45-year-old female suffered from dyspnea due to severe emphysema. She succumbed to right ventricular failure (specimen from autopsy).
- A section of the liver is shown. At low magnification, a distinct nodular architecture is observed. Fibrosis of portal tracts and bridging fibrous septae in between portal tracts are prominent. Portal tracts exhibit an inflammatory infiltrate consisting of lymphocytes and histiocytes; periportal necroinflammatory activity is also present. In addition, a marked proliferation of bile ductules can be seen.
- Periportal hepatocytes contain spherical eosinophilic intracytoplasmic inclusions which stain positive for PAS and are diastase resistant. Cells exhibiting inclusion bodies are most frequently localized in zone 1 followed by zone 2 and 3.
Genetics: alpha-1 antitrypsin (AAT) deficiency, one of the most common serious hereditary disorders, is inherited by an autosomal-recessive mode. The AAT gene is located on chromosome 14 and a high number of allelic variants have been described. The Z and S deficiency variants are both caused by single base-pair substitutions and account for the majority of deleterious variants found in patients with AAT deficiency. The homozygous ZZ variant causes the most severe phenotype. Patients with this variant only have approximately 15% of the normal amount of AAT. The SS variant may also be associated with severe lung disease. Patients with this genotype express around 60% of the normally observed amounts of AAT. Both point mutations lead to the substitution of a single amino-acid which prevents proper folding of the protein and as a consequence its retention in the endoplasmatic reticulum of the liver.
AAT-1 can be detected in the liver by immunohistochemistry.