究导致这种减少的真正机制。