Lipolysis-Stimulated Lipoprotein Receptor Gene Variants as a Cause of Progressive Familial Intrahepatic Cholestasis:...

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."