In homozygotes with ZZ genotype alpha-1-antitrypsin (α1AT) deficiency, mutant α1ATZ protein (α1ATZ) accumulates in hepatocytes, rather than being secreted into the blood. Homozygous individuals experience emphysema as a result of reduced levels of circulating α1AT in the lung with which to inhibit connective tissue breakdown. Homozygotes may also experience liver disease from the accumulation of α1ATZ within hepatocytes, which causes liver damage. A previous study indicated that the compound 4-phenylbutyrate (4-PBA) mediated a significant increase in release of α1ATZ from cells in tissue culture and in a mouse model of α1AT deficiency. The authors hypothesized that 4-PBA could be used to treat both the liver and lung disease of humans with α1AT deficiency.Methods:
In this preliminary, open label study the authors evaluated the effect of 14 days of oral 4-PBA therapy on α1AT blood levels in 10 patients with α1AT deficiency.Results:
There was no significant increase in α1AT blood level associated with 4-PBA administration. Symptomatic and metabolic side effects were significant.Conclusion:
4-PBA did not increase α1AT blood levels in humans with α1AT deficiency in this preliminary trial.