Study Maps Cellular Drivers of Fontan-Associated Liver Disease
May 22, 2026
A research team from the UPMC Children’s Hospital of Pittsburgh Heart Institute and Pittsburgh Liver Research Center published new findings on the cellular changes that drive liver disease in patients with single ventricle physiology who have Fontan circulation. The study, “Single-cell Spatial Transcriptomics Reveals Hepatocyte Reprogramming in Fontan Associated Liver Disease,” was published in the February 2026 JCI Insight and is the first cell-by-cell map of human Fontan-associated liver disease (FALD).
Medical Scientist Training Program student Brandon M. Lehrich, PhD, was the study's lead author. Anita Saraf, MD, PhD, of the UPMC Adult Congenital Heart Disease Center, was the senior author. Satdarshan P. Monga, MD, director of the Pittsburgh Liver Research Center, was the co-senior author. Also contributing to the study were Victor O. Morell, MD, chief, Division of Pediatric Cardiothoracic Surgery; Rakesh Sindhi, MD; Department of Surgery; Catherine Gestrich, DO, Division of Pediatric Pathology; and Silvia Liu, PhD, Department of Pharmacology and Chemical Biology.
“Very little is known about how the liver is affected in our complex single ventricle cardiac patients, yet we often need to make decisions about treatment and transplantation for abnormal liver findings in these patients,” Dr. Saraf says. “This study provides the first spatial transcriptomics map of the liver with progressive Fontan-associated liver disease and demonstrates that the liver's metabolic program is drastically altered.”
Study Overview and Highlights
The study conducted by Dr. Saraf and colleagues used a single-cell spatial transcriptomics platform, which measures gene activity in individual cells while tracking where each cell sits in the tissue, to look at liver samples from FALD patients with early and advanced fibrosis, along with a normal liver for comparison. The findings were checked in 18 more FALD patient samples covering the full range of Congestive Hepatic Fibrosis (CHF) scores, a tissue-based grading system that rates the degree of liver fibrosis in FALD on a scale of 0 to 4.
The team looked at liver samples from various stages of disease severity and identified 12 different cell types, including six kinds of liver cells. A new group of liver cells were present at four times higher frequency with advanced FALD as compared to early or normal liver. These cells had lost their metabolic identity, expressed markers of cell stress and secreted inflammatory proteins. The team called these cells "zonally ambiguous and stressed hepatocytes." In a healthy liver, cells in different areas do different jobs. In advanced FALD, that order broke down. The cells that normally line the central and outer parts of the liver disappeared, and middle-area cells took over.
The team also found what may be causing these changes. A signaling protein called WNT2, which is normally responsible for defining metabolic zones in the cells was made in the wrong place. In a healthy liver, WNT2 is produced only by blood vessel cells in the central area. In advanced FALD, blood vessel cells in the outer area were making it, too.
Heat shock protein 70 (HSP70), a sign of cell stress, tracked closely with CHF score. CHF score also tracked with how long a patient had been living with Fontan circulation.
The same changes were also seen in liver tissue from patients with end-stage liver disease from other causes, pointing to a shared pathway.
Potential Clinical Significance of the Research
The findings of this study may have direct value for Fontan patient care. HSP70 could work as a tissue marker of advanced fibrosis to help time combined heart-liver transplant, which is hard to plan today because biopsy carries risk and blood tests do also correspond well to disease state in these patients. The study also points to a possible source of GDF15, a protein that Dr. Saraf and colleagues have linked to clinical decline in Fontan patients, which may support efforts toward a blood test to track FALD without a biopsy.
The findings may also help support the future use of ursodeoxycholic acid in FALD, which has been linked to lower rates of liver cancer in these patients, by suggesting how it may protect liver cells. Because the same changes show up in more common forms of end-stage liver disease, future treatments for those conditions may also help Fontan patients.
“We hope our findings open new avenues for diagnosing FALD severity, enabling better decisions regarding the care of these patients,” Dr. Saraf says. “The study also provides insights into new therapies for FALD that we had not previously considered. Our goal is to help our patients live longer, healthier lives with fewer medical complications.”
Reference
Lehrich BM, Lewis JN, Meadows V, Schmitt L, Ningappa MB, Liu JJ, Liu S, Gestrich C, Morell VO, Sindhi R, Monga SP, Saraf A. Single-cell spatial transcriptomics reveals hepatocyte reprogramming in Fontan-associated liver disease. JCI Insight. 2026; Feb 24: e198823. Online ahead of print.
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