The Latest in Liver Research: 2022
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Twenty years ago, a grateful family of a child with biliary atresia had a vision to establish a “center without walls” at Children’s Hospital of Philadelphia (CHOP). Today, under the direction of Kathleen M. Loomes, MD, the Fred and Suzanne Biesecker Pediatric Liver Center supports almost 20 investigators engaged in basic, clinical and translational research in pediatric liver disease at CHOP, the University of Pennsylvania and other centers around the world. Through monthly meetings, these scientists exchange ideas and form new collaborations, leading to sentinel discoveries that continue to advance the field of pediatric liver disease.
Through studies to understand the underlying cause of biliary atresia, our goal is to discover new therapies.
Investigators in Australia documented several outbreaks of biliary atresia in livestock during times of drought, when pregnant animals were grazing on unusual plants, including Dysphania species. A team of CHOP investigators collaborated to obtain samples of the plant and isolate a novel isoflavenoid toxin, designated biliatresone, that caused biliary injury in zebrafish and mouse cholangiocytes.
Ongoing studies in zebrafish, mouse and cell culture models have identified specific pathways responsible for biliatresonemediated cholangiocyte injury. These studies have not only led to new experimental models for the study of biliary atresia but have elucidated mechanisms of injury that may become novel therapeutic targets.
Recent published research includes:
It is well known that biliary atresia occurs only in young infants, but until recently the factors underlying the unique susceptibility of the neonatal bile duct to injury had not been elucidated. CHOP liver researcher Rebecca G. Wells, MD, and her team conducted detailed studies of neonatal and adult bile ducts to identify specific structural differences. The cholangiocytes of the neonatal extrahepatic bile duct are immature, lacking a well-formed protective glycocalyx layer and mature cell-to-cell junctions. In addition, the submucosal space of the neonatal bile duct lacks the collagen and elastin characteristic of the adult bile duct. Taken together, these differences result in increased permeability of the neonatal bile duct and increased susceptibility to injury from bile acids in cholestasis.
Recent publication:
The etiology of biliary atresia is unknown, but genetic risk factors have been proposed. In collaboration with the Childhood Liver Disease Research Network, Nancy B. Spinner, PhD, FACMG, Chief of the Division of Genomic Diagnostics at CHOP, and her team completed a genomewide association study and an exome sequencing study in biliary atresia. They identified EFEMP1, a gene involved in remodeling of the extracellular matrix, as a new candidate biliary atresia susceptibility gene.
Recent publications:
Following liver transplantation, patients receive immunosuppression to prevent rejection of the graft. Currently, immunosuppression is “one size fits all,” but it would be ideal to personalize immunosuppression according to the individual patient’s state of immune activation or tolerance, thereby reducing long-term side effects and risk of infection or malignancy.
Increased activity of regulatory T cells (Tregs) is associated with tolerance to an allograft. The research of Wayne W. Hancock, MBBS, PhD, FRCPA, Chief of the Division of Transplantation Immunology, is focused on novel techniques for measuring Treg activity and therapeutic interventions to augment Treg function in transplant models. These types of studies may lead to new, tailored immunosuppressive therapies for transplant recipients.
Recent publications:
Currently acute cellular rejection of a liver allograft can only be diagnosed by liver biopsy. Brendan J. Keating, PhD, and Abraham Shaked, MD, PhD, are working to identify serum microRNA signatures as a non-invasive biomarker of rejection. The ability to diagnose rejection by a blood test would significantly advance patient care and the ability to tailor immunosuppression to each patient’s immune activation state.
Recent publications:
Studies are ongoing to determine if wearable devices can detect early, subtle changes in heart rate and other biological parameters that can allow early detection of COVID-19 and other infections in transplant patients.
Liver disease in children is rare; that’s why collaboration is so important to new discoveries, Dr. Loomes says. CHOP is an active participant in several landmark, ongoing national studies and clinical trials to learn more about liver disease, ways to improve management of the disease in children, and identify trends that may offer new clues for future therapies.
A few of these established studies include:
Clinicians and researchers at CHOP are also actively participating in dozens more site-specific and regional studies to investigate new or adjunct treatments for patients with liver disease, improve patients’ quality of life and prevent long-term liver damage.
“Not many FDA-approved treatments exist for pediatric liver diseases,” says Dr. Loomes. For more than 50 years, the Kasai procedure – and later liver transplant – were the only proven treatments for biliary atresia, for example.
“New drugs are being studied,” she adds, “And we’re hopeful these medications – as well as other interventions – can help patients remain healthy long term, to keep their own livers longer and, in some cases, avoid the need for a transplant entirely.”