The Renowned NIDDK Scientist, Physician and Educator Gives Grand Rounds Distinguished Clinical Research Scholar and Educator in Residence Lecture
Chronic liver disease extracts an extraordinary toll on the health and lives of Americans and the global population. In the U.S. alone, 4.5 million people have been diagnosed with the disease, one of the top 10 causes of death in the country.
There are an estimated 100 million people in North America living with liver disease, most of them undiagnosed. Yet compared to other chronic diseases, such as cancer, diabetes and heart disease, liver disease garners far less attention. But to those who study the disease and seek treatments and cures, "it's OK be a child of a lesser god," says Dr. Theo Heller.
The internationally renowned scientist, physician and educator shared that sentiment while presenting the Distinguished Clinical Research Scholar and Educator in Residence Lecture during NIH Clinical Center Grand Rounds on April 9.
Heller is a senior investigator and chief of the Translational Hepatology Section of the Liver Diseases Branch at the National Institute of Diabetes and Digestive and Kidney Disease, who has advanced the understanding of chronic liver disease progression and portal hypertension.
In a talk entitled "When the Symphony Becomes Discordant," Heller spoke broadly about disease models and the importance of asking the right questions, thinking far outside the box and laying down new roads of inquiry.
He described the challenge of understanding chronic liver disease and the complex interplay of its associated four horsemen: its cause or trigger, inflammation, fibrosis and the effects of cirrhosis and portal hypertension.
"Four things happening in the same liver at the same time. How do we sort that out? How do we think about that?" Heller posed.
Turning to his own research, Heller presented a precis of a multidisciplinary study of patients with Hepatitis C-related liver disease. The goal of Heller and his collaborators was to explore the portal vein, which provides a direct, albeit rarely studied view into the messages and functional connections the liver receives from the gut.
Using an extraordinary battery of tools, Heller and his team analyzed 29 patients with and without cirrhosis, examining factors such as inflammation, immune response, the microbiome and metabolism. The patients all had hepatitis C, which was treated and cleared.
Among the team's key findings: Liver transcriptome and metabolome analysis showed significant differences between patients with and without cirrhosis, even after their hepatitis C was cleared. The changes were centered around metabolic pathways, particularly in mitochondria and peroxisomes, cellular structures that function as energy production, cellular detoxification and recycling centers.
The researchers went on to examine pathways in the gut bacteria, the gut microbiome, that were most dramatically altered and correlated them with disease markers, or indicators. The team found that the top driver of these changes was the bacteria bacteroides vulgatus, a microbe found in the human gut.
Harmless under normal circumstances, bacteroides vulgatus breaks down complex carbohydrates known as glycans in the mucus lining of the intestines when they are deprived of a plant-rich diet.
"By thinning out the intestinal mucin, it can become a pathobiont [or harmful microbe] with implications for gut barrier dysfunction and inflammation," Heller said.
Overall, researchers found that such microbiome-liver interactions persisted even in the absence of the initial hepatitis C trigger, suggesting they play a fundamental role in liver disease progression.
Dr. Heller said his colleagues plan to extend this approach to study an incurable liver disease known as primary sclerosing cholangitis (PSC) across the disease spectrum. The goal, he said, is to identify early biomarkers and druggable targets related to the gut-liver axis that could help diagnose and treat liver disease before they progress to end-stage cirrhosis.
Heller opened his talk with an homage to medicine, research and the NIH Clinical Center. "It's a privilege to practice medicine and to be part of medicine and science in general," he said. "To be in this building is even more of a privilege."
Heller expressed his compassion for patients and his appreciation for the colleagues who make the Clinical Center "so magical."
He noted that approaches common in medicine today, such as the use of chemotherapy, statins, immunotherapy and antimicrobial prophylaxis, were once high-risk research undertakings pioneered at the Clinical Center.
Turning to liver diseases, Heller noted the many discoveries and treatments associated with hepatitis A, B, C, D, and E—all of them led by Clinical Center researchers.
"Go back to the beginning of recorded history," Heller said. "You'll find hepatitis outbreaks written about in papyrus in ancient Egypt. You find hepatitis B in mummies."
"These are scourges, plagues that have affected humans since the beginning of time." Now there are treatments and cures, Heller said, thanks to "this building."
- Sean Markey