Takaki Yugo, Umetsu Shuichiro, Sugino Yoshihiko, Yamashita Takahiro, Doi Takehiko, Imagawa Kazuo, Ito Shogo, Mihara Yutaro, Hayashi Hisamitsu, Inui Ayano
Department of Pediatric Gastroenterology and Hepatology, Japanese Red Cross Kumamoto Hospital, Kumamoto, Japan.
Department of Pediatric Hepatology and Gastroenterology, Saiseikai Yokohama-Shi Tobu Hospital, Yokohama, Japan.
Hepatol Res. 2025 Jul 18. doi: 10.1111/hepr.70003.
To investigate the genetic and molecular mechanisms underlying intrahepatic cholestasis associated with lipolysis-stimulated lipoprotein receptor (LSR) deficiency and to evaluate its potential role in conditions similar to progressive familial intrahepatic cholestasis (PFIC).
We studied a 4-year-old girl with no significant perinatal history who presented with symptoms of cholestasis-pruritus, poor weight gain, and darkened skin-by 6 months of age. Laboratory tests revealed mild cholestasis with elevated total bile acids and normal gamma-glutamyl transferase (GGT). A liver biopsy revealed chronic cholestasis and mild fibrosis. Whole-exome sequencing identified two compound heterozygous variants in the LSR gene, and immunostaining confirmed reduced LSR expression in the liver. The patient showed persistent cholestasis, normal GGT, and a clinical presentation suggestive of PFIC. Genetic testing revealed LSR gene variants, including a likely pathogenic duplication, confirming LSR deficiency. Despite treatment with ursodeoxycholic acid (UDCA), her pruritus persisted and growth remained stunted. Developmental delays were primarily noted in language acquisition.
This case suggests that LSR deficiency may contribute to a PFIC-like condition, thus broadening our understanding of the genetic causes of intrahepatic cholestasis. Children presenting with PFIC-like symptoms but without mutations in known PFIC genes should be evaluated for LSR deficiency. Further research is needed to elucidate LSR's role in liver function and its potential classification as a new PFIC subtype, "PFIC-14."
研究与脂肪分解刺激脂蛋白受体（LSR）缺乏相关的肝内胆汁淤积的遗传和分子机制，并评估其在类似于进行性家族性肝内胆汁淤积症（PFIC）的病症中的潜在作用。
我们研究了一名4岁女童，其围产期病史无明显异常，6个月大时出现胆汁淤积症状——瘙痒、体重增加缓慢和皮肤变黑。实验室检查显示轻度胆汁淤积，总胆汁酸升高，γ-谷氨酰转移酶（GGT）正常。肝活检显示慢性胆汁淤积和轻度纤维化。全外显子组测序在LSR基因中鉴定出两个复合杂合变异，免疫染色证实肝脏中LSR表达降低。该患者表现为持续性胆汁淤积、GGT正常，临床表现提示PFIC。基因检测发现LSR基因变异，包括一个可能致病的重复，证实存在LSR缺乏。尽管使用熊去氧胆酸（UDCA）治疗，她的瘙痒仍持续存在，生长发育仍然迟缓。发育迟缓主要表现在语言习得方面。
该病例表明LSR缺乏可能导致类似PFIC的病症，从而拓宽了我们对肝内胆汁淤积遗传原因的理解。对于出现类似PFIC症状但已知PFIC基因无突变的儿童，应评估是否存在LSR缺乏。需要进一步研究以阐明LSR在肝功能中的作用及其作为新的PFIC亚型“PFIC-14”的潜在分类。
