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Metastatic pulmonary calcification (MPC) is a subdiagnosed metabolic lung disease that is commonly associated with end-stage renal disease. This interstitial process is characterized by the deposition of calcium salts predominantly in the alveolar epithelial basement membranes. MPC is seen at autopsy in 60–75% of patients with renal failure. It is often asymptomatic, but can potentially progress to respiratory failure. Chest radiographs are frequently normal or demonstrate confluent or patchy airspace opacities. Three patterns visible on high-resolution computed tomography have been described: multiple diffuse calcified nodules, diffuse or patchy areas of ground-glass opacity or consolidation, and confluent high-attenuation parenchymal consolidation. The relative stability of these pulmonary infiltrates, in contrast to infectious processes, and their resistance to treatment, in the clinical context of hypercalcemia, are of diagnostic value. Scintigraphy with bone-seeking radionuclides may demonstrate increased radioactive isotope uptake. The resolution of pulmonary calcification in chronic renal failure may occur after parathyroidectomy, renal transplantation, or dialysis. Thus, the early diagnosis of MPC is beneficial. The aim of this review is to describe the main clinical, pathological, and imaging aspects of MPC.
Metastatic pulmonary calcification (MPC) is a metabolic lung disease characterized by the deposition of calcium in the pulmonary parenchyma. It occurs most often in association with conditions that directly or indirectly result in hypercalcemia. MPC may be of benign or malignant etiology [
]. Benign causes include chronic renal failure, primary and secondary hyperparathyroidism, excess exogenous administration of calcium and vitamin D, sarcoidosis, milk-alkali syndrome, osteoporosis, and osteitis deformans; the benign form may also occur following renal or liver transplantation and cardiac surgery. Malignant etiologies include massive osteolysis from metastases or multiple myeloma, parathyroid carcinoma, leukemia, lymphoma, breast carcinoma, synovial carcinoma, choriocarcinoma, malignant melanoma, and hypopharyngeal squamous carcinoma [
Pathological pulmonary calcification can be broadly divided into metastatic and dystrophic calcifications. MPC is defined as calcium deposition in normal lung tissue without prior tissue damage, and is related to chronically elevated serum calcium-phosphate product. In contrast, dystrophic calcification requires injured tissue, such as infected or inflamed lung tissue, even in the absence of increased serum calcium levels [
]. Benign MPC is known to be a long-term complication that occurs in patients with chronic renal failure accompanied by secondary hyperparathyroidism [
]. Despite the prevalence of this condition in patients with renal failure, MPC is rarely diagnosed antemortem, probably due to the poor sensitivity of standard chest radiographs for the identification of calcifications [
MPC is associated most frequently with an increased calcium-phosphate product as a result of hypercalcemia and/or hyperphosphatemia. This product is about 40 mg2/dl2 in normal subjects, and metastatic calcifications are most likely to develop when it exceeds 70 mg2/dl2 [
The serum phosphate level is low in primary hyperparathyroidism due to the phosphaturic effect of circulating parathyroid hormone (PTH); thus, the calcium-phosphate product is generally <60 mg2/d12 and metastatic calcification is rarely seen. MPC also occurs rarely in association with parathyroid carcinoma accompanied by high serum levels of calcium and PTH [
]. First, acidosis in the interdialytic interval has been postulated to leach calcium from bone, leading to its deposition in soft tissue during postdialysis alkalosis. Intermittent alkalosis also increases the activity of alkaline phosphatase, which catalyzes the release of phosphates. Second, hyperparathyroidism has been shown experimentally to contribute to pulmonary calcification in the presence and absence of uremia [
]. Third, uremia per se may alter the configuration of tissue proteins, rendering them more calcifiable. Finally, a reduced glomerular filtration rate causes hyperphosphatemia, which in turn elevates the calcium-phosphate product, favoring crystallization [
]. Liver transplant recipients receive large amounts of fresh frozen plasma, which contains sodium citrate, due to the coagulopathy associated with this procedure. The high plasma citrate level leads to metabolic alkalosis and hypocalcemia via the chelation of ionized calcium. Parathyroid hormone secretion is then triggered and calcium is deposited in soft tissues following the administration of a large amount of exogenous calcium [
The secretion of free hydrogen ions is an important local factor in the development of metastatic calcification. The lung, kidney, and stomach, three of the most frequently involved organs, are involved in free hydrogen ion secretion. This secretion creates an alkaline environment in which calcium salts may precipitate [
MPC or visceral calcification is composed primarily of whitlockite ([Ca, Mg]3PO4), which appears as an amorphous substance or as minute crystals, in contrast to the crystalline hydroxyapatite more commonly found in vascular calcification. Lesser amounts of pyrophosphate are also seen [
Macroscopically, the lungs are diffusely solidified in cases of MPC. They are heavy, with weights ranging from 590 g to 1800 g. Sectioning reveals irregular or well-delineated nodules scattered throughout the organ [
Microscopically, metastatic calcification has been seen within the lamina propria of the stomach, in tubules and interstitium of the kidneys, and in basement membranes of the epithelium and endothelium of alveoli in the lungs [
]. Regardless of the etiology or organ affected, calcifications appear on hematoxylin and eosin-stained slides as granular, lamellar, linear, and plate-like basophilic materials; they also show positivity in Von Kassa and Alizarin red staining [
Figure 1A 67-year-old man with metastatic pulmonary calcification. The pathological specimen demonstrates interstitial calcification, appearing as basophilic deposits along the alveolar septa (hematoxylin & eosin; original magnification, ×100).
Microscopic examination reveals fibrous widening of the alveolar septa, with infiltration of these walls by multiple areas of calcification and a few lymphocytes [
]. In mild cases, calcium deposits are present along the alveolar epithelial basement membrane and in alveolar capillary walls without significant desmoplasia or septal thickening [
]. Although pulmonary calcification generally progresses slowly and is often asymptomatic, several reports have described acute respiratory insufficiency with a rapidly progressive chest shadow that mimics pneumonia or pulmonary edema [
]. Clinically, the degree of respiratory distress is often uncorrelated with the degree of macroscopic calcification. Patients with extensive calcification may be asymptomatic, whereas those with subtle calcification or normal chest radiographs may have severe respiratory compromise [
]. Although the factors involved in the development of the more aggressive form of MPC are not fully understood, acceleration of the condition has been previously reported following failed renal transplantation [
] and not very useful for the diagnosis of MPC. Chest radiographs are frequently normal or demonstrate confluent or patchy airspace opacities (Fig. 2) simulating pulmonary edema or pneumonia [
]. The relative stability of these pulmonary infiltrates, in contrast to infectious processes, and their resistance to treatment are of diagnostic value [
]. The density of opacities is not sufficiently high to suggest calcification in most reported cases, but opacities are massively calcified or become progressively more dense when left untreated in some cases [
]. The difficulty of recognizing the calcific nature of these varying patterns may be explained by the small sizes of calcium deposits and the currently common use of a high-kilovoltage and low-contrast technique [
]. Advanced MPC can be easily recognized on a standard chest radiograph, but it should be differentiated from other causes of pulmonary calcification, particularly previous tuberculous infection [
Figure 2A 42-year-old man with metastatic pulmonary calcification. A. A scout image from a CT showing confluent airspace opacities in both upper lobes. CT scan with coronal reconstructions with (B) lung and (C) mediastinal windows showing consolidation areas with calcification in the upper lobes.
], most likely due to the availability and advantages of computed tomography (CT) for the assessment of patients suspected for other respiratory problems [
] in detecting small amounts of calcification. This modality is increasingly used in the diagnosis of MPC, thereby obviating the need for open lung biopsy [
Changes visible on CT are most marked in the upper zones of the lungs due to increased alkalinity at the apices, which encourages the deposition of calcium salts [
]. This process can be explained by the higher ventilation/perfusion ratio at the apices, which produces a lower partial pressure of carbon dioxide in arterial blood (PaCO2) and higher blood pH [
] (Figs. 3 and 4). The distribution of pulmonary calcification can be punctuate within nodular opacities, ring-like, or diffuse, involving the entire nodule or consolidation area [
]. These findings reflect the deposition of calcium salts in the alveolar walls around the terminal bronchioles; thus, the tree-in-bud appearance and bronchial wall thickening are not expected in MPC [
]. Interlobular septal thickening is also not observed in MPC; despite the potential expectation of such thickening due to the purely interstitial pathological process of MPC, it is absent because the predominant sites of calcium deposition seen on pathological examination are the alveolar septa and, to a lesser extent, the pulmonary arterioles and bronchioles [
Figure 3A 40-year-old woman with metastatic pulmonary calcification. A. High-resolution computed tomography at the level of the lower lobes shows a consolidation area in the basal posterior segment of the right inferior lobe associated with a few small nodules and bilateral ground-glass opacities. B. The soft-tissue window demonstrates extensive calcification within the consolidation area and scattered punctate foci of calcification. Note also the bilateral pleural effusion.
Figure 4A 67-year-old man with metastatic pulmonary calcification (same patient of Fig. 1). High-resolution CT at the level of the upper lobes shows nodular ground glass opacities in a predominately centrilobular distribution.
The most common parenchymal finding on HRCT is the presence of centrilobular ground-glass nodular opacities, with numerous fluffy and poorly defined nodules measuring 3–10 mm in diameter [
]. In the peripheral region of the secondary pulmonary lobules, the microchemical environment of the alveoli tends to become alkalosed in comparison with the central area. The characteristic distribution of areas of ground-glass attenuation may be explained by the differentiation of the acid-base balance between the peripheral and central regions of the secondary pulmonary lobules [
]. The combination of pulmonary and vascular calcification is said to be of diagnostic value for MPC, narrowing the differential diagnosis of the causes of pulmonary calcification [
]. In addition to pulmonary calcification, CT may also reveal extensive calcification of the myocardium, bronchial walls, small pulmonary arteries, superior vena cava, and the dura of the dorsal spine [
]. MPC has been shown to appear hyperintense on T1-weighted images and to have a higher lesion/muscle signal-intensity ratio on T1-weighted than on T2-weighted images [
]. In the absence of calcification, lung tissues with thickened and fibrotic alveolar walls should have higher lesion/muscle MRI signal intensity on proton-density and T2-weighted images than on T1-weighted images [
]. This signal behavior is explained by a shortening of the T1 relaxation time by a surface relaxation mechanism. The degree of T1 shortening is directly related to the surface area of the calcium crystals [
]. Only in cases in which the microscopic crystal surface area is very high can the T1 effect predominate, causing a net increase in MRI signal intensity [
]. The calcium particulates in MPC may cause a situation in which the effect of T1 shortening overcomes the effects of reduced proton density and T2 relaxivity; thus, the lesions demonstrate increased signal intensity on T1-weighted MRI [
MRI findings are useful for the characterization of calcium accumulation caused by a metabolic disorder, although nuclear imaging with technetium-99m-methylene diphosphonate (Tc99m-MDP) is a more specific and less expensive method for diagnosis [
Lungs affected by MPC demonstrate increased radioactive isotope uptake. Lung uptake is generally symmetrical and sufficiently dense to obliterate the rib outlines [
]. Renal uptake is variable. As renal excretion of pyrophosphate and phosphonate radiopharmaceuticals is a normal finding, the extent of renal uptake in cases of MPC represents a balance between decreased uptake due to impaired renal function and increased uptake secondary to parenchymal calcification [
]. Because alveolar septa are diffusely involved in MPC, diffusing capacity is decreased. Anatomical changes due to calcific deposits may lead to a restrictive syndrome [
MPC is the most likely cause of multifocal pulmonary parenchymal calcification in patients with chronic renal failure. The predilection of calcification for the upper lung area and its association with calcification in the vessels of the chest wall may support the diagnosis [
]. The differential diagnosis of MPC includes conditions that may lead to diffuse small calcified nodules, diffuse small high-attenuation non-calcified nodules, and high-attenuation consolidation [
Causes of diffuse small calcified nodules include infection, pulmonary metastasis, chronic hemorrhagic conditions, occupational and deposition diseases, and idiopathic disorders such as pulmonary alveolar microlithiasis. These nodules are most commonly secondary to dystrophic calcification in previously damaged lung parenchyma; they are frequently seen in patients with healed disseminated histoplasmosis and, rarely, as a sequela of miliary tuberculosis. Most of these patients have calcified hilar and/or mediastinal lymph nodes. Tiny widespread micronodular calcification is an uncommon sequela of varicella pneumonia. Metastatic malignancies that may lead to this pattern include osteogenic sarcoma, chondrosarcoma, mucin-producing adenocarcinomas, and thyroid malignancies [
]. It may also occur in treated metastases. Silicosis and coal workers' pneumoconiosis may have this aspect and are often associated with egg-shell calcification of hilar or mediastinal lymph nodes. The nodules are most prominent in the middle and upper lung zones and may calcify. Chronic hemorrhagic conditions (hemosiderosis) may also present as dense centrilobular nodular opacities. Recurrent episodes of alveolar hemorrhage over several years are characteristic of this entity. Secondary hemosiderosis due to mitral stenosis also may present with small multifocal calcified nodules. Calcified nodules may also be seen in accumulations of iron oxide (siderosis), tin oxide (stannosis), and barium dust (baritosis) in lung macrophages [
The differential diagnosis for diffuse small high-attenuation noncalcified nodules includes talcosis and mercury or acrylic cement embolism. Talcosis has been described in workers exposed to talc and drug abusers (endovenous administration). Early tomographic manifestations consist of a diffuse micronodular pattern with well-defined nodules, or diffuse ground-glass opacity. As the disease progresses, nodule confluence creates hyperdense consolidations or confluent perihilar masses. Panlobular emphysema with predominant lower lobe involvement has been described secondary to the endovenous injection of Ritalin (methylphenidate). Intravenous mercury injection is infrequent and most frequently related to attempted suicide and iatrogenic injection. It usually appears on CT as multiple small metallic spherules scattered diffusely throughout both lungs. Additional metallic deposits may be visible in the heart, abdominal vessels, and/or extremities. Pulmonary embolism caused by acrylic cement is a rare complication associated with vertebroplasty and may appear on CT as multiple radiopaque tubular areas of increased density corresponding to emboli in the segmental and subsegmental levels of the pulmonary arteries. The presence of perivertebral leakage contributes to this diagnosis [
In the presence of high-attenuation parenchymal consolidation, pulmonary alveolar microlithiasis, amiodarone toxicity, talcosis, iodinated oil embolism, and the aspiration or extravasation of contrast material must be considered [
]. The CT findings of amiodarone lung deposition include septal thickening, interstitial fibrosis, and high-attenuation focal or multifocal parenchymal opacities, usually peripheral in location. The association of dense lung air-space consolidations with high liver and/or spleen density is of diagnostic value. Iatrogenic causes of iodinated oil embolism occur after transcatheter oil chemoembolization or lymphangiography. CT findings consist of multifocal patchy areas of ground-glass attenuation and high-attenuation areas of consolidation and collapse. The characteristic radiographic and HRCT findings of pulmonary alveolar microlithiasis consist of innumerable bilateral, tiny, sand-like calcified micronodules. In patients with long-standing disease, the numerous adjacent nodules create areas of consolidation on CT. Other findings include calcified interlobular septa and small subpleural cysts [
The majority of patients with renal failure and non-progressive asymptomatic MPC do not require intervention, but treatments have been suggested and used with some success in patients with symptomatic disease [
]. Prompt management of secondary and tertiary hyperparathyroidism is necessary to avoid uncontrolled extraskeletal calcification, ischemic skin necrosis, pruritis, and hyperparathyroid bone disease [
]. Therapy with calcium and vitamin D supplementation is initiated, and parathyroidectomy is indicated if the condition is unresponsive to medical therapy [
]. Some authors have also suggested that nocturnal hemodialysis promotes superior control of the serum phosphate level and uremia compared withconventionalintermittent (three times weekly) hemodialysis [
]. This technique is promising in delaying the progression of calcification. Whether the discontinuation of vitamin D analogs in isolation affects the course of end-stage renal disease remains unclear, and it may in fact worsen hyperparathyroidism. However, some authors have suggested that the discontinuation of vitamin D therapy has some benefit [
]; some authors have reported the improvement or resolution of visceral calcification, whereas others have reported dramatic worsening of the disease course [
The aggressive management of acute hypercalcemia includes the administration of 0.9% saline in combination with two kinds of osteoclast inhibitor: calcitonin and bisphosphonate [
]. Galliumnitrate, another potent osteoclast inhibitor, may be used if bisphosphonate therapy is unsuccessful. The somatostatin analog octreotide has been shown to be effective in the treatment of hypercalcemia of malignancy due to PTH-related protein secretion [
MPC is a frequently asymptomatic and undiagnosed condition that is commonly associated with end-stage renal disease. Because it may progress to irreversible lung damage and respiratory failure, radiologists must be able to recognize the imaging patterns of this disease. MPC should be kept in mind when dialysis patients develop unexplained radiographic changes or pulmonary symptoms. HRCT or Tc99m-MDP bone scanning can be helpful for diagnosis and may obviate the need for open lung biopsy.
Conflict of interest statement
The authors have no conflict of interest.
References
Chan E.D.
Morales D.V.
Welsh C.H.
McDermott M.T.
Schwarz M.I.
Calcium deposition with or without bone formation in the lung.
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