Alpha-1 antitrypsin (A1AT; also known as α-1 proteinase inhibitor) is a serum glycoprotein which predominantly (80%) originates from hepatocytes.1
A1AT inhibits a wide variety of proteases (eg, neutrophil elastase and proteinase-3) to contribute to a proteinase/antiproteinase balance.2
It is postulated that this acute phase protein participates in limiting host tissue injury by proteases at sites of inflammation;3
a proposed critical function is the prevention of lung injury associated with disruption of connective tissue by neutrophil elastase enzyme.1
A1AT deficiency is an autosomal recessive genetic disorder caused by its defective production leading to both decreased activity in body tissues and deposition of excessive abnormal protein in the liver.1
While M is the normal allele for A1AT, there are over 80 variant mutations of the gene. The Z allele results in a glutamate to lysine mutation at position 342 while the S allele produces a glutamate to valine mutation at position 264. In individuals with SS, MZ and SZ genotypes, blood levels of A1AT are reduced to between 40% and 60% of normal levels (ie, those observed among MM individuals). Among those who do not smoke, this A1AT concentration is almost always sufficient to protect the lungs from the effects of elastase. However, among individuals with the ZZ genotype, A1AT levels are usually less than 15% of normal and these deficient patients can develop lung disease at a young age. In addition, those with the ZZ genotype can develop liver disease; this is associated with impaired A1AT secretion and its consequent accumulation in this specific tissue. Therefore, A1AT deficient patients can present with lung disease (eg, panacinar emphysema [chronic obstructive pulmonary disease], pneumothorax, asthma, and bronchiectasis) and liver disease (eg, hepatitis, cirrhosis, and hepatocellular carcinoma).4
People of northern and western European ancestry are at the greatest risk for A1AT deficiency and its associated diseases;5
4% carry the PiZ allele and between 1 in 1,500 and 1 in 2,500–3,000 are ZZ.
In addition to siderophores and ferrireductases, microbials employ proteases to mobilize host sources of iron to support their growth and replication.6
These proteases cleave iron-transport and -storage proteins allowing utilization of the metal by the microbe.7
Corroborating a potential interaction between metal homeostasis and proteases, elevated iron concentrations impact expression of proteases and their activities.9
Animal and human investigation similarly suggests a participation of proteases in iron homeostasis.13
The intratracheal instillation of a single dose of neutrophil elastase in an animal model increased lung iron concentrations. Iron homeostasis is disrupted among cystic fibrosis patients in whom airway elastase content and activity is excessive; cystic fibrosis patients have elevated iron and ferritin concentrations in both the sputum and bronchoalveolar lavage.
A participation of proteases also suggests a potential involvement of anti-proteases in iron homeostasis. A1AT is the antiprotease in greatest concentration in humans. A participation of A1AT in the iron homeostasis of humans has been previously suggested with observations of deficient patients developing cirrhosis characterized by significant iron accumulation.16
An involvement of neutrophil elastase and A1AT in disrupting iron homeostasis of the lung was supported by investigation which demonstrated a proteolytic cleavage of both iron-transport and -storage proteins with subsequent increase in nonheme tissue iron concentrations.17
Finally, patients treated with antiproteases, and thus altering protease activity, can show evidence of disruptions in iron homeostasis.18
We further explored the relationship between A1AT and iron homeostasis in humans by testing the postulate that its deficiency is associated with a systemic disruption in iron homeostasis.