This rare genetic disorder is associated with multiple symptoms of multiple organ systems, particularly affecting the liver and heart. The cause is a mutation on chromosome 1 or 20. The French physician Daniel Alagille was the first to describe the syndrome in 1969.
The incidence of Alagille syndrome is estimated to be approximately 1:80,000 to 1:100,000 [1]. In this autosomal-dominant inherited disease, a so-called differentiation protein for various tissues of the body is defective. The diagnosis is made on the basis of the typical clinical symptoms:
Multiple heart disease: Pulmonary stenosis
- Changes in the skeleton: shortened ulna, clinodactyly, butterfly vertebrae (Fig. 1).
- Facial dysmorphia: noticeably broad forehead, narrow chin, deep-set eyes, hypertelorism
- Cholestasis with icterus (especially common in neonates).
- Various disorders of the eyeball and optic nerve
Further investigations should be performed in newborns with corresponding symptoms. Final certainty about the presence of Alagille syndrome is provided by a genetic test (box) .
| Mutation on chromosome 1 or 20 The cause of Alagille syndrome (ALGS) can be mutations on two different chromosomes. According to this, two subtypes of the disease are distinguished: |
| – In one form, the mutation is located on chromosome 20 in gene locus p12. In this case the disease is called ALGS1. |
| – In ALGS2, the defect is located on chromosome 1, gene locus p13-p11, in the so-called NOTCH2 gene. |
| Every carrier of one of the above mutations also phenotypically develops ALGS. However, the expression of the disease varies greatly. Inheritance is by an autosomal dominant pathway. |
Symptom-oriented therapy
There is no causal therapy for Alagille syndrome; treatment is based on symptoms. The goal is to improve the bile secretion of the liver, reduce the pain caused by the disease and compensate for nutrient deficiencies. Bile stasis resulting from the remodeling of the bile ducts leads to jaundice, severe pruritus, and is also associated with impaired growth and failure to thrive due to decreased fat digestion [2]. Other effects of the syndrome, for example on the eyes, skeleton or face, remain without serious consequences for the child. In severe cases, surgical corrections are performed. If liver function is deficient, liver transplantation may be necessary.
Cholestatic pruritus: EMA approval of new therapeutic option
Based on clinical trials, FDA approval of maralixibat for the treatment of hepatic pruritus in children over 1 year of age with Alagille syndrome occurred in 2021 [3]. Since 2022, maralixibat (trade name: Livmarli®) has also been approved for this indication in the EU [4]. The benefit of the drug was investigated in two main studies [4]. In the first study, 31 children aged 1 to 18 years with Alagille syndrome were treated with maralixibat for 18 weeks. The 29 patients whose blood bile acid levels had decreased by at least 50% after the initial 18-week treatment with the drug subsequently received either placebo or maralixibat over a four-week period. The results showed that with continued treatment with maralixibat, bile acid levels remained low after four weeks, while there was a significant increase in patients who switched treatment to placebo. After a period of four weeks, all patients received maralixibat again and it was found that under this medication, blood levels decreased to those previously observed. In the study, the pruritus associated with the disease also improved.
| Maralixibat blocks the action of the apical sodium-dependent bile acid transporter (ASBT), which allows bile acids to be transported from the intestine back into the blood and liver. By inhibiting ASBT, the drug reduces the amount of bile acid transported from the intestine to the liver. This results in excess bile acid being removed from the body, reducing the accumulation of bile acid and relieving the symptoms of cholestatic pruritus. |
In the second study, eight children aged two months to 1 year participated [4]. The results showed that after 13 weeks of maralixibat treatment, patients had an average improvement in itch symptoms associated with the disease and a reduction in bile acid levels.
Literature:
- Alagille Syndrome, https://flexikon.doccheck.com/de/Alagille-Syndrom,(last accessed Aug 07, 2023).
- Alagille Syndrome, www.medizin.uni-tuebingen.de/de/das-klinikum/einrichtungen/zentren/kinderleberzentrum/gallenwege/alagille-syndrom,(last accessed Aug 07, 2023).
- Gonzales E, et al: Efficacy and safety of maralixibat treatment in patients with Alagille syndrome and cholestatic pruritus (ICONIC): a randomised phase 2 study. Lancet 2021; 398: 1581-1592.
- European Medicines Agency, www.ema.europa.eu/en/documents/overview/livmarli-epar-medicine-overview_de.pdf,(last accessed Aug. 07 , 2023).
- Rizwanullah, Saad M, Ahmad QT, et al: Alagille Syndrome in an Infant: A Rare Case Report. J Dig Dis Hepatol 2022: 6: 176. www.gavinpublishers.com/article/view/alagille-syndrome-in-an-infant-a-rare-case-report,(last accessed 07 Aug 2023).
HAUSARZT PRAXIS 2023; 18(8): 22
