Alpha-1 antitrypsin deficiency: Year of the Zebra 2024

Alpha-1 antitrypsin, or AAT, deficiency is a genetic disorder in which a protein called alpha-1 antitrypsin is absent or defective. The main function of AAT is to protect the lungs from damage caused by enzymes called proteases. These proteases can help fight off infections by breaking down proteins in bacteria, but they can also damage healthy tissues if their activity goes unchecked. Without AAT, the lung’s proteases break down the elastic fibers in the air sac walls, resulting in destruction of healthy lung tissue.

The severity of the disorder varies depending on the amount of AAT in the blood. While some mutations result in little to no AAT being made, others, like the most common mutation, called Pi*Z, result in a misfolded AAT protein that gets trapped in the liver where they are normally produced, causing damage and ultimately death of liver cells.

People with PiZ mutations are at risk of both lung disease and liver damage, whereas those with non-PiZ mutations only have an increased risk of lung disease.
Symptoms of alpha-1 antitrypsin deficiency typically involve the lungs and liver. Damage to the lungs can result in shortness of breath, as well as wheezing, increased mucus production, and a chronic cough due to inflammation of the airways.

Ultimately, the death of liver cells can lead to cirrhosis, a process in which healthy liver tissue is replaced with scar tissue. Long-term cirrhosis can lead to a number of complications, including easy bruising due to decreased production of clotting factors by the liver; jaundice, characterized by yellowing of the skin and eyes; and swelling in the abdomen and legs. In some cases, chronic cirrhosis can predispose individuals to hepatocellular carcinoma, which is the most common primary liver cancer. Aside from lung and liver manifestations, some individuals experience skin manifestations, including red nodules, bumps, or plaques in areas of the body with accumulation of subcutaneous fat like the buttocks, thighs, and abdomen.