Non-invasive biomarkers of Fontan-associated liver disease

Juliet Emamaullee; Sara Khan; Carly Weaver; Cameron Goldbeck; George Yanni; Rohit Kohli; Yuri Genyk; Shengmei Zhou; Nick Shillingford; Patrick M Sullivan; Cheryl Takao; Jon Detterich; Paul F Kantor; John D Cleveland; Cynthia Herrington; S Ram Kumar; Vaughn Starnes; Sarah Badran; Neil D Patel

doi:10.1016/j.jhepr.2021.100362

Non-invasive biomarkers of Fontan-associated liver disease

JHEP Rep. 2021 Sep 14;3(6):100362. doi: 10.1016/j.jhepr.2021.100362. eCollection 2021 Dec.

Authors

Juliet Emamaullee^{1

2

3}, Sara Khan², Carly Weaver³, Cameron Goldbeck^{1

2}, George Yanni^{2

3}, Rohit Kohli^{2

3}, Yuri Genyk^{1

2

3}, Shengmei Zhou^{2

4}, Nick Shillingford^{2

4}, Patrick M Sullivan^{2

5}, Cheryl Takao^{2

5}, Jon Detterich^{2

5}, Paul F Kantor^{2

5}, John D Cleveland^{1

2

5}, Cynthia Herrington^{1

2

5}, S Ram Kumar^{1

2

5}, Vaughn Starnes^{1

2

5}, Sarah Badran^{2

5}, Neil D Patel^{2

5}

Affiliations

¹ Department of Surgery, University of Southern California, Los Angeles, CA, USA.
² Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
³ Liver Transplant Program, Children's Hospital-Los Angeles, Los Angeles, CA, USA.
⁴ Department of Pathology, Children's Hospital-Los Angeles, Los Angeles, CA, USA.
⁵ Heart Institute, Children's Hospital-Los Angeles, Los Angeles, CA, USA.

Abstract

Background & aims: Fontan-associated liver disease (FALD) has emerged as an important morbidity following surgical palliation of single ventricle congenital heart disease. In this study, non-invasive biomarkers that may be associated with severity of FALD were explored.

Methods: A retrospective cohort of paediatric patients post-Fontan who underwent liver biopsy at a high volume at a paediatric congenital heart disease centre was reviewed.

Results: Among 106 patients, 66% were male and 69% were Hispanic. The mean age was 14.4 ± 3.5 years, and biopsy was performed 10.8 ± 3.6 years post-Fontan. The mean BMI was 20.8 ± 5 kg/m², with 27.4% meeting obesity criteria. Bridging fibrosis was observed in 35% of patients, and 10.4% of all patients had superimposed steatosis. Bridging fibrosis was associated with lower platelet counts (168.3 ± 58.4 vs. 203.9 ± 65.8 K/μl for congestive hepatic fibrosis score [CHFS] 0-2b, p = 0.009), higher bilirubin (1.7 ± 2.2 vs. 0.9 ± 0.7 mg/dl, p = 0.0090), higher aspartate aminotransferase-to-platelet ratio index [APRI] and fibrosis-4 [FIB-4] scores (APRI: 0.5 ± 0.3 vs. 0.4 ± 0.1, p <0.01 [AUC: 0.69] and FIB-4: 0.6 ± 0.4 vs. 0.4 ± 0.2, p <0.01 [AUC: 0.69]), and worse overall survival (median 2 years follow-up post-biopsy, p = 0.027). Regression modelling of temporal changes in platelet counts before and after biopsy correlated with fibrosis severity (p = 0.005).

Conclusions: In this large, relatively homogeneous adolescent population in terms of age, ethnicity, and Fontan duration, bridging fibrosis was observed in 35% of patients within the first decade post-Fontan. Bridging fibrosis was associated with worse survival. Changes in platelet counts, even years before biopsy, and APRI/FIB-4 scores had modest discriminatory power in identifying patients with advanced fibrosis. Steatosis may represent an additional risk factor for disease progression in obese patients. Further prospective studies are necessary to develop strategies to screen for FALD in the adolescent population.

Lay summary: In this study, the prevalence of Fontan-associated liver disease (FALD) in the young adult population and clinical variables that may be predictive of fibrosis severity or adverse outcomes were explored. Several lab-based, non-invasive markers of bridging fibrosis in FALD were identified, suggesting that these values may be followed as a prognostic biomarker for FALD progression in the adolescent population.

Keywords: ALP, alkaline phosphatase; ALT, alanine aminotransferase; APRI, AST-to-platelet ratio index; AST, aspartate aminotransferase; BMI, body mass index; BNP, brain natriuretic peptide; BUN, blood urea nitrogen; CBC, complete blood count; CHFS, congestive hepatic fibrosis score; CHLT, combined heart–liver transplantation; CVP, central venous pressure; Congenital heart disease; Congestive hepatopathy; ECMO, extracorporeal membrane oxygenation; FALD, Fontan-associated liver disease; FIB-4, fibrosis-4; GFR, glomerular filtration rate; GGT, gamma-glutamyl transferase; INR, international normalised ratio; IQR, interquartile range; LVAD, left ventricular assist device; MELD, model of end-stage liver disease; MELD-Na, MELD-sodium; MELD-XI, MELD without INR; NAFLD, non-alcoholic fatty liver disease; PELD, paediatric end-stage liver disease; PT, prothrombin time; PTT, partial thromboplastin time; TTE, transthoracic echocardiograms; Univentricular heart disease.