Alagille Syndrome
An illustration of liver tumors. Credit: Getty Images

Since the first report of Alagille syndrome (ALGS), in the late 1960s, it has been considered the most common form of genetic cholestatic liver disease.

In rare cases of ALGS, patients also develop hepatocellular carcinoma (HCC), with only about 30 cases being reported in the literature. This occurs in both children and adults with ALGS phenotypes ranging from subtle to severe and with varying degrees of liver involvement.

Recently, Schindler and Gilbert performed a comprehensive review of the literature and found 28 publications regarding HCC in ALGS patients. Most (n=21) cases involved children, who all had intrahepatic bile duct paucity and cholestasis prior to developing HCC. In addition, 16 pediatric patients reported a background of cirrhotic liver, although it should be noted that information on the presence/absence of liver cirrhosis was only available for 18 patients. The presence of other signs and symptoms, such as characteristic facies and eye, heart, or skeletal abnormalities, was highly variable.


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Among adult ALGS patients with HCC (n=13), most also presented with bile duct paucity and cholestasis. The exception was one patient who had an attenuated form of ALGS with no apparent liver involvement. Also, 4 patients had a background of liver cirrhosis, out of the 9 cases with information available. Similar to what was reported for pediatric patients, the presence of additional abnormalities was variable.

Read more about ALGS comorbidities

Schindler et al explained that “the occurrence of HCC in multiple individuals with subtle clinical features (and some with little to no apparent liver involvement) has caused some to suggest that ALGS-causing variants could contribute to the development of HCC by interfering with Notch signaling.”

The Influence of ALGS-Causing Variants

It is known that the NOTCH signaling pathway is important in the proper development of the biliary tree. “This is evidenced by the bile duct paucity caused by JAG1 and NOTCH2 mutations in human patients with ALGS and the biliary abnormalities observed in vertebrate animal models with reduced Notch signaling,” Adams and Jafar-Nejad said.

NOTCH signaling has also been associated with HCC and intrahepatic cholangiocarcinoma, although the underlying molecular mechanisms remain far from being completely understood.

Genetic data from ALGS patients that developed HCC is scarce. From the 5 patients who underwent genetic testing, 3 showed pathogenic JAG1 variants, 1 patient had a suspected pathogenic NOTCH2 variant, and 1 showed no pathogenic variant. The pathogenic JAG1 variants identified in ALGS patients included the missense variant c.551 G > A, p.Arg184His, the frameshift variant c.693_694del, p.Arg231Serfs*10, and an unspecified de novo variant in a protein-coding region.

“In JAG1 pathogenic variant-positive ALGS, the absence of functional protein results in a buildup of hepatic progenitor cells with an intermediate hepatobiliary phenotype incapable of differentiating into biliary cells,” Schindler et al explained. When damage is not repaired, it may promote the progression of preexisting liver disease and, consequently, the development of HCC.

The suspected pathogenic NOTCH2 variant identified was the c.5830G > A, p.Gly1944Ser. Out of the 4 patients with either JAG1 or NOTCH2 variants, only 1 had a family history of ALGS. Also, from the 5 patients with available genetic data, 4 had severe liver disease.

Schindler et al also searched the Catalogue of Somatic Mutations in Cancer (COSMIC) database for JAG1 and NOTCH2 variants. They found that 6 HCC samples (out of 3,289) had JAG1 variants and 24 had NOTCH2 variants. None of these variants have been previously identified in ALGS patients.

Final Considerations

Previous reports suggested that HCC developed as a consequence of ALGS-associated cholestasis. However, Schindler et al advise that there is currently no evidence that correlates seemingly milder ALGS phenotypes with a reduced risk for developing HCC.

“Our observation of HCC in two mildly-affected patients (ie, without overt liver involvement) points to a possible disease association, with the argument that ALGS-causing germline variants could predispose affected individuals to HCC by interfering with Notch signaling,” they said.

Therefore, Schindler et al believe their results “suggest that ALGS-causing variants could confer risk for developing HCC regardless of phenotypic severity and highlight a need for a cancer screening protocol that would enable early detection and treatment in this at-risk population.”

The treatment options for ALGS patients with HCC include chemotherapy, transcatheter arterial chemoembolization, biologics, resection, and liver transplantation. All approaches have their own advantages and disadvantages, but Valamparampil et al wrote that liver transplantation “is the best option because this ensures complete removal of the tumor and diseased liver at risk of developing [a] tumor in [the] future.”

In 2020, Galvez et al reported a rare case of recurrent HCC in an adult ALGS patient treated with transarterial chemoembolization followed by right hepatic lobectomy. “One year later, he developed HCC recurrence within Milan’s criteria and received a deceased donor liver transplant,” they explained. To their knowledge, this was the first case of its kind being reported in the literature.

Their patient (male, 41 years old) developed vascular complications after liver transplantation, which are known to occur in 6%-10% of cases. Therefore, their ultimate advice is to approach the pretransplant and posttransplant periods with a multidisciplinary plan. This, they say, “is paramount for successful outcomes in this rare subgroup of patients undergoing liver transplantation.”

Reference

Schindler EA, Gilbert MA, Piccoli DA, Spinner NB, Krantz ID, Loomes KM. Alagille syndrome and risk for hepatocellular carcinoma: need for increased surveillance in adults with mild liver phenotypes. Am J Med Genet Part A. 2021;185(3):719-731. doi:10.1002/ajmg.a.62028

Valamparampil JJ, Shanmugam N, Vij M, Reddy MS, Rela M. Hepatocellular carcinoma in paediatric patients with Alagille syndrome: case series and review of literature. J Gastrointest Cancer. 2020;51(3):1047-1052. doi:10.1007/s12029-020-00391-2

Adams J, Jafar-Nejad H. The roles of Notch signaling in liver development and disease. Biomolecules. 2019;9(10):608. doi:10.3390/biom9100608

Galvez D, Ruch B, Sharma A, Sydnor M, Levy M, Sharma A. Recurrent hepatocellular carcinoma in an adult with Alagille syndrome treated with liver resection followed by liver transplantation: a rare case report. Transplant Direct. 2020;6(10):e606. doi:10.1097/TXD.0000000000001055