Alagille syndrome (ALGS) is an autosomal dominant disorder caused by defects in the Notch signaling pathway. It is characterized by multisystemic features, including recurrent episodes of cholestasis and the presence of abnormal liver enzymes.
In some cases, patients might progress to severe, permanent cholestasis and portal fibrosis, requiring liver transplantation. The chance of survival to age 20 decreases by 20% in ALGS patients who receive a liver transplantation.
“Perioperative management of [liver transplantation] for [ALGS] patients can be particularly challenging, requiring a full understanding of the pathophysiology, as well as a careful preoperative evaluation of the multi-system comorbidities,” concluded Yang and colleagues in a study published in Annals of Transplantation. They added that clinicians should be aware of the “high prevalence of postoperative surgical complications.”
One of the main challenges when performing liver transplantation in ALGS is the still scarce clinical experience in administering anesthesia to these patients.
Read more about ALGS complications
ALGS has been associated with hepatocellular carcinoma, but not all hepatic lesions found in ALGS patients show malignancy. In fact, hepatocellular carcinoma is a rare complication of ALGS. Pediatric and adult ALGS patients may sporadically present benign hepatic nodules, also known as regenerative or regenerating nodules.
“Hepatic regenerative nodules have been reported in 30% of patients and can be confused with hepatocellular carcinoma,” Ayoub and Kamath explained. Therefore, proper differential diagnosis is of vital importance.
Clinical Presentation of CHRNs
Central hepatic regenerative nodules (CHRNs) are often incidental imaging findings in younger ALGS patients. “These patients may present with signs of portal hypertension (variceal bleeding and progressive hepatosplenomegaly) or cholestasis,” explained Andrews and Putra.
CHRNs are generally large (up to 13.2 cm), though smaller lesions have also been identified. When CHRNs are present, alpha-fetoprotein (AFP) values are within the normal range or slightly increased, without evidence of concurrent hepatocellular carcinoma. In addition, CHRNs are usually solitary entities. They occupy a central position within the liver and are generally associated with the portal vein, in the right, caudate or quadrate lobes (segments IV, V, VI, and VIII).
Imaging and Pathological Findings
For proper clinical management of ALGS, it is important to distinguish CHRNs from hepatocellular carcinoma. Several imaging and pathological findings support differential diagnosis. According to Andrews and Putra, CHRNs:
- Are large, homogeneous, and well-defined lesions, with a “hyperplastic” appearance
- Have similar density, intensity, and echogenicity to background liver
- Are typically located adjacent to portal vein
- Present vasculature coursing through the lesion.
When compared to the adjacent parenchyma, CHRNs show as nonencapsulated hepatic lesions with generally preserved architecture, less fibrosis, and more portal tracts with preserved interlobular bile ducts.
On the other hand, hepatocellular carcinomas:
- Have a less consistent localization and may be multiple
- Are usually well or moderately differentiated
- Are often accompanied by markedly increased AFP
- Appear hypoechoic or hyperechoic on ultrasound
- Are supported by early enhancement in the arterial phase and a wash-out phenomenon in the late phases on magnetic resonance imaging (MRI).
When concomitant hepatocellular carcinoma and CHRN occurred, imaging findings of the two lesions were different.
CHRNs are primarily assessed using hematoxylin-and-eosin (H&E) staining. Reticulin and trichrome stains are used to differentiate CHRNs from fibrotic/cirrhotic liver. H&E analysis of hepatocellular carcinomas shows architectural atypia, pseudoglandular architecture, and nuclear atypia.
Read more about ALGS differential diagnosis
Useful markers in hepatocellular carcinoma assessment include reticulin, cluster of differentiation 34 (CD34), glutamine synthetase, and glypican-3. However, “these stains should be interpreted carefully, and the pathologists should consider the clinical and radiological findings prior to making the diagnosis of hepatocellular carcinoma,” Andrews and Putra advised.
Treatment of CHRNs in ALGS Patients
According to Schindler et al, “regenerative nodules are relatively benign, homogenous masses that do not usually necessitate clinical intervention”.
In fact, no progression is observed in many cases for years, but up to 50% of ALGS patients that present CHRNs experience an average increase in nodules volume by 20 cm3 over an average period of 38.5 months. Progression to cirrhosis may require liver transplantation.
On the other hand, hepatocellular carcinoma needs proper treatment, including surgery and/or chemotherapy.
Therefore, Andrews and Putra advised that “clinicians and pathologists should be aware of this entity [CHRNs], as differentiating these nodules from hepatocellular neoplasms (hepatocellular carcinoma and hepatocellular adenoma) may allow for more conservative management in these patients.”
Andrews AR, Putra J. Central hepatic regenerative nodules in Alagille syndrome: a clinicopathological review. Fetal Pediatr Pathol. 2021;40(1):69-79. doi:10.1080/15513815.2019.1675834
Ayoub MD, Kamath BM. Alagille syndrome: diagnostic challenges and advances in management. Diagnostics. 2020;10(11):907. doi:10.3390/diagnostics10110907
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
Yang W-H, Zhang L, Xue F-S, Riaz A, Zhu Z-J. Pediatric liver transplantation for Alagille syndrome: anesthetic evaluation and perioperative management. Ann Transplant. 2020;25:e924282-e924282. doi:10.12659/AOT.924282