Foundations · Year 1 · from Foundations
Case 3: Alpha-1 Antitrypsin Deficiency (ER Stress)
Clinical Image
Source: Wikipedia - Alpha-1 antitrypsin deficiency - CC BY-SA 3.0
Case Presentation
A 45-year-old man with no significant past medical history and a 20 pack-year smoking history presents with progressive dyspnea on exertion over the past 2 years. Pulmonary function tests show severe obstructive lung disease with FEV1 35% predicted. CT chest reveals panacinar emphysema with basilar predominance, unusual for typical smoking-related emphysema which is usually upper lobe predominant. Serum alpha-1 antitrypsin level is markedly reduced at 35 mg/dL (normal 100-220). Genetic testing confirms homozygosity for the Z allele (Pi*ZZ). Liver function tests show mildly elevated transaminases and liver biopsy reveals PAS-positive, diastase-resistant globules representing accumulated mutant AAT protein in hepatocyte endoplasmic reticulum. The diagnosis is alpha-1 antitrypsin deficiency with both pulmonary and hepatic manifestations. He is counseled on smoking cessation (critical), started on AAT augmentation therapy with pooled human AAT infusions, and referred for liver monitoring given his hepatic involvement.
Key Learning Points
- The Z mutation (Glu342Lys) causes AAT to misfold in the ER, where it aggregates rather than being secreted - exemplifying ER stress and the unfolded protein response
- The disease has dual pathophysiology: liver disease from accumulated misfolded protein causing ER stress, and lung disease from insufficient circulating AAT allowing unopposed neutrophil elastase activity
- This case illustrates how a single amino acid change can disrupt protein folding, secretion, and function simultaneously