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KembaraXtra-Medicine – Amyloidosis
Amyloid is an altered, insoluble protein folded in β-pleated sheets that is deposited extracellularly. Amyloid can accumulate in one or many organs, causing organ dysfunction. Amyloidosis refers to a heterogeneous group of disorders characterized by deposition of an amorphous, extracellular fibrillar protein in various organs and tissues. Subtypes include primary amyloidosis (AL), secondary amyloidosis (AA), hereditary amyloidosis, and localized amyloidosis. ICD-10CM codes include E85.0 (non-neuropathic heredofamilial), E85.1 (neuropathic heredofamilial), E85.2 (heredofamilial, unspecified), E85.3 (secondary systemic), E85.4 (organ-limited), E85.8 (other), and E85.9 (unspecified).
Amyloidosis nomenclature is based on the amyloid protein precursor and associated clinical features. AL or AH derives from immunoglobulin light or heavy chain and is primary or localized, often associated with myeloma or macroglobulinemia. AA derives from serum amyloid A (SAA) and occurs as secondary amyloidosis or with familial Mediterranean fever and other familial periodic fever syndromes. ATTR derives from transthyretin and is familial or senile. A fibrinogen derives from fibrinogen and is associated with familial renal amyloidosis (Ostertag type). Aβ2M derives from β2-microglobulin and is dialysis-associated, including carpal tunnel syndrome. Aβ derives from amyloid-β precursor protein (ABPP) and is associated with Alzheimer disease. Apo A-I/A-II–related forms include apolipoprotein A-I (proteinuria) and apolipoprotein A-II (cardiac and neuropathy patterns). A lysozyme involves lysozyme deposition affecting the GI tract, liver, and kidneys. ALECT2 is noted as a renal form (leukocyte chemotactic factor 2 amyloidosis).
A major classification system (not exhaustive) includes: AA (serum amyloid A) causing systemic amyloidosis, often predominantly renal, linked to acquired or hereditary chronic inflammatory disease (formerly “secondary/reactive”); AL (monoclonal immunoglobulin light chains) causing systemic amyloidosis potentially involving many organs and associated with myeloma/monoclonal gammopathy/occult B-cell dyscrasias (formerly “primary”); and ATTR wild-type (normal plasma transthyretin) causing nonhereditary systemic amyloidosis with predominantly cardiac involvement (formerly “senile cardiac amyloidosis”). ATTR variant (genetic variants such as ATTR Met30, Ala60, Ile122) can cause familial amyloid polyneuropathy (FAP) often with prominent cardiomyopathy, and certain mutations (e.g., TTR Ile122) may produce predominantly cardiac involvement without neuropathy. Aβ2M (β2-microglobulin) causes dialysis-related amyloidosis with renal failure and long-term dialysis, with predominantly articular/periarticular involvement. Aβ causes cerebrovascular and intracerebral plaque amyloid in Alzheimer disease and may be familial. AApoAI (genetic variants of apolipoprotein AI) causes autosomal dominant systemic amyloidosis, typically nonneuropathic with visceral involvement—especially nephropathy—and minor wild-type deposits can occur in the aorta with aging. AApoAII causes autosomal dominant systemic amyloidosis with predominantly renal involvement. AFib (fibrinogen A α-chain variants) causes autosomal dominant systemic amyloidosis with nonneuropathic predominant nephropathy. ALys (lysozyme variants) causes autosomal dominant systemic amyloidosis with predominantly renal and GI involvement and can rarely present with hepatic rupture. ACys (cystatin C variant) is linked to hereditary cerebral hemorrhage with cerebral and systemic amyloidosis in Icelandic individuals. AGel (gelsolin variants) causes autosomal dominant systemic amyloidosis with predominantly cranial nerve involvement plus lattice corneal dystrophy and is described as most common in Finland.
In the United States, incidence is estimated at 1500–3500 new cases annually, with AL being the most common type. Amyloidosis primarily affects men ages 60–70 years. Common presenting symptoms include fatigue, dyspnea, edema, paresthesias, and weight loss, and other findings depend on organ involvement. Diagnosis should be considered in patients with a multisystem disorder involving the heart, kidney, liver, or nervous system. Renal involvement may present with nephrotic syndrome. Pulmonary involvement may cause fatigue and dyspnea. GI involvement is uncommon but may present with diarrhea, nausea, abdominal pain, and macroglossia. Cardiac involvement produces an infiltrative cardiomyopathy with preserved ejection fraction and diastolic dysfunction; in transthyretin-related disease, transthyretin dissociation leads to deposition of misfolded monomers as amyloid fibrils in the myocardium with subsequent cardiomyopathy and heart failure. Patients may have bleeding problems from factor X deficiency or fragile vessels infiltrated by amyloid; periorbital bleeding (“raccoon eyes”) is characteristic. Nervous system involvement can cause peripheral neuropathy, tendinopathy, muscle weakness, numbness, syncope, or dizziness, and associated autonomic neuropathy can be severely disabling. Syndromes in primary (AL) amyloidosis include nephrotic/nephrotic with renal failure (30%), hepatomegaly (24%), congestive heart failure (22%), carpal tunnel (21%), neuropathy (17%), and orthostatic hypotension (12%).
The common mechanism is deposition of Congo red–staining amyloid fibrils, but key subtype differences exist. AL is associated with an underlying clonal plasma cell disorder producing abnormal light chains with possible multi-organ deposition. AA has no plasma cell disorder and results from long-standing systemic inflammation (examples listed include tuberculosis, leprosy, malaria, untreated syphilis). Localized amyloidosis results from localized fibril synthesis without a plasma cell disorder. Familial amyloidosis includes forms due to transthyretin gene (TTR) mutations, with hepatocyte-derived transthyretin deposition in peripheral nerves and the heart.
Differential diagnosis depends on organ involvement. For renal disease consider toxin- or drug-induced necrosis, glomerulonephritis, renal vein thrombosis. For pulmonary disease consider sarcoidosis, connective tissue disease, infectious causes. For restrictive cardiomyopathy consider endomyocardial fibrosis or viral myocarditis. For carpal tunnel consider rheumatoid arthritis, hypothyroidism, overuse. For peripheral neuropathy consider alcohol abuse, vitamin deficiencies, diabetes mellitus.
Workup includes blood and urine testing for abnormal light chains, tests for target-organ damage, and histologic confirmation. Typical confirmation is via fat pad aspiration and bone marrow biopsy with Congo red staining. Recommended diagnostic evaluation includes CBC; chemistries and other labs (sodium, potassium, alkaline phosphatase, calcium, phosphorus, AST, bilirubin, creatinine, β2-microglobulin, glucose, cholesterol, uric acid, thyroid profile); serum and urine immunofixation; assays for immunoglobulin free light chains and immunoglobulins G, A, and M; cardiac markers (troponin, NT-proBNP); coagulation evaluation (factor X and prothrombin time); and cardiac/pulmonary assessment with chest x-ray, ECG, and echocardiogram with Doppler and strain imaging. Amyloid staging assigns 1 point each for FLC-diff ≥18 mg/dL, cTnT ≥0.025 ng/mL, and NT-proBNP ≥1800 pg/mL, producing stages I–IV (scores 0–3). Reported median survival (months) by stage is 94.1, 40.3, 14, and 5.8, respectively. Laboratory testing also includes SPEP/UPEP with immunofixation for light chains, routine labs such as BUN/creatinine, liver function tests, thyroid function, urine albumin, and biopsy confirmation; if fat pad biopsy is negative, biopsy of the affected organ may be required.
Imaging can help define organ involvement. Cardiac MRI may show a distinctive pattern. Two-dimensional Doppler echocardiography is useful for cardiac evaluation but is less sensitive than cardiac MRI. Nuclear imaging with technetium-labeled aprotinin may detect cardiac amyloidosis. Labeled diphosphonates are important for typing amyloidosis and diagnosing heart involvement in transthyretin cardiac amyloidosis, and bone scintigraphy may detect cardiac involvement earlier than echocardiography in transthyretin patients. Serum amyloid P (SAP) scintigraphy has high sensitivity for detecting deposits in liver, spleen, kidneys, adrenal glands, bones.
Acute/general management and disease-directed therapy depend on subtype and organ involvement. Patients with AL amyloidosis should be evaluated for autologous hematopoietic stem cell transplantation (HSCT); good candidates include those with good performance status, age <70, and limited organ involvement. tafamidis is an oral transthyretin stabilizer fda approved for adults with transthyretin-mediated amyloid cardiomyopathy (attr-cm) has been shown to decrease hospitalizations deaths in attr-cm. al, chemotherapy aims reduce production of amyloidogenic light chains by targeting clonal plasma cells; agents used multiple myeloma are effective, including melphalan prednisone, imids (thalidomide, lenalidomide) proteasome inhibitors also used. patients ineligible autologous hsct should receive melphalan- or bortezomib-based regimens. trials oligonucleotide drugs (inotersen, patisiran) have improvement clinical manifestations hereditary amyloidosis. who develop renal failure may require hemodialysis transplant. liver transplantation successfully familial secondary (aa) amyloidosis, recognition treatment the underlying disorder needed. newly diagnosed al show that adding daratumumab bortezomib, cyclophosphamide, dexamethasone associated higher hematologic complete response rates.< />pan>
Major treatment options include, for AL amyloidosis, IV melphalan with autologous stem cell rescue (G-CSF mobilized peripheral blood stem cell collection, IV melphalan 140–200 mg/m², autologous stem cell reinfusion), cyclic oral melphalan and dexamethasone (melphalan 0.22 mg/kg/day ×4 days; dexamethasone 20–40 mg/day ×4 days or weekly; repeat every 4 weeks), immunomodulators (lenalidomide 5–15 mg/day ×21 days with dexamethasone 20–40 mg weekly; repeat every 4 weeks), and proteasome inhibitors (IV bortezomib 0.7–1.6 mg/m² 1–2 times per week; repeat every 3–5 weeks). For AA amyloidosis, options include aggressive treatment of underlying inflammatory disease, medical or surgical treatment of infection, colchicine 1.2–1.8 mg/day for AA secondary to familial Mediterranean fever, and investigational antifibril drug eprodisate. For ATTR, options include orthotopic liver transplantation, transthyretin stabilizers (tafamidis, investigational diflunisal), and investigational oligonucleotide drugs (inotersen, patisiran).
Supportive treatment across all amyloidosis types is symptom- and organ-directed. For cardiac congestive failure, options include salt restriction 1–2 g/day and diuretics (furosemide, spironolactone, metolazone). For arrhythmias, consider pacemaker, automatic implantable cardiac defibrillator, and antiarrhythmics. For renal nephrotic syndrome, use salt restriction 1–2 g/day, elastic stockings and leg elevation, maintaining dietary protein, and an ACE inhibitor if blood pressure tolerates. For renal failure, use dialysis (long-term ambulatory peritoneal dialysis or hemodialysis). For autonomic nervous system orthostatic hypotension, options include midodrine, increased dietary salt or fludrocortisone depending on edema, and elastic stockings. For gastric atony/ileus, use small frequent low-fat feedings (6/day), oral nutritional supplements, jejunostomy tube feeding, or parenteral nutrition. For GI diarrhea, options include a low-fat diet (≤40 g), psyllium, loperamide, tincture of opium, and parenteral nutrition. For macroglossia, use a soft solid diet; partial glossectomy is rarely effective. For peripheral sensory neuropathy, avoid trauma and use medications such as gabapentin 100–300 mg three times daily, amitriptyline 25–50 mg at bedtime, or pregabalin 50–100 mg three times daily. For motor neuropathy with footdrop, use ankle-foot orthotics and physical therapy. For hematologic issues with intracutaneous bleeding, avoid trauma and antiplatelet agents; for factor X deficiency, use factor replacement (recombinant factor VIIa, prothrombin complex concentrates). Splenectomy may be considered for splenomegaly.
Prognosis is determined primarily by cardiac involvement and the amyloidosis form. In endomyocardial biopsy–documented cardiac amyloidosis, longer-term survival correlates more strongly with NYHA functional class than with ECG or echocardiographic variables. In AA amyloidosis, eradication of the predisposing disease slows and can occasionally reverse progression, with a median survival after diagnosis of 133 months. Patients with familial amyloidotic polyneuropathy often have a prolonged course of 10–15 years. Dialysis-associated amyloidosis progression can be improved with newer dialysis membranes that pass β2-microglobulin. Median survival in patients with overt congestive heart failure is approximately 6 months, compared with 30 months without CHF.
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