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This information was reviewed and approved by Karin A. Pacheco, MD, MSPH, Robert A. Sandhaus, MD, PhD, FCCP (11/1/2017).

Who is at risk to develop Alpha-1 liver disease?

Alpha-1 Antitrypsin Deficiency, or more simply Alpha-1, is a genetic condition that may cause liver disease in children and adults. Family history can be key to suspecting Alpha-1 liver disease include family members with emphysema, COPD, unexplained liver disease, or a diagnosis of Alpha-1.

To develop Alpha-1 liver disease, a person needs to inherit one abnormal Alpha-1 antitrypsin gene (DNA material) from each parent. People with two Alpha-1 Z genes are at greatest risk of Alpha-1 liver disease, although other rarer Alpha-1 genes may increase the risk of liver disease. The risk of liver disease in Alpha-1 increases if the person suffers additional liver injury such as from viral infections (hepatitis A, B or C, or HIV infection), from alcohol abuse, from fat deposition within the liver (fatty liver), from occupational exposures to liver-toxic chemicals or from association with other genetic diseases (e.g., hemochromatosis). If a person has one normal, M gene and one abnormal, Z gene, the risk to develop Alpha-1 liver disease is greatly reduced.

If a person has two abnormal Z genes, there is a higher risk of Alpha-1 liver disease. One out of four people with ZZ Alpha-1 will develop liver disease at some point in their lifetime. The liver disease can be present at birth, and up to 5 percent of infants develop severe liver disease during the first year of life often leading to liver transplant. After the first year of life, children are most commonly tested for Alpha-1 disease when they develop jaundice or elevations of their liver blood tests during other acute childhood illnesses. In adults, anyone with unexplained liver abnormalities such as elevated liver enzymes should be tested for Alpha-1.


Why do people with Alpha-1 develop liver disease?

Liver is the major site of alpha-1 antitrypsin protein production. The hepatocytes (liver’s structural cells) read the abnormal message encoded in their Z gene and produce the abnormal Z alpha-1 antitrypsin protein. This abnormal protein can form polymers (chains of multiple Z protein molecules) that cannot leave the hepatocytes. Liver damage occurs when the hepatocytes become clogged with these polymers and die off. Lung damage associated with Alpha-1 is different. The lung tissue is deficient in alpha-1 antitrypsin protein, because the protein trapped in the liver is unable to reach the lungs and other organs. It is “stuck” inside the liver’s hepatocytes. For this reason, alpha-1 antitrypsin augmentation therapy works for people with Alpha-1 lung disease but does not work for those with Alpha-1 liver disease.