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Amyloidosis: Review And Imaging Findings Siakallis Loizo, Tziakouri Shiakalli Chrysa MD,PhD, Georgiades, S. Christos MD PhD FSIR

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Cite this article as: Siakallis Loizo, Tziakouri Shiakalli Chrysa MD,PhD, Georgiades, S. Christos MD PhD FSIR, Amyloidosis: Review And Imaging Findings, Semin Ultrasound CT MRI , http://dx.doi.org/10.1053/j.sult.2013.12.006 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

AMYLOIDOSIS: REVIEW AND IMAGING FINDINGS Siakallis, Loizos (corresponding author) Department of Radiology Attikon University Hospital Rimini 1 street Chaidari, Athens Greece P.O: 12462 [email protected] / [email protected] Tziakouri Shiakalli Chrysa MD,PhD Interventional Radiologist (IRdipl.GR) Deputy Director Radiology Department Nicosia General Hospital Nicosia Cyprus Email: kithreas @cytanet.com.cy [email protected] Georgiades, S. Christos MD PhD FSIR Director, Vascular & Interventional Radiology American Medical Center

215 Spyrou Kyprianou Avenue Nicosia 2047 Cyprus [email protected] AMYLOIDOSIS: REVIEW AND IMAGING FINDINGS ABSTRACT Amyloidosis is a collection of pathophysiologically-related disease entities caused by the extracellular deposition of abnormal fibrillar proteins called amyloid. The accumulation of amyloid may be systemic involving many organs, or localized manifesting as infiltration of individual organs, or in the form of a focal, tumor-like lesion. Amyloidosis may develop in the setting of underlying conditions, usually chronic inflammatory diseases in which case it is termed secondary or it may involve no underlying disease and thus be primary or idiopathic. Amyloid infiltration leads to pathology through the disruption of normal tissue structure and function or through cytotoxic effects of intermediate forms of protein aggregates. Clinical manifestations of the disease vary and are non-specific, increasing the need of imaging during the investigation of the disease. Imaging findings are diverse and not pathognomonic, however combined with the patient’s clinical history they can raise the suspicion of amyloidosis and direct towards its confirmation by biopsy. Radiologists should be familiar with the appearance of amyloidosis in various modalities in order to aid the early identification of the disease and direct towards prompt treatment planning. Such knowledge will provide the radiologist with an opportunity to contribute to patient care and aid reducing the high morbidity and mortality of the disease.

INTRODUCTION Amyloidosis’ various manifestations share the underlying defect of protein misfolding and extracellular deposition of insoluble protein derivatives (1). The deposit is formed by three main constituents:

1.

a

fibrillar

protein

component

prone

to

aggregation,

2.

charged

glycosaminoglycans (GAGs) of the extracellular matrix and 3. the acute phase protein serum amyloid P. The participation of GAGs in amyloid (starch-like) formation gives the disease its name, as they stain blue with iodine.

Despite the various morphologic and geographic

manifestations, all amyloidoses share the same pathognomonic histologic characteristic: an affinity to Congo Red stain demonstrating apple-green birefringence under polarized light microscopy and the presence of rigid, 10-12 nm wide non-branching fibrils on electron microscopy, arranged primarily in a β-pleated sheet secondary structure (Figs. 1, 2) (2). The different manifestations of amyloidoses partly depend on the varying behavior of the different fibrillar proteins able to form localized or systemic amyloid deposits in humans (3). According to the Nomenclature Committee of the International Society of Amyloidosis, the classification of amyloid disease is based on the fibrillar protein component of amyloid among a group of approximately 30 amyloidogenic proteins identified in humans (Table 1). Such a classification is of vital importance for the exact recognition of amyloid pathophysiology and appropriate management in each case of amyloidosis (4). In hereditary and Amyloid Light-chain (AL) amyloidosis, accumulation/aggregation is triggered by mutations that render proteins (i.e. transthyretin, immunoglobulin) prone to misfolding. Secondary (AA) and A2β-Μ amyloidosis are characterized by high concentrations of specific proteins such as AA in patients with chronic inflammatory diseases and beta-2 microglobulin in

hemodialysis patients. Even concentrations of proteins with a low intrinsic amyloidogenic potential over prolonged periods of time can lead to amyloid accumulation as in the case of transthyretin in senile amyloidosis (2). Amyloidogenic precursors typically undergo partial unfolding and assemble into dimeric, then oligomeric aggregates which can have cyto-toxic properties (5). The aggregation of these amyloidogenic oligomers is influenced by local factors (proteolysis, pH etc.) and leads to the 10-12 nm wide cross-β-sheet amyloid fibrils (3). Amyloidosis can be systemic affecting more than one organ or tissue type, or less commonly (10-20% of cases) localized, affecting individual organs such as the intestine and the kidneys (6). Amyloid deposition becomes clinically significant once the organ function is compromised, either due to cytotoxic effects of prefibrillar aggregates (7) or due to the replacement of parenchymal tissue by amyloid deposits (3) or by virtue of mass effect. Systemic forms of the disease pose greater risks and can be progressive and fatal due to renal or cardiac involvement (3, 8). Primary amyloidosis is a clonal plasma cell disorder characterized by the accumulation of fibrilforming monoclonal immunoglobulin (Ig) light chains (LC) (and/or rarely heavy chains) and is therefore referred to as amyloid light chain Amyloidosis (AL) (3, 9). It is the most common type of systemic amyloidosis in developed countries with an incidence of 9 cases/million/per year (10) and a median survival of 1.4 years (11). Secondary amyloidosis (AA) is a result of long term accumulation of amyloid fibrils derived from the acute phase protein serum amyloid A (SAA) in the setting of chronic inflammatory diseases (such as rheumatoid arthritis, Reiter syndrome, ankylosing spondylitis, familial Mediterranean fever, Sjögren's syndrome, Rheumatoid arthritis etc.). The lifetime incidence of AA amyloidosis in patients with chronic inflammatory conditions is 1-5% (3, 12).

In the western world, the median survival has

improved with anti-inflammatory treatment and currently stands at approximately at >10 years after diagnosis (13). A form of the disease that does not pertain to either primary or secondary is the hereditary or senile systemic type in which mutant or wild type transthyretin (TTR) is the offending protein (2). Diagnosis (whether primary or secondary amyloidosis) is made by the microscopic appearance of amyloid in tissues. In systemic amyloidosis, subcutaneous fat tissue biopsy is indicative of the disease and where possible, biopsies of specific organs make the diagnosis of their involvement definite. However, imaging findings of amyloidosis is various and non-specific. Occasionally, modestly specific findings can suggest the presence of the disease and reflect the amyloid deposition and its consequences on organ function (14). A high index of suspicion, clinical awareness of predisposing conditions and the knowledge of the imaging features of amyloidosis in various modalities is valuable and can aid the early diagnosis and monitoring of this increasing condition. Gastrointestinal System The gastrointestinal system (GI) is the most commonly involved in systemic amyloidosis (up to 98%) in both Primary and Secondary amyloidosis (16). Endoscopic biopsy confirms the diagnosis of GI amyloidosis, with imaging findings usually lagging diagnostic specificity (17). Amyloid infiltration of the muscularis, the Auerbach plexus and the arterioles are the main mechanisms causing dysmotility and ischemia (respectively) both of which can be seen in GI amyloidosis. Symptoms can mimic other conditions and include gastro-esophageal reflux, constipation, diarrhea, early satiety and are mainly attributed to autonomic dysfunction.

Malabsorption and weight loss, abdominal pain, GI bleeding, obstruction and perforation are rare complications (12, 17). Many times the cross sectional study can be entirely negative, which does not exclude the disease. When present, imaging findings are usually seen in the small bowel, the most common site of GI involvement (bowel dilatation, contrast retention, diffuse (Fig. 3) or nodular (Fig. 4) wall thickening, intussusception, ischemia etc.). Imaging findings of the colon include colonic distension, bowel wall thickening (Fig. 5), luminal narrowing, intramural hemorrhage and perforation (Fig. 6) (17), but are also rare. Infiltration of the mesentery may also be evident (12, 16-19). On the other hand, gastric involvement is seen on biopsy specimens in up to 44% of all Al amyloidosis cases (20).

Despite common involvement, gastric and/or esophageal related

symptoms are rare and include heartburn, early satiety and nausea due to dysmotility as a result of infiltration of the esophageal wall and the Auerbach plexus (Fig. 7). Gastric outlet obstruction and hematemesis may occur due to infiltration of the stomach wall in the presence of ulcers or submucosal hematomas (12, 21). Cross sectional imaging with oral contrast can delineate the presence of diffuse (Fig. 8) or focal wall thickening (Fig. 9), which can also be calcified. Amyloid deposition may mimic tumors and resemble polyps or leiomyomas and ulcerations may be evident (15, 17). Hepatomegaly can result from either hepatic amyloid infiltration (a common event in systemic amyloidosis) or right heart failure due to cardiac involvement. Diffuse or patchy decreased hepatic parenchymal attenuation with or without calcification is another presentation of hepatic involvement (Figs. 10, 11) (16, 22). Amyloid deposition appears hyperechoic on US (Fig. 12).

MR findings include lesions that are isointense on T2-weighted imaging (T2WI) and hyperintense on T1-weighted imaging (T1WI) (16). Splenic involvement is usual in systemic amyloidosis (5-10%) and manifests with diffuse infiltration that appears as splenomegaly with or without calcifications, similar to hepatic involvement. MR findings in splenic infiltration include hyperintensity on T1WI and hypointensity on T2WI. If splenic infiltration compromises microvascular supply then there is poor contrast uptake in all modalities and all phases, a sign more specific for the disease (Fig. 13) (16, 17, 23). Rupture of the spleen can occur even without trauma and is a serious complication which in many cases is the initial manifestation of the disease. It has high 30-day mortality (16, 24). The gallbladder may be infiltrated demonstrating wall thickening on US and CT, mimicking acalculus cholecystitis (Fig. 14) (1, 15). Macroglossia, the sine qua non of the disease, occurs in 10-25% of patients with systemic AL amyloidosis due to intrinsic muscle infiltration and enlargement (Fig. 15) and is considered to be a pathognomonic feature of the disease (12, 25). Heart The heart is the most commonly involved organ in the chest, with amyloid accumulating in virtually any part of the heart: the myocardium, the atrial walls, the intra-atrial septum and the valve leaflets, leading to thickening that may be evident on imaging (Figs. 16, 17). Cardiac amyloidosis can be initially silent with rapid progression to systolic and diastolic dysfunction due to increased wall thickness and eventually to heart failure. The latter is a very poor prognostic sign resulting in an average life expectancy of 1-2 years. Cardiac biopsy, although definitive, poses great risks therefore the need for cardiac imaging is increased in cardiac amyloidosis (26, 27). Echocardiography may reveal concentric wall thickening or “granular/sparkling” appearance of the myocardium especially in the right ventricle, diastolic

dysfunction with normal or near normal ejection fraction, thickening of the intra-atrial septum and valves and pericardiac effusion (27, 28). Cardiac ultrasound features cannot be used in isolation and are often combined with electrocardiography to gauge the stage of the disease. Low QRS voltages with poor R wave progression is seen in up to 50% of amyloidosis patients (29, 30). Cardiac MRI offers the most specific signs of the disease (though still not pathognomonic), depicting myocardial wall thickening and ventricular dysfunction (Fig. 18). Late subendocardial and subpericardial gadolinium enhancement is an MRI finding which is characteristic for the disease and has been found to correlate with prognosis (Figs. 19, 20) (30, 31). Chest Pulmonary involvement can be found in approximately 50% of patients with amyloidosis and may present as a part of systemic disease or, more often, it can be localized in the respiratory system. Most of the times patients are asymptomatic Presenting symptoms include chronic cough, dyspnea and recurrent pneumonias, which overlap with symptoms from congestive heart failure. The most common mechanism of pathophysiology is the obstruction of bronchi or bronchioles due to interstitial wall thickening or mass effect due to a large focal amyloidoma (32). Findings of systemic disease include interlobular septal thickening or diffuse irregular lines, lymphadenopathy and multiple pulmonary nodules (27). Pulmonary involvement has three distinct morphologies: tracheobronchial involvement (50%), nodular parenchymal (45%) or the less common diffuse parenchymal amyloidosis (32). Imaging findings of the most common, tracheobronchial form, include nodules or diffuse thickening of the bronchi accompanied by obstructive parenchymal features such as post-obstructive pneumonias, diffuse (Fig. 21),

“budding tree” (Fig. 22) or mass-like (Fig. 23) infiltrates. Involvement of the trachea is not uncommon and manifests as diffuse wall thickening with calcifications (Fig. 24) or as focal mass lesion that may cause obstructive symptomatology (Fig. 25) (32). Nodular parenchymal amyloidosis demonstrates multiple nodules especially in a sub pleural distribution that grow slowly with a size ranging from subcentimeter to massive (up to 15 cm in diameter) (Figs. 26, 27). Such parenchymal lesions do not decrease in size, which can be used to distinguish it from infections after an empiric course of antibiotics. Irregular nodular calcification is seen in up to 50% of the cases (27, 33). The diffuse form has a poorer prognosis and one can see thickening of the interlobular septa, small nodules and reticular or confluent consolidative opacities (32). Mass like amyloidomas with or without calcifications may be demonstrated in the soft tissues of the chest wall (Fig. 28), the paraspinal regions (Fig. 29) and even the breast parenchyma (Fig. 30). Genitourinary The genitourinary tract/retroperitoneum are rarely involved in amyloidosis, presenting with nonspecific findings that can mimic other conditions such as tumors, retroperitoneal fibrosis or ureteral dysmotility. The main manifestation of kidney involvement is nephrotic syndrome affecting up to one third of secondary amyloidosis patients and can have a slow progression to renal failure. The underlying pathology involves nodular amyloid deposition along the glomerular basement membranes, with concomitant interstitial and vascular deposits appearing also frequently (Fig. 31) (8, 34). Imaging during the early, acute phase of the disease commonly demonstrates enlarged kidneys (hyperechoic on US) which later progress into small, contracted kidneys with cortical thinning in up to

50% of patients with systemic amyloidosis. Other less common findings include focal mass lesions in the renal parenchyma, amorphous calcifications in amyloid deposits (Fig. 32) and filling defects in the renal pelvis (15). Increased echogenicity of the renal parenchyma with preservation of the corticomedullary differentiation is a characteristic finding on ultrasonography (Fig. 33). Hydronephrosis may be present due to obstructive effects in the urinary tract (8, 15). Urinary bladder involvement is usually localized and its clinical manifestation includes painless hematuria and symptoms mimicking urinary tract infection (35). Imaging findings on CT and MR include mass like lesions in the bladder wall and less commonly, larger solitary lesions or diffuse wall thickening. Submucosal or intramural calcification usually depicted on CT is a finding suggestive but not diagnostic of the disease. MR imaging can be used to differentiate amyloid depositions from urothelial carcinoma due to their characteristic feature of decreased signal intensity of the bladder wall on T2WI (8, 36). The ureters are infrequently involved and such involvement presents as focal or diffuse lesions simulating urothelial carcinoma accompanied by wall thickening and narrowing of the ureters with linear submucosal or intramural calcifications. Hydronephrosis may develop due to obstruction.

The urethra may exhibit focal lesions with increased echogenicity on US

examination and low signal on T2-weighted MRI (8, 35). Seminal vesicle involvement may present with wall thickening on MRI and CT and low signal intensity on T2WI, making the differential diagnosis from prostate cancer via US-guided biopsy necessary (37). Retroperitoneal infiltration in the setting of systemic amyloidosis may be diffuse and cause encasement of retroperitoneal organs, the pancreas, the kidneys, the aorta, and the inferior vena cava (38). Diffuse replacement of the retroperitoneal fat with non-fatty soft tissue and the

formation of mass-like lesions may be evident on CT and MR imaging (Figs. 34, 35). Progressive focal or diffuse calcifications on CT may be suggestive of the disease (Fig. 36). On MR imaging, the intermediate signal intensity on T1WI and decreased signal intensity on T2WI as well as the signal drop off between opposed and in-phase gradient echo images are indicative of amyloid deposition, although not pathognomonic (8, 35). Such involvement presents with clinical signs and symptoms of retroperitoneal fibrosis and should be included in the differential diagnosis. Musculoskeletal System Amyloid involvement of bones, joints and muscles is not uncommon. However clinical manifestations are rare and often mistaken as or masked by coexisting inflammatory disorders (by rheumatoid arthritis in cases of secondary amyloidosis, or by the osteoarthropathies of chronic renal failure in cases of Aβ2Μ amyloidosis) (15, 39). Amyloid arthropathy usually manifests as progressive bilateral polyarthritis commonly affecting the shoulders, wrists, elbows, hips and knees (15, 39). Clinical manifestations include swelling, arthralgia and carpal tunnel syndrome. A rare pathognomonic sign of amyloidosis is the muscular tissue thickening that when evident in the shoulder is termed as the “shoulder pad sign” and is most commonly seen in AL amyloidosis (Fig. 37) (40). Later findings are similar to chronic degenerative disease and include subchondral erosions with sclerotic margins and juxtaarticular osteoporosis (Fig. 38). However, contrary to degenerative diseases, the absence of prominent joint-narrowing is helpful for differential diagnosis from Rheumatoid Arthritis (15, 39). MR imaging demonstrates diffuse synovial thickening with low signal intensity on T1WI with gadolinium enhancement and high signal intensity on T2WI unaffected after contrast

administration (Fig. 38) (39, 41). In A2βM amyloidosis, arthropathy can be destructive with narrowing of the joint space and spinal involvement may mimic spondylodiscitis with collapse of intravertebral spaces and erosions in the absence of osteophytes (39, 42). Bony infiltration by amyloid presents clinically with pain, fatigue (bone marrow infiltration), bone edema, pathological fractures or neurological symptoms in spinal involvement.

Lytic

lesions, bone destruction or pathologic fractures with or without calcification resembling chondrosarcoma, can be seen. Focal mass-like amyloid deposition (amyloidoma) may simulate neoplasia and osteopenia with cortical thinning/erosions and is indistinguishable from that deriving from primary disease in cases of multiple myeloma or chronic renal failure (25, 39, 43). MR imaging reveals low to intermediate signal on T1WI with gadolinium enhancement and low signal on T2WI due to T2 shortening, at sites of amyloid deposition. The latter is a valuable characteristic in differentiating amyloidomas from chondromas, chondrosarcomas and myelomatous lesions which demonstrate higher signal intensity on T2-weighted imaging (15, 39, 44). Muscle involvement is infrequent and is associated with cardiac involvement and poor prognosis. Common features include muscle hypertrophy (with muscle weakness), infiltration and rarely atrophy. MR imaging reveals a hypointense reticulated pattern of the subcutaneous fat accompanied by increased T2 signal intensity with minimal signal alteration in the muscle tissue (39, 45, 46). Head & Neck Amyloid deposition may also occur in the head and neck and may involve the larynx, the nasopharynx, the orbits, the tongue, the tracheobronchial tree and the base of the skull. The most

common head & neck site of involvement is the larynx (twice as often as any other head & neck organ) but is fortunately less aggressive and with better prognosis than amyloid deposits in other sites of the head & neck (44). Presenting symptoms of head & neck involvement depend on location. These include neck pain and the presence of a palpable mass and may be accompanied by hoarseness, difficulty breathing and rarely hemoptysis due to involvement of the airways (Fig. 39). More specific symptoms such as xerostomia or xerophthalmia and proptosis may accompany the infiltration of the salivary (Fig. 40) and the lacrimal glands respectively (15, 44, 47). Cervical lymph nodes are infrequently involved and appear enlarged with speckled calcification and areas of decreased attenuation on CT (Fig. 40) and demonstrate intermediate intensity on T1WI and decreased intensity on T2WI (13, 44, 47). Head & neck imaging may reveal localized tumor-like amyloidomas or diffuse infiltration with occasional punctate calcifications and may be accompanied by bone erosions (Fig. 39) and supporting ligament involvement (Fig. 41) especially when amyloid deposition occurs in the skull base. On MR imaging, head and neck amyloid deposits appear iso- or hypointense on T1WI and iso- to hyperintense in T2WI aiding the differentiation from lesions that appear hyperintense in T2WI such as chondrosarcomas (44, 47). Intraorbital involvement shows a predilection for the lacrimal gland region (Fig. 42). Summary Amyloidosis can involve any organ or tissue, focally or diffusely and presents with a wide spectrum of imaging findings in various modalities. The non-specific clinical and imaging characteristics of the disease emphasize the role of the general radiologist for the early detection

of the disease and proper direction towards diagnosis. Occasionally, specific findings offer an opportunity for definitive diagnosis, such as macroglossia or the “shoulder pad” sign. However, less specific findings can be just as useful if they are combined with clinical history of chronic inflammatory disease and a high index of suspicion.

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A

B

Figure 1. Core biopsy of the tongue in a patient with known involvement. H & E stain (A) shows infiltration of the musculature by pink, collagen-type extracellular material. Congo-red stain (B) shows strong affinity for the stain.

Same specimen (Congo Red) under polarized light

microscopy (C) shows apple green birefringence (arrow), characteristic of amyloid deposition.

C

A

B

Figure 2. Bone marrow needle biopsy in a patient with primary amyloidosis. Congo-red stain (A) shows replacement of the hemopoietic elements by red staining hyaline-like matrix. Polarized light examination (B) shows the diagnostic green birefringence of amyloid.

Figure 3. Axial contrast enhanced CT of the pelvis in a patient with amyloidosis presenting with diarrheas and abdominal pain. Diffusely thickened loops of small bowel (and colon) are noted (arrow).

Figure 4. Axial CT image of the abdomen after administration of oral contrast in a patient with Crohn’s disease. Persistent abdominal pain prompted the CT which resulted in biopsy because of the unusual (for Crohn’s disease) findings. The biopsy confirmed secondary amyloidosis.

Figure 5. Axial CT of the pelvis in a patient with chronic renal failure and congestive heart failure from primary amyloidosis. Findings include diffuse wall thickening prompting a biopsy, which confirmed amyloid infiltration.

Figure 6. Axial CT of the abdomen in a female with acute peritoneal signs. Ileus with dilated loops and fluid-fluid levels are noted. Endoscopy showed GI hemorrhage and biopsy confirmed amyloid deposition.

Figure 7. Axial CT of the chest in a patient with primary amyloidosis presenting with hematemesis. There is circumferential esophageal wall thickening (arrow). Endoscopic biopsy showed diffuse involvement with amyloid.

Figure 8. Axial contrast enhanced CT of the abdomen in a patient with primary systemic amyloidosis. Presenting symptoms included upper GI hemorrhage and diffuse abdominal pain. There is gastric wall thickening (arrow) and endoscopic biopsy confirmed involvement with amyloidosis.

Figure 9. Axial CT of the abdomen after oral and iv contrast administration in a patient with known plasma cell dyscrasia and amyloidosis who presented with chronic diffuse non-specific abdominal pain. There is focal gastric wall thickening along the superior portion of the greater curvature (arrow). Endoscopic biopsy revealed MALT and amyloid infiltration.

Figure 10. Axial CT of the abdomen after oral and iv administration of contrast in a patient presenting with diarrhea. The CT shows a heterogeneously enhancing liver parenchyma and ascites.

The

patient’s INR was 2 confirming hepatic dysfunction and a percutaneous liver biopsy confirmed amyloid infiltration.

Figure 11. Axial contrast enhanced CT of the liver in a patient with known primary amyloidosis presenting with lower extremity swelling. The CT revealed hepatomegaly and diffusely decreased parenchymal density. Percutaneous biopsy confirmed amyloid infiltration.

Figure 12. Ultrasound image of the liver in a patient with biopsy proven amyloidosis and right upper abdominal pain. Multiple hyperechoic foci are noted (arrows). On biopsy these foci represented peribiliary amyloid deposits.

Figure 13. Axial CT of the abdomen in a 58 year-old-man with plasma cell dyscrasia presenting with acute abdominal pain, peritoneal signs and unstable vitals. Peri-hepatic and high density peri-splenic fluid is noted, confirmed to be hemorrhage on surgery. infiltration.

Biopsies showed diffuse amyloid

Figure 14. Ultrasound of the right upper quadrant in a patient presenting with classic signs of cholecystitis. Wall thickening is noted (arrow). Pathologic examination of the specimen showed diffuse amyloid infiltration.

Figure 15. Mid-sagittal T1w MR image in a patient with known primary amyloidosis. Patient has a history of progressive speech and swallow impediment. MR images reveal an enlarged tongue (arrow), “macroglossia”, a characteristic sign on amyloidosis.

Figure 16. Axial contrast enhanced CT of the chest in a patient presenting with congestive heart failure. There is wall thickening of the left ventricle (arrow) and bilateral pleural effusions (stars). Despite LV thickening, the patient had decreased ejection fraction and cardiac biopsy was confirmatory of amyloidosis.

Figure 17. Axial contrast enhanced CT of the chest in a patient with dyspnea on exertion. The right ventricle is obliterated by a diffusely thickened wall (asterisk). Catheterization showed RV diastolic dysfunction and biopsy was diagnostic of amyloidosis.

Figure 18. Sagittal SSFP MR imaging in a patient with primary amyloidosis presenting chest pain and congestive heart failure. Left ventricular wall thickening was noted. Cardiac catheterization showed normal coronaries and a restrictive pattern. amyloidosis.

Myocardial biopsy was diagnostic of

Figure 19. Axial viability MR imaging of the heart in a patient with arrhythmia and dyspnea. Imaging reveals subendocardial late enhancement of the left ventricle (arrow). Amyloid infiltration was confirmed by myocardial biopsy.

Figure 20. Sagittal MR imaging of the heart in a patient presenting with symptoms similar to that of figure 19, i.e. arrhythmias and dyspnea. Imaging again shows circumferential subendocardial late enhancement of the left ventricle (arrow). Biopsy confirmed amyloid deposition.

Figure 21. Axial CT of the chest in a patient with progressive SOB. Patchy bilateral ground glass infiltrates and pleural effusions are noted. infiltration.

Biopsy showed interstitial thickening due to amyloid

Figure 22. Axial CT of the chest showing “budding tree” infiltrate in RML (arrow) and ground glass infiltrate in LLL (arrowhead) in a patient with SOB. infiltration.

Biopsy was diagnostic of amyloid

Figure 23. Axial CT of the chest in a patient with antibiotic resistant recurrent pneumonias, shows a pleuralbased mass lesion in the left lower lobe (arrowhead) and multiple nodules in the right lower lobe (arrow). Biopsy showed amyloid deposition.

Figure 24. Mid sagittal reconstructed CT image in a patient with chronic SOB shows a diffusely calcified tracheal wall. Endoscopic biopsy was diagnostic of amyloid infiltration.

Figure 25. Mid-sagittal reconstructed CT of the chest in a patient with stridor shows a partially obstructing upper tracheal mass (arrow). Biopsy diagnosed an amyloidoma.

Figure 26. Axial CT of the chest in a patient with known amyloidosis presenting with dyspnea shows miliary pattern. Infiltrate of the right lower lung is also seen.

Figure 27. Axial CT of the chest in a 50-year-old patient with SOB shows an infiltrate in the right lung and a “budding tree” process (arrow) in the left lung. Biopsy showed a bronchiolitis and postobstructive pneumonia type picture with amyloid deposition.

Figure 28. Axial CT of the chest in a patient with a tender mass shows a calcified, lytic expansile mass originating in the left chest wall. Excisional biopsy showed this to be an amyloidoma.

Figure 29. Axial CT of the chest in a patient with primary amyloidosis presenting with chest and back pain, shows a posterior mediastinal mass. Biopsy showed an amyloidoma.

Figure 30. Axial CT of the chest in a woman with palpable left breast nodules (arrow), shows soft tissue density nodules some of which are calcified. Biopsy was diagnostic of amyloidomas.

A

B

Figure 31. Hematoxylin and eosin stain (A) demonstrating eosinophilic amyloid deposits (arrowhead) and Congo Red staining (B) revealing amyloid deposits (arrowhead), in a patient with known systemic amyloidosis and new onset renal failure.

Figure 32. Axial CT of the abdomen in a patient with known amyloidosis and right flank pain shows a small right renal cortical mass with focal calcifications (arrow). Biopsy showed amyloid infiltration.

Figure 33. Amyloidosis in a 59-year-old woman with slowly progressive renal insufficiency. Sagittal US image shows diffuse increased echogenicity in the renal cortex with a renal size at the top limit of normal. Biopsy results were diagnostic of amyloidosis.

A

B

Figure 34. Axial contrast enhanced CT of the abdomen at diagnosis (A) and 1-year later (B) in a patient with incidentally detected left retroperitoneal nodule (arrowhead). Biopsy showed amyloidoma which calcified on follow up.

Figure 35. Axial contrast CT image shows a large retroperitoneal mass (arrow) surrounding the abdominal aorta, superior mesenteric artery, and renal arteries. Percutaneous needle biopsy demonstrated amyloid infiltration.

Figure 36. Axial CT of the abdomen in a patient with amyloidosis and chronic abdomional pain complaints shows multiple focal calcifications in the mesentery, right retroperitoneum and left perinephric space (arrows). Figure

Figure 37. Axial CT of the shoulders in a female presenting to the emergency room complaining of upper extremity weakness and bilateral shoulder pain. Physical exam showed a cachectic elderly female with well-developed shoulder girdle musculature (“Shoulder-pad” sign). Bilateral diffuse enlargement of the shoulder musculature is noted (arrows). Biopsy was compatible with amyloid infiltration.

A

Figure 38. Patient with known systemic amyloidosis presenting with bilateral hip and knee pain. Axial CT (A) shows multiple erosions of the femoral heads (arrows). Synovial biopsy showed amyloid infiltration. Coronal T2 weighted MRI of the knees (B) shows diffuse synovial thickening and increased signal intensity. Synovial biopsy showed amyloid infiltration.

Figure 39. Axial contrast enhanced CT of the neck in a patient with known amyloidosis and new onset neck pain shows a mass in the Fossa of Rosenmuller causing bony erosion. Biopsy was diagnostic of amyloidoma.

A

B

Figure 40. Sequential axial contrast-enhanced CT images of the neck from a patient with primary amyloidosis shows bilateral diffuse enlargement of the parotid glands (A, arrows) and lymph nodes (B). Biopsy also demonstrated amyloid infiltration.

Figure 41. Axial (A) and mid-sagittal MR (B) images of the cervical spine in a patient with known amyloidosis and new onset neurological findings show thickening of the ligaments surrounding the spinal cord at the level of C1–2 (arrows).

Figure 42. Axial CT of the head in a patient with systemic amyloidosis presenting with proptosis and xerophthalmia demonstrates a soft tissue mass in the right lacrimal gland region (arrow). Biopsy revealed amyloid infiltration.

Table 1. Amyloidosis Nomenclature according to amyloid precursor Name of

Fibrillar Protein Amyloid

Amyloid

Precursor

Distribution

Immunoglobulin

Systemic or

Type

Amyloidosis Form, Syndrome

Acquired

Primary amyloidosis, B-cell dyscrasia, commonly myltiple myeloma

Protein

AL

light

localized

chain

AA

Serum amyloid A Systemic

Acquired

Secondary amyloidosis, outcome of chronic inflammation / infection (Famileal Meditteranean Fever, rheumatoid arthritis, Reiter syndrome, ankylosing spondylitis, familial Mediterranean fever, Sjögren's syndrome, Rheumatoid arthritis etc)

Ab-2M

Beta 2

Acquired

Chronic renal haemodialysis

- microglobulin

Systemic

failure

/

ATTR

Transthyretin

Systemic

Hereditary Prototypical Familial polyneuropathy (FAP)

ATTR

Transthyretin

Systemic

Acquired

amyloid

Senile heart, vessels

Table 1. The table presents some of the common amyloidosis subtypes according to the protein precursor prone to aggregation. Such amyloid precursors interact with glycosaminoglycans (GAGs) and serum amyloid P precipitating the amyloid complex. The protein component determines the name and characteristics of the disease and is specific for each subtype of amyloidosis. Primary and secondary amyloidosis account for the vast majority of cases. Primary amyloidosis is abbreviated AL due to the accumulation of fibril-forming monoclonal immunoglobulin (Ig) light chains (LC). Secondary amyloidosis is abbreviated AA due to serum Amyloid A, an acute phase protein that accumulates in the setting of chronic inflammatory states (4).

Amyloidosis: review and imaging findings.

Amyloidosis is a collection of pathophysiologically related disease entities caused by the extracellular deposition of abnormal fibrillar proteins cal...
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