Snapshot A 24-year-old woman with a past medical history of atopic dermatitis presents to an urgent care center for dyspnea on exertion. She reports that for the past few months, she has become increasingly short of breath with exertion, particularly during exercise. She denies any other symptoms and denies having ever smoked or been exposed chronically to second-hand smoke. Close examination into her pediatric records shows a documented history of hepatomegaly but no workup. Labs reveal significantly decreased alpha-1 antitrypsin and increased transaminitis. She is given nebulized ipratropium and albuterol, a course of steroids, and referred for regular treatments with alpha-1 antitrypsin. Introduction Clinical definition alpha-1 antitrypsin deficiency is characterized by early-onset emphysema cirrhosis Genetics autosomal codominant SERPINA1 gene Epidemiology Demographics young adults often without a history of smoking Risk factors family history smoking exacerbates illness ETIOLOGY 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 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 Diagnostic testing studies ↑ prothrombin time ↓ alpha-1 antitrypsin level ↑ liver enzymes genetic testing confirms diagnosis liver biopsy often not needed findings PAS+ globules in hepatocytes 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 DIAGNOSIS Diagnostic criteria diagnosed with ↓ alpha-1 antitrypsin levels and confirmed with genetic testing or liver biopsy Treatment First-line alpha-1 antitrypsin infusion indication patients with symptoms of COPD standard COPD treatment Second-line liver transplant indication decompensated cirrhosis hepatocellular carcinoma outcomes liver transplant will help patients maintain normal levels of donor’s alpha-1 antitrypsin Other treatments vaccinations influenza pneumococcus minimize alcohol consumption Complications Hepatocellular carcinoma regular surveillance liver ultrasound alpha-fetoprotein