Pediatric Hepatology: Shaping Care Through Research

Pediatric liver disease presents several clinical challenges. Some babies develop progressive liver injury, eventually requiring transplant. After transplant, children face lifelong immunosuppression with potential toxicity.

The Pediatric Liver Center at UCSF Benioff Children’s Hospitals is addressing these problems through innovative research initiatives. The team’s recent National Institutes of Health (NIH)-funded trials and translational science could inform how clinicians manage these conditions and care for children after transplant.

Current liver disease research initiatives include:

1. Understanding immune tolerance in the neonatal liver

Amar Nijagal, MD, a pediatric surgeon and physician-scientist at UCSF, secured a four-year, $3.17 million R01 grant from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). He and his team are studying the critical window during which the neonatal liver transitions from producing blood cells to processing nutrients. During this period, infants become susceptible to diseases such as biliary atresia, which produces a degree of fibrosis typically seen only in adults with decades of chronic liver disease.

As principal investigator, Nijagal and his team are examining proteins expressed by liver macrophages (immune cells that patrol tissues in search of threats). One such protein, macrophage receptor with collagenous structure (MARCO), sits on the surface of macrophages and acts as a sensor that helps regulate inflammatory response.

Scientists originally thought MARCO and similar scavenger receptors were nonspecific cleanup proteins. Nijagal's work shows MARCO may fine-tune a specific anti-inflammatory pathway to reduce immune responses. “We’re trying to understand how macrophages in the neonatal liver create an environment that promotes tolerance or allows disease to progress,” he explains.

The Nijagal Lab is using two approaches in this effort:

• Gene editing.CRISPR-Cas9, a gene-editing technology, enables researchers to deactivate, eliminate or insert DNA sequences. UCSF scientists are using CRISPR-Cas9 to eliminate MARCO signaling on human macrophages, allowing a precise investigation of this receptor's role in immune regulation.
• Direct portal vein injection.Surgically injecting proteins into the liver's main blood supply enables researchers to identify specific T cells responding to those proteins. “We can enumerate and understand antigen-specific responses within the liver with remarkable precision,” Nijagal notes. “Prior work involved feeding animals antigens or injecting them intravenously. This combination of immunology and surgical techniques enables unprecedented understanding of liver function.”

This research represents a paradigm shift in pediatric liver disease treatment. “We’re not just examining the diseases; we’re looking at the underlying mechanisms that predispose patients to them,” Nijagal says. “If you think of these diseases like a tree, treatment has always focused on the foliage. We’re examining the soil that produced the tree.”

Nijagal points out that they’re not drawing a straight line from macrophage work to any specific disease. “If we identify critical mechanisms, perhaps a sensor protein that's important for controlling immune responses, we could enhance or block it,” he explains. “This would let us control the dysregulated immune responses we see in diseases such as biliary atresia.”

The end goal of this research is to change the soil before the tree grows. “If we can understand why the neonatal liver tolerates certain antigens and rejects others, we can potentially intervene earlier,” he says. “We could more effectively manage diseases that currently have limited treatment options.”

 2. Tailoring immunosuppression after liver transplant

Pediatric gastroenterologist and hepatologist Emily Perito, MD, and her colleagues are focused on optimizing long-term outcomes for children after liver transplantation. A multicenter NIH trial, led by UCSF transplant surgeon Sandy Feng, MD, PhD, could change how clinicians manage immunosuppression after transplant.

The trial involves 12 centers nationwide and aims to identify biomarkers that could predict which children can safely minimize immunosuppressive medications.

“This trial is one example of how we’re moving toward precision medicine in transplant,” Perito explains. “Not every child needs the same level of immunosuppression long term. But right now, we don’t have reliable ways to identify who can safely reduce this therapy.”

A decade ago, UCSF led small trials that completely stopped immunosuppression in select patients. This worked for a small subset. Most pediatric transplant recipients need some ongoing immunosuppression for long-term graft survival.

Chronic immunosuppression is known to increase risks of infection and malignancies that escalate over a child’s lifetime. Conversely, inadequate immunosuppression can lead to rejection and graft loss. “If we can identify biomarkers that tell us a child can take less immunosuppression without affecting graft health, we can potentially reduce their medication burden and associated risks,” Perito says.

UCSF’s research – including efforts to better tailor immunosuppression – has contributed to strong outcomes in pediatric liver transplant. The team cares for some of the most critically ill patients, yet survival rates are consistently among the highest in the country.

This research also reflects UCSF’s commitment to transplant patients that extends far beyond the immediate postoperative period. “We’re thinking about these kids’ lives over decades,” she notes. “How do we optimize their health not just in the first year after transplant, but ideally 10, 20 or even 80 years out?”

Multidisciplinary, collaborative approach

The integration of research excellence with a multidisciplinary clinical model sets the UCSF Pediatric Liver Center apart. The team includes hepatologists, liver and transplant surgeons, nutritionists, pathologists and specialized nursing staff who collaborate seamlessly.

“We’ve created streamlined access for families,” Perito says. “They have a single point of contact, and we coordinate care across all the specialties they need. It’s easier for families, and it’s easier for the physicians who are partnering with us in their care.”

The center offers consultations and second opinions while maintaining a collaborative relationship with referring providers. “We want to be a resource – whether that’s a one-time consultation, ongoing shared care or a phone call to discuss a complex case,” Perito says.

For most liver conditions, early referral means the team can optimize care before the disease progresses and options become more limited. “We can often be most helpful when we’re involved early,” Perito notes. “But we’re also here for second opinions or to help troubleshoot challenging cases at any stage.”

To refer a patient to the UCSF Pediatric Liver Center, visit our referral page or call (877) 822-4453.