Alagille syndrome (ALGS) is an autosomal dominant developmental disorder characterized by abnormalities in the eyes, heart, liver, and bones. Patients with ALGS may also have a characteristic facial appearance that includes a prominent forehead, deep-set eyes, and a pointy chin and nose. Studies have shown that this disease is driven by dysfunction in the Notch signaling pathway. 

“To date, 694 pathogenic variants in JAG1 and 19 pathogenic variants in NOTCH2 have been described in individuals with clinical features of Alagille syndrome,” Schindler and colleagues wrote in the American Journal of Medical Genetics. 

ALGS is suspected when patients present with biliary damage and cholestasis. A laboratory cholestasis workup will reveal markedly elevated levels of bilirubin, cholesterol, gamma-glutamyltransferase, and alkaline phosphatase.


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When laboratory findings reveal cholestasis, physicians usually follow up with liver ultrasonography, which may uncover a small or absent gallbladder. In around 30% of patients, hepatic regenerative nodules can be detected that are sometimes mistaken for hepatocellular carcinoma. 

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“Lastly, in any patient where Alagille syndrome is suspected, formal echocardiography, dedicated vertebral radiography, slit-lamp examination of the eyes, and renal ultrasonography with doppler should be performed,” Ayoub and Kamath wrote in Diagnostics. 

Reports have emerged that patients with ALGS are more likely to develop hepatocellular carcinoma compared with the general population. Hepatocellular carcinoma has been seen in patients with phenotypes of varying degrees of severity, leading some to suspect that hepatocellular cancer is caused by interference with Notch signaling. The merit of this theory is debatable, as the role of Notch in the development of hepatocellular carcinoma has not been established. 

It should be noted that Notch signaling dysfunction has been documented in other types of cancer such as pancreatic, breast, and ovarian. However, Notch signaling can play an oncogenic or tumor-suppressing role depending on various factors such as the surrounding tumor microenvironment. In regard to hepatocellular carcinoma, some studies suggest that Notch acts as a tumor suppressor, while other, in vitro, studies that use cancer cell lines suggest that Notch activation promotes hepatocellular carcinoma. 

“Conflicting findings warrant further examination of the downstream impacts of Notch dysfunction, as the mechanism of its involvement in hepatocellular carcinoma is likely complex,” Schindler and colleagues wrote. 

Initially, scientists hypothesized that hepatocellular carcinoma develops due to the cholestasis seen in patients with ALGS. However, patients with a milder phenotype of the disease with lower levels of cholestasis do not seem to have a lower risk of developing hepatocellular carcinoma. 

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The average age at which hepatocellular carcinoma is detected and diagnosed in patients with ALGS is 9 years, while the average age for an ALGS diagnosis is within the first 3 to 4 months of life. This means that it is highly unlikely that both conditions are diagnosed together, giving the opportunity for hepatocellular carcinoma to develop undetected. 

Studies demonstrate that the most common therapeutic approach to hepatocellular carcinoma remains palliative, highlighting the unfortunate reality that many cases are only diagnosed at an advanced stage. 

Case Study of a Patient With Hepatocellular Carcinoma 

In Radiology Case Reports, Schoen and colleagues presented the case of an adult with ALGS who was diagnosed with hepatocellular carcinoma. 

A 38-year-old gentleman presented with acute right upper quadrant pain. He was previously diagnosed with ALGS but was lost to follow-up for the last 8 years. 

A physical examination revealed mild discomfort in the right upper abdomen but was otherwise unremarkable. Laboratory results revealed highly elevated levels of gamma-glutamyl transferase (1456 U/L) and alpha-fetoprotein (187 U/dL), as well as mildly elevated levels of transaminases (70 U/dL) and alkaline phosphatase (233 U/L). 

An abdominal computed tomographic scan without contrast was conducted that revealed signs of chronic liver disease, including a 14-cm hypoattenuating mass in his right hepatic lobe. The scan also revealed that the patient had splenomegaly. Magnetic resonance imaging demonstrated that the mass had arterial hyperenhancement, a washout appearance, and central necrosis. 

“T1- weighted images sequence also demonstrated areas of high signal intensity suspicious of internal hemorrhage,” Schoen et al wrote. “Hepatocellular carcinoma was considered in the differential diagnosis.” 

The patient underwent a right hepatectomy and the histopathological results confirmed the diagnosis of hepatocellular carcinoma. The liver parenchyma demonstrated portal tract fibrosis, ductopenia, as well as moderate levels of lymphoid infiltrate. Further analysis of the hepatic nodule revealed a solid architecture with focal areas of pseudoacinar structures. Enlarged nuclei and conspicuous nucleoli were also reported. 

The patient passed away 3 months later due to infectious complications. 

This case study demonstrates that hepatocellular carcinoma can develop later in adulthood, even when ALGS is diagnosed earlier. Because the patient was lost to follow-up, we cannot be certain whether his physicians would have picked up the diagnosis of hepatocellular carcinoma if he had continued with his appointments. 

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It is important for physicians treating patients with ALGS to note that hepatocellular carcinoma can arise from a background of ALGS and to screen for this cancer accordingly. As in the case with most cancers, early diagnosis leads to early treatment, which usually translates into improved clinical outcomes. 

References

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 phenotypesAm J Med Genet A. 2021;185(3):719-731. doi:10.1002/ajmg.a.62028

Schoen K, Ribeiro CMF, Gonçalves MC, de Souza ARM, Porta G, Horvat N. Hepatocellular carcinoma in an adult with Alagille syndrome: case report and literature reviewRadiol Case Rep. 2020;16(1):90-93. doi:10.1016/j.radcr.2020.09.027

Ayoub MD, Kamath BM. Alagille syndrome: diagnostic challenges and advances in managementDiagnostics (Basel). 2020;10(11):907. doi:10.3390/diagnostics10110907