A case of amyloidosis (questions)

 

What is amyloidosis?

 

Amyloidosis is a clinical disorder caused by extracellular deposition of insoluble abnormal fibrils, derived from aggregation of misfolded normally soluble protein.

 

What is the classification of amyloidosis?

 

1) Systemic AA amyloidosis. Formerly known as secondary amyloidosis, is a complication of chronic inflammatory conditions or any disorder associated with a sustained acute-phase response in which there is markedly increased production of serum amyloid A protein (SAA). Renal disease dominates the clinical picture in AA amyloidosis, and the condition almost always presents with proteinuria and renal failure. Regression of AA amyloid following suppression of SAA production may lead to reversal of organ dysfunction. Clinically significant involvement of the heart is very rare.  

 

2) Systemic AL amyloidosis. Previously known as primary amyloidosis, is the most commonly diagnosed form of clinical amyloid disease in developed countries. The AL fibrils are derived from monoclonal immunoglobulin light chains and consist of the whole or part of the variable (VL) domain. Almost any B-cell dyscrasia, including myeloma, lymphomas, and macroglobulinaemia may be complicated by AL amyloidosis, but more than 80% of cases are associated with subtle and otherwise “benign” monoclonal gammopathies. Multiorgan infiltration is typical. It occurs equally in men and women, usually over the age of 50 years but as early as the third decade. The heart is affected pathologically in up to 90% of AL patients, in 50% of whom diastolic heart failure with physical signs of right heart failure is a presenting feature. Conversely, _5% of patients with AL amyloidosis involving the heart have clinically isolated cardiac disease.

 

3) Hereditary systemic amyloidosis is caused by deposition of amyloid fibrils derived from genetic variants of transthyretin (TTR), apolipoprotein A-I, lysozyme, or fibrinogen alpha-chain and other extremely rare variants. Clinical syndromes include cardiomyopathy, nephropathy, or neuropathy, though the heart is most prominently involved in variant TTR type, which is associated with more than 100 different TTR mutations, most often with associated neuropathy. This entity is not rare; indeed, the amyloidogenic TTR Val122Ile variant is present in 4% of African Americans, and 23% of African Americans with cardiac amyloidosis have this variant.

 

4) Senile systemic amyloidosis (SSA) is caused by deposition of amyloid fibrils derived from normal wild-type transthyretin and almost always presents as a slowly progressive, infiltrative amyloid cardiomyopathy. Senile systemic amyloidosis is exceptionally rare in those younger than 60 years of age, but its prevalence ranges from 25% to 36% in those older than 80 years of age. There is a large male predominance, and senile systemic amyloidosis has a major predilection for the heart. Patients usually present with congestive heart failure, with carpal tunnel syndrome being the only common accompanying extracardiac manifestation.

Normal-voltage electrocardiogram (ECG) with a left anterior fascicular block and thickened left ventricular (LV) walls on echocardiography are characteristic. Despite the older age and greater myocardial infiltration, the median SSA survival of 75 months is greater than for AL amyloidosis. The slowly progressive nature, despite greater myocardial infiltration, distinguishes SSA from AL amyloidosis. Diagnosis is often surmised but can be achieved definitively by the demonstration of TTR type amyloid on either cardiac or, occasionally, other (e.g., rectal) biopsy, along with absence of mutations in the TTR gene. There is no specific therapy available, and death is usually due to congestive heart failure or arrhythmias.

 

What are the features suggestive of amyloidosis on cardiac testing?

 

1)    ECG:

1-     The low precordial and limb lead voltage

2-     pseudoinfarction pattern as evidenced by QS waves in 2 consecutive leads

 

2)    ECHO:

1-     LV wall thickenening

2-     Granular or sparkling appearance of the myocardium

3-     Early stages: abnormal relaxation with decreased early diastolic filling velocity (E), increased late diastolic filling velocity (A), and reduced E/A ratio

4-     Advanced stages have restrictive filling abnormalities characterized by shortened E deceleration time and isovolumetric relaxation time

5-     Pericardial effusion

6-     Valvular thickening

 

3)    MRI:

1-     Findings of restrictive cardiomyopathies

2-     Delayed post-gadolinium enhancement images reveal diffuse subendocardial enhancement 

3-     abnormal myocardial and blood-pool gadolinium kinetics

 

How would 99mTc-DPD myocardial uptake help to diagnose subtypes of amyloidosis?

 

DPD scintigraphy was demonstrated to be 100% accurate for distinction between TTR-related and AL etiology, as a selective uptake of DPD is only observed in TTR-related cardiac amyloidosis.

 

In the absence of the 99m Tc-DPD isotope availability, similar selectivity for transthyretin type amyloid can be expected from the alternative bone-seeking isotope 99m Tc-pyrophosphate. In fact, myocardial accumulation of either isotope is highly specific for cardiac amyloidosis. Their purportedly low sensitivity for detection of cardiac amyloidosis in prior studies ( as low as 20%) did not take into account the various types of amyloidosis. There are clearly different uptake characteristics of bone-seeking isotopes in AL and TTR  amyloidosis, ie poor in AL amyloidosis and avid in TTR amyloidosis.

 

References:

 

[1-8]1.         Selvanayagam, J.B., et al., Evaluation and management of the cardiac amyloidosis. J Am Coll Cardiol, 2007. 50(22): p. 2101-10.

2.         Falk, R.H., Diagnosis and management of the cardiac amyloidoses. Circulation, 2005. 112(13): p. 2047-60.

3.         Furukawa, K., et al., Cardiac positron-emission tomography images with an amyloid-specific tracer in familial transthyretin-related systemic amyloidosis. Circulation, 2012. 125(3): p. 556-7.

4.         Kapoor, P., et al., Cardiac amyloidosis: a practical approach to diagnosis and management. Am J Med, 2011. 124(11): p. 1006-15.

5.         Leone, O., et al., New pathological insights into cardiac amyloidosis: implications for non-invasive diagnosis. Amyloid, 2012. 19(2): p. 99-105.

6.         Rapezzi, C., et al., Transthyretin-related amyloidoses and the heart: a clinical overview. Nat Rev Cardiol, 2010. 7(7): p. 398-408.

7.         Rossi, P., et al., 99mTc DPD is the preferential bone tracer for diagnosis of cardiac transthyretin amyloidosis. Clin Nucl Med, 2012. 37(8): p. e209-10.

8.         Zeldenrust, S.R. and L.T. Cooper, Getting to the heart of the matter: cardiac involvement in transthyretin-related amyloidosis. Eur Heart J, 2012.