AL Cardiac Amyloidosis in Resource-Limited Settings

Abstract

Amyloid light chain (AL) cardiac amyloidosis remains a diagnostic challenge in resource-limited settings. We present 3 cases with varying heart failure presentations, all demonstrating concentric left ventricular hypertrophy with characteristic apical sparing strain pattern on echocardiography. Serum free light chains were consistently abnormal, though immunofixation was negative in 2 patients. Traditional screening biopsies were negative in 2 cases, requiring endomyocardial biopsy for diagnosis. Mass spectrometry for amyloid typing was unavailable; immunofluorescence performed in 1 patient confirmed lambda light chain deposition. All patients received CyBorD-based therapy; 1 patient additionally accessed daratumumab abroad and showed marked improvement, while another died within 6 months on CyBorD alone. These cases highlight the heterogeneous presentation of presumed AL amyloidosis and underscore how diagnostic barriers contribute to delayed diagnosis and more advanced disease at presentation, emphasizing the urgent need for improved diagnostic capabilities and therapeutic accessibility in resource-constrained settings.

Visual Summary

Amyloid light chain (AL) cardiac amyloidosis carries a poor prognosis largely determined by the degree of cardiac involvement at diagnosis and access to effective plasma cell–directed therapy.¹ Although advances in imaging and anti-CD38 containing regimens have improved outcomes in specialized centers, real-world diagnosis and management remain challenging, particularly in resource-limited settings. We present 3 cases illustrating well-recognized diagnostic challenges, including the need for endomyocardial biopsy (EMB) after negative extracardiac sampling and prolonged diagnostic delays, examining how these are further amplified by structural and resource-related barriers—including the lack of mass spectrometry for subtype confirmation—and the gap between guideline recommendations and real-world feasibility (Table 1).

Table 1.

History, Diagnostic Testing, and Follow-Up for 3 Patients With AL Cardiac Amyloidosis

	Patient 1	Patient 2	Patient 3
Demographics
Age, y	53	69	63
Sex	Male	Male	Female
Comorbidities, cardiac	Atrial fibrillation	None	Hypertension
Comorbidities, noncardiac	Carotid artery thrombosis	Rheumatoid arthritis	None
Diagnostic data
NT-proBNP (ng/L)	35,000	13,593	461
High-sensitivity troponin T (pg/mL)			41
Troponin T (μg/L)	0.168	0.092
Creatinine (mg/dL)	0.79	1.04	1.13
Hemoglobin (g/dL)	13.6	12.9	13.2
Albumin	3.3	3.8	2.7
Alkaline phosphatase	154	69	63
Serum k (mg/L)	45.3	383	32.7
Serum l (mg/L)	380	15.36	192.98
k/l ratio	0.11	24.47	0.17
SIFE	IgG monoclonal gammopathy	No monoclonal gammopathy	No monoclonal gammopathy
Bone marrow biopsy	Plasma cells involving 5% of bone marrow, with lambda light chain restriction	Plasma cells involving 30% of bone marrow	Flow cytometry revealed 10% polyclonal plasma cells, however, with light chain restriction
Echocardiographic findings	LVEF 23%, severe LVH, GLS –3.9% with apical sparing, biatrial enlargement, small pericardial effusion	LVEF 49%, moderate LVH, GLS –10.6% with apical sparing, biatrial enlargement, grade 3 diastolic dysfunction, small pericardial effusion	LVEF 70%, moderate LVH, GLS –11.1% with apical sparing, mild biatrial enlargement, grade 2 diastolic dysfunction
99mTC-PYP	1	0	0
TTR pathogenic mutation	Unavailable at the time	None	None
Mayo 2004 stage (European modification)	IIIB	IIIB	IIIA
Time from initial medical contact to suspicion of cardiac amyloidosis	2 y 3 mo	3 y	1 y 3 mo
Presenting symptoms at initial medical encounter	Dyspnea on exertion	Lower limb edema	Lower limb edema, nephrotic syndrome
Follow-up
Treatment	CyBorD	CyBorD, daratumumab	CyBorD
Outcome	Deceased 5 mo after presentation	Alive at 48 mo after presentation, NYHA functional class II	Alive at 25 mo after presentation, NYHA functional class II

99mTC-PYP = Tc-99m pyrophosphate; CyBorD = cyclophosphamide, bortezomib, and dexamethasone; GLS = global longitudinal strain; k/l = kappa/lambda; LVEF = left ventricular ejection fraction; LVH = left ventricular hypertrophy; NT-proBNP = N-terminal pro–B-type natriuretic peptide; SIFE = serum immunofixation electrophoresis; TTR = transthyretin.

Case Series

Case 1

A 53-year-old man with atrial fibrillation and internal carotid artery thrombosis (diagnosed 2 years ago), on warfarin, presented with 1-year progressive exertional dyspnea. Examination revealed bilateral lower extremity edema and reduced breath sounds at lung bases.

Transthoracic echocardiography (TTE) demonstrated severe concentric left ventricular hypertrophy (LVH), biventricular systolic dysfunction, and markedly reduced global longitudinal strain (GLS; −3.9%) with apical sparing. Cardiac magnetic resonance imaging showed diffuse subendocardial late gadolinium enhancement involving all 4 cardiac chambers, along with bilateral pleural effusions. Native T1 mapping and extracellular volume fraction quantification were unavailable given lack of postprocessing software.

Serum free light chains (SFLCs) showed disproportionately elevated lambda (380 mg/L) versus kappa (45.3 mg/L), with a kappa/lambda ratio of 0.11. Immunofixation identified monoclonal IgG lambda. Technetium-99m pyrophosphate (99mTC-PYP) scintigraphy was performed simultaneously with hematologic work-up as part of our institutional parallel testing protocol, however, given the presence of monoclonal gammopathy, its results were not interpreted for amyloid transthyretin (ATTR) amyloidosis evaluation. Fat pad biopsy confirmed Congo red–positive amyloid deposition, consistent with amyloid involvement; however, definitive subtype classification could not be established given the unavailability of mass spectrometry–based tissue typing both at the local hospital and within the country. Given the hematologic profile, AL amyloidosis was the presumed diagnosis.

Cyclophosphamide, bortezomib, and dexamethasone (CyBorD) therapy was initiated; however, only a partial hematologic response was achieved (lambda: 140 mg/L). Despite treatment, the patient developed decompensated heart failure and died 6 months after diagnosis (Figure 1).

Figure 1.

Multimodal Imaging in a Patient With AL Amyloidosis (Case 1)

(A) Electrocardiogram showing atrial fibrillation with controlled ventricular response, low voltage complexes (red arrows), and a pseudoinfarct pattern in V₁-V₂ (blue arrows). (B) Long-axis view demonstrates marked concentric left ventricular hypertrophy (yellow arrows) and mild pericardial effusion (white asterisk). (C) Reduced global longitudinal strain of −3.9% with apical-sparing pattern. (D) Late gadolinium enhancement sequence in 2-chamber view showing diffuse pathological gadolinium deposition, predominantly subendocardial (yellow arrow). (E) 99mTc-PYP scintigraphy showing biventricular uptake less than bone (Perugini grade 1). AL = amyloid light chain; LA = left atrium; LV = left ventricle.

Case 2

A 69-year-old man with a history of rheumatoid arthritis presented with persistent lower extremity edema, progressive dyspnea, orthopnea, and a 10-kg weight loss over 5 months. Eight months prior, he had been hospitalized for lower extremity edema and proteinuria, which remained without a definitive diagnosis. Examination showed jugular venous distention and peripheral edema.

TTE revealed concentric LVH, mildly reduced ejection fraction (49%), impaired GLS (−10.6%) with apical sparing, and biatrial enlargement. SFLC showed markedly elevated kappa (383 mg/L) with a kappa/lambda ratio of 24.47, yet immunofixation was negative.

Fat pad and salivary gland biopsies were Congo red–negative. Bone marrow showed 30% to 40% plasma cell infiltration. Given negative extracardiac biopsies despite strong clinical suspicion, EMB confirmed amyloid deposition by Congo red staining. Staging was performed with whole-body computed tomography and skeletal survey (positron emission tomography scan was not available); no lytic lesions or CRAB (calcium elevation, renal failure, anemia, and bone disease) criteria were identified, supporting a diagnosis of smoldering rather than overt multiple myeloma. As in case 1, proteomics-based subtype confirmation was unavailable; AL cardiac amyloidosis with smoldering multiple myeloma was presumed based on the clonal plasma cell dyscrasia and clinical profile.

CyBorD was initiated for 2 cycles, followed by a third cycle of bortezomib monotherapy, achieving only a partial hematologic response (kappa: 155 mg/L). Despite this partial response, clinical deterioration occurred with refractory volume overload, requiring triple diuretic therapy (furosemide, spironolactone, and dapagliflozin). Because of limited local access, the patient traveled to the United States for daratumumab therapy, which was initiated 5 weeks after completing CyBorD-based treatment. After just 1 cycle, a very good partial response was achieved (kappa: 38.28 mg/L, kappa/lambda ratio: 3.63). The patient completed a total of 4 months of Dara-CyBorD therapy, after which he chose to return to his home country and did not initiate maintenance treatment abroad. Subsequent follow-up locally demonstrated a complete hematologic response (kappa: 21.69 mg/L, kappa/lambda ratio: 1.55). Given the unavailability of daratumumab at our institution, lenalidomide was pragmatically initiated as maintenance therapy 17 months after completing daratumumab-based treatment, targeting the underlying plasma cell dyscrasia, in the absence of a feasible alternative. He remains stable on this regimen, with cardiac imaging showing progressive regression of pathological findings over the follow-up period (Figure 2).

Figure 2.

Multimodality Cardiac Imaging Before and After Daratumumab Treatment (Case 2)

(A) Baseline ECG showing sinus rhythm with low-voltage complexes, right bundle branch block, left posterior hemiblock, and PR interval of 200 ms. (B) Ten-month post-daratumumab ECG demonstrates higher voltage complexes and shortened PR interval of 160 ms. Global longitudinal strain bull's eye plot (C) at baseline and (D) at 28 months after daratumumab completion, reflecting a gradual recovery trajectory (GLS: −10.6% at baseline, −11.1% at 5 months, −17.9% at 14 months). Cardiac MRI 4-chamber cine frames at end-diastole showing (E) baseline and (F) findings at 10 months after daratumumab completion, with corresponding late gadolinium enhancement views demonstrating myocardial involvement (yellow arrows) at (G) baseline and (H) post-treatment. ECG = electrocardiogram; GLS = global longitudinal strain; LA = left atrium; LV = left ventricle; MRI = magnetic resonance imaging; RA = right atrium; RV = right ventricle.

Case 3

A 63-year-old woman with hypertension and treated thyroid cancer presented with nephrotic syndrome. Renal biopsy showed focal podocytopathy. Screening TTE revealed moderate concentric LVH, preserved ejection fraction (70%), impaired GLS (−12.4%) with apical sparing, and biatrial enlargement.

SFLC showed elevated lambda (192.28 mg/L) with a kappa/lambda ratio of 0.17, but immunofixation was negative. Bone marrow biopsy revealed a polyclonal lambda-predominant plasmacytosis (10% of cellularity) alongside a CD20/BCL2-positive B-cell lymphoid infiltrate consistent with marginal zone lymphoma, representing a concurrent but distinct clonal process. Fat pad and salivary gland biopsies were Congo red–negative. ATTR amyloidosis was excluded by negative 99mTC-PYP scintigraphy and genetic testing.

EMB confirmed amyloid deposition by Congo red staining; immunohistochemistry (IHC) further demonstrated lambda light chain deposition, providing subtype classification in the absence of mass spectrometry. AL amyloidosis was thus diagnosed on the basis of tissue IHC in conjunction with the clonal lambda excess on SFLC. The concurrently identified marginal zone lymphoma did not meet treatment criteria and was managed expectantly. CyBorD was initiated. After 2 cycles, favorable hematologic response occurred, with kappa/lambda normalization to 0.88.

Discussion

AL amyloidosis remains diagnostically challenging worldwide, and our case series reflects this complexity in a resource-limited setting, where both confirmatory diagnostic tools and internationally established therapies are largely inaccessible.²

While diagnostic delay is a well-recognized feature of AL amyloidosis^1,3—as evidenced by our case series—in our context, it was further compounded by limited physician awareness, the absence of formal referral pathways, and the concentration of expertise within a small number of institutions in the capital city; barriers that disproportionately affect patients from provincial and rural areas. These observations underscore the importance of recognizing cardiac red flags—including unexplained ventricular wall thickening, restrictive physiology, low-voltage electrocardiograms, atrial arrhythmias, and disproportionately severe heart failure—alongside extracardiac manifestations such as autonomic neuropathy, nephrotic-range proteinuria, hepatomegaly, macroglossia, periorbital purpura, and carpal tunnel syndrome.^1,3

When extracardiac biopsy is nondiagnostic, EMB remains the gold standard across all settings.² Congo red positivity establishes amyloid deposition but is insufficient for subtyping amyloid without additional testing. Mass spectrometry with laser microdissection is the gold standard for subtyping, yet it remains unavailable across much of the world,⁴ and IHC carries recognized limitations in sensitivity and specificity.⁵ Subtype misclassification carries direct therapeutic consequences, as AL and ATTR amyloidosis require fundamentally different treatment strategies. In our series, proteomics-based subtyping was not feasible locally, and international sample referral was precluded by the absence of interinstitutional agreements—a structural gap beyond the control of individual clinicians. Subtype diagnosis relied on integration of clinical, hematologic, and imaging data—pragmatically justified but carrying inherent uncertainty.

Regarding scintigraphy, we acknowledge that current recommendations advise against its use in the presence of abnormal SFLC or positive immunofixation; however, at our institution it is performed in parallel with hematologic work-up for all patients with suspected amyloidosis. This simultaneous multimodality approach is consistent with the 2023 European guidelines⁶ and reflects local operational realities, including intermittent unavailability of FLC reagents and a prior laboratory practice of withholding SFLC quantification when immunofixation was negative. We acknowledge that, given the ongoing global radiotracer shortages, a sequential approach reserving scintigraphy for cases with high ATTR suspicion would be preferable; however, in our context, parallel testing reduces diagnostic delays in a population where late presentation is common.

The therapeutic landscape of AL amyloidosis has evolved rapidly with the introduction of proteasome inhibitors and monoclonal antibodies.^1,7 Daratumumab-based regimens have demonstrated superior hematologic and organ response rates in randomized trials, most notably the ANDROMEDA study,⁸ and real-world evidence of associated cardiac structural improvement is increasingly documented. In case 2, daratumumab was associated not only with deep hematologic response but also with concordant improvements in electrocardiographic voltages, GLS, and regression of late gadolinium enhancement on cardiac magnetic resonance imaging. Accumulating evidence indicates that such cardiac responses are increasingly recognized and are associated with improved outcomes, including near-normal life expectancy among patients who achieve them.⁹

Despite guideline recommendations supporting daratumumab-based regimens as first-line therapy,^1,3 access remains highly variable worldwide. In our setting, daratumumab was unavailable locally; only 1 patient accessed it by traveling abroad—imposing a substantial financial and logistical burden that is not feasible for most patients in our region. The remaining 2 patients would likely have been candidates had access been available, suggesting that the therapeutic gap directly affected achievable response depth and potentially overall disease trajectory. Notably, partial hematologic response—the best outcome achievable without daratumumab in this case series—is suboptimal, as residual free light chains continue to deposit in target organs, perpetuating cardiac damage and limiting organ recovery. These disparities, compounded by prolonged diagnostic delays that narrowed therapeutic eligibility, may contribute to outcomes that differ markedly from those reported in clinical trials and specialized referral centers, underscoring the critical gap between evidence-based recommendations and real-world feasibility in low- and middle-income countries.

Our experience suggests several actionable strategies to improve early diagnosis of AL cardiac amyloidosis. These include maintaining a high index of suspicion in patients with unexplained heart failure and increased ventricular wall thickness, and recognizing the extracardiac red flags outlined above. Early incorporation of strain imaging,³ systematic SFLC screening regardless of immunofixation result,² and prompt referral for invasive biopsy when noninvasive results are discordant are equally essential. At the health-system level, reducing geographic barriers to specialized care, raising awareness among nonspecialist physicians, and establishing interinstitutional networks for advanced diagnostic testing and access to novel therapies are critical priorities to narrow the gap between evidence-based recommendations and real-world outcomes in AL amyloidosis.

Conclusions

These cases illustrate the clinical heterogeneity and persistent diagnostic challenges of AL cardiac amyloidosis, particularly in resource-limited settings. Delayed recognition and restricted access to specialized pathology and contemporary therapies continue to shape patient outcomes, underscoring the need for early diagnostic vigilance and equitable access to disease-modifying treatments.

Visual Summary.

Real-World Barriers in AL Amyloidosis

AL = amyloid light chain; IHC = immunohistochemical; SFLC = serum-free light chain.

Funding Support and Author Disclosures

The authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Take-Home Messages

• •When proteomics is unavailable, integrated clinical, hematologic, imaging, and histological data may support a presumptive AL amyloidosis diagnosis, acknowledging therapeutic implications.
• •Diagnostic delays and limited access to daratumumab-based regimens significantly worsen outcomes in resource-limited settings.
• •Reducing geographic barriers, raising physician awareness, and strengthening interinstitutional networks are essential to bridge the gap between guidelines and real-world care.