LUNG DISEASE Alpha-1 antitrypsin deficiency-associated lung disease is characterized by progressive degenerative and destructive changes in the lungs (emphysema, commonly of the panacinar type). Emphysema is a chronic, usually slowly progressive illness, which most commonly causes shortness of breath. Other symptoms may include chronic cough, phlegm production, and wheezing. Frequent respiratory infections may also occur. Serious changes that occur in the lungs and other organs of the body may develop by the time the person reaches the age of 40 – 50 years (but may also occur only later in life). Some individuals with severe deficiency of A1AT never develop emphysema and have a normal life, especially if they never smoke. Individuals affected by A1AD often experience long diagnostic delays and visits to many different health care providers before the diagnosis is made for the first time.
Pulmonary function tests may reveal reduction in expiratory air flow, hyperinflation, low diffusing capacity, and a CT scan of the chest may show loss of lung tissue that may not be apparent on breathing test results. An abnormal level of oxygen in the arterial blood (arterial hypoxemia), with or without the retention of carbon dioxide, may also occur, especially if the lung disease is advanced.
Most commonly, changes are evident in the lower lung zones of plain chest X-rays or CT scans (about 2/3 of cases), though more classic changes of emphysema that affect predominantly the upper lung zones also occur in a minority of individuals.
LIVER DISEASE Liver disease caused by A1AD may occur during infancy, childhood, adolescence, or only newly during adulthood. Symptoms in infancy include prolonged yellow appearance of the skin (jaundice), mildly elevated liver enzymes, and symptoms of cholestasis (e.g., jaundice, dark urine, pale stools and itching). Other symptoms may include enlarged liver, bleeding, an abnormal accumulation of fluids within the abdominal cavity (ascites), feeding difficulties, and poor growth or failure to thrive. Children and adolescents with this disorder may have symptoms of mildly elevated liver enzymes, severe liver dysfunction, portal hypertension and/or severe liver dysfunction. They may also become easily fatigued, or experience decreased appetite, swelling of the legs or abdomen, and/or enlargement of the liver (hepatomegaly). A1AD-associated liver disease findings in adults are any or all of the following: chronic active hepatitis, cirrhosis, portal hypertension, and hepatocellular carcinoma.
Other complications that may occur are an increase of the pressure within blood vessels in the liver (portal hypertension) that may cause bleeding from the esophagus or stomach, easy bruising, fluid accumulation in the chest, abnormally enlarged vessels within the stomach or esophagus, and/or a generally increased bleeding risk. Laboratory tests of liver function may have abnormal results and the assessment of patients for and with liver disease increasingly depend on imaging studies (i.e., liver ultrasound, etc.).
Later in the course of the cirrhosis, drowsiness may occur because the liver is unable to properly dispose of the waste products of protein metabolism (urea). A late symptom of this disorder may include an increased susceptibility to infection.
Chronic degenerative changes in the liver (scarring or cirrhosis) eventually develop in up to 30-40% of individuals with severe deficiency of A1AT, especially in individuals who escape the associated emphysema. Because the mechanism of the liver disease (i.e., accumulation of unsecreted protein within the liver cells) differs from that of the emphysema (i.e., proteolytic damage to the lung support tissues), liver disease may occur separately from the emphysema (though both may co-occur in some individuals).
PANNICULITIS The dermatologic manifestation of A1AD is a rare form of skin disease called panniculitis. Panniculitis appears to affect males and females equally, occurs at any age, and may occur in individuals with various A1AT genotypes, not confined to those associated with severe deficiency of A1AT.
Panniculitis seems to develop in only a few patients with A1AD (approximately 1 per thousand individuals with the most common form of severe deficiency, so-called PI*ZZ). The pathogenesis of panniculitis and why it occurs so rarely is unknown, though the observed favorable effects of augmenting serum levels of A1AD with infused, purified A1AD protein suggests that panniculitis may be on the basis of unopposed proteolytic activity in the skin.
The skin lesions of panniculitis associated with A1AD begin as nodules that are tender, red and inflamed (erythematous), hardened (indurated), and occur beneath the skin (subcutaneous), often with an irregular border. The panniculitis often widely affects the torso or extremities, and is characterized by ulceration in addition to serosanguineous (serum and blood) drainage and accompanying systemic symptoms, including fever.
In some patients, direct trauma often precedes the development of the lesions.
