Pulmonary Alveolar Microlithiasis: From Clinicopathologic Description to Molecular Pathogenesis and Emerging Therapies

Pulmonary alveolar microlithiasis (PAM) is a rare autosomal recessive lung disease in which calcium phosphate microliths fill the alveoli; more than 1000 cases have been reported worldwide. Although its cause remained unknown for decades, loss-of-function variants in SLC34A2, which encodes the sodium-phosphate cotransporter NPT2b, are now known to explain nearly all genetically tested cases; failure to clear phosphate from the alveolar lining fluid leads to microlith formation, and an epithelial Npt2b-knockout mouse reproduces the human phenotype. Diagnosis now rests mainly on characteristic high-resolution CT and, increasingly, on genotyping rather than lung biopsy. The course is usually slow but variable; in published series followed for 10 to 49 years after diagnosis, a substantial proportion of patients, though not all, progressed to respiratory failure, whereas others remained stable for decades. No drug has proven efficacy; lung transplantation is the only established therapy for end-stage disease, and no allograft recurrence has been documented. Preclinical data support phosphate restriction, EDTA lavage and gene-directed approaches. However, controlled trials with more genotype–phenotype correlation and prospective natural-history data are still needed.