Pulmonary alveolar microlithiasis
Pulmonary alveolar microlithiasis is caused by mutations of the type IIb sodium phosphate cotransporter gene, which by an unknown mechanism leads to the accretion of calcified microliths in the lungs. Almost invariably the patient is symptom free when the diagnosis is made after a chest radiograph is taken incidentally (or during family screening) and reveals profuse small calcified nodules. Patients usually survive 10–20 years from diagnosis, lung transplantation being the only effective treatment in severe cases.
Pulmonary alveolar microlithiasis is a very rare disorder, with less than 600 cases reported since its initial description in 1918. It is remarkable for a number of unusual if not unique features. Tiny calcified concretions, 0.05 to 5 mm in size, concentrically laminated, form progressively in the alveolar spaces, usually with some degree of interstitial fibrosis. As their profusion slowly increases, they produce a striking ‘whiteout’ appearance on the chest radiograph as the border of one intensely radio-opaque microlith overlaps that of another, even if the two are not immediately adjacent. Progression commonly leads to death from respiratory failure, but only after a decade or two. There is a strong tendency for cases to occur within families, reflecting the genetic cause. There is no effective means of therapy apart from transplantation.
Aetiology, genetics, pathogenesis, and pathology
The clustering of cases within families is most consistent with autosomal recessive inheritance, and a study in 2006 indicates that the disease arises from mutations of the type IIb sodium phosphate cotransporter gene on chromosome 4. This will doubtless stimulate further elucidation of the causal mechanisms, and advantage may be taken of the serendipidous discovery that a strain of laboratory mice (mutant nackt mice) appears to develop the disease.
No abnormality of calcium metabolism has been demonstrated, and analytical studies—including X-ray energy spectroscopy and microscopic infrared spectroscopy—have shown no evidence of mineral dust deposition. Nor is there evidence of an initiating infection. Heavily calcified alveolar microliths have also been noted complicating mitral stenosis. These are thought to arise from the organization of chronic alveolar exudates, raising the possibility that in the presence of impaired phosphate transport any alveolar exudate might lead to the production of calcified microliths. They are characteristically rounded or oval in alveolar microlithiasis, but are irregular and bosselated with mitral stenosis. Both types show massive calcification, and both may be associated with bone formation (hydroxyapatite) and interstitial fibrosis.
In 2004 Mariotta and colleagues reviewed all 576 published cases. Most had arisen in Europe (43%) or Asia (41%), and overall one-third (but 44% amongst 48 Italian cases) had positive family histories. The disease usually presents in middle age, but any age may be involved and both sexes are equally represented.
Almost invariably the patient is symptom free when an initial film is taken for incidental reasons, and there may be wonder that this can be possible when the radiograph is grossly abnormal. This is a consequence of there being no associated cellular, exudative, fibrotic, or vascular disruption of normal physiological processes in the early stages of the disease. Physical signs are conspicuous by their absence for most of the long course of the disease, although crackles, clubbing (even hypertrophic pulmonary osteoarthropathy) and signs of respiratory failure may be observed ultimately as the alveolar spaces are progressively filled with microliths and fibrosis of the interstitium advances. Shunting occurs at alveolar–capillary level causing hypoxaemia, and the bronchial circulation contributes increasingly to pulmonary venous return. In some cases subpleural cysts give rise to spontaneous pneumothoraces, and pleural adhesions may become prominent.
Although death supervened rapidly in the reported cases of two newborn infants, survival of 10 to 20 years is characteristic, and may be much longer. In most symptomatic cases there is slowly progressive breathlessness with dry cough. Haemoptysis and chest pain occur occasionally. The lungs stiffen, ventilation becomes restricted, and gas transfer is impaired. Eventually respiratory failure and cor pulmonale supervene. At death, extensive areas of the chest radiograph show a dense ‘whiteout’ appearance due to the considerable accumulation of calcium, the lungs are difficult to cut, and they sink in water.
The radiographic appearances of profuse, small, calcified nodules are almost diagnostic, particularly in moderately advanced cases when the dense ‘whiteout’ picture is seen but symptoms are still absent or unimpressive (Fig. 126.96.36.199). Early cases are occasionally simulated by sarcoidosis or healed chicken pox pneumonia. Biopsy, bronchoalveolar lavage, or expectorated sputum should provide diagnostic material (the microliths themselves), in less advanced cases (the microliths themselves), but with transbronchial biopsy it may prove difficult to close the forceps and extract them through the fibre-optic bronchoscope. Initially the chest radiograph shows a mere haziness of the lower zones, and CT may be invaluable in demonstrating the nodular shadows and their calcific nature. It may also confirm an early predominance for the basal and posterior segments. High-resolution images may also demonstrate the presence of interstitial fibrosis. As the profusion and size of the calcified concretions increase, the lung fields become diffusely and densely opaque. Measurement of lung function during the asymptomatic stage reveals little or no abnormality, the affected subject remaining well for many years.
Treatment and prognosis
Corticosteroids, calcium chelating agents, bisphosphonates, and bronchoalveolar lavage have not proved to be effective therapies, and treatment is merely supportive in the absence of lung transplantation. A detailed description of a 37-year-old man presenting in respiratory failure recorded severe hypoxia and pulmonary hypertension. Considerable intrapulmonary shunting was demonstrated, which was greatly improved by nasal continuous positive airway pressure, but not by conventional supplemental oxygen therapy. This presumably reflects the dominant effect of the disease in restricting alveolar ventilation over impairing gas diffusion. Although lung transplantation experience is necessarily limited in such a rare disorder, it clearly provides the most optimistic outlook for advanced disease. Survival otherwise is of the order 10–20 years from disease recognition.
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