Diagnostic challenges in systemic light chain( AL) amyloidosis: A retrospective evaluation of biopsy yeild and typing strategies in an Indian tertiary care centre

Abstract

Abstract Introduction: Amyloidosis comprises a heterogeneous group of protein misfolding disorders characterized by the extracellular deposition of insoluble amyloid fibrils. In AL amyloidosis, fibrils derive from monoclonal immunoglobulin light chains produced by abnormal plasma cells. Clinical manifestations vary based on organ involvement—most commonly cardiac and renal—with subtle, nonspecific presentations often delaying diagnosis. Evaluation involves monoclonal protein detection (serum free light chains, immunofixation), organ imaging, and tissue biopsy with Congo red staining as the diagnostic gold standard. While surrogate site biopsies (e.g., bone marrow, fat pad) are safer and more accessible, target organ biopsies offer higher diagnostic yield. Confirmatory amyloid typing—preferably by mass spectrometry—is essential to guide therapy but often limited by availability in resource-constrained settings. This study examines biopsy strategies, diagnostic yield, and typing practices in patients evaluated for amyloidosis at a tertiary care center in India. Objectives: To assess biopsy site selection, diagnostic yield, site-specific sensitivity, and amyloid typing practices in patients with clinical suspicion of AL amyloidosis. Methods: We conducted a retrospective study of patients evaluated between 2002 and mid-2024. Cases were identified through electronic records using keywords “amyloid” and “amyloidosis.” Inclusion criteria were: (1) biopsy-confirmed amyloid deposition, and/or (2) cardiac phenotype -elevated wall thickness, diastolic dysfunction, or apical sparing pattern on echocardiography /cardiac MRI findings typical of amyloid cardiomyopathy and abnormal serum free light chain profiles. Patients with incomplete diagnostic workup or non-AL types (e.g., AA or transthyretin amyloidosis) were excluded. Patients were categorized based on predominant organ involvement. Biopsies were classified as target (e.g., kidney) or surrogate (e.g., bone marrow, fat pad, GI tract). Histopathology findings, biopsy yield, and typing methods were extracted. Outcomes were assessed via documented clinical and histologic records. Descriptive statistics were used for demographic and clinical variables. Diagnostic sensitivity was calculated by biopsy site. Group comparisons were performed using Wilcoxon rank-sum, Pearson's chi-square, or Fisher's exact tests, with R software. Results: A total of 184 patients met inclusion criteria. Median age was 59 years (IQR: 53–67), with 68% male (n=125). Cardiac involvement was the most common phenotype, seen in 34% (n=63). Biopsy was performed in 182 patients (98.9%), with ≥2 biopsy sites sampled in 67% (n=122). Surrogate sites were biopsied in 82.6% (n=152). Amyloid deposition was identified in 74% of patients who underwent biopsy (n=135). The overall sensitivity was 74% for target organ biopsies and 40% for surrogate sites. Among the 47 biopsy-negative cases (26%), 49% (n=23) had undergone only a single-site biopsy. The most frequently biopsied surrogate site was bone marrow (n=131, 86%), followed by abdominal fat pad (n=39, 32%). Amyloid was detected in 29% of fat pad biopsies (n=16). The kidney was the most commonly sampled target organ (n=58), with a high diagnostic yield of 87% (n=51).Amyloid typing was performed in only 14% of biopsy-positive patients (n=19). Among these, 42% (n=8) underwent mass spectrometry-based typing, while 58% (n=11) were typed using immunohistochemistry, with or without immunofluorescence. Conclusion: This study highlights the diagnostic complexities in evaluating suspected AL amyloidosis, particularly in resource-limited settings. In this large retrospective cohort, surrogate site biopsies had markedly lower diagnostic yield compared to target organ biopsies. Multi-site sampling improves detection, and the lack of access to mass spectrometry significantly hampers definitive amyloid typing in resource-limited settings.