Wild-type (senile) amyloidosis other diagnostic studies: Difference between revisions
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Feature tracking software applied to cine CMR datasets for assessment of left ventricular strain has shown good agreement between CMR and 2D Echo-derived myocardial longitudinal strain measurements (63) with apical sparing in longitudinal strain (64). | Feature tracking software applied to cine CMR datasets for assessment of left ventricular strain has shown good agreement between CMR and 2D Echo-derived myocardial longitudinal strain measurements (63) with apical sparing in longitudinal strain (64). | ||
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=== Genetic testing === | === Genetic testing === | ||
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* Monitoring of these cardiac biomarkers is being employed to monitor treatment | * Monitoring of these cardiac biomarkers is being employed to monitor treatment | ||
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|Histopathological diagnosis | |||
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* EMB with histopathology remains the gold standard for diagnosis of cardiac amyloidosis. | |||
* Histopathology demonstrates deposition of amorphous deposits of amyloid fibrils in the heart. | |||
* The binding of Congo red stain to the deposited amyloid fibrils leads to characteristic apple-green birefringence under polarized light microscopy and an intense yellow-green fluorescence is seen when binding to thioflavin. | |||
* Precursor protein identification can be accomplished by immunohistochemistry, electron microscopy, or mass spectrometry (preferred), depending upon institutional expertise. | |||
* Adjunctive laboratory tests to rule out AL include assaying for other organ dysfunction (e.g., proteinuria, alkaline phosphatase) and directly measuring the circulating light chains in plasma. | |||
* EMB is associated with risks of complications such as | |||
** Ventricular free-wall perforation | |||
** Arrhythmia | |||
** Conduction abnormalities | |||
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Revision as of 16:36, 5 November 2019
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Wild-type (senile) amyloidosis Microchapters |
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Differentiating Wild-type (senile) amyloidosis from other Diseases |
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Overview
Other Diagnostic Studies
Nuclear imaging
Nuclear imaging has emerged as important non-invasive tool in the diagnosis of suspected ATTR cardiac amyloidosis due to wide availability at a low cost, having few contraindications and the capacity to differentiate from other cardiomyopathies. Bone-avid tracers, like 99mTc-DPD (technetium-3,3-diphosphono-1,2-propanodicar-boxylic acid), 99mTc-PYP (technetium-pyrophosphate) and 99mTc-HMDP [technetium-hydroxymethylene diphosphonate (Tc-HMDP)] have been shown to have high sensitivity and specificity for differentiating patients with ATTR CA, irrespective of genotype, from patients with AL-CA or others with HFpEF (32-37). The exact mechanism by which these radiotracers differentially accumulate in myocardium is not completely clear but may be due to differences in deposited amyloid proteins (38,39), higher calcium levels seen during the repair process (40) and/or higher degree of tissue microcalcifications in ATTR compared to AL cardiac amyloidosis (41). Irrespective of the mechanism, an international consensus document has confirmed that the combination of grade 2 or 3 cardiac uptake on a bone-avid tracer scan in the setting of absent monoclonal protein by serum immunofixation electrophoresis (IFE), urine IFE, and serum free light chain assay is diagnostic of ATTR cardiac amyloidosis as compared to AL-CA or other wall thickening diseases (42). Bokhari et al. (37) described a standardized imaging protocol using 99mTc-PYP to diagnose ATTR CA using Heart/Contralateral ratio ≥1.5. Nuclear imaging with 99mTc-DPD (43) and 99mTc-PYP (44) can diagnose the presence of cardiac involvement prior to any overt echocardiographic abnormalities and can predict major adverse cardiac events (34,35,39,43). Future studies are needed to establish the role of bone-avid nuclear tracers for the early identification of ATTRwt-CA, differentiating it from ATTRm-CA (confirmed by genetic testing) and evaluation of subsequent outcomes.
Scintigraphy imaging, which is inherently qualitative, falls short of being able to quantify the radioactivity at the affected sites thus cannot be used in assessing disease burden and response to therapy. Positron emission tomography (PET) is a nuclear modality that can circumvent this problem, emerging as a promising tool in the monitoring and management of cardiac amyloidosis. Recently discovered amyloid binding PET tracers 18-F florbetapir (45,46) and 11C-Pittsburgh compound B (PiB) (47,48) can identify both AL and ATTR cardiac amyloidosis. Case reports have shown cardiac uptake of another PET tracer [18F]-sodium fluoride only in patients with ATTRwt-CA and ATTRm-CA, but not in ones with AL-CA (49,50).
Cardiovascular magnetic resonance
CMR is an important diagnostic and prognostic tool for cardiac amyloidosis. Various techniques utilizing different tissue imaging timing, with and/or without gadolinium contrast, and strain can provide detailed information about the presence, location, and distribution of hypertrophy, as well as cardiac function. One major drawback of using CMR is that gadolinium contrast is contraindicated in patients with moderate to severe kidney disease.
T1 sequence of CMR, a composite measure of extracellular matrix and myocardial cells, with the use of gadolinium can help differentiate extracellular tissue thickening due to myocardial hypertrophy vs. extracellular deposition. Utilizing pre- and post-contrast T1 mapping, extracellular volume (ECV) can be calculated and is a direct measurement of the cardiac interstitium (51). ECV expansion can detect amyloid fibrils infiltration in AL and ATTR cardiac amyloidosis earlier than conventional testing and is quantitative marker of the amyloid burden lending itself with the potential use in early diagnosis and disease monitoring (52,53). Marked increased non-contrast T1 relaxation times also seen in patients who have interstitial infiltration by amyloid fibrils and has good correlation with disease severity, future prognosis, and the potential to track changes over time (from natural progression or disease modifying therapy) (54-56). One of the major advantages of T1 mapping is that it does not require contrast which is contraindicated in advanced kidney disease, however, currently this technique has limited clinical availability due to technical challenges related to sequence- and vendor-specific differences (57,58).
The myocardial deposition of amyloid fibrils in ATTR-CA increases ECV which serves as a reservoir for gadolinium accumulation leading to characteristic continuum of late gadolinium enhancement (LGE) (59). In the early stages of the disease there usually is no LGE enhancement that progresses to subendocardial and finally transmural (in non-ischemic pattern) LGE enhancement at the late stages (Figure 2), which also tracks with increasing ECV and a worse prognosis (58,60). In contrast, a diffuse-subendocardial patterns is most commonly described in AL-CA disease (58,60), which has led to CMR based LGE scoring system that seems to differentiate between ATTR and AL cardiomyopathies (61). Future studies are necessary to establish similarities and differences between the LGE in patients with ATTRm-CA and ATTRwt-CA.
Traditional LGE imaging technique depends on normal myocardium to enhance the diseased area and has been limited in ATTR-CA due to difficult nulling, which have led to early and advanced disease misclassification. Phase-sensitive inversion recovery (PSIR) sequence that reduces the need for an optimal null point setting [initially described CMR evaluation of myocardial infarction (62)] makes LGE assessment in cardiac amyloidosis faster and operator-independent (58).
Feature tracking software applied to cine CMR datasets for assessment of left ventricular strain has shown good agreement between CMR and 2D Echo-derived myocardial longitudinal strain measurements (63) with apical sparing in longitudinal strain (64).
Genetic testing
Once diagnosis of ATTR is confirmed via EMB with histology, it is important to offer DNA sequencing for the transthyretin gene (especially in clinical research studies) since the presence of a pathologic mutation can affect clinical trial options, predict sites of organ involvement, and have relevance for family members. The absence of amino acid sequence abnormalities by mass spectrometry is consistent with ATTRwt-CA, although mass spectrometry cannot detect all transthyretin mutations.
| Cardiac biomarkers |
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| Histopathological diagnosis |
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