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Improving AATD care with early diagnosis and management

CE / CME

Improving AATD Care Through Early Diagnosis and Multidisciplinary Management: A Call to Action

Physician Assistants/Physician Associates: 1.00 AAPA Category 1 CME credit

Nurse Practitioners/Nurses: 1.00 Nursing contact hour

Physicians: maximum of 1.00 AMA PRA Category 1 Credit™

Released: June 12, 2025

Expiration: June 11, 2026

Rohit Loomba
Rohit Loomba, MD, MHSc
CME/CE Information

Activity

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Course Completed

Pathophysiology of AATD-LD

AAT is predominantly synthesized in the liver and secreted into the blood. It normally inhibits neutrophil proteinases and protects the body during inflammation. In addition, it is an acute-phase response protein.

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Mutant Z encodes synthesis in the liver, where it accumulates and does not secrete. Serum levels that are "deficient" leave the lungs susceptible to injury. This occurs due to a deficiency of functional AAT protein levels in the blood. By contrast, AAT accumulation in the liver triggers an injury cascade that starts with the “accumulation” of the mutant protein and leads to cell death, regeneration, progressive fibrosis, cirrhosis, and hepatocellular carcinoma (HCC).1-3 

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Overview of AATD: Liver vs Lung Disease

Approximately 50% of Americans with AATD, which is approximately 1 in every 3000 to 5000 people, may develop reduced lung function over time. In comparison, only approximately 10% of adults with AATD will go on to develop liver disease. In a longitudinal Swedish study, 7% of patients with AATD developed cirrhosis and 2% developed HCC. Lung disease in particular is related to AATD because reduced AAT leads to increased activity of neutrophil elastase in the lungs. This occurs because of a deficiency in the serum of functional AAT. Then the accumulation and improper polymerization of AAT in hepatocytes leads to liver disease.

Although AATD is a genetic disease, the symptom causation is different in its related liver vs lung disease. Furthermore, the most common variant that is associated with both AATD-related lung and liver disease is the ZZ variant.3-6

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Genetic Drivers of AATD

There are clear genetic drivers of AATD-related lung and liver disease. The SERPINA1 mutation is an autosomal codominant inheritance. It is associated with the “M” wild-type allele, as more than 98% of the population is homozygous for MM. The “Z” variant is the most common disease-related allele, among others, including “S.”

ZZ mutations are typically seen in 1 person for every 1500 to 3000 people in the United States and Europe. Furthermore, 90% of patients with AATD have the ZZ mutation. The “SZ” mutation can also develop ZZ-like disease, but the risk for this is much lower.

Finally, MZ heterozygous carriers make up approximately 2% of the population. That is 1 in every 50 people. In addition, MZ is a genetic modifier of other liver diseases, adding a small but persistent risk.7-9

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Distribution of Pi*Z Frequencies Around the World

This slide shows the global distribution of Pi*Z. You can see there are certain areas that are known to have a high frequency of Pi*Z, in particular, northern Europe, the United States, and Canada. You can also see that disease prevalence is higher in Australia, New Zealand, and parts of southeast Asia and eastern Africa. The prevalence of this disease is significant in these geographic areas.10

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AATD Genetics

The Pi*ZZ genotype causes 90% of severe AATD cases. As illustrated on this slide, serum AAT levels are associated with specific genotypes. Serum levels in patients with MM typically range from approximately 100-150 mg/dL, whereas serum levels in patients with MZ range between 50-100 mg/dL, SZ are below 90 mg/dL, and ZZ are below 30-50 mg/dL. Normal AAT levels range between 90-175 mg/dL, with 110 mg/dL often being the cutoff point for considering more testing.

Compared with those with the Pi*MM genotype the estimated prevalence among White individuals is 1 in every 2000 people for ZZ, 1 in every 500 people for SZ, and 1 in every 50 people for MZ. The odds ratio for developing cirrhosis is approximately 20 times higher for ZZ, 3-5 times higher for SZ, and 1.7 times higher for MZ. Then approximately 1% of adults with ZZ and 10% of adults with MZ have liver transplantation performed in Europe. There are no data available on SZ. HCC risk is significantly increased in those with ZZ (23-45 times higher) and SZ (7 times higher). Additional studies are needed to determine the exact HCC risk for MZ.11,12

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Clinical Presentation Highly Variable

The clinical presentation of AATD is highly variable. Sometimes infants may present with neonatal cholestatic hepatitis (approximately 20% of all newborns with ZZ). Most infants with ZZ have their hepatitis resolved spontaneously and are well by 18 years of age.

Adolescent patients may develop hepatitis or cirrhosis, but liver transplantation or death are uncommon. Then young adults and middle-aged adults may develop asthma, chronic obstructive pulmonary disease (COPD), or liver disease, but liver disease is uncommon. Older adults with AATD go on to develop COPD, emphysema, bronchiectasis, hepatitis, cirrhosis, and in rare instances, HCC.13

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Genetic and Environmental Factors Play a Major Role

Genetic and environmental factors play a major role in the progression of AATD-related diseases. This includes smoking as it increases the risk of lung disease. Although we do not have significant data as to whether smoking affects liver disease, emerging evidence shows that there is an association between cigarette smoking and chronic liver diseases. So it is important to tell patients to avoid or abstain from smoking, particularly if they have the ZZ mutation, to protect their lungs.

Obesity is associated with a higher risk for disease progression across the spectrum of liver diseases. The presence of metabolic syndrome is especially important in adult liver diseases, which can lead to progressive fibrosis. Neonatal cholestasis presents a moderate risk (approximately 5%) for severe liver disease during childhood.

Click below to listen to Dr. Loomba’s comments on this topic.

Then there is evidence that liver diseases may worsen with progressive or higher consumption of alcohol. And individuals who drink excessively—particularly those with overweight or obesity—have a higher risk of developing cirrhosis and liver problems, though there is no known association between alcohol and AATD-related lung disease.5,14-17

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General Outcomes and Prognoses of AATD-LD

Although there is no specific treatment for AATD-associated liver disease, there are many novel therapies being studied in clinical trials. In addition, liver transplantation has proven highly successful in both children and adults. AATD accounts for approximately 3% of all liver transplantations in pediatric patients. Among those patients with AATD and liver transplantation, the 1-year survival rate is more than 90% and the 5-year survival rate is 83%. Worse outcomes are loosely associated with elevated gamma-glutamyl (GGT) transferase levels in children and elevated aspartate transaminase (AST) levels in adults.

Patients should avoid cigarette smoking, which is associated with risk for progressive lung disease. I also advise my patients to abstain from alcohol because of its risk for progressive liver disease.1

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Disease Risk

Liver transplantation or death in childhood occurs in approximately 3% of patients with AATD. There is a 10% to 40% risk for adult liver disease, and 20% to 40% lifetime risk for cirrhosis that increases in older age. HCC risk is elevated but difficult to quantify. However, the risk is particularly high in those who develop cirrhosis. Therefore, once patients are diagnosed with cirrhosis related to AATD-related liver disease, I recommend that healthcare professionals (HCPs) complete routine screening and surveillance for HCC. Finally, there is a 40% to 60% lifetime risk for severe lung disease among patients with AATD.18

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