Emerging treatment approaches for the systemic amyloidoses
2005; Elsevier BV; Volume: 68; Issue: 3 Linguagem: Inglês
10.1111/j.1523-1755.2005.00535.x
ISSN1523-1755
Autores Tópico(s)Pancreatitis Pathology and Treatment
ResumoA 57-year-old man was diagnosed with AL amyloidosis after presenting with nephrotic syndrome. He had been well until 6 months earlier, when he noticed intermittent ankle swelling. He sought medical attention approximately 2 months later because of increased swelling of his legs and progressive fatigue. The Nephrology Forum is funded in part by grants from Amgen, Incorporated; Merck & Co., Incorporated; and Dialysis Clinic, Incorporated. At that time, his urinary protein excretion was 7.4 g/day. Serum creatinine was 0.9 mg/dL and serum albumin 3.1 g/dL. A renal biopsy disclosed amorphous material in the mesangium that was birefringent under polarized light when stained with Congo red dye. Immunofluorescence was positive for lambda light chain in the glomerular capillary walls, mesangium, and tubulointerstitium. Electron microscopy revealed randomly dispersed fibrils with a diameter of 10 nm throughout the mesangium and interstitium. A monoclonal IgG lambda protein and a monoclonal free lambda light chain were evident by immunofixation electrophoresis (IFE) of the serum and urine, respectively. Bone marrow biopsy had 5% plasma cells with lambda light chain predominance. Additional clinical evaluation was remarkable for orthostatic hypotension and hepatomegaly. Alkaline phosphatase was 480 U/L; other liver enzymes were normal. An electrocardiogram showed normal voltage, and ventricular wall thickness was normal by echocardiography. Three months later, the patient underwent treatment with high-dose intravenous melphalan (200 mg/m2) and autologous peripheral blood stem cell transplantation. Just prior to treatment, the urinary protein excretion was 10 g/day and serum creatinine 1.3 mg/dL. The peri-transplant course was notable for anasarca, mucositis, a transient increase in serum creatinine to 3.2 mg/dL, and a neutropenic fever. Six months after treatment, a bone marrow biopsy showed fewer than 5% plasma cells with no light chain isotype predominance. The monoclonal immunoglobulin protein was no longer evident by serum or urine IFE. Together, these findings suggested a hematologic remission, and annual evaluations during the subsequent 4 years have shown no evidence of a recurrence of the plasma cell dyscrasia. Urinary protein excretion decreased progressively to 3.0 g/day, 1.1 g/day, 0.7 g/day, and 0.3 g/day at years 1, 2, 3, and 4, respectively. Serum creatinine concentration has fluctuated between 1.0 and 1.3 mg/dL during the 4 years following treatment. Serum alkaline phosphatase was 170 U/mL at the most recent visit, and hepatomegaly was no longer appreciable by physical examination. A 42-year-old woman with a family history of amyloidosis was evaluated after amyloid was identified in a duodenal biopsy specimen. The patient's mother had systemic amyloidosis due to a mutation in transthyretin (TTR) that resulted in a substitution of methionine for valine at amino acid position 30 (Val30Met). The disease manifestations in the mother included sensorimotor neuropathy, autonomic neuropathy, cardiac disease, and subnephrotic-range proteinuria. The mother's symptoms began at approximately 40 years of age, and she died in 1980 at age 53. The patient (that is, the daughter) was found to have subnephrotic-range proteinuria one year earlier and underwent abdominal fat aspiration that was negative for amyloid by Congo red staining. Upper endoscopy was performed because of vitamin D deficiency, and amyloid was present in the duodenal biopsy specimen obtained during the procedure. The patient felt well and had no symptoms other than supraventricular tachycardia that began shortly after the birth of her fourth child and was controlled with atenolol. Physical examination that included a detailed evaluation by a neurologist was unremarkable. Electrocardiogram revealed left anterior fascicular block with normal voltage. Echocardiography disclosed that wall thickness, valves, and ventricular function all were normal. Serum creatinine was 1.0 mg/dL, and a 24-hour urine collection contained 1.8 g protein. Isoelectric focusing studies of the serum revealed abnormal migration of TTR protein, and subsequent DNA studies disclosed the presence of a Val30Met TTR mutation. At present, the patient is being followed closely in anticipation of orthotopic liver transplantation when the manifestations of amyloidosis become more pronounced. Dr. Laura M. Dember (Associate Professor of Medicine, Renal Section, and Renal Section and Amyloid Treatment and Research Program, Boston University School of Medicine, Boston, Massachusetts): These cases describe two patients with systemic amyloidosis. Patient 1 has amyloid light chain (AL) amyloidosis, and Patient 2 has familial amyloidosis of the TTR type. The patient with AL amyloidosis underwent treatment with high-dose chemotherapy and autologous stem cell transplantation, and the patient with TTR amyloidosis is being followed closely in anticipation of future orthotopic liver transplantation. Although these treatment approaches appear to be quite different, they are similar in that they both target the source of the amyloidogenic protein. In AL amyloidosis, the source of the amyloidogenic protein is clonal plasma cells in the bone marrow, and in familial TTR amyloidosis, the source is the liver. In addition, both treatments are aggressive approaches that have substantial toxicity but offer the possibility of fully eliminating new amyloid production. Targeting the source of the amyloidogenic protein has been the most widely employed and most successful treatment approach for the systemic amyloidoses to date. However, with advances in the understanding of the processes involved in amyloid fibril formation and tissue deposition, treatments directed at other targets are being developed, and some are being tested in clinical trials. This Nephrology Forum will focus on current and emerging approaches for the treatment of the systemic amyloidoses. My discussion of treatment will be organized around the therapeutic targets rather than the specific type of amyloidosis. The amyloidoses are a group of diseases in which proteins that are normally soluble deposit extracellularly in tissues as insoluble fibrils. The fibrils have a characteristic beta-pleated sheet configuration that renders them avid for Congo red dye. Classification of the amyloidoses is based on the precursor proteins that form the amyloid fibrils, and the distribution of amyloid deposition as either systemic or localized (Table 1)1.Westermark P. Benson M.D. Buxbaum J.N. et al.Amyloid fibril protein nomenclature—2002.Amyloid. 2002; 9: 197-200Crossref PubMed Scopus (179) Google Scholar. In systemic amyloidosis, the amyloidogenic protein is produced at a site distant from the sites of deposition. In contrast, in localized forms (for example, Alzheimer's disease), the amyloid deposition occurs at the site of production of the amyloidogenic protein. Here we will focus on the systemic amyloidoses.Table 1Types of amyloidosisDiseasePrecursor proteinAmyloid proteinOrgan involvementSystemic forms AL amyloidosisImmunoglobulin light chainALKidney, heart, liver, GI tract, spleen, nervous system, soft tissue, thyroid, adrenals AA amyloidosisSerum amyloid A (SAA)AAKidney, liver, GI tract, spleen, autonomic nervous system, thyroid Familial amyloidosisTransthyretin, apolipoprotein AI, apolipoprotein AII, fibrinogen Aα chain, lysozyme, gelsolin, cystatin CATTR, AApoAI, AApoAII, AFibA, ALys, AGel, ACysVaries with amyloid protein and mutation. Kidney affected in TTR, ApoAI, Apo AII, FibAα, and Lys disease Senile systemic amyloidosisTransthyretin (wild-type)ATTRHeart, soft tissue Dialysis-related amyloidosisBeta-2 microglobulinAβ2MPeriarticular tissue, boneLocalized forms Localized ALImmunoglobulin light chainALTracheobronchial tree, bladder, ureter Alzheimer's diseaseAβ protein precursorAβBrain Creutzfeldt-Jakob diseasePrion proteinAPrPBrain Type 2 diabetes mellitusIslet amyloid polypeptideAIAPPPancreas Open table in a new tab AL amyloidosis, the most common of the systemic amyloidoses, reportedly affects 5 to 12 persons/million/year, although autopsy studies suggest that the actual incidence might be higher2.Skinner M. Sanchorawala V. Seldin D.C. et al.High-dose melphalan and autologous stem-cell transplantation in patients with AL amyloidosis: An 8-year study.Ann Intern Med. 2004; 140: 85-93Crossref PubMed Scopus (500) Google Scholar. The amyloidogenic protein in AL amyloidosis is an immunoglobulin light chain or light chain fragment produced by clonal plasma cells in the bone marrow. The plasma cell burden is usually low and typically comprises 5% to 10% of the cells in the bone marrow3.Sanchorawala V. Wright D.G. Seldin D.C. et al.An overview of the use of high-dose melphalan with autologous stem cell transplantation for the treatment of AL amyloidosis.Bone Marrow Transplant. 2001; 28: 637-642Crossref PubMed Scopus (147) Google Scholar. However, approximately 10% to 15% of patients with AL amyloidosis have associated multiple myeloma4.Kyle R.A. Gertz M.A. Primary systemic amyloidosis: Clinical and laboratory features in 474 cases.Semin Hematol. 1995; 32: 45-59PubMed Google Scholar. In AL disease, amyloid deposition can occur in any organ except for the central nervous system. The organs most frequently involved are the kidney and the heart4.Kyle R.A. Gertz M.A. Primary systemic amyloidosis: Clinical and laboratory features in 474 cases.Semin Hematol. 1995; 32: 45-59PubMed Google Scholar,5.Falk R.H. Comenzo R.L. Skinner M. The systemic amyloidoses.N Engl J Med. 1997; 337: 898-909Crossref PubMed Scopus (1013) Google Scholar. Kidney involvement usually manifests as nephrotic syndrome and progressive impairment of renal function. Not all patients with renal involvement have proteinuria. Amyloid deposition that is restricted to the renal vasculature or tubulointerstitium reduces the glomerular filtration rate but causes minimal proteinuria. Amyloid deposition in the myocardium results in a restrictive cardiomyopathy. The left-ventricular wall is concentrically thickened with normal or reduced cavity size. The ventricular ejection fraction can be normal or only modestly decreased despite substantial amyloid infiltration, but impaired ventricular filling limits cardiac output6.Dubrey S.W. Cha K. Anderson J. et al.The clinical features of immunoglobulin light-chain (AL) amyloidosis with heart involvement.QJM. 1998; 91: 141-157Crossref PubMed Scopus (392) Google Scholar. Low voltage on the electrocardiogram is often present and reflects the infiltrative, rather than a hypertrophic, basis for the ventricular wall thickening. Liver involvement produces hepatomegaly that can be massive. Elevation in alkaline phosphatase with only a mild elevation in transaminases is characteristic of hepatic amyloidosis, in which infiltration of the sinusoids rather than direct hepatocyte injury occurs7.Park M.A. Mueller P.S. Kyle R.A. et al.Primary (AL) hepatic amyloidosis: clinical features and natural history in 98 patients.Medicine (Baltimore). 2003; 82: 291-298Crossref PubMed Scopus (153) Google Scholar. Autonomic nervous system disease can produce severe orthostatic hypotension and early satiety from delayed gastric emptying. Symmetric sensory neuropathy that progresses in a distal to proximal pattern is the usual manifestation of peripheral nervous system involvement. Soft tissue amyloid deposition produces carpal tunnel syndrome, skin nodules, periarticular infiltration, alopecia, nail dystrophy, macroglossia, submandibular gland enlargement, and hoarseness. Macroglossia is extremely rare in the non-AL amyloidoses. Other sites of amyloid deposition in AL disease include the lung, pleura, thyroid gland, and adrenal glands4.Kyle R.A. Gertz M.A. Primary systemic amyloidosis: Clinical and laboratory features in 474 cases.Semin Hematol. 1995; 32: 45-59PubMed Google Scholar,8.Berk J.L. Keane J. Seldin D.C. et al.Persistent pleural effusions in primary systemic amyloidosis: Etiology and prognosis.Chest. 2003; 124: 969-977Crossref PubMed Scopus (86) Google Scholar. The rate of disease progression is variable and depends somewhat on organ involvement. Overall survival in series published in the 1990s is approximately 12 to 24 months. Patients with clinically evident cardiac involvement have a median survival of approximately 6 months4.Kyle R.A. Gertz M.A. Primary systemic amyloidosis: Clinical and laboratory features in 474 cases.Semin Hematol. 1995; 32: 45-59PubMed Google Scholar, 9.Kyle R.A. Gertz M.A. Greipp P.R. et al.A trial of three regimens for primary amyloidosis: Colchicine alone, melphalan and prednisone, and melphalan, prednisone, and colchicine.N Engl J Med. 1997; 336: 1202-1207Crossref PubMed Scopus (600) Google Scholar, 10.Skinner M. Anderson J. Simms R. et al.Treatment of 100 patients with primary amyloidosis: A randomized trial of melphalan, prednisone, and colchicine versus colchicine only.Am J Med. 1996; 100: 290-298Abstract Full Text PDF PubMed Scopus (308) Google Scholar, 11.Gertz M.A. The classification and typing of amyloid deposits.Am J Clin Pathol. 2004; 121: 787-789Crossref PubMed Scopus (46) Google Scholar. AA amyloidosis, also referred to as secondary amyloidosis, occurs in the setting of chronic inflammatory conditions. The amyloidogenic precursor protein is serum amyloid A (SAA), an acute-phase reactant synthesized by the liver. Several different SAA proteins can form amyloid deposits12.Kluve-beckerman B. Dwulet F.E. Benson M.D. Human serum amyloid A. Three hepatic mRNAs and the corresponding proteins in one person.J Clin Invest. 1988; 82: 1670-1675Crossref PubMed Google Scholar,13.Watson G. Faulkes D.J. Woo P. The fifth serum amyloid A-related gene sequence, GSAA4, is SAA3.Scand J Immunol. 1994; 40: 265-268Crossref PubMed Scopus (2) Google Scholar. The most common inflammatory diseases that underlie AA amyloidosis in developed countries are rheumatoid arthritis, inflammatory bowel disease, and familial Mediterranean fever (FMF), an autosomal-recessive disorder now known to be due to mutations in the gene encoding pyrin14.International FMF CONSORTIUM Ancient missense mutations in a new member of the RoRet gene family are likely to cause familial Mediterranean fever.Cell. 1997; 90: 797-807Abstract Full Text Full Text PDF PubMed Scopus (1224) Google Scholar. Chronic infections such as osteomyelitis, bronchiectasis, and tuberculosis still lead to the development of AA amyloidosis in some parts of the world. The distribution of organ involvement is somewhat more restricted in AA amyloidosis than in AL disease. Most patients with AA amyloidosis have renal involvement. The liver, spleen, autonomic nervous system, and thyroid also can be involved, but in contrast to AL amyloidosis, cardiac involvement is rare. In general, AA amyloidosis progresses more slowly than does AL disease, but the course is variable and tends to parallel that of the underlying inflammatory condition15.Gertz M.A. Kyle R.A. Secondary systemic amyloidosis: Response and survival in 64 patients.Medicine (Baltimore). 1991; 70: 246-256Crossref PubMed Scopus (315) Google Scholar,16.Lachmann H.J. G.H. Goodman H.J.B. Gallimore J. et al.Characteristic and clinical outcome of 340 patients with systemic AA amyloidosis.Amyloid and Amyloidosis: 10th International Symposium on Amyloidosis CRC Press. edited by Grateau GKR, Kyle R, Skinner M. 2004: 173-175Google Scholar. In the familial amyloidoses, a gene mutation inherited in an autosomal-dominant manner results in a single amino acid substitution that renders a plasma protein amyloidogenic. Mutations in the TTR gene are the most common cause of familial amyloidosis. Approximately 100 TTR mutations have been identified. Most of these mutations are amyloidogenic; however, several mutations appear to be non-pathogenic17.Saraiva M.J. Transthyretin mutations in hyperthyroxinemia and amyloid diseases.Hum Mutat. 2001; 17: 493-503Crossref PubMed Scopus (165) Google Scholar. A protective role of some of these non-amyloidogenic mutations is suggested by the lack of amyloid disease in compound heterozygous individuals who have inherited one TTR allele with an amyloidogenic mutation and one allele with a non-amyloidogenic mutation17.Saraiva M.J. Transthyretin mutations in hyperthyroxinemia and amyloid diseases.Hum Mutat. 2001; 17: 493-503Crossref PubMed Scopus (165) Google Scholar,18.Coelho T.C.R. Sousa A. Alves I.L. et al.Compound heterozygotes of transthyretin Met 30 and transthyretin Met 119 are protected from the devastating effects of familial amyloid polyneuropathy.Neuromuscular Disord. 1996; 6: S20Abstract Full Text PDF Google Scholar. Amyloidogenic variants of apolipoprotein AI, apolipoprotein AII, fibrinogen A α-chain, lysozyme, gelsolin, and cystatin C underlie less common forms of familial systemic amyloidosis1.Westermark P. Benson M.D. Buxbaum J.N. et al.Amyloid fibril protein nomenclature—2002.Amyloid. 2002; 9: 197-200Crossref PubMed Scopus (179) Google Scholar. The clinical features of familial amyloidosis vary depending on the underlying amyloidogenic protein and the particular amino acid affected by the mutation. For example, peripheral and autonomic neuropathy are the typical manifestations in patients with the Val30Met TTR mutation, while cardiomyopathy is the predominant manifestation in individuals with the Val122Ile TTR mutation19.Jacobson D.R. Pastore R.D. Yaghoubian R. et al.Variant-sequence transthyretin (isoleucine 122) in late-onset cardiac amyloidosis in black Americans.N Engl J Med. 1997; 336: 466-473Crossref PubMed Scopus (396) Google Scholar. In senile systemic amyloidosis, wild-type TTR rather than a mutated form of the protein forms amyloid deposits predominantly, but not exclusively, in the heart. The disease tends to develop in elderly individuals and can result in cardiomyopathy that usually is not as severe or rapidly progressive as that associated with AL amyloidosis20.Westermark P. Sletten K. Johansson B. et al.Fibril in senile systemic amyloidosis is derived from normal transthyretin.Proc Natl Acad Sci U S A. 1990; 87: 2843-2845Crossref PubMed Scopus (561) Google Scholar. Dialysis-related amyloidosis occurs as a result of deposition of β-2 microglobulin amyloid in peri-articular tissue and bone21.Drueke T.B. Beta-2-microglobulin and amyloidosis.Nephrol Dial Transplant. 2000; 15: 17-24Crossref PubMed Scopus (128) Google Scholar. It typically occurs in patients who have been dialysis-dependent for many years. β-2 microglobulin is amyloidogenic when present at high concentrations but not when present at physiologic concentrations. The serum concentration of β-2 microglobulin is markedly increased in patients with dialysis dependence because of reduced clearance by the kidneys, and probably also because of increased production due to dialysis-associated stimuli. Although a high concentration of β-2 microglobulin appears to be required for the development of dialysis-associated amyloidosis, other factors are likely important, as most patients with elevated serum β-2 microglobulin levels do not develop disease, and the concentration of β-2 microglobulin does not correlate with the severity of disease. Modification of β-2 microglobulin by advanced glycation end products, oxidation, or other constituents of the uremic environment might play a role in amyloid fibril formation, but evidence for this is inconclusive21.Drueke T.B. Beta-2-microglobulin and amyloidosis.Nephrol Dial Transplant. 2000; 15: 17-24Crossref PubMed Scopus (128) Google Scholar, 22.Miyata T. Oda O. Inagi R. et al.Beta 2-microglobulin modified with advanced glycation end products is a major component of hemodialysis-associated amyloidosis.J Clin Invest. 1993; 92: 1243-1252Crossref PubMed Scopus (398) Google Scholar, 23.Miyata T. Inagi R. Iida Y. et al.Involvement of beta 2-microglobulin modified with advanced glycation end products in the pathogenesis of hemodialysis-associated amyloidosis. Induction of human monocyte chemotaxis and macrophage secretion of tumor necrosis factor-alpha and interleukin-1.J Clin Invest. 1994; 93: 521-528Crossref PubMed Scopus (339) Google Scholar, 24.Niwa T. Miyazaki S. Katsuzaki T. et al.Immunohistochemical detection of advanced glycation end products in dialysis-related amyloidosis.Kidney Int. 1995; 48: 771-778Abstract Full Text PDF PubMed Scopus (51) Google Scholar, 25.Capeillere-blandin C. Delaveau T. Descamps-latscha B. Structural modifications of human beta 2 microglobulin treated with oxygen-derived radicals.Biochem J. 1991; 277: 175-182Crossref PubMed Scopus (77) Google Scholar. Carpal tunnel syndrome, tenosynovitis, destructive spondyloarthropathy, peri-articular soft tissue swelling, bone fractures, and arthralgias involving the shoulders, knees, wrists, and small joints of the hands are the typical clinical manifestations of dialysis-related amyloidosis. β-2 microglobulin amyloid deposits also have been identified in the gastrointestinal tract, heart, and blood vessels of patients with dialysis dependence, but the occurrence of clinically evident extra-articular disease is rare26.Choi H.S. Heller D. Picken M.M. et al.Infarction of intestine with massive amyloid deposition in two patients on long-term hemodialysis.Gastroenterology. 1989; 96: 230-234Abstract PubMed Google Scholar. The process of amyloid fibril formation begins with abnormal folding of a protein that is normally soluble Figure 1. The abnormal folding can result from a single amino acid mutation, from a proteolytic cleavage event, or from intrinsic properties that only become pathogenetically significant when the protein is present in high concentrations or in the presence of specific local environmental factors27.Kelly J.W. Towards an understanding of amyloidogenesis.Nat Struct Biol. 2002; 9: 323-325Crossref PubMed Scopus (92) Google Scholar,28.Merlini G. Bellotti V. Molecular mechanisms of amyloidosis.N Engl J Med. 2003; 349: 583-596Crossref PubMed Scopus (1303) Google Scholar. The abnormally folded intermediates aggregate into contiguous beta sheet polypeptide chains that form protofilaments with no appreciable likeness to the original precursor protein. An amyloid fibril is comprised of four to six of these protofilaments twisted around each other. One of the remarkable aspects of amyloidogenesis is that despite the marked diversity in structure and function of the amyloidogenic precursor proteins, amyloid fibrils are morphologically indistinguishable. The electron microscopic appearance and size of the fibrils, the x-ray diffraction pattern, the beta-pleated sheet configuration, and the ordered intercalation of Congo red dye that confers birefringence under polarized light are common to all amyloid fibrils28.Merlini G. Bellotti V. Molecular mechanisms of amyloidosis.N Engl J Med. 2003; 349: 583-596Crossref PubMed Scopus (1303) Google Scholar. In addition, all types of amyloid deposits, irrespective of the fibril type, contain constituents including serum amyloid P (SAP) protein, heparan sulfate proteoglycan, apolipoprotein E, laminin, and type IV collagen29.Pepys M.B. Hutchinson W.L. Gallimore J.R. et al.Amyloid P component: A critical reveiw.Amyloid. 1997; 4: 274-295Crossref Scopus (163) Google Scholar,30.Kisilevsky R. The relation of proteoglycans, serum amyloid P and apo E to amyloidosis current status, 2000.Amyloid. 2000; 7: 23-25Crossref PubMed Scopus (42) Google Scholar. Local factors influence both amyloid fibril formation and tissue deposition. The composition of basement membranes or extracellular matrix can contribute to targeting of amyloid to specific tissues. Glycosaminoglycan (GAG) moieties of proteoglycans appear to promote fibrillogenesis by stabilizing or inducing conformational changes in amyloidogenic precursors that favor fibril formation, and by providing protection from proteolysis during fibril formation and after tissue deposition31.Scholefield Z. Yates E.A. Wayne G. et al.Heparan sulfate regulates amyloid precursor protein processing by BACE1, the Alzheimer's beta-secretase.J Cell Biol. 2003; 163: 97-107Crossref PubMed Scopus (142) Google Scholar, 32.Yamaguchi I. Suda H. Tsuzuike N. et al.Glycosaminoglycan and proteoglycan inhibit the depolymerization of beta2-microglobulin amyloid fibrils in vitro.Kidney Int. 2003; 64: 1080-1088Abstract Full Text Full Text PDF PubMed Scopus (79) Google Scholar, 33.Zhu H. Yu J. Kindy M.S. Inhibition of amyloidosis using low-molecular-weight heparins.Mol Med. 2001; 7: 517-522Crossref PubMed Google Scholar, 34.Ancsin J.B. Kisilevsky R. Serum amyloid A peptide interactions with glycosaminoglycans. Evaluation by affinity chromatography.Methods Mol Biol. 2001; 171: 449-456Crossref PubMed Scopus (13) Google Scholar, 35.Stevens F.J. Kisilevsky R. Immunoglobulin light chains, glycosaminoglycans, and amyloid.Cell Mol Life Sci. 2000; 57: 441-449Crossref PubMed Scopus (60) Google Scholar. Local pH can affect the relative stabilities of the abnormal and normal conformations of the precursor protein and thus favor or retard fibrillogenesis. Experimental models suggest that amyloid fibrils themselves act as “seeds” within tissues, generating additional fibril formation by promoting amyloidogenic conformational changes in the soluble precursor protein36.Jarrett J.T. Berger E.P. Lansbury Jr., P.T. The carboxy terminus of the beta amyloid protein is critical for the seeding of amyloid formation: Implications for the pathogenesis of Alzheimer's disease.Biochemistry. 1993; 32: 4693-4697Crossref PubMed Scopus (1662) Google Scholar. Two mechanisms have been proposed to explain organ dysfunction in amyloidosis. The first, sometimes referred to as the “amyloid hypothesis,” is the direct disruption of tissue architecture and function by amyloid accumulation. That large quantities of deposited amyloid would have a deleterious impact on the surrounding tissue is easily appreciated from histologic examination of affected organs. In the kidney, the mesangium often appears to be essentially replaced with amyloid, and marked alterations in the components of the glomerular basement membrane are readily apparent by ultrastructural examination. In the heart, amyloid infiltration causes thickening and stiffening of the ventricular wall; these changes result in impaired diastolic filling and reduced stroke volume. Several observations suggest that processes other than displacement of normal structures also are important contributors to the manifestations of amyloidosis27.Kelly J.W. Towards an understanding of amyloidogenesis.Nat Struct Biol. 2002; 9: 323-325Crossref PubMed Scopus (92) Google Scholar. Demonstrations of interactions between AA or TTR amyloid fibrils and the receptor for advanced glycosylation end products (RAGE), and induction of specific signal transduction pathways by these interactions, suggest that local cellular activation might contribute to the pathogenesis of amyloidosis37.Yan S.D. Zhu H. Zhu A. et al.Receptor-dependent cell stress and amyloid accumulation in systemic amyloidosis.Nat Med. 2000; 6: 643-651Crossref PubMed Scopus (273) Google Scholar,38.Sousa M.M. Du yan S. Fernandes R. et al.Familial amyloid polyneuropathy: Receptor for advanced glycation end products-dependent triggering of neuronal inflammatory and apoptotic pathways.J Neurosci. 2001; 21: 7576-7586Crossref PubMed Google Scholar. Additionally, discrepancies between structural findings and clinical outcomes indicate that the amount of amyloid accumulation does not fully account for disease manifestations. For example, despite indistinguishable echocardiographic features among patients with AL and TTR cardiac amyloidosis, the severity of heart failure and the cardiac mortality rate are substantially greater in AL compared with TTR disease39.Dubrey S.W. Cha K. Skinner M. et al.Familial and primary (AL) cardiac amyloidosis: Echocardiographically similar diseases with distinctly different clinical outcomes.Heart. 1997; 78: 74-82Crossref PubMed Scopus (161) Google Scholar. Direct toxicity of amyloidogenic precursor proteins is suggested by findings that cellular oxidant stress is increased and that contractility and relaxation are impaired when cultured cardiomyocytes are exposed to amyloidogenic light chains40.Brenner D.A. Jain M. Pimentel D.R. et al.Human amyloidogenic light chains directly impair cardiomyocyte function through an increase in cellular oxidant stress.Circ Res. 2004; 94: 1008-1010Crossref PubMed Scopus (256) Google Scholar. Similarly, TTR folding intermediates and aggregates are cytotoxic in vitro [41, 42], and TTR aggregates have been detected in neuronal tissue in the absence of amyloid in patients with amyloidogenic TTR mutations42.Sousa M.M. Cardoso I. Fernandes R. et al.Deposition of transthyretin in early stages of familial amyloidotic polyneuropathy: Evidence for toxicity of nonfibrillar aggregates.Am J Pathol. 2001; 159: 1993-2000Abstract Full Text Full Text PDF PubMed Scopus (300) Google Scholar. The functional significance of the non-fibrillar TTR deposits in these patients is not clear. However, the possibility that precursor proteins and/or their folding intermediates are toxic has important implications for treatment strategies. Demonstrations that several amyloidogenic proteins are capable of forming ion-permeable channels have led to the hypothesis that channel formation in cell membranes underlies the cytotoxicity43.Kagan B.L. Azimov R. Azimova R. Amyloid peptide channels.J Membr Biol. 2004; 202: 1-10Crossref PubMed Scopus (147) Google Scholar. Each of the steps in the pathway from precursor protein to amyloid deposition is a potential target for treatment of the amyloidoses. Substantial progress has been made during the past several years in the design of new therapeutic approaches based on several of these targets Table 2.Table 2Treatment targets for the systemic amyl
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