Pulmonary alveolar microlithiasis: two case reports and review of the literature

Data source and study selection

A PubMed search with the terms “pulmonary alveolar microlithiasis” was performed. Articles were restricted to those published in the English language with the exception of the study by Puhr [[1]. Additional articles were identified from the reference lists of the identified papers.

Epidemiology

PAM is thought to be an autosomal recessive disease with <600 patients reported worldwide [[6–11]. The disease predominates in a few countries, particularly Turkey, Italy and the USA [[11, 12]. Sporadic and familial cases are reported. Familial cases account for ∼30–50% of the reported cases [[7, 11, 12]. In most reports, no sex predilection was seen [[11]. However, both female [[8] and male [[7, 12] predominance have been described. An excess of males are reported in sporadic cases [[10]. In familial cases, both sexes are affected with equal frequency [[7, 10].

Aetiology

Although the aetiology of PAM remains unclear, mutations of the SLC34A2 gene, which encodes a type IIb sodium-dependent phosphate co-transporter (NaP_i-IIb), are considered to be the cause of the disease [[5]. SLC34A2 is primarily expressed in the lung and here only in alveolar type II cells [[5, 13]. These cells are responsible for production of surfactant. Loss of function of the gene due to mutations may lead to a decreased cell uptake of phosphate, which in turn may lead to formation of intra-alveolar microliths as a result of phosphate-chelating calcium in the extracellular fluid [[5, 14].

NaP_i-IIb is a member of the solute carrier family SLC34, the sodium-phosphate co-transporter family. The family consists of three members; NaP_i-lla (SLC34A1), NaP_i-llb (SLC34A2) and NaP_i-llc (SLC34A3), all representing type ll sodium/phosphate co-transporters. Type II Na/Pi-co-transporters are expressed in several tissues and play a major role in the homeostasis of inorganic phosphate [15].

Genetic characteristics

There are four earlier reports describing mutations in patients with PAM. Corut et al. [5] examined a large consanguineous family with six affected individuals, and six other unrelated affected patients. A total of six different homozygous mutations in the SLC34A2 gene were reported; two frame-shifts, one chain termination, one amino acid substitution, one deletion and, in the family, a deletion spanning the minimal promoter and exon-1 was detected [5]. Huqun et al. [13] identified two different homozygous mutations in the SLC34A2 gene in six patients, which were unrelated except for two siblings. Inbreeding was certain in three of the patients. A frame-shift mutation was identified in two unrelated patients, and a mutation causing splicing failure, leading to a premature termination of the protein, in the remaining four patients [13]. Ishihara et al. [16] found a homozygous deletion in SLC34A2 gene in one case. Dogan et al. [17] identified a frame-shift mutation in the SLC34A2 gene in a 10-member family. Three siblings were homozygous, and both parents (consanguineous marriage) and one sibling were heterozygous for the mutation. All siblings with the homozygous mutation were diagnosed with PAM [17].

Olauson et al. [18] reported one case with PAM where no disease-causing mutations or single nucleotide polymorphism were found in the SLC34A2 gene. The authors suggested that PAM might be a polygenic disorder arising from mutations other than those in SLC34A2 [18].

The severity of the disease may depend on the type of mutation. Thus, it was found that the mutation in exon 12 causes a truncation of the protein and a possible decreased activity of the protein [5], while mutations in exons 7 and 8 cause total loss of function of the protein [13]. PAM was found to have full penetrance since none of the unaffected members in the large family studied were homozygous for the disease haplotype [5]. Assuming full penetrance, an increased turnover of the alveolar epithelial cells, e.g. due to inflammation or smoking, may influence the onset of the symptoms in patients with a decreased activity of the SLC34A2, and thereby accelerate the development of symptoms. In support of this, smokers had a more severe clinical phenotype than nonsmokers, as observed by Corut et al. [5]. In the two cases presented here, both had a deletion in exon 12, and one may speculate that the early onset of the disease in case two may be due to smoking. However, these associations remain to be investigated in a larger number of patients with PAM.

Clinical features

The disease is usually discovered from birth up to 40 yrs of age, and is mostly diagnosed incidentally during pulmonary radiography of the chest for other reasons [7, 8, 12, 19]. Many patients have no clinical symptoms, and most of the cases either have normal pulmonary function or a mild restrictive pattern [11, 19].

In symptomatic patients, typical complaints are dyspnoea, nonproductive cough, chest pain and asthenia [11]. Although the clinical course varies, the disease is usually slowly progressive. In some patients, the disease remains static, while it in others worsens over time, progressing into pulmonary fibrosis, respiratory failure and cor pulmonale [12, 19, 20].

Elevated serum concentrations of surfactant protein (SP)-A and SP-D have been seen in PAM, with a tendency of increasing levels as the disease progress. Therefore, SP-A and SP-D have been suggested to be useful serum markers in monitoring the disease activity and progression [21].

Although the SLC34A2 gene is involved in phosphate homeostasis in several organs, including the lung [14, 15], blood levels of calcium and phosphate are usually normal in PAM [2, 19, 22, 23]. However, one case has been reported with slightly low normal serum phosphate and low 24-h urinary excretion of phosphate and calcium [18], and another with serum calcium below normal [24]. In addition, a few cases with mild hypercalcaemia [25–27], and one case with hyperphosphataemia have been reported [25]. Interestingly, Olauson et al. [18] found a reduction in the phosphaturic hormone fibroblast growth factor 23 in a case with PAM, suggesting the possibility of a compensatory mechanism for maintaining normal serum phosphate through increased renal reabsorption of phosphate.

Radiological characteristics

The characteristic chest radiograph reveals a picture of fine sand-like micronodulation of calcific densities bilaterally, described as a sandstorm, involving mainly the middle and lower zones [2, 7, 8, 12]. Calcified micronodules, ground-glass opacities, interlobular septal thickening, pleural and subpleural calcification and cysts are typical radiological findings seen in HRCT [17, 28–35].

Pathological characteristics

The radiographic appearance is pathognomonic. However, fibreoptic broncoscopy with BAL showing microliths or histological examination of a lung biopsy (fig. 4) is sometimes required to confirm the diagnosis [7, 8, 12]. Macroscopic examination at autopsy shows heavy and large lungs, and the cut surface is hard due to numerous microliths. Typical findings within the alveolar spaces are numerous calcified bodies, concentrically laminated with an onion skin-like appearance. The microliths usually range from 50 to 1,000 μm in diameter [22, 25, 35–39], although microliths up to 5,000 μm in size have been reported [40]. The microliths are mainly composed of calcium and phosphorus and, to a lesser degree, of varying amounts of iron, magnesium, potassium and copper. Variable degrees of fibrosis are shown in the lung interstitium [22, 25, 36–38, 40].

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Figure 4.

Case 1. Lung section from a patient with pulmonary alveolar microlithiasis showing calcified microliths localised in the intra-alveolar spaces. Haematoxylin and eosin staining. Original magnification: a) ×40 and b) ×200.

Extrapulmonary manifestations and comorbidity

As SLC34A2 is expressed in other tissues, mutations in the gene might be involved in extra-pulmonary calcifications. NaPi-IIb has been detected in various tissues such as kidney, prostate, pancreas, small intestine, uterus, ovary, testis, mammary glands, thyroid gland, salivary glands, trachea, liver and placenta [14, 41]. Recently, NaP_i-IIb has been identified in a human aortic valve [42].

Extrapulmonary calcifications have been reported in different cases of PAM, such as medullary nephrocalcinosis and/or nephrolithiasis [6, 18, 25, 26, 43], calcification of the lumbar sympathetic chain and possible testicular involvement [23], punctate calcifications in the seminal vesicles [44], and epididymal and periurethral calcifications causing obstructive azospermia [45].

Cardiac comorbidity has only been described in a very few cases of PAM. Four cases with mitral stenosis have been reported, of whom one also had aortic valve stenosis [38, 46, 47]. Furthermore, one case with mitral and aortic valve calcification has been described in a renal transplant recipient [48]. In addition, a case with concomitant valve calcification, cholelithiasis and idiopathic medullary nephrocalcinosis has been described [49]. Two cases with pericardial calcification have also been reported [50, 51].

Reported comorbidities in PAM include milk-alkali syndrome [25], diaphyseal aclasia [52], autosomal recessive Waardenburg-anophthalmia syndrome [53], hypertrophic pulmonary osteoarthropathy [54], pectus excavatum [55] and lymphocytic interstitial pneumonitis [56]. Furthermore, a case with PAM after varicella zoster virus infection, in a patient with antiphospholipid syndrome and discoid lupus erythematosus, has been reported [57].

Extrapulmonary calcifications are not commonly described in earlier reports. This may be due to under-reporting. Another possible explanation could be variability in the penetrance of the mutation. Whether extrapulmonary calcifications are caused by mutations in the SLC34A2 gene remains unclear, further investigations are needed to elucidate the possible connection.

Treatment

There is no known effective treatment for PAM, with the exception of lung transplantation [3, 31, 35, 58–61]. To our knowledge, recurrence of the disease after lung transplantation has not been reported.

Observational studies have found therapeutic BAL to be ineffective [62–64], except for symptomatic improvement in one case, without improvement in conventional pulmonary radiography and HRCT [36].

Corticosteroids are generally considered to be ineffective. However, only a few authors have reported on the effect of corticosteroids. Badger et al. [26] found steroids ineffective after 48 days of treatment. Freiberg et al. [65] reported on one case, in which no additional clinical improvement was seen after 2 weeks of treatment with prednisolone (40 mg daily). In one case, treatment with prednisolone (20 mg daily) for 6 months showed improvement on wheezing and chest tightness, but symptoms recurred when the treatment was discontinued. The patient had normal lung function and the authors discussed the possibility that the patient was suffering from asthma in addition to PAM, and that the symptoms might be caused by an inflammatory reaction due to the microliths or to some other respiratory irritant [36].

Treatment with corticosteroid and hydroxychloroquine showed clinical improvement in an 8-month-old infant [66], and improvement of pulmonary function and exercise tolerance was seen with corticosteroid therapy only in another child with PAM and lymphocytic interstitial pneumonitis [56]. A patient with PAM, after a varicella zoster virus infection, and concomitant antiphospholipid syndrome and discoid lupus erythematosus was treated with inhaled steroids (200 μg budesonide per day) and showed symptomatic improvement [57]. One of our cases (case one) was treated with high doses of prednisolone, before the diagnosis was proven, without any benefits.

A recent report describes beneficial effects of long-term treatment with disodium etidronate in two cases with PAM, diagnosed in childhood (9 and 11 yrs of treatment, respectively) [67]. Treatment with disodium etidronate showed improvement in the general condition and radiological stabilisation in a child with PAM [68]. Other studies have found no significant clinical or radiological improvement with the treatment [69, 70]. Didronate did not have an effect in either of our patients. The lack of efficacy in our patients might be due to an insufficient duration of treatment, the maximum duration of treatment being 2 yrs in case two. Another possible explanation could be that the chelating agents only inhibit the development of microliths, rather than dissolve already formed elements.

In severe PAM with respiratory failure and hypoxia, palliative treatment with oxygen improves subjective daytime function and oxygenation [65].

Long-term course

Long-term survival is still uncertain. There are only a few reports with long-term follow-up data. Furthermore, due to the variability of the clinical course of the disease, the time of the diagnosis may not reflect the onset of the disease.

Some authors have reported survival of >20 yrs [3, 6, 10, 18, 39, 52, 58, 62, 64, 67, 71], and only a few cases with a follow-up period of >40 yrs after the diagnosis have been reported [10, 12, 22]. However, most cases only have up to 10 yrs of follow-up time after the initial diagnosis [3, 6, 9, 23, 25, 31, 36, 38, 47, 48, 54, 56, 58, 59, 61, 66, 68–70, 72, 73]. Tachibana et al. [74] presented data on the long-term course of 53 Japanese patients with PAM. 28 of these patients were diagnosed during childhood. During a follow-up period of 10–49 yrs, 18 out of 53 patients died of respiratory insufficiency due to PAM [74].