Two Kinds of Cardiac Amyloidosis in One Patient: A Case Report

INTRODUCTION

Amyloidosis is a progressive and debilitating disease that can be systemic or organ-limited. It results from insoluble homomeric amyloid fibrils, composed of a variety of serum proteins, that gradually replace normal tissue in various body organs. Immunoglobulin light chain (AL) amyloidosis, wild-type transthyretin amyloidosis (ATTRwt), and hereditary amyloidosis (ATTRm) are the common causes of amyloid cardiomyopathy. Although each of these diseases has unique features, there is an appreciable overlap in clinical presentation. In addition, there is the potential for two discrete types of amyloidosis to coexist in the same patient, a phenomenon rarely reported in the literature.^1-4 In the past, little effective treatment was available for the cardiac amyloidosis, and therefore the definite diagnosis of different types of cardiac amyloidosis was often neglected in the clinical setting. However, as more selective therapies have become available, making the correct diagnosis of cardiac amyloidosis has become mandatory to provide proper therapy. Herein, we reported a complex case with two different types of cardiac amyloidosis which required a myocardial biopsy to make a definite diagnosis.

CASE

An 83-year-old Taiwanese man with hypertension presented with progressively exertional dyspnea for months. He was an ex-smoker, and took bisoprolol, losartan, and nicorandil for hypertension control. An electrocardiogram showed sinus rhythm, poor R-wave progression, and nonspecific ST-T changes (Figure 1A). A coronary angiogram showed patent coronary arteries (Figure 1B), and echocardiography showed severe concentric left ventricular hypertrophy (mean wall thickness 16 mm) (Figure 1C). Based on the clinical symptoms, an elevated plasma brain natriuretic peptide level (427.2 pg/mL) and preserved left ventricular ejection fraction (65%), heart failure with preserved ejection fraction (HFpEF) was diagnosed (Figure 1D). Several "red flag" signs were found during work-up for HFpEF. First, a disproportionately low QRS voltage with left ventricular hypertrophy was noted on electrocardiography. Second, the electrocardiography showed a pseudo-infarction pattern (qs pattern). Third, reduced global longitudinal strain with apical sparing, which was defined as the "cherry on top" sign, was shown on echocardiography (Figure 1E). These signs and symptoms raised the suspicion of cardiac amyloidosis.

Figure 1.

(A) Electrocardiogram showed sinus rhythm, poor R-wave progression, nonspecific ST-T changes and QS pattern at V1-V3. (B) Coronary angiography showed patent coronary arteries. (C) Transthoracic echocardiogram of parasternal long axis view with M-mode showed left ventricular hypertrophy (17 mm in the basal septum and 15 mm in the posterior wall). (D) Duplex of mitral inflow showed mitral valve (MV) peak E 49.4 cm/s and MV peak A 62.2 cm/s, indicating diastolic dysfunction. (E) Global longitudinal strain showed reduced longitudinal systolic strain with apical sparing. (F) Cardiac magnetic resonance (CMR) with post-contrast image showed diffuse subendocardial late gadolinium enhancement (arrow). (G) CMR with pre-contrast T1 image of short axis view showed a significantly elevated T1 signal to 1,022 ms. (H) CMR with extracellular volume fraction (ECV) maps of short axis view showed increased ECV to 42.2%. (I) ^99mTc-PYP scintigraphy with single photon emission computed tomography(SPECT)/computed tomography (CT) confirmed radiotracer uptake in the myocardium. (J) ^99mTc PYP scintigraphy with SPECT showed moderate cardiac uptake equal to bone with mildly attenuated bone uptake, which was classified as grade 2 according to the Semi-quantitative Visual Grading of Myocardium system. (K) The heart-to-contralateral lung ratio was 1.4569.

Further cardiac magnetic resonance imaging supported the impression of cardiac amyloidosis by showing late gadolinium enhancement of the myocardium (Figure 1F) with native T1 mapping of 1022 ms (Figure 1G) and extracellular volume of 42.2% (Figure 1H). Electrophoresis revealed an elevated free kappa light chain in both serum and urine, which favored AL amyloidosis. However, a ^99mtechnetium pyrophosphate scintigraphy scan also showed abnormally increased radiotracer activity throughout the myocardium (visual score: 2 and heart-to-contralateral lung ratio: 1.46) (Figure 1I, 1J & 1K), which increased the likelihood of ATTR cardiac amyloidosis.

Due to the ambiguous results, the patient subsequently underwent an endomyocardial biopsy of the right ventricular septum. Pathology showed myocardial tissue with amyloid deposition as seen on Congo red staining under polarized light. Interestingly, both AL and ATTR amyloidosis were positive in immunochemistry staining. The AL stain was mainly located at perivascular areas (Figure 2A, 2B & 2C), and the ATTR stain was in the myocardium and contributed to major amyloid disposition in the heart tissue (Figure 2D, 2E & 2F). Genetic tests for ATTR mutations were negative, which confirmed the diagnosis of ATTRwt. An endoscopic gastric mucosal biopsy, large intestine mucosal biopsy, and percutaneous fat pad biopsy were also performed. However, only AL amyloid deposition was found in the extracardiac tissue biopsy. Subsequently, mixed-type cardiac amyloidosis and systemic light-chain amyloidosis were diagnosed.

Figure 2.

Endomyocardial biopsy of the right ventricular was done. (A, B & C) Immunohistochemistry of kappa light chain revealed kappa deposition located at perivascular areas (arrowheads). (D, E & F) Immunohistochemistry of monoclonal-transthyretin revealed transthyretin deposition in the myocardium (arrows).

DISCUSSION

Recent studies have revealed that amyloidosis is an immensely underdiagnosed cause of HFpEF, particularly ATTRwt. In autopsies of patients aged 85 years or older, ATTRwt has been identified in up to 25% of the patients.⁵ Another autopsy study found ATTRwt in 40% of patients with HFpEF diagnosed after age 65 years.⁶ Despite this surprisingly high prevalence, a correct diagnosis of cardiac amyloidosis can be challenging and easily missed in clinical practice. Our case demonstrated the co-existence of two different types of amyloidosis in an individual patient, an uncommon presentation that was observed in less than 1% of cases in the cohort reported by Sidiqi et al.¹ Although uncommon, identifying the nature and source of the amyloidogenic protein is critical for proper management.

Screening for plasma cell dyscrasia is a crucial step during the diagnosis of cardiac amyloidosis. However, it is important to note that plasma cell dyscrasia does not necessarily confirm AL amyloidosis, as monoclonal gammopathy of unknown significance (MGUS) or myeloma may coexist with TTR amyloidosis. A high prevalence (39%) of coexistent MGUS with ATTRwt amyloidosis was reported by Phull et al., with an MGUS rate higher than that in the general population.⁷ They found that 39% of the ATTRwt patients had an MGUS, 27% of the patients had a monoclonal gammopathy based on an abnormal serum immunofixation electrophoresis, and an additional 12% of the patients had light chain monoclonal gammopathy based on an abnormal serum free light chain assay ratio.⁷ In addition, the incidence rates of MGUS, myeloma, and ATTRwt were higher in the elderly, and the prevalence of these diseases may have been higher due to effective therapies.

The concurrence of AL amyloidosis and ATTRwt amyloidosis is difficult to distinguish clinically. By following the diagnostic algorithm proposed by Falk et al.,⁸ the co-existence of both AL amyloidosis and ATTR amyloidosis can easily be missed. If plasma-cell dyscrasia is present, ATTR cardiomyopathy can be excluded in the diagnostic algorithm. Furthermore, even if a cardiac or non-cardiac biopsy is performed, if comprehensive immunohistochemical staining including ATTR and AL stains is not done, mixed ATTR and AL cardiomyopathy can still be missed. An additional ^99mTc PYP scan is helpful in this situation, especially in cases with high clinical suspicion.⁹ When the clinical picture is incongruent with the diagnosis of cardiac amyloidosis, a cardiac biopsy with comprehensive immunohistochemical staining is needed to confirm the diagnosis. Although typing of amyloidosis using immunohistochemical methods has been reported to have pitfalls owning to technical limitations and challenges,^10,11 it is much more available than mass spectrometry in clinical practice. Through careful interpretation, immunohistochemical staining of the myocardium can help to clarify the types of cardiac amyloidosis and allow for appropriate treatment.

LEARNING POINTS

The concurrence of two different types of amyloidosis in patients with cardiac amyloidosis may occur. A ^99mTc PYP scan is non-invasive and helpful to identify patients who require an endomyocardial biopsy when the clinical picture is ambiguous. Immunohistochemical staining is important to help identify the correct type and ensure proper treatment.

DECLARATION OF CONFLICT OF INTEREST

All authors have no conflict of interest to declare.