Snapshot A 23-year-old man with a past medical history of depression presents to his primary care physician for increasing shortness of breath. He reports that this occurs especially when he exercises. His family history is pertinent for lung disease in multiple family members, but he is not sure which lung disease. He reports that when he smokes socially, the shortness of breath becomes acutely worse. A chest radiograph shows a flattened diaphragm, and laboratory evaluation reveals increased lever enzymes. He is sent to the genetic counselor for genetic testing. Introduction Clinical definition alpha-1 antitrypsin deficiency is characterized by early-onset emphysema cirrhosis Epidemiology demographics young adults often without a history of smoking risk factors family history smoking exacerbates illness Pathogenesis alpha-1 antitrypsin is a serine protease inhibitor synthesized in the liver inhibits proteolysis by enzymes, particularly elastase decrease or dysfunctional alpha-1 antitrypsin is usually caused by misfolded gene product increased proteolysis of alveoli by neutrophil elastase accumulation of the misfolded alpha-1 antitrypsin polymers in hepatocytes proteolysis and damage to vessels may cause vasculitis Genetics autosomal codominant SERPINA1 gene Presentation Symptoms chronic obstructive pulmonary disease (COPD) onset at age 40-50 years dyspnea on exertion wheezes cough sputum production liver disease that may progress to cirrhosis onset in childhood hepatomegaly abdominal pain Imaging Chest radiograph findings flattened diaphragm Computed tomography of chest findings panacinar emphysema Studies Serum labs ↑ prothrombin time ↓ alpha-1 antitrypsin level ↑ liver enzymes genetic testing confirms diagnosis Invasive studies liver biopsy findings PAS+ globules in hepatocytes Diagnostic criteria diagnosed with ↓ alpha-1 antitrypsin levels and confirmed with genetic testing or liver biopsy Differential Asthma distinguishing factor typically not associated with liver disease and presents at a younger age Autoimmune hepatitis distinguishing factor typically not associated with COPD or ↓ alpha-1 antitrypsin levels Treatment Lifestyle minimize alcohol consumption Medical vaccinations influenza pneumococcus alpha-1 antitrypsin infusion indication patients with symptoms of COPD standard COPD treatment Surgical liver transplant indication decompensated cirrhosis hepatocellular carcinoma outcomes liver transplant will help patients maintain normal levels of donor’s alpha-1 antitrypsin Complications Hepatocellular carcinoma regular surveillance liver ultrasound alpha-fetoprotein