The Overlooked Liver Side of Alpha-1 Antitrypsin Deficiency

Alpha-1 antitrypsin deficiency (AATD) is caused by a mutation in the SERPINA1 gene, but it shows up as two distinct diseases: one in the lungs and one in the liver. Tami Nussbaum, M.D., MBA, global medical affairs lead for the GI pipeline at Takeda, explained that the alpha-1 antitrypsin (AAT) protein is made in liver cells and normally travels to the lungs, where it neutralizes another protein that would otherwise damage lung tissue.

The SERPINA1 mutation causes AAT to be produced with the wrong shape. Misfolded protein cannot be properly secreted from the liver into the bloodstream, and it also tends to stick to itself, forming toxic clumps called polymers inside liver cells. Over time, that buildup drives a progressive injury pattern: fibrosis, or scarring, followed by cirrhosis, and in some cases the need for a liver transplant or the development of hepatocellular carcinoma, a form of liver cancer.

A disease that hides in plain sight

Nussbaum said the central problem with AATD, in both its lung and liver forms, is that it is underrecognized. The liver side is especially difficult because most patients have no symptoms in the early stages. By the time liver disease is discovered, it may already be advanced, sometimes to the point of needing a transplant. Nussbaum cited data showing that only around 10% of people with alpha-1 liver disease are properly diagnosed.

Delayed identification carries real consequences: Some patients are not diagnosed until they reach decompensated cirrhosis or other serious complications, by which point the disease has already caused lasting harm.

Three pathways, one destination

Nussbaum described three ways patients typically enter the AATD story, all of which should lead to a liver evaluation:

• Liver disease first. A multisociety expert panel recently published the first clear case definition for alpha-1 liver disease, identifying it in adults with the PiZZ genotype who have recurrently elevated liver enzymes or evidence of significant liver fibrosis. The gap, Nussbaum said, is that these patients are not always tested for alpha-1 in the first place.
• Lung disease first. Many patients are followed by pulmonologists for lung symptoms, which can appear earlier than liver symptoms, but they don’t always receive a liver assessment.
• A known ZZ mutation. Some people learn they carry the ZZ mutation through family testing or routine genetic testing, without a specific reason tied to symptoms.

Nussbaum said all three groups should ultimately be referred to a hepatologist or otherwise assessed for liver involvement, but fragmented pathways between specialties mean that connection often doesn’t happen.

Family testing remains underused

Because AATD is genetic and runs in families, Nussbaum pointed to family testing as another missed opportunity. Even though the condition is heritable, family screening has not been broadly adopted, leaving relatives of diagnosed patients unaware of their own risk.

What the new consensus guidance changes

The framework Nussbaum referenced was published in Gastroenterology as a multisociety expert panel consensus, convened by the American Gastroenterological Association with the American Association for the Study of Liver Diseases, the European Association for the Study of the Liver and the Alpha-1 Foundation. It establishes the first standardized nomenclature, case definition and diagnostic staging approach for alpha-1 antitrypsin deficiency-associated liver disease (AATD-LD), which the panel says remains underdiagnosed.