Patients who develop spontaneous pneumothorax may not respond to conservative treatment with chest tube placement [82] and may require early surgical pleurodesis.

Patients with end-stage disease—especially those with right heart failure or chronic hypoxemic respiratory failure— should be referred to regional lung transplant centers. Optimal timing is not clear given the insidious nature of PAM and the lack of prognostic biomarkers or models [4]. As of late 2019, UNOS had records of lung transplantation being performed in 20 PAM patients [83–89]. The most common approach was bilateral lung transplantation (15/20 patients), although single lung transplantation has also been performed. Pleural adhesions and calci cations may make resection of the native lung during transplantation more technically dif cult, but strategies exist to mitigate risk [87, 90]. Transplant outcomes for PAM patients have not been compared to outcomes of patients with other lung diseases, but available reports in the world literature are reassuring. Importantly, since the rst transplant for PAM almost 30 years ago, no recurrence of alveolar microlithiasis has been reported in the allografts, as would be expected based on our new understanding of disease pathogenesis [21].

Summary

PAM is a hereditary disease characterized by the deposition of calcium phosphate crystals in the alveoli of the lungs caused by mutations in the type IIb sodium phosphate co-­ transporter. Patients typically present in their second or third decade of life and are often asymptomatic or only mildly dyspneic at the time of diagnosis, even when the imaging suggests extensive lung involvement. Characteristic chest tomography with widespread microcalci cations, diffuse ground-glass opacities, and dense airspace consolidations is frequently diagnostic, especially in the setting of a positive family history. Progressive disease ultimately results in worsening exertional dyspnea and respiratory failure. Treatment is primarily supportive. In patients with end-stage disease, lung transplantation may be an option; and timely referral for evaluation is essential. Recent development of an animal model has led to promising avenues of inquiry for further trials.

Box 27.1 Clinical Vignette

A 24-year-old male graduate student presents to clinic for evaluation of abnormal chest imaging. He had recently injured his shoulder in a minor car accident, and X-ray incidentally noted a diffuse micronodular pattern that prompted computed tomography of the chest.

He is asymptomatic. He has no environmental or occupational exposures. He is unsure whether there is any family history of respiratory diseases. Physical examination and laboratory data are unremarkable. Patient grew up in a region with endemic tuberculosis, so consecutive acid-fast bacilli smears and cultures are obtained and return negative. Given characteristic imaging, he is diagnosed with pulmonary alveolar microlithiasis. Whole genome sequencing for SLC34A2 reveals a mutation consistent with the diagnosis.

The patient’s clinical status remains stable for decades until he develops insidious onset progressive dyspnea on exertion and requires supplemental oxygen. He is ultimately referred for bilateral lung transplant, which he undergoes successfully.

Box 27.2 Diagnostic Criteria

De nite PAM

Characteristic HRCT ndings PLUS

Histopathologic evidence of PAM on expectorated sputum, bronchoalveolar lavage, transbronchial biopsies, or surgical lung biopsy

OR

SLC34A2 mutation OR

Affected rst degree relative

Likely PAM

Characteristic HRCT ndings

AND

No alternate diagnosis

Based on algorithm recently proposed by our group (Kosciuk P, Meyer C, Wikenheiser-Brokamp KA, McCormack FX Eur Respir Rev 2020). No validated criteria exist at present.

References

1.\Malpighi M. Manoscritti vol XII foglio 81. Marcello Malpighi e i suoi seritti sugli organii del respiro. Anzalone M, editor. Bologna; 1966.

2.\Harbitz F. Extensive calci cation of the lungs as a distinct disease. Arch Intern Med. 1918;XXI(1):139–46.

3.\Puhr L. Mikrolithiasis alveolaris pulmonum. Virchows Arch. 1933;290(1):156–60.

2015;24(138):607–20.

5.\Ucan ES, et al. Pulmonary alveolar microlithiasis: review of Turkish reports. Thorax. 1993;48(2):171–3.

6.\Tiedjen KU, Kosberg R, Kruger G. Pulmonary microlithiasis following iodine lipiodol lymphography? Radiologe. 1986;26(10):460–3.

7.\Chang AR. Pulmonary alveolar microlithiasis. Pathology. 1980;12(2):164–7, 282–3.

8.\Sosman MC, et al. The familial occurrence of pulmonary alveolar microlithiasis. Am J Roentgenol Radium Therapy, Nucl Med. 1957;77(6):947–1012.

9.\Mariotta S, et al. Pulmonary alveolar microlithiasis: review of Italian reports. Eur J Epidemiol. 1997;13(5):587–90.

10.\Hagiwara K, Johkoh T, Tachibana T. Pulmonary alveolar microlithiasis. In: Trapnell BC, Panos RJ, McCormack F, editors. Molecular basis of lung disease, insight from rare lung disorders. New Jersey: Humana Press; 2009.

11.\Huqun, et al. Mutations in the SLC34A2 gene are associated with pulmonary alveolar microlithiasis. Am J Respir Crit Care Med. 2007;175(3):263–8.

12.\Moran CA, et al. Pulmonary alveolar microlithiasis. A clinicopathologic and chemical analysis of seven cases. Arch Pathol Lab Med. 1997;121(6):607–11.

13.\Portnoy LM, Amadeo B, Hennigar GR. Pulmonary alveolar microlithiasis. An unusual case (associated with Milk-alkali syndrome). Am J Clin Pathol. 1964;41:194–201.

14.\Siddiqui NA, Fuhrman CR. Best cases from the AFIP: pulmonary alveolar microlithiasis. Radiographics. 2011;31(2):585–90.

15.\Kawakami M, Sato S, Takishima T. Electron microscopic studies on pulmonary alveolar microlithiasis. Tohoku J Exp Med. 1978;126(4):343–61.

16.\Barnard NJ, et al. Pulmonary alveolar microlithiasis. A new analytical approach. Histopathology. 1987;11(6):639–45.

17.\Chalmers AG, Wyatt J, Robinson PJ. Computed tomographic and pathological ndings in pulmonary alveolar microlithiasis. Br J Radiol. 1986;59(700):408–11.

18.\Pracyk JB, et al. Composition of lung lavage in pulmonary alveolar microlithiasis. Respiration. 1996;63(4):254–60.

19.\Malhotra B, et al. Pulmonary alveolar microlithiasis with calci ed pleural plaques. Lung India. 2010;27(4):250–2.

20.\Pant K, et al. Pulmonary alveolar microlithiasis with pleural calci - cation and nephrolithiasis. Chest. 1990;98(1):245–6.

21.\Samano MN, et al. Lung transplantation for pulmonary alveolar microlithiasis: a case report. Clinics (Sao Paulo). 2010;65(2):233–6.

22.\Ghosh GC, et al. Pulmonary alveolar microlithiasis: a rare cause of right heart failure. BMJ Case Rep. 2013;2013:bcr2013010218.

23.\Terada T. Pulmonary alveolar microlithiasis with cor pulmonale: an autopsy case demonstrating a marked decrease in pulmonary vascular beds. Respir Med. 2009;103(11):1768–71.

24.\Corut A, et al. Mutations in SLC34A2 cause pulmonary alveolar microlithiasis and are possibly associated with testicular microlithiasis. Am J Hum Genet. 2006;79(4):650–6.

25.\Zhang XD, et al. Pulmonary alveolar microlithiasis: a case report and review of the literature. Exp Ther Med. 2018;15(1):831–7.

26.\Izumi H, et al. A novel SLC34A2 mutation in a patient with pulmonary alveolar microlithiasis. Hum Genome Var. 2017;4:16047.

27.\Dogan OT, Ozsahin SL, Gul E, et al. A frame-shift mutation in the SLC34A2 gene in three patients with pulmonary alveolar microlithiasis in an inbred family. Intern Med. 2010;49(1):45–9.

28.\Ishihara Y, Hagiwara K, Zen K, Huqun, Hosokawa Y, Natsuhara A. A case of pulmonary alveolar microlithiasis with an intragenetic deletion in SLC34A2 detected by a genome-wide SNP study. Thorax. 2009;64(4):365–67.

29.\Ozcelik U, et al. Long-term results of disodium etidronate treatment in pulmonary alveolar microlithiasis. Pediatr Pulmonol. 2010;45(5):514–7.

30.\Ozbudak IH, Bassorgun CI, Ozbilim G, et al. Pulmonary alveolar microlithiasis with homozygous c.316G > C (p.G106R) mutation: a case report. Turk Patoloji Derg. 2012;28(3):282–5.

31.\Dandan S, et al. Novel deletion of SLC34A2 in Chinese patients of PAM shares mutation hot spot with fusion gene SLC34A2-ROS1 in lung cancer. J Genet. 2018;97(4):939–44. PMID: 30262706.

32.\Ma T, et al. A pedigree with pulmonary alveolar microlithiasis: a clinical case report and literature review. Cell Biochem Biophys. 2014;70(1):565–72.

33.\Zhong YQ, Hu CP, Cai XD, Nie HP. [A novel mutation of the SLC34A2 gene in a Chinese pedigree with pulmonary alveolar microlithiasis]. Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2009;26(4):365–68.

34.\Yin X, Wang H, Wu D, Zhao G, Shao J, Dai Y. SLC34A2 Gene mutation of pulmonary alveolar microlithiasis: report of four cases and review of literatures. Respir Med. 2013;107(2):217–22.

35.\Wang H, Yin X, Wu D, Jiang X. SLC34A2 gene compound heterozygous mutation identi cation in a patient with pulmonary alveolar

microlithiasis and computational 3D protein structure prediction. Meta Gene. 2014;2:557–64.

36.\Proesmans M, et al. Pulmonary alveolar microlithiasis: a case report and review of the literature. Eur J Pediatr. 2012;171(7):1069–72. https://doi.org/10.1007/s00431-012-1678-8. Epub 4 Feb 2012. PMID: 22311166.

37.\Yang W, et al. Elevated expression of SLC34A2 inhibits the viability and invasion of A549 cells. Mol Med Rep. 2014;10(3):1205–14.

38.\Traebert M, et al. Expression of type II Na-P(i) cotransporter in alveolar type II cells. Am J Phys. 1999;277(5):L868–73.

39.\Hashimoto M, et al. Isolation and localization of type IIb Na/ Pi cotransporter in the developing rat lung. Am J Pathol. 2000;157(1):21–7.

40.\Sabbagh Y, et al. Intestinal npt2b plays a major role in phosphate absorption and homeostasis. J Am Soc Nephrol. 2009;20(11):2348–58.

41.\Schiavi SC, et al. Npt2b deletion attenuates hyperphosphatemia associated with CKD. J Am Soc Nephrol. 2012;23(10):1691–700.

42.\Saito A, et al. Modeling pulmonary alveolar microlithiasis by epithelial deletion of the Npt2b sodium phosphate cotransporter reveals putative biomarkers and strategies for treatment. Sci Transl Med. 2015;7(313):313ra181.

43.\Takahashi H, et al. Elevated serum surfactant protein a and D in pulmonary alveolar microlithiasis. Respirology. 2006;11(3):330–3.

44.\Monabati A, Ghayumi MA, Kumar PV. Familial pulmonary alveolar microlithiasis diagnosed by bronchoalveolar lavage. A case report. Acta Cytol. 2007;51(1):80–2.

45.\Caffrey PR, Altman RS. Pulmonary alveolar microlitbiasis occurring in premature twins. J Pediatr. 1965;66:758–63.

46.\Mariotta S, et al. Pulmonary alveolar microlithiasis: report on 576 cases published in the literature. Sarcoidosis Vasc Diffuse Lung Dis. 2004;21(3):173–81.

47.\Meyer HH, Gilbert ES, Kent G. A clinical review of pulmonary microlithiasis. J Am Med Assoc. 1956;161(12):1153–7.

48.\Coetzee T. Pulmonary alveolar microlithiasis with involvement of the sympathetic nervous system and gonads. Thorax. 1970;25(5):637–42.

49.\Sandhyamani S, et al. Pulmonary alveolar microlithiasis. Indian J Chest Dis Allied Sci. 1982;24(1):33–5.

50.\Arslan A, et al. Pulmonary alveolar microlithiasis associated with calci cations in the seminal vesicles. J Belg Radiol. 1996;79(3):118–9.

51.\Kanat F, Teke T, Imecik O. Pulmonary alveolar microlithiasis with epididymal and periurethral calci cations causing obstructive azospermia. Int J Tuberc Lung Dis. 2004;8(10):1275.

52.\Qublan HS, Athamneh I, Al-Kaisi NS. Azoospermia associated with testicular and pulmonary microlithiasis. J Diagn Med Sonograp. 2003;19(3):192–4.

53.\Sumikawa H, et al. Pulmonary alveolar microlithiasis: CT and pathologic ndings in 10 patients. Monaldi Arch Chest Dis. 2005;63(1):59–64.

54.\Kim B, Winter TC 3rd, Ryu JA. Testicular microlithiasis: clinical signi cance and review of the literature. Eur Radiol. 2003;13(12):2567–76.

55.\Middleton WD, Teefey SA, Santillan CS. Testicular microlithiasis: prospective analysis of prevalence and associated tumor. Radiology. 2002;224(2):425–8.

56.\Miller FN, Sidhu PS. Does testicular microlithiasis matter? A review. Clin Radiol. 2002;57(10):883–90.

57.\Prakash UB, et al. Pulmonary alveolar microlithiasis. A review including ultrastructural and pulmonary function studies. Mayo Clin Proc. 1983;58(5):290–300.

58.\Tachibana T, Hagiwara K, Johkoh T. Pulmonary alveolar microlithiasis: review and management. Curr Opin Pulm Med. 2009;15(5):486–90.

59.\Balikian JP, Fuleihan FJ, Nucho CN. Pulmonary alveolar microlithiasis. Report of ve cases with special reference to roentgen manifestations. Am J Roentgenol Radium Therapy, Nucl Med. 1968;103(3):509–18.

60.\Cluzel P, et al. Pulmonary alveolar microlithiasis: CT ndings. J Comput Assist Tomogr. 1991;15(6):938–42.

61.\Deniz O, et al. High resolution computed tomographic features of pulmonary alveolar microlithiasis. Eur J Radiol. 2005;55(3):452–60.

62.\Marchiori E, et al. Pulmonary alveolar microlithiasis: high-­ resolution computed tomography ndings in 10 patients. J Bras Pneumol. 2007;33(5):552–7.

63.\Francisco FA, et al. Can chest high-resolution computed tomography ndings diagnose pulmonary alveolar microlithiasis? Radiol Bras. 2015;48(4):205–10.

64.\Gasparetto EL, et al. Pulmonary alveolar microlithiasis presenting with crazy-paving pattern on high resolution CT. Br J Radiol. 2004;77(923):974–6.

65.\Belem LC, et al. Metastatic pulmonary calci cation: state-­ of-­the-art review focused on imaging ndings. Respir Med. 2014;108(5):668–76.

66.\Chatterji R, Gaude GS, Patil PV. Pulmonary alveolar microlithiasis: diagnosed by sputum examination and transbronchial biopsy. Indian J Chest Dis Allied Sci. 1997;39(4):263–7.

67.\Martinez-Giron R, Martinez-Torre S. Calci ed Curschmann’s spirals and microliths in sputum smears from a case of pulmonary alveolar microlithiasis. Diagn Cytopathol. 2017;45(12):1116–8.

68.\Arpag H, et al. A case of pulmonary alveolar microlithiasis diagnosed by transbronchial biopsy. Turk Thorac J. 2017;18(4):134–6.

69.\Castellana G, et al. Pulmonary alveolar microlithiasis: clinical features, evolution of the phenotype, and review of the literature. Am J Med Genet. 2002;111(2):220–4.

70.\Watts NB, et al. Intermittent cyclical etidronate treatment of postmenopausal osteoporosis. N Engl J Med. 1990;323(2):73–9.

71.\Allgrove J. Biphosphonates. Arch Dis Child. 1997;76(1):73–5. 72.\Mariotta S, et al. Pulmonary microlithiasis. Report of two cases.

Respiration. 1997;64(2):165–9.

73.\Kumazoe H, et al. “Reversed halo sign” of high-resolution computed tomography in pulmonary sarcoidosis. J Thorac Imaging. 2009;24(1):66–8.

74.\Ozcelik U, et al. Treatment and follow-up of pulmonary alveolar microlithiasis with disodium editronate: radiological demonstration. Pediatr Radiol. 2002;32(5):380–3.

75.\Jankovic S, et al. Pulmonary alveolar microlithiasis in childhood: clinical and radiological follow-up. Pediatr Pulmonol. 2002;34(5):384–7.

76.\Cakir E, et al. Response to disodium etidronate treatment in three siblings with pulmonary alveolar microlithiasis. Respiration. 2015;89(6):583–6.

77.\Emiralioglu N, et al. Diagnosis and treatment of pulmonary alveolar microlithiasis. Pediatr Int. 2016;58(8):805–7.

78.\Taille C, et al. Calcium-solubilizing sodium thiosulfate failed to improve pulmonary alveolar microlithiasis: evaluation of calcium content with CT scan. Respir Med Res. 2019;75:10–2.

79.\Palombini BC, et al. Bronchopulmonary lavage in alveolar microlithiasis. Chest. 1981;80(2):242–3.

80.\Palombini BC, et al. Bronchopulmonary lavage in alveolar microlithiasis. Anaesth Intensive Care. 1978;6(3):265.

81.\Mascie-Taylor BH, et al. A case of alveolar microlithiasis: observation over 22 years and recovery of material by lavage. Thorax. 1985;40(12):952–3.

82.\Devine OP, Harborne AC. Pneumothorax secondary to pulmonary alveolar microlithiasis. Clin Case Rep. 2018;6(4):764–5.

83.\Jackson KB, et al. Single lung transplantation for pulmonary alveolar microlithiasis. J Heart Lung Transplant. 2001;20(2):226.

84.\Stamatis G, et al. Sequential bilateral lung transplantation for pulmonary alveolar microlithiasis. Ann Thorac Surg. 1993;56(4):972–5.

85.\Borrelli R, et al. Right single-lung transplantation for pulmonary alveolar microlithiasis. Eur J Cardiothorac Surg. 2014;45(2):e40.

86.\Bonnette P, et al. Bilateral single lung transplantation. Complications and results in 14 patients. Eur J Cardiothorac Surg. 1992;6(10):550–4.

87.\Edelman JD, et al. Bilateral sequential lung transplantation for pulmonary alveolar microlithiasis. Chest. 1997;112(4):1140–4.

88.\Alrossais NM, et al. Pulmonary hypertension and polycythemia secondary to pulmonary alveolar microlithiasis treated with sequential bilateral lung transplant: a case study and literature review. Am J Case Rep. 2019;20:1114–9.

89.\Jindal A, et al. Pulmonary alveolar microlithiasis: a rare disease treated with lung transplantation, rst case from India. Lung India. 2019;36(6):546–9.

90.\Shigemura N, et al. Lung transplantation for pulmonary alveolar microlithiasis. J Thorac Cardiovasc Surg. 2010;139(3):e50–2.