Alpha-1 Antitrypsin Deficiency (AATD)

Alpha-1 antitrypsin deficiency (AATD) must be differentiated from other disease processes similarly impacting the liver and the lungs.

Differential Diagnosis of Liver Diseases

Autoimmune hepatitis is a chronic liver disease where the body’s immune system attacks liver cells causing continuous inflammation and necrosis of hepatocytes, which progresses to cirrhosis and possibly liver failure.1 There are several methods of testing that are used to diagnose autoimmune hepatitis. Blood tests measure specific liver enzymes and autoantibodies like antinuclear antibodies (ANA) and anti-smooth muscle antibodies (SMA). Ultrasound and CT scans, as well as a liver biopsies, also may be used to identify autoimmune hepatitis.2 

In AATD, the blood tests may show elevated liver enzymes, as in autoimmune hepatitis, indicating hepatocyte inflammation and destruction.3 However, autoimmune antibodies would not be present in AATD as they denote autoimmune disease. Also, low serum alpha-1 antitrypsin levels and isoelectric focusing would indicate AATD as the primary cause of liver disease.4 

Viral Hepatitis is inflammation of the liver resulting from a viral infection, usually caused by Hepatitis A (HAV), Hepatitis B (HBV), or Hepatitis C (HCV) viruses. Jaundice, malaise, abdominal pain, fatigue, and nausea are the symptoms of acute liver disease from these viruses. Hepatitis B and C may lead to chronic infections.5 Blood tests are used to determine the type of viral hepatitis (HAV, HBV, or HCV), severity of infection, and whether the individual is currently contagious or not. Sometimes, imaging studies like ultrasound or CT scans and a liver biopsy are used to diagnose viral hepatitis.6 

Differential Diagnosis of Lung Diseases

Bronchiectasis is a rare disease that is usually secondary to an infectious disease process involving abnormal and permanent distortion of one or more bronchi of the lungs. Bronchiectasis is a comorbidity of AATD. AATD tends to be the underlying disease process when an individual has both AATD and bronchiectasis.7 The US Bronchiectasis Research Registry indicates 9.4% of individuals diagnosed with bronchiectasis have also been diagnosed with severe AATD.8 The current recommendations of the European Respiratory Society are to screen for AATD as the possible cause of bronchiectasis only when emphysema is affecting the basilar lobes of the lungs. For all other newly diagnosed individuals with bronchiectasis, only three etiological tests are recommended including differential blood count, serum immunoglobulins, and tests for allergic bronchopulmonary aspergillosis. The authors of a 2020 study questioned why all individuals diagnosed with bronchiectasis are not tested for AATD since confirmation of an AATD diagnosis may improve the course of treatment for individuals with bronchiectasis.9 

Bronchitis involves inflammation of the bronchial tubes which extend from the trachea to the small alveolar sacs where gas exchange occurs in the lungs. It commonly occurs in patients with acute respiratory infections that cause frequent coughing, but it must be differentially diagnosed from influenza and pneumonia among other infections.10 The clinical definition of chronic bronchitis is the presence of a continuous productive cough for 3 or more months during 2 consecutive years.11 Bronchitis is a comorbidity of AATD. If an individual is diagnosed with chronic bronchitis, since it is a type of chronic obstructive pulmonary disease, the recommendation is to rule out AATD as an underlying cause.12

Chronic obstructive pulmonary disease (COPD) is a general term used to describe various diseases that are characterized primarily by impaired airflow on exhalation. Three main diseases that encompass COPD are asthma, emphysema, and chronic bronchitis. In COPD, pathological changes occur in the lung tissue due to exposure to noxious environmental inhalants, mainly cigarette smoke.11 COPD is a comorbidity of AATD. A way to differentially diagnose AATD from the classic forms of COPD without AATD would be to examine chest x-ray imaging. In the majority of AATD patients, destruction of the basal panlobular portions of the lungs occurs first, resulting in a hyperlucent appearance more at the bottom of the lungs on imaging because healthy alveolar tissue is absent. In classic COPD caused by cigarette smoking, the apical lung tissue is destroyed first progressing to a more centrilobular deterioration along the main bronchioles.13 Current recommendations of the Medical and Scientific Advisory Committee of the Alpha-1 Foundation suggest that every individual with any form of COPD be tested for AATD.12 

Cystic fibrosis (CF) is one of the ree most common rare diseases (in addition to AATD and Down Syndrome) that affect European ancestry.14 CF involves a disease process that involves multiple organ systems, but mainly affects the lungs and pancreas.15 Patients with CF typically produce a very sticky, viscous mucus that is difficult to clear out of the airways and promotes collection and entrapment of bacteria causing increased infections and inflammation. CF is the result of a CTFR (protein transmembrane conductance regulator) gene mutation causing a lack of chloride channel transport proteins in mucous membranes.16 CF is diagnosed via genetic testing, a sweat chloride test, and a complete clinical examination at a CF-accredited care center.17 

Emphysema is a lung disease within the categorization of chronic obstructive pulmonary disease (COPD) that is defined as a permanent enlargement of the air spaces distal to the terminal bronchioles which is accompanied by alveolar destruction and without notable fibrotic changes. This results in disruption of gas exchange in the alveoli leading to progressive entrapment of unoxygenated air and impairment of airflow on exhalation. It is a comorbidity with AATD.18 If an individual has AATD and emphysema, low levels or no level of serum alpha-1 antitrypsin protein would be present along with symptoms of emphysema. Current recommendations of the Medical and Scientific Advisory Committee of the Alpha-1 Foundation suggest that every individual with any form of COPD (including emphysema) be tested for AATD.12 

Primary ciliary dyskinesia (Kartagener Syndrome) describes defective motility of the cilia, or tiny hairs lining the mucus membranes of the upper airways. This makes mucus clearance of the airways difficult, resulting in chronic sinus and respiratory infections.19 Kartagener Syndrome is a subdivision of primary ciliary dyskinesia that usually involves a distinct triad of clinical manifestations, including: 

  • situs inversus, which occurs when the organs of the chest and abdomen have mirror image locations from their normal positions 20
  • chronic sinusitis
  • bronchiectasis21

Primary ciliary dyskinesia is diagnosed through genetic testing or biopsy of lung or sinus tissue.22 A study using information from the US Bronchiectasis Research Registry contrasted the clinical presentations of patients suffering from AATD and those suffering from primary ciliary dyskinesia. The major difference between the two diseases was that mycobacterial infections were found in a greater percentage of individuals with AATD, whereas Pseudomonas aeruginosa more commonly infected individuals with primary ciliary dyskinesia.8


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Reviewed by Harshi Dhingra, MD, on 7/1/2021.