lipids

Alagille syndrome can result in a range of pathologies, most significantly liver disease. Dyslipidemia is another condition that can be caused by Alagille syndrome, but it does not get much attention.

The usual cause of dyslipidemia in Alagille syndrome is the paucity of the intrahepatic bile duct commonly seen in patients. If cholestatic dyslipidemia is not managed urgently, liver transplantation is the only recourse for prolonged survival. 

Here, we will describe 2 case studies detailing patients with Alagille syndrome who were diagnosed with severe dyslipidemia and explore what we can learn from them.


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Cholestatic Liver Disease After Cardiac Surgery 

In the Journal of the Endocrine Society, Nakajima and colleagues wrote about a child with Alagille syndrome who presented with severe dyslipidemia.

The 2-month-old boy was referred for cardiac surgery due to a diagnosis of pulmonary artery atresia. After birth, he developed severe repetitive episodes of cyanosis, prompting angiocardiographic imaging to be carried out, revealing pulmonary artery atresia. The patient underwent a successful Blalock-Taussig procedure at 3 months of age.

At 4 months of age, the boy was diagnosed with cholestatic liver disease with jaundice. His biochemistry results included total cholesterol of 408 mg/dL and triglycerides of 564 mg/dL.  

An abdominal MRI recreated hepatosplenomegaly. The patient was prescribed oral ursodeoxycholic acid for intrahepatic cholestasis and hyperlipidemia. He was also prescribed fat-soluble vitamins. 

Read more about Alagille syndrome etiology

At 9 months of age, the patient’s levels of total cholesterol and triglycerides remain abnormally high and he was duly started on oral pravastatin at a dose of 1 mg/day. At 11 months, oral fenofibrate was added because the patient’s dyslipidemia remained unresolved. 

At 12 months, the patient’s biochemistry results revealed his total cholesterol had risen to 1780 mg/dL and his triglyceride level was 635 mg/dL. This was despite the patient being on 4 mg/day of pravastatin and 16 mg/day of fenofibrate.

The boy’s physicians switched his statins to atorvastatin, which finally improved his dyslipidemia. At 24 months of age, the child’s serum total cholesterol and triglyceride levels were reported to be around the normal range.

Hypercholesterolemia in an Infant 

Hannoush and colleagues wrote a case study of a patient with Alagille syndrome who presented with severe hypercholesterolemia. It was published in the Journal of Clinical Endocrinology & Metabolism. 

A full-term infant was diagnosed with pulmonary valve stenosis at 1 month of age. In his first year of life, he presented with failure to thrive, intermittent pruritus, jaundice, and multiple skin nodules that appeared to be xanthomas. 

A physical examination revealed a thin infant with a short stature for his age, icteric conjunctiva, a broad forehead, and frontal bossing. In addition, his physicians detected a 2/6 systolic murmur at the second left supraclavicular space. The patient also had hepatomegaly, a barrel chest, and multiple yellowish and firm papules on his flexor and extensor areas. 

The boy was diagnosed with butterfly vertebrae of T4, T6, and T8, a horseshoe kidney, and embryotoxon in the left eye. Laboratory workup revealed a total cholesterol level of 2370 mg/dL. Biopsy of his skin lesions confirmed they were xanthomas. 

The child was referred to a lipidologist who considered a diagnosis of homozygous familial hypercholesterolemia. However, there was no evidence of hypercholesterolemia in the child’s parents, which ruled out the diagnosis, together with his relatively low apolipoprotein B value. Alagille syndrome was then suspected, which was confirmed by genetic testing. 

Read more about Alagille syndrome treatment 

The variant identified in the JAG1 gene is predicted to result in premature truncation of the protein product encoded by that gene. The child was started on ursodiol, which was well-tolerated.

The patient experienced improvements in his pruritus. He continues to be followed up by a multidisciplinary team consisting of a pediatrician, gastroenterologist, cardiologist, geneticist, endocrinologist, and ophthalmologist. 

Beyond Liver Pathology

An inadequate appreciation of the severity of a patient’s signs and symptoms may lead to the inevitable need for liver transplantation, which is itself a high-risk surgical procedure. The success of liver transplantation is heavily dependent on the presence of other comorbidities. 

The fact that dyslipidemia occurred in both cases illustrates how important it is that cardiovascular risk assessment be conducted in patients with Alagille syndrome.

As published in Hepatology, Janowski and colleagues found that 82% of children with Alagille syndrome who were studied presented with abnormal lipid profiles. Although the risk factors for cardiovascular disease are multifaceted, the research team wrote, “Hypercholesterolemia is a well-known cardiovascular risk factor associated with atherosclerosis and arterial stiffening in liver disease.”

In the Journal of Nutrition and Metabolism, Mosca and colleagues likewise advocated for a risk assessment for future cardiovascular events in patients with dyslipidemia. Physicians should ask pertinent questions about the patient’s dietary choices and lifestyle. If a patient with dyslipidemia does not actively pursue a healthy lifestyle, physicians should gently nudge the patient towards making positive changes in those areas, regardless of the underlying cause of the dyslipidemia. 

However, nutritional and lifestyle modifications may not be enough. Hannoush et al wrote, “Patients with Alagille syndrome should be managed by a multidisciplinary medical team to provide monitoring and support of the multiple systems affected. Close follow-up of growth, development, nutritional status, liver function tests, and cardiac function is needed.” 

References

Nakajima H, Tsuma Y, Fukuhara S, Kodo K. A case of infantile Alagille syndrome with severe dyslipidemia: new insight into lipid metabolism and therapeuticsJ Endocr Soc. 2022;6(3):bvac005. doi:10.1210/jendso/bvac005

Hannoush ZC, Puerta H, Bauer MS, Goldberg RB. New JAG1 mutation causing Alagille syndrome presenting with severe hypercholesterolemia: case report with emphasis on genetics and lipid abnormalitiesJ Clin Endocrinol Metab. 2017;102(2):350-353. doi:10.1210/jc.2016-3171

Mosca S, Araújo G, Costa V, et al. Dyslipidemia diagnosis and treatment: risk stratification in children and adolescentsJ Nutr Metab. 2022;2022:4782344. doi:10.1155/2022/4782344

Janowski K, Obrycki Ł, Litwin M, et al. Cardiovascular risk assessment in children with chronic cholestatic liver diseasesJ Pediatr Gastroenterol Nutr. 2020;71(5):647-654. doi:10.1097/MPG.0000000000002874