“The continuation of achieving our goals hinges on detecting, testing, finding and helping every Alpha. We have increased our efforts to detect Alphas with liver disease by adding a pilot program to screen for liver disease at the 2026 A1F Education Days. Early detection is necessary for better outcomes and our mission to improve the lives of those affected by Alpha-1. In order to achieve this, papers like this are so important to provide recommendations to aid clinicians in finding Alphas, testing and diagnosing them early in their journey. There is much hope on the horizon with potential therapies in the pipeline for liver affected Alphas, we are working and collaborating to expedite discovery and the approval of new therapies and treatments through our research registry and with focused programs,” said Scott Santarella, A1F President & CEO.
Key takeaways:
- Alpha-1 antitrypsin deficiency-associated liver disease is largely underrecognized.
- Defining nomenclature and diagnostic criteria is key to improving outcomes for patients.
A multinational, multidisciplinary group of experts has created a consensus document to guide diagnosis, staging and management of adults with alpha-1 antitrypsin deficiency-associated liver disease, as well as advance research efforts.
Paul Kwo, MD, FAASLD, director of hepatology and professor of medicine at Stanford University, was part of the panel that convened under the auspices of AGA in collaboration with American Association for the Study of Liver Diseases, European Association for the Study of the Liver and Alpha-1 Foundation. The document was published in Gastroenterology.
“Although this is a rare disorder, all hepatologists and gastroenterologists encounter patients with AATD-LD as do primary care physicians,” Kwo said. “But, overall, the disorder itself remains substantially underdiagnosed.”
The group zeroed in specifically on patients with the PiZZ genotype.
“Globally, there are approximately 250,000 people with the PiZZ genotype, and around 80,000 to 100,000 in the U.S.,” Kwo said. “But despite these numbers, there remains a high rate of underdiagnosis: As many as 95% of individuals with the PiZZ genotype remain undiagnosed.”
Not receiving a diagnosis can be particularly concerning for patients with the PiZZ genotype, according to Kwo. “This genotype causes deleterious liver disease and lung disease,” he said. “Anywhere from 20% to 33% of these patients with PiZZ can develop significant fibrosis over time, and approximately 10% develop clinically significant liver disease, such as fibrosis, cirrhosis and hepatocellular carcinoma. This was the background for this consensus document.”
Variability in terminology and diagnostic approaches contributes to these diagnostic challenges, Kwo added. “It has hampered the ability to identify and diagnose affected adults,” he said.
Previous groups have attempted to define terminology and identify biomarkers with limited success. “There was a need for precise definitions to support early diagnosis and risk stratification,” Kwo said.
Defining terminology was not the only impetus for publishing this new set of recommendations. “This genetic disorder is being addressed with a variety of therapeutic approaches, with novel therapies in development [which] hopefully will become available in the near future,” he added.
The collaboration between the professional societies was “highly successful,” according to Kwo.
“It was clear that the societies were aligned in the need for creating this document,” he said. “We hoped to aid clinicians in case finding, referring these patients for appropriate therapy and providing a framework to make sure research efforts are aligned. The goal in all of this is to provide optimal outcomes for this underserved and undiagnosed patient population.”
“It is our goal at A1F to promote detection of liver disease in Alphas. We have piloted a program at the 2026 A1F Education Days to offer Alphas a free FibroScan to screen for signs of liver disease. It is our goal to make Alphas aware of their risk and provide access to a free screening, and follow-up protocols. Through our Research Registry, Alphas can learn about clinical trials in Alpha-1 liver disease and the many novel therapies and therapeutic approaches that are in development, “ said Jon Hagstrom, Chair of A1F Board of Directors.
Key recommendations
The document contains proposals to improve diagnosis and management of AATD-LD, as well as advance research for therapeutic development. They include:
Pulmonary monitoring: If lung function is used as a stopping rule, a significant decline in forced expiratory volume in 1 second (FEV1) or transfer coefficient of carbon monoxide (KCO) should require a reduction of at least 20%, confirmed on two or more consecutive tests. Low FEV1% predicted value inclusion criteria should be considered, particularly if patients are on augmentation therapy and carefully monitored.
Nomenclature: Alpha-1 antitrypsin deficiency-associated liver disease (AATD-LD)
Definition:Adults with PiZZ genotype who exhibit recurrently elevated liver enzymes and/or evidence of significant liver fibrosis.
Case detection and diagnostic testing: Diagnostic evaluation of chronic liver disease should include testing for AATD by determining the serum alpha-1 antitrypsin level. Genotyping is necessary to identify carrier genotypes.
Staging and monitoring: Individuals with the PiZZ genotype should undergo noninvasive liver fibrosis staging, including liver stiffness measurement and blood-based assessments. Liver biopsy is not required, although it may be indicated in select cases to establish or exclude additional factors contributing to liver disease.
HCC surveillance and transplant referral: Early consideration for liver transplantation is warranted in patients with decompensatedAATD-LD. Any patient with decompensation — including ascites, variceal bleeding or hepatic encephalopathy — should be referred to a center with expertise in transplant hepatology and AATD-LD.
Clinical trial inclusion and endpoints: The ideal study population would include PiZZ individuals with significant liver fibrosis (F2-F4). A one-stage improvement in fibrosis stage over a 2-year period should be sufficient as a primary endpoint in phase 3 clinical trials.
“This paper redefining rare liver disease and defining the nomenclature and diagnostic criteria truly is key to improving outcomes for Alpha-1 patients. 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. There is 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,” stated Dr. Virginia Clark, professor of medicine and program director of gastroenterology fellowship in the division of gastroenterology, hepatology and nutrition at the University of Florida and A1F BOD Physician/Director.
Early referral, appropriate staging
Kwo stressed that each of these recommendations fills a critical gap in care for this patient population.
“It is important that people with PiZZ are appropriately staged for the presence or absence of fibrosis, given the 20-fold increased risk of fibrosis compared to wild-type,” he said. “The multisociety group proposed that patients with the PiZZ genotype — those with elevated liver enzymes or elevated liver fibrosis — are at highest risk for developing liver disease. Because the risk is so much higher in these patients, the term AATD-LD should be applied only to those adults who have the PiZZ genotype.”
Regarding staging and monitoring, Kwo stressed that the Z allele is driving cases of AATD-LD with the PiZZ genotype. “Genotyping is important and is recommended for all adults with a low serum alpha-1 antitrypsin levels,” he said.
While diagnosis of AATD-LD can move forward without a biopsy, Kwo noted that conventional protocols for HCC screening and transplant referral apply. “For HCC screening, this means that those with AATD-LD cirrhosis [could] be managed just like those with cirrhosis from other etiologies,” he said. “Ultrasound and alpha-fetoprotein should be done every 6 months, consistent with current societal guidelines.”
Development of ascites, bleeding or decomposition all warrant consideration for transplant referral, as with other liver conditions, according to Kwo. “Early referral is recommended for patients with decompensated liver due to alpha-1 antitrypsin,” he said.
Regarding clinical trial inclusion and endpoints, Kwo noted that the pipeline contains agents in phase 1, 2 and 3 studies.
“Individuals with clinically significant fibrosis should be included in trials for AATD-LD,” he said. “FEV1 predicted value should be greater than 50%. However, if there are novel mechanisms that increase the release of functional alpha-1 antitrypsin into the circulation, a lower value of FEV1 could be considered.”
An adaptive trial design with pulmonary safety should be considered in this patient population, according to Kwo. “The primary manifestation of AATD is pulmonary, not in the liver,” he said. “For novel agents, one would expect pulmonary function to improve. If an investigational therapy has a good safety profile, enrollment can be more inclusive if the trial moves forward.”
Given the importance of pulmonary manifestations in this disease, Kwo stressed that a persistent decline in FEV1 or KCO should serve as a benchmark for patient management in trials where lung function is used as a stopping rule. When testing novel therapies for those with AATD-LD, “we recommended that a persistent change in FEV1 or KCO of 20% is considered clinically significant if it is confirmed in consecutive visits,” he said.
Kwo hopes that these consensus recommendations will signify a paradigm shift in the management of AATD-LD. “It is an exciting time for individuals who have this disorder,” he said. “The key thing gastroenterologists and hepatologists need to know is that they must be alert to identify this pool of patients. The majority of people are not diagnosed, and we need to find them.”
Vigilance in the clinic for abnormal liver chemistry with alpha-1 antitrypsin levels is paramount.
“We need to make sure to assess patients for alpha-1 antitrypsin deficiency and liver disease who are referred with elevated liver tests and/or concern for fibrosis,” Kwo said. “We are entering an era with potential therapies for this disorder currently in development.”
He added: “Hopefully, over time, these therapies will demonstrate that they can prevent liver-related outcomes. This will be a major advance if we can halt the progression of a disease that can lead to cirrhosis, decompensation and hepatocellular cancer.”
For more information:
Paul Kwo, MD, can be reached at pkwo@stanford.edu.
Published by:
Healio Logo – Gastroenterology
Sources/Disclosures
Source:
Loomba R, et al. Gastroenterology. 2025;doi:10.1053/j.gastro.2025.12.012.
Disclosures: Kwo reports consulting for Aligos, HepQuant, Inventiva, Lygenesis, Madrigal Pharmaceuticals, Mirum Pharma, Precision BioSciences and Tune Therapeutics; receiving grant support from 89Bio, Akero Therapeutics, Altimmune, AusperBio, Inventiva, Salix Pharmaceuticals, Takeda Pharmaceuticals, Target Registries, Ultragenyx and Vir Biotechnology; and serving on advisory boards of Amgen, Arbutus Biopharma, AusperBio, Gilead Sciences, GSK, Novo Nordisk, Target Registries and Ultragenyx. Please see the study for all other authors’ relevant financial disclosures.
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