Pulmonary Alveolar Microlithiasis

Pulmonary alveolar microlithiasis is a rare autosomal recessive disease in which calcium phosphate microliths (calcospherites) fill the alveoli. It is caused by loss-of-function variants in SLC34A2, which encodes a sodium phosphate transporter on type II pneumocytes.

About 1000 cases have been described, with clusters in Turkey, Japan, Italy and India, and many are familial. It is diagnosed at any age, often in the third to fifth decade, and is often found by chance on a striking radiograph in people with few symptoms. It progresses slowly over decades.

Pathophysiology. Loss of the transporter impairs clearance of phosphate from the alveolar fluid, so calcium phosphate crystallises into concentric lamellated stones in the airspaces. Microliths provoke fibrosis and, over time, restrictive lung disease, pulmonary hypertension and respiratory failure.

Many have no symptoms for years, with a radiograph far more abnormal than the patient. Later there is cough, exertional dyspnoea, chest pain, clubbing, cyanosis and signs of cor pulmonale. Extrapulmonary calcification (testicular, renal, gallbladder, prostate) occurs. Spontaneous pneumothorax can occur.

Respiratory failure, haemoptysis or pneumothorax need urgent care.

• Chest radiograph: diffuse fine sand like micronodular opacities in both lungs ("sandstorm" appearance), densest in the lower and middle zones, obscuring the heart and diaphragm borders, and sometimes a black pleural line.
• High resolution CT: diffuse tiny calcified nodules (under 1 mm), subpleural cysts, thickened septa with calcification and ground glass.
• Bronchoalveolar lavage with microliths, and transbronchial or surgical biopsy showing lamellated calcospherites in the alveoli, though imaging with history is often enough.
• Lung function: normal early, then restriction with low DLCO and hypoxaemia.
• Technetium bone scan showing diffuse lung uptake. Genetic testing for SLC34A2 variants.
• Family screening by radiograph and genetic test, since siblings are often affected.
• Serum calcium and phosphate are normal, which separates it from metabolic calcification.

Differential diagnosis.

• Miliary tuberculosis and healed varicella or histoplasmosis calcification
• Sarcoidosis
• Silicosis and other pneumoconiosis
• Pulmonary alveolar proteinosis
• Haemosiderosis
• Metastatic pulmonary calcification (renal failure, hypercalcaemia)
• Pulmonary amyloidosis

• No proven disease modifying therapy. Whole lung lavage does not remove the microliths durably.
• Etidronate (a bisphosphonate) 5 to 10 mg/kg daily (usually 400 mg daily) has been tried to slow calcification, with mixed results, and bone health is monitored. Corticosteroid has no benefit.
• Supportive care: oxygen when PaO2 is 7.3 kPa or less, pulmonary rehabilitation, vaccination against influenza, pneumococcus and COVID-19, treatment of infection, and smoking avoidance.
• Pulmonary hypertension and cor pulmonale treated by specialist teams, with diuretics for oedema.
• Lung transplantation for end stage respiratory failure, with no recurrence reported in several cases.
• Genetic counselling for the family, with screening of siblings.
• Pneumothorax: drain, with early pleurodesis for recurrence.

Complications and prognosis. Slow progression over decades, with respiratory failure, pulmonary hypertension and early death in many affected individuals by the fifth to sixth decade, and wide variation.

Monitoring. Spirometry, DLCO, oxygen saturation and walk test every 6 to 12 months, echocardiography yearly, and chest imaging every 1 to 2 years.

Referral and escalation. Refer to a respiratory physician with expertise in rare lung disease, and to the transplant centre for progressive disease.