CONTENTS
- Pulmonary alveolar microlithiasis (PAM)
- Metastatic pulmonary calcification (MPC)
- Differential diagnosis of pulmonary calcification & ossification
- Questions & discussion
abbreviations used in the pulmonary section: 8
- ABPA: Allergic bronchopulmonary aspergillosis 📖
- AE-ILD: Acute exacerbation of ILD 📖
- AEP: Acute eosinophilic pneumonia 📖
- AFB: Acid-fast bacilli
- AIP: Acute interstitial pneumonia (Hamman-Rich syndrome) 📖
- ANA: Antinuclear antibody 📖
- ANCA: Antineutrophil cytoplasmic antibodies 📖
- ARDS: Acute respiratory distress syndrome 📖
- ASS: Antisynthetase syndrome 📖
- BAL: Bronchoalveolar lavage 📖
- BiPAP: Bilevel positive airway pressure 📖
- CEP: Chronic eosinophilic pneumonia 📖
- CF: Cystic fibrosis 📖
- COP: Cryptogenic organizing pneumonia 📖
- CPAP: Continuous positive airway pressure 📖
- CPFE: Combined pulmonary fibrosis and emphysema 📖
- CTD-ILD: Connective tissue disease associated interstitial lung disease 📖
- CTEPH: Chronic thromboembolic pulmonary hypertension 📖
- DAD: Diffuse alveolar damage 📖
- DAH: Diffuse alveolar hemorrhage 📖
- DIP: Desquamative interstitial pneumonia 📖
- DLCO: Diffusing capacity for carbon monoxide 📖
- DRESS: Drug reaction with eosinophilia and systemic symptoms 📖
- EGPA: Eosinophilic granulomatosis with polyangiitis 📖
- FEV1: Forced expiratory volume in 1 second 📖
- FVC: Forced vital capacity 📖
- GGO: Ground-glass opacity 📖
- GLILD: Granulomatous and lymphocytic interstitial lung disease 📖
- HFNC: High flow nasal cannula 📖
- HP: Hypersensitivity pneumonitis 📖
- IPAF: Interstitial pneumonia with autoimmune features 📖
- IPF: Idiopathic pulmonary fibrosis 📖
- IVIG: Intravenous immunoglobulin 📖
- LAM: Lymphangioleiomyomatosis 📖
- LIP: Lymphocytic interstitial pneumonia 📖
- MAC: Mycobacterium avium complex 📖
- MCTD: Mixed connective tissue disease 📖
- NIV: Noninvasive ventilation (including CPAP or BiPAP) 📖
- NSIP: Nonspecific interstitial pneumonia 📖
- NTM: Non-tuberculous mycobacteria 📖
- OHS: Obesity hypoventilation syndrome 📖
- OP: Organizing pneumonia 📖
- OSA: Obstructive sleep apnea 📖
- PAP: Pulmonary alveolar proteinosis 📖
- PE: Pulmonary embolism 📖
- PFT: Pulmonary function test 📖
- PLCH: Pulmonary Langerhans cell histiocytosis 📖
- PPFE: Pleuroparenchymal fibroelastosis 📖
- PPF: Progressive pulmonary fibrosis 📖
- PVOD/PCH Pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis 📖
- RB-ILD: Respiratory bronchiolitis-associated interstitial lung disease 📖
- RP-ILD: Rapidly progressive interstitial lung disease 📖
- TNF: Tumor necrosis factor
- UIP: Usual interstitial pneumonia 📖
basics
- Pulmonary alveolar microlithiasis (PAM) is a rare, idiopathic interstitial lung disease that involves diffuse, sand-like calcified microliths occurring in the alveolar space.
- PAM is due to mutations in the SLC3A2 gene that encodes type IIb sodium-dependent phosphate cotransporter (NPT2b) in alveolar type 2 cells. Deficiency leads to an inability to clear phosphorus ions from the alveolar space.
epidemiology
- This is exceedingly rare, with only a few hundred cases reported.
- Usually occurs in young adults, commonly in their 20s-50s.
- Caused by an autosomal recessive mutation in the SLC34A2 gene.
symptoms
- Presentation is variable:
- May initially be diagnosed radiographically in an asymptomatic patient.
- Patients may present with fulminant respiratory failure. (32892884)
- Most patients will present with gradually progressive dyspnea, cough, and/or hypoxemia.
- Clubbing is usually present with severe disease.
- Eventually, PAM usually leads to progressive respiratory failure.
radiology
- Radiologic findings are generally much more striking than clinical manifestations.
- Most common presentation is fine, sand-like micronodular lung calcification.
- Lesions are usually <1 mm.
- The distribution often has a predominance in the lower lobes. On CT scan, lesions may tend to occur in a subpleural, perilobular, and peribronchovascular distribution.
- Dense opacities may eventually produce complete radiographic opacification of the lung (with silhouetting of the diaphragm, mediastinum, and cardiac borders). (32892884)
- Other findings:
- Septal thickening may occur (often with apparent calcification). (Walker 2019)
- Black pleura sign: a linear radiolucency at the pleural boundaries may be seen, likely due to subpleural cystic changes. (Murray 2022)
- Soft tissue or bone windows on CT scan may be utilized to more clearly define the calcified nature of lesions.
diagnosis
- Diagnosis can generally be based upon the following elements:
- Classic radiological appearance on CT scan. (32892884)
- Radiographic findings are disproportionately severe as compared to symptoms.
- Compatible epidemiology (~20-50 years old).
- Genetic testing may help prove the diagnosis.
- Additional diagnostic options:
- Invasive procedures are not usually needed. Bronchoscopy with transbronchial biopsy may show intra-alveolar microcalcifications. Bronchoalveolar lavage and even sputum may reveal lamellar microliths.
- Technetium-99m bone scans usually show diffuse uptake of radiotracer into the lungs. (Walker 2019)
treatment
- There don't appear to be any disease-specific therapies.
- Supplemental oxygen for advanced disease.
- Lung transplantation is the only definitive therapy.
prognosis
- Prognosis is variable. The disease may progress gradually over decades, or it may deteriorate more rapidly.
basics/definitions
- Metastatic pulmonary calcification (MPC) is calcification of normal tissues. This shouldn't be confused with dystrophic pulmonary calcification, in which calcification occurs within injured lung tissue (e.g., histoplasmosis).
epidemiology
- (1) Usually MPC is due to chronic renal failure on hemodialysis with secondary hyperparathyroidism.
- A calcium-phosphate product >70 mg²/dL² correlates with metastatic calcification, but MPC can occur at lower values.
- Autopsy studies detect metastatic pulmonary calcification in ~70% of patients previously on hemodialysis. (Fishman 2023)
- (2) Hypercalcemia of other etiologies:
- Malignancy (e.g., multiple myeloma, sarcoma).
- Primary hyperparathyroidism.
- Hypervitaminosis D.
- Milk-alkali syndrome.
- Orthotopic liver transplantation.
- Rarely, metastatic pulmonary calcification may occur in patients without any obvious biochemical abnormality. (Walker 2019)
clinical symptoms
- Metastatic pulmonary calcification is usually asymptomatic. Calcification seen on imaging doesn't correlate with pulmonary function testing abnormalities. (31916972)
- Chronic dyspnea or cough may occur.
- A small fraction of patients may develop progressive disease with pulmonary fibrosis, cor pulmonale, and respiratory failure.
chest radiograph
- Chest radiograph is notoriously insensitive for MPC.
- If abnormalities are seen, they are usually nonspecific (e.g., ill-defined nodules, interstitial infiltrates, or airway disease).
CT scan
- Three general patterns of calcification may occur in the lungs, which are not mutually exclusive:
- (1) Diffuse, centrilobular pattern is most common.
- Diffuse, small fluffy nodules are 3-10 mm in size.
- Predominantly involving the upper lung zones.
- Calcification may be seen, but not always. The pattern of calcification may be stippled, diffuse, or occasionally ring-like. (Walker 2019)
- (2) Diffuse or patchy ground-glass opacities.
- (3) Dense consolidation, often in a lobar distribution:
- A consolidated wedge of nearly calcified lung may be seen.
- This may mimic pneumonia.
- High attenuation (>100 Hounsfield units) can help support the diagnosis of MPC. (Fishman 2023)
- (1) Diffuse, centrilobular pattern is most common.
- There is often an upper lobe predominance, likely because the upper lobe is better ventilated and has a lower pH (which favors calcification).
- Calcium is often seen in blood vessels within the chest wall (especially between the pectoralis major and minor muscles). When combined with parenchymal calcification, this is highly suggestive for MPC. Other structures that may be calcified include the pulmonary arteries and the left atrial wall. (Walker 2019)
- Stability over time may help differentiate MPC from other pathologies such as infection, pulmonary edema, or organizing pneumonia. (36338254)
- Calcification is evident on CT scan in only 60% of cases. (Fishman 2023) Technetium-methylene diphosphonate bone scintigraphy may be used to clarify equivocal cases. This may eliminate the need for a lung biopsy. (Murray 2022)
bronchoscopy
- Bronchoscopy is not the preferred diagnostic approach. However, if a bronchoscopy happens to be performed, the airway may reveal white deposits.
treatment
- Treatment of symptomatic disease is directed at lowering the calcium-phosphate product, for example:
- Management of any hyperparathyroidism (e.g., with calcimimetic agents, which decrease PTH secretion).
- Oral phosphate binders.
- Bisphosphonates (to reduce absorption of bone phosphate).
- Increased dialytic intensity to more effectively control phosphate and uremia. (31916972)
- Prognosis is generally favorable, but some patients may progress to respiratory insufficiency.
definitions & nomenclature:
- Calcification = calcium deposition.
- Metastatic calcification = a process that originates outside of the lung (e.g., hypercalcemia).
- Dystrophic calcification = abnormal lung tissue becomes calcified.
- Ossification = formation of mature bone.
dystrophic calcification
granulomatous disorders
- Histoplasmosis.
- Sarcoidosis.
- Tuberculosis.
- Coccidioidomycosis.
viral and parasitic infections
- Varicella zoster infection (VZV).
- Pneumocystis.
- Paragonimiasis.
pulmonary vascular calcifications
- Pulmonary hypertension.
occupational lung diseases
- Coal workers pneumoconiosis.
- Silicosis.
other
- Amyloidosis.
metastatic pulmonary calcification
- Diffuse calcification of normal tissue, often related to hypercalcemia.
- Discussed further above. 📖
pulmonary alveolar microlithiasis
- Genetic disorder causing sand-like microliths to occur throughout the lungs.
- Discussed further above. 📖
diffuse pulmonary ossification
Diffuse pulmonary ossification is defined as mature bone formation within lung tissue. Two forms exist, although there may be some overlap.
nodular form of DPO (diffuse pulmonary ossification):
- Bone deposition occurs in the alveoli, which may generate a pattern of small centrilobular nodules.
- This is usually due to chronic pulmonary vascular congestion caused by heart failure, especially chronic mitral stenosis. (34246392)
dendriform type of DPO (diffuse pulmonary ossification):
- Basics: Branching bone spicules develop in the interstitium and alveolar septa.
- Epidemiology: Usually affects men >60 years old. (29863893)
- Causes include:
- Chronic lung diseases (e.g., emphysema, and especially idiopathic pulmonary fibrosis).
- Chronic gastric acid aspiration. (34246392)
- Idiopathic.
- Symptoms and pulmonary function tests are usually reflective of the underlying lung disease (the ossification itself doesn't seem to cause any direct problems). (29863893)
- Radiology:
- CT scan often shows a lacework of interstitial densities.
- There is often an underlying interstitial lung disease.
- Technetium-99m bone scan will be positive, but this is generally unlikely to add useful clinical information. (29863893)
- Treatment: Management is geared towards treating any underlying disease. No treatments are known to treat the diffuse pulmonary ossification itself. (29863893)
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References
- 29863893 Kadambi A, Epelbaum O, Rozenshtein A. A Bone to Pick with a Lung Disease. Ann Am Thorac Soc. 2018 Apr;15(4):506-508. doi: 10.1513/AnnalsATS.201707-612CC [PubMed]
- 32892884 Dodge DL, Cherian SV, Ali YD, Murzabdillaeva A, Hu Z, Estrada-Y-Martin RM. A 35-Year-Old Woman With Progressive Dyspnea and Cough. Chest. 2020 Sep;158(3):e103-e106. doi: 10.1016/j.chest.2020.02.068 [PubMed]
- 36338254 Sain B, Mukherjee S, Chakraborty R, Chaudhuri M. A 31-year-old female patient with chronic kidney disease presenting with persistent cough. Breathe (Sheff). 2022 Mar;18(1):210141. doi: 10.1183/20734735.0141-2021 [PubMed]
Books:
- Shah, P. L., Herth, F. J., Lee, G., & Criner, G. J. (2018). Essentials of Clinical pulmonology. In CRC Press eBooks. https://doi.org/10.1201/9781315113807
- Shepard, JO. (2019). Thoracic Imaging The Requisites (Requisites in Radiology) (3rd ed.). Elsevier.
- Walker C & Chung JH (2019). Muller’s Imaging of the Chest: Expert Radiology Series. Elsevier.
- Palange, P., & Rohde, G. (2019). ERS Handbook of Respiratory Medicine. European Respiratory Society.
- Rosado-De-Christenson, M. L., Facr, M. L. R. M., & Martínez-Jiménez, S. (2021). Diagnostic imaging: chest. Elsevier.
- Murray & Nadel: Broaddus, V. C., Ernst, J. D., MD, King, T. E., Jr, Lazarus, S. C., Sarmiento, K. F., Schnapp, L. M., Stapleton, R. D., & Gotway, M. B. (2021). Murray & Nadel’s Textbook of Respiratory Medicine, 2-Volume set. Elsevier.
- Fishman's: Grippi, M., Antin-Ozerkis, D. E., Cruz, C. D. S., Kotloff, R., Kotton, C. N., & Pack, A. (2023). Fishman’s Pulmonary Diseases and Disorders, Sixth Edition (6th ed.). McGraw Hill / Medical.