1. CASE CONFERENCE

2. 30 year old AAF with PMH of –
Autoimmune hepatitis May got her 1st liver, was rejected with in 2 days got her 2nd liver on May
Complicated by Hepatic artery stenosis, recurrent cholangitis and billiary stricture s/p stent
CKD- went on HD Jan 23, 2013
DM-2
Adrenal insufficiency

3. Transferred from Albert Einstein for liver transplant evaluation.
Was admitted for bright red blood per rectum
We were consulted for pre-op Pulmonary risk stratification.
Does not follow with any Pulmonologist as out
Patient.
NO cough, no chest pain. Can walk at slow pace, gets sob when fluid builds up in her belly.
Never got intubated due to pneumonia or any other lung disease.
Denies any history of lung disease. No fever, no night sweats, no recent weight loss. No travel history, no exposure to TB.
FH- Non contributory
SH- Non Smoker, No drugs, No Etoh, Worked as a cashier at store part time.

4. ASA
Ciprofloxacin 250 po daily
Aranesp 100 mcg
Feso4
Lasix
Lactulose
Procrit
Renvela
Prograf
Ursodiol
Prilosec
Rifaxamine
Lantus
Prednisone 7.5 mg po daily
Vitamin D 5000 Units

5. Vitals- 112/ /min
Rr % RA
AAOx3 chronically ill appearing, very pleasant
Jaundiced, pallor positive, no cynosis or clubbing, no lymphadenopathy, mild pitting edema.
Malampatti class -1.
Chest mild decreased breath sounds generalised but no crackles wheezes
S1 and S2 normal no loud P2.
Abd- Soft surgical scar, mild ascities, non tender, BS –n
CNS- Grossly non focal
Ext- mild pitting edema.

6. Labs-
CBC- HB- 8.2, WBC- 10.1, Platelet 121
Chemistry- Bicarb 21, creatinine 4.6, BUN- 32
Calcium 8.2, Phos 3.8
LFTs- Bilirubin- 5.4
Albumin- 2.6
AST- 43
ALT- 52

7. Chest X-ray
ADD

8. PFTs FVC- 2 ( 64) VC-2.08 FEV1- 1.71 ( 65) Fev1/ fvc- 86
TLC (57)
RV/tlc- 25
DLCO- 42
4.5 seconds.

9. 2D echo Normal LV Function, Mild Mr
Normal RV function, Pa pressure- 20

18. Diffrential ??

19.   There  are  numerous  patchy  coarse  pleural  and  peripheral  parenchymal calcifications  seen  in  all  lung  lobes,  most  prominent  in  the  right middle  and  left  upper  lobes.  Possible  causes  include  pulmonary calcification  following  liver  transplant,  alternatively. 
These findings  may  represent  dystrophic  calcification  following  a hemorrhagic  pulmonary  infarcts  or  alveolar  hemorrhage.  Correlation with  prior  imaging,  if  available,  is  recommended.    There  is  a  minimal left-sided  pleural  effusion.  There  is  no  pneumothorax.  
The  thyroid  gland  is  unremarkable.  The  central  airways  are  clear. There  is  mild  cardiomegaly.  A  right-sided  double  lumen  central catheter  terminates  in  right  atrium.  Limited  unenhanced  evaluation  of the  vasculature  show  the  pulmonary  artery  and  aorta  having  a  grossly normal  course  and  caliber.  The  esophagus  is  unremarkable. 
Incidentally  noted  are  coarse  calcifications  within  the  region  of  the IVC,  the  right  diaphragmatic  crus,  the  spleen,  the  posterior  wall  of the  stomach,  the  splenic  artery  and  the  paraspinous  muscles  

20. There is no mediastinal, axillary or upper abdominal lymphadenopathy
There  is  no  mediastinal,  axillary  or  upper  abdominal  lymphadenopathy.   A  common  bile  duct  stent  is  present,  and  a  pigtail  catheter  terminates and  gallbladder  fossa.  Incidentally  noted  is  mild  pneumobilia,  due  to common  bile  duct  stent.  The  gallbladder  is  surgically  absent.  Also noted  are  embolization  coils  within  the  right  lobe  of  the  liver. .
The visualized  liver  and  stomach  are  otherwise  unremarkable.  The  partially imaged  spleen  appears  enlarged.  The  bones  appear  osteopenic.  There  is partially  imaged  foreign  body  in  the  posterior  right  kidney  and,  which may  represent  a  partially  imaged  stent.   IMPRESSION:  1.  Numerous  coarse  pleural  and  peripheral  parenchymal  calcifications in  all  lung  lobes.  Of  uncertain  etiology  and  possible  causes  include pulmonary  calcification  following  liver  transplant  in  a  patient  with renal  insufficiency.  Alternatively  these  findings  may  represent dystrophic  calcification  following  hemorrhagic  pulmonary  infarcts  or alveolar  hemorrhage.  Please  compare  to  prior  CT  imaging,  if  available.   2.  Mild  cardiomegaly. 3.  Probable  splenomegaly.

21. 5/29/11 cxray
CXRay- No active disease

22. 6/09/11 CT

25. CT- 6/7/2011
Persistent changes

26. 6/21/2011
Persistent changes

27. 07/2011

28. Increased calcification

29. 1/15/13

30. Specific symptoms are often lacking, but calcification may be a marker of disease severity and its chronicity. -Predisposing to pulmonary calcification and ossification include Hypercalcemia, a local alkaline environment, and previous lung injury. Factors such as enhanced alkaline phosphatase activity, active angiogenesis, and mitogenic effects of growth factors may also contribute.

31. The clinical classification of pulmonary calcification includes both-
Dystrophic calcification:
When the deposition occurs in dead or dying tissues
it occurs with normal serum levels of calcium
Metastatic calcification:
The deposition of calcium salts in normal tissues
It almost always reflects some derangement in calcium metabolism (hypercalcemia)

32. CAUSES OF PULMONARY CALCIFICATION
II. Dystrophic calcification
A. Granulomatous disorders
1. Histoplasmosis
2. Coccidioidomycosis
3. Tuberculosis
4. Sarcoidosis
B. Viral infections
1. Postvaricella pneumonia
2. Smallpox handler’s lung
C. Parasitic infections
1. Paragonomiasis
2. Pneumocystosis
D. Amyloidosis
E. Pulmonary vascular calcifications
1. Vascular grafts
2. Pulmonary hypertension
3. Congenital high flow
4. Hemosiderosis
F. Coal worker’s pneumoconiosis
G. Silicosis
III. Idiopathic
A. Pulmonary alveolar microlithiasis
I. Metastatic
A.Benign causes
1. Chronic renal insufficiency on hemodialysis
2. Orthotopic liver transplantation
3. Primary hyperparathyroidism
4. Excess exogenous administration of calcium and vitamin D (milk-alkali
syndrome)
5. Hypervitaminosis D
6. Osteopetrosis
7. Osteitis deformans (Paget’s disease)
B. Malignant causes
1. Parathyroid carcinoma
2. Multiple myeloma
3. Lymphoma/leukemia
4. Hypopharyngeal squamous cell carcinoma
5. Synovial sarcoma
6. Breast carcinoma
7. Choriocarcinoma

33. CAUSES OF PULMONARY OSSIFICATION
I. Idiopathic pulmonary ossification
II. Preexisting pulmonary disorder
A. Idiopathic pulmonary fibrosis
B. Pulmonary amyloidosis
C. Chronic busulfan therapy
D. Acute respiratory distress syndrome
E. Hamman-Rich syndrome
F. Sarcoidosis
G. Histoplasmosis
H. Tuberculosis
I. Metastatic breast cancer
J. Pulmonary metastases of osteogenic sarcoma
K. Metastatic melanoma
III. Preexisting cardiac disorder
A. Mitral stenosis
B. Chronic left ventricular failure
C. Idiopathic hypertrophic subaortic stenosis
IV. Preexisting extracardiopulmonary disorder
A. Primary and secondary hyperparathyroidism
B. Hypervitaminosis D
C. Pyloric stenosis with alkalosis

34. PROPOSED MECHANISMS OF ECTOPIC LUNG CALCIFICATION AND OSSIFICATION
The mechanism(s) of lung calcification with or without ossification is not precisely known. No single factor is responsible

35. Two physiologic requirements for metastatic calcium deposition are the release of excess calcium salts from bone and their transport through the circulation . The inorganic component of bone is comprised of apatite minerals with the chemical formula Ca3(PO4)2. (*)
For conditions that promote calcium release from bone, such as an elevated hydrogen ion concentration, the liberated Ca3(PO4)2and CaCO3 salts are transported via the blood in soluble form.
This is primarily as calcium hypophosphate (CaHPO4), which then reprecipitates as Ca 3(PO4)2 and CaCO3 salts in tissues that have a favorable physicochemical environment such as an alkaline pH and a propitious chemical stoichiometry (*).
*Mulligan RM. Metastatic calcification. Arch Pathol 1947;43:177–230

36. Role of Relative and Absolute Calcium Excess
Metastatic calcification
normal or even low serum calcium levels, an elevated calcium–phosphate product of more than 70 (normal -40 mg ) favors this process (18, 32).
normal calcium–phosphate product, it has been hypothesized that previous or current azotemia, an elevated parathyroid hormone, and/or exogenous vitamin D “sensitize” the tissues
Previous priming with a calcifying factor, followed by exposure to a challenging agent (e.g. calcium salts, tissue injury, or physical stress), is the basis for pulmonary calcification
18.Kempter H, Hagner G, Savaser AN, Huben H, Mingguillon C. Metastatic pulmonary calcification in a patient with nonsecretory multiple
myeloma. Respiration 1986;49:77–80.
32. Neff M, Yakin S, Gupta S, Berger H. Extensive metastatic calcification of the lung in an azotemic patient. Am J Med 1974;56:103–109.

37. Pulmonary parenchymal granulomas and mediastinal and
hilar lymphadenopathy associated with fungal diseases, tuberculosis, and sarcoidosis may calcify even in the face of normal serum calcium levels.
Macrophages within granulomas may also produce 1,25 vitamin D, thereby increasing intestinal absorption of calcium and phosphate and providing an additive or synergistic factor that promotes calcification in these tissues (41, 42).
This may occur in the absence of detectable increases in serum calcium levels, similar to the ability of supplemental vitamin D and calcium to increase bone density without necessarily raising serum calcium levels.
41. Bell NH, Sharg J, Shaw S, Turner RT. Hypercalcaemia associated with increased circulatory 1,25 dihydroxyvitamin-D in a patient with pulmonary tuberculosis. Calcif Tissue Int 1985;37:588–591.
42. Kerr DNS. Hypercalcemia and metastatic calcification. Cardiovasc Res 1997;36:293–297.

38. Role of an Alkaline Environment
Calcium salts precipitate in an alkaline environment.
The pH of the blood in the lung is more alkalotic compared with other organs because of CO2 removal.
The upper lobe predilection of some pulmonary calcific disorders is explained by a higher blood pH (approximately 7.51) and lower Pa CO2 (approximately 30 mm Hg) at the apex compared with the relatively lower pH at the base.
This difference is accounted for by the higher ventilation–perfusion ratio at the lung apex (ventilation–perfusion ratio approximately 3.3) compared with the base (ventilation– perfusion ratio approximately 0.63)

40. The calcification is not particularly common in patients with either hypercalcemia or alkalosis alone, alkalosis may, synergistically, predispose to ectopic calcification when other risk factors are present.
Cessation of pulmonary blood flow can lead to pulmonary calcification. Attributed to tissue alkalosis due to decreased CO2 delivery and hyperventilation.
Alkaline phosphatase, abundantly expressed by alveolar type II cells and non ciliated bronchiolar (Clara) cells (55), calcium–phosphate product by catalyzing the production of free phosphate, exhibit optimum activity at an alkaline pH (53), alkalosis may in addition predispose to ectopic calcification by this mechanism.
Alkaline phosphatase also enhances osteoblastic activity and thus may be necessary for pulmonary ossification to occur.
53. Moss DW, Henderson AR. Clinical enzymology. In: Burtis CA, Ashwood ER, editors. Tietz textbook of clinical chemistry. Philadelphia: W.B. Saunders; p. 617–721.
55. Edelson JD, Shannon JM, Mason RJ. Alkaline phosphatase: a marker of alveolar type II cell differentiation. Am Rev Respir Dis 1988; 138:1268–1275

41. Role of Lung Injury or Fibrosis

42. This “initiation phase” of dystrophic calcification is followed by a “propagation phase,”
Early fall in pH, followed by a shift to a neutral or alkaline pH as injury continues (58).
The calcium binding phosphoprotein osteopontin appears to play a role in dystrophic calcification.
The presence of collagen also enhances the rate of crystal growth, may be the mechanism by which calcification and subsequent ossification occur in the diffuse pulmonary fibrotic disorders
IL-4 to affect differentiation of macrophages into osteoclasts, the latter required for bone remodeling and absorption (59).
58. Cotran RS, Kumar V, Robbins SL. Cellular injury and cellular death: pathologic basis of disease. Philadelphia: W.B. Saunders; p. 1–34.
59. Akagawa KS, Takasuka N, Nozaki Y, Komuro I, Azuma M, Ueda M, Naito M, Takahashi K. Generation of CD1RelB dendritic cells
and tartrate-resistant acid phosphatase-positive osteoclast-like multinucleated giant cells from human monocytes. Blood 1996;88:4029–4039.

43. Chest Roentgenogram
Is useful for the detection of pleural calcification, hilar-mediastinal lymph node calcification, calcified lung nodules, and with less sensitivity, diffuse parenchymal calcification. Diffuse calcification is often mistaken for another process such as pulmonary edema or intrapulmonary hemorrhage, as it appears as nondiscrete infiltrates Localized pulmonary calcification is often confused with infarction, pneumonia, or malignancy (8, 32, 48, 69–71).
69. Firooznia H, Pudlowski R, Golimbu C, Rafie M, McCauley D. Diffuse interstitial calcification of the lungs in chronic renal failure mimicking pulmonary edema. AJR Am J Roentgenol 1977;129:1103–1105.
70. Mootz JR, Sagel SS, Roberts TH. Roentgenographic manifestations of pulmonary calcifications: a rare cause of respiratory failure in chronic renal disease. Radiology 1973;107:55–60.
71. Smith JC, Stanton LW, Kramer NC, Parrish AE. Nodular pulmonary calcification in renal failure. Am Rev Respir Dis 1969;100:723–728.

44. Computed Tomography
1) multiple calcified and/or apparently noncalcified nodules distributed diffusely or more localized to the certain regions. 2) diffuse or patchy areas of ground glass opacification or illdefined patchy infiltrate 3) a relatively dense area(s) of consolidation that mimics a lobar community acquired pneumonia.

45. A “ring” pattern of nodular calcification was also described with metastatic calcification secondary to chronic renal disease (50).
To confirm metastatic calcification on CT scan, 1-mm (HRCT) images of the mediastinal windows with or without densitometry measurements should be performed (74). This reveals the high-attenuation characteristic of calcified tissues (44).
Hounsfield unit value of greater than 100 in the lung parenchyma may indicate calcified densities, due to signal averaging, an area with less than 100 Hounsfield units does not necessarily exclude parenchymal calcification.
50. Lingam RK, Teh J, Sharma A, Friedman E. Metastatic pulmonary calcification
in renal failure: a new HRCT pattern. Br J Radiol 2002;
75:74–77.

47. 99mTc-MDP Bone Scintigraphy
HRCT mediastinal images and 99mTc-MDP bone scintigraphy are
relatively specific for pulmonarycalcification and ossification.
However
1)The presence of dense lesions on lung window
images will not distinguish between noncalcified and calcified
opacities and conversely,
2) because of signal averaging, the failure to detect calcification
or ossification on mediastinal images does not unequivocably
exclude the possibility if the calcified lesions are microscopic,
if there is a relatively large soft tissue component, and/or if standard
10-mm slices are imaged
One advantage of the CT scan is that
the thorax and lung parenchyma can also be evaluated in detail.
The advantage of scintigraphy is that other organs can be concurrently
evaluated for metastatic calcification or ossification

48. CRF acidosis leaches calcium and phosphate from bone.
2) Increased PTH secretion .
3) Intermittent alkalosis, which often accompanies HCO3 HD, predisposes to soft tissue precipitation of calcium salts. This is supported by the observation that metastatic soft tissue calcification is accelerated following hemodialysis
4) the decreased glomerular filtration of phosphate may contribute to an elevated serum calcium–phosphate product. 
assume various shapes and are primarily located in the thickened fibroproliferative interstitium of the lungs

49. In 91 patients who underwent orthotopic liver transplantation,chest radiographs, despite their relative insensitivity, detectedpulmonary calcification in 5.2% . 
The mechanism is unclear- Complicating renal failure, acid-base abnormalities, and the administration of exogenous calcium and citrate have been proposed as contributing events.
 Elevated plasma citrate concentrations caused by the administration of packed red blood cells could lead to metabolic alkalosis and calcium chelation, prompting parathyroid release of parathyroid hormone.
This gains support from the observation that the patients with calcification had higher levels of phosphorus and calcium postoperatively and had received more intraoperative blood products, all containing exogenous calcium
Libson E, Wechsler RJ, Steiner RM. Pulmonary calcinosis following orthotopic liver transplantation. J Thorac Imaging 1993;8:305–308.

50. Rarely, progressive respiratory insufficiency and death may ensue.
In extensive pulmonary calcification, a restrictive physiology, a decreased diffusion capacity, and hypoxemia result.
Rarely, progressive respiratory insufficiency and death may ensue.
99mTc-MDP scintigraphy or mediastinal images on HRCT scan may be diagnostic of metastatic calcification without need for further investigation.
Specific treatment is aimed at correction of isolated hyperphosphatemia or elevated calcium–phosphate product, if present.
Successful renal transplantation may ameliorate metastatic pulmonary calcification (91), and conversely, renal graft failure and persistent uremia may accelerate, by some unexplained mechanism, the ectopic calcification
91. Fulladosa X, Gonzales MT, Cruzado JM, Andres E, Castelao AM, Grino JM, Alsina J. Metastatic calcifications in severe secondary hyperparathyroidism: evolution after renal transplantation. Transplant Proc 1995;27:2272–2276.

51. What else can we offer to this patient ??
Admitted again with leg pain.
Pfts were repeated not much change.

52. Pulmonary Calcification Associated with Granulomatous Disorders
Diffuse nodular calcification associated with healed histoplasmosis. (A) The chest radiograph revealed small, well-circumscribed calcified lesions distributed diffusely but more prominent in the right mid-lung field. (B) A lung window image of the CT scan confirms the fine dense nodules, but the mediastinal image (C) revealed a paucity of calcifiedlesions. This discrepancy is likely because 10-mm slices were obtained, resulting in a signal averaging effect

53. TB Number of chest calcifications.
Dystrophic calcification may manifest in parenchymal granulomas, mediastinal lymph nodes, and fibronodular areas of lung involvement.
Diffuse nodular calcification of the lungs may follow treatment of a hematogenous infection.
Roussos and coworkers recently showed that patients with tuberculosis can develop hypercalcemia caused by excessive production of endogenous 1,25 vitamin D, thus further predisposing to dystrophic pulmonary calcification .
Thearly granulomatous inflammation without necrosis lacked phosphatase activity.
Clinically, tuberculous calcification enhances tissue friability at surgery but is generally inconsequential and does not affect mortality.

54. In unusual instances, sarcoidosis may produce multiple micronodular calcifications, radiographically similar to Pulmonary Alveolar Microlithiasis.
In contrast, however, their histologic features are distinct: In sarcoidosis, calcification is confined to the epitheloid granulomas, and in PAM, there are distinct intra-alveolar microliths.
VIRAL
The infiltrates usually resolve over time, but in some cases, asymptomatic miliary calcifications appear 3 to 5 years following the acute eventexposure to a smallpox patient, radiographic studies often showed poorly defined nodular opacities, attributed to a modified variola pneumonia.

55. Varicella Pneumonia

56. P. carinii infection
“bubbly” appearance in which aggregates of punctate calcification were admixed with P. carinii cysts (28). An important diagnosticpearl is that this pattern was not associated with the typical intra- alveolar foamy exudate seen with active pneumocystosis.

57. Pulmonary Calcification Associated with Amyloidosis
Because amyloid fibrils have an affinity for calcium, secondary calcification can occur in amyloidosis .
The calcified lung lesions associated with diffuse parenchymal amyloidosis are typically characterized radiographically by interstitial or mixed interstitial-alveolar infiltrates, admixed with varying degrees of calcification—rarely ossification— and located predominantly in the subpleural regions of the mid and lower lung zones (Figures 10A and 10B).
The appearance of calcification in amyloidosis is unusual, but its presence is often the first indication of primary amyloidosis.

59. Pulmonary Vascular calcificationConditions
Producing increased vascular wall shear stress or high flow are presumed to be important for the formation of dystrophic PVC for the following reasons:
(1) There is an increased susceptibility of vascular grafts to calcification 
(2) There are PVCs in clinical states associated with increases in either vessel wall shear stress or increased pulmonary blood flow and pulmonary hypertension
(3) in utero development of PVC with severe volume overload has been seen