What is the role of Alpha-1 Antitrypsin (A1AT) in liver workup?

Alpha-1 Antitrypsin and Its Role in Liver Workup

What is Alpha-1 Antitrypsin?

Alpha-1 antitrypsin (AAT) is a 52-kD glycoprotein synthesized primarily in hepatocytes that functions as a protease inhibitor, with its major biological role being inhibition of neutrophil elastase. 1 Normal serum concentrations range from 120–200 mg/dl, and the protein is encoded by a gene on chromosome 14q31-32.3. 1

Role in Liver Workup

When to Test for AAT Deficiency in Liver Disease

AAT deficiency should be tested in all patients with liver disease of unknown cause, as it represents a common genetic cause of both pediatric and adult liver disease. 2 Specific indications include:

• Neonatal cholestasis (AAT deficiency is a common cause) 1
• Unexplained chronic liver disease at any age 2
• Cirrhosis without clear etiology, particularly in never-smokers 1
• Incidental finding of periodic acid–Schiff-positive (PAS-positive) globules on liver biopsy 1
• End-stage liver disease requiring transplantation evaluation 1

Diagnostic Approach

Serum phenotyping by isoelectric focusing is the gold standard for diagnosing AAT deficiency, not liver biopsy. 1, 3 The diagnostic algorithm proceeds as follows:

1. Initial screening: Measure serum AAT level 2

   • Level ≥23 mmol/L (≥1.2 g/L) excludes severe deficiency 2
   • Level <11 mmol/L (<0.57 g/L) indicates severe deficiency 2

2. Confirmatory testing: Perform phenotyping by isoelectric focusing to identify specific genotype (PIZZ, PIMZ, PI*SZ, etc.) 1, 2

3. Liver biopsy role: Reserved exclusively for staging liver disease severity in patients with clinically overt disease, NOT for establishing the diagnosis 1, 3

Pathophysiology of AAT-Related Liver Disease

The mechanism differs fundamentally from lung disease. Liver injury results from accumulation of mutant AAT Z protein within the endoplasmic reticulum of hepatocytes (the "accumulation theory"), not from low serum levels. 1, 3 Approximately 80–90% of synthesized Z protein is retained intracellularly rather than secreted, forming characteristic PAS-positive polymers. 1

Clinical Patterns and Risk Factors

Most PI*ZZ individuals are clinically healthy throughout childhood despite liver enzyme abnormalities in early life, but cirrhosis can manifest at any age with peak incidence in elderly never-smokers. 1, 3 Key risk factors include:

• Male sex confers increased cirrhosis risk 1, 3
• PI*ZZ phenotype carries highest risk 1
• Heterozygotes (PI*MZ) have much smaller risk, primarily when combined with alcohol or hepatitis C 1
• In heterozygotes with active liver disease, AAT levels may be normal, requiring phenotyping for diagnosis 1

Management and Monitoring

No specific medical therapy exists for AAT-related liver disease; intravenous augmentation therapy does NOT benefit the liver. 1, 3 Management consists of:

• Hepatitis A and B vaccination (mandatory) 1, 3
• Regular physical examination, liver function tests, and ultrasound 1, 3
• In patients ≥50 years with decompensated cirrhosis: periodic CT imaging for hepatocellular carcinoma surveillance (α-fetoprotein is insensitive) 1, 3
• Regular liver function tests in elderly AAT-deficient patients even without symptoms 1, 3
• Liver transplantation remains the only definitive treatment for advanced disease 1, 3

Critical Pitfalls to Avoid

1. Do not rely on serum AAT levels alone in heterozygotes with active liver disease—levels may be normal; phenotyping is required 1

2. Do not perform liver biopsy to diagnose AAT deficiency—use it only for staging known disease 1, 3

3. Do not prescribe IV augmentation therapy for liver disease—it provides no hepatic benefit despite raising serum levels 1, 3

4. Do not overlook family screening—first-degree relatives should be tested regardless of symptoms 2