Alpha-1 Antitrypsin Deficiency and Splenic Infarcts or Pulmonary Granulomas
Alpha-1 antitrypsin deficiency does not cause splenic infarcts, but it is strongly associated with pulmonary granulomas specifically in the context of Wegener's granulomatosis (granulomatosis with polyangiitis). 1
Pulmonary Granulomas: Established Association
The association between AAT deficiency and granulomatous disease is well-documented through the link with C-ANCA-positive vasculitis, particularly Wegener's granulomatosis. 1
Evidence for Granulomatosis with Polyangiitis (Wegener's)
Multiple international studies have confirmed a strong relationship between heterozygous and homozygous PI*Z AAT deficiency and small vessel-necrotizing vasculitides, particularly Wegener's granulomatosis and microscopic polyangiitis. 1
Approximately 2% of all patients with anti-PR-3-positive (C-ANCA-positive) multisystemic vasculitis are PI*Z homozygotes, with additional patients being heterozygotes. 1
In cohorts of C-ANCA-positive patients across France, Sweden, Austria, Australia, UK, and Denmark, the Z allele frequency ranged from 5.6% to 17.6%, compared to 0.9% to 2.4% in control subjects. 1
Wegener's granulomatosis presents with necrotizing granulomatous lesions affecting the lungs and upper respiratory tract, and is strongly associated with C-ANCA/PR3-ANCA positivity (84-85%). 2
Mechanism of Association
The PI*Z variant for AAT deficiency may have an adverse accelerative effect on vasculitic processes once they start, rather than being merely an etiologic risk factor. 1
The relative lack of AAT could promote protease-antiprotease imbalance, allowing unopposed tissue destruction by proteinase-3 (PR-3), a neutrophil elastase-like serine protease with potent tissue-destructive capacity. 1
AAT is a major physiologic inhibitor of PR-3 in extracellular fluid, and subnormal AAT response in vasculitic patients may enhance risk of fatal outcomes. 1
Clinical Implications
Diagnostic testing for AAT deficiency is indicated for all patients with C-ANCA-positive vasculitis or Wegener's granulomatosis. 1
Patients with abnormal AAT phenotypes have significantly higher vasculitis activity scores (BVAS) and anti-PR3 antibody concentrations. 3
Some reports suggest amelioration of vasculitis signs with alpha-1 antiprotease augmentation treatment. 1
Splenic Infarcts: No Established Association
There is no documented association between alpha-1 antitrypsin deficiency and splenic infarcts in the medical literature or clinical guidelines. 1
Recognized Organ Manifestations of AAT Deficiency
The established organ manifestations include:
Pulmonary emphysema (most prevalent clinical consequence and major cause of disability and death) 1, 4
Liver disease (cirrhosis, hepatocellular carcinoma, with lifetime risk of 30-40% for cirrhosis) 1
Necrotizing panniculitis (rare complication with necrotic lesions in subcutis and dermis) 1
Systemic vasculitides (Wegener's granulomatosis with pulmonary granulomas, microscopic polyangiitis) 1
Bronchiectasis (saccular and cylindrical, with or without emphysema) 1
Important Caveat
The NHLBI Registry of 1,129 AAT-deficient patients failed to reveal an association of death with any condition other than lung and liver disease, suggesting that other organ manifestations, while possible, are not major contributors to morbidity and mortality. 1
Clinical Recommendation
If a patient with AAT deficiency presents with splenic infarcts, investigate alternative etiologies including thromboembolic disease, hematologic malignancies, hypercoagulable states, endocarditis, or other vasculitides unrelated to AAT deficiency. 1
If pulmonary granulomas are identified, strongly consider evaluation for C-ANCA-positive vasculitis (Wegener's granulomatosis) with anti-PR3 antibody testing and appropriate tissue biopsy. 1, 2, 3