How Common is α-1-Antitrypsin Deficiency?

Patient Presentation
A 4-year-old male came to clinic with a 3 day history of rhinorrhea and cough. The night before he developed a fever to 101.5°F. and was complaining of left ear pain. He had received ibuprofen with relief. He was drinking and urinating well. The past medical history was positive for α-1-Antitrypsin Deficiency diagnosed in the neonatal period because of prolonged jaundice.

The pertinent physical exam showed a mildly-ill appearing male with normal vital signs except for a temperature of 100.6°F. His growth parameters were between 10-50%. HEENT showed moderate clear rhinorrhea, normal pharynx, and a supprative effusion behind the left tympanic membrane with distorted landmarks. His right tympanic membrane was slightly erythematous but not bulging and without fluid. His lungs were clear. His abdomen was soft, and non-tender without organomegaly. His skin was normal. The diagnosis of left supprative otitis media was made in a patient with α-1-antitrypsin deficiency. The pediatrician prescribed amoxicillin for the ear infection. The parent said, “He’s had that before and it wasn’t a problem. We just want to stay away from any medicines that could cause liver problems because of his problem though.” The patient receive his seasonal influenza vaccine that day also.

α-1-Antitrypsin Deficiency (A1AT) is a common single-gene mutation disease that is homozygous recessive. The normal allele is called M and the most common abnormal allele is Z. There are other alleles though. The gene codes for one of the primary protease inhibitors in the serum, thus those who are homozygous for the Z gene are sometimes referred to as “PIZZ” or “PIZ.” α-1-Antitrypsin is found in all body tissues but is especially important in the serum and lung. As noted it is one of the primary neutrophil protease inhibitors in the serum, and acts to neutralize these enzymes when they leak into the extracellular fluid during inflammation. The Z mutation causes the synthesis of an abnormal protein which is retained in the hepatocytes and accumulates instead of being secreted. This can cause chronic liver disease including cirrhosis and hepatic failure. The Z mutation also causes emphysema in young to middle-aged adults. The natural history of the disease process can be quite variable.

Pediatric patients may be asymptomatic or present with cholestatic hepatitis, hepatomegaly, and nutrition/growth problems. Other important problems include chronic liver disease with cirrhosis and fibrosis (lifetime risk ~50% for ZZ patients). Hepatocellular carcinoma risk is increased. The lungs are particularly sensitive to A1AT. Lung infections, asthma, and emphysema occur and smoking or second-hand smoke increases the risk of serious lung disease. Lung disease more commonly presents in the adult population. Panniculitis and secondary vasculitis have also been reported in the literature. Treatment is supportive and can include organ transplant of the liver or lung. Treatment by giving α-1-Antitrypsin has not been very successful.

Learning Point
A1AT is one of the most common single gene mutations occurring in ~ 1:2,000 – 3,500 births in North American and European populations. There are ~100,000 people affected in the United States but the disease can be unrecognized and thus undiagnosed. This is particularly true because of the variation in the disease presentation.

As this is one of the most common genetic mutations, potentially it is a candidate for neonatal screening and further studies have been called for.

Questions for Further Discussion
1. What is in the differential diagnosis of conjugated hyperbilirubinemia? A review can be found here.
2. What is in the differential diagnosis of unconjugated hyperbilirubinemia? A review can be found here.
3. What are indications for solid organ transplantation?

Related Cases

To Learn More
To view pediatric review articles on this topic from the past year check PubMed.

Evidence-based medicine information on this topic can be found at, the National Guideline Clearinghouse and the Cochrane Database of Systematic Reviews.

Information prescriptions for patients can be found at MedlinePlus for this topic: alpha-1-Antitrypsin Deficiency.

To view current news articles on this topic check Google News.

To view images related to this topic check Google Images.

To view videos related to this topic check YouTube Videos.

Fregonese L, Stolk J. Hereditary alpha-1-antitrypsin deficiency and its clinical consequences. Orphanet J Rare Dis. 2008 Jun 19;3:16.

Teckman J, Pardee E, Howell RR, Appropriateness of newborn screening for α1-antitrypsin deficiency. J Pediatr Gastroenterol Nutr. 2014 Feb;58(2):199-203.

Lane CR, Tonelli AR. Lung transplantation in chronic obstructive pulmonary disease: patient selection and special considerations. Int J Chron Obstruct Pulmon Dis. 2015 Oct 9;10:2137-46.

Online Mendelian Inheritance in Man. Alpha-1-Antitrypsin Deficiency; A1ATD. Available from the Internet at (rev. 8/4/16, cited 2/13/17).

Gotzsche PC, Johansen HK. Intravenous alpha-1 antitrypsin augmentation therapy for treating patients with alpha-1 antitrypsin deficiency and lung disease. Cochrane Database Syst Rev. 2016 Sep 20;9:CD007851.

Donna M. D’Alessandro, MD
Professor of Pediatrics, University of Iowa Children’s Hospital