A Case of Infantile Alagille Syndrome With Severe Dyslipidemia: New Insight into Lipid Metabolism and Therapeutics

Abstract

Alagille syndrome (AGS) is an autosomal dominant genetic disorder characterized by congenital heart disease, hepatic cholestasis, dyslipidemia, and characteristic facies since infancy. Cholestatic hypercholesterolemia in patients diagnosed with AGS is occasionally refractory and resistant to conventional treatments. We report the case of a 4-month-old boy diagnosed with AGS and refractory dyslipidemia due to cholestatic liver disease. He had repeated episodes of cyanosis due to pulmonary artery atresia since birth and underwent a Blalock–Taussig shunt procedure at 3 months of age. At 4 months, cholestatic hyperbilirubinemia deteriorated to a serum total bilirubin level of 19.9 mg/dL. At 12 months, a laboratory test revealed severe dyslipidemia (serum total cholesterol, 1796 mg/dL; serum triglycerides (TG), 635 mg/dl), and the presence of xanthomas. A pathogenic variant of the JAG1 gene (c.1326G>A, p.Trp442X) was detected through genetic testing. Oral ursodeoxycholate normalized hyperbilirubinemia with a subtle improvement in dyslipidemia. Combination therapy with pravastatin and fenofibrate did not successfully improve dyslipidemia. At the age of 20 months, altering pravastatin to atorvastatin was effective in normalizing serum cholesterol and triglycerides with no adverse events. Combination therapy with atorvastatin and fenofibrate was successful in improving refractory dyslipidemia in a child with AGS. Atorvastatin is a well-known strong statin that can lower serum cholesterol, and fenofibrate can lower serum TG levels. We propose that atorvastatin could be taken into consideration for the treatment of persistent hyperlipidemia in patients diagnosed with AGS, because atorvastatin upregulates bile acid synthesis and lipoprotein scavenging, and inhibits intrinsic cholesterol production.

Alagille syndrome: an orphan disease in Colombia and summary of recent advances in treatment and survival – a case report

“…One of the greatest interests in basic science, translational, clinical, and outcome research in rare diseases is to gain a deeper understanding of the etiopathogenesis and pathophysiology of these diseases in order to develop diagnostic tools and interventions that are effective, efficient, and safe 3 – 5 . Although it has been described that the genotype–phenotype correlation is determinant in Alagille syndrome, published case reports and case series show similar characteristics, which vary in intensity and timing of presentation according to timely multidisciplinary management 4 – 6 , 8 , 10 . Thus, in some cases where there are organized programs for diagnosis and follow-up of neonatal diseases, early diagnosis can be established and treatment can be initiated to reduce the impact of multisystemic complications and improve survival 10 , 11 .…”

“…Nakajima et al . 4 also reported a case in Japan of an infant with severe dyslipidemia who had difficulties in the management of the condition until ~20 months of age, when his lipid profile was normalized 4 .…”

“…During the first decade of life, children present with portal hypertension, protein synthesis dysfunction, severe pruritus, dyslipidemia, and pathologic bone fractures, which may subsequently culminate in hepatocellular carcinoma 2 , 3 . For this reason, it has been considered a powerful line of research in the last decades, advancing diagnostic and therapeutic techniques based on genetics and clinical biochemistry 4 , 5 . At present, there are few existing treatments, and liver transplantation is the only available solution 5 .…”