Latest information on COVID-19

Acute liver failure in kids may be caused by immune system dysfunction

Prompt liver biopsies and immune-suppressing treatment could promote healing and prevent liver transplants in many children affected by acute liver failure.

- By Erin Digitale, null

Rebecca McKenzie and her colleagues found that a new way of treating children with severe liver disease could help them avoid the need for liver transplants.
Norbert von der Groeben

A new mode of treating a sudden, severe form of childhood liver disease could potentially avert dozens of pediatric liver transplants in the United States each year, according to research from the Stanford University School of Medicine and Lucile Packard Children’s Hospital Stanford.

The new study, a series of nine case reports published, found that an immune-system attack on the liver may explain many cases of pediatric acute liver failure, in which a healthy child’s liver fails without apparent cause over a few days or weeks. Until now, the cause of this disease has been mysterious, and liver transplant has been the only treatment. The findings show that early, aggressive use of existing immune-suppressing therapies could save many children’s livers.

“We believe the large majority of these cases can be explained by dysfunction of the immune system,” said Rebecca McKenzie, MD, a postdoctoral scholar in gastroenterology and the lead author of the study, which was posted online in June in Pediatric Transplantation. “And probably a good majority of these children, if they’re treated early, don’t need a liver transplant.”

Acute liver failure is responsible for 10-15 percent of pediatric liver transplants, or about 50-80 U.S. transplants each year. Unlike heart- and kidney-failure patients, who can be temporarily supported with a pump or dialysis to assist their failing organ, children with acute liver failure often need an immediate organ transplant to survive. But receiving a transplant has drawbacks, such as possible surgical complications and side effects from a lifetime of immune-suppressing medications. In addition, because donor organs are in short supply, averting transplantation benefits not just the patient whose liver is saved, but also another person who can receive the donor organ instead.

Diagnosing immune-system attack

In the new study, patients received extensive diagnostic testing, including liver biopsies, to confirm that their disease was caused by an immune-system attack. The testing ruled out the possibility that active infections were responsible for liver failure, an important distinction because infection is treated differently from immune dysfunction. The liver biopsies showed that the children’s livers had high levels of cytotoxic (“cell-killing”) CD8+ T cells, confirming that an autoimmune attack was underway.

After diagnosis, all nine of the children were treated with the immune-suppressing steroid medication methylprednisolone, and all nine also received intravenous immunoglobulin, an immune treatment derived from donor blood that can counteract auto-antibodies from the patient’s blood or modulate the immune system in other ways. All patients showed improved liver function, as assessed by blood tests, within 24-72 hours, and one patient who had already been placed on the waiting list for transplant recovered enough to be removed from the list. Four other patients stayed healthy enough to remain off the list for, and not need, liver transplants.

We believe the large majority of these cases can be explained by dysfunction of the immune system.

However, the remaining four patients still needed liver transplants. All of the patients who received transplants had liver biopsies showing extensive necrosis, or tissue death, suggesting that by the time they were diagnosed, the damage to their livers was too advanced to be reversed.

Of the five patients who did not need a liver transplant, three went on to experience bone marrow failure and need bone marrow transplants. This observation, coupled with previous reports of both pediatric and adult liver transplant patients suffering aplastic anemia — a lack of blood cells caused by bone marrow failure — suggests that in some patients, liver and bone marrow failure may be a single syndrome, perhaps caused by an immune-system attack on both organs.

“A widely used treatment for bone-marrow failure involves using medications to suppress the immune system that are similar to those administered after liver transplant,” McKenzie said. “When someone receives a liver transplant, the new organ gives them a bit of a stem cell transfusion, and they also receive very high doses of immunosuppressants, so it’s possible that liver transplantation has been treating bone marrow failure in some patients without our really being aware of it.”

Testing larger groups of children

The best way to advance the research would be a multicenter clinical trial to test methylprednisolone and intravenous immunoglobulin in a larger group of children, McKenzie said.

“We hope to better understand the connection between liver and bone-marrow failure,” McKenzie said. “Perhaps with more aggressive or better-tailored immune suppression, we might avoid both of these complications.”

Kenneth Cox, MD, professor of pediatric gastroenterology at Stanford, is senior author of the study. Other Stanford co-authors are William Berquist, MD, professor of pediatric gastroenterology; Kari Nadeau, MD, PhD, associate professor of pediatric immunology and allergy; Christine Louie, MD, resident in pathology; Sharon Chen, MD, instructor in pediatric infectious diseases; Richard Sibley, MD, professor of pathology; Bertil Glader, MD, PhD, professor of pediatric hematology and oncology; Wendy Wong, MD, clinical associate professor of pediatric hematology and oncology; Lawrence Hoffman, MD, professor of radiology; and Carlos Esquivel, MD, PhD, professor of surgery in multi-organ transplantation.

Nadeau, Glader and Cox are members of Stanford’s Child Health Research Institute. McKenzie, Berquist, Nadeau, Chen, Sibley, Glader, Wong, Hoffman, Esquivel and Cox are clinicians at Lucile Packard Children’s Hospital Stanford.

The study was funded by a Transplant and Tissue Engineering Center of Excellence Grant from Stanford University.

Stanford Medicine integrates research, medical education and health care at its three institutions - Stanford University School of Medicine, Stanford Health Care (formerly Stanford Hospital & Clinics), and Lucile Packard Children's Hospital Stanford. For more information, please visit the Office of Communication & Public Affairs site at

2021 ISSUE 2

Unlocking the secrets of the brain

COVID-19 Updates

Stanford Medicine is closely monitoring the outbreak of novel coronavirus (COVID-19). A dedicated page provides the latest information and developments related to the pandemic.