Liver disease in alpha1-antitrypsin deficiency detected by screening of 200,000 infants.
ABSTRACT We prosepctively studied 200,000 newborns to determine the frequency and clinical characteristics of alpha1-antitrypsin deficiency. One hundred and twenty Pi Z, 48 Pi SZ, two PI Z-and one Pi S-infants were identified and followed to the age of six months. Fourteen of 120 Pi Z infants had prolonged obstructive jaundice, nine with severe clinical and laboratory evidence of liver disease. Five had only laboratory evidence of liver disease. Eight other Pi Z infants had minimal abnormalities in serum bilirubin and hepatic enzyme activity and variable hepatosplenomegaly. All 22 Pi Z infants with hepatic abnormalities, two thirds of whom were made, appeared healthy at six months of age. Ninety-eight Pi Z infants did not have clinical liver disease, but liver-function tests gave abnormal results in 44 of 84 at three months, and in 36 of 60 at six months of age. The number of small-for-gestational-age infants was greater (P less than 0.001) among those with clinical liver disease. None of the 48 Pi SZ infants had clinical liver disease, but 10 of 42 at three months and one of 22 at six months of age had abnormal liver function. The Pi Z and Pi SZ phenotypes are associated with covert or readily apparent hepatic dysfunction in the first three months of life.
- Frontiers in Bioscience 01/2004; 9(1-3):2873. · 4.25 Impact Factor
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ABSTRACT: Emphysema and liver cirrhosis can be caused by the Z mutation (Glu342Lys) in the serine protease inhibitor ?1-antitrypsin (?1AT), which is found in more than 4% of the Northern European population. Homozygotes experience deficiency in the lung concomitantly with a massive accumulation of polymers within hepatocytes, causing their destruction. Recently, it was proposed that Z-?1AT polymerizes by a C-terminal domain swap. In this study, small-angle x-ray scattering (SAXS) was used to characterize Z-?1AT polymers in solution. The data show that the Z-?1AT trimer, tetramer, and pentamer all form ring-like structures in strong support of a common domain-swap polymerization mechanism that can lead to self-terminating polymers.Biophysical journal. 10/2014; 107(8):1905-12.
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ABSTRACT: Alpha-1 antitrypsin (AAT) deficiency remains an underrecognized genetic disease with predominantly pulmonary and hepatic manifestations. AAT is derived primarily from hepatocytes; however, macrophages and neutrophils are secondary sources. As the natural physiological inhibitor of several proteases, most importantly neutrophil elastase (NE), it plays a key role in maintaining pulmonary protease-antiprotease balance. In deficient states, unrestrained NE activity promotes damage to the lung matrix, causing structural defects and impairing host defenses. The commonest form of AAT deficiency results in a mutated Z AAT that is abnormally folded, polymerized, and aggregated in the liver. Consequently, systemic levels are lower, resulting in diminished pulmonary concentrations. Hepatic disease occurs due to liver aggregation of the protein, while lung destruction ensues from unopposed protease-mediated damage. In this review, we will discuss AAT deficiency, its clinical manifestations, and augmentation therapy. We will address the safety and tolerability profiles of AAT replacement in the context of patient outcomes and cost-effectiveness and outline future directions for work in this field.Therapeutics and Clinical Risk Management 01/2015; 11:143-51. · 1.34 Impact Factor