Respiratory Medicine (2014) 108, 668e676

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REVIEW

Metastatic pulmonary calcification: State-of-the-art review focused on imaging findings

Luciana Camara Belem a,1, Glaucia Zanetti a,2,Arthur Soares Souza Jr.b,3, Bruno Hochhegger c,4,Marcos Duarte Guimaraes d,5, Luiz Felipe Nobre e,6,Rosana Souza Rodrigues a,f,7, Edson Marchiori a,*

a Federal University of Rio de Janeiro, Rio de Janeiro, Brazilb Medical School of Rio Preto and Ultra X, Sao Jose do Rio Preto, SP, Brazilc Santa Casa de Porto Alegre, Porto Alegre, Rio Grande do Sul, Brazild AC Camargo Cancer Center, Sao Paulo, Brazile Santa Catarina Federal University, Florianopolis, Brazilf D’OR Institute for Research and Education, Rio de Janeiro, Brazil

Received 15 October 2013; accepted 29 January 2014Available online 6 February 2014

KEYWORDSMetastatic pulmonarycalcification;Imaging;Lung diseases;Metabolic diseases

* Corresponding author. Rua Thomazfax: þ55 21 26299017.

E-mail addresses: lubelem@globbrunohochhegger@gmail.com (B. HoNobre), rosana.souzarodrigues@gmail1 Avenida Ayrton Senna, 111 apto 402 Rua Coronel Veiga, 733/504, Centr3 Rua Cila 3033, CEP 15015-800 Sao4 Rua Joao Alfredo, 558/301, CEP 905 Rua Paulo Orozimbo, 726, Aclimac6 R. Desemb, Pedro Silva, 2800, ap.7 Rua Marques de Sao Vicente 429/6

0954-6111/$ - see front matter ª 201http://dx.doi.org/10.1016/j.rmed.20

Summary

Metastatic pulmonary calcification (MPC) is a subdiagnosed metabolic lung disease that iscommonly associated with end-stage renal disease. This interstitial process is characterizedby the deposition of calcium salts predominantly in the alveolar epithelial basement mem-branes. MPC is seen at autopsy in 60e75% of patients with renal failure. It is often asymptom-atic, but can potentially progress to respiratory failure. Chest radiographs are frequentlynormal or demonstrate confluent or patchy airspace opacities. Three patterns visible onhigh-resolution computed tomography have been described: multiple diffuse calcified nodules,diffuse or patchy areas of ground-glass opacity or consolidation, and confluent high-

Cameron, 438, Valparaiso, CEP 25685.120 Petropolis, Rio de Janeiro, Brazil. Tel.: þ55 24 22492777;

o.com (L.C. Belem), glauciazanetti@gmail.com (G. Zanetti), asouzajr@gmail.com (A.S. Souza),chhegger), marcosduarte500@gmail.com (M.D. Guimaraes), luizfelipenobresc@gmail.com (L.F..com (R.S. Rodrigues), edmarchiori@gmail.com (E. Marchiori).5, Barra da Tijuca, CEP 22793-000 Rio de Janeiro, Brazil. Tel.: þ55 21 2433 3399.o, CEP 25655-504 Petropolis, Rio de Janeiro, Brazil. Tel.: þ55 24 22429156.Jose do Rio Preto, Brazil. Tel.: þ55 17 32242536.050-230 Porto Alegre, Brazil. Tel.: þ55 51 32864230.ao, CEP 01535-001 Sao Paulo, SP, Brazil. Tel.: þ55 11 32085327.303B, Coqueiros, CEP 88080-701 Florianopolis, Santa Catarina, Brazil. Tel.: þ55 48 32491860.01, Gavea, CEP 22451-041 Rio de Janeiro, Brazil. Tel.: þ55 21 32058430.

4 Elsevier Ltd. All rights reserved.14.01.012

Metastatic pulmonary calcification 669

attenuation parenchymal consolidation. The relative stability of these pulmonary infiltrates, incontrast to infectious processes, and their resistance to treatment, in the clinical context ofhypercalcemia, are of diagnostic value. Scintigraphy with bone-seeking radionuclides maydemonstrate increased radioactive isotope uptake. The resolution of pulmonary calcificationin 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 mainclinical, pathological, and imaging aspects of MPC.ª 2014 Elsevier Ltd. All rights reserved.

Contents

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 669Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 669Pathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 670Pathology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 670Clinical manifestations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 671Clinical course . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 671Imaging findings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 671

Chest radiographs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .671Computed tomography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .672Magnetic resonance imaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .673Nuclear medicine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .673Pulmonary function tests . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .673

Imaging criteria for differential diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 673Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 674Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 674Conflict of interest statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 675References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 675

Introduction

Metastatic pulmonary calcification (MPC) is a metaboliclung disease characterized by the deposition of calcium inthe pulmonary parenchyma. It occurs most often in asso-ciation with conditions that directly or indirectly result inhypercalcemia. MPC may be of benign or malignant etiology[1,2]. Benign causes include chronic renal failure, primaryand secondary hyperparathyroidism, excess exogenousadministration of calcium and vitamin D, sarcoidosis, milk-alkali syndrome, osteoporosis, and osteitis deformans; thebenign form may also occur following renal or liver trans-plantation and cardiac surgery. Malignant etiologies includemassive osteolysis from metastases or multiple myeloma,parathyroid carcinoma, leukemia, lymphoma, breast car-cinoma, synovial carcinoma, choriocarcinoma, malignantmelanoma, and hypopharyngeal squamous carcinoma[1,3e9].

Pathological pulmonary calcification can be broadlydivided into metastatic and dystrophic calcifications. MPCis defined as calcium deposition in normal lung tissuewithout prior tissue damage, and is related to chronicallyelevated serum calcium-phosphate product. In contrast,dystrophic calcification requires injured tissue, such asinfected or inflamed lung tissue, even in the absence ofincreased serum calcium levels [1,2]. MPC occurs rarely inpatients with normal renal function, normal calcium and

phosphate levels, and no underlying pulmonary disease[10]. The aim of this review is to describe the main clinical,pathological, and imaging aspects of MPC.

Epidemiology

Histological changes of MPC are seen at autopsy in 60e75%of patients who had previously undergone hemodialysis[1,11e13]. Benign MPC is known to be a long-term compli-cation that occurs in patients with chronic renal failureaccompanied by secondary hyperparathyroidism [11]. Pri-mary hyperparathyroidism infrequently produces metasta-tic calcification [5]. Among hematological malignancies,myeloma is the most common cause of cancer-associatedhypercalcemia, seen in 20e30% of cases [14]. MPC occursrarely in association with leukemia, although several caseshave been described [7,8,15]. Despite the prevalence ofthis condition in patients with renal failure, MPC is rarelydiagnosed antemortem, probably due to the poor sensi-tivity of standard chest radiographs for the identification ofcalcifications [16] and the high frequency of cardiorenalcomplications in these patients [17]. Fewer cases of MPChave been reported recently, suggesting that the incidenceof MPC or visceral calcification is declining [18]. This trendmay be related to improved dialysis techniques [19] and thewidespread use of phosphate binding agents and vitamin D

670 L.C. Belem et al.

analogs, which allow better control of calcium and phos-phate levels [20].

Figure 1 A 67-year-old man with metastatic pulmonarycalcification. The pathological specimen demonstrates inter-stitial calcification, appearing as basophilic deposits along thealveolar septa (hematoxylin & eosin; original magnification,�100).

Pathogenesis

MPC is associated most frequently with an increasedcalcium-phosphate product as a result of hypercalcemiaand/or hyperphosphatemia. This product is about40 mg2/dl2 in normal subjects, and metastatic calcifica-tions are most likely to develop when it exceeds70 mg2/dl2 [21].

The serum phosphate level is low in primary hyper-parathyroidism due to the phosphaturic effect of circu-lating parathyroid hormone (PTH); thus, the calcium-phosphate product is generally <60 mg2/d12 and metasta-tic calcification is rarely seen. MPC also occurs rarely inassociation with parathyroid carcinoma accompanied byhigh serum levels of calcium and PTH [22].

Several factors predispose dialysis patients to thedeposition of calcium salts in the viscera [1]. First, acidosisin the interdialytic interval has been postulated to leachcalcium from bone, leading to its deposition in softtissue during postdialysis alkalosis. Intermittent alkalosisalso increases the activity of alkaline phosphatase, whichcatalyzes the release of phosphates. Second, hyperpara-thyroidism has been shown experimentally to contribute topulmonary calcification in the presence and absence ofuremia [1,5]. Third, uremia per se may alter the configu-ration of tissue proteins, rendering them more calcifiable.Finally, a reduced glomerular filtration rate causes hyper-phosphatemia, which in turn elevates the calcium-phosphate product, favoring crystallization [1,23].

Vitamin D supplementation may contribute to calcifica-tion, as hypervitaminosis D has been associated with met-astatic and vascular calcifications [23]. In addition, vitaminD utilization in dialysis patients may be associated with ortrigger metastatic calcification [24].

Asymptomatic pulmonary calcification is a well-knowncomplication following orthoptic liver transplantation [4].Liver transplant recipients receive large amounts of freshfrozen plasma, which contains sodium citrate, due to thecoagulopathy associated with this procedure. The highplasma citrate level leads to metabolic alkalosis and hy-pocalcemia via the chelation of ionized calcium. Para-thyroid hormone secretion is then triggered and calcium isdeposited in soft tissues following the administration of alarge amount of exogenous calcium [4].

The secretion of free hydrogen ions is an important localfactor in the development of metastatic calcification. Thelung, kidney, and stomach, three of the most frequentlyinvolved organs, are involved in free hydrogen ion secre-tion. This secretion creates an alkaline environment inwhich calcium salts may precipitate [25]. The lung is one ofthe primary sites of metastatic calcium deposition in pa-tients with hypercalcemia [26,27].

MPC or visceral calcification is composed primarily ofwhitlockite ([Ca, Mg]3PO4), which appears as an amorphoussubstance or as minute crystals, in contrast to the crystal-line hydroxyapatite more commonly found in vascularcalcification. Lesser amounts of pyrophosphate are alsoseen [28].

Pathology

Macroscopically, the lungs are diffusely solidified in cases ofMPC. They are heavy, with weights ranging from 590 g to1800 g. Sectioning reveals irregular or well-delineatednodules scattered throughout the organ [29].

Microscopically, metastatic calcification has been seenwithin the lamina propria of the stomach, in tubules andinterstitium of the kidneys, and in basement membranes ofthe epithelium and endothelium of alveoli in the lungs [21].MPC is an interstitial process [11] characterized by thedeposition of calcium salts predominantly in the alveolarepithelial basement membranes [11,30], with a particularaffinity for elastic tissue [31]. It can also occur in thealveolar capillary walls, bronchial walls, and, to a lesserextent, bronchioles and media of pulmonary arterioles[11,30]. Regardless of the etiology or organ affected, cal-cifications appear on hematoxylin and eosin-stained slidesas granular, lamellar, linear, and plate-like basophilic ma-terials; they also show positivity in Von Kassa and Alizarinred staining [32,33]. Strong hematoxylin staining in thealveolar septa (Fig. 1) and the walls of small pulmonaryvessels and bronchi is characteristic of MPC [34,35].

Microscopic examination reveals fibrous widening of thealveolar septa, with infiltration of these walls by multipleareas of calcification and a few lymphocytes [29]. Thealveolar lumen is often filled with exudate or calcification,sometimes surrounded by fibroblast proliferation [29]. Aforeign-body giant cell reaction to the calcium may beobserved [36]. In mild cases, calcium deposits are presentalong the alveolar epithelial basement membrane and in

Figure 2 A 42-year-old man with metastatic pulmonarycalcification. A. A scout image from a CT showing confluentairspace opacities in both upper lobes. CT scan with coronalreconstructions with (B) lung and (C) mediastinal windowsshowing consolidation areas with calcification in the upperlobes.

Metastatic pulmonary calcification 671

alveolar capillary walls without significant desmoplasia orseptal thickening [20]. However, when calcification is se-vere, a desmoplastic reaction may occur and result ininterstitial fibrosis [11,21,37]. This fibrosis, rather than thecalcium per se, is thought to account for the developmentof respiratory symptoms and disturbed pulmonary function[20].

Clinical manifestations

The clinical manifestations of MPC are usually minimal, butthis condition occasionally causes dyspnea and chronic,non-productive cough [38]. Because its benign clinicalcourse, MPC is rarely diagnosed [4]. Although pulmonarycalcification generally progresses slowly and is oftenasymptomatic, several reports have described acute res-piratory insufficiency with a rapidly progressive chestshadow that mimics pneumonia or pulmonary edema[26,39,40]. Clinically, the degree of respiratory distress isoften uncorrelated with the degree of macroscopic calci-fication. Patients with extensive calcification may beasymptomatic, whereas those with subtle calcification ornormal chest radiographs may have severe respiratorycompromise [41].

Clinical course

MPC usually develops over a long period of time, but it mayoccur relatively acutely within several weeks to months[5,26,39]. In dialysis patients, it is usually related to thelength of survival [42]. Although the factors involved in thedevelopment of the more aggressive form of MPC are notfully understood, acceleration of the condition has beenpreviously reported following failed renal transplantation[1,3] or hypercalcemia [36]. Resolution of pulmonarycalcification in chronic renal failure may occur after para-thyroidectomy, renal transplantation, or dialysis[40,43,44]. Spontaneous resolution of changes has alsobeen described in patients with MPC [31].

Imaging findings

Chest radiographs

Plain-film findings are non-specific [12] and not very usefulfor the diagnosis of MPC. Chest radiographs are frequentlynormal or demonstrate confluent or patchy airspace opac-ities (Fig. 2) simulating pulmonary edema or pneumonia[20,26,31,40,45], despite the exclusively interstitial loca-tion of calcium pathologically [36]. MPC can also appear asdiscrete or confluent calcified nodules or as a diffuseinterstitial process [37,46]. The latter manifestation tendsto occur when calcification is only moderate, and has areticular pattern typical of interstitial disease [20]. Therelative stability of these pulmonary infiltrates, in contrastto infectious processes, and their resistance to treatmentare of diagnostic value [4]. However, as these patients arehighly immunosuppressed, infection should always beexcluded [4]. The density of opacities is not sufficientlyhigh to suggest calcification in most reported cases, but

672 L.C. Belem et al.

opacities are massively calcified or become progressivelymore dense when left untreated in some cases [47]. Thedifficulty of recognizing the calcific nature of these varyingpatterns may be explained by the small sizes of calciumdeposits and the currently common use of a high-kilovoltage and low-contrast technique [38,39,46].Advanced MPC can be easily recognized on a standard chestradiograph, but it should be differentiated from othercauses of pulmonary calcification, particularly previoustuberculous infection [48].

Dual-energy digital chest radiography has been reportedto be more sensitive [20,47,48] and accurate than standardchest radiography for the detection of MPC [20]. However,this technique is not widely used [20,47], most likely due tothe availability and advantages of computed tomography(CT) for the assessment of patients suspected for otherrespiratory problems [12].

Figure 3 A 40-year-old woman with metastatic pulmonarycalcification. A. High-resolution computed tomography at thelevel of the lower lobes shows a consolidation area in the basalposterior segment of the right inferior lobe associated with afew small nodules and bilateral ground-glass opacities. B. Thesoft-tissue window demonstrates extensive calcification withinthe consolidation area and scattered punctate foci of calcifi-cation. Note also the bilateral pleural effusion.

Figure 4 A 67-year-old man with metastatic pulmonarycalcification (same patient of Fig. 1). High-resolution CT at thelevel of the upper lobes shows nodular ground glass opacities ina predominately centrilobular distribution.

Computed tomography

CT, especially high-resolution CT (HRCT), is much moresensitive than chest radiography [12] in detecting smallamounts of calcification. This modality is increasingly usedin the diagnosis of MPC, thereby obviating the need foropen lung biopsy [3,37]. Whereas calcification is seldomapparent on radiographs, it is evident on HRCT in approxi-mately 60% of cases [37].

Changes visible on CT are most marked in the upperzones of the lungs due to increased alkalinity at the apices,which encourages the deposition of calcium salts [12]. Thisprocess can be explained by the higher ventilation/perfu-sion ratio at the apices, which produces a lower partialpressure of carbon dioxide in arterial blood (PaCO2) andhigher blood pH [1].

Although the infiltrate is histologically interstitial innature, the HRCT appearance of MPC can mimic airspacedisease [37,49]. Three patterns of MPC have been described[47]: multiple diffuse calcified nodules [3,37], diffuse orpatchy areas of ground-glass opacity or consolidation [37],and confluent high-attenuation parenchymal consolidationwith a predominantly lobar distribution [3] (Figs. 3 and 4).The distribution of pulmonary calcification can be punc-tuate within nodular opacities, ring-like, or diffuse,involving the entire nodule or consolidation area[31,37,45,47,50]. These findings reflect the deposition ofcalcium salts in the alveolar walls around the terminalbronchioles; thus, the tree-in-bud appearance and bron-chial wall thickening are not expected in MPC [51]. Inter-lobular septal thickening is also not observed in MPC;despite the potential expectation of such thickening due tothe purely interstitial pathological process of MPC, it isabsent because the predominant sites of calcium depositionseen on pathological examination are the alveolar septaand, to a lesser extent, the pulmonary arterioles andbronchioles [37].

The most common parenchymal finding on HRCT is thepresence of centrilobular ground-glass nodular opacities,with numerous fluffy and poorly defined nodules measuring3e10 mm in diameter [4,12,30,31,37,45,49]. These opaci-ties may or may not contain foci of calcification [47]. Thepulmonary nodules are more clearly defined on CT [36]. In

Metastatic pulmonary calcification 673

the peripheral region of the secondary pulmonary lobules,the microchemical environment of the alveoli tends tobecome alkalosed in comparison with the central area. Thecharacteristic distribution of areas of ground-glass attenu-ation may be explained by the differentiation of the acid-base balance between the peripheral and central regionsof the secondary pulmonary lobules [52].

More severe interstitial calcification can result in denseareas of consolidation [31]. Alternatively, multiple lobularground-glass opacities [52] or, less commonly, denseairspace consolidation with a lobar distribution, may bevisible [3,37]. Airspace consolidation is rarely seen [37].

A frequent associated finding is calcification in the ves-sels of the chest wall [36,37,45,47]. The combination ofpulmonary and vascular calcification is said to be of diag-nostic value for MPC, narrowing the differential diagnosis ofthe causes of pulmonary calcification [37]. In addition topulmonary calcification, CT may also reveal extensivecalcification of the myocardium, bronchial walls, smallpulmonary arteries, superior vena cava, and the dura of thedorsal spine [37]. Soft-tissue window settings are useful todemonstrate extensive calcification [31].

Magnetic resonance imaging

The most common appearance of calcified tissues on mag-netic resonance imaging (MRI) is a signal void or reduction insignal intensity [53]. MPC has been shown to appearhyperintense on T1-weighted images and to have a higherlesion/muscle signal-intensity ratio on T1-weighted than onT2-weighted images [53,54]. In the absence of calcification,lung tissues with thickened and fibrotic alveolar walls shouldhave higher lesion/muscle MRI signal intensity on proton-density and T2-weighted images than on T1-weighted im-ages [53]. The MRI appearance of MPC is unusual and similarto certain calcified brain lesions that appear hyperintenseon T1-weighted MRI [55,56]. This signal behavior isexplained by a shortening of the T1 relaxation time by asurface relaxation mechanism. The degree of T1 shorteningis directly related to the surface area of the calcium crystals[53]. The T1 shortening of water protons in calcified tissuescan be attributed to the surface effects of diamagneticcalcium particles [53]. Water protons adhering to crystalsurfaces relax more quickly than do those that are distantfrom these surfaces [53], although calcium also causes achange in T2 relaxivity and proton density [56]. The latterfactors reduce MRI signal intensity and nullify any potentialincrease in signal intensity caused by T1 shortening [54].Only in cases in which the microscopic crystal surface area isvery high can the T1 effect predominate, causing a net in-crease in MRI signal intensity [56]. These MRI signal varia-tions are directly influenced by the concentration andsurface area of calcium salts [56]. Reductions in hydrogenproton density and T2 relaxivity cannot overcome theincreased signal intensity caused by T1 shortening [56]. Withcalcium concentrations >30e40%, T1-weighted signal in-tensity declines progressively [56]. The calcium particulatesin MPC may cause a situation in which the effect of T1shortening overcomes the effects of reduced proton densityand T2 relaxivity; thus, the lesions demonstrate increasedsignal intensity on T1-weighted MRI [53].

Nuclear medicine

MRI findings are useful for the characterization of calciumaccumulation caused by a metabolic disorder, althoughnuclear imaging with technetium-99m-methylenediphosphonate (Tc99m-MDP) is a more specific and lessexpensive method for diagnosis [53]. Radionuclide imagingis probably the most sensitive technique for the earlydetection of MPC [29,48]. Some authors have recommendedthe use of scintigraphy as part of the evaluation of dyspneain patients with chronic renal failure [4]. Tc99m-MDP is alabeled organic analog of pyrophosphate that affixes tohydroxyapatite crystals in bone and calcium crystals inmitochondria [18]. Tc99m-MDP bone scanning may be usedto detect extraosseous calcification [18]. Despite the af-finity of MDP for hydroxyapatite, whitlockite also appearsto take up the tracer [1].

Lungs affected by MPC demonstrate increased radioac-tive isotope uptake. Lung uptake is generally symmetricaland sufficiently dense to obliterate the rib outlines [28].Uptake is also commonly seen in the left upper quadrant ofthe abdomen and has been attributed to uptake in thegastric wall [57]. Renal uptake is variable. As renal excre-tion of pyrophosphate and phosphonate radiopharmaceu-ticals is a normal finding, the extent of renal uptake incases of MPC represents a balance between decreased up-take due to impaired renal function and increased uptakesecondary to parenchymal calcification [28].

Pulmonary function tests

The findings of pulmonary function tests are usually normalin patients with MPC [31]. Because alveolar septa arediffusely involved in MPC, diffusing capacity is decreased.Anatomical changes due to calcific deposits may lead to arestrictive syndrome [3,50]. Restrictive and diffusion de-fects may appear, even when chest radiography appearsnormal [11]. Vital capacity has been inversely correlatedwith the histological severity of calcification [11]. Patientsmay also develop hypoxemia [3,50,58] and die from pro-gressive respiratory failure. In some cases, respiratoryfailure is rapid and acute [59].

Imaging criteria for differential diagnosis

MPC is the most likely cause of multifocal pulmonaryparenchymal calcification in patients with chronic renalfailure. The predilection of calcification for the upper lungarea and its association with calcification in the vessels ofthe chest wall may support the diagnosis [60]. The differ-ential diagnosis of MPC includes conditions that may lead todiffuse small calcified nodules, diffuse small high-attenuation non-calcified nodules, and high-attenuationconsolidation [45].

Causes of diffuse small calcified nodules include infec-tion, pulmonary metastasis, chronic hemorrhagic condi-tions, occupational and deposition diseases, and idiopathicdisorders such as pulmonary alveolar microlithiasis. Thesenodules are most commonly secondary to dystrophic calci-fication in previously damaged lung parenchyma; they arefrequently seen in patients with healed disseminated

674 L.C. Belem et al.

histoplasmosis and, rarely, as a sequela of miliary tuber-culosis. Most of these patients have calcified hilar and/ormediastinal lymph nodes. Tiny widespread micronodularcalcification is an uncommon sequela of varicella pneu-monia. Metastatic malignancies that may lead to thispattern include osteogenic sarcoma, chondrosarcoma,mucin-producing adenocarcinomas, and thyroid malig-nancies [2]. It may also occur in treated metastases. Sili-cosis and coal workers’ pneumoconiosis may have thisaspect and are often associated with egg-shell calcificationof hilar or mediastinal lymph nodes. The nodules are mostprominent in the middle and upper lung zones and maycalcify. Chronic hemorrhagic conditions (hemosiderosis)may also present as dense centrilobular nodular opacities.Recurrent episodes of alveolar hemorrhage over severalyears are characteristic of this entity. Secondary hemosi-derosis due to mitral stenosis also may present with smallmultifocal calcified nodules. Calcified nodules may also beseen in accumulations of iron oxide (siderosis), tin oxide(stannosis), and barium dust (baritosis) in lung macrophages[45].

The differential diagnosis for diffuse small high-attenuation noncalcified nodules includes talcosis andmercury or acrylic cement embolism. Talcosis has beendescribed in workers exposed to talc and drug abusers(endovenous administration). Early tomographic manifes-tations consist of a diffuse micronodular pattern with well-defined nodules, or diffuse ground-glass opacity. As thedisease progresses, nodule confluence creates hyperdenseconsolidations or confluent perihilar masses. Panlobularemphysema with predominant lower lobe involvement hasbeen described secondary to the endovenous injection ofRitalin (methylphenidate). Intravenous mercury injection isinfrequent and most frequently related to attempted sui-cide and iatrogenic injection. It usually appears on CT asmultiple small metallic spherules scattered diffuselythroughout both lungs. Additional metallic deposits may bevisible in the heart, abdominal vessels, and/or extremities.Pulmonary embolism caused by acrylic cement is a rarecomplication associated with vertebroplasty and mayappear on CT as multiple radiopaque tubular areas ofincreased density corresponding to emboli in the segmentaland subsegmental levels of the pulmonary arteries. Thepresence of perivertebral leakage contributes to this diag-nosis [45].

In the presence of high-attenuation parenchymalconsolidation, pulmonary alveolar microlithiasis, amiodar-one toxicity, talcosis, iodinated oil embolism, and theaspiration or extravasation of contrast material must beconsidered [3,33,45]. The CT findings of amiodarone lungdeposition include septal thickening, interstitial fibrosis,and high-attenuation focal or multifocal parenchymalopacities, usually peripheral in location. The association ofdense lung air-space consolidations with high liver and/orspleen density is of diagnostic value. Iatrogenic causes ofiodinated oil embolism occur after transcatheter oil che-moembolization or lymphangiography. CT findings consist ofmultifocal patchy areas of ground-glass attenuation andhigh-attenuation areas of consolidation and collapse. Thecharacteristic radiographic and HRCT findings of pulmonaryalveolar microlithiasis consist of innumerable bilateral,tiny, sand-like calcified micronodules. In patients with long-

standing disease, the numerous adjacent nodules createareas of consolidation on CT. Other findings include calci-fied interlobular septa and small subpleural cysts [33,45].

Treatment

The majority of patients with renal failure and non-progressive asymptomatic MPC do not require interven-tion, but treatments have been suggested and used withsome success in patients with symptomatic disease[1,35,50]. Although the optimal treatment of MPC is notknown, attempts to normalize calcium and phosphatebiochemistry have been the mainstays of therapy [12].Bisphosphonate has been suggested to normalize calcium inhypercalcemic patients and to halt the progression ofcalcification [35].

Isolated hyperphosphatemia and tertiary hyperparathy-roidism may also be treated with phosphate binders [9].Prompt management of secondary and tertiary hyperpara-thyroidism is necessary to avoid uncontrolled extraskeletalcalcification, ischemic skin necrosis, pruritis, and hyper-parathyroid bone disease [61]. Therapy with calcium andvitamin D supplementation is initiated, and para-thyroidectomy is indicated if the condition is unresponsiveto medical therapy [9].

An increase in the dialysis dose is indicated for patientswith end-stage renal disease [1,58]. Some authors have alsosuggested that nocturnal hemodialysis promotes superiorcontrol of the serum phosphate level and uremia comparedwithconventionalintermittent (three times weekly) hemo-dialysis [62]. This technique is promising in delaying theprogression of calcification. Whether the discontinuation ofvitamin D analogs in isolation affects the course of end-stage renal disease remains unclear, and it may in factworsen hyperparathyroidism. However, some authors havesuggested that the discontinuation of vitamin D therapy hassome benefit [58]. Conflicting findings with regard to MPCfollowing renal transplantation have been published [18];some authors have reported the improvement or resolutionof visceral calcification, whereas others have reporteddramatic worsening of the disease course [1,36,46].

The aggressive management of acute hypercalcemiaincludes the administration of 0.9% saline in combinationwith two kinds of osteoclast inhibitor: calcitonin andbisphosphonate [7]. Galliumnitrate, another potent osteo-clast inhibitor, may be used if bisphosphonate therapy isunsuccessful. The somatostatin analog octreotide has beenshown to be effective in the treatment of hypercalcemia ofmalignancy due to PTH-related protein secretion [63].

Conclusion

MPC is a frequently asymptomatic and undiagnosed condi-tion that is commonly associated with end-stage renal dis-ease. Because it may progress to irreversible lung damageand respiratory failure, radiologists must be able torecognize the imaging patterns of this disease. MPC shouldbe kept in mind when dialysis patients develop unexplainedradiographic changes or pulmonary symptoms. HRCT orTc99m-MDP bone scanning can be helpful for diagnosis andmay obviate the need for open lung biopsy.

Metastatic pulmonary calcification 675

Conflict of interest statement

The authors have no conflict of interest.

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