What are the key lessons associated with alpha-1 antitrypsin (A1AT) deficiency?

Key Lesions Associated with Alpha-1 Antitrypsin Deficiency

Alpha-1 antitrypsin deficiency causes three primary pathological lesions: panacinar emphysema predominantly in the lung bases, hepatic cirrhosis with characteristic PAS-diastase positive inclusions in hepatocytes, and small vessel necrotizing vasculitis, particularly Wegener's granulomatosis. 1, 2

Pulmonary Lesions

Panacinar Emphysema

• The hallmark pulmonary lesion is panacinar emphysema with a distinctive basilar predominance, contrasting with the apical distribution seen in typical smoking-related emphysema 1, 2
• Emphysema represents the most prevalent clinical consequence and is the major cause of disability and death in AAT deficiency 1, 2
• The pathophysiology involves loss of protection against neutrophil elastase (NE), which destroys lung architecture when AAT levels fall below the protective threshold of 11 mmol/L (0.57 g/L) 1, 3, 4

Bronchiectasis

• Small cystic bronchiectasis occurs in a subset of patients, though the exact frequency and clinical manifestations require further characterization 1
• Bronchiectasis without evident etiology in adults warrants testing for AAT deficiency 1, 2

Hepatic Lesions

PAS-Diastase Positive Inclusions

• The pathognomonic hepatic finding is PAS-diastase (PAS-D) positive inclusions within hepatocytes, representing accumulated Z protein polymers in dilated endoplasmic reticulum 1
• These inclusions result from loop-sheet polymerization of the mutant Z protein, which becomes retained in the ER and causes hepatocyte cytotoxicity 1

Critical caveat: PAS-D inclusions are neither 100% sensitive nor specific for the PIZ allele—they can occur in 4% of PIMM individuals with alcoholic cirrhosis or hepatoma, and may be absent in some Z carriers 1

Cirrhosis and Hepatocellular Carcinoma

• Liver cirrhosis develops in a subset of AAT-deficient individuals, with particularly high incidence in elderly never-smokers in Swedish cohorts 1
• Hepatocellular carcinoma represents a late complication, especially in those with established cirrhosis 1
• Cholestatic liver disease may present in infancy, typically resolving by adolescence 2

Vascular Lesions

Small Vessel Necrotizing Vasculitis

• A strong association exists between PI*Z deficiency (both homozygous and heterozygous states) and C-ANCA positive small vessel vasculitides, particularly Wegener's granulomatosis and microscopic polyangiitis 1
• The Z allele frequency in C-ANCA positive vasculitis patients ranges from 5.6% to 17.6% across multiple European and Australian cohorts, compared to 0.9% to 2.4% in control populations 1
• Multiple case reports link PI*Z deficiency to systemic vasculitis and glomerulonephritis 1

Other Associated Lesions

Panniculitis

• Relapsing panniculitis occurs less frequently but represents a recognized cutaneous manifestation of severe AAT deficiency 5

Inflammatory and Autoimmune Associations

• Heterozygotes for the Z allele show increased risk of anterior uveitis, rheumatoid arthritis, and various collagen vascular diseases, though these associations are weak and controversial 1
• These associations rarely impact clinical management and do not routinely justify phenotyping or genotyping 1

Pathophysiological Mechanisms

The dual mechanism of injury explains the lesion distribution:

• Loss-of-function in the lung: Deficient AAT allows unopposed neutrophil elastase activity, destroying elastin and lung parenchyma 1, 4
• Toxic gain-of-function in the liver: Polymerized Z protein accumulates in hepatocytes, causing direct cellular injury through ER stress and polymer toxicity 1

Important clinical pearl: Cigarette smoke oxidizes the critical methionine residue at AAT's active site, rendering even normal levels of AAT inefficient at inhibiting neutrophil elastase—this explains why smoking dramatically accelerates emphysema development in AAT deficiency 4