Which of the following statements regarding alpha-1-antitrypsin deficiency is/are correct?

a. Alpha-1-antitrypsin is a plasma elastase inhibitor

b. Most homozygous patients develop chronic obstructive pulmonary disease

d. Intracellular accumulation of abnormal protein occurs in hepatocytes

Alpha 1-antitrypsin (a-1-AT) is a plasma protease inhibitor with elastase as a major physiological substrate. Synthesis, posttranslational modification, and secretion occur primarily in the hepatocyte. Disease-causing alleles are inherited in an autosomal recessive manner. Homozygotes have only 15 to 20% of the normal plasma levels of a-1-AT. Defects in normal a-1-antitrypsin expression and processing, brought about as a result of mutation, can lead to pathology in the lung and liver.

Diminished levels of a-1-AT in the blood result in an imbalance between proteases and protease inhibitors, allowing destruction of lung parenchyma. Chronic obstructive pulmonary disease is the most common clinical manifestation of a-1- AT deficiency, with basal lung parenchyma most severely affected.

 The liver is the primary site of a-1-AT biosynthesis. In some cases, alteration in the protein sequence of a-1-AT prevents normal post-translational processing and results in the intracellular accumulation of large quantities of abnormal protein, detectable as intracytoplasmic inclusions. One pathologic consequence of abnormal protein accumulation is the development of liver injury.