Tytgat Institute for Liver and Intestinal Research, Department of gastroenterology and Hepatology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
Hepatology. 2012 Oct;56(4):1391-400. doi: 10.1002/hep.25748.
Pruritus is a seriously disabling symptom accompanying many cholestatic liver disorders. Recent experimental evidence implicated the lysophospholipase, autotaxin (ATX), and its product, lysophosphatidic acid (LPA), as potential mediators of cholestatic pruritus. In this study, we highlight that increased serum ATX levels are specific for pruritus of cholestasis, but not pruritus of uremia, Hodgkin's disease, or atopic dermatitis. Treatment of patients with cholestasis with the bile salt sequestrant, colesevelam, but not placebo, effectively reduced total serum bile salts and fibroblast growth factor 19 levels, but only marginally altered pruritus intensity and ATX activity. Rifampicin (RMP) significantly reduced itch intensity and ATX activity in patients with pruritus not responding to bile salt sequestrants. In vitro, RMP inhibited ATX expression in human HepG2 hepatoma cells and hepatoma cells overexpressing the pregnane X receptor (PXR), but not in hepatoma cells in which PXR was knocked down. Treatment of severe, refractory pruritus by the molecular adsorbents recirculation system or nasobiliary drainage improved itch intensity, which, again, correlated with the reduction of ATX levels. Upon reoccurrence of pruritus, ATX activity returned to pretreatment values.
Serum ATX activity is specifically increased in patients with cholestatic, but not other forms of, systemic pruritus and closely correlates with the effectiveness of therapeutic interventions. The beneficial antipruritic action of RMP may be explained, at least partly, by the PXR-dependent transcriptional inhibition of ATX expression. Thus, ATX likely represents a novel therapeutic target for pruritus of cholestasis.
瘙痒是许多胆汁淤积性肝病伴随的一种严重致残症状。最近的实验证据表明，溶血磷脂酶、自分泌酶（ATX）及其产物溶血磷脂酸（LPA）可能是胆汁淤积性瘙痒的潜在介质。在这项研究中，我们强调血清 ATX 水平升高是胆汁淤积性瘙痒的特异性标志物，但不是尿毒症、霍奇金病或特应性皮炎瘙痒的标志物。用胆汁盐螯合剂考来烯胺治疗胆汁淤积症患者，而非安慰剂，可有效降低总血清胆汁盐和成纤维细胞生长因子 19 水平，但仅轻微改变瘙痒强度和 ATX 活性。利福平（RMP）可显著降低对胆汁盐螯合剂无反应的瘙痒症患者的瘙痒强度和 ATX 活性。在体外，RMP 抑制人 HepG2 肝癌细胞和过表达妊娠相关 X 受体（PXR）的肝癌细胞中的 ATX 表达，但不抑制 PXR 敲低的肝癌细胞中的 ATX 表达。通过分子吸附再循环系统或鼻胆管引流治疗严重难治性瘙痒症可改善瘙痒强度，这再次与 ATX 水平的降低相关。瘙痒再次发作时，ATX 活性恢复至治疗前水平。
血清 ATX 活性在胆汁淤积性而非其他形式的全身性瘙痒症患者中特异性升高，与治疗干预的有效性密切相关。RMP 的有益止痒作用可能至少部分解释为其通过 PXR 依赖性转录抑制 ATX 表达。因此，ATX 可能代表胆汁淤积性瘙痒症的一种新的治疗靶点。
