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FAQs for AATD-LD
Alpha-1 Antitrypsin Deficiency in Liver Disease: Frequently Asked Questions

Released: December 10, 2024

Expiration: December 09, 2025

Virginia Clark
Virginia Clark, MD, MS
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Key Takeaways
  • Screening and testing for alpha-1 antitrypsin deficiency (AATD), including genotyping, are crucial for accurate diagnosis.
  • Despite a lack of currently available treatments, accurate diagnosis of AATD is needed for patients to enroll in clinical trials and to be eligible for treatments that may be available in the future.
  • A multidisciplinary approach to the diagnosis and treatment of AATD and related diseases is important to ensure patients and their families are receiving appropriate support.

Introduction
Alpha-1 antitrypsin deficiency (AATD) can involve the lungs and liver as well as the skin and is poorly diagnosed throughout the world. Learn more about its diagnosis and management from experts who recently answered FAQs in a live satellite symposium.

What can healthcare professionals (HCPs) do to improve the diagnosis of AATD?
In general, HCPs do a nice job screening patients with cirrhosis or metabolic dysfunction–associated steatotic liver disease (MASLD) for AATD, but some cases are still missed. In one study, investigators examined participants in UK Biobank and determined that among 140 patients with the ZZ genotype, only 6.4% were diagnosed with AATD. Therefore, HCPs need to ensure that more patients receive an accurate diagnosis. 

What do you consider the most significant unmet need in AATD-associated liver disease (AATD-LD) management?
Improved detection of AATD through testing. Since there is no treatment for AATD at present, many individuals are not being tested. However, fazirsiran, an investigational RNA interference compound, is currently being tested in phase III trials. Once the promise of a therapy is available, hopefully testing and diagnosis will improve.

What role do multidisciplinary care teams play in addressing the unmet needs of patients with AATD-LD?
Most patients, both those with liver and lung disease, go undiagnosed or are misdiagnosed. Many adults with the ZZ genotype have been told that their problems are related to alcohol use, another issue, or MASLD and do not receive a correct diagnosis until after seeking a second, third, or fourth opinion. The same is true in patients with lung disease who are not tested initially despite being symptomatic. HCPs must ensure that all patients are being followed and tested for both lung and liver disease to ensure patients may qualify for potential clinical trials and treatments that may be coming in the future.

What nonhepatic cancers have been seen in individuals with AATD?
Individuals who are ZZ have a known risk for developing hepatic cancer.  The risks of non-hepatic cancers are less well defined.  Some small studies suggested an increased risk for lung cancer in AATD but mostly in those with underlying COPD.  A more recent study of the Swedish National AATD registry compared the risk of non-hepatic cancers in a ZZ population to the general population and found the incidence per 1000 person years of non-hepatic cancers were also increased compared to the general population (8.5 vs. 6.6).  The analysis for non-hepatic cancers included cancer of the digestive, reproductive and genitourinary organs, breast cancer, pulmonary, lymphoma, and all other organ systems grouped together.   

Do individuals with the SS genotype survive, and what is their prevalence?
People with the SS genotype are healthy; they do not develop liver disease nor lung disease. I don't think we really know what the prevalence is at a population level.

Can AATD cause liver disease to progress?
Liver disease from other causes does progress faster in individuals with MZ, and these patients are likely seen in the clinic more often than those with ZZ. We know from studies on patients with the MZ genotype who also have MASLD they are more likely to receive a liver transplant and are much more likely to get decompensation faster than patients with MASLD without fibrosis. In addition, a study using the UK Biobank showed individuals with the MZ genotype are at the highest genetic risk for cirrhosis.

In patients with an unknown genotype and threshold AAT levels, is there another method of diagnosis?
Yes. Historically, a diagnosis could be made by subjecting a patient’s serum to an electrophoretic gel and visualizing how the alpha-1 protein migrates. The presence of Z protein results in a certain band pattern, whereas the presence of S or M protein results in a different band pattern. At present, genetic testing, which likely involves polymerase chain reaction amplification of genomic DNA, a buccal swab, or peripheral blood leukocytes, is much easier, faster, and cost-effective. If a patient has already undergone a liver transplant, the protein phenotype will not be helpful, and if a patient recently had a plasma infusion, the results will be abnormal. 

Moreover, studies have shown that the majority of individuals with the MZ genotype do not have globular inclusions on liver biopsy, but Z protein is accumulated in the liver, so the presence of globules is not sufficient for a diagnosis of AATD. Ultimately, patients must be genotyped, and there are very good resources, including patient advocacy groups, available in the US and many other countries that can help patients get tested and provide support for both patients and their families.

Your Thoughts?
How do you ensure that your patients are appropriately screened and tested for AATD? Get involved in the discussion by answering the polling question and posting a comment below.

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In your practice, what do you find to be the most common barrier to appropriate screening and diagnosis of AATD?

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