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AL amyloidosis

Etiology: - monoclonal gammopathy of undetermined significance (MGUS) - multiple myeloma (10%) [1] - Waldenstrom's macroglobulinemia (rare) [1] Pathology: 1) monoclonal plasma cell disorder a) overproduction of monoclonal light chains (80% lambda) b) a localized amyloidosis involving a single organ with deposition of light chains may occur 2) fibrils contain NH2 terminal amino acid residues of the variable end of monoclonal light chain, generally Ig lambda 3) increased risk of hemorrhage a) systemic fibrinolysis b) acquired factor X deficiency c) increased vascular fragility Clinical manifestations: 1) renal manifestations - nephrotic syndrome (28%) - progressive worsening of renal function - generalized edema (anasarca) - foamy urine - nephromegaly 2) cardiac - chronic heart failure (17%) - restrictive cardiomyopathy - diastolic heart failure > systolic heart failure - jugular venous distension [8] - pulmonary crackles [8] - arrhythmia - chest pain - orthostatic hypotension (11%) 3) peripheral neuropathy (17%) - distal sensory neuropathy progresses to motor neuropathy - paresthesias, neuropathic pain - carpal tunnel syndrome (21%) - autonomic neuropathy 4) gastrointestinal - dysphagia - macroglossia is associated with amyloidosis - submandibular gland enlargement - gastrointestinal bleeding, iron-deficiency anemia - gastroparesis - small intestine bacterial overgrowth - ileus - malabsorption - steatorrhea - chronic liver failure - portal hypertension, esophageal varices - hepatosplenomegaly - cholestasis 4) liver - hepatosplenomegaly - ascites - varices - portal hypertension 5) hematologic - bleeding diathesis - periorbital purpura [8] - coagulation factor X deficiency 6) musculoskeletal - symmetric arthropathy - muscle pseudohypertropy 7) also see amyloidosis Laboratory: 1) complete blood count (CBC) - anemia - iron studies may be consistent with iron deficiency 3) serum chemistries a) serum beta-2 microglobulin - median survival is 33 months when < 2.7 ug/mL b) elevated serum alkaline phosphatase - 1st indicator of liver involvement c) serum albumin: hypoalbuminemia [1] d) serum creatinine elevated e) elevated serum N-terminal pro-B-type natriuretic peptide & serum troponin-T predicts poor prognosis [1] 4) urinalysis: bland urine sediment [1] 5) 24 hour urine protein: nephrotic syndrome 6) urine protein electrophoresis a) albuminuria b) may show free light chains (Ig lambda) 7) urine appearance: urine may appear foamy 8) serum protein electrophoresis is generally normal - serum albumin may be low 9) immunofixation electrophoresis (IFE) may show free light chains - overproduction of monoclonal light chains (80% lambda) - may be referred to as immunoglobulin G lambda [8] 10) coagulation tests - prolonged prothrombin time PT & aPTT - coagulation factor X deficiency Special laboratory: 1) tissue biopsy a) clonal plasmacytosis (5-10%) b) Congo red-staining amyloid deposits - apple-green birefringence under polarized light [1] c) abdominal subcutaneous fat aspirate (positive in 80%) d) biopsy of rectum (80% positive) e) bone marrow biopsy (case with 5% plasma cells in bone marrow) [8] 2) amyloid typing of biopsy specimen to confirm AL amyloidosis - immunohistochemical stain 3) submucosal hematomas on GI endoscopy 4) electromyography & nerve conduction studies - distal sensorimotor polyneuropathy 5) electrocardiogram: - low voltage, pseudo-infact pattern, arrhythmias 6) echocardiography - restrictive cardiomyopathy - granular appearance - left ventricular hypertrophy Radiology: - renal ultrasound: nephromegaly [1] - joint space widening on plain radiographs - magnetic resonance imaging: - cardiac MRI: late gadolinium enhancement (abnormal) - periarticular soft tissue muscle infiltration Complications: - 20% of patients with AL amyloidosis also have multiple myeloma or other lymphoproliferative disorder [1] Differential diagnosis: - MUGUS: heart failure & renal failure unlikely - multiple myeloma: - heart failure unlikely - > 10% plasma cells in bone marrow - AA amyloidosis: polyclonal gammopathy Management: 1) median survival is 1 year (overall) a) < 3-4 months with CHF & LVEF < 40% b) nephrotic syndrome alone: 2.5 years c) peripheral neuropathy alone: 5 years 2) chemotherapy (albiet unsatisfactory) directed towards plasma cell dyscrasia a) low plasma cell proliferation rate b) prednisone + melphalan may be of some benefit, especially in patients with nephrotic syndrome but without renal insufficiency or cardiac involvement 3) autologous hematopoietic stem cell transplantation of benefit in a subset of patients [1] (same protocol as for multiple myeloma) 4) high-dose melphalan with stem cell transplantation rescue no better than standard-dose melphalan plus dexamethasone [4] 5) combination of cyclophosphamide, bortezomib, & dexamethasone may benefit a subset of patients [2] - addition of daratumumab to combination associated with higher frequencies of hematologic complete response 53% vs 18%, but mortality unchanged

Related

light-chain deposition disease; Light chain nephropathy renal amyloidosis; amyloid nephropathy

General

amyloidosis

References

  1. Medical Knowledge Self Assessment Program (MKSAP) 11, 15, 16, 17, 18, 19. American College of Physicians, Philadelphia 1998, 2009, 2012, 2015, 2018, 2022. - Medical Knowledge Self Assessment Program (MKSAP) 19 Board Basics. An Enhancement to MKSAP19. American College of Physicians, Philadelphia 2022
  2. Mikhael JR et al. Cyclophosphamide-bortezomib-dexamethasone (CyBorD) produces rapid and complete hematologic response in patients with AL amyloidosis. Blood 2012 May 10; 119:4391. PMID: 22331188 - Venner CP et al. Cyclophosphamide, bortezomib, and dexamethasone therapy in AL amyloidosis is associated with high clonal response rates and prolonged progression-free survival. Blood 2012 May 10; 119:4387. PMID: 22331187
  3. van Gameren II, Hazenberg BP, Bijzet J, van Rijswijk MH. Diagnostic accuracy of subcutaneous abdominal fat tissue aspiration for detecting systemic amyloidosis and its utility in clinical practice. Arthritis Rheum. 2006 Jun;54(6):2015-21 PMID: 16732553
  4. Jaccard A, Moreau P, Leblond V, Leleu X et al High-dose melphalan versus melphalan plus dexamethasone for AL amyloidosis. N Engl J Med. 2007 Sep 13;357(11):1083-93. PMID: 17855669
  5. Kumar S, Dispenzieri A, Lacy MQ et al Revised prognostic staging system for light chain amyloidosis incorporating cardiac biomarkers and serum free light chain measurements. J Clin Oncol. 2012 Mar 20;30(9):989-95 PMID: 22331953
  6. Gillmore JD, Wechalekar A, Bird J et al Guidelines on the diagnosis and investigation of AL amyloidosis. Br J Haematol. 2015 Jan;168(2):207-18. PMID: 25312307
  7. Kastritis E, Palladini G, Minnema MC et al Daratumumab-Based Treatment for Immunoglobulin Light-Chain Amyloidosis. N Engl J Med 2021; 385:46-58 PMID: 34192431 https://www.nejm.org/doi/full/10.1056/NEJMoa2028631
  8. NEJM Knowledge+ Hematology