Transthyretin (ATTR) cardiac amyloidosis may be because of mutant transthyretin causing familial amyloid cardiomyopathy (FAC) or wild-type transthyretin causing systemic senile amyloidosis (SSA). Histologic confirmation is often challenging and may require endomyocardial biopsy (EMB). The purpose of this study was to determine the frequency of amyloid protein deposition in positive noncardiac organ biopsy or fat aspiration in patients with ATTR cardiac amyloidosis. The medical records of 286 patients (mean age 66 ± 11, 85% men) with a diagnosis of ATTR cardiac amyloidosis at our institution who underwent noncardiac biopsy or subcutaneous fat aspiration were reviewed, including 186 patients (65%) with FAC and 100 patients (35%) with SSA. One hundred and thirty-one patients (46%) had EMB, all of which were positive. There were 210 patients (73%) with positive noncardiac tissue sampling, including 175 patients (94%) with FAC and 35 patients (35%) with SSA (p <0.001). There were 141 patients (76%) with FAC and 84 patients (84%) with SSA who underwent fat aspiration, and 67% and 14% were positive, respectively, whereas 100 (54%) and 64 (64%) underwent bone marrow biopsy, and 41% and 30% were positive, respectively. Rectal and sural nerve biopsies were performed in 52 (28%) and 54 (29%) patients with FAC and were positive in 81% and 83%, respectively. Biopsy of other noncardiac sites was performed with relatively lower frequency. In conclusion, although EMB is more commonly required to establish the diagnosis of SSA than FAC, noncardiac biopsy or fat aspiration could be considered as initial testing in patients evaluated for ATTR cardiac amyloidosis with characteristic echocardiography findings.
Systemic amyloidosis is a heterogeneous group of disorders caused by extracellular deposition of misfolded proteins that can lead to cardiomyopathy. Classification of amyloidosis is according to protein type and includes immunoglobulin-derived primary systemic amyloidosis (AL), transthyretin (ATTR) amyloidosis, and secondary systemic amyloidosis. ATTR cardiac amyloidosis can be further categorized as familial disease arising from misfolding of a mutated or variant transthyretin protein (familial amyloid cardiomyopathy [FAC]) or sporadic disease caused by misaggregation of wild-type transthyretin protein (systemic senile amyloidosis [SSA]). Diagnosis of ATTR amyloidosis requires histologic identification of amyloid deposition by Congo red staining. Endomyocardial biopsy (EMB) remains the gold standard for the diagnosis and however is invasive and associated with a risk of complications. ATTR cardiac amyloidosis may be diagnosed without EMB in the presence of characteristic cardiac imaging findings in association with a positive biopsy of another organ or tissue. The utility of obtaining tissue samples from noncardiac sites by organ biopsy or fine needle fat pad aspiration has been described in patients with AL amyloidosis; however, little is known about the value for patients with suspected ATTR cardiac amyloidosis. The purpose of this report was to examine the frequency of a positive noncardiac organ biopsy or abdominal fat aspiration for detecting systemic amyloid deposition in a large cohort of patients with known ATTR cardiac amyloidosis.
Methods
From January 1990 to April 2013, 286 patients seen at our institution with a diagnosis of ATTR cardiac amyloidosis and biopsy of ≥1 noncardiac site were identified, after excluding 36 patients with only EMB performed. The demographic, clinical, laboratory, histologic, and genotyping data of this cohort were reviewed. All patients had a tissue diagnosis of amyloidosis established with typical apple-green birefringence on Congo red staining of EMB specimen or biopsy of a noncardiac site. Those without positive EMB had a positive biopsy of a noncardiac site or fat aspiration in the presence of clinical features and typical echocardiographic findings, including end-diastolic thickness of the ventricular septum >12 mm in the absence of other causes for ventricular hypertrophy. Patients were categorized as having either a diagnosis of FAC or SSA based on clinical findings, family history, and the results of genetic testing. This study was approved by the Mayo Clinic Institutional Review Board. All patients provided written informed consent granting access to their medical records for research purposes.
Noncardiac organ biopsy or abdominal fat aspiration was performed as previously described and was considered positive if the specimen contained material stained with Congo red that demonstrated characteristic apple-green birefringence with polarized light. The type of amyloid was determined by immunohistochemical techniques or mass spectrometry. Genotyping was performed in genomic DNA obtained using polymerase chain reaction amplification assays and sequencing of TTR exons 1 to 4 as previously described. If genotyping was not available, the diagnosis of FAC was made based on a strong family history and/or genotyping of an affected family member.
Left ventricular end-diastolic diameter and interventricular septum and posterior wall thickness were measured by M-mode or 2-dimensional echocardiography from the parasternal views at end-diastole and used to calculate the left ventricular mass indexed to body surface area. Left ventricular ejection fraction was measured by M-mode using the Quinones formula or biplane volumetric Simpson method. Diastolic and right heart function parameters were assessed as recommended by the current guidelines.
Data are expressed as mean ± SD for continuous variables and as frequency with percentage for categorical variables. Comparisons among groups were based on 2-sided t tests for continuous variables and Pearson’s chi-square test for categorical variables. All p values were 2 sided, and a value of ≤0.05 was considered statistically significant. Statistical analyses were performed using SAS version 9.2 statistical software (SAS Institute Inc., Cary, North Carolina).
Results
Of the 286 ATTR cardiac amyloidosis patients included, 186 (65%) were diagnosed with FAC and 100 (35%) with SSA. Patient clinical characteristics are listed in Table 1 . Patients with SSA were significantly older and more likely to be men than patients with FAC. As expected, patients with FAC had more neuropathy and paresthesia compared with patients with SSA, whereas patients with SSA had more symptoms of heart failure such as dyspnea and edema ( Table 1 ). Echocardiographic data for the study population and for patient subgroups with FAC and SSA are listed in Table 2 and demonstrate typical finding characteristics of cardiac amyloidosis.
| Parameter | Study Population (n = 286) | Familial Amyloidosis (n = 186) | Senile Amyloidosis (n = 100) | p Value |
|---|---|---|---|---|
| Age (yrs) | 66 ± 11 | 62 ± 10 | 75 ± 6 | <0.001 |
| Men | 244 (85) | 151 (81) | 93 (93) | 0.007 |
| Caucasian | 244 (85) | 154 (83) | 90 (90) | 0.14 |
| African-American | 20 (7) | 17 (9) | 3 (3) | |
| Other/unknown | 22 (8) | 15 (8) | 7 (7) | |
| Body mass index (kg/m 2 ) | 26 ± 4 | 25 ± 5 | 26 ± 4 | 0.024 |
| Dyspnea | 109 (40) | 51 (28) | 58 (58) | <0.001 |
| Edema | 102 (37) | 51 (28) | 51 (51) | <0.001 |
| Light headedness | 49 (18) | 31 (17) | 18 (18) | 0.69 |
| Weight loss | 91 (33) | 76 (42) | 15 (15) | <0.001 |
| Peripheral neuropathy | 108 (39) | 102 (57) | 6 (6) | <0.001 |
| Paresthesia | 132 (48) | 114 (63) | 18 (18) | <0.001 |
| Carpal tunnel syndrome | 95 (35) | 61 (34) | 34 (34) | 0.71 |
| Rhythm | ||||
| Sinus | 252 (88) | 174 (94) | 78 (78) | <0.001 |
| Atrial fibrillation/flutter | 34 (12) | 12 (6) | 22 (22) |
| Parameter | Study Population (n = 286) | Familial Amyloidosis (n = 186) | Senile Amyloidosis (n = 100) | p Value |
|---|---|---|---|---|
| LV end-diastolic diameter (mm) | 47 ± 6 | 47 ± 6 | 47 ± 7 | 0.42 |
| LV end-systolic diameter (mm) | 33 ± 8 | 32 ± 8 | 35 ± 9 | 0.05 |
| LV septal wall thickness (mm) | 17 ± 5 | 16 ± 5 | 17 ± 4 | 0.11 |
| LV posterior wall thickness | 15 ± 4 | 15 ± 4 | 16 ± 3 | 0.016 |
| LVEF (%) | 50 ± 16 | 53 ± 16 | 47 ± 15 | 0.005 |
| LV mass index (g/m 2 ) | 171 ± 58 | 165 ± 60 | 184 ± 51 | 0.043 |
| Deceleration time (ms) | 187 ± 50 | 191 ± 51 | 180 ± 47 | 0.14 |
| Mitral E velocity (m/s) | 0.8 ± 0.2 | 0.8 ± 0.2 | 0.8 ± 0.2 | 0.66 |
| Mitral A velocity (m/s) | 0.5 ± 0.3 | 0.6 ± 0.3 | 0.4 ± 0.2 | <0.001 |
| Mitral E/A ratio | 1.6 ± 1.0 | 1.3 ± 1.1 | 2.8 ± 1.2 | <0.001 |
| Mitral valve thickening | 119 (37) | 74 (40) | 38 (38) | 0.77 |
| Estimated PASP (mm Hg) | 41 ± 12 | 40 ± 12 | 43 ± 12 | 0.18 |
| Pericardial effusion | 92 (32) | 59 (32) | 33 (33) | 0.83 |
Organ biopsy and fat aspiration results are listed for the study population in Table 3 . There were 210 patients (73%) with either a positive noncardiac biopsy or a positive fat aspiration, including 175 patients (94%) with FAC and 35 patients (35%) with SSA (p <0.001; Figure 1 ). Fat aspiration was the most commonly performed method of noncardiac tissue sampling (79% of patients, with 47% positive; Figure 1 ), followed by bone marrow biopsy (57% of patients, with 37% positive). Other less commonly biopsied organs included the rectum, kidney, carpal ligament, liver, small intestine, and sural nerve ( Table 3 ).
| Organ Biopsy/Tissue Sampling Site | Study Population (n = 286) | Familial Amyloidosis (n = 186) | Senile Amyloidosis (n = 100) | p Value |
|---|---|---|---|---|
| Endomyocardial | ||||
| Performed | 131 (46) | 42 (23) | 89 (89) | <0.001 |
| Positive | 131 (100) | 42 (100) | 89 (100) | — |
| Rectum | ||||
| Performed | 56 (20) | 52 (28) | 4 (4) | <0.001 |
| Positive | 44 (79) | 42 (81) | 2 (50) | 0.15 |
| Kidney | ||||
| Performed | 10 (3) | 9 (5) | 1 (1) | 0.09 |
| Positive | 8 (80) | 7 (78) | 1 (100) | 0.60 |
| Carpal ligament | ||||
| Performed | 7 (2) | 7 (4) | 0 | 0.05 |
| Positive | 7 (100) | 7 (100) | — | — |
| Liver | ||||
| Performed | 6 (2) | 6 (3) | 0 | 0.07 |
| Positive | 3 (50) | 3 (50) | — | — |
| Small intestine | ||||
| Performed | 32 (11) | 29 (16) | 3 (3) | 0.001 |
| Positive | 19 (59) | 17 (59) | 2 (67) | 0.93 |
| Bone marrow | ||||
| Performed | 164 (57) | 100 (54) | 64 (64) | 0.10 |
| Positive | 60 (37) | 41 (41) | 19 (30) | 0.17 |
| Fat aspirate | ||||
| Performed | 225 (79) | 141 (76) | 84 (84) | 0.11 |
| Positive | 106 (47) | 94 (67) | 12 (14) | <0.001 |
| Sural nerve | ||||
| Performed | 54 (19) | 54 (29) | 0 | <0.001 |
| Positive | 45 (83) | 45 (83) | — | — |
| Other | ||||
| Performed | 64 (22) | 54 (29) | 10 (10) | <0.001 |
| Positive | 47 (73) | 43 (80) | 4 (40) | 0.05 |
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