Given this patient's symptoms of early satiety, abdominal swelling, abdominal pain, and diarrhea in the presence of a liver nodule with an elevated AFP level, hepatocellular carcinoma (HCC) should be at the top of the differential diagnosis. In individuals with liver cirrhosis or other chronic liver diseases, AFP level >200 ng/mL is often considered a strong indicator of liver cancer. Therefore, the most appropriate next step in her management is a liver biopsy, which is the reference standard for the diagnosis of HCC.

Stool alpha-1 antitrypsin is used to diagnose protein-losing enteropathy (PLE) and is not useful in diagnosing HCC. Hepatic dysfunction from failing Fontan physiology is a reason to consider liver transplant referral, but addressing the possibility of HCC would be a higher priority. Liver ultrasonography and follow-up in 6 months is useful for monitoring purposes in patients with Fontan-associated liver disease (FALD) but is not sufficient for the diagnosis of HCC, which was strongly suggested in this case by her elevated AFP level.

The Fontan procedure, a surgical palliation for congenital heart disease (CHD) with single-ventricle physiology, directs systemic venous blood into the pulmonary arteries without an intervening ventricle. Contemporary 20-year survival estimates following the Fontan procedure are 83-90%, with improved current survival trends compared with earlier surgical eras.^1,2 Chronically elevated central venous pressures are a consequence of this circulation and can lead to several long-term complications including decreased exercise tolerance, atrial arrhythmias, thromboembolism, PLE, and FALD.¹

Over the long term, FALD is expected to eventually affect all Fontan patients. FALD encompasses the spectrum of functional and structural alterations of the liver including liver dysfunction, fibrosis, portal hypertension, cirrhosis, liver nodules, and HCC.³ The pathophysiology of FALD includes elevated systemic venous pressure leading to inefficient liver drainage and creating chronic passive congestion and noninflammatory fibrogenesis.⁴ The clinical presentation of FALD is variable and may include elevated liver enzyme levels, abnormal synthetic function, esophageal or gastric varices, thrombocytopenia, splenomegaly, ascites, and encephalopathy. The 2018 American Heart Association/American College of Cardiology (AHA/ACC) Guideline for the Management of Adults With CHD recommends periodic laboratory studies to assess hepatic function and surveillance imaging (ultrasonography with or without elastography, magnetic resonance imaging, or CT) for noninvasive detection of fibrosis, cirrhosis, and HCC.⁵ Liver nodules in FALD are common and usually correspond to areas of hypervascular regeneration, such as focal nodular hyperplasia or adenomas. In cirrhosis, however, hepatocytes within regenerative nodules can undergo dysplastic changes that can eventually progress to HCC. The incidence of HCC in patients with FALD has been estimated to be nearly 5% by 20 years after the Fontan procedure.⁶ A liver biopsy is recommended in patients with FALD and nodules suggestive of HCC. In general, HCC carries poor prognosis; among Fontan patients who develop HCC, the estimated 1-year survival rate is approximately 80% and the 3-year rate is approximately 64%.⁷ Surveillance with markers such as AFP may aid in risk stratification for patients with a Fontan palliation diagnosed with FALD, and can likely improve survival.⁸ Initiating HCC surveillance with regular imaging and AFP testing is therefore reasonable when imaging or clinical evidence of FALD, particularly cirrhosis, is found.

The presence of hepatic dysfunction is considered a strong predictor of late mortality for patients with Fontan palliation and requires serial follow-up.^1,9 Scoring systems, such as MELD-XI (Model for End-Stage Liver Disease Excluding INR) and VAST (varices, ascites, splenomegaly, and thrombocytopenia) have been applied in Fontan patients to evaluate the relationship between liver dysfunction and patient outcomes. Elevated scores are predictive of major adverse outcomes including death, transplant, and HCC.^8,9

References

1. Khairy P, Fernandes SM, Mayer JE Jr, et al. Long-term survival, modes of death, and predictors of mortality in patients with Fontan surgery. Circulation. 2008;117(1):85-92. doi:10.1161/CIRCULATIONAHA.107.738559
2. Inai K, Inuzuka R, Ono H, et al. Predictors of long-term mortality among perioperative survivors of Fontan operation. Eur Heart J. 2022;43(25):2373-2384. doi:10.1093/eurheartj/ehab826
3. Agnoletti G, Ferraro G, Bordese R, et al. Fontan circulation causes early, severe liver damage. Should we offer patients a tailored strategy?. Int J Cardiol. 2016;209:60-65. doi:10.1016/j.ijcard.2016.02.041
4. Téllez L, Rodríguez-Santiago E, Albillos A. Fontan-associated liver disease: a review. Ann Hepatol. 2018;17(2):192-204. doi:10.5604/01.3001.0010.8634
5. Stout KK, Daniels CJ, Aboulhosn JA, et al. 2018 AHA/ACC guideline for the management of adults with congenital heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol. 2019;73(12):e81-e192. doi:10.1016/j.jacc.2018.08.1029
6. Kogiso T, Sagawa T, Taniai M, et al. Risk factors for Fontan-associated hepatocellular carcinoma. PLoS One. 2022;17(6):e0270230. Published 2022 Jun 17. doi:10.1371/journal.pone.0270230
7. Rosenthal BE, Hoteit MA, Lluri G, et al. Characteristics and survival outcomes of hepatocellular carcinoma after the Fontan operation. JACC Adv. 2025;4(4):101646. doi:10.1016/j.jacadv.2025.101646
8. Onishi H, Toh N, Baba K, Kotani Y, Kasahara S, Otsuka M. Hepatocellular carcinoma in Fontan-associated liver disease: incidence, risk stratification, and surveillance implications. Hepatol Commun. 2026;10(3):e00910. Published 2026 Feb 26. doi:10.1097/HC9.0000000000000910
9. Elder RW, McCabe NM, Hebson C, et al. Features of portal hypertension are associated with major adverse events in Fontan patients: the VAST study. Int J Cardiol. 2013;168(4):3764-3769. doi:10.1016/j.ijcard.2013.06.008