Alpha1-Antitrypsin Deficiency Clinical Presentation

Updated: Feb 10, 2017
  • Author: Dora E Izaguirre Anariba, MD, MPH; Chief Editor: John J Oppenheimer, MD  more...
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Not all the population with alpha1-antitrypsin deficiency (AATD) develops attributable disease. [2] The presentation of disease depends on the type of mutation associated with AATD However, most of the symptoms secondary to AATD are limited to the respiratory system. [1] Liver diseases such as cirrhosis and chronic hepatitis are the result of the abnormal accumulation of AAT within the hepatocytes and hepatoma, and emphysema due to loss of the proteolytic protection of the lung are the two major clinical presentations of AATD of the PiZZ type. Less common associations are panniculitis and an increase in the association of cytoplasmic antineutrophil cytoplasmic antibody‒positive vasculitis. [5]

The initial symptoms of alpha1-antitrypsin deficiency include cough, sputum production, and wheezing. Symptoms are initially intermittent, and, if wheezing is the predominant symptom, patients often are told they have asthma. If recurrent episodes of cough are most prominent, patients may be treated with multiple courses of antibiotics and evaluated for sinusitis, postnasal drip, or gastroesophageal reflux.

Dyspnea is the symptom that eventually dominates AATD (84%). [1]

Similar to other forms of emphysema, the dyspnea of AATD is initially evident only with strenuous exertion. Over several years, it eventually limits even mild activities.

Patients with AATD frequently develop dyspnea 20-30 years earlier (at age 30-45 y) than do smokers with emphysema and normal alpha1-antitrypsin levels.

Cigarette smoking accelerates the progression of emphysema in patients with AATD. Symptoms develop about 10 years earlier in alpha1-antitrypsin-deficient individuals who smoke regularly.

By the time dyspnea becomes the dominant manifestation and a diagnosis is established, most patients will have seen several physicians over several years. Efforts to improve the interval between the onset of symptoms and the diagnosis of AATD have been disappointing. Between 1968 and 2003, a significant improvement has not been noted in the average interval (approximately 8.3 +/- 6.9 y) and the number of medical evaluations before an initial diagnosis is made. [2, 9] It should be noted, however, that improvement has been shown in AATD detection in older individuals. [9]

Based on a large clinical population study, Bornhorst et al suggested that early diagnosis of AATD is sporadic and average age of diagnosis is 45.5 ± 9.5 years, as noted in other surveys. [7]

Often this diagnosis is missed, as it presents similarly to other more common illnesses such as asthma, COPD, or chronic cough. Thus, the healthcare provider must have a high level of suspicion and consider AATD in the differential diagnosis.


Physical Examination

No single physical sign confirms a diagnosis of alpha1-antitrypsin deficiency (AATD) emphysema. Signs characteristic of increased respiratory work, airflow obstruction, and hyperinflation eventually develop but are dependent on the severity of emphysema at the time of diagnosis.

Increased respiratory work is evident as tachypnea, scalene and intercostal muscle retraction, and tripod position.

Airflow obstruction manifests as pursed-lip breathing, wheezing, and pulsus paradoxus.

Hyperinflation results in barrel chest, increased percussion note, decreased breath sound intensity (see breath sound assessment video, below), and distant heart sounds.

Breath sound assessment. Video courtesy of Therese Canares, MD, and Jonathan Valente, MD, Rhode Island Hospital, Brown University.

Patients with mild emphysema generally have no abnormal findings on physical examination. Even moderate disease may be evident only when a complicating acute infection occurs. Most of the signs generally considered a part of emphysema (from any cause) are signs of moderate-to-severe disease. Mild-to-moderate disease is easily missed if the physician relies solely on physical findings.

In those with unexplained liver disease with or without respiratory symptoms should be evaluated for AATD. Assessment for signs for stigmata of chronic liver disease, and panniculitis must be performed. Hepatomegaly can be seen, but is not specific for AATD.



Alpha1-antitrypsin deficiency (AATD) is an uncommon but not rare disease. It is underdiagnosed. [1, 2] The responsible genetic defect affects 1 in 3000-5000 individuals, making it 1 of the 3 most common lethal genetic diseases among whites. (The other 2 common fatal genetic defects are cystic fibrosis and Down syndrome.) Fortunately, not every individual with AATD develops clinically significant disease. [2]

The major biochemical activity of the alpha1-antitrypsin molecule is inhibition of several neutrophil-derived proteases (eg, trypsin, elastase, proteinase 3, cathepsin G). Therefore, the protein is more accurately termed alpha1-antiprotease. However, most physicians, and virtually all patients, refer to the disease as alpha1-antitrypsin deficiency, and doctors and patients often refer to those who are affected as "alphas."

Hepatocytes synthesize alpha1-antiprotease. After its release from the liver, alpha1-antiprotease circulates unbound and diffuses into interstitial and alveolar lining fluids. Its principal function in the lung is to inactivate neutrophil elastase, an enzyme that is released during normal phagocytosis of organisms or particles in the alveoli.

Alpha1-antiprotease constitutes about 95% of all the antiprotease activity in human alveoli, and neutrophil elastase is considered the protease largely responsible for alveolar destruction. In patients with the Z allele, the alpha1-antitrypsin produced has a lysine substituted for glutamate. This results in spontaneous polymerization within the endoplasmic reticulum of the hepatocyte, which leads to decreased serum levels of alpha1-antitrypsin and thus a deficiency of peripheral alpha1-antitrypsin.

Additionally, the accumulation of intrahepatic alpha1-antitrypsin is thought to result in apoptosis of hepatocytes. This initially can manifest as laboratory abnormalities, but also can progress to hepatitis, followed by fibrosis and cirrhosis. [10]

In healthy persons, alpha1-antiprotease serves as a protective screen that prevents alveolar wall destruction. The lungs have a large surface area and are continuously exposed to a high burden of airborne pathogens, which results in a cellular immune response. This is characterized by local release of oxidants and proteases. The presence of alpha1-antiprotease serves to keep these proteases in check and protect the lungs from unregulated protease activity. Individuals with the alpha1-antitrypsin genetic defect do not release alpha1-antiprotease from the liver, and serum and alveolar levels of the protein are low. Consequently, alveoli lack antiprotease protection. The imbalance of proteases-antiproteases in the alveoli leads to unopposed neutrophil elastase digestion of elastin and collagen in the alveolar walls and progressive emphysema.

Alveolar cell apoptosis may also play an important role in emphysema pathogenesis. Recent evidence suggests that alpha1-antiprotease may inhibit alveolar cell apoptosis and protect against emphysema in the absence of neutrophilic inflammation. [11]

Cigarette smoking accelerates the onset of symptomatic disease by approximately 10 years, producing an increase in the number of neutrophils (and neutrophil elastase) in the alveolus and inactivating the remaining small amounts of antiprotease. [1] Other factors that can accelerate the onset or worsen symptoms of disease include infections and exposures to dust and fumes, which can also cause the recruitment of neutrophils to the alveoli.

Other than cigarette smoking, the role of environmental exposures on spirometric decline in patients with alpha1-antitrypsin deficiency has been uncertain. Banauch et al investigated the possible interaction of alpha1-antitrypsin deficiency and short-term massive pollution in New York City Fire Department (FDNY) rescue workers responding to the World Trade Center (WTC) collapse. In the first 4 years after the event, they found significant accelerated declines in spirometry and increased respiratory symptoms. Declines were related to the degree of exposure at the disaster site and to the degree of AATD. [12] These results support the theory that environmental factors other than cigarette smoke may play a role in the progression of lung disease in alpha1-antitrypsin-deficient patients. However, the size of the study was very small, and care should be taken in generalizing this theory given the unique nature of the WTC disaster. Further studies are needed.

The production of alpha1-antiprotease is controlled by a pair of genes at the protease inhibitor (Pi) locus. The SERPINA1 (formerly known as Pi) gene responsible for encoding alpha1-antitrypsin is located on chromosome 14 and is highly pleomorphic, with more than 100 allelic variants (denoted by letters). [1] The variants are classified based on serum levels of alpha1-antitrypsin protein. M alleles are the most common and normal variants. Most patients with clinical disease are homozygous SS or ZZ or heterozygous MS, MZ, or SZ.

Nearly 24 variants of the alpha1-antiprotease molecule have been identified, and all are inherited as codominant alleles. The most common (90%) allele is M (PiM), and homozygous individuals (MM) produce normal amounts of alpha1-antiprotease (serum levels of 20-53 µmol/L or 150-350 mg/dL).

The most common form of alpha1-antitrypsin deficiency is associated with allele Z, or homozygous PiZ (ZZ). Serum levels of alpha1-antitrypsin in these patients are about 3.4-7 µmol/L, 10-15% of normal serum levels. Serum levels greater than 11 µmol/L appear to be protective. [1, 4] Emphysema develops in most (but not all) individuals with serum levels less than 9 µmol/L.

Other genotypes associated with severe alpha1-antitrypsin deficiency include PiSZ, PiZ/Null, and PiNull. The S gene is more frequent among individuals of Spanish or Portuguese descent, whereas the frequency of the Z gene is highest in patients of Northern or Western European descent.

Patients with the PiSZ phenotype have a 20-50% increased likelihood of developing emphysema compared with MM homozygotes. Serum levels of patients with PiSZ alpha1-antitrypsin deficiency are 75-120 mg/dL.

Patients with the null gene for alpha1-antitrypsin will not produce any alpha1-antitrypsin and are high risk for emphysema (100% by the age of 30 years). None with the null gene develop liver disease because of a lack of production, and thus accumulation, of alpha1-antitrypsin in the hepatocytes. The null gene is the least common of the known alleles associated with alpha1-antitrypsin deficiency.

Carriers or heterozygotes (MZ, MS or M/Null) have levels approximately 35% of normal levels, but they do not develop disease.



Alpha1-antitrypsin-deficient patients are subject to all the complications characteristic of patients with chronic obstructive pulmonary disease from cigarette smoking. Complications may include pneumothorax, pneumonia, acute exacerbation of airflow obstruction, and respiratory failure.