Liver disease is one of the major contributors to healthcare utilization in the world. In the United States alone, chronic liver disease and cirrhosis account for around 45,000 deaths annually; globally, the figure rises to around 2 million. 

Liver disease can be caused by a number of factors, for example: hepatitis C (9%), hepatitis B (2%), and excessive alcohol consumption (2%). However, the leading type of liver disease is nonalcoholic fatty liver disease, accounting for around 60% of chronic liver disease cases. 

Chronic liver disease has an insidious and often slow way of progressing from bad to worse. Once it is diagnosed, complications may arise, the 2 most common being cirrhosis (1.2 million deaths annually worldwide) and liver cancer (around 800,000 deaths annually worldwide). 

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In the US, liver disease places a great burden on healthcare utilization. In a year, chronic liver diseases account for more than 1 million outpatient visits and around 300,000 emergency department visits. Around a quarter of the cases get readmitted, despite concerted efforts by healthcare leaders to reduce this figure. 

To tackle the assault of liver disease on patients and our healthcare system, it is important to identify sources of the problem. A small number of liver disease cases are driven by rare, chronic diseases such as Alagille syndrome (ALGS). 

Understanding the Scale of the Problem 

Alagille syndrome is a genetic disease primarily characterized by its hepatic involvement. Scientists have not been able to identify what drives liver disease in some patients more than others. Suffice it to say that there is great heterogeneity in its phenotype with respect to hepatic involvement. 

“The full spectrum of ALGS-related liver involvement remains unknown, and detailed analyses of real-world natural history data are lacking,” Vandriel and colleagues wrote in a study published in the AASLD Journal.

The researchers reported that a study group, the Global Alagille Alliance (GALA), was established in 2018 to better understand the natural history of liver disease in an international cohort of patients diagnosed with ALGS. This project encompassed 67 pediatric centers from 29 countries. All children diagnosed with ALGS from January 1997 to August 2019 were considered eligible for this study. 

Read more about Alagille syndrome etiology 

The research team focused on identifying the prevalence of the various manifestations of liver disease among pediatric patients with ALGS, chief among them neonatal cholestasis, a history of pruritus and/or xanthomas, hepatic fibrosis, and a history of having undergone hepatobiliary surgery. 

The team managed to identify 1433 children with ALGS from the GALA database who met their inclusion criteria. They discovered that 95% of the patients reported liver involvement, with 85% having presented with neonatal cholestasis. Around 74% experienced pruritus, while 25% experienced xanthomas. 

Among the 85% of patients identified to have neonatal cholestasis (1184 patients), 345 underwent liver transplantation, while 4 underwent a combined liver-kidney transplantation. An additional 14 patients who did not present with neonatal cholestasis underwent liver transplantation. 

In terms of prognosis, Vandriel and colleagues discovered that the native liver survival rate was 66.8% at 5 years. At 10 years, the figure fell to 54.4%; at 18 years, it fell further to 40.3%. In addition, the risk of death without transplantation was 6.1% at 5 years, 7.8% at 10 years, and 9.3% at 18 years. 

Read more about Alagille syndrome epidemiology 

“The GALA study provides a comprehensive real-world analysis of liver disease in more than 1400 children with ALGS from 29 countries,” the authors of the study concluded. “With 40% of children with ALGS surviving to adulthood with native liver, adult hepatologists also need to be aware of ALGS and its complex manifestations.” 

Future Directions 

Because an overwhelming proportion of patients with ALGS have liver disease, a national database tracking the prevalence of ALGS, such as the one devised by the GALA group, is welcome, if only to enrich our epidemiological understanding of liver disease.

In fact, the burden of suffering from secondary liver disease, cirrhosis, or related complications is in many ways similar to the suffering of patients who have liver disease as their sole diagnosis. The question from a research point of view is whether a curative option can be found, and if not, whether therapies that significantly reduce the symptoms of liver disease can be produced. 

“Investment and innovation are vital to maintain adequate surveillance of [chronic liver disease] and develop strategies to reduce its burden,” Moon and colleagues wrote in Clinical Gastroenterology and Hepatology. “Continued attempts to track the burden of liver disease will help identify priorities for clinical care improvements, research investment, and health policy initiatives.” 


Vandriel SM, Li LT, She H, et al. Natural history of liver disease in a large international cohort of children with Alagille syndrome: results from the GALA studyHepatology. 2022;10.1002/hep.32761. doi:10.1002/hep.32761

Moon AM, Singal AG, Tapper EB. Contemporary epidemiology of chronic liver disease and cirrhosisClin Gastroenterol Hepatol. 2020;18(12):2650-2666. doi:10.1016/j.cgh.2019.07.060