Concurrent TTR and AL Amyloidosis

Abstract

Background

Amyloidosis is a disorder characterized by misfolded protein deposits in organs, often manifesting as cardiac disease.

Case Summary

A 60-year-old male with a history of isolated proteinuria and recent fat biopsy–proven transthyretin (TTR) amyloidosis was referred to us for evaluation of cardiac involvement with amyloidosis. He underwent a technetium pyrophosphate scan which showed Perugini grade 3 uptake concerning for cardiac involvement. His persistent proteinuria and serum IgG kappa monoclonal protein raised suspicion for light-chain (AL) amyloidosis. Endomyocardial biopsy confirmed TTR cardiac amyloidosis, while a subsequent kidney biopsy and bone marrow evaluation revealed renal-limited AL kappa amyloidosis.

Discussion

This rare presentation highlights the challenge of distinguishing between TTR and AL amyloidosis, especially with atypical features. It underscores the necessity for tissue diagnosis and mass spectrometry in complex cases, even with seemingly concordant noninvasive findings.

Visual Summary

History of Present Illness

A 60-year-old otherwise healthy male was referred to our center due to concerns of cardiac amyloidosis. The patient was previous seen by a nephrologist for long-standing isolated proteinuria with otherwise normal renal function, and underwent a kidney biopsy that was positive for amyloidosis based on Congo red staining and stained negative by immunofluorescence for all immune reactants (including all Ig classes and both light chain isotopes). The patient subsequently had a fat pad biopsy, which was noted to be consistent with transthyretin (TTR) amyloidosis based on liquid chromatography tandem mass spectrometry. He denied any chest pain, shortness of breath, orthopnea, paroxysmal nocturnal dyspnea, palpitations, or neuropathy. Additionally, he had no preceding history of any orthopedic problems including back pain, arthritis, carpal tunnel syndrome, rotator cuff tears, or biceps tendon rupture. He was also physically active and reported no limitations in physical activity (NYHA functional class I). Vital signs were notable for a blood pressure of 110/60 mm Hg, heart rate of 65 beats/min, and respiratory rate 14 breaths per minute, with an oxygen saturation of 98% on room air. Physical examination revealed a regular heart rhythm, no audible heart murmurs, normal respiratory sounds, no peripheral edema, and jugular venous pressure of 8 cm H₂O. His family history was notable for wild-type TTR amyloidosis in his father as well.

Take-Home Messages

• •Clinicians must maintain a high index of suspicion for AL amyloidosis, especially in the presence of atypical features like significant proteinuria or monoclonal gammopathy even if noninvasive testing (pyrophosphate scan) suggests TTR amyloidosis.
• •AL amyloidosis is a medical emergency, and any delay in diagnosis results in adverse prognosis.

Past Medical History

The patient had a known history of proteinuria, with no other past medical history.

Differential Diagnosis

Given the positive Congo red staining on kidney and positive fat pad biopsy for TTR amyloid, TTR cardiac amyloidosis was highest on the differential. Given the significant proteinuria, immunoglobulin light-chain (AL) amyloidosis was also on the differential. Other types of amyloidosis that are rare but can present with proteinuria include-AA amyloidosis, which is often cause by chronic inflammatory conditions, and AApoAI amyloidosis, which can also present with kidney or heart involvement.

Investigations

He had an electrocardiogram that was notable for sinus bradycardia, with low voltage in limb leads (Figure 1). An echocardiogram showed a left ventricular ejection fraction of 55% to 60% (measured by Simpson's biplane method), interventricular and posterior wall thickness of 1.1 cm (normal: 0.6-0.9 cm), grade 1 diastolic dysfunction, and decreased medial and lateral tissue doppler velocities of 5 and 10 cm/s, respectively (Figures 2A and 2B).

Figure 1.

Electrocardiogram

Electrocardiography-sinus bradycardia, normal PR, normal QRS and low voltage in limb leads (marked by arrows).

Figure 2.

Transthoracic Echocardiogram

(A) Transthoracic echocardiogram showing standard parasternal long axis view with normal left ventricular size and function, mild left ventricular hypertrophy. (B) Apical 4-chamber view showing normal biventricular size and function.

He underwent a technetium pyrophosphate (99mTc-PYP) scan with planar and single-photon emission computed tomograhpy imaging at rest and at 180 minutes, which was strongly suggestive of TTR cardiac amyloidosis (Perugini grade 3), assuming no monoclonal proteins. He also underwent workup to rule out AL amyloidosis with serum and urine immunofixation, and free light chains along with cardiac biomarkers for prognostication summarized in Table 1. Due to the significant proteinuria and positive serum immunofixation for IgG kappa monoclonal protein, we performed an endomyocardial biopsy to evaluate for AL amyloidosis, which was notable for diffuse amyloid deposition on hematoxylin and eosin staining, Congo red and crystal violet staining (Figures 3A to 3C).

Table 1.

Laboratory Values

	Result	Reference Range
White blood cell count (× 103), cells/μL	4.98	3.12-8.44
Hemoglobin, g/dL	14.2	12.6-17
Platelets (× 103), cells/μL	285	156-325
Creatinine, mg/dL	0.73	0.7-1.3
eGFR, mL/min/1.73 m2	>90	≥60
NT pro-BNP, pg/mL	142	0-177
High-sensitivity troponin, pg/mL	8	0-15
Free kappa light chain, mg/dL	1.77	0.33-1.94
Free λ light chain, mg/dL	1.23	0.57-2.63
Free kappa/λ light chain ratio	1.44	0.26-1.65
Total protein, g/dL	5.8	6.1-8.5
Albumin, g/dL	3.3	3.9-5.2
Alpha 1 protein, g/dL	0.2	0.2-0.4
Alpha 2 protein, g/dL	0.9	0.6-0.9
Beta globulin, g/dL	0.7	0.6-1
Gamma globulin, g/dL	0.9	0.8-1.8
IgG, mg/dL	1,096	700-1,600
IgA, mg/dL	146	103-501
IgM, mg/dL	63	40-230
SPEI, gm/dL	Monoclonal IgG kappa 0.6	—
UPEI, mg/g	No monoclonal protein; urine protein/creatinine = 5,113 (normal <200)	—

eGFR = estimated glomerular filtration rate; NT-proBNP = N-terminal pro–B-type natriuretic peptide; SPEI = serum protein electrophoresis with immunofixation; UPEI = urine protein electrophoresis with immunofixation.

Figure 3.

Endomyocardial Biopsy

(A) Hematoxylin and eosin staining of myocardial tissue at 40× magnification reveals extensive interstitial accumulation of acellular, eosinophilic, amorphous material separating and displacing adjacent cardiomyocytes. In affected regions, myocytes appear compressed and atrophic, consistent with chronic structural remodeling due to extracellular amyloid infiltration. Arrow indicating presence of eosinophilic amorphous material separating and displacing adjacent cardiomegaly consistent with amyloid deposition. (B) Congo red staining identifies these deposits as amyloid, exhibiting intense congophilia. Under polarized light (not shown), the deposits display the characteristic apple-green birefringence, consistent with a β-pleated sheet structure. (C) Crystal violet staining further confirms the presence of amyloid, highlighting the extracellular deposits as magenta-colored aggregates. Together, these findings demonstrate widespread myocardial amyloid infiltration with associated degenerative changes. Scale bars = 60 μm.

The amyloid subtype was subsequently confirmed to be TTR by laser microdissection followed by mass spectrometry–based proteomic analysis. Additionally, genetic testing was negative confirming the diagnosis of wild-type TTR cardiac amyloidosis.

Patient continued to have nephrotic range proteinuria with reduced serum albumin 3.3 g/dL and creatinine of 0.7 mg/dL along with serum immunofixation positive for IgG kappa M protein. He was referred to nephrology and underwent a repeat kidney biopsy. The biopsy showed congophilic amyloid deposits diffusely and segmentally involving the glomerular mesangium and peripheral capillary walls. Corresponding fibrillar deposits of mean 9 nm diameter were observed by electron microscopy (Figure 4). The deposits stained negative by direct immunofluorescence for IgG, IgM, IgA, C3, C1, and kappa and λ light chains, requiring proteomic typing. Mass spectrometry–based amyloid subtyping was consistent with AL kappa-type amyloid. He was referred to hematology and underwent a repeat bone marrow biopsy, which confirmed a kappa AL-restricted plasma cell clone, and t(11; 14) positivity in CD138-selected cells by fluorescence in situ hybridization.

Figure 4.

Electron Microscopy

Electron microscopy performed on the kidney biopsy shows aggregates of randomly oriented fibrils that range from 8 to 10 nm in diameter infiltrating a glomerular basement membrane (∼25,000).

Management

The patient was started on tafamidis for TTR amyloidosis with cardiac involvement and simultaneously started on a Dara-VCD (daratumumab-cyclophosphamide, bortezomib and dexamethasone) regimen by hematology for management of renal limited AL amyloidosis.

Outcomes and Follow-Up

The patient continues to be active and engaging in physical activity. He has completed 6 cycles of Dara-VCD, and the M spike has decreased from 0.6 mg/dL to 0.3 mg/dL. A bone marrow biopsy showed a decrease in clonal plasma cell count. The patient continues to have proteinuria with a normal renal function.

Discussion

Amyloidosis, a rare disorder characterized by misfolded protein deposits in organs, often manifests as cardiac disease. The 2 most common culprits are TTR, a protein produced primarily in the liver, and immunoglobulin ALs, produced by B cells in the bone marrow and the lymph nodes. Both can lead to heart failure with similar electrocardiographic and echocardiographic findings. Electrocardiographic findings may include low voltage and a pseudo-infarct pattern, and echocardiographic hallmarks include thickened heart walls with small left ventricular cavity size, biatrial enlargement, and relative sparing of the apex with strain imaging, which is also sometimes referred to as “cherry-on-top” appearance. However, distinguishing between AL and TTR amyloidosis is crucial for effective treatment. While AL amyloidosis often presents with renal failure, proteinuria, neuropathy, autonomic dysfunction, and cardiac manifestations, TTR cardiac amyloidosis is more often preceded by musculoskeletal manifestations like carpal tunnel syndrome, lumbar spinal stenosis, and a history of joint replacements. Some of the physical signs specific for AL amyloidosis include macroglossia and orbital purpura.¹

The first step in evaluation for cardiac amyloidosis is ruling out AL amyloidosis with immunofixation (in serum and urine) and free light chains assay. A 99mTc-PYP scan is the next step if these tests are normal. A 99mTc-PYP scan showing moderate to intense uptake (grade 2 or 3) is highly specific and has a near-perfect positive predictive value for transthyretin amyloid cardiomyopathy cardiac amyloidosis, but its sensitivity is only about 70%. This high accuracy is reliable only when a monoclonal protein is absent. However, significant pyrophosphate uptake (grade 2 or 3) can occur in over 20% of patients with AL cardiac amyloidosis. Therefore, if clinical suspicion for cardiac amyloidosis remains high despite a negative pyrophosphate scan, or if a monoclonal protein is detected, an endomyocardial biopsy is recommended to definitively establish the diagnosis.² Our patient underwent an endomyocardial biopsy, which confirmed the diagnosis of TTR cardiac amyloidosis; however, the positive immunofixation for IgG kappa monoclonal protein and the persistent nephrotic range proteinuria prompted us to consider a kidney biopsy again, which is not typically associated with TTR amyloidosis.

The treatment landscape of TTR amyloidosis is evolving and has changed particularly with introduction of TTR stabilizers in the last decade.^3,4 The promising results of the HELIOS-B trial, demonstrating the efficacy of TTR silencers, herald a significant expansion of treatment options for TTR cardiac amyloidosis.⁵ Additionally, there is tremendous interest in newer therapies as well in particular use of monoclonal antibodies to remove the amyloid that is currently in phase 3 trial as well as the use of CRISPR-Cas9 (clustered regularly interspaced short palindromic repeats and CRISPR-associated protein 9) system in phase 3 trial to create in vivo genetic editing in the TTR gene, thus stopping TTR production.^6,7

The addition of daratumumab to cyclophosphamide, bortezomib, and dexamethasone has significantly improved outcomes in AL amyloidosis, resulting in higher rates of complete hematologic response, prolonged organ deterioration–free survival, and overall survival.⁸ The use of venetoclax in the patients harboring the t(11:14) translocation has also been shown to be effective as salvage therapy.⁹ Early diagnosis and treatment delays have remained the Achilles heel for these disease entities. This has reduced to a certain degree for transthyretin amyloid cardiomyopathy amyloidosis with ability to accurately provide a diagnosis without a biopsy for most patients. However, AL amyloidosis relies on tissue diagnosis. More widespread use of free AL assays and immunofixation have certainly improved but remains suboptimal. Patients with heart failure or kidney dysfunction attributable to AL amyloidosis may continue to have organ dysfunction despite control of the hematological process, as is the current case for this patient. The organ response typically follows the hematological response and, in some cases, may be delayed by a few months to years.

There have been a few case reports/series of concurrent TTR and AL amyloidosis. The largest series report included 17 patients with concurrent TTR and AL cardiac amyloidosis; however a case of TTR cardiac amyloidosis and isolated renal AL amyloidosis has not been noted previously in literature.¹⁰ The management of both these conditions are different and should be treated with a multidisciplinary team involving hematologists, cardiologists, and nephrologists, given the multiorgan involvement. Our case does not have cardiac involvement for AL amyloidosis as noted on the endomyocardial biopsy, which grants overall a favorable prognosis for his disease process.

This case underscores the critical importance of maintaining a high index of suspicion when diagnosing TTR amyloidosis, especially in the presence of atypical features such as significant proteinuria or monoclonal gammopathy. Although advanced imaging techniques and biopsies of affected organs can aid in diagnosis, the potential for concurrent or mixed amyloidosis necessitates thorough investigation.

Conclusions

This case highlights the diagnostic challenges associated with concurrent TTR and AL amyloidosis. Biopsy of the involved organ remains the gold standard for definitive diagnosis and should be pursued whenever there is suspicion of AL amyloidosis, even in the presence of a presumed diagnosis of TTR amyloidosis.

Visual Summary.

Flowchart Summary of the Patient Presentation and Diagnostic Workup

Funding Support and Author Disclosures

Dr Maurer was supported by National Institutes of Health grants R01HL139671 and AG081582. Dr Chakraborty has served as a consultant or on the advisory board for Jannsen, Sanofi, Alexion, and Adaptive Biotech. Dr Maurer has received institutional research funding from Alnylam Pharmaceuticals, Attralus, BridgeBio, Intellia, and Ionis; and personal fees from Alnylam Pharmaceuticals, AstraZeneca, Attralus, Intellia, and Novo Nordisk. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.