Relationship between monoclonal gammopathy and cardiac amyloid type

Abstract

Background

Proper identification of cardiac amyloid type is essential for patient management, and has historically relied upon immunohistochemical- or immunofluorescence-based methods, often correlated with serum and urine protein electrophoresis (SPEP and UPEP) with immunofixation electrophoresis (IFE), and/or free light chain immunoassay (FLC). The recent implementation of mass spectrometry-based proteomic analysis for clinical amyloid typing allows us to determine the validity of these tests to predict amyloid type. Validity of SPEP/UPEP/IFE and FLC assays in cardiac amyloid prediction was examined.

Methods

Retrospective analysis of two tertiary care populations (n=143, 2001–2010), of cardiac biopsy-proven amyloidosis, was performed.

Results

Amyloid of transthyretin (ATTR) type was found in 81 (57%) of 143 patients and immunoglobulin light chain amyloid was found in the remaining 62 (43%). SPEP/UPEP/IFE detected a monoclonal gammopathy in 76 individuals, 56 with AL and 20 with ATTR amyloid and was overall a poor predictor of AL amyloid in this patient population: specificity (75%; 95% CI, 65-83%) and positive predictive value (PPV 74%; 95% CI, 63–82%). The FLC assay detected an abnormal kappa/lambda ratio in 61 patients, 53 with AL and 8 with ATTR amyloid and was a better predictor of AL amyloid type in this patient population: specificity (90%, 95% CI, 82–95%) and PPV (87%, 95% CI, 76–93%).

Conclusions

ATTR was the predominant amyloid type in this large cohort of endomyocardial biopsies characterized by mass spectrometry. Although FLC performs better than SPEP/UPEP/IFE, the performance of blood and urine studies for monoclonal proteins are not adequate to classify amyloid type.

Summary

This large-scale retrospective analysis of cardiac amyloidosis shows that blood and urine monoclonal protein studies are not, by themselves, robust predictors of cardiac amyloid type in patients undergoing endomyocardial biopsy.

Introduction

Cardiac amyloidosis is a major cause of restrictive cardiomyopathy, a disease associated with high morbidity and mortality in middle aged and elderly adults. The most frequently described proteins that cause cardiac amyloidosis have historically been free kappa (κ) or lambda (λ) light chains as a result of a plasma cell dyscrasia [1], [2], [3], [4]. Light chain amyloidosis (AL) involving the heart causes a rapidly deteriorating clinical scenario with anticipated median survival of 3.7 months among those patients with advanced cardiac disease [5]. Transthyretin amyloidosis (ATTR) is the other frequently encountered cause of cardiac amyloidosis. It is responsible for both senile amyloidosis occurring in elderly individuals and hereditary forms of cardiotropic or systemic amyloidosis occurring in middle-aged individuals [6]. In the latter disease, numerous mutations have been described, of which V122I is the most common in the United States, particularly among African-Americans [7]. ATTR manifests more slowly than AL and the median survival is approximately 6 years from diagnosis [8].

The proper typing of cardiac amyloid is essential for optimal patient care because treatment options for cardiac amyloidosis vary widely based on the amyloid type. Treatment of AL amyloidosis is directed at the plasma cell clone, i.e., chemotherapy. Aggressive treatment of hereditary ATTR may require both liver and cardiac transplantation. Often, individuals with senile amyloidosis are too old to be considered for cardiac transplantation. However, pharmaceutical therapies are being developed to target ATTR which might benefit this population [9]. In addition, selected patients with ATTR cardiac amyloidosis may be treated with implantation of a ventricular assist device, either as a bridge to transplantation or as destination therapy [10].

The diagnosis of cardiac amyloidosis is generally made via one of two pathways: (1) a patient has classic clinical symptoms, electrocardiographic, echocardiographic, and/or cardiac magnetic resonance imaging (MRI) findings for amyloidosis, and the amyloid tissue diagnosis is made on another tissue; or (2) a patient has an endomyocardial cardiac biopsy that either expectedly or unexpectedly reveals amyloidosis. Most diagnoses of AL cardiac amyloid are made through the first pathway.

Amyloid typing has historically relied on immunohistochemical or immunofluorescent studies performed on endomyocardial biopsies [1], [2]. Depending on the institution, a panel of antibodies targeting κ, λ, TTR and other possible amyloid types have been employed [1], [2], [4]. Interpreting these staining panels has been difficult and fraught with problems relating to tissue fixation and other inducers of artifact [11], [12], [13], [14]. The ability to accurately predict amyloid type varies from institution to institution with only “amyloid centers” claiming to achieve consistently robust results, although no well-designed studies have been done to validate this notion. To confirm the determination of amyloid type, pathologists have often relied on ancillary tests such as serum and/or urine protein electrophoresis and immunofixation electrophoresis (SPEP/UPEP/IFE) to correlate with the immunohistochemical staining interpretation [15]. Likewise, some clinicians have also been reliant on these ancillary tests to determine the amyloid type in the heart.

SPEP/UPEP/IFE assays are used to find and identify clonal immunoglobulins. These studies are used in a variety of clinical settings, predominantly related to the diagnosis and management of plasma cell dyscrasias where they have great value. A more recently developed free light chain immunoassay (FLC, Freelite; The Binding Site, San Diego, CA, USA) uses antisera that distinguish free from bound κ and λ light chains [16]. This test is typically used for prognosis and management of myeloma and immunoglobulin light chain (AL) amyloidosis and for risk stratification of monoclonal gammopathy of undetermined significance. Although it was not designed or tested for this purpose, it has more recently been used in conjunction with SPEP/UPEP/IFE in the workup of cardiac amyloidosis cases. Historically, the presence of a monoclonal gammopathy in the context of amyloidosis compelled physicians to make a diagnosis of AL amyloidosis, but it is becoming increasingly clear that such an assumption is fallacious [17], [18].

In 2008, the Mayo Clinic developed a clinical mass spectrometry test to determine amyloid type in surgical pathology tissues [11]. This assay, and similar tests performed elsewhere, has become the clinical gold standard in amyloid typing with over 98% sensitivity and specificity, replacing immunohistochemical determination of amyloid at both the Mayo Clinic and The Johns Hopkins Hospital. Shortly after adopting this test, we identified multiple cases of cardiac amyloid that were determined to be ATTR amyloidosis in patients who also had a concurrent monoclonal gammopathy. While such findings have been reported, there has never been an analysis of the performance characteristics of SPEP/UPEP/IFE and FLC studies to differentiate AL from transthyretin (ATTR) cardiac amyloid [6], [17]. We have determined the performance of these tests and created a diagnostic algorithm for determining cardiac amyloid type.