What is Pulmonary Alveolar Microlithiasis?
Pulmonary alveolar microlithiasis (PAM) is an ultrarare autosomal recessive genetic lung disease characterized by widespread accumulation of calcium phosphate microliths (tiny stones) within the alveolar spaces, caused by loss-of-function mutations in the SLC34A2 gene encoding a sodium-phosphate cotransporter. 1
Pathophysiology
PAM results from deficiency of the sodium-phosphate cotransporter NPT2B, which leads to:
- Elevated phosphate levels in the alveolar lumen
- Progressive deposition of hydroxyapatite (calcium phosphate) crystals in alveolar spaces
- The crystals accumulate over time, eventually causing respiratory insufficiency 1, 2
This is fundamentally a disorder of pulmonary phosphate homeostasis - the defective transporter cannot remove phosphate from the alveolar space, leading to crystal formation 1.
Genetics and Inheritance
- Autosomal recessive inheritance pattern - both parents must carry the mutation
- High correlation with consanguinity (related parents)
- Most common variants are single nucleotide biallelic changes in SLC34A2, though larger deletions occur
- Genetic counseling should be offered to families with PAM history, including preimplantation/prenatal testing options 3
Clinical Presentation
A hallmark feature is the striking discrepancy between minimal symptoms and dramatic radiologic findings - patients often appear relatively well despite extensive lung involvement 3, 2.
Early Disease:
- Often discovered incidentally on routine chest X-rays in asymptomatic individuals
- May be found through family screening 1
- Patients typically have no symptoms despite extensive radiographic abnormalities
Progressive Disease:
- Slowly progressive course over decades
- Shortness of breath develops gradually
- Cough
- Eventually culminates in respiratory failure, typically in late middle age 1, 4
- Right heart failure may develop in advanced stages 4
Diagnostic Features
Radiologic Findings:
- "Sandstorm" or "snowstorm" appearance on chest X-ray - countless tiny opacities throughout both lungs 3, 5
- High-resolution CT shows widespread micronodular opacities
- Early phase findings can be mistaken for miliary tuberculosis or sarcoidosis 5
Nuclear Medicine:
- Bone scintigraphy with methylene diphosphonate shows diffuse increased uptake in the lungs due to calcium deposits binding the radiopharmaceutical 4
Diagnostic Approach:
Genetic testing for SLC34A2 mutations is the preferred diagnostic method to verify diagnosis and identify the specific disease-causing variant 3. When genetic testing is unavailable, diagnosis requires invasive procedures:
- Transbronchial forceps biopsy
- Cryobiopsy
- Surgical lung biopsy showing microliths in alveolar spaces 3
Management
No definitive treatment exists for PAM - current management is limited to supportive measures 1, 3.
Supportive Care:
- Vaccinations (pneumococcal, influenza) for prevention
- Supplemental oxygen therapy when hypoxemia develops
- Monitoring for pulmonary hypertension and right heart failure 3
End-Stage Disease:
Bilateral lung transplantation is the only option for end-stage PAM and should be considered when:
- Increasing oxygen requirements develop
- Evidence of pulmonary hypertension emerges 5
Prognosis
- Slow progression over decades in most cases
- Variable clinical course among patients
- May progress to severe pulmonary disease with respiratory failure and potential death 3
- Recent advances in understanding pathogenesis suggest potential future therapeutic approaches targeting the underlying phosphate transport defect 1
Important Distinction from PAP
PAM is completely different from pulmonary alveolar proteinosis (PAP) - PAM involves calcium phosphate crystal deposition, while PAP involves surfactant accumulation. They are distinct diseases with different pathophysiology, genetics, and management approaches.