Aamann Luise, Ørntoft Nikolaj, Vogel Ida, Grønbaek Henning, Becher Naja, Vilstrup Hendrik, Ott Peter, Lildballe Dorte Launholt
a Department of Hepatology and Gastroenterology , Aarhus University Hospital , Aarhus , Denmark.
b Department of Clinical Genetics , Aarhus University Hospital , Aarhus , Denmark.
Scand J Gastroenterol. 2018 Mar;53(3):305-311. doi: 10.1080/00365521.2017.1422800. Epub 2018 Jan 5.
A few adult and adolescent patients with even severe cholestatic liver disease remain unexplained after standard diagnostic work-up. We studied the value of genetic examination in such patients and developed a panel of eight genes with known cholestatic associations.
Thirty-three patients with unexplained cholestasis despite a thorough clinical work-up were examined for sequence variations in the coding regions of the ABCB4, ABCB11, ABCC2, ABCG5, ATP8B1, JAG1, NOTCH2, and UGT1A1 genes and the promoter region of UGT1A1 by massive parallel sequencing of DNA extracted from whole blood. Hepatologists and clinical geneticists evaluated the causal potential of genetic variants.
In 9/33 patients (27%), we identified genetic variants as a certain causal factor and in further 9/33 (27%) variants as a possible contributing factor. In most cases, a detailed family history was necessary to establish the importance of genetic variants. Genetic causes were identified in 6/13 women (46%) with intrahepatic cholestasis during pregnancy and persisting abnormal biochemistry after delivery.
Our study suggests that a small number of well-known genetic variants are involved in at least 27-54% of patients with unexplained cholestasis. An expanded panel will likely explain more cases. This motivates genetic testing of these patients. Genetic testing, however, cannot stand alone but should be combined with a clinical genetic work-up in collaboration between hepatologists and clinical geneticists.
一些成年和青少年患者即使患有严重的胆汁淤积性肝病，在经过标准诊断检查后仍病因不明。我们研究了基因检测在这类患者中的价值，并开发了一个包含八个已知与胆汁淤积相关基因的检测组合。
对33例尽管经过全面临床检查但仍病因不明的胆汁淤积患者，通过对全血提取的DNA进行大规模平行测序，检测ABCB4、ABCB11、ABCC2、ABCG5、ATP8B1、JAG1、NOTCH2和UGT1A1基因编码区以及UGT1A1启动子区域的序列变异。肝病学家和临床遗传学家评估了基因变异的致病可能性。
在9/33例患者（27%）中，我们确定基因变异为确定的致病因素，另有9/33例（27%）的变异为可能的致病因素。在大多数情况下，需要详细的家族史来确定基因变异的重要性。在6/13例孕期发生肝内胆汁淤积且产后生化指标持续异常的女性患者（46%）中发现了遗传病因。
我们的研究表明，少数已知的基因变异至少与27%-54%病因不明的胆汁淤积患者有关。扩大检测组合可能会解释更多病例。这促使对这些患者进行基因检测。然而，基因检测不能单独进行，而应在肝病学家和临床遗传学家的合作下，与临床基因检查相结合。
