Alpha-1 antitrypsin deficiency

Inherited protease inhibitor (serpin) disorder with low or dysfunctional alpha-1 antitrypsin. Leads to uninhibited elastase causing early panacinar emphysema, and misfolded AAT protein accumulating in hepatocytes causing cirrhosis.

• Major genetic cause of COPD in younger adults and a preventable cause of cirrhosis. Often underdiagnosed; recognizing it early allows interventions (e.g., avoid smoking, augmentation therapy) to slow lung damage and monitor for liver complications. Commonly tested as early emphysema in a nonsmoker or neonatal hepatitis.

• Lung: Adult-onset emphysema (usually 30–50s) with chronic dyspnea, cough, and recurrent bronchitis. Clues are early COPD in a patient with minimal or no smoking history, often misdiagnosed as asthma. Emphysema is panacinar and classically basilar (lower lobe–predominant).
• Liver: Neonatal cholestasis (prolonged jaundice in an infant) in ~10% of cases; some infants develop hepatitis/cirrhosis, while others recover. In adulthood, cirrhosis can develop by middle age (15% of adults), with signs like hepatomegaly, elevated LFTs, or portal hypertension. Affected individuals have increased risk of hepatocellular carcinoma.
• Rarely, panniculitis (painful skin nodules from inflammation of subcutaneous fat) occurs, or vasculitis (C-ANCA positive) – these clues in a patient with lung or liver issues should raise suspicion for AAT deficiency.

1. Maintain a high index of suspicion: test any patient with early emphysema (<45 years old), basilar emphysema, minimal smoking history, unexplained chronic liver disease, or a family history of COPD/liver disease.
2. Initial workup: measure serum alpha-1 antitrypsin level. A very low level (often <50–80 mg/dL, normal ~100–300) is highly suggestive. If low, confirm diagnosis by phenotype or genotype testing (e.g., Pi typing to detect S/Z alleles).
3. Pulmonary evaluation: perform spirometry (typically shows irreversible obstructive pattern like COPD) and imaging. CT scan often reveals bullous emphysema in lower lobes. Consider testing family members if one individual is diagnosed.
4. Hepatic evaluation: check LFTs and ultrasound in AATD patients. If etiology of liver disease is unclear, a liver biopsy can show characteristic PAS-positive, diastase-resistant globules in hepatocytes (accumulated misfolded AAT protein) – a classic diagnostic finding.
5. Follow guidelines: professional societies (ATS/ERS) recommend at least once AAT level testing in all patients with COPD or difficult-to-control asthma, as well as in otherwise unexplained liver disease.

1. Lifestyle: Smoking cessation is absolutely critical (smoking greatly accelerates lung destruction). Also avoid other lung irritants, ensure vaccinations (flu, pneumococcal) to prevent respiratory infections.
2. Pulmonary management: Treat as COPD – bronchodilators (inhaled beta-agonists, anticholinergics), inhaled steroids if needed, pulmonary rehab, and prompt antibiotics for infections. For eligible patients (typically with moderate airflow obstruction, e.g. FEV₁ 25–80% predicted), consider IV AAT augmentation therapy (pooled human AAT infusions) to slow emphysema progression.
3. Liver management: There is no specific medication to remove the accumulated AAT in the liver. Monitor liver function and screen for cirrhosis complications (ultrasound for HCC, endoscopy for varices if cirrhotic). Manage cirrhosis with standard supportive care (nutrition, avoid alcohol, etc.).
4. Transplantation: In end-stage lung disease from AATD, lung transplant is an option (improves lung function but the liver disease remains). In advanced liver cirrhosis, liver transplant can cure the liver disease and also provides a new source of AAT (curative for the enzyme deficiency).

• Panacinar = alpha-1 (think AAT deficiency) vs. centrilobular = cigarettes (smoking COPD): AATD classically destroys the entire acinus in lung bases, whereas smoking emphysema starts centrilobular in apices.
• Liver biopsy buzzword: PAS-positive globules in hepatocytes that resist diastase digestion = misfolded A1AT protein retained in the liver.
• Emphysema in a young adult + unexplained cirrhosis in the same patient? That combination is a red flag for alpha-1 antitrypsin deficiency.

• Continued smoking or frequent respiratory infections in an AATD patient → rapid decline in lung function (accelerated emphysema progression). These patients must be counseled intensively to avoid smoking.
• Signs of advanced cirrhosis in AATD (e.g. new ascites, coagulopathy, encephalopathy) → indicates liver failure; high risk for hepatocellular carcinoma. Such findings should prompt evaluation for liver transplant.

1. Unexplained early COPD, emphysema, or neonatal cholestasis → suspect AAT deficiency.
2. Order a serum AAT level. If low (below normal range) → proceed to confirmatory genotype or phenotype testing for Pi variants (e.g., ZZ, SZ).
3. If AATD confirmed → counsel patient on strict smoking avoidance (and avoid second-hand smoke or occupational dust). Perform baseline PFTs and liver tests.
4. Initiate appropriate therapy: COPD management (inhalers, etc.), consider augmentation therapy if criteria met, and address liver health (vaccinations for hepatitis, avoid hepatotoxins).
5. Follow-up plan: monitor lung function periodically (spirometry) and liver status (periodic LFTs, imaging for cirrhosis). Encourage screening of siblings or family members for AATD.

• A 35-year-old non-smoker with chronic shortness of breath and basilar emphysema on chest imaging is found to have low serum AAT levels → Alpha-1 antitrypsin deficiency (early panacinar emphysema).
• A 2-month-old infant with persistent jaundice, elevated liver enzymes, and liver biopsy showing PAS-positive, diastase-resistant granules in hepatocytes → Alpha-1 antitrypsin deficiency (neonatal hepatitis leading to cirrhosis).