Although TT and RT prolongations are peculiar features of AL Amyloidosis, they do not predict bleeding manifestations. Other coagulation abnormalities such as factor X deficiency, enhanced fibrinolysis, and amyloid angiopathy seem to correlate better with

Deficiencies in specific coagulation factors in have long been recognized and along with factor X, acquired deficiencies in factor IX, factor II and factor VII have also been described (16). Hypofibrinogenemia has also been observed in systemic AL amyloidosis in association

Hyperfibrinolysis related to a reduced level of α2-antiplasmin or to a complex formed with plasmin can be associated with either bleeding manifestations or abnormal coagulation tests in patients with amyloidosis. Bleeding diathesis associated with a shortened clot lysis time and elevated FDP is pathognomonic. The pathogenesis appears to be related to a reduced

Increased urokinase plasminogen activator activity also has been observed a patient with primary amyloidosis. Immunoprecipitation studies showed that single-chain urokinase plasminogen activator was the main fibrinolytic agonist in the patient's plasma. Treatment

level of α2-antiplasmin, often secondary to complex formation with plasmin (18, 19).

with disseminated intravascular coagulation and increased fibrinolysis (17).

important roles in determing the haemostatic abnormalities.

deposits.

clinical symptoms (15).

Definition of cardiac involvement (cardiomegaly, pleural effusions, and Kerley B lines on the chest radiograph) (21) over the past three decades has been supplanted by echocardiography. A granular sparkling appearance with wall thickening, diastolic relaxation abnormalities, right ventricular dysfunction and abnormal echocardiography strain have all been shown to be associated with prognosis (22). Serum cardiac biomarkers have been recently introduced and serum troponin T and N-terminal pro-brain natriuretic peptide (NT-proBNP) are now widely available. Using a cutoff value of 0.035 mcg/L Troponin T and 332 pg/mL NT-proBNP, patients can be classified into three stages: Stage I both biomarkers low (33% incidence); Stage II, only 1 marker high (37% ); Stage III both values high (30% incidence) . The reported median survivals are 26.4, 10 and 3.5 months, respectively for Stages I, II, III (23).

The cardiac biomarkers values have been validated in different cohorts of patients treated with either conventional chemotherapy or stem cell transplantation (SCT) (24). Stage III patients are at high mortality risk in SCT studies and also are poor candidates for clinical trials of standard agents (25).

Echocardiography is one of the earliest tests employed in the investigation of suspected heart disease. The specificity of the echocardiographyc findings increases in the presence of the clinical manifestations suggestive of myocardial amyloidosis. The earliest finding in cardiac amyloidosis is suggested by reduced diastolic mitral inflow velocities upon Doppler imaging (26, 27).

A granular sparkling texture of the myocardium with increased thickness is strongly suggestive of cardiac amyloid infiltration with a specificity approaching 81%. The addition of the finding of increased septal diameter remarkably increases the specificity of ventricular wall thickness parameter; an interventricular septum thickness of more than 15 mm is also considered a poor prognostic sign (28).The thickness of the left ventricular walls correlates with reduced survival. Low voltage/mass ratio strongly favors the diagnosis of amyloid myocardial infiltration (29). Typical clinical presentation of cardiac amyloidosis with specific echocardiographyc findings such as dilated atria, interatrial septal hypertrophy > 7 mm, thickened valves and right ventricular free wall has been proposed as diagnostic of cardiac amyloidosis even without an endomyocardial biopsy (30).

The diagnosis can be confirmed by endomyocardial biopsy and the extent of involvement appears as the most important determinant of clinical outcome as cardiac troponin and NTproBNP have been shown to be potent prognostic indicators, the suppression of amyloidogenic serum light chains by treatment and reductions in NT-proBNP have been associated with improved outcome.

Circulating amyloidogenic light chains interact with cardiac cell membrane constituents and other local matrix components. Extracellular space amyloid deposition causes myocardial damage by direct cell toxicity mediated by the formation of light chain oligomers (31). The

Cardiovascular Complications in Patients with AL Amyloidosis 57

is an early event. Another gene that was significantly different between AL and MM was the chemokine SDF-1, which is comparatively more highly expressed in AL PCs. However, SDF-1 levels in normal PCs are higher than those expressed in AL (36, 37). Whereas over expression of SDF-1 has been implicated in preventing apoptosis, promoting proliferation and metastatic spread in a number of neoplastic diseases through interactions with CXCR4, it is apparent that the relatively high levels of SDF-1 in normal and AL PCs have a paradoxical effect. This paradox can be explained by the binding of SDF-1 to CXCR4 which results in activation of the suppressors of cytokine signaling (SOCS) proteins, in particular, SOCS-3, which can negatively regulate CXCR4 function without interfering with surface

Clonal AL plasma cells express recurring cytogenetic abnormalities, including t(11,14), gain 11q, del 13q, and gain 1q.Interestingly, t(11;14) was associated with worse overall survival in a recent study of AL patients (38). Over expression of cyclin D1 (CCND1 located on chromosome 11q13) in purified AL plasma cells occurs in one-half of AL patients and is associated with unique pathobiologic characteristics at diagnosis: including high frequencies of light-chain only M proteins and kappa light chains, increased cardiac biomarker levels,

The therapy aim for AL amyloidosis is to eliminate the clonal plasma cells producing the toxic precursor protein. Once a case of amyloidosis is recognized, it is vital to precisely determine the type of amyloid as the prognosis and treatment differ considerably among the various types. The management of heart failure in patients with amyloidosis remains challenging. Judicious diuretics use and salt restriction with avoidance of intravascular volume depletion remains the mainstay of the treatment. Angiotensin-converting enzyme inhibitors and Angiotensin-II receptor blockers are poorly tolerated in cardiac amyloidosis. The role of calcium channel blockers and digoxin is limited and probably detrimental. This is due to an exaggerated negative inotropic effect. A high incidence of sudden death in

Heart transplantation remains a controversial option because of the systemic involvement and the potential recurrence of graft Amyloidosis (41). In primary amyloidosis, heart transplantation is only a palliative procedure and consequent supportive chemotherapy should be considered. The long-term prognosis is poor (39% survival at 4 years in one study and 30% at 5 years in another, even with adjuvant chemotherapy. Sequential heart and

Active agents in the treatment of the amyloid include corticosteroids (prednisone, dexamethasone), alkylating agents (melphalan, cyclophosphamide), immunomodulatory drugs (thalidomide, lenalidomide) and proteasome inhibitors (bortezomib).Conventional chemotherapy based on melphalan and prednisone was introduced in 1972 can achieve a median survival of 12 to 18 months and in patients with severe cardiac failure, continuous, oral, daily melphalan has been used as palliative method (43). Based on the observation that dexamethasone as single agent was able to produce hematological and organ responses, melphalan and dexamethasone have been later used in combination in this setting (44). Melphalan and dexamethasone is still now considered a front-line therapy, inducing a hematological response of 67% of the time with a 33% of CR and an organ response rate of 48% in a phase II study of 45 patients. A 5-year follow-up the study showed a median PFS of

autologous stem cell transplantation for primary amyloidosis has been reported (42).

receptor expression.

**5. Therapy**

and poorer overall survival (39).

patients treated with digoxin has been reported (40).

pathologic features are thickening of all four chambers, biatrial dilatation, a normal or mildly dilated right ventricle and a left ventricular cavity that is normal or small. Myocardial cells are separated and distorted by amyloid deposition. Intramyocardial vessels are frequently infiltrated by amyloid, resulting in impaired vasodilatation, which may result in myocardial ischemia. Rarely amyloid deposits have been found in epicardial vessels resulting in obstructive coronary artery disease indistinguishable on coronary angiography from cholesterol-laden plaques. The predominant manifestation of amyloid heart disease is congestive failure (32).

Accumulation of amyloid in the myocardial interstitium results in late gadolinium enhancement, often with a predominant diffuse, global and subendocardial distribution that matches the distribution of amyloid on histology although other more focal patterns have also been reported. This is associated with substantial alteration in gadolinium kinetics, with faster washout of gadolinium from blood and myocardium than normal (33). Some studies have suggested that gadolinium kinetics may be even more predictive than echocardiography or serum markers. The value of the Cardiovascular Magnetic Resonance (CMR) measurements may in part be due to the fact that cardiac amyloid burden cannot be measured satisfactorily by other techniques, and therefore CMR may offer a fundamental new window into the cardiac pathology in this disease (34). Recognition that T1 mapping in cardiac amyloidosis may be significantly more predictive of poor prognosis than the other currently used measures ,its use may be justified when early and more intensive chemotherapy is planned .

A number of the gadolinium kinetics parameters have been significantly associated with mortality, but the one with greatest discriminatory value was the intra-myocardial T1 gradient after gadolinium injection, with 95% accuracy at a threshold value of 23 ms (Kaplan Meier analysis P = 0.002). Although further experience and reproduction of these results by other centers is necessary, the technique is in principle straightforward and could be implemented on most 1.5T scanners (35).

#### **4. Gene expression and cytogenetic abnormalities**

Gene expression profiling studies have revealed subsets of genes associated with the development of amyloidosis. A unique molecular profile for AL amyloidosis may be relevant to the development of disease.

The comparison of gene expression profiles between AL, normal BM and myeloma plasma cells has revealed that AL plasma cells had an intermediate transcription profile. A few genes may be of particular relevance in understanding the differences in the pathobiology of these two disease entities. One of these, TNFRSF7, a member of the tumor necrosis factor (TNR) receptor superfamily which codes for CD27, a marker expressed on memory B cells and is important in controlling maturation and apoptosis of plasma cells, has a higher average expression in AL plasma cells. CD27 has been postulated to be important in the oncogenesis of myeloma, since MM plasma cells (PC) do not express this marker, whereas normal PCs do, and the expression of CD27 declines with the more advanced stages of MM. CD27 interacts with its ligand CD70, and this interaction is thought to be important in the differentiation of plasma cells. Interestingly, the tail of CD27 binds a proapoptotic protein, Siva, and CD27-70 interaction may activate a death signal that determines the life span of PCs.

CD27 expression is progressively down regulated in the transition from normal plasma cells to MGUS to MM to myeloma cell lines suggesting that molecular mechanism in AL disease is an early event. Another gene that was significantly different between AL and MM was the chemokine SDF-1, which is comparatively more highly expressed in AL PCs. However, SDF-1 levels in normal PCs are higher than those expressed in AL (36, 37). Whereas over expression of SDF-1 has been implicated in preventing apoptosis, promoting proliferation and metastatic spread in a number of neoplastic diseases through interactions with CXCR4, it is apparent that the relatively high levels of SDF-1 in normal and AL PCs have a paradoxical effect. This paradox can be explained by the binding of SDF-1 to CXCR4 which results in activation of the suppressors of cytokine signaling (SOCS) proteins, in particular, SOCS-3, which can negatively regulate CXCR4 function without interfering with surface receptor expression.

Clonal AL plasma cells express recurring cytogenetic abnormalities, including t(11,14), gain 11q, del 13q, and gain 1q.Interestingly, t(11;14) was associated with worse overall survival in a recent study of AL patients (38). Over expression of cyclin D1 (CCND1 located on chromosome 11q13) in purified AL plasma cells occurs in one-half of AL patients and is associated with unique pathobiologic characteristics at diagnosis: including high frequencies of light-chain only M proteins and kappa light chains, increased cardiac biomarker levels, and poorer overall survival (39).

#### **5. Therapy**

56 Amyloidosis – An Insight to Disease of Systems and Novel Therapies

pathologic features are thickening of all four chambers, biatrial dilatation, a normal or mildly dilated right ventricle and a left ventricular cavity that is normal or small. Myocardial cells are separated and distorted by amyloid deposition. Intramyocardial vessels are frequently infiltrated by amyloid, resulting in impaired vasodilatation, which may result in myocardial ischemia. Rarely amyloid deposits have been found in epicardial vessels resulting in obstructive coronary artery disease indistinguishable on coronary angiography from cholesterol-laden plaques. The predominant manifestation of amyloid heart disease is

Accumulation of amyloid in the myocardial interstitium results in late gadolinium enhancement, often with a predominant diffuse, global and subendocardial distribution that matches the distribution of amyloid on histology although other more focal patterns have also been reported. This is associated with substantial alteration in gadolinium kinetics, with faster washout of gadolinium from blood and myocardium than normal (33). Some studies have suggested that gadolinium kinetics may be even more predictive than echocardiography or serum markers. The value of the Cardiovascular Magnetic Resonance (CMR) measurements may in part be due to the fact that cardiac amyloid burden cannot be measured satisfactorily by other techniques, and therefore CMR may offer a fundamental new window into the cardiac pathology in this disease (34). Recognition that T1 mapping in cardiac amyloidosis may be significantly more predictive of poor prognosis than the other currently used measures ,its use may be justified when early and more intensive

A number of the gadolinium kinetics parameters have been significantly associated with mortality, but the one with greatest discriminatory value was the intra-myocardial T1 gradient after gadolinium injection, with 95% accuracy at a threshold value of 23 ms (Kaplan Meier analysis P = 0.002). Although further experience and reproduction of these results by other centers is necessary, the technique is in principle straightforward and could be

Gene expression profiling studies have revealed subsets of genes associated with the development of amyloidosis. A unique molecular profile for AL amyloidosis may be

The comparison of gene expression profiles between AL, normal BM and myeloma plasma cells has revealed that AL plasma cells had an intermediate transcription profile. A few genes may be of particular relevance in understanding the differences in the pathobiology of these two disease entities. One of these, TNFRSF7, a member of the tumor necrosis factor (TNR) receptor superfamily which codes for CD27, a marker expressed on memory B cells and is important in controlling maturation and apoptosis of plasma cells, has a higher average expression in AL plasma cells. CD27 has been postulated to be important in the oncogenesis of myeloma, since MM plasma cells (PC) do not express this marker, whereas normal PCs do, and the expression of CD27 declines with the more advanced stages of MM. CD27 interacts with its ligand CD70, and this interaction is thought to be important in the differentiation of plasma cells. Interestingly, the tail of CD27 binds a proapoptotic protein, Siva, and CD27-70

CD27 expression is progressively down regulated in the transition from normal plasma cells to MGUS to MM to myeloma cell lines suggesting that molecular mechanism in AL disease

interaction may activate a death signal that determines the life span of PCs.

congestive failure (32).

chemotherapy is planned .

implemented on most 1.5T scanners (35).

relevant to the development of disease.

**4. Gene expression and cytogenetic abnormalities**

The therapy aim for AL amyloidosis is to eliminate the clonal plasma cells producing the toxic precursor protein. Once a case of amyloidosis is recognized, it is vital to precisely determine the type of amyloid as the prognosis and treatment differ considerably among the various types. The management of heart failure in patients with amyloidosis remains challenging. Judicious diuretics use and salt restriction with avoidance of intravascular volume depletion remains the mainstay of the treatment. Angiotensin-converting enzyme inhibitors and Angiotensin-II receptor blockers are poorly tolerated in cardiac amyloidosis. The role of calcium channel blockers and digoxin is limited and probably detrimental. This is due to an exaggerated negative inotropic effect. A high incidence of sudden death in patients treated with digoxin has been reported (40).

Heart transplantation remains a controversial option because of the systemic involvement and the potential recurrence of graft Amyloidosis (41). In primary amyloidosis, heart transplantation is only a palliative procedure and consequent supportive chemotherapy should be considered. The long-term prognosis is poor (39% survival at 4 years in one study and 30% at 5 years in another, even with adjuvant chemotherapy. Sequential heart and autologous stem cell transplantation for primary amyloidosis has been reported (42).

Active agents in the treatment of the amyloid include corticosteroids (prednisone, dexamethasone), alkylating agents (melphalan, cyclophosphamide), immunomodulatory drugs (thalidomide, lenalidomide) and proteasome inhibitors (bortezomib).Conventional chemotherapy based on melphalan and prednisone was introduced in 1972 can achieve a median survival of 12 to 18 months and in patients with severe cardiac failure, continuous, oral, daily melphalan has been used as palliative method (43). Based on the observation that dexamethasone as single agent was able to produce hematological and organ responses, melphalan and dexamethasone have been later used in combination in this setting (44). Melphalan and dexamethasone is still now considered a front-line therapy, inducing a hematological response of 67% of the time with a 33% of CR and an organ response rate of 48% in a phase II study of 45 patients. A 5-year follow-up the study showed a median PFS of

Cardiovascular Complications in Patients with AL Amyloidosis 59

expanded the armamentarium against AL. The central challenges of this decade will be how

[1] Lachmann HJ, Booth DR, Booth SL, et al. Misdiagnosis of hereditary amyloidosis as AL

[2] Comenzo RL, Zhou P, Fleisher M, Clark B, Teruya-Feldstein J. Seeking confidence in the

[3] Vrana JA, Gamez JD, Madden BJ, Theis JD, Bergen HR 3d, Dogan A. Classification of

[4] Gertz MA, Comenzo R, Falk RH, et al. Definition of organ involvement and treatment

[5] Lebovic D, Hoffman J, Levine BM, et al. Predictors of survival in patients with systemic

[6] Kyle RA, Gertz MA. Primary systemic amyloidosis: clinical and laboratory features in

[7] Kyle RA, Gertz MA. Primary systemic amyloiodosis: clinical and laboratory features in

[8] Mumford A, O'Donnell J, Gillmore J, et al. Bleeding symptoms and coagulation abnormalities in 337 patients with AL-amyloidosis. *Br J Hematol*. 2000;110:454460. [9] Sucker C, Hetzel GR, Grabensee B, et al. Amyloidosis and bleeding: pathophisiology,

[10] Hoshino Y, Hatake K, Muroi K, et al. Bleeding tendency caused the deposit of amyloid substance in the perivascular region. *Intern Med*. 1993;32(11):879-881. [11] Choufani E, Sanchowarala V, Ernst T, et al. Acquired factor X deficiency in patients

[12] Greipp PR, Kyle RA, Bowie EJ. Factor X deficiency in primary amyloidosis:resolution

[13] Rosenstein ED, Itzkowitz SH, Penziner AS, et al. resolution of factor X deficiency in primary amyloidosis following splenectomy. *Arch Intern Med*. 1983;143(3):597-599. [14] Gamba G, Montani N, Anesi E, et al. Clotting alterations in primary systemic

[15] Galbraith PA, Sharma N, Parker WL, et al. Acquired factor X deficiency. Altered plasma

[16] Korsan-Bengsten K, Hjort PF, Ygge J. Acquired factor X deficiency in a patient with

antithrombin activity and association with amyloidosis. *JAMA*. 1974;230(12):1658-

with amyloid light-chain amyloidosis: incidence, bleeding manifestations, and

analysis in clinical biopsy specimens. *Blood*. 2009;114:4957-4959.

France, 18-22 April 2004. *Am J Haematol*. 2005;79:319-328.

diagnosis and therapy. *Am J Kidney Dis*. 2006;47(6):947-55.

response to high dose chemotherapy. *Blood*. 2001; 97:1885-1887.

after splenectomy. *N Engl J Med*. 1979;301(19):1050-1051.

amyloidosis. *Thromb Diath Haemorragh.* 1962;7:558-566.

amyloidosis. *Haematologica.* 2000;85(3):289-92.

474 cases. Seminar Hematol. 1995;32:45-49.

474 cases. Semin Hematol. 1995;32:45-59.

diagnosis of systemic AL (Ig light-chain) amyloidosis: patients can have both monoclonal gammopathies and hereditary amyloid proteins. *Blood*. 2006;107:3489-

amyloidosis by laser microdissection and mass spectrometry-based proteomic

response in immunoglobulin light chain amyloidosis (AL): a consensus opinion from the 10th International Symposium on Amyloid and Amyloidosis, Tours,

light-chain amyloidosis and cardiac involvement initially ineligible for stem cell transplantation and treated with oral melphalan and dexamethasone. *Br J Haematol*.

to combine these agents and how to bring forth new ones for approval.

(primary) amyloidosis. *N Engl J Med*. 2002;346:1786-1791.

**6. References**

3491.

2008;143:369-373.

1660.

3.8 years and OS of 5.1 years. Subsequent studies have later confirmed the efficacy of this combination (45).

Amyloid therapy remained unchanged until the introduction of stem cell transplantation (SCT) wich was designed to target rapidly the amyloidogenic light chain production by the clonal plasma cell populations. High rates of hematological and organ response have now been documented in multiple centers with long-term data reported and median survivals of over a decade for SCT patients achieving complete response. The high rate of treatmentrelated mortality (5 to 10% even at experienced centers) would explain the failure to show a survival advantage when compared to standard therapy in a large prospective randomized trial (46). Risk-adapted SCT, which tailors the melphalan dose according to age and risk status of the patient, may improve early survival (47). To compensate for the loss of efficacy due to attenuated conditioning, adjuvant therapy post SCT for patients not achieving a CR has been tested. Thalidomide and dexamethasone or bortezomib and dexamethasone has been used as adjuvant therapy post SCT with CR rates at 12 months post SCT of 39% and 65% of evaluated patients (48).

The propensity for sudden cardiac death, the frequency of multi-organ involvement and the problem of progressive organ disease and drug-related side effects has limited clinical research in amyloid. The first novel agent to be tested in relapsed AL was thalidomide. Initially it was poorly tolerated at high doses but showed efficacy at moderate doses in combination with dexamethasone and alkylating agents (melphalan or cyclophosphamide) resulting in hematological and organ responses. Current reccomendations suggest to start with thalidomide at a dose of 50 mg daily and it can be increased if tolerated (49).

Lenalidomide has been combined with dexamethasone in two studies with hematological response of 41% and 67% respectively. Several phase I/II combining Lenalidomide and dexamethasone with an alkylating agent (melphalan or cyclophosphamide) have been recently completed. In a phase 1/2 dose-escalation study of lenalidomide in combination with melphalan and dexamethasone. A complete hematological response was achieved in 42% at the dose of 15 mg of lenalidomide per day. After a median follow-up of 19 months, estimated 2-year overall survival (OS) and event-free survival (EFS) were 80.8% and 53.8% respectively (50).

In a preliminary report on a phase II study of the thalidomide derivative pomalidomide with weekly dexamethasone in AL amyloidosis patients previously treated with SCT and alkylating agents lenalinamide or thalidomide one-third achieved a hematological response by 6 months, highlighting the promising anti amyloid effect of this potent immunomodulatory drug (51).

Bortezomib is a selective inhibitor of the 26S proteasome, a protein complex involved in the regulation of degradation of aberrant proteins as well as for the regulation of other proteins involved in the regulation of apoptosis, and cell-cycle progression.

Single agent Bortezomib in a phase I dose escalation study achieved hematological responses in 50% of patients and CR in 20%. A multicenter study of 94 AL amyloid patients treated with bortezomib with or without dexamethasone has reported hematological responses in 71% and CR in 25% of patients; cardiac response was documented in 29% of subjects (52). Bortezomib is currently being evaluated in combination with melphalan and dexamethasone in 2 trials in Europe and USA.

The past decade has seen significant advances in the treatment of patients with AL, leading to improvement s in both quality of life and survival. The novel agents have significantly expanded the armamentarium against AL. The central challenges of this decade will be how to combine these agents and how to bring forth new ones for approval.

#### **6. References**

58 Amyloidosis – An Insight to Disease of Systems and Novel Therapies

3.8 years and OS of 5.1 years. Subsequent studies have later confirmed the efficacy of this

Amyloid therapy remained unchanged until the introduction of stem cell transplantation (SCT) wich was designed to target rapidly the amyloidogenic light chain production by the clonal plasma cell populations. High rates of hematological and organ response have now been documented in multiple centers with long-term data reported and median survivals of over a decade for SCT patients achieving complete response. The high rate of treatmentrelated mortality (5 to 10% even at experienced centers) would explain the failure to show a survival advantage when compared to standard therapy in a large prospective randomized trial (46). Risk-adapted SCT, which tailors the melphalan dose according to age and risk status of the patient, may improve early survival (47). To compensate for the loss of efficacy due to attenuated conditioning, adjuvant therapy post SCT for patients not achieving a CR has been tested. Thalidomide and dexamethasone or bortezomib and dexamethasone has been used as adjuvant therapy post SCT with CR rates at 12 months post SCT of 39% and

The propensity for sudden cardiac death, the frequency of multi-organ involvement and the problem of progressive organ disease and drug-related side effects has limited clinical research in amyloid. The first novel agent to be tested in relapsed AL was thalidomide. Initially it was poorly tolerated at high doses but showed efficacy at moderate doses in combination with dexamethasone and alkylating agents (melphalan or cyclophosphamide) resulting in hematological and organ responses. Current reccomendations suggest to start

Lenalidomide has been combined with dexamethasone in two studies with hematological response of 41% and 67% respectively. Several phase I/II combining Lenalidomide and dexamethasone with an alkylating agent (melphalan or cyclophosphamide) have been recently completed. In a phase 1/2 dose-escalation study of lenalidomide in combination with melphalan and dexamethasone. A complete hematological response was achieved in 42% at the dose of 15 mg of lenalidomide per day. After a median follow-up of 19 months, estimated 2-year overall survival (OS) and event-free survival (EFS) were 80.8% and 53.8%

In a preliminary report on a phase II study of the thalidomide derivative pomalidomide with weekly dexamethasone in AL amyloidosis patients previously treated with SCT and alkylating agents lenalinamide or thalidomide one-third achieved a hematological response by 6 months, highlighting the promising anti amyloid effect of this potent

Bortezomib is a selective inhibitor of the 26S proteasome, a protein complex involved in the regulation of degradation of aberrant proteins as well as for the regulation of other proteins

Single agent Bortezomib in a phase I dose escalation study achieved hematological responses in 50% of patients and CR in 20%. A multicenter study of 94 AL amyloid patients treated with bortezomib with or without dexamethasone has reported hematological responses in 71% and CR in 25% of patients; cardiac response was documented in 29% of subjects (52). Bortezomib is currently being evaluated in combination with melphalan and

The past decade has seen significant advances in the treatment of patients with AL, leading to improvement s in both quality of life and survival. The novel agents have significantly

involved in the regulation of apoptosis, and cell-cycle progression.

with thalidomide at a dose of 50 mg daily and it can be increased if tolerated (49).

combination (45).

65% of evaluated patients (48).

respectively (50).

immunomodulatory drug (51).

dexamethasone in 2 trials in Europe and USA.

Cardiovascular Complications in Patients with AL Amyloidosis 61

[35] Moon JC, McKenna WJ, McCrohon JA, Elliott PM, Smith GC, Pennell DJ. Toward

[37] Zhan F, Barlogie B, Arzoumanian V, Huang Y, Williams DR, Hollmig K, Pineda-Roman

[39] Comenzo RL, Hofman JE, Hassoun H, Landau H, Iyer L, Zhou P. Pathobiologic

[40] Falk RH. Diagnosis and management of the cardiac amyloidoses. *Circulation.*

[41] Shan KB, Inoue Y, Mehra MR. Amyloidosis and the heart. A comprehensive review.

[42] Kholovà I, Kautzner J. Current treatment in cardiac amyloidosis. *Curr Treat Options*

[45] Palladini G, Russo P, Nuvolone M., et al. Treatment with oral melphalan plus

[46] Mhaskar R, Kumar A, Behera M, et al. Role of high-dose chemotherapy and autologous

[48] Landau H, Hassoun H, Bello C, et al. Adjuvant bortezomib and dexamethasone

[49] Palladini G, Perfetti V, Perlini S, et al. The combination of thalidomide and

[50] Moreau P, Jaccard A, Benboubker L, et al. Lenalidomide in combination with melphalan

review*. Biol Blood Marrow Transplant.* 2009;15:893-902. Epub 2009 Apr 2. [47] Cohen AD, Zhou P, Chou J, et al. Risk-adapted autologous stem cell transplantation

results of a phase II trial. *Br J Haematol.* 2007;139:224-233.

with primary amyloidosis (AL). *Blood*. 2005;105:2949-2951.

amyloidosis [abstract]. *Amyloid.* 2010;17(s1):80.

[43] Kyle RA, Bayrd ED. Amyloidosis: Review of 236 cases. *Medicine*. 1975;54:271-299. [44] Palladini G, Perfetti V, Obici L, et al. Association of melphalan and high-dose

cardiovascular magnetic resonance. *J Am Coll Cardiol*. 2003;41:1561-7. [36] Guikema JE, Hovenga S, Vellenga E, et al. CD27 is heterougeneously expressed in

myeloma is linked to good prognosis. *Blood.* 2007 15;109(4):1692-700. [38] Bochtler T, Hegenbart U, Cremer FW, et al. Evaluation of the cytogenetic aberration

karyotypic instability. *Blood.* 2008;111:4700-4705

*Arch Intern Med.* 2006;166:180*-*1813. [PubMed]

*Cardiovasc Med.* 2006;8:468-473. [PubMed]

AL amyloidosis (AL) [abstract]. *Amyloid.* 2010;17(s1):61.

*Haematol* 2003;121:3643

2005;112:2047-60. [PubMed]

2938. Epub 2003 Dec 18.

110:787-788.

Aug 19.

clinical risk assessment in hyperthophic cardiomyopathy with gadolinium

multiple myeloma: low CD27 expression in patients with high-risk disease. *Br J*

M, Tricot G, van Rhee F, Zangari M, Dhodapkar M, Shaughnessy JD Jr. Geneexpression signature of benign monoclonal gammopathy evident in multiple

pattern in amyloid light-chain amyloidosis as compared with monoclonal gammopathy of undetermined significance reaveals common pathways of

associations of plasma cell (PC) overexpression of *Cyclin D1 (CCND1)* in systemic

dexamethasone is effective and well tolerated in patients with AL (primary) amyloidosis who are ineligible for stem cell transplantation. *Blood.* 2004;103:2936-

dexamethasone produces long-term remissions in AL amyloidosis. *Blood*. 2007;

hematopoietic cell transplantation n primary systemic amyloidosis: A systematic

with adjuvant dexamethasone +/- thalidomide for systemic light chain amyloidosis:

following risk-adapted melphalan and stem cell transplant in systemic AL

intermediate-dose dexamethasone is an effective but toxic treatment for patients

and dexamethasone in patients with newly AL amyloidosis: a multicentre phase I/II dose escalation study [abstract]. *Blood*. 2010 Dec 2;116(63):4777-82. Epub 2010

[17] McPherson RA, Onstad JW, Ugoretz RG, Wolf PL. Coagulopathy in amyloidosis: combined deficiency of factors IX and X. *Am J Hematol.* 1977;3:225-35. [18] Liebman H, Chinowsky M, Valdin J, et al. Increased fibrinolysis and amyloidosis*. Arch*

[19] Takahashi H, Koike T, Yoshida N, et al. Excessive fibrinolysis in suspected amyloidosis:

[20] Liebman HA, Crfagno MK, Weitz IC, et al. Excessive fibrinolysis in amyloidosis

[21] Desai HV, Aronow WS, Peterson SJ, Frishman WH. Cardiac amyloidosis: Approaches to

[22] Koyama J, Falk RH. Prognostic significance of strain Doppler imaging in light-chain

[23] Dispenzieri A, Gertz MA, Kyle RA, et al. Serum cardiac troponins and N-terminal pro-

[24] Kumar S, Dispenzieri A, Gertz MA. High dose melphalan versus melphalan plus

[25] Dispenzieri A, Lacy MQ, Zeldenrust SR, et al. The activity of lenalidomide with or

[26] Cueto-Garcia L, Tajik AJ, Kyle RA, et al. Serial echocardiographic observations in

[28] Selvanaygam JB, Hawkins PN, Paul B, Myerson SG, Neubauer S. Evaluation and

[29] Kothari SS, Ramakrishnan S, Bahl VK. Cardiac Amyloidosis- An Update. *Indian Heart J.*

[31] Koyama J, Ray-Sequin PA, Falk RH. Longitudinal myocardial function assessed by

[33] Sueyoshi E, Sakamoto I, Okimoto T, Hayashi K, Tanaka K, Toda G. Cardiac amyloidosis:

[34] Cheng AS, Banning AP, Mitchell AR, Neubauer S, Selvanayagam JB. Cardiac changes in

contrast-enhanced MRI. *Cardiovasc Intervent Radiol.* 2006;29:710-2.

with AL (primary) Cardiac amyloidosis. *Circulation.* 2003;107:2446-2452. [32] Maceira Am, Joshi J, Prasad SK, et al. Cardiovascular Magnetic resonance in cardiac

dexamethasone for AL amyloidosis. *N Engl J Med*. 2008;358:91.

with Al (primary) amyloidosis. *Am J Cardiol.* 2002;89:1067-71.

[30] Simons M. Amyloid cardiomyopathy in Updateonline 12.3

amyloidosis. *Circulation*. 2005;111:186-193.

factor fragment in plasma. *AM J Hematol.* 1986;23(2):153-66.

diagnosis and management. *Cardiol Rev*. 2010;18:1-11.

amyloidosis. *JACC Cardiovasc Imaging*. 2010;3:333-342.

demonstration of plasmin-alpha 2-plasmin inhibitor complex and von Willebrand

associated with elevated plasma single-chain urokinase. *Am J Clin Pathol*. 1992;

brain natriuretic peptide: A staging system for primary systemic amyloidosis. *J Clin*

without dexamethasone in patients with prmary systemic amyloidosis. *Blood*. 2007;

patients with primary systemic amyloidosis: an introduction to the concept of early (asymptomatic) amyloid infiltration of the heart. *Mayo Clin Proc.* 1984;59:589-97. [27] Koyama J, Ray-Sequin PA, Davidoff R, et al. Usefulness of pulsed tissue Doppler

imaging for evaluating systolic and diastolic left ventricular function in patients

management of the cardiac amylodosis. *J Am Coll Cardiol.* 2007;50:2101-10

tissue velocity, strain, and strain rate tissue Doppler Echocardiography in patients

typical imaging findings and diffuse myocardial damage demonstrated by delayed

systemic amyloidosis: visualisation by magnetic resonance imaging. *Int J Cardiol.*

*Intern Med.* 1983; 143(4):678-82.

98(5):534-541.

[PubMed]

2004;56:197-203.

2006;113:E21-3.

*Oncol*. 2004;22:3751-3757.

109:465-470. Epub 2006 Sep 28.

**5**

**Pulmonary Manifestations of Amyloidosis**

Amyloidosis is a disease characterized by the deposition of abnormal proteins in extracellular tissue. The deposits originate from serum derived or locally produced proteins. (Sipe et al., 2010) The term "amyloid" was first used by Rudolph Virchow in 1854. (Saleiro et al., 2008) According to the Nomenclature Committee of the International Society of Amyloidosis 2010 recommendations, an amyloid fibril protein must occur in tissue deposits and exhibit affinity for Congo red and green birefringence when viewed by polarization microscopy. Furthermore, the protein must have been unambiguously characterized by protein sequence analysis (DNA sequencing in the case of familial diseases). In this chapter, we will focus on the pulmonary manifestations of amyloid. We will discuss the classification, presentation, symptoms, diagnostic testing and therapeutic options with

Amyloidosis had been classified over the years based on the site of deposition and presence or absence of other diseases. (Thompson & Citron, 1983) The term "Generalized" or "Systemic" had been used to describe deposition in multiple anatomic sites and "localized" used to describe deposition in one anatomic site. The term "secondary" used to describe patients with coexistent disease like multiple myeloma and "primary" for patients with no

Amyloid in the respiratory tract has been classified by authors at The Mayo Clinic as associated with systemic amyloidosis and localized pulmonary disease. (Utz et al., 1996) The most common cause of the respiratory amyloid disease is secondary to systemic AL Amyloidosis which accounts for up to 80% of pulmonary amyloid. (Pitz et al., 2006) Moreover, it has been reported that 88% of patients with systemic amyloid have pulmonary

Amyloidosis localized to the respiratory tract was first recognized by Lesser in 1877. (Lesser, 1877) Amyloidosis at present is best classified by the protein fibrils and then by the location of sites involved clinically. To date, there are 27 known extracellular fibril proteins identified in humans. Table 1 lists some of the common protein subunits. Clinically there are three broad classifications of pulmonary involvement. The amyloid deposition may predominantly

**1. Introduction**

regards to amyloid in the respiratory tract.

such coexistent disease. (Utz et al., 1996)

disease. (Smith et al., 1979)

**2. Classification of pulmonary amyloidosis**

*1Cancer Treatment Centers of America, Eastern Regional Medical Center,*

Mark E. Lund1,2, Priya Bakaya2 and Jeffrey B. Hoag1,2

*2Drexel University College of Medicine,*

*Philadelphia, PA,*

*USA*

### **Pulmonary Manifestations of Amyloidosis**

Mark E. Lund1,2, Priya Bakaya2 and Jeffrey B. Hoag1,2

*1Cancer Treatment Centers of America, Eastern Regional Medical Center, 2Drexel University College of Medicine, Philadelphia, PA, USA*

#### **1. Introduction**

62 Amyloidosis – An Insight to Disease of Systems and Novel Therapies

[51] Dispenzieri A, Gertz MA, Hayman SR, et al. A pilot study of pomalidomide and

[52] Kastritis E, Wechalekar AD, Dimopoulos MA, et al. Bortezomib with or without

[53] Wechalekar AD, Lachmann HJ, Offer M, et al. Efficacy of bortezomib in systemic AL

3854]. *Blood.* 2009;114.

298.

28:1031-1037. Epub 2010 Jan 19.

dexamethasone in previously treated light chain amyloidosis patients [abstract

dexamethasone in primary systemic (light-chain) amyloidosis. *J Clin Oncol* 2010;

amyloidosis with relapsed/refractory clonal disease. *Haematologica.* 2008;93:295-

Amyloidosis is a disease characterized by the deposition of abnormal proteins in extracellular tissue. The deposits originate from serum derived or locally produced proteins. (Sipe et al., 2010) The term "amyloid" was first used by Rudolph Virchow in 1854. (Saleiro et al., 2008) According to the Nomenclature Committee of the International Society of Amyloidosis 2010 recommendations, an amyloid fibril protein must occur in tissue deposits and exhibit affinity for Congo red and green birefringence when viewed by polarization microscopy. Furthermore, the protein must have been unambiguously characterized by protein sequence analysis (DNA sequencing in the case of familial diseases). In this chapter, we will focus on the pulmonary manifestations of amyloid. We will discuss the classification, presentation, symptoms, diagnostic testing and therapeutic options with regards to amyloid in the respiratory tract.

Amyloidosis had been classified over the years based on the site of deposition and presence or absence of other diseases. (Thompson & Citron, 1983) The term "Generalized" or "Systemic" had been used to describe deposition in multiple anatomic sites and "localized" used to describe deposition in one anatomic site. The term "secondary" used to describe patients with coexistent disease like multiple myeloma and "primary" for patients with no such coexistent disease. (Utz et al., 1996)

#### **2. Classification of pulmonary amyloidosis**

Amyloid in the respiratory tract has been classified by authors at The Mayo Clinic as associated with systemic amyloidosis and localized pulmonary disease. (Utz et al., 1996) The most common cause of the respiratory amyloid disease is secondary to systemic AL Amyloidosis which accounts for up to 80% of pulmonary amyloid. (Pitz et al., 2006) Moreover, it has been reported that 88% of patients with systemic amyloid have pulmonary disease. (Smith et al., 1979)

Amyloidosis localized to the respiratory tract was first recognized by Lesser in 1877. (Lesser, 1877) Amyloidosis at present is best classified by the protein fibrils and then by the location of sites involved clinically. To date, there are 27 known extracellular fibril proteins identified in humans. Table 1 lists some of the common protein subunits. Clinically there are three broad classifications of pulmonary involvement. The amyloid deposition may predominantly

Pulmonary Manifestations of Amyloidosis 65

Pulmonary nodules of amyloid deposits can be found in the larynx, tracheobronchial tree and lung parenchyma. Discrete nodular deposits in the larynx were described in 1919 (New, 1919). Tracheobronchial amyloidosis is characterized by deposits in the trachea and large bronchi. This is the most common form of primary pulmonary amyloidosis. (Sugihara et al., 2006) Isolated tracheal disease is very rare with less than 20 cases reported in the literature as of 2006. (Sharma & Katlic, 2006) It typically presents in the fifth and sixth decade of life and is slightly more common in females than males. (Berk et al., 2002) As previously mentioned, tracheobronchial amyloid deposition can occur in two forms: nodular or unifocal disease and diffuse submucosal disease. Tracheobronchial amyloidosis has been associated with tracheobronchopathia osteochondroplastica (TBO) by some authors. (Jones & Chatterji, 1977) Tracheobronchopathia osteochondroplastica is a disorder characterized by the deposition of calcified or cartilaginous submucosal nodules in the airways. (Capizzi et al., 2000) The uncertainty is related to the fact that most patients with TBO do not show

In a retrospective review of a series at The Mayo Clinic of 17 patients with biopsy proven tracheobronchial amyloidosis concluded that this form of pulmonary amyloid appeared to be a type of localized amyloid, with protein fibril deposition only present in the tracheobronchial tree. (Utz et al., 1996) This form is quite rare with less than 150 cases published in the medical literature. Although tracheobronchial amyloidosis often follows a relatively stable course, it can present with significant morbidity in patients with extensive airway involvement. It may require repeated therapeutic bronchoscopies in an attempt to prevent progression of airway involvement. Three patterns of airway involvement have been described by Berk et al: (1) proximal, (2) mid or main bronchial, and (3) distal disease. (Berk et al., 2002) Although tracheobronchial amyloidosis is most commonly caused by the AL form of amyloid fibril deposition, AA amyloidosis has also been reported in a case of tracheobronchial amyloidosis complicating mediastinal fibrosis. (Hoag & Yung, 2008)

Diffuse amyloid deposition in the lung parenchyma is usually associated with systemic AL amyloidosis. It is characterized by widespread amyloid deposition involving small vessels and the interstitium. There is little association between the extent of amyloid deposition in the lung and level of functional compromise. A Mayo clinic series included 35 patients who had pulmonary involvement with primary systemic amyloidosis. Celli and coauthors reported case series of 12 patients with AL lung disease, of which only 1 patient his clinical outcome dictated by his pulmonary involvement. (Celli, 1978) Cordier and colleagues reported that only 10% of patient deaths were due to AL lung disease in their series. (Cordier, 1986) Pathologists at John Hopkins have examined the association between cardiac and pulmonary amyloid. (Smith et al., 1979) They found that all patients with pulmonary amyloid deposition had cardiac amyloid disease. They concluded that histologic and clinical pulmonary disease in AL patients was principally a marker of severe cardiac infiltration.

Amyloid nodules in the lung parenchyma are usually incidental findings on chest radiographs and usually need to be differentiated from neoplastic lesions. These nodules are typically located peripherally or subpleurally, and they can also be bilateral in some cases. If

**2.1 Tracheobronchial amyloidosis**

**2.2 Diffuse interstitial amyloid**

**2.3 Nodular amyloidosis**

evidence of amyloid deposition. (Mimori et al., 1998)

involve the tracheobronchial tree with nodules or submucosal infiltration. There can also be predominant interstitial localization. A third presentation is with single or multiple pulmonary parenchymal nodular deposits. A combination of radiographic and bronchoscopic studies provides this classification of pulmonary amyloidosis. Interestingly, it is uncommon for interstitial and tracheobronchial involvement to develop in the same patient.

Table 1. Classification of Pulmonary Amyloidosis with Commonly Encountered Symptoms, Radiographic Findings, and Treatment Modalities

involve the tracheobronchial tree with nodules or submucosal infiltration. There can also be predominant interstitial localization. A third presentation is with single or multiple pulmonary parenchymal nodular deposits. A combination of radiographic and bronchoscopic studies provides this classification of pulmonary amyloidosis. Interestingly, it is uncommon for interstitial and tracheobronchial involvement to develop in the same

Symptoms Imaging Treatment

Round nodules with sharp margins, subpleural and peripheral, may be cavitary, can be PET avid

Tracheal and bronchial wall thickening, postobstructive pneumonia, atelectasis

Interlobular septal thickening, traction bronchiectasis

Extrathoracic nodes more common, often calcify with an eggshell or popcorn pattern

Opacity on CXR Pleural studing on

CT

Table 1. Classification of Pulmonary Amyloidosis with Commonly Encountered Symptoms,

Observation Local treatment Bronchoscopic (if in larynx) Lobectomy (very rarely)

Observation Local treatment with laser therapy External Beam Radiation Surgery (rarely)

Usually requires systemic treatment with chemotherapy and/or stem cell transplant

Observation Bronchoscopic (Stenting) Surgical (rarely)

Thoracentesis Chest tube PleurX catheter Chemical or Mechanical pleurodesis

patient.

Tracheobronchial

Diffuse Alveolar-Septal

Pleural Effusion

Classification Amyloid

Protein Fibril Type

Nodular AL Incidental

AL, Rare AA

AL, AA, ATTR

Adenopathy AL Incidental

Finding Cough Dyspnea

Cough Dyspnea Hemoptysis

Cough Dyspnea Lethargy

Finding Compression of the airway Wheezing Cough Dyspnea

cough, lethargy

AL Dyspnea,

Radiographic Findings, and Treatment Modalities

#### **2.1 Tracheobronchial amyloidosis**

Pulmonary nodules of amyloid deposits can be found in the larynx, tracheobronchial tree and lung parenchyma. Discrete nodular deposits in the larynx were described in 1919 (New, 1919). Tracheobronchial amyloidosis is characterized by deposits in the trachea and large bronchi. This is the most common form of primary pulmonary amyloidosis. (Sugihara et al., 2006) Isolated tracheal disease is very rare with less than 20 cases reported in the literature as of 2006. (Sharma & Katlic, 2006) It typically presents in the fifth and sixth decade of life and is slightly more common in females than males. (Berk et al., 2002) As previously mentioned, tracheobronchial amyloid deposition can occur in two forms: nodular or unifocal disease and diffuse submucosal disease. Tracheobronchial amyloidosis has been associated with tracheobronchopathia osteochondroplastica (TBO) by some authors. (Jones & Chatterji, 1977) Tracheobronchopathia osteochondroplastica is a disorder characterized by the deposition of calcified or cartilaginous submucosal nodules in the airways. (Capizzi et al., 2000) The uncertainty is related to the fact that most patients with TBO do not show evidence of amyloid deposition. (Mimori et al., 1998)

In a retrospective review of a series at The Mayo Clinic of 17 patients with biopsy proven tracheobronchial amyloidosis concluded that this form of pulmonary amyloid appeared to be a type of localized amyloid, with protein fibril deposition only present in the tracheobronchial tree. (Utz et al., 1996) This form is quite rare with less than 150 cases published in the medical literature. Although tracheobronchial amyloidosis often follows a relatively stable course, it can present with significant morbidity in patients with extensive airway involvement. It may require repeated therapeutic bronchoscopies in an attempt to prevent progression of airway involvement. Three patterns of airway involvement have been described by Berk et al: (1) proximal, (2) mid or main bronchial, and (3) distal disease. (Berk et al., 2002) Although tracheobronchial amyloidosis is most commonly caused by the AL form of amyloid fibril deposition, AA amyloidosis has also been reported in a case of tracheobronchial amyloidosis complicating mediastinal fibrosis. (Hoag & Yung, 2008)

#### **2.2 Diffuse interstitial amyloid**

Diffuse amyloid deposition in the lung parenchyma is usually associated with systemic AL amyloidosis. It is characterized by widespread amyloid deposition involving small vessels and the interstitium. There is little association between the extent of amyloid deposition in the lung and level of functional compromise. A Mayo clinic series included 35 patients who had pulmonary involvement with primary systemic amyloidosis. Celli and coauthors reported case series of 12 patients with AL lung disease, of which only 1 patient his clinical outcome dictated by his pulmonary involvement. (Celli, 1978) Cordier and colleagues reported that only 10% of patient deaths were due to AL lung disease in their series. (Cordier, 1986) Pathologists at John Hopkins have examined the association between cardiac and pulmonary amyloid. (Smith et al., 1979) They found that all patients with pulmonary amyloid deposition had cardiac amyloid disease. They concluded that histologic and clinical pulmonary disease in AL patients was principally a marker of severe cardiac infiltration.

#### **2.3 Nodular amyloidosis**

Amyloid nodules in the lung parenchyma are usually incidental findings on chest radiographs and usually need to be differentiated from neoplastic lesions. These nodules are typically located peripherally or subpleurally, and they can also be bilateral in some cases. If

Pulmonary Manifestations of Amyloidosis 67

Pulmonary amyloid may present with symptoms or may be found as an incidental finding on thoracic imaging. Patients present to pulmonologists in a number of ways: patients with systemic amyloidosis may present with respiratory symptoms; localized forms of amyloid may be detected incidentally on imaging or biopsy; and patients may present with respiratory symptoms that warrant pulmonary workup leading to the diagnosis of amyloidosis. (Lachmann & Hawkins, 2006; Sipe et al., 2010; Thompson & Citron, 1983) Tracheobronchial amyloidosis usually presents in fifth decade of life with symptoms of cough, dyspnea, wheezing, and hemoptysis. (Berk et al., 2002) In addition, hoarseness is

The most common symptoms of amyloid involvement with the respiratory system are cough, wheezing, dyspnea on exertion, and hemoptysis; none of which are uniquely specific to the diagnosis of pulmonary amyloidosis. One elderly male presented with diffuse alveolar hemorrhage. (Shenin et al., 2010) Amyloid nodules in the lung parenchyma are most often asymptomatic and are usually incidental findings on imaging studies; however, they sometimes can produce space occupying effects, most often if they limit either air or blood flow in the lungs. These nodules tend to calcify, and sometimes they may cavitate. They can cause lumenal narrowing of the airways and thus may lead to post obstructive atelectasis and/or pneumonia. Diffuse alveolar-septal amyloidosis related to systemic AL disease may present with symptoms of dyspnea or even more frightening symptoms of hemoptysis due to dissection of pulmonary arteries infiltrated by amyloid protein deposits (Cools et al., 1996; Road et al., 1985) or massive pulmonary embolism related to thrombosis of inferior vena cava. Mediastinal or hilar adenopathy is less common than extrathoracic adenopathy in patients with systemic AL disease. However, these patients may sometimes present with cervical nodes that may enlarge, become tender or recede in periods mimicking sarcoidosis. Pleural effusions in patients with amyloidosis will cause dyspnea and may at

When systemic amyloid disease is present, consideration for pulmonary evaluation for amyloid involvement should be based upon symptoms and clinical suspicion. The delay from time of presentation to the diagnosis of pulmonary involvement has been up to 17 months in some series. (O'Regan et al., 2000) In a patient with systemic amyloidosis, exercise limitation or cough should prompt an evaluation for lung involvement. In the setting of isolated pulmonary disease, amyloid is often low on the differential diagnosis. Pulmonary amyloidosis can be evaluated with plain films, computed tomography, bronchoscopy and pulmonary function testing. Figure 1 depicts an algorithm of a diagnostic approach for

As previously described, the nodular form amyloidosis is most often an incidental finding on thoracic imaging. The plain chest radiograph can be normal in as many as half of patients with pulmonary nodular amyloidosis. (O'Regan et al., 2000) Amyloid nodules are generally described as rounded with sharp, discreet margins, and they are occasionally cavitary

**4. The clinical presentation of pulmonary amyloidosis**

times require repeated thoracenteses to relieve symptoms.

**5. Diagnosis of pulmonary amyloid 5.1 General considerations for diagnosis**

patients with systemic amyloidosis.

**5.2 Radiographic evaluation**

frequently reported.

these lesions are located more centrally, airflow limitation may occur leading to symptomatic presentations. Moreover, these amyloid lesions may cavitate. (Cordier et al., 1986) AL amyloidosis is a well recognized complication of Sjogren's syndrome and is most often associated with localized nodular pulmonary amyloidosis. An association with benign hypergammaglobulinemic purpura has been reported in one patient. (Bignold et al., 1980)

#### **3. Other manifestations of thoracic amyloidosis**

#### **3.1 Adenopathy**

Hilar and mediastinal adenopathy are commonly associated with the AL form of systemic amyloidosis, and rarely adenopathy is present in localized pulmonary disease. (Lachmann & Hawkins, 2006) The majority of patients with amyloid-associated lymphadenopathy have detectable circulating monoclonal immunoglobulin which are typically associated with very low grade lymphoplasmacytic lymphoma or Waldenstrom's macroglobulinemia. (Plockinger et al., 1993) Plockinger et al. reported a case of nodular amyloidosis of hilar lymph nodes with no evidence of a paraprotein immunoglobulins or light chains present on immunoelectrophoretic analyses of the plasma and urine. Amyloid infiltrated nodes frequently calcify in a "popcorn" pattern or an "eggshell" conformation. (Gross, 1981)

#### **3.2 Pleural effusions**

Pleural effusions have also been reported in patients with systemic amyloid disease. The incidence of pleural effusion in amyloidosis is not known. Effusions can be unilateral or bilateral, and they can present with either exudative or transudative chemistries. (Berk et al., 2003) One of the first reports of amyloid-associated pleural effusion included five patients by Kavuru and colleagues. (Kavuru et al., 1990) These authors found that pleural effusions in the majority of their patients (60%in their series) were believed related to either congestive heart disease or nephrotic syndrome, and only 40% of pleural effusions were "idiopathic". Despite this they found that even those patients with transudative effusions had pleural infiltration with amyloid on biopsy. The Amyloid Program at Boston University reported their 7 year experience with 636 patients. (Berk et al., 2003) Thirty five patients in this series (6%) had large recurrent pleural effusions along with another 10-15% with less significant effusions. They compared patients with primary systemic amyloidosis and coincident cardiomyopathy without pleural effusions and patients with recurrent large pleural effusions. They noted exudative chemistries in pleural fluid of 37% of their patients along with chylothorax in another two patients. In contrast to the conclusions drawn by Kavuru et al., their hypothesis was that direct amyloid infiltration of the parietal pleural was responsible for large recurrent pleural effusions. Their claim was supported by thoracoscopic descriptions of pleural studding and histologic evidence of amyloid infiltrating pleural surfaces on biopsy. (Kavuru et al., 1990) After extensive comparisons between the two groups using echocardiography, they concluded that cardiac dysfunction alone was not sufficient to produce the pleural effusions in their cohort. The paucity of chylous effusions in patients with AL amyloid despite the propensity of mediastinal lymphadenopathy points towards direct amyloid infiltration of lymph nodes by amyloid as the cause of chylothorax as opposed to a compression of lymph nodes. Although uncommon, pleural effusions in patients with primary pulmonary amyloidosis can be hemorrhagic. (BoydKing et al., 2009)

these lesions are located more centrally, airflow limitation may occur leading to symptomatic presentations. Moreover, these amyloid lesions may cavitate. (Cordier et al., 1986) AL amyloidosis is a well recognized complication of Sjogren's syndrome and is most often associated with localized nodular pulmonary amyloidosis. An association with benign hypergammaglobulinemic purpura has been reported in one patient. (Bignold et al., 1980)

Hilar and mediastinal adenopathy are commonly associated with the AL form of systemic amyloidosis, and rarely adenopathy is present in localized pulmonary disease. (Lachmann & Hawkins, 2006) The majority of patients with amyloid-associated lymphadenopathy have detectable circulating monoclonal immunoglobulin which are typically associated with very low grade lymphoplasmacytic lymphoma or Waldenstrom's macroglobulinemia. (Plockinger et al., 1993) Plockinger et al. reported a case of nodular amyloidosis of hilar lymph nodes with no evidence of a paraprotein immunoglobulins or light chains present on immunoelectrophoretic analyses of the plasma and urine. Amyloid infiltrated nodes frequently calcify in a "popcorn" pattern or an "eggshell" conformation. (Gross, 1981)

Pleural effusions have also been reported in patients with systemic amyloid disease. The incidence of pleural effusion in amyloidosis is not known. Effusions can be unilateral or bilateral, and they can present with either exudative or transudative chemistries. (Berk et al., 2003) One of the first reports of amyloid-associated pleural effusion included five patients by Kavuru and colleagues. (Kavuru et al., 1990) These authors found that pleural effusions in the majority of their patients (60%in their series) were believed related to either congestive heart disease or nephrotic syndrome, and only 40% of pleural effusions were "idiopathic". Despite this they found that even those patients with transudative effusions had pleural infiltration with amyloid on biopsy. The Amyloid Program at Boston University reported their 7 year experience with 636 patients. (Berk et al., 2003) Thirty five patients in this series (6%) had large recurrent pleural effusions along with another 10-15% with less significant effusions. They compared patients with primary systemic amyloidosis and coincident cardiomyopathy without pleural effusions and patients with recurrent large pleural effusions. They noted exudative chemistries in pleural fluid of 37% of their patients along with chylothorax in another two patients. In contrast to the conclusions drawn by Kavuru et al., their hypothesis was that direct amyloid infiltration of the parietal pleural was responsible for large recurrent pleural effusions. Their claim was supported by thoracoscopic descriptions of pleural studding and histologic evidence of amyloid infiltrating pleural surfaces on biopsy. (Kavuru et al., 1990) After extensive comparisons between the two groups using echocardiography, they concluded that cardiac dysfunction alone was not sufficient to produce the pleural effusions in their cohort. The paucity of chylous effusions in patients with AL amyloid despite the propensity of mediastinal lymphadenopathy points towards direct amyloid infiltration of lymph nodes by amyloid as the cause of chylothorax as opposed to a compression of lymph nodes. Although uncommon, pleural effusions in patients with primary pulmonary amyloidosis can be

**3. Other manifestations of thoracic amyloidosis**

**3.1 Adenopathy**

**3.2 Pleural effusions**

hemorrhagic. (BoydKing et al., 2009)

#### **4. The clinical presentation of pulmonary amyloidosis**

Pulmonary amyloid may present with symptoms or may be found as an incidental finding on thoracic imaging. Patients present to pulmonologists in a number of ways: patients with systemic amyloidosis may present with respiratory symptoms; localized forms of amyloid may be detected incidentally on imaging or biopsy; and patients may present with respiratory symptoms that warrant pulmonary workup leading to the diagnosis of amyloidosis. (Lachmann & Hawkins, 2006; Sipe et al., 2010; Thompson & Citron, 1983) Tracheobronchial amyloidosis usually presents in fifth decade of life with symptoms of cough, dyspnea, wheezing, and hemoptysis. (Berk et al., 2002) In addition, hoarseness is frequently reported.

The most common symptoms of amyloid involvement with the respiratory system are cough, wheezing, dyspnea on exertion, and hemoptysis; none of which are uniquely specific to the diagnosis of pulmonary amyloidosis. One elderly male presented with diffuse alveolar hemorrhage. (Shenin et al., 2010) Amyloid nodules in the lung parenchyma are most often asymptomatic and are usually incidental findings on imaging studies; however, they sometimes can produce space occupying effects, most often if they limit either air or blood flow in the lungs. These nodules tend to calcify, and sometimes they may cavitate. They can cause lumenal narrowing of the airways and thus may lead to post obstructive atelectasis and/or pneumonia. Diffuse alveolar-septal amyloidosis related to systemic AL disease may present with symptoms of dyspnea or even more frightening symptoms of hemoptysis due to dissection of pulmonary arteries infiltrated by amyloid protein deposits (Cools et al., 1996; Road et al., 1985) or massive pulmonary embolism related to thrombosis of inferior vena cava. Mediastinal or hilar adenopathy is less common than extrathoracic adenopathy in patients with systemic AL disease. However, these patients may sometimes present with cervical nodes that may enlarge, become tender or recede in periods mimicking sarcoidosis. Pleural effusions in patients with amyloidosis will cause dyspnea and may at times require repeated thoracenteses to relieve symptoms.

#### **5. Diagnosis of pulmonary amyloid**

#### **5.1 General considerations for diagnosis**

When systemic amyloid disease is present, consideration for pulmonary evaluation for amyloid involvement should be based upon symptoms and clinical suspicion. The delay from time of presentation to the diagnosis of pulmonary involvement has been up to 17 months in some series. (O'Regan et al., 2000) In a patient with systemic amyloidosis, exercise limitation or cough should prompt an evaluation for lung involvement. In the setting of isolated pulmonary disease, amyloid is often low on the differential diagnosis. Pulmonary amyloidosis can be evaluated with plain films, computed tomography, bronchoscopy and pulmonary function testing. Figure 1 depicts an algorithm of a diagnostic approach for patients with systemic amyloidosis.

#### **5.2 Radiographic evaluation**

As previously described, the nodular form amyloidosis is most often an incidental finding on thoracic imaging. The plain chest radiograph can be normal in as many as half of patients with pulmonary nodular amyloidosis. (O'Regan et al., 2000) Amyloid nodules are generally described as rounded with sharp, discreet margins, and they are occasionally cavitary

Pulmonary Manifestations of Amyloidosis 69

polychondritis, tracheobronchial tuberculosis, pulmonary hyalinizing granuloma, tracheobronchopathia osteochondroplastica along with tracheobronchial amyloidosis. (Bhadra et al., 2010; Carter & Patchefsky, 1998; Gibbaoui et al., 2004) Circumferential calcification involving the membranous airway should suggest amyloidosis as other forms

Positron emission tomography (PET) may demonstrate increased uptake of 18F-flourodeoxyglucose (FDG) in patients with nodular amyloidosis. (Currie et al., 2005; Kung et al., 2003; Seo et al., 2010) From the studies of PET with pathology confirming amyloidosis, the standardized uptake value (SUV) ranged from 1.8 to 6.81, suggesting the need for biopsy to exclude malignancy. Coincident pulmonary nodular amyloid and adenocarcinoma has been reported in a patient with systemic AL amyloidosis. (Miyazaki et al., 2011) An uncharacteristic speculated appearance of the nodule in question in this case highlights the need for careful review of thoracic imaging in conjunction with a high index of suspicion. Coincident carcinoma and amyloid deposits have been described in thyroid

Pulmonary function testing (PFT) in patients with pulmonary involvement of amyloidosis is similarly variable due to the variety of presentations. Overall, pulmonary functions can be normal or exhibit obstructive or restrictive disease. When tracheobronchial amyloidosis is present, the most common finding is airflow limitation as demonstrated by a reduced ratio of forced expiratory volume in the 1st second (FEV1) to forced vital capacity (FVC) of less than 70%. The severity is dependent on the degree and location of amyloid deposition. In as series of patients with tracheobronchial amyloidosis from Boston, those with proximal disease tended to have more severe airflow limitation than those with more distal disease, although both groups had significant air trapping present with elevated residual volumes. (O'Regan et al., 2000) With the nodular form of pulmonary amyloidosis, direct compression of central airways may lead to obstructive patterns on PFTs. Evidence of a fixed upper airway obstruction not only suggests central airway disease but also portends a higher

Restriction may be present as would be expected in patients with significant pleural effusion, or in very severe cases of diffuse alveolar-septal disease. Diffusing capacity for

The bronchoscopic findings of pulmonary amyloidosis vary with the classification of disease. In patients with interstitial or pulmonary nodular disease the endobronchial appearance on bronchoscopy may be entirely normal. In contradistinction to the interstitial variety, those with tracheobronchial amyloidosis commonly have significant visible pathology. The lesions of tracheobronchial amyloid can be nodular, sessile, or polyploidy. The sessile lesions have been described as hard yellow plaques that may be expansive or thinner longitudinal irregularities. Cobblestoning of the mucosa may be present. The sessile lesions may cause significant airway stenosis, and these regions of stenosis can be diffuse. The nodules or polypoid lesions may suggest endolumenal carcinoma to both the experienced and inexperienced bronchoscopist. These nodules are usually firm, non mobile, and covered with hypervascular mucosa. Because of the hypervascularity in conjunction with the infiltrated submucosa, the endobronchial lesions in tracheobronchial amyloidosis

probability of progressive central obstructive disease. (Bhadra et al., 2010)

of airway thickening do not involve this portion.

medullary carcinoma. (Westermark et al., 2007)

carbon monoxide is most often preserved.

**5.4 Diagnostic bronchoscopic findings**

**5.3 Pulmonary function testing**

Fig. 1. Flow diagram of a decision pathway for the evaluation and treatment of respiratory amyloidosis

in appearance. One case report found that a lesion of amyloid measured 282 Hounsfield units, which is significantly less dense than blood. (M'Rad et al., 1988) Pulmonary nodular amyloidosis are predominantly subpleural and peripheral with a random distribution.

Imaging of patients with diffuse alveolar-septal disease may show infiltrative opacities on chest plain radiographs. In systemic amyloidosis, diffuse interstitial disease is most common. This may be reticular nodular on computed tomography imaging. Interlobular septal thickening and diffuse irregular lines with some honeycombing can be seen at the lung bases peripherally, and traction bronchiectasis can also be seen. Some report that diffuse cystic changes may predominate. (Wink, 2003)

Tracheal and bronchial wall thickening or discrete tumor masses may be a CT finding of tracheobronchial amyloid. The presence of multifocal masses with calcification should prompt a differential diagnosis of carcinoma, Wegener's Granulomatosis, relapsing

Diagnosis of Amyloidosis

Systemic or Localized Disease

Fig. 1. Flow diagram of a decision pathway for the evaluation and treatment of respiratory

in appearance. One case report found that a lesion of amyloid measured 282 Hounsfield units, which is significantly less dense than blood. (M'Rad et al., 1988) Pulmonary nodular amyloidosis are predominantly subpleural and peripheral with a random distribution. Imaging of patients with diffuse alveolar-septal disease may show infiltrative opacities on chest plain radiographs. In systemic amyloidosis, diffuse interstitial disease is most common. This may be reticular nodular on computed tomography imaging. Interlobular septal thickening and diffuse irregular lines with some honeycombing can be seen at the lung bases peripherally, and traction bronchiectasis can also be seen. Some report that

Tracheal and bronchial wall thickening or discrete tumor masses may be a CT finding of tracheobronchial amyloid. The presence of multifocal masses with calcification should prompt a differential diagnosis of carcinoma, Wegener's Granulomatosis, relapsing

Systemic Disease

● I-SAP scintigraphy ●24 hr urinaryprotein ●Liver Function Testing ●Electrocardiogram ●Echocardiogram

123

Systemic Therapy

Chamotherapy Stem Cell Transplantation

+Chemothrerapy

 Localized to Respiratory Tract

●Chest Radiography ●Computed Tomography ●Pulmonary Function Testing

 Localized Treatment ●Bronchoscopic ●External Beam Radiation

diffuse cystic changes may predominate. (Wink, 2003)

●Bronchoscopy

 Pathologic and Immunohistochemical analysis

 Confirmation with Congo Redstaining and polarizing microscopy

Observation

amyloidosis

polychondritis, tracheobronchial tuberculosis, pulmonary hyalinizing granuloma, tracheobronchopathia osteochondroplastica along with tracheobronchial amyloidosis. (Bhadra et al., 2010; Carter & Patchefsky, 1998; Gibbaoui et al., 2004) Circumferential calcification involving the membranous airway should suggest amyloidosis as other forms of airway thickening do not involve this portion.

Positron emission tomography (PET) may demonstrate increased uptake of 18F-flourodeoxyglucose (FDG) in patients with nodular amyloidosis. (Currie et al., 2005; Kung et al., 2003; Seo et al., 2010) From the studies of PET with pathology confirming amyloidosis, the standardized uptake value (SUV) ranged from 1.8 to 6.81, suggesting the need for biopsy to exclude malignancy. Coincident pulmonary nodular amyloid and adenocarcinoma has been reported in a patient with systemic AL amyloidosis. (Miyazaki et al., 2011) An uncharacteristic speculated appearance of the nodule in question in this case highlights the need for careful review of thoracic imaging in conjunction with a high index of suspicion. Coincident carcinoma and amyloid deposits have been described in thyroid medullary carcinoma. (Westermark et al., 2007)

#### **5.3 Pulmonary function testing**

Pulmonary function testing (PFT) in patients with pulmonary involvement of amyloidosis is similarly variable due to the variety of presentations. Overall, pulmonary functions can be normal or exhibit obstructive or restrictive disease. When tracheobronchial amyloidosis is present, the most common finding is airflow limitation as demonstrated by a reduced ratio of forced expiratory volume in the 1st second (FEV1) to forced vital capacity (FVC) of less than 70%. The severity is dependent on the degree and location of amyloid deposition. In as series of patients with tracheobronchial amyloidosis from Boston, those with proximal disease tended to have more severe airflow limitation than those with more distal disease, although both groups had significant air trapping present with elevated residual volumes. (O'Regan et al., 2000) With the nodular form of pulmonary amyloidosis, direct compression of central airways may lead to obstructive patterns on PFTs. Evidence of a fixed upper airway obstruction not only suggests central airway disease but also portends a higher probability of progressive central obstructive disease. (Bhadra et al., 2010)

Restriction may be present as would be expected in patients with significant pleural effusion, or in very severe cases of diffuse alveolar-septal disease. Diffusing capacity for carbon monoxide is most often preserved.

#### **5.4 Diagnostic bronchoscopic findings**

The bronchoscopic findings of pulmonary amyloidosis vary with the classification of disease. In patients with interstitial or pulmonary nodular disease the endobronchial appearance on bronchoscopy may be entirely normal. In contradistinction to the interstitial variety, those with tracheobronchial amyloidosis commonly have significant visible pathology. The lesions of tracheobronchial amyloid can be nodular, sessile, or polyploidy. The sessile lesions have been described as hard yellow plaques that may be expansive or thinner longitudinal irregularities. Cobblestoning of the mucosa may be present. The sessile lesions may cause significant airway stenosis, and these regions of stenosis can be diffuse.

The nodules or polypoid lesions may suggest endolumenal carcinoma to both the experienced and inexperienced bronchoscopist. These nodules are usually firm, non mobile, and covered with hypervascular mucosa. Because of the hypervascularity in conjunction with the infiltrated submucosa, the endobronchial lesions in tracheobronchial amyloidosis

Pulmonary Manifestations of Amyloidosis 71

demonstrated by decreasing FEV1. Radiographic imaging may show areas of atelectasis or hyperinflation due to progression of obstructing endobronchial disease. Due to the relative

The outcome of patients with pulmonary amyloidosis reported in the literature is variable. From a series of 21 patients with primary pulmonary amyloidosis, the median survival was 16 months and no patients were alive at five years. (Utz et al., 1996) The survival of this cohort was much shorter than would be expected in comparison to patients with systemic amyloidosis without pulmonary involvement. As some have suggested that respiratory failure is rarely the direct cause of death in patients with amyloidosis, it seems that its presence is a marker of more severe disease. In contrast, in another series over 15 years with 10 patients reported survival averaged 8 years. (O'Regan et al., 2000) In this series death was

Due to the variability of amyloid involvement in the pulmonary system, the treatment for respiratory amyloidosis ranges from observation to bronchoscopic or surgical resection based on severity and symptomatology. Management decisions are mostly based on an individual basis. Systemic amyloidosis can be treated with chemotherapy while localized

Infiltrative and systemic disease has been amenable to chemotherapy with oral melphalan and prednisone. (Kyle et al., 1997) A prospective study done at The Mayo Clinic in patients with systemic amyloidosis showed that combination therapy with melphalan, prednisone and colchicine or melphalan and prednisone resulted in prolonged survival compared to colchicine alone. The median duration of survival after randomization was 8.5 months in the colchicine group, 18 months in the group assigned to melphalan and prednisone, and 17 months in the group assigned to melphalan, prednisone, and colchicine (p<0.001). (Wechalekar et al., 2008) The National Amyloidosis Center in The United Kingdom has divided its treatment strategies for systemic AL disease into low dose, intermediate and high dose regimens. They recommend one of the intermediate dose regimens involving riskadapted CTD (cyclophosphamide, thalidomide and dexamethasone) or oral mel-dex (melphalan, dexamethasone) as first line therapy, and autologous stem cell transplantation as an alternative treatment. (Cohen et al., 2007) Stem cell transplantation has been attempted with variable success in more severe disease. Recent phase 2 trials in systemic amyloidosis showed that risk-adapted Stem Cell Transplant with adjuvant thalidomide and dexamethasone is feasible and results in low treatment related mortality and high hematological and organ response rates in patients. (Cohen et al., 2007) There are several ongoing trials at amyloid centers in the United States and internationally, and physicians are encouraged to refer their patients to be enrolled in these studies in order to determine best

In light of poor responses of tracheobronchial amyloid to systemic therapy, the majority of these patients will require endobronchial therapy. Bronchoscopic therapies remain the key

rarity of this condition the most appropriate method of surveillance is not known.

**7. Management of pulmonary amyloidosis**

predominantly caused by respiratory complications.

forms are typically treated with local interventions.

**7.1 Chemotherapy**

practices.

**7.2 Therapeutic bronchoscopy**

to airway management in these patients.

are quite friable, and bleed easily with minimal bronchoscopic contact. (Hoag & Yung, 2008) In contradistinction to tracheobronchopathia osteochondroplastica (TBO), the membranous trachea and mainstem airways are not spared. Tracheobronchial amyloidosis was associated with TBO in 22% in one series. (Piazza et al., 2003)

Ultimately, the diagnosis of pulmonary amyloidosis requires histologic confirmation. An excellent overview of the pathologic features of pulmonary amyloidosis has been published. (Katzenstein, 1997) Congo red staining that produces green birefringence under polarized light remains the gold standard for diagnosis. Classic teaching is that these lesions have a tendency to bleed. An increased risk of hemorrhage during biopsies of amyloidotic tissues may result from increased fragility of involved blood vessels, reduced elasticity of tissues and rarely to an acquired deficiency of clotting factors 9 or 10. So while endolumenal forceps biopsy is required, preparation for potential airway bleeding is advisable. Strange et al. reported on the fatal hemorrhage and air embolism complicating a routine transbronchial biopsy of a patient with pulmonary amyloidosis. (Strange et al., 1987) Treatment with low level Neodymium: Yttrium Aluminum Garnet (Nd:YAG) laser or argon plasma coagulation (APC) can be effective in controlling bleeding from the central airway amyloid lesion. Both approaches offer non contact therapy. Application of electrocautery can create rebleeding by disruption of the coagulum. The non-contact therapies (APC and Nd:YAG Laser) does not disrupt the bleeding site and remove the coagulum created by its application. Pretreatment with endobronchial epinephrine injections into the lesions may decrease the bleeding risk.

Effective biopsy may be obtained by the use of Wang needle or endobronchial forceps. Biopsy of the lesions may be difficult due to calcifications, and small biopsy specimens are open to sampling errors. False positive results also do occur in routine practice, usually as a result of poor Congo red staining. A confirmatory stain with Thioflavine T, which fluoresces yellow-green, may be helpful. (Saleiro et al., 2008) Any bronchoscopic finding suggesting tracheobronchopathia osteochondroplastica should be stained with Congo red due to the similarity of endobronchial appearance. (Bhadra et al., 2010) When the tissue is too calcified or when the operator feels uncomfortable with handling larger volume bleeding open surgical biopsy may be warranted.

Like any tumor mass, malignant or non-malignant, post obstructive pneumonia can develop in pulmonary amyloidosis. Protected brush samples or clean bronchoalveolar lavage for culture should be obtained when there is a high grade stenosis or evidence of mucopurulent drainage.

Once histologic evaluation with Congo red staining has been performed, immunochemistry to determine protein fibril type should be performed. Anatomical and functional evaluation of the various organs involved in systemic amyloidosis should also be performed. (Hawkins et al., 1990) Radiolabeled Serum Amyloid P (SAP) component localizes specifically to amyloid deposits *in vivo* in proportion to the amount of amyloid present and enables diagnosis, quantification and monitoring of amyloid to be performed scintigraphically. (Hazenberg et al., 2007)

#### **6. Follow up of the patient with pulmonary amyloid**

Several non-invasive methods of surveilling the progress of disease include computed tomography imaging and pulmonary function testing, especially serial spirometry. Proximal disease can present as pattern of fixed airway obstruction on flow volume loops, (Lachmann et al., 2006) or progression of disease may be apparent with progression flow limitation as

are quite friable, and bleed easily with minimal bronchoscopic contact. (Hoag & Yung, 2008) In contradistinction to tracheobronchopathia osteochondroplastica (TBO), the membranous trachea and mainstem airways are not spared. Tracheobronchial amyloidosis was associated

Ultimately, the diagnosis of pulmonary amyloidosis requires histologic confirmation. An excellent overview of the pathologic features of pulmonary amyloidosis has been published. (Katzenstein, 1997) Congo red staining that produces green birefringence under polarized light remains the gold standard for diagnosis. Classic teaching is that these lesions have a tendency to bleed. An increased risk of hemorrhage during biopsies of amyloidotic tissues may result from increased fragility of involved blood vessels, reduced elasticity of tissues and rarely to an acquired deficiency of clotting factors 9 or 10. So while endolumenal forceps biopsy is required, preparation for potential airway bleeding is advisable. Strange et al. reported on the fatal hemorrhage and air embolism complicating a routine transbronchial biopsy of a patient with pulmonary amyloidosis. (Strange et al., 1987) Treatment with low level Neodymium: Yttrium Aluminum Garnet (Nd:YAG) laser or argon plasma coagulation (APC) can be effective in controlling bleeding from the central airway amyloid lesion. Both approaches offer non contact therapy. Application of electrocautery can create rebleeding by disruption of the coagulum. The non-contact therapies (APC and Nd:YAG Laser) does not disrupt the bleeding site and remove the coagulum created by its application. Pretreatment with endobronchial epinephrine injections into the lesions may decrease the bleeding risk. Effective biopsy may be obtained by the use of Wang needle or endobronchial forceps. Biopsy of the lesions may be difficult due to calcifications, and small biopsy specimens are open to sampling errors. False positive results also do occur in routine practice, usually as a result of poor Congo red staining. A confirmatory stain with Thioflavine T, which fluoresces yellow-green, may be helpful. (Saleiro et al., 2008) Any bronchoscopic finding suggesting tracheobronchopathia osteochondroplastica should be stained with Congo red due to the similarity of endobronchial appearance. (Bhadra et al., 2010) When the tissue is too calcified or when the operator feels uncomfortable with handling larger volume bleeding open

Like any tumor mass, malignant or non-malignant, post obstructive pneumonia can develop in pulmonary amyloidosis. Protected brush samples or clean bronchoalveolar lavage for culture should be obtained when there is a high grade stenosis or evidence of mucopurulent

Once histologic evaluation with Congo red staining has been performed, immunochemistry to determine protein fibril type should be performed. Anatomical and functional evaluation of the various organs involved in systemic amyloidosis should also be performed. (Hawkins et al., 1990) Radiolabeled Serum Amyloid P (SAP) component localizes specifically to amyloid deposits *in vivo* in proportion to the amount of amyloid present and enables diagnosis, quantification and monitoring of amyloid to be performed scintigraphically.

Several non-invasive methods of surveilling the progress of disease include computed tomography imaging and pulmonary function testing, especially serial spirometry. Proximal disease can present as pattern of fixed airway obstruction on flow volume loops, (Lachmann et al., 2006) or progression of disease may be apparent with progression flow limitation as

with TBO in 22% in one series. (Piazza et al., 2003)

surgical biopsy may be warranted.

drainage.

(Hazenberg et al., 2007)

**6. Follow up of the patient with pulmonary amyloid**

demonstrated by decreasing FEV1. Radiographic imaging may show areas of atelectasis or hyperinflation due to progression of obstructing endobronchial disease. Due to the relative rarity of this condition the most appropriate method of surveillance is not known.

#### **7. Management of pulmonary amyloidosis**

The outcome of patients with pulmonary amyloidosis reported in the literature is variable. From a series of 21 patients with primary pulmonary amyloidosis, the median survival was 16 months and no patients were alive at five years. (Utz et al., 1996) The survival of this cohort was much shorter than would be expected in comparison to patients with systemic amyloidosis without pulmonary involvement. As some have suggested that respiratory failure is rarely the direct cause of death in patients with amyloidosis, it seems that its presence is a marker of more severe disease. In contrast, in another series over 15 years with 10 patients reported survival averaged 8 years. (O'Regan et al., 2000) In this series death was predominantly caused by respiratory complications.

Due to the variability of amyloid involvement in the pulmonary system, the treatment for respiratory amyloidosis ranges from observation to bronchoscopic or surgical resection based on severity and symptomatology. Management decisions are mostly based on an individual basis. Systemic amyloidosis can be treated with chemotherapy while localized forms are typically treated with local interventions.

#### **7.1 Chemotherapy**

Infiltrative and systemic disease has been amenable to chemotherapy with oral melphalan and prednisone. (Kyle et al., 1997) A prospective study done at The Mayo Clinic in patients with systemic amyloidosis showed that combination therapy with melphalan, prednisone and colchicine or melphalan and prednisone resulted in prolonged survival compared to colchicine alone. The median duration of survival after randomization was 8.5 months in the colchicine group, 18 months in the group assigned to melphalan and prednisone, and 17 months in the group assigned to melphalan, prednisone, and colchicine (p<0.001). (Wechalekar et al., 2008) The National Amyloidosis Center in The United Kingdom has divided its treatment strategies for systemic AL disease into low dose, intermediate and high dose regimens. They recommend one of the intermediate dose regimens involving riskadapted CTD (cyclophosphamide, thalidomide and dexamethasone) or oral mel-dex (melphalan, dexamethasone) as first line therapy, and autologous stem cell transplantation as an alternative treatment. (Cohen et al., 2007) Stem cell transplantation has been attempted with variable success in more severe disease. Recent phase 2 trials in systemic amyloidosis showed that risk-adapted Stem Cell Transplant with adjuvant thalidomide and dexamethasone is feasible and results in low treatment related mortality and high hematological and organ response rates in patients. (Cohen et al., 2007) There are several ongoing trials at amyloid centers in the United States and internationally, and physicians are encouraged to refer their patients to be enrolled in these studies in order to determine best practices.

#### **7.2 Therapeutic bronchoscopy**

In light of poor responses of tracheobronchial amyloid to systemic therapy, the majority of these patients will require endobronchial therapy. Bronchoscopic therapies remain the key to airway management in these patients.

Pulmonary Manifestations of Amyloidosis 73

less friable and erythematous airway post radiation on a subsequent bronchoscopy. They treated the patient based on the hypothesis that plasma cells that secrete amyloidogenic protein are radiosensitive. Other hypotheses proffered include radiation injures cells other than plasma cells that may secrete amyloidogenic proteins, and free radicals generated by radiation may modify and enhance the degradation of amyloid protein deposits. Combined endobronchial and radiation therapy have demonstrated a similar beneficial effect. (Kalra et al., 2001). The authors know of no reports utilizing high dose rate brachytherapy for endobronchial disease. It stands to reason that this too would be a potentially viable option.

Large recurrent pleural effusions in patients with amyloidosis will often require repeated thoracenteses followed by pleurodesis. (Berk et al., 2003; Berk et al., 2005) In a case series reporting on 35 patients with recurrent amyloid pleural effusions at Boston University, chest tubes were placed in 18 patients after a failure of diuresis and intermittent thoracenteses. Seven patients had the chest tube removed without chemical pleurodesis because of unremitting large volume drainage. Eight patients underwent talc slurry pleurodesis via chest tube with symphysis achieved in those with output less than 100 ml/day while in those patients with more than 200 ml/day, the pleurodesis failed uniformly. Video-assisted thoracoscopic surgery with talc insufflation achieved success in 2 patients, and another 2

In conclusion, although amyloid in the respiratory tract is not a common occurrence, physicians should be aware of the various manifestations. Symptoms of pulmonary amyloidosis are very non specific and hence require a high degree of clinical suspicion. The workup should include a complete physical examination, pulmonary function testing, appropriate clinical imaging followed by biopsies and pathology confirmation of amyloid. The treatment strategy needs to be individualized to the particular patient's clinical status and symptomatology, and may range from close observation to locally directed and systemic therapeutic options. Airway interventions, including debulking of amyloidomas with rigid bronchoscopy, laser photoablation, or airway stents should be performed by an experienced interventional pulmonologist or thoracic surgeon. This will help reduce the risks of these therapies and allow the most expansive treatment options in a rare condition

Future therapies will focus on strategies that involve preventing formation or propagation of insoluble beta-pleated sheets and/or enhance their degradation. Two ubiquitous molecules, serum amyloid P (SAP) and heparin sulfate proteoglycan (HSP), promote beta pleated sheet formation and inhibition of proteolytic degradation. (Gillmore et al., 2010)

Berk JL, O'Regan A, Skinner M. (2002). Pulmonary and tracheobronchial amyloidosis. Semin

Berk JL, Keane J, Seldin DC, Sanchorawala V, Koyama J, Dember LM, Falk RH. (2003).

Persistent pleural effusions in primary systemic amyloidosis: etiology and

Drugs that target these molecules may be of interest in the future.

Respir Crit Care Med. Vol 23, No. 2, (Apr 2002), pp. 155-65

prognosis. *Chest.* Vol. 124, No. 3, (Sep 2003), pp. 969-977

patients had PleurX™ catheters placed for continued intermittent drainage.

**7.4 Pleural drainage**

**8. Conclusions**

with un-defined best practices.

**9. References**

Ablative therapy with Neodymium: Yttrium Aluminum Garnet (Nd:YAG) or Carbon Dioxide (CO2) laser has been fairly successful. It appears that amyloid is very sensitive to photoablation. (Saleiro et al., 2008) Nd:YAG laser therapy is the most commonly utilized and is not only ablative but has significant hemostatic effects which is of particular benefit in these friable lesions. Laser ablation is the standard of care for endobronchial amyloidosis. In a retrospective series of 32 patients over 19 years, sixteen had persistent asymptomatic endolumenal disease. (Piazza et al., 2003) Two patients had endolumenal procedures with subsequent requirement of surgical resection. Each patient had no evidence of recurrent endolumenal amyloid after 5 to 8 years. Herman et al. reported on 13 cases of tracheobronchial amyloid successfully treated with Nd:YAG laser. (Herman et al., 1985) Follow up of another patient with CT imaging showed stabilization of the lesions after laser resection. (M'Rad et al., 1988) In a series by Diaz-Jimenez three of 11 laser ablations required termination because of significant hemorrhage. (Diaz-Jimenez et al., 1999)

In addition to photoablative strategies, cryotherapy has also been utilized to treat tracheobronchial amyloidosis. (Maiwand et al., 2001) Like other endolumenal therapies, multiple treatments (21 procedures over an 11 year follow up) over the patient's disease course are often required.

Rigid bronchoscopy has been utilized to mechanically debulk the amyloid lesions and for serial dilation of stenotic airways. In addition, the rigid bronchoscope has been used to help with potential bleeding when undergoing biopsy or laser photoablation. Placement of silicone stents has been utilized in conjunction with the ablative therapies to help prolong the airway stability. (Yang et al., 2003)

The use of airway stents after dilation may also be considered in select patients. Serial therapeutic bronchoscopies are not uncommon. (Gibbaoui et al., 2004) If large mediastinal amyloid masses or lymphadenopathy cause central airway obstruction airway stenting is an option. As in all benign airways disease it is always preferential to implant a silicone stent. If a self expanding metallic stent is the only option, the authors recommend a fully covered stent. Operator experience should not be the determinant of the type of stent placed. Because of the complex nature of these patients, the high risk of significant bleeding, and the potential for repeated procedural requirements, it is recommended that these patients be referred to a formally trained interventional pulmonologist or thoracic surgeon with significant experience in managing high grade central airway obstruction.

Localized tracheobronchial amyloidosis can cause post obstructive pneumonia. (Daniels et al., 2007) When evidence suggests a post obstructive state, appropriate empiric antibiotics should be started. Once bronchoscopic cultures are obtained, a strategy of proper deescalation of therapy should be employed based upon the culture results.

#### **7.3 Radiation therapy**

External beam radiotherapy has been successfully utilized in tracheobronchial amyloidosis in a patient believed not to be a candidate for endolumenal therapy due to the diffuse nature of the airways disease. (Monroe et al., 2004) A total of 24 Gy was delivered in 12 fractions, and colchicine was given as an adjunctive therapy. Improvements were measured by sequential pulmonary function testing, radiographic imaging, bronchoscopic evaluation, and performance status.

Kurrus et al. published a case report demonstrating a benefit of external beam radiation (20 Gy in 10 fractions) in causing local response in a patient with localized tracheobronchial disease. (Kurrus et al., 1998) The authors noted decreased thickness of the airway wall and less friable and erythematous airway post radiation on a subsequent bronchoscopy. They treated the patient based on the hypothesis that plasma cells that secrete amyloidogenic protein are radiosensitive. Other hypotheses proffered include radiation injures cells other than plasma cells that may secrete amyloidogenic proteins, and free radicals generated by radiation may modify and enhance the degradation of amyloid protein deposits. Combined endobronchial and radiation therapy have demonstrated a similar beneficial effect. (Kalra et al., 2001). The authors know of no reports utilizing high dose rate brachytherapy for endobronchial disease. It stands to reason that this too would be a potentially viable option.

#### **7.4 Pleural drainage**

72 Amyloidosis – An Insight to Disease of Systems and Novel Therapies

Ablative therapy with Neodymium: Yttrium Aluminum Garnet (Nd:YAG) or Carbon Dioxide (CO2) laser has been fairly successful. It appears that amyloid is very sensitive to photoablation. (Saleiro et al., 2008) Nd:YAG laser therapy is the most commonly utilized and is not only ablative but has significant hemostatic effects which is of particular benefit in these friable lesions. Laser ablation is the standard of care for endobronchial amyloidosis. In a retrospective series of 32 patients over 19 years, sixteen had persistent asymptomatic endolumenal disease. (Piazza et al., 2003) Two patients had endolumenal procedures with subsequent requirement of surgical resection. Each patient had no evidence of recurrent endolumenal amyloid after 5 to 8 years. Herman et al. reported on 13 cases of tracheobronchial amyloid successfully treated with Nd:YAG laser. (Herman et al., 1985) Follow up of another patient with CT imaging showed stabilization of the lesions after laser resection. (M'Rad et al., 1988) In a series by Diaz-Jimenez three of 11 laser ablations required

In addition to photoablative strategies, cryotherapy has also been utilized to treat tracheobronchial amyloidosis. (Maiwand et al., 2001) Like other endolumenal therapies, multiple treatments (21 procedures over an 11 year follow up) over the patient's disease

Rigid bronchoscopy has been utilized to mechanically debulk the amyloid lesions and for serial dilation of stenotic airways. In addition, the rigid bronchoscope has been used to help with potential bleeding when undergoing biopsy or laser photoablation. Placement of silicone stents has been utilized in conjunction with the ablative therapies to help prolong

The use of airway stents after dilation may also be considered in select patients. Serial therapeutic bronchoscopies are not uncommon. (Gibbaoui et al., 2004) If large mediastinal amyloid masses or lymphadenopathy cause central airway obstruction airway stenting is an option. As in all benign airways disease it is always preferential to implant a silicone stent. If a self expanding metallic stent is the only option, the authors recommend a fully covered stent. Operator experience should not be the determinant of the type of stent placed. Because of the complex nature of these patients, the high risk of significant bleeding, and the potential for repeated procedural requirements, it is recommended that these patients be referred to a formally trained interventional pulmonologist or thoracic surgeon with

Localized tracheobronchial amyloidosis can cause post obstructive pneumonia. (Daniels et al., 2007) When evidence suggests a post obstructive state, appropriate empiric antibiotics should be started. Once bronchoscopic cultures are obtained, a strategy of proper de-

External beam radiotherapy has been successfully utilized in tracheobronchial amyloidosis in a patient believed not to be a candidate for endolumenal therapy due to the diffuse nature of the airways disease. (Monroe et al., 2004) A total of 24 Gy was delivered in 12 fractions, and colchicine was given as an adjunctive therapy. Improvements were measured by sequential pulmonary function testing, radiographic imaging, bronchoscopic evaluation,

Kurrus et al. published a case report demonstrating a benefit of external beam radiation (20 Gy in 10 fractions) in causing local response in a patient with localized tracheobronchial disease. (Kurrus et al., 1998) The authors noted decreased thickness of the airway wall and

termination because of significant hemorrhage. (Diaz-Jimenez et al., 1999)

significant experience in managing high grade central airway obstruction.

escalation of therapy should be employed based upon the culture results.

course are often required.

**7.3 Radiation therapy**

and performance status.

the airway stability. (Yang et al., 2003)

Large recurrent pleural effusions in patients with amyloidosis will often require repeated thoracenteses followed by pleurodesis. (Berk et al., 2003; Berk et al., 2005) In a case series reporting on 35 patients with recurrent amyloid pleural effusions at Boston University, chest tubes were placed in 18 patients after a failure of diuresis and intermittent thoracenteses. Seven patients had the chest tube removed without chemical pleurodesis because of unremitting large volume drainage. Eight patients underwent talc slurry pleurodesis via chest tube with symphysis achieved in those with output less than 100 ml/day while in those patients with more than 200 ml/day, the pleurodesis failed uniformly. Video-assisted thoracoscopic surgery with talc insufflation achieved success in 2 patients, and another 2 patients had PleurX™ catheters placed for continued intermittent drainage.

#### **8. Conclusions**

In conclusion, although amyloid in the respiratory tract is not a common occurrence, physicians should be aware of the various manifestations. Symptoms of pulmonary amyloidosis are very non specific and hence require a high degree of clinical suspicion. The workup should include a complete physical examination, pulmonary function testing, appropriate clinical imaging followed by biopsies and pathology confirmation of amyloid. The treatment strategy needs to be individualized to the particular patient's clinical status and symptomatology, and may range from close observation to locally directed and systemic therapeutic options. Airway interventions, including debulking of amyloidomas with rigid bronchoscopy, laser photoablation, or airway stents should be performed by an experienced interventional pulmonologist or thoracic surgeon. This will help reduce the risks of these therapies and allow the most expansive treatment options in a rare condition with un-defined best practices.

Future therapies will focus on strategies that involve preventing formation or propagation of insoluble beta-pleated sheets and/or enhance their degradation. Two ubiquitous molecules, serum amyloid P (SAP) and heparin sulfate proteoglycan (HSP), promote beta pleated sheet formation and inhibition of proteolytic degradation. (Gillmore et al., 2010) Drugs that target these molecules may be of interest in the future.

#### **9. References**

Berk JL, O'Regan A, Skinner M. (2002). Pulmonary and tracheobronchial amyloidosis. Semin Respir Crit Care Med. Vol 23, No. 2, (Apr 2002), pp. 155-65

Berk JL, Keane J, Seldin DC, Sanchorawala V, Koyama J, Dember LM, Falk RH. (2003). Persistent pleural effusions in primary systemic amyloidosis: etiology and prognosis. *Chest.* Vol. 124, No. 3, (Sep 2003), pp. 969-977

Pulmonary Manifestations of Amyloidosis 75

Herman DP, Colchen A, Milleron B, Bentata-Pessayre M, Personne C, Akoun G. (1985). The

Hoag JB, Yung RC. (2008). An unexpected finding of endobronchial amyloidosis in a patient

Jones AW, Chatterji AN. (1977). Primary tracheobronchial Amyloidosis with

Kalra S, Utz JP, Edell ES, Foote RL. (2001). External-beam radiation therapy in the treatment

Katzenstein, A. (1997) Chapter 7 Systemic Diseases involving the Lung, In: Katzenstein and

Kavuru MS, Adamo JP, Ahmad M, Mehta AC, Gephardt GN. (1990). Amyloidosis and

Kung J, Zhuang H, Yu JQ, Duarte PS, Alavi A. (2003). Intense flourodeoxyglucose activity in

Kurrus JA, Hayes JK, Hoidal JR, Menendez MM, Elstad MR. (1998). Radiation therapy for tracheobronchial amyloidosis. *Chest*. Vol. 114, No. 5, (Nov 1998), pp. 1489-92 Kyle RA, Gertz MA, Greipp PR, Witzig TE, Lust JA, Lacy MQ, Therneau TM. (1997). A trial

Lachmann HJ, Hawkins PN. (2006). Amyloidosis and lung. *Chron Respir Dis.* Vol. 3, No. 4,

Maiwand MO, Nath AR, Kamath BSK. (2001). Cryosurgery in the treatment of tracheobronchial amyloidosis. *J Bronchol*. Vol. 8, No. 2, (Apr 2001), pp. 95-7 Mimori Y, Rikimaru T, Mitsui T, Shiraishi T, Kinoshita M, Oizumi K. (1998). Localized

Miyazaki D, Yazaki M, Ishii W, Matsuda M, Hoshii Y, Nara K, Nakayama J, Ikeda SI. (2011).

Monroe AT, Walia R, Zlotecki RA, Jantz MA. (2004). Tracheobronchial Amyloidosis: A case

New GB. (1919). Amyloid Tumors of the upper air passages*. Laryngoscope.* Vol. 29, No. 6, pp.

O'Regan A, Fenlon HM, Beamis JF Jr., Steele MP, Skinner M, Berk JL. (2000).

series of 13 cases. Rev Mal Respir. Vol. 2, No. 1, pp. 19-23

with mediastinal fibrosis. *J Bronchol.* Vol. 15, No. 1, pp. 61-3

Pleural Disease. *Chest*. Vol. 98, No. 1, (Jul 1990), pp. 20-3

Saunders, 0-7216-5575-9, Philadelphia

28, No. 12, (Dec 2003), pp. 975-6

17, (Apr 24, 1997), pp. 1202-7

2011), pp. 243-6

327-41

No. 2, (Feb 2004), pp. 784-789

*Rev Pneumol Clin*. Vol. 44, No. 6, pp. 260-5

*Medicine*. Vol. 79, No. 2, (Mar 2000), pp 69-79

268-72

pp. 853-6

treatment of tracheobronchial amyloidosis using a bronchial laser. Apropos of a

tracheobronchopathia osteoplastica. Br J Dis Chest. Vol. 71, No. 4, (Oct 1977), pp.

of diffuse tracheobronchial amyloidosis. *Mayo Clin Proc*. Vol. 76, No. 8, (Aug 2001),

Askins Surgical Pathology of Non-neoplastic Lung Disease , pp.(168-192) W.B.

pulmonary amyloid lesions on positron emission tomography. *Clin Nucl Med*. Vol.

of three regimens for primary amyloidosis: colchicine alone, melphalan and prednisone, and melphalan, prednisone and colchicine. *N Engl J Med.* Vol. 336, No.

pp. 203-214Lesser A. (1877). Ein Fall von Enchondroma osteiodes mixtum der lunge mit partieller amyloid Entortung. *Virchows Arch (Path Anat)* Vol. 69, pp 404-408 M'Rad S, Le Thi Huong D, Wechsler B, Monsigny M, Buthiau D, Colchen A, Godeau P.

(1988). Localized tracheobronchial amyloidosis. A new case studies with x-ray computed tomographic and nuclear magnetic resonance. Review of the literature.

amyloidosis of the lower respiratory tract. *J Bronchol*. Vol 5, No. 4, (Oct 1998), pp. 316-8

A rare lung nodule consisting of adenocarcinoma and amyloid deposition in a patient with primary systemic AL amyloidosis. *Intern Med*. Vol. 50, No. 3, (Feb

report of successful treatment with external bean radiation therapy. Chest. Vol. 125,

Tracheobronchial amyloidosis: The Boston University experience from 1984 to 1999.

Berk JL. (2005). Pleural effusions in systemic amyloidosis. *Curr Opin Pulm Med*. Vol. 11, No.

Bhadra K, Butnor KJ, Davis GS. (2010). A Bronchoscopic Oddity Nodular Tracheobronchial Amyloid. *J Bronhcol Interven Pulmonol*. Vol. 17, No. 3, (Jul 2010), pp. 248-52 Bignold LP, Martyn M, Basten A. (1980). Nodular pulmonary amyloidosis associated with

BoydKing A, Sharma O, Stevenson K. (2009). Localized interstitial pulmonary amyloid:

Capizzi SA, Betancourt E, Prakash UB. (2000). Tracheobronchial amyloidosis. *Mayo Clin*

Carter, D., Patchefsky,AS. (1998) Chapter 9 Spindle Cell Tumors of the Lung, In: Tumors

Celli BR, Rubinow A, Cohen AS, Brody JS. (1978). Patterns of pulmonary involvement in

Cohen AD, Zhou P, Chou J, Tenuya-Feldstein J, Reich L, Hassoun H, Levine B, Filippa DA,

Cools FJ, Kockx MM, Borchxstaens GE, Heuvel PV, Cuykens JJ. (1996). Primary systemic

Cordier JF, Loire R, Brune J. (1986). Amyloidosis of the lower respiratory tract. Clinical and

Currie GP, Rossiter C, Dempsey OJ, Legge JS. (2005). Pulmonary amyloid and PET scanning.

Daniels JT, Cury JD, Diaz J. (2007). An unusual cause of postobstructive Pneumonia. *Chest*.

Diaz-Jimenez JP, Rodriguez A, Ballarin JIM, Castro MJ, Argemi TM, Manresa F. (1999). Diffuse tracheobronchial amyloidosis*. J Bronchol*. Vol. 6, No. 1, (Jan 1999), pp. 13-7 Gibbaoui H, Abouchacra S, Yaman M. (2004). A case of primary diffuse tracheobronchial amyloidosis. Ann Thorac Surg. Vol. 77, No. 5, (May 2004), pp. 1832-4 Gillmore JD, Tennent GA, Hutchinson WL, Gallimore JR, Lachmann HL, Goodman HJB,

systemic amyloidosis. Br J Haematol. Vol. 148, No. 5, (Mar 2010), pp. 760-7 Gross BH. (1981). Radiographic manifestations of lymph node involvement in amyloidosis.

Hawkins PN, Lavender JP, Pepys MB. (1990). Evaluation of systemic amyloidosis by

Hazenberg BP, van Rijswijk MH, Lub-de Hooge MN, Vellenga E, Haagsma EB, Posthumus

amyloidosis. J Nucl Med. Vol. 48, No. 6, (Jun 2007), pp. 865-72

systemic amyloidosis. *Chest.* Vol. 74, No. 5, (Nov 1978), pp. 543-547

phase II trial. *Br J Haematol*. Vol. 139, No. 2, (Oct 2007), pp. 224-33

*Respir Med*. Vol. 99, No. 11, (Nov 2005), pp. 1463-4

*Radiology.* Vol. 138, No. 1, (Jan 1981), pp. 11-14

323, No. 8, (Aug 23, 1990), pp. 508-513

Vol. 131, No. 3, (Mar 2007), pp. 930-933

benign hypergammaglobulinemic purpura. *Chest*. Vol. 78, No. 2, (Aug 1980), pp. 334-6

a case report and review of the literature. Curr Opin Pulmon Med. Vol. 15, No. 5,

and Tumor-like Lesions of the Lung, pp.(286-365) W.B. Saunders, 0-7216-3312-9,

Riedel E, Kewalrammani T, Stubblefield MD, Fleisher M, Nimer S, Comenzo RL. (2007). Risk-adapted autologous stem cell transplantation with adjuvant dexamethasone + thalidomide for systemic light-chain amyloidosis: results of

amyloidosis complicated by massive thrombosis. *Chest.* Vol. 110, No. 1, (Jul 1996),

pathologic features in a series of 21 patients. *Chest.* Vol. 90, No. 6, (Dec 1986), pp.

Offer M, Millar DJ, Petrie A, Hawkins PN, Pepys MB. (2010). Sustained pharmacological depletion of serum amyloid P component in patients with

scintigraphy with 123I –labelled serum amyloid P component. *N Engl J Med.* Vol.

MD, Jager PL. (2007). Diagnostic performance and prognostic value of extravascular retention of 123I-labeled serum amyloid P component in systemic

4, (Jul 2005), pp. 324-8

(Sep 2009), pp. 517-20

Philadelphia

pp. 282-4

827-831

*Proc*. Vol. 75, No. 11, (Nov 2000), pp. 1148–52

**6**

*Turkey*

**Causal or Causal Relationship**

**Systemic Amyloidosis – From Inflammation**

*1Zonguldak Karaelmas University, Faculty of Dentistry, Department of Periodontology*

Although recent decades have provided significant advances in our understanding of the pathology and pathogenesis of AA amyloidosis, the mechanism and etiopathological factors promoting amyloidosis are largely unknown (Elimowa et al., 2009). Its pathogenesis is multifactorial, involving many variables such as primary structure of the precursor protein, acute-phase response, the presence of non-fibril protein, receptors, lipid metabolism and proteases (Röcken and Shakespeare, 2002). This pathogenetic process centers on the conversion of normally soluble proteins into insoluble fibrillar aggregates that disrupt tissue structure and cause disease. The organ distribution pattern of amyloid deposits and the resulting disease outcome depend on the origin and type of fibrillar protein deposited (Glenner, 1980; Kisilevski, 1992). Hence, amyloidosis is classified on the basis of the origin and biochemical composition of the precursor proteins that form the fibrillar deposits. The two most common forms of systemic amyloidosis are light-chain (AL) amyloidosis and reactive (AA or secondary) amyloidosis due to chronic inflammatory diseases. Beta-2 microglobulin amyloidosis is a common complication associated with long term hemodialysis. Hereditary systemic amyloidoses are a group of autosomal dominant disorders caused by mutations in the genes of several plasma proteins. In this section, we focus on the more common of these conditions, which are systemic AA amyloidosis, oral focal infections especially chronic periodontitis, and familial amyloidosis especially auto-

inflammatory diseases (Glenner, 1980; Kisilevski, 1992; Grateau et al., 2005).

Systemic AA amyloidosis, representing approximately 45 percent of generalized amyloidoses are inflammatory arthritis (Rheumatoid arthritis), chronic infections (Bronchiectasis, tuberculosis, chronic cutaneous infections, osteomyelitis), Immunodeficiency status, other conditions predisposing to chronic infections (Injected drug abuse, epidermolysis bullosa, paraplegia), Hereditary periodic fevers (Familial Mediterranean fever, Hyperimmunglobulin D syndrome, TNF receptor-associated periodic syndrome), Inflammatory bowel disease (Crohn's disease, ulcerative colitis), Neoplasia, Systemic vasculitis (Behçet's disease, systemic lupus erythematosis), others (Sarcoidosis). Reactive systemic AA amyloidosis is a

**1. Introduction**

**to Amyloidosis – A Trouble Connection**

*2Ondokuz Mays University, Faculty of Medicine, Department of Nephrology*

**Between Oral Diseases and**

Murat İnanç Cengiz1 and Kuddusi Cengiz2

### **Causal or Causal Relationship Between Oral Diseases and Systemic Amyloidosis – From Inflammation to Amyloidosis – A Trouble Connection**

Murat İnanç Cengiz1 and Kuddusi Cengiz2

*1Zonguldak Karaelmas University, Faculty of Dentistry, Department of Periodontology 2Ondokuz Mays University, Faculty of Medicine, Department of Nephrology Turkey*

#### **1. Introduction**

76 Amyloidosis – An Insight to Disease of Systems and Novel Therapies

Piazza C, Cavaliere S, Foccoli P, Toninelli C, Bolzoni A, Peretti G. (2003). Endoscopic

Pitz MW, Gibson IW, Johnston JB. (2006). Isolated Pulmonary Amyloidosis: Case report ande review of the Literature. *Am J Hematol*. Vol. 81, No. 3, (Mar 2006), pp. 212-3 Plockinger B, Muller MR, Eskersberger F. (1993). Isolated amyloidosis of hilar lymph node.

Road JD, Jacques J, Sparling JR. (1985). Diffuse alveolar septal amyloidosis presenting with

Saleiro S, Hespanhol V, Magalhaes A. (2008). Endobronchial amyloidosis. J Bronchol. Vol.

Seo JH, Lee SW, Ahn BC, Lee J. (2010). Pulmonary amyloidosis mimicking multiple

Sharma D, Katlic MR. (2006). Localized Tracheal Amyloidosis. *J Bronchol*. Vol. 13, No. 1, (Jan

Shenin M, Xiong W, Naik M, Sandorfi N. (2010). Primary amyloidosis causing diffuse alveolar hemorrhage. *J Clin Rheumatol*. Vol. 16, No. 4, (Jun 2010), pp. 175-7 Sipe JD, Benson MD, Buxbaum JN, Ikeda S, Merlini G, Saraiva MJ, Westemark P. (2010).

Smith RR, Hutchins GM, Moore GW, Humphrey RL. (1979). Type and distribution of

Strange C, Heffner JE, Collins BS, Brown FM, Sahn SA. (1987). Pulmonary hemorrhage and

Sugihara E, Dambara T, Okamoto M, Sonobe S, Koga H, Inui A, Aiba M, Isonuma H,

Thompson PJ, Citron KM. (1983). Amyloid and the lower respiratory tract. *Thorax*. Vol. 38,

Utz JP, Swensen SJ, Gertz MA. (1996). Pulmonary Amyloidosis. The Mayo Clinic Experience

Wechalekar AD, Hawkins PN, Gillmore JD. (2008). Perspectives in treatment of AL

Westermark P, Benson MD, Buxbaum JN, (2007). A primer of amyloid nomenclature.

Wink JS. (2003). An unusual presentation of an uncommon disease: A diffuse cystic

Yang S, Chia SY, Chuah KL, Eng P. (2003). Tracheobronchial amyloidosis treated with rigid bronchoscopy and stenting. Surg Endosc. Vol. 17, No. 4, (Apr 2003), pp. 658-9

amyloidosis. *Br J Haematol.* Vol. 140, No. 4, (Feb 2008), pp. 365-77

*Arch Otorhinolaryngol*. Vol. 260, No. 7, (Aug 2003), pp. 349-54

*Langenbecks Arch Chir*. Vol. 378, No. 3, pp. 167-70

17, No. 3-4, (September–December 2010) pp. 101–104

*Am J Med.* Vol. 66, No. 1, (Jan 1979), pp. 96-104

*Bronchol*. Vol. 13, No. 4, (Oct 2006), pp. 191-3

*Amyloid*. Vol. 14, No. 3, (Sep 2007), pp. 179-83

124, No. 4 suppl, (Oct 2003), pp. 280S

Vol. 92, No. 2, (Aug 1987), pp. 367-9

No. 2, (Feb 1983), pp. 84-87

407-413

*Dis.* Vol. 132, No. 6, (Dec 1985), pp. 1368-70

15, No. 2, (Apr 2008), pp. 95-99

pp. 376-9

2006), pp. 19-20

management of laryngo-tracheobronchial amyloidosis: as seroes of 32 patients. *Eur*

recuurent hemoptysis and medial dissection of pulmonary arteries. *Am Rev Respir*

metastatic lesions on F-18 FDG PET/CT. *Lung Cancer*. Vol. 67, No. 3, (Mar 2010),

Amyloid fibril protein nomenclature: 2010 recommendations from the nomenclature committee of the International Society of Amyloidosis. *Amyloid*. Vol.

pulmonary parenchymal and vascular amyloid: Correlation with cardiac amyloid.

air embolism complicating transbronchial biopsy in pulmonary amyloidosis. Chest.

Hayashida Y. (2006). Clinical features of 10 patients with pulmonary amyloidosis. *J*

from 1980 to 1993. *Annals of Internal Medicine.* Vol. 124, No. 4, (Feb 15, 1996), pp.

radiologic pattern in a patient with localized pulmonary amyloidosis. Chest. Vol.

Although recent decades have provided significant advances in our understanding of the pathology and pathogenesis of AA amyloidosis, the mechanism and etiopathological factors promoting amyloidosis are largely unknown (Elimowa et al., 2009). Its pathogenesis is multifactorial, involving many variables such as primary structure of the precursor protein, acute-phase response, the presence of non-fibril protein, receptors, lipid metabolism and proteases (Röcken and Shakespeare, 2002). This pathogenetic process centers on the conversion of normally soluble proteins into insoluble fibrillar aggregates that disrupt tissue structure and cause disease. The organ distribution pattern of amyloid deposits and the resulting disease outcome depend on the origin and type of fibrillar protein deposited (Glenner, 1980; Kisilevski, 1992). Hence, amyloidosis is classified on the basis of the origin and biochemical composition of the precursor proteins that form the fibrillar deposits. The two most common forms of systemic amyloidosis are light-chain (AL) amyloidosis and reactive (AA or secondary) amyloidosis due to chronic inflammatory diseases. Beta-2 microglobulin amyloidosis is a common complication associated with long term hemodialysis. Hereditary systemic amyloidoses are a group of autosomal dominant disorders caused by mutations in the genes of several plasma proteins. In this section, we focus on the more common of these conditions, which are systemic AA amyloidosis, oral focal infections especially chronic periodontitis, and familial amyloidosis especially autoinflammatory diseases (Glenner, 1980; Kisilevski, 1992; Grateau et al., 2005).

Systemic AA amyloidosis, representing approximately 45 percent of generalized amyloidoses are inflammatory arthritis (Rheumatoid arthritis), chronic infections (Bronchiectasis, tuberculosis, chronic cutaneous infections, osteomyelitis), Immunodeficiency status, other conditions predisposing to chronic infections (Injected drug abuse, epidermolysis bullosa, paraplegia), Hereditary periodic fevers (Familial Mediterranean fever, Hyperimmunglobulin D syndrome, TNF receptor-associated periodic syndrome), Inflammatory bowel disease (Crohn's disease, ulcerative colitis), Neoplasia, Systemic vasculitis (Behçet's disease, systemic lupus erythematosis), others (Sarcoidosis). Reactive systemic AA amyloidosis is a

Causal or Causal Relationship Between Oral Diseases and

**2. Periodontal infection and systemic health**

teeth and then their premature loss (Pihlstrom et al., 2005).

interactions or accumulation of dental plaque;

c. deficit of the host immune system.

ensuing economic benefits.

several causes:

Systemic Amyloidosis – From Inflammation to Amyloidosis – A Trouble Connection 79

have presented evidence of close relationships between periodontal and systemic diseases, the majority of findings are limited to epidemiological studies, while the etiological details remain unclear (Inaba and Amano,2010). Hence, periodontal diseases may be an overlooked source of inflammation in amyloid patients. Because of APRs that increase during the course of periodontal diseases is the cause of the etiopathogenesis of AA amyloidosis. Prior to, periodontal disease have not been investigated in the secondary amyloidosis with unknown etiology. Furthermore, in approximately 6 to 11.84% of causes of systemic AA amyloidosis

Clarification of the importance of oral focal infection requires controlled epidemiological studies and, probably, a better understanding of the etiology and the clinicopathological features of periodontal disease and medical diseases. Before adequate data are available, caution should be exercised in implicating periodontal disease or any other oral infection in the causation of major medical disorders like mortal systemic AA amyloidosis. Thus, the aim of this chapter is to emphasize that periodontal diseases may be considered as an etiological factor for amyloidosis. It is hereby suggested that periodontal evaluation should be performed as part of a routine medical assessment process. Preventing or treating periodontal disease might prevent or at least alleviate the progression of systemic AA amyloidosis. In terms of medical economics, understanding of the relationship between chronic periodontitis and systemic diseases has potential to change health policy, with

This chapter reviews the periodontal disease, auto-inflammatory syndromes relevant to oral health and suggested association of familial Mediterranean fever (FMF) and Behçet's disease

Periodontal diseases are a group of bacterial inflammatory diseases of the supporting tissues of the teeth, in 1999, a classification of periodontal diseases has been proposed (Armitage, 1999). Periodontal diseases are common, initially bacteria-driven, chronic inflammatory condition leading to the formation of infected periodontal pockets, destruction of deep collagenous structures of the periodontium and alveolar bone, excessive mobility of the

The cause of these common inflammatory conditions is the dental plaque. In 1 mm3 of dental plaque weighing approximately 1mg. more than 108 bacteria are present and over 300 species have been isolated and characterized in these deposits. Normally, the oral microbial community and the host immune response are in equilibrium which allows for periodontal health to the maintained, but pathology can occur when the balance is compromised for

a. modification of the environmental conditions of the site, caused by either bacterial

b. reduction in the proportion of benefical bacteria, such as those producing inhibitory substances, caused by bacterial interactions or the use of systemic antibiotics; and

The progression from gingivitis to periodontitis is characterized by periodontal pocket development, which favours further plaque accumulation and a shift in its qualitative composition (Pizzo et al., 2010). In July 1998, the American Academy of periodontology launched an effort to educate the public about new discoveries: infections in the mouth may play an important role in disorders involving other parts of the body (Scannapieco, 1998). At

no underlying disease can be found (Lachmann et al., 2007; Paydaş, 1999).

potential complication of any disorder that gives rise to a sustained acute-phase response, and the list of chronic inflammatory, infective or neoplastic disorders that can underlie it is almost without limit (Lachmann and Hawkins, 2006).

Amyloid fibrils are derived from the cleavage fragments of the circulating acute-phase reactant (APR) serum amyloid A protein (SAA) (Pras et al., 1968). SAA is an apolipoprotein of high-density lipoprotein (HDL) which, like C-reactive protein (CRP), is synthesized by hepotocytes under the transcriptional regulation of cytokines including interleukin (IL)-1, IL–6, tumor necrosis factor (TNF)-alfa, beta and acute-phase reactants (APRs), either alone or combination, have been shown to affect SAA synthesis at the transcriptional level (Yamada, 1998). In the circulation, SAA levels may increase by 1000-fold in response to injury, infection, and inflammation, and thus SAA has properties resembling a classical positive APR. Because concentration of APRs may be correlated with the amount of damaged tissue, measurements of SAA are of value in the assessment of acivity and response to therapy during several inflammatory diseases (Malle and De Beer, 1996; Lachmann et al., 2005). Although AA amyloid can develop rapidly, the median latency between presentation with a chronic inflammatory disorder and clinically significant amyloidosis is almost two decades (Lachmann et al., 2005). The prognosis of AA amyloidosis depends on the degree of renal function and whether the underlying inflammatory disease can be suppressed. AA amyloidosis does not occur in the absence of an acute-phase response or without elevated SAA levels (Lachmann et al., 2007; Röcken and Shakespeare, 2002).