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'''Pulmonary Alveolar Microlithiasis'''
'''Pulmonary Alveolar Microlithiasis'''


Pulmonary alveolar microlithiasis (PAM) is a rare, autosomal recessive disorder of pulmonary phosphate metabolism caused by accumulation of intra-alveolar calcium phosphate crystals. Mutations in the SLC34A2 gene<ref name="Huqun 2007">{{cite journal|last1=Huqun|last2=Izumi|first2=S|last3=Miyazawa|first3=H|last4=Ishii|first4=K|last5=Uchiyama|first5=B|last6=Ishida|first6=T|last7=Tanaka|first7=S|last8=Tazawa|first8=R|last9=Fukuyama|first9=S|last10=Tanaka|first10=T|last11=Nagai|first11=Y|last12=Yokote|first12=A|last13=Takahashi|first13=H|last14=Fukushima|first14=T|last15=Kobayashi|first15=K|last16=Chiba|first16=H|last17=Nagata|first17=M|last18=Sakamoto|first18=S|last19=Nakata|first19=K|last20=Takebayashi|first20=Y|last21=Shimizu|first21=Y|last22=Kaneko|first22=K|last23=Shimizu|first23=M|last24=Kanazawa|first24=M|last25=Abe|first25=S|last26=Inoue|first26=Y|last27=Takenoshita|first27=S|last28=Yoshimura|first28=K|last29=Kudo|first29=K|last30=Tachibana|first30=T|last31=Nukiwa|first31=T|last32=Hagiwara|first32=K|title=Mutations in the SLC34A2 gene are associated with pulmonary alveolar microlithiasis|journal=Am J Respir Crit Care Med|date=2007|volume=175|issue=3|page=263-268|pmid=17095743}}</ref><ref name="Corut 2006">{{cite journal|last1=Corut|first1=A|last2=Senyigit|first2=A|last3=Ugur|first3=SA|last4=Altin|first4=S|last5=Ozcelik|first5=U|last6=Calisir|first6=H|last7=Yildirim|first7=Z|last8=Gocmen|first8=A|last9=Tolun|first9=A|title=Mutations in SLC34A2 cause pulmonary alveolar microlithiasis and are possibly associated with testicular microlithiasis|journal=Am J Hum Genet|date=2006|volume=79|issue=4|page=650-656|pmid=16960801}}</ref> result in deficiency of the Npt2b sodium, phosphate co-transporter, known to be expressed in alveolar type II cells, as well as in the mammary gland, and to a lesser extent in intestine, kidney, skin, prostate and testes. As the disease progresses, the lung fields become progressively opacified on the chest radiograph, and hypoxemia, pulmonary inflammation, lung fibrosis, pulmonary hypertension, and respiratory failure ensue, usually in middle age. The clinical course of PAM can be highly variable, with some patients remaining asymptomatic for decades. There is no effective treatment, and the mechanisms of microlith formation, inflammation and fibrogenesis are not known.
Pulmonary alveolar microlithiasis (PAM) is a rare, inherited disorder of lung phosphate balance that is associated with small stone formation in the airspaces of the lung. Mutations in the the gene SLC34A2<ref name="Huqun 2007">{{cite journal|last1=Huqun|last2=Izumi|first2=S|last3=Miyazawa|first3=H|last4=Ishii|first4=K|last5=Uchiyama|first5=B|last6=Ishida|first6=T|last7=Tanaka|first7=S|last8=Tazawa|first8=R|last9=Fukuyama|first9=S|last10=Tanaka|first10=T|last11=Nagai|first11=Y|last12=Yokote|first12=A|last13=Takahashi|first13=H|last14=Fukushima|first14=T|last15=Kobayashi|first15=K|last16=Chiba|first16=H|last17=Nagata|first17=M|last18=Sakamoto|first18=S|last19=Nakata|first19=K|last20=Takebayashi|first20=Y|last21=Shimizu|first21=Y|last22=Kaneko|first22=K|last23=Shimizu|first23=M|last24=Kanazawa|first24=M|last25=Abe|first25=S|last26=Inoue|first26=Y|last27=Takenoshita|first27=S|last28=Yoshimura|first28=K|last29=Kudo|first29=K|last30=Tachibana|first30=T|last31=Nukiwa|first31=T|last32=Hagiwara|first32=K|title=Mutations in the SLC34A2 gene are associated with pulmonary alveolar microlithiasis|journal=Am J Respir Crit Care Med|date=2007|volume=175|issue=3|page=263-268|pmid=17095743}}</ref><ref name="Corut 2006">{{cite journal|last1=Corut|first1=A|last2=Senyigit|first2=A|last3=Ugur|first3=SA|last4=Altin|first4=S|last5=Ozcelik|first5=U|last6=Calisir|first6=H|last7=Yildirim|first7=Z|last8=Gocmen|first8=A|last9=Tolun|first9=A|title=Mutations in SLC34A2 cause pulmonary alveolar microlithiasis and are possibly associated with testicular microlithiasis|journal=Am J Hum Genet|date=2006|volume=79|issue=4|page=650-656|pmid=16960801}}</ref> result in loss of a key sodium, phosphate co-transporter (called Npt2b), known to be expressed in distal airway epithelial cells alveolar type II cells, as well as in the mammary gland, and to a lesser extent in intestine, kidney, skin, prostate and testes. As the disease progresses, the lung fields become progressively more dense (white) on the chest xray, and low oxygen level, lung inflammation and fibrosis, elevated pressures in the lung blood vessels, and respiratory failure ensue, usually in middle age. The clinical course of PAM can be highly variable, with some patients remaining asymptomatic for decades, and others progressing more rapidly. There is no effective treatment, and the mechanisms of stone formation, inflammation and scarring are not known.


'''Signs and symptoms'''
'''Signs and symptoms'''
⚫
Patients typically have no symptoms until the third or fourth decade of life. In most cases, the disease is discovered incidentally on routine chest Xray. The most common symptoms include the following:<ref name="Mariotta 2004">{{cite journal|last1=Mariotta|first1=S|last2=Ricci|first2=A|last3=Papale|first3=M|last4=DeClementi|first4=F|last5=Sposato|first5=B|last6=Guidi|first6=L|last7=et al.|title=Pulmonary alveolar microlithiasis: report on 576 cases published in the literature|journal=Sarcoidosis Vasc Diffuse Lung Dis|date=2004|volume=21|issue=3|page=173-181|pmid=15554073}}</ref><ref name="Castellana 2003">{{cite journal|last1=Castellana|first1=G|last2=Lamorgese|first2=V|title=Pulmonary alveolar microlithiasis. World cases and review of the literature|journal=Respiration|date=2003|volume=70|issue=5|page=549-555|pmid=14665786}}</ref><ref name="Tachibana 2009">{{cite journal|last1=Tachibana|first1=T|last2=Hagiwara|first2=K|last3=Johkoh|first3=T|title=Pulmonary alveolar microlithiasis: review and management|journal=Curr Opin Pulm Med|date=2009|volume=15|issue=5|page=486-490|pmid=19617834}}</ref><ref name="Lauta 2003">{{cite journal|last1=Lauta|first1=VM|title=Pulmonary alveolar microlithiasis: an overview of clinical and pathological features together with possible therapies|journal=Respir Med|date=2003|volume=97|issue=10|page=1081-1085|pmid=14561014}}</ref><ref name="Korn 1992">{{cite journal|last1=Korn|first1=MA|last2=Schurawitzki|first2=H|last3=Klepetko|first3=W|last4=Burghuber|first4=OC|title=Pulmonary alveolar microlithiasis: findings on high-resolution CT|journal=AJR Am J Roentgenol|date=1992|volume=158|issue=5|page=981-982|pmid=1566701}}</ref>
Patients typically remain asymptomatic until the third or fourth decade of life. Most patients are asymptomatic at diagnosis with changes in the lung parenchyma found incidentally.
⚫
The most common symptoms include the following:<ref name="Mariotta 2004">{{cite journal|last1=Mariotta|first1=S|last2=Ricci|first2=A|last3=Papale|first3=M|last4=DeClementi|first4=F|last5=Sposato|first5=B|last6=Guidi|first6=L|last7=et al.|title=Pulmonary alveolar microlithiasis: report on 576 cases published in the literature|journal=Sarcoidosis Vasc Diffuse Lung Dis|date=2004|volume=21|issue=3|page=173-181|pmid=15554073}}</ref><ref name="Castellana 2003">{{cite journal|last1=Castellana|first1=G|last2=Lamorgese|first2=V|title=Pulmonary alveolar microlithiasis. World cases and review of the literature|journal=Respiration|date=2003|volume=70|issue=5|page=549-555|pmid=14665786}}</ref><ref name="Tachibana 2009">{{cite journal|last1=Tachibana|first1=T|last2=Hagiwara|first2=K|last3=Johkoh|first3=T|title=Pulmonary alveolar microlithiasis: review and management|journal=Curr Opin Pulm Med|date=2009|volume=15|issue=5|page=486-490|pmid=19617834}}</ref><ref name="Lauta 2003">{{cite journal|last1=Lauta|first1=VM|title=Pulmonary alveolar microlithiasis: an overview of clinical and pathological features together with possible therapies|journal=Respir Med|date=2003|volume=97|issue=10|page=1081-1085|pmid=14561014}}</ref><ref name="Korn 1992">{{cite journal|last1=Korn|first1=MA|last2=Schurawitzki|first2=H|last3=Klepetko|first3=W|last4=Burghuber|first4=OC|title=Pulmonary alveolar microlithiasis: findings on high-resolution CT|journal=AJR Am J Roentgenol|date=1992|volume=158|issue=5|page=981-982|pmid=1566701}}</ref>
* dyspnea
* dyspnea
* dry cough
* dry cough
Line 16: Line 15:


'''Pathogenesis'''
'''Pathogenesis'''
The composition of the alveolar fluid in the lungs is maintained by the transepithelial transport of a variety of solutes across the alveolar epithelium. Type II alveolar cells have many important functions in the lung, including the production of pulmonary surfactant. Phospholipids are essential constituents of pulmonary surfactant. It is speculated that the inability of type II alveolar cells to remove phosphorus ions from the alveolar space may lead to microlith formation in the extracellular fluid.<ref name="Tachibana 2009" /><ref name="Poelma 2004">{{cite journal|last1=Poelma|first1=DL|last2=Ju|first2=MR|last3=Bakker|first3=SC|last4=Zimmermann|first4=LJ|last5=Lachmann|first5=BF|last6=van Iwaarden|first6=JF|title=A common pathway for the uptake of surfactant lipids by alveolar cells|journal=Am J Respir Cell Mol Biol|date=2004|volume=30|issue=5|page=751-758|pmid=14644915}}</ref>
Type II alveolar cells have many important functions in the lung, including the production of pulmonary surfactant, maintenance of fluid balance and composition in the airspace. Phospholipids are that make up pulmonary surfactant are broken down by macrophages, releasing phosphate into the alveolar lining fluid. The loss of the Npt2b phosphate transported eliminates the ability of alveolar type II cells to pump phosphorus ions from the alveolar space back into the bloodstream, and leads to microlith formation.<ref name="Tachibana 2009" /><ref name="Poelma 2004">{{cite journal|last1=Poelma|first1=DL|last2=Ju|first2=MR|last3=Bakker|first3=SC|last4=Zimmermann|first4=LJ|last5=Lachmann|first5=BF|last6=van Iwaarden|first6=JF|title=A common pathway for the uptake of surfactant lipids by alveolar cells|journal=Am J Respir Cell Mol Biol|date=2004|volume=30|issue=5|page=751-758|pmid=14644915}}</ref>


'''Genetics'''
'''Genetics'''
PAM is hereditary and familial cases have been reported in frequencies ranging from 36% to 61%.<ref name="Castellana 2003" /> Impaired activity of the SLC34A2 gene is responsible for PAM.<ref name="Huqun 2007" /><ref name="Senyigit 2001">{{cite journal|last1=Senyiğit|first1=A|last2=Yaramiş|first2=A|last3=Gürkan|first3=F|last4=Kirbaş|first4=G|last5=Büyükbayram|first5=H|last6=Nazaroğlu|first6=H|last7=Alp|first7=MN|last8=Topçu|first8=F|title=Pulmonary alveolar microlithiasis: a rare familial inheritance with report of six cases in a family. Contribution of six new cases to the number of case reports in Turkey|journal=Respiration|date=2001|volume=68|issue=2|page=204-209|pmid=11287838}}</ref><ref name="Tachibana 2009" /><ref name="Corut 2006" /><ref name="Huqun 2006">{{cite journal|last1=Huqun|last2=Izumi|first2=S|last3=Miyazawa|first3=H|last4=Ishii|first4=K|last5=Uchiyama|first5=B|last6=Ishida|first6=T|last7=et al.|title=The autozygous segments predicted by a genome-wide SNP typing revealed mutations in the type IIb sodium phosphate cotransporter (SLC34A2) causing pulmonary alveolar microlithiasis|journal=Proc Am Thorac Soc|date=2006|volume=3|page=A102}}</ref><ref name="Hagiwara 2009">{{cite book|last1=Hagiwara|first1=K|last2=Johkoh|first2=T|last3=Tachibana|first3=T|title=Pulmonary alveolar microlithiasis|date=2009|publisher=Humana Press|location=New Jersey}}</ref> The SLC34A2 gene encodes a membrane protein that is expressed primarily in the apical portions of alveolar type II cells[Traebert 1999] and is the most abundant phosphate carrier in the lungs.<ref name="Tachibana 2009" />
PAM is hereditary and another involved family member can be identified in 36% to 61% of cases.<ref name="Castellana 2003" /> Impaired activity of the SLC34A2 gene is responsible for PAM.<ref name="Huqun 2007" /><ref name="Senyigit 2001" /><ref name="Tachibana 2009" /><ref name="Corut 2006" /><ref name="Huqun 2006" /><ref name="Hagiwara 2009" /> The SLC34A2 gene encodes a membrane protein that is expressed primarily in the apical portions of alveolar type II cells<ref name="Traebert 1999">{{cite journal|last1=Traebert|first1=M|last2=Hattenhauer|first2=O|last3=Murer|first3=H|last4=Kaissling|first4=B|last5=Biber|first5=J|title=Expression of type II Na-P(i) cotransporter in alveolar type II cells|journal=Am J Physiol|date=1999|volume=277|issue=5 Pt 1|page=868-873|pmid=10564169}}</ref> and is the most abundant phosphate carrier in the lungs.<ref name="Tachibana 2009" />


'''Pathology'''
'''Pathology'''
Line 27: Line 26:


'''''Radiology'''''
'''''Radiology'''''
Chest radiographs of patients with PAM usually reveal diffuse, scattered, bilateral areas of micronodular calcifications, producing a "sandstorm” appearance that first involves the inferior portions and then the middle and upper portions of the lungs.<ref name="Mariotta 2004" />
Chest radiographs of patients with PAM usually reveal bilateral diffuse micronodular calcifications, producing a "sandstorm” appearance that first involves the inferior portions and then the middle and upper portions of the lungs.<ref name="Mariotta 2004" />


'''''High-Resolution Computed Tomography'''''
'''''High-Resolution Computed Tomography'''''
The most common findings are diffuse ground-glass attenuation and subpleural linear calcifications. Tomographic alterations are predominant in the inferior and posterior portions of the lungs.<ref name="Marchiori 2007">{{cite journal|last1=Marchiori|first1=E|last2=Gonçalves|first2=CM|last3=Escuissato|first3=DL|last4=Teixeira|first4=KI|last5=Rodrigues|first5=R|last6=Barreto|first6=MM|last7=Esteves|first7=M|title=Pulmonary alveolar microlithiasis: high-resolution computed tomography findings in 10 patients|journal=J Bras Pneumol|date=2007|volume=33|issue=5|page=552-557|pmid=18026653}}</ref><ref name="Cluzel 1991">{{cite journal|last1=Cluzel|first1=P|last2=Grenier|first2=P|last3=Bernadac|first3=P|last4=Laurent|first4=F|last5=Picard|first5=JD|title=Pulmonary alveolar microlithiasis: CT findings|journal=J Comput Assist Tomogr|date=1991|volume=15|issue=6|page=938-942|pmid=1939772}}</ref><ref name="Schmidt 1996">{{cite journal|last1=Schmidt|first1=H|last2=Lörcher|first2=U|last3=Kitz|first3=R|last4=Zielen|first4=S|last5=Ahrens|first5=P|last6=König|first6=R|title=Pulmonary alveolar microlithiasis in children|journal=Pediatr Radiol|date=1996|volume=26|issue=1|page=33-36|pmid=8598991}}</ref><ref name="Deniz 2005">{{cite journal|last1=Deniz|first1=O|last2=Ors|first2=F|last3=Tozkoparan|first3=E|last4=Ozcan|first4=A|last5=Gumus|first5=S|last6=Bozlar|first6=U|last7=Bilgic|first7=H|last8=Ekiz|first8=K|last9=Demirci|first9=N|title=High resolution computed tomographic features of pulmonary alveolar microlithiasis|journal=Eur J Radiol|date=2005|volume=55|issue=3|page=452-460|pmid=16129256}}</ref><ref name="Hoshino 1998">{{cite journal|last1=Hoshino|first1=H|last2=Koba|first2=H|last3=Inomata|first3=S|last4=Kurokawa|first4=K|last5=Morita|first5=Y|last6=Yoshida|first6=K|last7=Akiba|first7=H|last8=Abe|first8=S|title=Pulmonary alveolar microlithiasis: highresolution CT and MR findings|journal=J Comput Assist Tomogr|date=1998|volume=22|issue=2|page=245-248|pmid=9530388}}</ref><ref name="Gasparetto 2004">{{cite journal|last1=Gasparetto|first1=EL|last2=Tazoniero|first2=P|last3=Escuissato|first3=DL|last4=Marchiori|first4=E|last5=Frare|first5=E|last6=Silva|first6=RL|last7=Sakamoto|first7=D|title=Pulmonary alveolar microlithiasis presenting with crazy-paving pattern on high resolution CT|journal=Br J Radiol|date=2004|volume=77|issue=923|page=974-976|pmid=15507428}}</ref> Additionally, the medial aspects of the lungs appear to be more heavily involved than the lateral aspects.<ref name="Deniz 2005" /> Ground-glass opacities, probably due to small calculi in the air space, are the most common finding in children and in patients with early-stage PAM.<ref name="Schmidt 1996" />
The most common findings on HRCT are diffuse hyperdense ground-glass attenuation and subpleural linear calcifications, often most predominant in the inferior and posterior portions of the lungs.<ref name="Marchiori 2007">{{cite journal|last1=Marchiori|first1=E|last2=Gonçalves|first2=CM|last3=Escuissato|first3=DL|last4=Teixeira|first4=KI|last5=Rodrigues|first5=R|last6=Barreto|first6=MM|last7=Esteves|first7=M|title=Pulmonary alveolar microlithiasis: high-resolution computed tomography findings in 10 patients|journal=J Bras Pneumol|date=2007|volume=33|issue=5|page=552-557|pmid=18026653}}</ref><ref name="Cluzel 1991">{{cite journal|last1=Cluzel|first1=P|last2=Grenier|first2=P|last3=Bernadac|first3=P|last4=Laurent|first4=F|last5=Picard|first5=JD|title=Pulmonary alveolar microlithiasis: CT findings|journal=J Comput Assist Tomogr|date=1991|volume=15|issue=6|page=938-942|pmid=1939772}}</ref><ref name="Schmidt 1996">{{cite journal|last1=Schmidt|first1=H|last2=Lörcher|first2=U|last3=Kitz|first3=R|last4=Zielen|first4=S|last5=Ahrens|first5=P|last6=König|first6=R|title=Pulmonary alveolar microlithiasis in children|journal=Pediatr Radiol|date=1996|volume=26|issue=1|page=33-36|pmid=8598991}}</ref><ref name="Deniz 2005">{{cite journal|last1=Deniz|first1=O|last2=Ors|first2=F|last3=Tozkoparan|first3=E|last4=Ozcan|first4=A|last5=Gumus|first5=S|last6=Bozlar|first6=U|last7=Bilgic|first7=H|last8=Ekiz|first8=K|last9=Demirci|first9=N|title=High resolution computed tomographic features of pulmonary alveolar microlithiasis|journal=Eur J Radiol|date=2005|volume=55|issue=3|page=452-460|pmid=16129256}}</ref><ref name="Hoshino 1998">{{cite journal|last1=Hoshino|first1=H|last2=Koba|first2=H|last3=Inomata|first3=S|last4=Kurokawa|first4=K|last5=Morita|first5=Y|last6=Yoshida|first6=K|last7=Akiba|first7=H|last8=Abe|first8=S|title=Pulmonary alveolar microlithiasis: highresolution CT and MR findings|journal=J Comput Assist Tomogr|date=1998|volume=22|issue=2|page=245-248|pmid=9530388}}</ref><ref name="Gasparetto 2004">{{cite journal|last1=Gasparetto|first1=EL|last2=Tazoniero|first2=P|last3=Escuissato|first3=DL|last4=Marchiori|first4=E|last5=Frare|first5=E|last6=Silva|first6=RL|last7=Sakamoto|first7=D|title=Pulmonary alveolar microlithiasis presenting with crazy-paving pattern on high resolution CT|journal=Br J Radiol|date=2004|volume=77|issue=923|page=974-976|pmid=15507428}}</ref> Additionally, the medial aspects of the lungs appear to be more heavily involved than the lateral aspects.<ref name="Deniz 2005" /> Ground-glass opacities, probably due to small calculi in the air space, are the most common finding in children and in patients with early-stage PAM.<ref name="Schmidt 1996" />


'''''Magnetic Resonance Imaging'''''
'''''Magnetic Resonance Imaging'''''
Line 36: Line 35:


'''Pulmonary Function Studies'''
'''Pulmonary Function Studies'''
Pulmonary function tests, arterial blood gases, ventilation perfusion relationships, and O2 diffusing capacity are normal in the initial stages of PAM. As the disease progresses, pulmonary function tests reveal typical features of a restrictive defect with reduced forced vital capacity (FVC) and elevated forced expiratory volume in 1 s/FVC.
Pulmonary function tests, arterial blood gases, ventilation perfusion relationships, and O2 diffusing capacity are normal in the initial stages of PAM. As the disease progresses, pulmonary function tests reveal typical features of a restrictive defect with reduced forced vital capacity (FVC) and elevated forced expiratory volume in FEV1/FVC.


'''Diagnosis'''
'''Diagnosis'''
Line 42: Line 41:


'''Pharmacological Treatment'''
'''Pharmacological Treatment'''
To date, no treatment has been proven to effectively prevent the progression of PAM. Currently, the only effective therapy is lung transplantation, especially when it is performed before the disease progresses to an advanced stage.<ref name="Stamatis 1993">{{cite journal|last1=Stamatis|first1=G|last2=Zerkowski|first2=HR|last3=Doetsch|first3=N|last4=Greschuchna|first4=D|last5=Konietzko|first5=N|last6=Reidemeister|first6=JC|title=Sequential bilateral lung transplantation for pulmonary alveolar microlithiasis|journal=Ann Thorac Surg|date=1993|volume=56|issue=4|page=972-975|pmid=8215680}}</ref>
To date, no treatment has been proven to effectively reverse or prevent the progression of PAM. Lung transplantation is an option for end stage disease, but is typically only recommended as a last resort when quality of life is significantly impaired.<ref name="Stamatis 1993">{{cite journal|last1=Stamatis|first1=G|last2=Zerkowski|first2=HR|last3=Doetsch|first3=N|last4=Greschuchna|first4=D|last5=Konietzko|first5=N|last6=Reidemeister|first6=JC|title=Sequential bilateral lung transplantation for pulmonary alveolar microlithiasis|journal=Ann Thorac Surg|date=1993|volume=56|issue=4|page=972-975|pmid=8215680}}</ref>


Etidronate is a bisphosphonate and can reduce the formation of calcium hydroxyapatite crystals. It has led to clinical and radiological improvements in few cases.<ref name="Ozcelik 2010">{{cite journal|last1=Ozcelik|first1=U|last2=Yalcin|first2=E|last3=Ariyurek|first3=M|last4=Ersoz|first4=DD|last5=Cinel|first5=G|last6=Gulhan|first6=B|last7=Kiper|first7=N|title=Long-term results of disodium etidronate treatment in pulmonary alveolar microlithiasis|journal=Pediatr Pulmonol|date=2010|volume=45|page=514-517|pmid=20425862}}</ref>
Etidronate is a bisphosphonate and can reduce the formation of calcium hydroxyapatite crystals. It has led to clinical and radiological improvements in few cases.<ref name="Ozcelik 2010">{{cite journal|last1=Ozcelik|first1=U|last2=Yalcin|first2=E|last3=Ariyurek|first3=M|last4=Ersoz|first4=DD|last5=Cinel|first5=G|last6=Gulhan|first6=B|last7=Kiper|first7=N|title=Long-term results of disodium etidronate treatment in pulmonary alveolar microlithiasis|journal=Pediatr Pulmonol|date=2010|volume=45|page=514-517|pmid=20425862}}</ref>

Revision as of 23:25, 22 November 2015

Pulmonary Alveolar Microlithiasis

Pulmonary alveolar microlithiasis (PAM) is a rare, inherited disorder of lung phosphate balance that is associated with small stone formation in the airspaces of the lung. Mutations in the the gene SLC34A2[1][2] result in loss of a key sodium, phosphate co-transporter (called Npt2b), known to be expressed in distal airway epithelial cells alveolar type II cells, as well as in the mammary gland, and to a lesser extent in intestine, kidney, skin, prostate and testes. As the disease progresses, the lung fields become progressively more dense (white) on the chest xray, and low oxygen level, lung inflammation and fibrosis, elevated pressures in the lung blood vessels, and respiratory failure ensue, usually in middle age. The clinical course of PAM can be highly variable, with some patients remaining asymptomatic for decades, and others progressing more rapidly. There is no effective treatment, and the mechanisms of stone formation, inflammation and scarring are not known.

Signs and symptoms Patients typically have no symptoms until the third or fourth decade of life. In most cases, the disease is discovered incidentally on routine chest Xray. The most common symptoms include the following:[3][4][5][6][7]

  • dyspnea
  • dry cough
  • chest pain
  • sporadic hemoptysis
  • asthenia
  • pneumothoraces

Pathogenesis Type II alveolar cells have many important functions in the lung, including the production of pulmonary surfactant, maintenance of fluid balance and composition in the airspace. Phospholipids are that make up pulmonary surfactant are broken down by macrophages, releasing phosphate into the alveolar lining fluid. The loss of the Npt2b phosphate transported eliminates the ability of alveolar type II cells to pump phosphorus ions from the alveolar space back into the bloodstream, and leads to microlith formation.[5][8]

Genetics PAM is hereditary and another involved family member can be identified in 36% to 61% of cases.[4] Impaired activity of the SLC34A2 gene is responsible for PAM.[1][9][5][2][10][11] The SLC34A2 gene encodes a membrane protein that is expressed primarily in the apical portions of alveolar type II cells[12] and is the most abundant phosphate carrier in the lungs.[5]

Pathology PAM may be confined to certain areas or show diffuse distribution through the lungs.[6] Lung biopsy and autopsy specimens demonstrate characteristic intra-alveolar lamellar microliths.[6][13] Calcium deposits in the alveoli begin in the lower lobes and spread over a period of years throughout the lungs.[3]

Imaging Studies

Radiology Chest radiographs of patients with PAM usually reveal bilateral diffuse micronodular calcifications, producing a "sandstorm” appearance that first involves the inferior portions and then the middle and upper portions of the lungs.[3]

High-Resolution Computed Tomography The most common findings on HRCT are diffuse hyperdense ground-glass attenuation and subpleural linear calcifications, often most predominant in the inferior and posterior portions of the lungs.[14][15][16][17][18][19] Additionally, the medial aspects of the lungs appear to be more heavily involved than the lateral aspects.[17] Ground-glass opacities, probably due to small calculi in the air space, are the most common finding in children and in patients with early-stage PAM.[16]

Magnetic Resonance Imaging On magnetic resonance imaging (MRI), the calcific lesions usually show hypointensity or a signal void on T1- and T2-weighted images.

Pulmonary Function Studies Pulmonary function tests, arterial blood gases, ventilation perfusion relationships, and O2 diffusing capacity are normal in the initial stages of PAM. As the disease progresses, pulmonary function tests reveal typical features of a restrictive defect with reduced forced vital capacity (FVC) and elevated forced expiratory volume in FEV1/FVC.

Diagnosis PAM is usually diagnosed on the basis of a typical radiological pattern, namely a very fine, sand-like micronodulation of calcific density diffusely involving both lungs, with basal predominance. Many authors argue that this pattern precludes the need for a lung biopsy in most cases.[3][14][20] After PAM is diagnosed in a given patient, family members should be screened by chest radiography, and parents should be counseled that future children are also at risk of developing the disease.[21]

Pharmacological Treatment To date, no treatment has been proven to effectively reverse or prevent the progression of PAM. Lung transplantation is an option for end stage disease, but is typically only recommended as a last resort when quality of life is significantly impaired.[22]

Etidronate is a bisphosphonate and can reduce the formation of calcium hydroxyapatite crystals. It has led to clinical and radiological improvements in few cases.[23]

Epidemiology Since the disease was first described in 1918, over 500 case reports have appeared in the literature.[24] PAM is associated with consanguinity. The incidence is higher in Turkey, Japan, India and Italy.[25] The mean age at diagnosis is 35 years based on the cases reported in the literature.

References

  1. ^ a b Huqun; Izumi, S; Miyazawa, H; Ishii, K; Uchiyama, B; Ishida, T; Tanaka, S; Tazawa, R; Fukuyama, S; Tanaka, T; Nagai, Y; Yokote, A; Takahashi, H; Fukushima, T; Kobayashi, K; Chiba, H; Nagata, M; Sakamoto, S; Nakata, K; Takebayashi, Y; Shimizu, Y; Kaneko, K; Shimizu, M; Kanazawa, M; Abe, S; Inoue, Y; Takenoshita, S; Yoshimura, K; Kudo, K; Tachibana, T; Nukiwa, T; Hagiwara, K (2007). "Mutations in the SLC34A2 gene are associated with pulmonary alveolar microlithiasis". Am J Respir Crit Care Med. 175 (3): 263-268. PMID 17095743.
  2. ^ a b Corut, A; Senyigit, A; Ugur, SA; Altin, S; Ozcelik, U; Calisir, H; Yildirim, Z; Gocmen, A; Tolun, A (2006). "Mutations in SLC34A2 cause pulmonary alveolar microlithiasis and are possibly associated with testicular microlithiasis". Am J Hum Genet. 79 (4): 650-656. PMID 16960801.
  3. ^ a b c d Mariotta, S; Ricci, A; Papale, M; DeClementi, F; Sposato, B; Guidi, L; et al. (2004). "Pulmonary alveolar microlithiasis: report on 576 cases published in the literature". Sarcoidosis Vasc Diffuse Lung Dis. 21 (3): 173-181. PMID 15554073. {{cite journal}}: Explicit use of et al. in: |last7= (help)
  4. ^ a b Castellana, G; Lamorgese, V (2003). "Pulmonary alveolar microlithiasis. World cases and review of the literature". Respiration. 70 (5): 549-555. PMID 14665786.
  5. ^ a b c d Tachibana, T; Hagiwara, K; Johkoh, T (2009). "Pulmonary alveolar microlithiasis: review and management". Curr Opin Pulm Med. 15 (5): 486-490. PMID 19617834.
  6. ^ a b c Lauta, VM (2003). "Pulmonary alveolar microlithiasis: an overview of clinical and pathological features together with possible therapies". Respir Med. 97 (10): 1081-1085. PMID 14561014.
  7. ^ Korn, MA; Schurawitzki, H; Klepetko, W; Burghuber, OC (1992). "Pulmonary alveolar microlithiasis: findings on high-resolution CT". AJR Am J Roentgenol. 158 (5): 981-982. PMID 1566701.
  8. ^ Poelma, DL; Ju, MR; Bakker, SC; Zimmermann, LJ; Lachmann, BF; van Iwaarden, JF (2004). "A common pathway for the uptake of surfactant lipids by alveolar cells". Am J Respir Cell Mol Biol. 30 (5): 751-758. PMID 14644915.
  9. ^ Cite error: The named reference Senyigit 2001 was invoked but never defined (see the help page).
  10. ^ Cite error: The named reference Huqun 2006 was invoked but never defined (see the help page).
  11. ^ Cite error: The named reference Hagiwara 2009 was invoked but never defined (see the help page).
  12. ^ Traebert, M; Hattenhauer, O; Murer, H; Kaissling, B; Biber, J (1999). "Expression of type II Na-P(i) cotransporter in alveolar type II cells". Am J Physiol. 277 (5 Pt 1): 868-873. PMID 10564169.
  13. ^ Barnard, NJ; Crocker, PR; Blainey, AD; Davies, RJ; Ell, SR; Levison, DA (1987). "Pulmonary alveolar microlithiasis. A new analytical approach". Histopathology. 11 (6): 639-645. PMID 3623431.
  14. ^ a b Marchiori, E; Gonçalves, CM; Escuissato, DL; Teixeira, KI; Rodrigues, R; Barreto, MM; Esteves, M (2007). "Pulmonary alveolar microlithiasis: high-resolution computed tomography findings in 10 patients". J Bras Pneumol. 33 (5): 552-557. PMID 18026653.
  15. ^ Cluzel, P; Grenier, P; Bernadac, P; Laurent, F; Picard, JD (1991). "Pulmonary alveolar microlithiasis: CT findings". J Comput Assist Tomogr. 15 (6): 938-942. PMID 1939772.
  16. ^ a b Schmidt, H; Lörcher, U; Kitz, R; Zielen, S; Ahrens, P; König, R (1996). "Pulmonary alveolar microlithiasis in children". Pediatr Radiol. 26 (1): 33-36. PMID 8598991.
  17. ^ a b Deniz, O; Ors, F; Tozkoparan, E; Ozcan, A; Gumus, S; Bozlar, U; Bilgic, H; Ekiz, K; Demirci, N (2005). "High resolution computed tomographic features of pulmonary alveolar microlithiasis". Eur J Radiol. 55 (3): 452-460. PMID 16129256.
  18. ^ Hoshino, H; Koba, H; Inomata, S; Kurokawa, K; Morita, Y; Yoshida, K; Akiba, H; Abe, S (1998). "Pulmonary alveolar microlithiasis: highresolution CT and MR findings". J Comput Assist Tomogr. 22 (2): 245-248. PMID 9530388.
  19. ^ Gasparetto, EL; Tazoniero, P; Escuissato, DL; Marchiori, E; Frare, E; Silva, RL; Sakamoto, D (2004). "Pulmonary alveolar microlithiasis presenting with crazy-paving pattern on high resolution CT". Br J Radiol. 77 (923): 974-976. PMID 15507428.
  20. ^ Sahin, U; Yildiz, M; Bircan, HA; Akkaya, A; Candir, O (2004). "Absence of pulmonary uptake of Tc-99m methylenediphosphonate in alveolar microlithiasis". Ann Nucl Med. 18 (8): 695-698. PMID 15682851.
  21. ^ Helbich, TH; Wojnarovsky, C; Wunderbaldinger, P; Heinz-Peer, G; Eichler, I; Herold, CJ (1997). "Pulmonary alveolar microlithiasis in children: radiographic and high- resolution CT findings". AJR Am J Roentgenol. 168 (1): 63-65. PMID 8976922.
  22. ^ Stamatis, G; Zerkowski, HR; Doetsch, N; Greschuchna, D; Konietzko, N; Reidemeister, JC (1993). "Sequential bilateral lung transplantation for pulmonary alveolar microlithiasis". Ann Thorac Surg. 56 (4): 972-975. PMID 8215680.
  23. ^ Ozcelik, U; Yalcin, E; Ariyurek, M; Ersoz, DD; Cinel, G; Gulhan, B; Kiper, N (2010). "Long-term results of disodium etidronate treatment in pulmonary alveolar microlithiasis". Pediatr Pulmonol. 45: 514-517. PMID 20425862.
  24. ^ Mariotta, S; Guidi, L; Mattia, P; Torrelli, L; Pallone, G; Pedicelli, G; Bisetti, A (1997). "Pulmonary microlithiasis. Report of two cases". Respiration. 64 (2): 165-169. PMID 9097354.
  25. ^ Castellana, G; Gentile, M; Castellana, R; Fiorente, P; Lamorgese, V (2002). "Pulmonary alveolar microlithiasis: clinical features, evolution of the phenotype, and review of the literature". Am J Med Genet. 111 (2): 220-224. PMID 12210357.
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