Texas Children's Hospital, Baylor College of Medicine, Houston, TX.
University of California, San Francisco, San Francisco, CA.
J Pediatr Gastroenterol Nutr. 2021 Aug 1;73(2):169-177. doi: 10.1097/MPG.0000000000003153.
To advance our understanding of monogenic forms of intrahepatic cholestasis.
Analyses included participants with pathogenic biallelic mutations in adenosine triphosphate (ATP)-binding cassette subfamily B member 11 (ABCB11) (bile salt export pump; BSEP) or adenosine triphosphatase (ATPase) phospholipid transporting 8B1 (ATP8B1) (familial intrahepatic cholestasis; FIC1), or those with monoallelic or biallelic mutations in adenosine triphosphate (ATP)-binding cassette subfamily B member 4 (ABCB4) (multidrug resistance; MDR3), prospectively enrolled in the Longitudinal Study of Genetic Causes of Intrahepatic Cholestasis (LOGIC; NCT00571272) between November 2007 and December 2013. Summary statistics were calculated to describe baseline demographics, history, anthropometrics, laboratory values, and mutation data.
Ninety-eight participants with FIC1 (n = 26), BSEP (n = 53, including 8 with biallelic truncating mutations [severe] and 10 with p.E297G or p.D482G [mild]), or MDR3 (n = 19, including four monoallelic) deficiency were analyzed. Thirty-five had a surgical interruption of the enterohepatic circulation (sEHC), including 10 who underwent liver transplant (LT) after sEHC. Onset of symptoms occurred by age 2 years in most with FIC1 and BSEP deficiency, but was later and more variable for MDR3. Pruritus was nearly universal in FIC1 and BSEP deficiency. In participants with native liver, failure to thrive was common in FIC1 deficiency, high ALT was common in BSEP deficiency, and thrombocytopenia was common in MDR3 deficiency. sEHC was successful after more than 1 year in 7 of 19 participants with FIC1 and BSEP deficiency. History of LT was most common in BSEP deficiency. Of 102 mutations identified, 43 were not previously reported.
In this cohort, BSEP deficiency appears to be correlated with a more severe disease course. Genotype-phenotype correlations in these diseases are not straightforward and will require the study of larger cohorts.
深入了解肝内胆汁淤积症的单基因形式。
分析包括腺苷三磷酸（ATP）结合盒亚家族 B 成员 11（ABCB11）（胆汁盐输出泵；BSEP）或 ATP 酶磷脂转运蛋白 8B1（ATP8B1）（家族性肝内胆汁淤积症；FIC1）的双等位基因突变或 ATP 结合盒亚家族 B 成员 4（ABCB4）（多药耐药；MDR3）的单等位基因突变或双等位基因突变的参与者，前瞻性纳入 2007 年 11 月至 2013 年 12 月之间的遗传原因引起的肝内胆汁淤积纵向研究（LOGIC；NCT00571272）。计算汇总统计数据以描述基线人口统计学、病史、人体测量学、实验室值和突变数据。
分析了 98 名 FIC1（n = 26）、BSEP（n = 53，包括 8 名双等位基因突变截断[严重]和 10 名 p.E297G 或 p.D482G[轻度]）或 MDR3（n = 19，包括 4 名单等位基因）缺乏的患者。35 例接受了肠肝循环手术中断（sEHC），其中 10 例在 sEHC 后进行了肝移植（LT）。大多数 FIC1 和 BSEP 缺乏症患者在 2 岁时出现症状发作，但 MDR3 缺乏症的发作较晚且更具变异性。瘙痒在 FIC1 和 BSEP 缺乏症中几乎普遍存在。在保留肝脏的患者中，FIC1 缺乏症中生长不良很常见，BSEP 缺乏症中丙氨酸转氨酶升高很常见，MDR3 缺乏症中血小板减少很常见。在 19 名 FIC1 和 BSEP 缺乏症患者中，sEHC 在 1 年以上后成功进行了 7 次。BSEP 缺乏症的 LT 病史最常见。在鉴定的 102 个突变中，有 43 个以前没有报道过。
在本队列中，BSEP 缺乏症似乎与更严重的疾病过程相关。这些疾病的基因型-表型相关性并不简单，需要研究更大的队列。
