In this section you will get a chance to test your knowledge and learn more through four clinical patient cases. The patient cases have been developed together with medical professionals and are based on experiences with ATTR-CM patients.
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83-year-old male
61-year-old male
75-year-old female
71-year-old male
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In this section you will continuously receive new facts and test results for this patient.
Use the headings below during the case to access and interpret information about the patient.
HistoryNew!
ECGNew!
ECHONew!
cMRINew!
ScintigraphyNew!
AL amyloidosis testNew!
Case 1
Background
An 83-year-old great-grandfather of five was admitted for cardiac-related complaints, including chest pain and lack of energy, having previously been physically active and playing garden games with his family.
N-terminal pro B-type natriuretic peptide (NT-proBNP): 2699 ng/L
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1 of 5
Take part of the patient history and the results from the clinical examination.
To evaluate this patient further, what would be your next step?
Send patient for an electrocardiogram (ECG) and echocardiogram (ECHO)
Well done, you chose the preferable answer. Because clinical examination revealed regular signs of heart failure (HF), amyloidosis would not be expected at this stage. Further investigations are therefore needed. An ECHO is the most commonly used imaging tool in HF and cardiac amyloidosis (CA) and, when combined with an ECG, can reveal detailed information.
Recommend treatment for cardiovascular and blood pressure complaints
Not optimal, see the marked preferable answer. To achieve the correct diagnosis, further investigations are required. Treatment for cardiovascular and blood pressure complaints would not be the first plan of action.
Investigate coronary artery disease (CAD)
Not optimal, see the marked preferable answer. This would not be the first option as the patient has previously diagnosed CAD, which doesn’t appear to be an immediate issue, based on clinical examination. An angiogram would not assist with a diagnosis of transthyretin amyloid (ATTR) amyloidosis; thus, the diagnosis might be missed, so other diagnostic investigations are required.
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2 of 5
The patient was referred for ECHO and ECG. In addition, the patient was also referred for cardiac magnetic resonance imaging (cMRI). Based on the results thus far, which “red flags” for CA do you see?
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3 of 5
This patient is an elderly male with a history of cardiac complaints. Diagnostic tests show increased intra-ventricular septum thickness (IVST) and posterior wall thickness (PWT) from the ECHO, and no LVH from the ECG examination. cMRI results were inconclusive. Relative apical strain (apical sparing pattern) and increased right ventricular (RV) wall thickness together increases the suspicion.
Based on the information so far, what do you do?
Suspect hypertrophic cardiomyopathy (HCM)
Not optimal, see the marked preferable answer. Because of the conflicting results from ECHO/ECG and cMRI, we cannot be certain if the patient has HCM; therefore, further testing is necessary. ECHO/ECG findings indicate that HCM is less likely, given that there is concentric increased wall thickness, lack of systolic anterior motion, increased RV wall thickness and no LVH detected via ECG. This strengthens the case for CA. No further testing is needed.
Continue to investigate CA (e.g. AL or ATTR amyloidosis)
Well done, you chose the preferable answer. Because of the conflicting results from ECHO/ECG and cMRI, we cannot be certain if the patient has HCM; therefore, further testing is necessary. ECHO/ECG findings indicate that HCM is less likely, given that there is concentric increased wall thickness, lack of systolic anterior motion, increased RV wall thickness and no LVH detected via ECG. This strengthens the case for CA. No further testing is needed.
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4 of 5
To evaluate this patient further, which tests would you recommend next?
AL amyloidosis testing* and nuclear scintigraphy
Well done, you chose the preferable answer. At this stage it could potentially be AL and/or transthyretin amyloid cardiomyopathy (ATTR-CM), which is why it is necessary to test both for final diagnosis. Rule out AL amyloidosis by testing M-component, free light chain (FLC) assay in serum/urine and protein electrophoresis with immunofixation in serum/urine. For ATTR-CM, nuclear scintigraphy is a non-invasive, fast, and relatively inexpensive option compared with biopsy. Combining AL amyloidosis testing with nuclear scintigraphy can be part of a diagnostic algorithm to ensure that all patients with heightened clinical suspicion for ATTR-CM undergo the correct investigative procedures to obtain a definitive diagnosis.
Refer to hematology
Not optimal, see the marked preferable answer. This approach could provide inconclusive results and is therefore not recommended. At this stage it could potentially be AL and/or ATTR-CM, which is why it would be good to conduct both tests for final diagnosis. Combining tests to investigate AL amyloidosis with nuclear scintigraphy can be part of a diagnostic algorithm to ensure that all patients with heightened clinical suspicion for ATTR-CM undergo the correct investigative procedures to obtain a definitive diagnosis.
* Free light chain (FLC) assay in serum/urine and protein electrophoresis with immunofixation in serum/urine.
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5 of 5
As a next step, the patient was referred for 99mTc-DPD nuclear scintigraphy and AL amyloidosis testing*.
Take a look at the test results. What are your conclusions?
AL amyloidosis confirmed
Not optimal, see the marked preferable answer. AL amyloidosis is ruled out because the test results were within normal ranges.
ATTR amyloidosis confirmed
Well done, you chose the preferable answer. The combination of ECHO/ECG, nuclear scintigraphy, and AL amyloidosis testing* has provided us with enough clues to establish the correct diagnosis of ATTR amyloidosis and rule out AL amyloidosis.
ATTR amyloidosis suspected but fat biopsy is required
Not optimal, see the marked preferable answer. A fat biopsy is not required to confirm the diagnosis of ATTR amyloidosis, as non-invasive nuclear scintigraphy in combination with tests outruling AL amyloidosis can often be sufficient, provided stringent criteria are met. Fat and/or other biopsies are required for a definitive diagnosis if AL amyloidosis is suspected.
* Free light chain (FLC) assay in serum/urine and protein electrophoresis with immunofixation in serum/urine.
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Summary
AL amyloidosis could be ruled out due to negative results of the AL amyloidosis tests. ATTR amyloidosis is confirmed by Grade 3 scintigraphy findings. Subsequent genetic testing is recommended in some centers; this patient was found to be negative for a mutation in the transthyretin gene. Consequently, wild-type ATTR-CM is confirmed.
Key take home messages Echocardiographic features in a patient with presumed HF with preserved ejection fraction (HFpEF) or HF with mid-range ejection fraction (HFmrEF; not all patients have HFpEF) revealed a hypertrophic phenotype and concentric increased wall thickness, with increased relative wall thickness (RWT), no LVH on ECG, and a strain pattern consistent with CA, while cMRI results were inconclusive. Suspicion of ATTR amyloidosis was confirmed through a non-invasive route.
Applying this knowledge in your practice Clinical features, both through imaging modalities and patient characteristics, can help differentiate CA from HCM. Early application of appropriate imaging techniques and a swift ruling out of HCM allows for a rapid, non-invasive diagnosis of ATTR-CM.
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Test results New!
In this section you will continuously receive new facts and test results for this patient.
Use the headings below during the case to access and interpret information about the patient.
HistoryNew!
ECHONew!
ECGNew!
ScintigraphyNew!
AL amyloidosis testNew!
Cardiac biopsyNew!
Case 2
Background
A 61-year-old male plumber and former professional athlete, with a previously healthy, active lifestyle presents with lethargy and fatigue. He reports to have felt weaker, with a lower capacity to work in the past 3 years. Last year, the patient had a coronary artery bypass graft.
The patient came into the hospital with acute severe chest pain and cold sweats.
During clinical examination it was revealed that the patient has an inferior ST elevation myocardial infarction (STEMI) with a three-vessel disease. The patient was sent for a percutaneous coronary intervention (PCI) in the left circumflex artery. The patient had an N-terminal pro B-type natriuretic peptide (NT-proBNP) biomarker value of 1554 ng/L. An electrocardiogram (ECG) and echocardiogram (ECHO) were performed.
Start
1 of 5
Check the patient history, ECHO and ECG results and consider if there are any “red flags” that can cause suspicion about cardiac amyloidosis (CA). Which “red flags” for CA do you see?
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2 of 5
The patient revealed a thick septum (17 mm) and a LV thickness discordance in relation to QRS voltage, both of which are “red flags” for CA. To evaluate this patient further, which tests would you recommend?
Refer to haematology
Not optimal, see the marked preferable answer. This approach could provide inconclusive results and is therefore not recommended.
Light-chain (AL) amyloidosis testing* and nuclear scintigraphy of the heart
Well done, you chose the preferable answer. AL amyloidosis testing* is crucial to rule out AL amyloidosis. Ruling out AL amyloidosis in combination with nuclear scintigraphy of the heart can be part of a diagnostic algorithm to ensure that all patients with heightened clinical suspicion for transthyretin cardiac amyloidosis (ATTR-CM) undergo the correct investigative procedures to obtain a definitive diagnosis.
All of the above
Not optimal, see the marked preferable answer. AL amyloidosis testing*, scintigraphy, and biopsy should provide enough information for a diagnosis.
* Free light chain (FLC) assay in serum/urine and protein electrophoresis with immunofixation in serum/urine.
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3 of 5
The patient was tested for AL amyloidosis and nuclear scintigraphy was performed. In parallel, a fat biopsy was taken that turned out to be negative for amyloid. Take a look at the results from the AL testing and the nuclear scintigraphy.
Based on the results thus far, what is your conclusion?
No amyloid, something else
Not optimal, see the marked preferable answer.
Wild-type ATTR (ATTRwt) amyloidosis
Not optimal, see the marked preferable answer. It could potentially be difficult to see wild-type amyloid fibrils on a fat biopsy. Sufficient material is required, as well as an expert to analyze the samples. The patient is also relatively young for an ATTRwt diagnosis.
Hereditary ATTR (ATTRv) amyloidosis
Not optimal, see the marked preferable answer. To distinguish between ATTRwt and ATTRv amyloidosis, a blood test to screen for genetic mutations causing ATTRv amyloidosis is necessary. The absence of these genetic mutations will confirm a diagnosis of ATTRwt amyloidosis.
Unsure
Well done, you chose the preferable answer. We have not yet tested for genetics.
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4 of 5
To evaluate this patient further, what do you do next?
Cardiac biopsy and genetic testing
Well done, you chose the preferable answer. Because of the conflicting findings, cardiac biopsy would be recommended in this case, but genetic testing is also important, as the patient is relatively young.
Other tests
Not optimal, see the marked preferable answer. It is important not to rely solely on one diagnostic technique when CA is suspected. However, in this instance, continuing with additional tests could result in a delayed diagnosis.
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5 of 5
The patient was referred for a cardiac biopsy and genetic testing. The genetic testing turned out to be negative for a mutation in the transthyretin (TTR) gene. You now have all you need to diagnose the patient. Take a look at the test results.
What is your diagnosis?
AL amyloidosis
Not optimal, see the marked preferable answer. AL amyloidosis can be ruled out with the AL amyloidosis testing*.
ATTRwt amyloidosis confirmed
Well done, you chose the preferable answer. Based on all the findings – the strong positive scintigraphy results, the increased IVST, and the positive cardiac biopsy results – ATTRwt amyloidosis can be confirmed.
ATTRwt amyloidosis suspected but not confirmed
Not optimal, see the marked preferable answer. We have all the diagnostic information we need for this case. Further testing will only cause unnecessary delay in diagnosis.
* Free light chain (FLC) assay in serum/urine and protein electrophoresis with immunofixation in serum/urine.
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Summary
AL amyloidosis was ruled out due to normal hematological findings; ATTR amyloidosis was detected in the heart biopsy. Note, the fat biopsy was negative, but in ATTRwt amyloidosis, negative fat biopsy does not necessarily indicate a lack of ATTR amyloidosis. Genetic testing is recommended in some centers for such cases and the patient was found to be negative for a mutation in the transthyretin (TTR) gene. Consequently, ATTRwt amyloidosis was confirmed.
Key take home messages It is important to hold suspicion at any sign of ATTR amyloidosis, such as increased wall thickness, and investigate further. Note, this case did not show an apical sparing that is often seen in ATTR-CM. Further, the patient had a Grade 3 positive scintigraphy scan, but it was unclear if the positive uptake of DPD was caused by acute STEMI.
Combining knowledge of clinical signs and nuclear scintigraphy can help to assess the presence of amyloid burden in the heart and need for biopsy. Fat biopsy is not always conclusive for ATTRwt amyloidosis; thus, a diagnosis of ATTRwt amyloidosis should not be disregarded in this situation. Since the fat biopsy was inconclusive and there was uncertainty as to whether the acute STEMI potentially led to the uptake of 99mTc-DPD, a cardiac biopsy was performed, showing massive CA.
Applying this knowledge in your practice Due to overlapping symptomatology with other cardiac conditions, such as lethargy, ATTR amyloidosis may not be initially assumed. Investigations such as nuclear scintigraphy, combined with tests out ruling AL amyloidosis enable a differential diagnosis of ATTR amyloidosis to be achieved.
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Test results New!
In this section you will continuously receive new facts and test results for this patient.
Use the headings below during the case to access and interpret information about the patient.
HistoryNew!
ECGNew!
ECHONew!
Cardiac biomarkersNew!
AL amyloidosis testNew!
ScintigraphyNew!
Case 3
Background
A 75-year-old female, with a history of atrial fibrillation (AF) and stroke, presented with tachycardia and shortness of breath. The patient history included irritable bowel syndrome (IBS), mild polyneuropathy, and hay fever. She had surgery for carpal tunnel syndrome 5 years ago.
Start
1 of 4
Due to her cardiological symptoms the patient was referred for an electrocardiogram (ECG), echocardiogram (ECHO), and biomarker analysis. Based on the results this far, which “red flags” for cardiac amyloidosis (CA) do you see?
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2 of 4
This elderly patient has a history of AF, stroke, and dyspnea. Diagnostic tests performed show increased interventricular septal thickness on ECHO, but normal voltage on ECG examination. Cardiac biomarkers were significantly elevated. A level of suspicion for CA remains due to an increase in wall thickness and increased N-terminal pro-B-type natriuretic peptide (NT-proBNP) and Troponin T levels.
From the evidence you have seen so far, what do you suspect?
Wild-type ATTR (ATTRwt) amyloidosis
Not optimal, see the marked preferable answer. To distinguish between wild-type and hereditary ATTR amyloidosis (ATTRv), a blood test to screen for genetic mutations causing ATTRv is necessary. The absence of these genetic mutations will confirm a diagnosis of ATTRwt amyloidosis.
Light-chain (AL) amyloidosis
Not optimal, see the marked preferable answer. Although NT-proBNP is typically higher in AL amyloidosis than in transthyretin amyloid cardiomyopathy (ATTR-CM), further laboratory testing is needed to confirm or rule out AL amyloidosis.
Unsure
Well done, you chose the preferable answer. More information is needed to make the right diagnosis.
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3 of 4
How would you proceed?
Cardiac biopsy
Not optimal, see the marked preferable answer. A cardiac biopsy is associated with risk for the patient and should be avoided, if possible.
AL amyloidosis testing* and nuclear scintigraphy
Well done, you chose the preferable answer. Combining AL amyloidosis testing* with nuclear scintigraphy can be part of a diagnostic algorithm to ensure that all patients with heightened clinical suspicion for ATTR-CM undergo the correct investigative procedures to obtain a definitive diagnosis. Nuclear scintigraphy is non-invasive, fast, and relatively inexpensive compared with biopsy and in combination with tests ruling out AL amyloidosis, nuclear scintigraphy can be used to diagnose ATTR-CM patients.
Nuclear scintigraphy
Not optimal, see the marked preferable answer. High-grade cardiac uptake on nuclear scintigraphy has high sensitivity and specificity for ATTR-CM; however, we also need to rule out AL amyloidosis.
* Free light chain (FLC) assay in serum/urine and protein electrophoresis with immunofixation in serum/urine.
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4 of 4
You now have all you need to diagnose the patient. Take a look at the test results.
What is your diagnosis?
AL amyloidosis
Not optimal, see the marked preferable answer. AL amyloidosis was ruled out with different AL amyloidosis tests.
ATTR-CM confirmed
Well done, you chose the preferable answer. Based on the strong positive scintigraphy results, and thickened intraventricular septum, the patient was diagnosed with ATTR-CM.
ATTR-CM suspected but not confirmed
Not optimal, see the marked preferable answer. Based on the strong positive scintigraphy results, and thickened intraventricular septum, the patient was diagnosed with ATTR-CM.
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Summary
Based on the strong positive scintigraphy results, and thickened intraventricular septum, the patient was diagnosed with ATTR-CM. AL amyloidosis was ruled out with different AL amyloidosis tests. In this case, genetic testing was also performed and revealed that the patient had hereditary ATTRv-CM.
Key take home messages Suspicion of ATTRv amyloidosis should not be limited to young/middle-aged individuals; onset of symptoms can also occur in later years. Although low voltages on an ECG in the setting of increased LV wall thickness is a classic feature of CA and is commonly seen in AL amyloidosis, many ATTR-CM patients do not have low voltages, but instead have a discrepancy between the presence of LV hypertrophy on imaging with normal, or low-normal, voltages on ECG. In addition, the genotype in ATTRv amyloidosis influences the degree and progression of HF.
Applying this knowledge in your practice Symptoms of non-cardiac involvement, including carpal tunnel syndrome and polyneuropathy, should not be disregarded, as these can be valuable “red flags” for ATTR-CM.
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Test results New!
In this section you will continuously receive new facts and test results for this patient.
Use the headings below during the case to access and interpret information about the patient.
HistoryNew!
ECGNew!
ECHONew!
cMRINew!
ScintigraphyNew!
AL amyloidosis testNew!
Case 4
Background
A 71-year-old retired man went to a primary care center due to syncope. The patient had a concentric left ventricular hypertrophy (LVH), and the biomarker analysis showed highly elevated N-terminal pro-B-type natriuretic peptide (NT-proBNP; >35000 ng/L).
The patient´s condition worsened and after 3 months the patient was referred to a cardiology specialist clinic.
The clinical examination revealed the following:
Increased dyspnea
Increased weight by 10 kg
Swollen periphery
Kidney failure
Proteinuria and hypoalbuminemia
Start
1 of 4
Take a look at the results thus far. The biomarker, NT-proBNP, is universally elevated in cardiac amyloidosis (CA). A level of 300 ng/L and above is a sign of heart failure (HF), but in this patient the levels are markedly increased most probably due to renal failure and nephrotic syndrome.
To evaluate this patient further, what would be your next step?
Refer for electrocardiogram (ECG) and echocardiogram (ECHO)
Well done, you chose the preferable answer. Because clinical examination revealed regular signs of HF, amyloidosis would not be expected at this stage. Further investigations are therefore needed. An ECHO is the most commonly used imaging tool in HF and CA and, when combined with an ECG, can reveal detailed information.
Chest X-ray
Not optimal, see the marked preferable answer. A chest X-ray is not required at this stage. We need to investigate the cause of HF.
cMRI
Not optimal, see the marked preferable answer. Would be good to always start with ECG and ECHO. Cardiac magnetic resonance imaging (cMRI) findings in CA often depend on the quality of the software, the machine, and the experience of the clinician; therefore, results must be interpreted with caution.
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2 of 4
The patient was sent for ECHO and ECG; additionally, a cMRI was performed. Look at the results on the left and consider if any “red flags” raise a suspicion about CA. Based on the results thus far, which “red flags” for CA do you see?
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3 of 4
The ECHO findings increased suspicion of cardiac amyloid deposition. The cMRI findings were not helpful in this case. This patient is an elderly male with a history of syncope. Diagnostic tests show high levels of NT-proBNP suggestive of HF. ECHO findings indicate a hypertrophic phenotype with associated infiltrative features, including increased thickness of the interatrial septum and right ventricular free wall. The patient also had kidney failure. So, based on these findings, CA is suspected.
What would you do next?
Nuclear scintigraphy
Not optimal, see the marked preferable answer. It is always important to rule out AL amyloidosis due to its progressive feature and poor prognosis.
Refer to hematology
Not optimal, see the marked preferable answer. This approach could provide inconclusive results and is therefore not recommended.
Light-chain (AL) amyloidosis testing*
Well done, you chose the preferable answer. If CA is suspected, it is always important to rule out AL amyloidosis at an early stage due to its rapid progression and poor prognosis.
* Free light chain (FLC) assay in serum/urine and protein electrophoresis with immunofixation in serum/urine.
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4 of 4
The patient was tested for AL amyloidosis but in parallel was also sent for 99mTc-DPD nuclear scintigraphy. Based on these results, are you ready to diagnose the patient?
Based on everything you know, what is your answer?
Yes, definite diagnosis of AL amyloidosis
Not optimal, see the marked preferable answer. It is now a high suspicion that this could be AL amyloidosis, but a fat biopsy (or target organ) and bone marrow biopsy is recommended to get a definite diagnosis. When AL amyloidosis is concluded, the patient should be referred to a hematologist.
No, fat and bone marrow biopsy
Well done, you chose the preferable answer. There is a high suspicion that this could be AL amyloidosis. A fat biopsy (or target organ) and bone marrow biopsy is recommended since a histologic conformation and amyloid typing is needed for a definite diagnosis. When AL amyloidosis is concluded, the patient should be referred to a hematologist.
No, I believe the patient could have ATTR amyloidosis
Not optimal, see the marked preferable answer. AL amyloid testing results indicate AL amyloidosis.
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Summary
Positive results on AL amyloidosis testing (FLC assay in serum/urine and protein electrophoresis with immunofixation in serum/urine), together with non- or low-grade scintigraphy findings, is a strong indication of AL amyloidosis. Fat biopsy and bone marrow biopsy is needed to confirm the diagnosis of AL amyloidosis and the patient should instantly be referred to a hematologist. It is possible for patients to have concurrent AL and ATTR amyloidosis. When suspicion of ATTR amyloidosis cannot be ruled out with only scintigraphy and serum/urine analysis, histologic typing may be required.
Key take home messages Differential diagnosis is critical; patients with hypertrophy and some evidence of amyloidosis should undergo tests for AL amyloidosis as well as nuclear scintigraphy, in order to execute as early a diagnosis as possible.
Applying this knowledge in your practice For non-invasive diagnosis, testing for AL amyloidosis must always be performed alongside testing with nuclear scintigraphy.
