WASHINGTON—Blood levels of mutant Z polymer could be used as a biomarker for liver disease activity in patients with the inherited disease homozygous Z allele (ZZ) alpha-1 antitrypsin deficiency, new research suggests.
In the study, presented at The Liver Meeting 2022, high circulating levels of Z polymer were found to be associated with liver injury, fibrosis and inflammation.
In patients with alpha-1 antitrypsin deficiency (AATD), mutant protein is retained in the liver instead of being processed by the endoplasmic reticulum and then secreted in the blood (Biomolecules 2022;12[3]:380). This triggers an injury cascade and damages the liver, said investigator Anandini Suri, MD, a pediatric gastroenterology fellow with Saint Louis University Health and Cardinal Glennon Children’s Hospital, in St. Louis.
Dr. Suri and her co-investigators sought to determine whether increased circulating Z polymer levels are associated with advanced disease in adults with AATD (abstract 5002). They studied records from 93 patients enrolled in a five-year prospective cohort of homozygous ZZ AATD adults at three U.S. sites—Saint Louis University, Boston University and the University of California, San Diego—looking at demographics, physical exams, laboratory findings and other data, including elastography scores and lung function tests. Liver biopsies were done at enrollment unless patients had known cirrhosis. The investigators determined serum Z polymer levels using the 2C1 antibody in an ELISA-based assay. Of all 93 study participants, 82 had biopsies available for interpretation.
The investigators divided patients into two fibrosis groups based on Ishak scores. Groups were similar in sex, race and age at diagnosis. Only 1.5% of patients were tested for AATD due to liver symptoms, yet 33.3% had advanced liver disease, Dr. Suri said. “This means that liver disease is often silent, but by the time there are clinical symptoms, the liver damage is significant.”
Most biopsies (84%) had mild features of inflammation and steatosis. Among 54 patients not on augmentation therapy, mean Z polymer levels were 12.1 mcg/mL. Higher circulating Z polymer levels were associated with increased liver fibrosis (10.7 mcg/mL for minimal fibrosis vs. 15.1 mcg/mL for significant fibrosis; P=0.03).
Higher Z polymer levels also were associated with increased portal inflammation (10.6 mcg/mL for absent to mild vs. 17.0 mcg/mL for moderate to marked; P=0.03) and lobular necrosis (10.6 mcg/mL for no acidophil bodies vs. 19.3 mcg/mL for few acidophil bodies; P=0.0109) as well as changes in the liver injury markers gamma-glutamyl transferase, alanine aminotransferase and aspartate aminotransferase. The researchers also observed a negative correlation between Z polymer levels and lung function as measured by forced expiratory volume in 1 second testing, indicating that Z polymer levels could potentially be used as a single test to detect liver and lung injury in these patients.
Dr. Suri said further research is needed to help determine how to incorporate polymer levels into clinical care and study enrollments.
—Karen Blum
Dr. Suri reported no relevant financial disclosures.
This article is from the April 2023 print issue.