Virginia Clark, MD, is a professor of medicine and program director of the gastroenterology fellowship in the division of gastroenterology, hepatology, and nutrition at the University of Florida.

Virginia Clark, MD

 remains a challenging and often underrecognized cause of liver disease. While the condition is genetically well-defined, predicting which individuals will develop clinically significant hepatic fibrosis has remained elusive.

Historically, liver biopsy has been the standard approach for staging fibrosis and monitoring progression in AATD, but its invasiveness, cost, and patient burden have limited widespread longitudinal use. At the same time, noninvasive imaging techniques such as vibration-controlled transient elastography (VCTE) have grown rapidly in hepatology as a tool to assess liver stiffness without biopsy, but long-term, head-to-head data comparing these modalities in AATD have been slim.

American Association for the Study of Liver Diseases (AASLD) The Liver Meeting 2025

, Virginia Clark, MD, an associate professor of medicine and the program director of the gastroenterology fellowship in the division of gastroenterology, hepatology & nutrition at the University of Florida, presented 3-year longitudinal data seeking to address this gap in research, highlighting VCTE’s similar performance to biopsy for staging F2/F3 fibrosis in this patient population.

The study included patients with AATD-LD and a Pi*ZZ genotype from the Alpha-1 Liver Fibrosis/Natural History Study at the University of Florida. Liver fibrosis was assessed at baseline and year 3 by liver biopsy and VCTE. The performance of VCTE versus liver biopsy was determined according to the area under the receiver operating curve (AUC) and previously defined VCTE thresholds. Liver disease progression, defined as ≥ 1 stage advancement in fibrosis, regression, defined as ≥ 1 stage reduction in fibrosis, or stable disease, defined as no change in fibrosis stage, were assessed.

Results showed the optimal F2 cut-off values were 6.3 at baseline and 6.1 at year 3 for both reliable VCTE (AUC baseline 0.82; Year 3, 0.88) and any VCTE (AUC baseline 0.79; Year 3, 0.86). The optimal F3 cut-off value was 8.8 at baseline for both reliable VCTE (AUC 0.95) and any VCTE (AUC 0.94); at Year 3, the optimal cut-off value was 6.1 for reliable VCTE (likely owing to the small sample size for F3; AUC 0.87) and 9.2 for any VCTE (AUC 0.86).

Among patients with both liver biopsy and reliable VCTE results, 46 and 45 were staged by liver biopsy or reliable VCTE, respectively; at year 3, 17 (37.0%) and 12 (26.7%) progressed, 21 (45.7%) and 22 (48.9%) were stable, and 8 (17.4%) and 11 (24.4%) regressed, respectively. Among patients with both liver biopsy and any VCTE, 50 and 49 were staged by liver biopsy or any VCTE, respectively; at year 3, 17 (34.0%) and 15 (30.6%) progressed, 25 (50.0%) and 23 (46.9%) were stable and 8 (16.0%) and 11 (22.4%) regressed, respectively.

For additional insight into the landscape of AATD and her research presented at AASLD, the editorial team of 

: What clinical uncertainty or gap in research inspired your study?

: Alpha-1 antitrypsin deficiency is a rare disease, so long-term data from follow up that's paired with biopsies has really been missing. There's been data published using FibroScan or VCTE long-term without biopsies, and it's been very informative about progression of disease, but this research fills that gap.

: How did you go about comparing biopsy and VCTE in this research? What were some of the key findings?

: What we did, the way this study was set up initially, was just really to look for the natural history of liver disease and progression of fibrosis, ultimately, by biopsy. The participants in this study had biopsy at baseline and then 3 year follow up, and they had FibroScans, VCTE done at each interval, year follow up up to 3 years, and that allowed us to compare the progression of liver disease by both fibrosis stage on biopsy with the progression of disease with VCTE.

What we found was that there was nice concordance between individuals who had fibrosis on biopsy and the predicted fibrosis stage by VCTE. In addition, in those that progressed disease, you could tell both by biopsy and by VCTE.

: What are the clinical implications of these data?

: The clinical implications of having a noninvasive test that we know has a reasonable concordance with the biopsy that can pick up progression and disease is very patient friendly for monitoring. This is a disease state that has no therapeutic intervention that we can offer, so at this moment, we're just risk stratifying by monitoring for liver disease with fibrosis progression. There's a lot of therapies on the horizon, and it may well be that we can screen individuals who have alpha-1 with noninvasive tests and make a decision on future care. Right now, that’s a pie in the sky, but that is definitely our goal.

: Where is more research still needed moving forward?

: More research is definitely needed in terms of the reproducibility of our our findings in establishing cut-offs for what it means to have stages of fibrosis and disease, and to understand if the continuum that we see, which was that VCTE was a little lower than at higher stages of fibrosis, can be reproduced.

Editors’ note: Clark reports relevant disclosure with Novo Nordisk, Takeda, and Vertex.

Clark V, Thomas D, Lebovic G, et al. Performance of vibration-controlled transient elastography relative to biopsy for liver fibrosis staging in patients with alpha-1 antitrypsin deficiency-associated liver disease and a Pi*ZZ genotype. Presented at the American Association for the Study of Liver Diseases (AASLD) The Liver Meeting 2025. Washington, DC. November 7-11, 2025.

National Organization for Rare Disorders. Alpha-1 Antitrypsin Deficiency. March 21, 2024. Accessed November 9, 2025. 

https://rarediseases.org/rare-diseases/alpha-1-antitrypsin-deficiency/

Articles

Alpha-1 antitrypsin deficiency (AATD) is a genetically defined but often underrecognized cause of liver disease, with challenges in predicting significant hepatic fibrosis. Historically, liver biopsy has been the standard for fibrosis staging, but its invasiveness limits its use. Noninvasive techniques like vibration-controlled transient elastography (VCTE) are emerging as alternatives. Recent data presented at AASLD 2025 showed VCTE's comparable performance to biopsy in staging fibrosis in AATD patients. The study highlights VCTE's potential as a patient-friendly, noninvasive monitoring tool, though further research is needed for reproducibility and establishing cut-offs.

Clark reviews findings from a 3-year longitudinal study comparing VCTE to liver biopsy for staging F2/F3 fibrosis in patients with AATD liver disease.

VCTE’s Potential for Monitoring AATD Liver Disease, With Virginia Clark, MD

Virginia Clark, MD: Understanding Fazirsiran’s Potential in AATD Liver Disease

New data from the open-label extension of the phase 2b SEQUOIA study of fazirsiran support the investigational small interfering RNA therapy’s long-term safety and efficacy in patients with 

The Liver Meeting 2024 from the American Association for the Study of Liver Diseases (AASLD)

 in San Diego, California, by Virginia Clark, MD, a professor of medicine and program director of the gastroenterology fellowship in the division of gastroenterology, hepatology, and nutrition at the University of Florida.

, Clark described AATD as being frequently overlooked and underdiagnosed, explaining the importance of establishing the presence of fibrosis and cirrhosis to determine the next steps in disease management.

In the absence of an approved therapeutic option for the treatment of AATD-associated liver disease, transplantation is the only choice for patients who develop more severe complications. For patients with stage 2 or 3 fibrosis who fall in the “gray zone” and are at high risk of progression, Clark pointed to the promise of investigational agents in clinical trials.

“These new therapeutic agents may have the potential to reduce the toxic burden of the alpha-1 within the liver, and that may change the trajectory of what their disease does over time,” she explained.

A hepatocyte-targeted investigational RNA interference therapeutic, fazirsiran is designed to degrade alpha-1 antitrypsin and mutant misfolded Z alpha-1 antitrypsin (Z-AAT) messenger RNA in hepatocytes, subsequently reducing protein synthesis and inhibiting further accumulation of Z-AAT polymers to allow normal cellular mechanisms to dispose of mutant proteins.

The SEQUOIA trial enrolled 40 adults with Pi*ZZ AATD who were randomly assigned to receive fazirsiran at doses of 25 mg, 100 mg, or 200 mg, or placebo for ≤ 148 weeks. One-year findings showed treatment with fazisiran resulted in sustained, dose-dependent reductions in Z-AAT concentration and improved histological findings, including periodic acid-Schiff staining with diastase digestion (PAS+D) globule burden, a hallmark of AATD-associated liver disease.

Patients with fibrosis at screening and a post-dose liver biopsy at week 48, 72, and 96 entered the open-label extension and received fazirsiran 200 mg every 12 weeks for a total treatment period of ≤ 197 weeks. In total, 23 patients received ≥1 dose of fazirsiran during the open-label extension, 14 of whom received fazirsiran (FAZ–FAZ cohort) and 9 of whom received placebo (PBO–FAZ cohort) during the double-blind study phase.

“No real pulmonary complications were seen over placebo and the pulmonary function tests were stable, so that is very encouraging in the short-term,” Clark explained.

In addition to stable mean percent predicted pulmonary function in both cohorts and improved mean laboratory measures in the PBO–FAZ cohort, results showed serum Z-AAT levels reduced by a mean of 36.3% (Standard deviation [SD], 34.1) for the FAZ–FAZ cohort and 85.5% (SD, 13.1) for the PBO–FAZ cohort. Among the 20 patients who reported a treatment-emergent adverse event in the open-label extension, most were mild or moderate and 1 led to study withdrawal.

“The findings were very consistent with what we'd already seen in the first 2 studies, which was decreased liver tests and stain reduction in how much alpha-1 could be measured within the serum,” Clark said. “Overall, the results were very promising, quite consistent, and really support further development of this drug for treatment of alpha-1.”

Editors’ note: Clark has relevant disclosures with Vertex, Takeda, and Novo Nordisk.

Clark V, Strange C, Strnad P, et al. Long-term safety and efficacy of fazirsiran in patients with alpha-1 antitrypsin deficiency-associated liver disease enrolled in the phase 2 placebo-controlled SEQUOIA trial. Paper presented at: AASLD’s The Liver Meeting 2024. San Diego, California. November 15-19, 2024.

Brooks, A. SEQUOIA: Fazirsiran Reduces Serum, Liver Z-AAT Concentrations, Improves Hepatic Globule Burden. HCPLive. July 10, 2024. Accessed December 17, 2024. 

https://www.hcplive.com/view/sequoia-fazirsiran-reduces-serum-liver-z-aat-concentrations-improves-hepatic-globule-burden

Videos

Clark reviews open-label extension data from the phase 2b SEQUOIA study of fazirsiran for AATD liver disease.