Amyloidosis

Mayo staging system for immunoglobulin light chain (AL) amyloidosis (2012)​[93]Kumar S, Dispenzieri A, Lacy MQ, et al. Revised prognostic staging system for light chain amyloidosis incorporating cardiac biomarkers and serum free light chain measurements. J Clin Oncol. 2012 Mar 20;30(9):989-95. http://www.ncbi.nlm.nih.gov/pubmed/22331953?tool=bestpractice.com

Based on the following three prognostic markers:

• N-terminal pro-B-type natriuretic peptide (NT-proBNP) ≥1800 ng/L

• Cardiac troponin T (cTnT) ≥0.025 micrograms/L

• Difference between involved and uninvolved serum free light chains (dFLC) ≥180 mg/L.

Each prognostic marker is assigned a score of 1. Stage is determined based on the total score:

• Stage I: total score = 0

• Stage II: total score = 1

• Stage III: total score = 2

• Stage IV: total score = 3

Conversion tables for use of B-type natriuretic peptide (BNP) instead of NT-proBNP, and for use of cardiac troponin I (cTnI) or high-sensitivity cTnT (hs-cTnT) instead of cTnT, have been published.[61]National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: systemic light chain amyloidosis [internet publication]. https://www.nccn.org/guidelines/category_1 [104]Muchtar E, Kumar SK, Gertz MA, et al. Staging systems use for risk stratification of systemic amyloidosis in the era of high-sensitivity troponin T assay. Blood. 2019 Feb 14;133(7):763-6. https://www.sciencedirect.com/science/article/pii/S0006497120428009?via%3Dihub http://www.ncbi.nlm.nih.gov/pubmed/30545829?tool=bestpractice.com ​​ 

Mayo staging system for immunoglobulin light chain (AL) amyloidosis (2004) with European modifications[92]Dispenzieri A, Gertz MA, Kyle RA, et al. Serum cardiac troponins and N-terminal pro-brain natriuretic peptide: a staging system for primary systemic amyloidosis. J Clin Oncol. 2004 Sep 15;22(18):3751-7. http://www.ncbi.nlm.nih.gov/pubmed/15365071?tool=bestpractice.com [94]Wechalekar AD, Schonland SO, Kastritis E, et al. A European collaborative study of treatment outcomes in 346 patients with cardiac stage III AL amyloidosis. Blood. 2013 Apr 25;121(17):3420-7. https://www.doi.org/10.1182/blood-2012-12-473066 http://www.ncbi.nlm.nih.gov/pubmed/23479568?tool=bestpractice.com

Based on the following risk factors:

• N-terminal pro-B-type natriuretic peptide (NT-proBNP) ≥332 ng/L

• Cardiac troponin T (cTnT) ≥0.035 microgram/L; or cardiac troponin I (cTnI) ≥0.1 microgram/L

Stage is determined based on the presence of these risk factors (an NT-proBNP cutoff of 8500 ng/L is used to subclassify stage III):

• Stage I: no risk factors

• Stage II: 1 risk factor

• Stage IIIA: 2 risk factors (with NT-proBNP 332 to <8500 ng/L)

• Stage IIIB: 2 risk factors (with NT-proBNP ≥8500 ng/L)

Conversion tables for use of B-type natriuretic peptide (BNP) instead of NT-proBNP, and high-sensitivity cTnT (hs-cTnT) instead of cTnT or cTnI, have been published.[61]National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: systemic light chain amyloidosis [internet publication]. https://www.nccn.org/guidelines/category_1 [104]Muchtar E, Kumar SK, Gertz MA, et al. Staging systems use for risk stratification of systemic amyloidosis in the era of high-sensitivity troponin T assay. Blood. 2019 Feb 14;133(7):763-6. https://www.sciencedirect.com/science/article/pii/S0006497120428009?via%3Dihub http://www.ncbi.nlm.nih.gov/pubmed/30545829?tool=bestpractice.com

Hematologic treatment response criteria for AL amyloidosis[105]Palladini G, Dispenzieri A, Gertz MA, et al. New criteria for response to treatment in immunoglobulin light chain amyloidosis based on free light chain measurement and cardiac biomarkers: impact on survival outcomes. J Clin Oncol. 2012 Dec 20;30(36):4541-9. http://jco.ascopubs.org/content/30/36/4541.long http://www.ncbi.nlm.nih.gov/pubmed/23091105?tool=bestpractice.com

• Complete response (CR): normal serum free light chain (FLC) levels with a normal kappa/lambda ratio and negative serum and urine immunofixation

• Very good partial response (VGPR): difference between involved and uninvolved serum FLC (dFLC) <40 mg/L

• Partial response (PR): dFLC decrease ≥50%

• No response: response is less than PR

A modification to this criteria has been proposed that uses negative serum and urine immunofixation, along with involved FLC ≤20 mg/L or dFLC ≤10 mg/L, as a criteria for CR (i.e., instead of a normal serum FLC ratio), which may provide improved survival discrimination.[106]Muchtar E, Gertz MA, Lacy MQ, et al. Refining amyloid complete hematological response: Quantitative serum free light chains superior to ratio. Am J Hematol. 2020 Nov;95(11):1280-7. http://www.ncbi.nlm.nih.gov/pubmed/32681737?tool=bestpractice.com

ASNC/AHA/ASE/EANM/HFSA/ISA/SCMR/ SNMMI expert consensus recommendations: diagnostic criteria[107]Dorbala S, Ando Y, Bokhari S, et al. ASNC/AHA/ASE/EANM/HFSA/ISA/SCMR/SNMMI expert consensus recommendations for multimodality imaging in cardiac amyloidosis: part 2 of 2 - diagnostic criteria and appropriate utilization. Circ Cardiovasc Imaging. 2021 Jul;14(7):e000030. https://www.ahajournals.org/doi/full/10.1161/HCI.0000000000000030 http://www.ncbi.nlm.nih.gov/pubmed/34196222?tool=bestpractice.com ​​

Histological diagnosis of cardiac amyloidosis: Endomyocardial biopsy (amyloidogenic light chain, amyloidogenic transthyretin [ATTR], other subtypes)

• Endomyocardial biopsy positive for cardiac amyloidosis with Congo red staining with apple-green birefringence under polarized light; typing by immunohistochemistry and/or mass spectrometry at specialized centers.

Histological diagnosis of cardiac amyloidosis: Extracardiac biopsy (ATTR)

• ATTR cardiac amyloidosis is diagnosed when the following criteria are met:

  1. Extracardiac biopsy proven AL amyloidosis, and

  2. Typical cardiac imaging features.

Histological diagnosis of cardiac amyloidosis: Extracardiac biopsy (amyloidogenic light chain)

• Amyloidogenic light chain cardiac amyloidosis is diagnosed when the following criteria are met:

  1. Extracardiac biopsy proven AL amyloidosis, and

  2. Typical cardiac imaging features, or

  3. Abnormal cardiac biomarkers: abnormal age-adjusted NT-pro BNP or abnormal Troponin T/I/Hs-Troponin (with all other causes for these changes excluded).

Clinical diagnosis of ATTR cardiac amyloidosis: 99mTc-PYP, DPD, HMDP

• ATTR cardiac amyloidosis is diagnosed when the following criteria are met:

  1. 99mTc-PYP, DPD, HMDP Grade 2 or 3 myocardial uptake of radiotracer, and

  2. Absence of a clonal plasma cell process as assessed by serum FLCs and serum and urine immunofixation, and

  3. Typical cardiac imaging features.

Typical imaging features of cardiac amyloidosis: any of the following imaging features (with all other causes for these cardiac manifestations, including hypertension, reasonably excluded)

• Echocardiography (ATTR/amyloidogenic light chain)

  1. Left ventricular (LV) wall thickness >12 mm

  2. Relative apical sparing of global LS ratio (average of apical LS/average of combined mid+basal LS >1)

  3. ≥ Grade 2 diastolic dysfunction.

• Cardiac magnetic resonance (ATTR/amyloidogenic light chain)

  1. LV wall thickness >upper limit of normal for sex

  2. Global extracellular volume >0.40

  3. Diffuse late gadolinium enhancement

  4. Abnormal gadolinium kinetics typical for amyloidosis, myocardial nulling prior to blood pool nulling.

• PET: 18F-florbetapir or 18F-florbetaben PET (ATTR/amyloidogenic light chain)

  1. Target to background (LV myocardium to blood pool) ratio >1.5

  2. Retention index >0.030 minute^-1.