Many observations support the hypothesis that a familiar inherited trait is involved according to an autosomal recessive transmission. Several cases (up to six) were diagnosed in the same family [11]. Family occurrence was found up to 31.4 % and most cases were siblings. Other authors [5, 7] found this percentage to be higher. The difference could be due to the absence of family screening for educational or economic reasons, especially in the developing countries.

In the past it was assumed that calcium salt deposits in the alveoli were due to changes in calcium metabolism because of some unknown defect. The widely endorsed hypothesis suggested an abnormality involving the carbonic anhydrase enzyme at the alveolar surface, with consequent alkalinity in the alveoli, calcium precipitation and development of calcospherites. Other hypotheses considered the first step of the disease to be the consequence of the arrival of calcified mycetes, transported into the alveoli by inhaled air; others took it to be the consequence of a diet rich in calcium salts, e.g. milk (milk alkali syndrome), or of the prolonged inhalation of dust or powdered substances (“snuff syndrome”), or changes in pulmonary haemodynamics due to mitral stenosis. Calcium metabolism was reported to be normal in most cases.

In 2006, a mutation of SLC34A2 gene was for the first time proved to occur in PAM patients [12]. This gene is a member of the solute carrier family 34 (sodium phosphate), member 2 – SLC34A2, which plays a major role in the homeostasis of inorganic phosphate [12], and it was shown by immunohistochemistry to be expressed in lungs only in alveolar type II cells, which are responsible for surfactant production [15].

The gene regulates the normal production of type IIb sodium-dependent (NaPi-IIb) phosphate transporter [16]. The function of this protein, encoded by the member 2 of SLC34A gene (SLC34A2), is to uptake liberated phosphate from the alveolar fluid for surfactant production [12]. The type II cells produce pulmonary surfactant, of which phospholipids are essential constituents; outdated surfactant is taken up by type II cells for recycling and degradation, and by alveolar macrophages only for degradation. Degraded phospholipids release phosphate that should be cleared from the alveolar space [17] (Fig. 20.3a). Dysfunction of SLC34A2 reduces the clearance of phosphate and leads to the formation of microliths composed of calcium and phosphate [13, 18] (Fig. 20.3b).

PAM is a recessively inherited disease and is not caused by environmental factors. It has full penetrance, since none of the unaffected members is homozygous for the disease haplotype [12]. The homozygous mutations in SLC34A2 determine symptomatic PAM, while the heterozygous carriers are asymptomatic. The identification of the gene responsible for PAM facilitates genetic diagnosis and gives hope for a genetic therapy [14, 19].

Calcium deposits within the alveoli begin at the lower lobes and in 20–30 years or more they extend to the whole lungs. Calculi have a round or ovoidal shape and range from 0.01 to 2.8 mm in diameter (Fig. 20.4). In the early stages, the alveolar septa are intact and gas exchanges are normal. Microliths progressively increase in number inside the alveoli, until they occupy the entire alveolar space and come into contact with the walls which in the advanced stages are pressed, injured and replaced by fibrous tissue. Upon opening of the chest, lungs reveal an increase in volume and weight, they are not collapsible and, upon cutting, they reveal a granular and irregular surface; the resistance of the lung parenchyma is markedly increased, almost as if it were a stone. This was precisely the picture that Malpighi [19] described in 1686 in the postmortem report of a young man – “…Pulmones turgidi graves et compactae substantiae inaequaliter nigri. Interius in vesciculis pulmonum innumeri lapilli reperti sunt …” (The lungs were heavy and compact with patches of black. Countless small stones were found in the interior of the lungs); this has also been identified as the first case of PAM reported in the literature. In all autoptic observations, the weight of the lungs is reported to be significantly increased up to 6.190 kg. Several authors have studied the structure and the composition of the microliths in an attempt to explain the pathogenesis of the disease. So it was thus observed that these concretions are irregularly concentric and laminated, and that they consist of calcium salts. Transmission or scanning electron microscopy of microlith fragments revealed spectra where calcium and phosphorus have peak intensities, and a 2:1 ratio of calcium over phosphorus, which is consistent with a Ca₂PO₃ content. Deposits of iron, zinc, aluminium and magnesium are frequently found in the fragments.