Pulmonary alveolar microlithiasis

Abstract

Pulmonary alveolar microlithiasis (PAM) is a fascinating rare lung disease that is associated with the accumulation of hydroxyapatite microliths within the lumen of the alveolar spaces. In most patients, PAM is discovered incidentally on radiographs performed for other purposes, and the typical disease course is characterised by slowly progressive respiratory insufficiency over decades. Recent genetic analyses that have revealed that the deficiency of the sodium-phosphate cotransporter NPT2B is the cause of PAM have enabled the development of powerful animal models that inform our approach to disease management and treatment. Here we review the epidemiology and molecular pathophysiology of PAM, as well as the diagnostic approach, clinical manifestations, radiographic and pathologic features, and clinical management of the disease. Although there are no proven treatments for PAM, progress in our understanding of disease pathogenesis is providing insights that suggest strategies for trials.

FIGURE 1

Radiographic findings in pulmonary alveolar microlithiasis. a) Chest radiograph depicting a fine, sand-like micronodular pattern with basilar predominance. b, c) High-resolution computed tomography with posterior lower lobe and anterior upper lobe micronodules, interlobular septal thickening, subpleural emphysema with predominance of small cysts. d) Mediastinal windows reveal calcific burden in the parenchyma and most concentrated in a peripheral septopleural location.

FIGURE 2

Pathologic findings in pulmonary alveolar microlithiasis (PAM). a) Lung explant from a 2-year-old boy transplanted for PAM showing lung regions with accentuation of the interlobular septa by microlith accumulations (arrow) and other regions with more diffuse accumulations of granular, gritty microliths (*). b, c) Histological sections showing microliths along interlobular septa (b, arrow) and areas with more diffuse microlith accumulations (c). d) Varying sized microliths are present both in the alveolar spaces and interstitium. e) The microliths are characteristically concentrically laminated calcified spherules. f) Calcium can be demonstrated in the microliths by Von Kossa stain. b–e) Haematoxylin and eosin stain; original magnifications ×20 (b, c), ×200 (d), ×1000 (e, f).

FIGURE 3

Scanning electron microscopy (SEM) and energy-dispersive spectroscopy (EDAX) of pulmonary alveolar microlithiasis (PAM). a, b) Microliths isolated from explanted lungs demonstrating a) the characteristic spherical structure and b) inorganic elemental signature. Microlith (white arrow) in bronchoalveolar lavage (BAL) fluid with SEM (c) and EDAX characteristics that are similar to explant controls, demonstrating feasibility of using SEM and EDAX as a diagnostic BAL test for PAM. Note carbon spike associated with debris from lavage. Kα, Kβ and Lα represent X-rays emitted as electrons return to K and/or L electron shell. d) Inorganic elemental analysis of BAL microliths.

FIGURE 4

Diagnostic algorithm for patients with suspected pulmonary alveolar microlithiasis (PAM). Obtaining a family and genetic testing history is key. Thereafter, diagnostic modalities progress from least invasive to most invasive. HRCT: high-resolution computed tomography; BAL: bronchoalveolar lavage; VAT: video-assisted thoracoscopic biopsy.

FIGURE 5

Other examples of diffuse lung calcification. Computed tomography depicting examples of a, d) amyloidosis with calcified masses, lymphadenopathy and rare cysts, b, e) silicosis with peri-lymphatic calcified nodules, eggshell lymph node calcifications and conglomerate fibrosis, c) metastatic pulmonary calcification in chronic renal failure characterised by lobular ground-glass opacity with interlobular septal sparing and f) healed granulomas due to histoplasmosis with maximum intensity projection reformats.