Alagille syndrome (ALGS) is a devastating disease caused by genetic mutations in the NOTCH signaling pathway. Its most prominent clinical features are bile duct paucity, chronic cholestasis, peripheral pulmonary stenosis, and dysmorphic facial features. 

The clinical presentation of ALGS can be heterogenous; its hepatic involvement is almost always its most severe manifestation, but it is more accurately described as a multisystem disease. Other lesser known features of ALGS include neurovascular events and kidney disease—conditions that increase morbidity and can cause death if left untreated. 

“The management of a multisystem disease like Alagille syndrome warrants a multidisciplinary approach and may require the involvement of a gastroenterologist, cardiologist, ophthalmologist, nephrologist, hepatologist, liver transplant specialist, geneticist, nutritionist, and child development expert, depending on the age and specific organ defects of the patient,” Alqahtani and colleagues write in the American Journal of Case Reports. 


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However, liver disease in particular is a pressing problem because it is impossible to predict the development of end-stage liver disease; that is to say, there are no genetic or phenotypic features that can alert physicians about the possibility or speed in which liver disease develops. 

Read more about Alagille syndrome etiology 

With end-stage liver disease, patients experience a significant deterioration in their quality of life because of symptoms like refractory pruritus and xanthomatosis secondary to severe cholestasis. Pruritus can be debilitating in every sense of the word, preventing patient with ALGS from carrying out activities of daily living and isolating them from their social circles. 

To make matters worse, the arrival of end-stage liver disease usually coincides with the maturation of other comorbidities, meaning that patients can find their overall health deteriorating with alarming acuity. These comorbidities can synergistically accelerate liver failure. 

Liver transplantation remains the only treatment option for patients with ALGS who have developed end-stage liver disease. Below is a case study presented by Alqahtani and colleagues that describes a patient with ALGS who underwent a living donor liver transplant. 

A Matter of Priorities

The case report details a 3-year-old boy diagnosed with ALGS at 2 weeks of age. He has most of the defining features of the disease: characteristic facies, butterfly vertebrae with coarctation of the aorta, peripheral branch pulmonary artery stenosis, G6PD deficiency (his mother was a known carrier of G6PD deficiency), direct hyperbilirubinemia, and cholestasis.

The patient’s surgeons performed a right pulmonary artery dilation procedure for his pulmonary artery stenosis. Postsurgery, his right ventricular systemic blood pressure remained at 60% of predilation pressure. Angiograms revealed a significantly improved right pulmonary artery diameter. 

The boy’s cardiac condition continued to improve, and attention turned toward his liver disease. He had a calculated model for end-stage liver disease score of 21, which prompted his surgeons to agree on liver transplantation as a reasonable course of action. His paternal uncle was his liver donor. 

“The surgery performed was a living related donor liver transplant using a left lateral segment to generate a 285-gram graft,” the authors wrote. 

Read more about Alagille syndrome comorbidities

Post-transplant, the patient was transferred to the pediatric intensive care unit for close observation. The boy was observed to be in stable condition, with no anesthetic complications or need for vasoactive drugs. After a week, he was discharged and followed-up at the hepatic transplant clinic. 

Clinical Decision-Making 

In the case of the patient mentioned earlier, his surgeons prioritized remedying his pulmonary artery stenosis as a result of problematic echocardiogram findings. Only once the patient’s cardiac condition was optimized was he considered for liver transplantation to ensure that the risks of cardiac complications are minimized during transplant surgery. 

“The severity of cardiac anomalies is the deciding factor for the success rate of liver transplantation,” Alqahtani and colleagues write. “In addition to intraoperative difficulties, the long-term usage of antirejection therapy drugs can cause atherosclerosis, nephrotoxicity, and bone changes.” 

Studies have shown that cardiac comorbidities are one of the main causes of mortality in children with ALGS. Around 1 in 8 children with ALGS will have cardiovascular malformations such as tetralogy of Fallot, aortic stenosis, and atrial or ventricular septal defects. 

Read more about Alagille syndrome prognosis 

Approximately one-quarter of children with ALGS will need liver transplantation in childhood; parents of children with this disease should be informed of this reality. Post-transplantation, the news is good, with 1-year survival ranges from 71% to 100%. 

If a liver transplant procedure is successful, patients and their families/caregivers still need to be prepared for a lifetime of living with this disease. For the rest of the patient’s life, he or she will need to undergo comprehensive health assessments and follow-ups. The risk of clinical deterioration, unfortunately, is an ever-present reality. 

“Successful perioperative management of Alagille syndrome patients relies on effective communication and cooperation between multidisciplinary team members,” Yang and colleagues write in Annals of Transplantation. “Monitoring and optimizing of growth, development, diet, and nutritional status should be emphasized by multidisciplinary team members, since growth retardation is known to occur in 50–90% of patients with Alagille syndrome.” 

References

Alqahtani OJ, Ahmad RN, Abolkhair AB, Alrashid AD. Management of patients with Alagille syndrome undergoing living donor liver transplantation: a report of 2 casesAm J Case Rep. 2022;23:e936513. doi:10.12659/AJCR.936513

Yang WH, Zhang L, Xue FS, Riaz A, Zhu ZJ. Pediatric liver transplantation for Alagille Syndrome: anesthetic evaluation and perioperative managementAnn Transplant. 2020;25:e924282. doi:10.12659/AOT.924282