AATD Genotypes, AAT Levels, and Lung Versus Liver Disease Risk

In "AATD Genotypes, AAT Levels, and Lung Versus Liver Disease Risk," the panel works through what different alleles and serum levels mean for patients.

Dr. Haumschild asks Dr. Barjaktarevic how AAT levels correlate with disease severity and what follows when levels fall outside the normal range. Dr. Barjaktarevic first separates the two organs. Lung disease results from deficiency, while liver disease arises from a different mechanism, the accumulation of abnormal protein polymers that creates an inflammatory environment in the liver.

For the lungs, he describes an organ exposed to the environment with every breath. AAT helps maintain balance against proteases, comparing the imbalance to bleach that cleans the airway but burns tissue if left unchecked. Smoking, fumes, and wildfire smoke raise protease activity, so the same level can mean very different things in two people. This is why no linear line connects level to clinical presentation.

Individuals with two abnormal genes, especially ZZ, have levels near 15 percent of normal. They face the highest risk even without smoking, and most of the data come from this group. The M allele is normal, Z is severely abnormal, and S sits in between. MZ and SZ individuals also develop more disease, and the FDA treats 11 micromolar as a putative protective threshold that separates severe from less severe deficiency.

Heterogeneity is striking, with some ZZ patients keeping healthy lungs into older age and others developing devastating disease young. MZ carriers have roughly 60 percent of normal levels and number in the millions. Their added risk of asthma and COPD is real but hard to apply to any one patient. He adds that circulating Z polymers and AAT's role in immune modulation may cause harm beyond the lungs.

Dr. Sandhaus adds that the P allele produces normal levels of a protein that does not work, so additional testing is needed.

Our next episode, "Building a Primary Care Pathway to AATD Testing," turns to Dr. Kuhn on why primary care clinicians are not the problem and how order sets and defaults can make testing routine.