Understanding Cystic Fibrosis Liver Disease

How do you bridge the gap between decades of research and clinical practice — and how might that work evolve the collective understanding of a destructive pediatric disease?

People with cystic fibrosis (CF) are born with a genetic mutation that causes the body’s fluid secretions — normally slippery and conductive — to become thick and sticky. Since these altered secretions most often cause blockages in the lungs and lead to decreased breathing function, CF is generally considered a lung disease. But these changes can also affect the digestive system, including the pancreas and liver, the latter of which has been historically understudied. At Children’s Hospital Colorado, home to the largest pediatric cystic fibrosis research center in the nation, hepatologist Michael Narkewicz, MD, has spent 40 years researching the link between cystic fibrosis and the liver. Now, researchers are closer than ever to understanding not only the risks of this disease, but also how to potentially mitigate its progression.

Investigating cystic fibrosis and the liver

Roughly 30% to 50% of people with CF will see the disease manifest to their liver, but in most of those individuals, it does not influence their overall health outcome. A small percentage of that group, however, will face more significant challenges. “About 7% to 10% of people with CF develop what we now call advanced cystic fibrosis hepatobiliary involvement or what used to be called advanced cystic fibrosis liver disease,” Dr. Narkewicz explains. “Our research is focused on trying to identify who’s at risk for advanced hepatobiliary involvement and why, in the hopes of developing interventional trials that could prevent CF hepatobiliary disease.”

Four decades have passed since Dr. Narkewicz first began studying how cystic fibrosis evolves into a liver disease, and in that time, understanding of the disease has undergone a transformation of its own. “We initially thought it was because the cystic fibrosis protein, which sits on bile ducts in the liver, did not function properly. The job of that protein is to add water to your bile so that it can flow properly,” he says. Biopsies from children with cystic fibrosis liver disease show plugs in their bile ducts, which initially led researchers to believe that the dysfunctional cystic fibrosis protein thickened bile and caused liver inflammation, resulting in fibrosis, or tissue scarring, from which the primary disease derives its name.

“As we’ve evolved, we’ve realized that there are abnormalities in the liver’s blood vessels that develop in some people with CF that lead to fibrosis, but the end result, no matter what the mechanism is, is that people have really advanced scarring of their liver,” Dr. Narkewicz says. “And those with advanced scarring have a shortened lifespan and more complications including nutritional or pulmonary challenges.”

Advanced cystic fibrosis liver disease research

Dr. Narkewicz served as principal investigator on the Cystic Fibrosis Liver Disease Network (CFLD-NET) for nearly two decades. That work, which was supported by the Cystic Fibrosis Foundation and the National Institutes of Health, aimed to identify which patients were at risk of advanced liver disease and how providers could better identify them.

One early breakthrough of the CFLD-NET proved that ultrasound technology provided an affordable, effective way to determine when a CF patient had at least a 50% risk of developing advanced liver disease. Dr. Narkewicz and his team built upon that success by collaborating with radiologists to develop standardized order sets for these ultrasounds, which ensure a consistent, comprehensive approach to how the scans are conducted and evaluated.

These standardized ultrasounds are also used in a calculation created by the CFLD-NET, which has been adopted by providers around the world to signal potential liver involvement before a patient’s cystic fibrosis progresses. “We developed this prognostic algorithm where you can plug in age, ultrasound finding and a blood test called the GGT-to-platelet ratio that will identify any individual’s risk,” Dr. Narkewicz says. “Then, we collaborate closely to review all patients who are identified as at risk of having liver disease in that space.”

These findings demonstrate the power of translational research — the phase of discovery where findings are directly applied to clinical pathways, bridging the gap between information and impact.

Caring for cystic fibrosis and the liver

Scientific advancement in pediatrics — like those Dr. Narkewicz has helped bring
to light throughout his career — can have life-changing impacts and must be handled responsibly. This is especially true when sharing new discoveries with families. For instance, when Dr. Narkewicz and his team prepared to implement their ultrasound methods, they knew it would mean delivering the hard news to families that in addition to the lung complications of cystic fibrosis, their child might also develop liver disease. Anticipating these challenges, the team used standardized scripts to share the ultrasound results in a supportive, empathetic way.

“We tested whether those scripts impacted the parents’ perceptions of their kids’ quality of life and health outcomes,” Dr. Narkewicz says. “We proved that you could add tests that have a little bit of uncertainty to them, but if you approach them in a systematic way and you have standardized language, you will not have a negative impact on how parents perceive their child’s disease.”

Thanks to this evolution in understanding from the lab to the bedside, providers now have the power to help patients with cystic fibrosis liver disease lead longer, less complicated lives. “Even if we may not have a direct therapy for this, we’re going to identify these patients much earlier,” Dr. Narkewicz says. “We can manage the disease and its consequences effectively without a liver transplant, and that’s a good thing.”