From Alpha-1 Foundation

What is Alpha-1?

Alpha-1 Fast Facts

Alpha-1 Antitrypsin Deficiency (Alpha-1) is a genetic/hereditary condition that leads to decreased circulating levels of alpha-1 antitrypsin (AAT) and significantly increases the risk of serious lung disease in adults and liver disease in infants, children and adults. Over 100 abnormal alleles have been identified for the AAT gene and of these about 1/3 are known to cause deficiency. The most common abnormal genes are the S and Z alleles, named according the speed of migration in an isoelectric focusing gel. Normal genes are labeled M (e.g.: M1, M2, M3, M4). Some abnormal alleles lead to a non-translatable gene product and therefore produce no AAT, these are the Null alleles. The most common genotype associated with Alpha-1 is ZZ (also referred to as PiZ). There are about 100,000 people with the ZZ phenotype in the US although less than 10% have been detected to date. Another deficient gene combination is SZ. Statistically SZ should be more common in the US than ZZ, however, since people with SZ are less likely to get lung or liver problems than those with two Z genes, fewer individuals with SZ have been identified.

AAT is a protein with potent protease inhibitor activity. The main function of AAT is to protect normal lung tissue from proteolytic attack during inflammation, such as that caused by infection and inhaled irritants such as tobacco smoke. In addition, tobacco smoke causes oxidative inactivation of AAT, even in people without Alpha-1. It is now known that the low circulating levels of AAT in Alpha-1 are due to abnormal folding of the defective AAT in the endoplasmic reticulum of the liver leading to polymerization and accumulation of AAT in hepatocytes. Since the liver is the primary source of circulating AAT, this accounts for the decreased circulating levels of this important protein. The accumulation of polymerized abnormal protein in the hepatocytes appears to be the cause of the increased risk of cirrhosis and liver failure in individuals with Alpha-1.

Diseases most commonly associated with Alpha-1:

• Emphysema

• Chronic bronchitis

• Bronchiectasis

• COPD

• Cirrhosis

• Neonatal hepatitis

• Hepatocellular carcinoma

• Necrotizing panniculitis

• Non-tuberculous mycobacterial infection

• Increased risk of chronic/chronic active hepatitis

The most common signs and symptoms of disease caused by Alpha-1:

• Shortness of breath

• Dyspnea on exertion

• Wheezing

• Chronic cough and sputum production (chronic bronchitis)

• Recurring upper respiratory infections

• Jaundice

• Ascites and/or peripheral edema

• Portal hypertension

• Gastrointestinal bleeding

• Asthma unresponsive to maximal medical therapy

• Unexplained liver disease or increased LFTs

Alpha-1 has been identified in virtually all populations and ethnic groups.  It is estimated that about 1 in every 2,500 Americans have Alpha-1.

Individuals with Alpha-1 may remain healthy throughout their lives. Early diagnosis and avoidance of risk factors, such as cigarette smoking, can help prevent Alpha-1 from causing disease.

An estimated 20 million people have one normal and one defective AAT gene (carriers). Carriers may pass the defective gene on to their children and there is evidence for some increased risk of lung and liver disease in carriers, as well.

Alpha-1 can lead to emphysema and is often misdiagnosed as asthma or smoking-related Chronic Obstructive Pulmonary Disease (COPD). It is critical to remember that Alpha-1 is a laboratory diagnosis, not a clinical diagnosis. You can’t definitively make the diagnosis based on the patient’s medical history or physical examination. Diagnosis is made by a simple blood test.

Alpha-1 is the most common known genetic risk factor for emphysema and COPD.

About 3% of all people diagnosed with COPD may have undetected Alpha-1.

Alpha-1 can lead to liver disease. The most serious liver diseases are cirrhosis and liver cancer.

The World Health Organization (WHO), American Thoracic Society (ATS) and the European Respiratory Society (ERS) recommend that all individuals with COPD be tested for Alpha-1. In addition, adults with incompletely reversible asthma, unexplained bronchiectasis and unexplained liver disease should be tested as well as individuals who are relatives of known affected patients. Find out more about Testing for Alpha-1.

In determining the propriety of any specific test, the physician should apply his or her own professional judgment to the specific clinical circumstances presented by the individual patient. It may be prudent, however, to document in the patient’s record the rationale for any significant deviation from this guideline.

The Alpha-1 Foundation supports testing for individuals at risk for Alpha-1 Antitrypsin Deficiency. In response to concerns surrounding testing and the benefit of an early diagnosis, the Medical University of South Carolina (MUSC), with the support of the Alpha-1 Foundation, has developed a free and confidential opportunity for testing. This opportunity comes in the form of a research study called the Alpha-1 Coded Testing (ACT) Study. Additionally, the Alpha-1 Research Registry was established by the Alpha-1 Foundation at MUSC to facilitate research initiatives and promote the development of improved treatments and a cure for Alpha-1. The Registry is a confidential database made up of individuals diagnosed with Alpha-1 and individuals identified as Alpha-1 Carriers. Also located at MUSC is the Alpha-1 Association Genetic Counseling Center. The genetic counselor is available to provide support and information to patients, caregivers, and health care professionals regarding disease manifestations, testing options, treatments, and research.