You are in: eMedicine Specialties > Rheumatology > Miscellaneous Inflammatory Arthritis Amyloidosis, OverviewArticle Last Updated: Aug 11, 2006AUTHOR AND EDITOR INFORMATIONSection 1 of 11
 
Author: Bruce A Baethge, MD, Rheumatology Fellowship Program Director, Professor of Internal Medicine, Department of Internal Medicine, Division of Rheumatology, University of Texas Medical Branch at Galveston Bruce A Baethge is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians, American College of Rheumatology, Arthritis Foundation, and Association of Subspecialty Professors Coauthor(s): Daniel R Jacobson, MD, Associate Professor, Department of Medicine, Division of Hematology, New York University School of Medicine Editors: Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine; Lawrence H Brent, MD, Associate Professor of Medicine, Thomas Jefferson University; Chair, Program Director, Department of Medicine, Division of Rheumatology, Albert Einstein Medical Center; Alex J Mechaber, MD, FACP, Assistant Dean for Medical Curriculum, Associate Professor of Medicine, Division of General Internal Medicine, University of Miami Miller School of Medicine; Arthur Weinstein, MD, Professor of Medicine, Georgetown University Medical Center; Associate Chairman, Department of Medicine, Director, Section of Rheumatology, Washington Hospital Center Author and Editor Disclosure Synonyms and related keywords: amyloid diseases, primary amyloidosis, secondary amyloidosis, myeloma-associated amyloidosis, familial amyloidosis, localized amyloidosis, senile amyloidosis, senile cardiac amyloidosis, light chain amyloidosis, AL, familial amyloid polyneuropathy, transport protein transthyretin, TTR, ATTR, systemic amyloidosis, A amyloidosis, AA, heavy chain amyloidosis, AH, beta2-microglobulin amyloidosis, Aβ2M, familial renal amyloidosis, apolipoprotein AI amyloidosis, AapoAI, fibrinogen amyloidosis, AFib, lysozyme amyloidosis, ALys, apolipoprotein AII amyloidosis, AapoAII, beta protein amyloid, Ab, prion protein amyloidosis, APrP, cystatin C amyloidosis, ACys, gelsolin amyloidosis, AGel, atrial natriuretic factor amyloidosis, AANF, keratoepithelin amyloidosis, AKE, lactoferrin amyloidosis, ALac, calcitonin amyloidosis, ACal, islet amyloid polypeptide amyloidosis, AIAPP, prolactin amyloid, Apro, keratin amyloid, Aker DEFINITION OF AMYLOIDOSISSection 2 of 11
 
Amyloidosis is a clinical disorder caused by extracellular deposition of insoluble abnormal fibrils that injure tissue. The fibrils are formed by the aggregation of misfolded, normally soluble proteins. In humans, about 23 different unrelated proteins are known to form amyloid fibrils in vivo. All types of amyloid consist of a major fibrillar protein that defines the type of amyloid (approximately 90%) plus various minor components. Although each type of fibril may be associated with a distinct clinical picture, all share certain physical and pathologic properties, as follows:
For excellent patient education resources, visit eMedicine's Brain and Nervous System Center. Also, see eMedicine's patient education article Mad Cow Disease and Variant Creutzfeldt-Jakob Disease. CLASSIFICATION SYSTEMS: HISTORICAL (CLINICAL BASED) AND MODERN (BIOCHEMICAL BASED)Section 3 of 11
Historical classification systems (clinical based) Until the early 1970s, the idea of a single amyloid substance predominated. Various descriptive classification systems were proposed based on the organ distribution of amyloid deposits and clinical findings. Most classification systems included primary (ie, in the sense of idiopathic) amyloidosis, in which no associated clinical condition was identified, and secondary amyloidosis, ie, associated with chronic inflammatory conditions. Some classification systems included myeloma-associated, familial, and localized amyloidosis. The modern era of amyloidosis classification began in the late 1960s with the development of methods to solubilize amyloid fibrils. These methods permitted chemical amyloid studies. Descriptive terms such as primary amyloidosis, secondary amyloidosis, and others (eg, senile amyloidosis), which are not based on etiology, provide little useful information and are no longer recommended. Modern amyloidosis classification (biochemical based) Amyloid is now classified chemically. The amyloidoses are referred to with a capital A (for amyloid) followed by an abbreviation for the fibril protein. For example, in most cases formerly called primary amyloidosis and in myeloma-associated amyloidosis, the fibril protein is an immunoglobulin light chain or light chain fragment (abbreviated L); thus, patients with these amyloidoses are now said to have light chain amyloidosis (AL). Similarly, in most cases previously termed senile cardiac amyloidosis and in many cases previously termed familial amyloid polyneuropathy, the fibrils consist of the transport protein transthyretin (TTR); these diseases are now termed ATTR. Proteins that form amyloid fibrils differ in size function, amino acid sequence, and native structure but become insoluble aggregates that are similar in structure and properties. Protein misfolding results in formation of fibrils that show a common beta sheet pattern based on x-ray diffraction. Twenty-three different fibril proteins are described in human amyloidosis with variable clinical features. The major types of human amyloid are outlined and discussed individually in Table 1. Table 1. Human Amyloidoses
* Islet amyloid polypeptide amyloidosis SYSTEMIC AMYLOIDOSESSection 4 of 11
A amyloidosis The precursor protein is a normal-sequence apo-SAA (serum amyloid A protein), which is an acute phase reactant that circulates in the serum bound to high-density lipoprotein. A amyloidosis (AA) occurs in various chronic inflammatory disorders, chronic local or systemic microbial infections, and, occasionally, with neoplasms. Some of the conditions associated with AA include the following:
Typical organs involved include the kidney, liver, and spleen. Worldwide, AA is the most common systemic amyloidosis; it was formerly termed secondary amyloidosis. Colchicine prevents renal failure due to amyloid deposition in familial Mediterranean fever; no proven therapy exists in settings other than the treatment of underlying inflammatory condition and the reduced production of the precursor protein apo-SAA. For details, see Amyloidosis, AA (Inflammatory). Light chain amyloidosis The precursor protein is a clonal immunoglobulin light chain or light chain fragment. AL is a monoclonal plasma cell disorder closely related to multiple myeloma; some patients fulfill diagnostic criteria for multiple myeloma. Typical organs involved include the heart, kidney, peripheral nerve, gastrointestinal tract, respiratory tract, and nearly any other organ. AL includes former designations of primary amyloidosis and myeloma-associated amyloidosis. Treatment usually mirrors the management of multiple myeloma (ie, chemotherapy). Selected patients have received benefit from high-dose melphalan and autologous stem-cell transplantation, with reports of prolonged survival in recent studies. Iododoxorubicin, a molecule that binds to and solubilizes amyloid fibrils, is undergoing clinical study. For more information, see Amyloidosis, Immunoglobulin-Related. Heavy chain amyloidosis In a few cases, immunoglobulin chain amyloidosis fibrils contain only heavy chain sequences rather than light chain sequences, and the disease is termed heavy chain amyloidosis (AH) rather than AL. For more information, see Amyloidosis, Immunoglobulin-Related. Transthyretin amyloidosis The precursor protein is the normal- or mutant-sequence TTR, a transport protein synthesized in the liver and choroid plexus. TTR is a tetramer of 4 identical subunits of 127 amino acids each. Normal-sequence TTR forms amyloid deposits in the cardiac ventricles of elderly people (ie, >70 y); this disease is also termed senile cardiac amyloidosis. The prevalence of TTR cardiac amyloidosis increases progressively with age, affecting 25% or more of the population older than 90 years. Normal-sequence ATTR can be an incidental autopsy finding, or it can cause clinical symptoms (eg, heart failure, arrhythmias). Point mutations in TTR increase the tendency of TTR to form amyloid. Amyloidogenic TTR mutations are inherited as an autosomal dominant disease with variable penetrance. More than 60 amyloidogenic TTR mutations are known. The most prevalent TTR mutations are TTR Val30Met (common in Portugal, Japan, and Sweden), and TTR Val122Ile (carried by 3.9% of African Americans). Amyloidogenic TTR mutations cause deposits primarily in the peripheral nerves, heart, gastrointestinal tract, and vitreous. Treatment for mutant-sequence amyloidogenic TTR is liver transplantation or supportive care. For normal-sequence amyloidogenic TTR, the treatment is supportive care. For details, see Amyloidosis, Transthyretin-Related. Beta2-microglobulin amyloidosis The precursor protein is a normal beta2-microglobulin (b2M), which is the light chain component of the major histocompatibility complex. In the clinical setting, Ab2M is associated with patients on dialysis and, rarely, patients with renal failure who are not on dialysis. b2M is normally catabolized in the kidney. In patients with renal failure, the protein accumulates in the serum. Conventional dialysis membranes do not remove b2M; therefore, serum levels can reach as high as 30-60 times the reference range values in patients on hemodialysis. Musculoskeletal involvement is common and is characterized by deposits in the carpal ligaments, synovium, and bone, resulting in carpal tunnel syndrome, destructive arthropathy, bone cysts, and fractures. Other organs involved include the heart, gastrointestinal tract, liver, lungs, prostate, adrenals, and tongue. Treatment includes renal transplantation, which may arrest amyloid progression. For details, see Amyloidosis, Beta2M (Dialysis-Related). HEREDITARY RENAL AMYLOIDOSESSection 5 of 11
Consider these diseases when a renal biopsy demonstrates amyloid deposition and when they are likely diagnoses (rather than AL or AA) because the family history suggests an autosomal dominant disease. Again, the definitive diagnosis is made using immunohistologic staining of the biopsy material with antibodies specific for the candidate amyloid precursor proteins. For details, see Amyloidosis, Familial Renal. Apolipoprotein AI amyloidosis (AapoAI) is an autosomal dominant amyloidosis caused by point mutations in the apoAI gene. Usually, this amyloidosis is a prominent renal amyloid. Some kindreds have peripheral neuropathy or cardiac disease. ApoAI (likely of normal sequence) also is the fibril precursor in localized amyloid plaques in the aortae of elderly people. Fibrinogen amyloidosis (AFib) is an autosomal dominant amyloidosis caused by point mutations in the fibrinogen alpha chain gene. Lysozyme amyloidosis (ALys) is an autosomal dominant amyloidosis caused by point mutations in the lysozyme gene. Apolipoprotein AII amyloidosis (AapoAII) is an autosomal dominant amyloidosis caused by point mutations in the apoAII gene. The 2 kindreds described with this disorder have each carried a point mutation in the stop codon, leading to production of an abnormally long protein. CENTRAL NERVOUS SYSTEM AMYLOIDOSES AND OTHER LOCALIZED AMYLOIDOSESSection 6 of 11
Central nervous system amyloidosesBeta protein amyloid The amyloid beta precursor protein (AbPP), which is a transmembrane glycoprotein, is the precursor protein in beta protein amyloid (Ab). Three distinct clinical settings are as follows:
Prion protein amyloidosis The precursor protein in prion protein amyloidosis (APrP) is a prion protein, which is a plasma membrane glycoprotein. The etiology is either infectious (ie, kuru) or genetic (ie, Creutzfeldt-Jakob disease [CJD], Gerstmann-Sträussler-Scheinker [GSS] syndrome, fatal familial insomnia [FFI]). The infectious unit is the prion protein, which induces a conformational change in a homologous protein encoded by a host chromosomal gene. Patients with CJD, GSS, and FFI carry autosomal dominant amyloidogenic mutations in the prion protein gene; therefore, the amyloidosis forms even in the absence of an infectious trigger. Similar infectious animal disorders include scrapie in sheep and goats and bovine spongiform encephalitis (ie, mad cow disease). Cystatin C amyloidosis The precursor protein in cystatin C amyloidosis (ACys) is cystatin C, which is a cysteine protease inhibitor that contains a point mutation. This condition is clinically termed HCHWA, Icelandic type. ACys is autosomal dominant. Clinical presentation includes multiple strokes and mental status changes beginning in the second or third decade of life. Many of the patients die by age 40 years. This disease is documented in a 7-generation pedigree in northwest Iceland. The pathogenesis is one of mutant cystatin that is widely distributed in tissues, but fibrils form only in the cerebral vessels; therefore, local conditions must play a role in fibril formation. Non-amyloid beta cerebral amyloidosis (chromosome 13 dementias) Two syndromes (British and Danish familial dementia) that share many aspects of clinical Alzheimer disease have been identified. Findings include the presence of neurofibrillary tangles, parenchymal preamyloid and amyloid deposits, cerebral amyloid angiopathy, and amyloid-associated proteins. Both conditions have been linked to specific mutations on chromosome 13; they cause abnormally long protein products (ABri and ADan) that ultimately result in different amyloid fibrils. Other localized amyloidosesGelsolin amyloidosis The precursor protein in gelsolin amyloidosis (AGel) is the actin-modulating protein gelsolin. Amyloid fibrils include a gelsolin fragment that contains a point mutation. Two amyloidogenic gelsolin mutations are described. One example is Asp187Asn, which is endemic in southeast Finland. Clinical characteristics include slowly progressive cranial neuropathies, distal peripheral neuropathy, and lattice corneal dystrophy. Atrial natriuretic factor amyloidosis The precursor protein is atrial natriuretic factor (ANF), a hormone controlling salt and water homeostasis, and it is synthesized by the cardiac atria. Amyloid deposits are localized to the cardiac atria. This condition is highly prevalent in elderly people and generally is of little clinical significance. Atrial natriuretic factor amyloidosis (AANF) is most common in patients with long-standing congestive heart failure, presumably because of persistent ANF production. No relation exists to the amyloidoses that involve the cardiac ventricles (ie, AL, ATTR). Keratoepithelin amyloidosis and lactoferrin amyloidosis Point mutations occur in a gene termed BIGH3, which encodes keratoepithelin and leads to autosomal dominant corneal dystrophies characterized by the accumulation of corneal amyloid. Some BIGH3 mutations cause amyloid deposits, and others cause nonfibrillar corneal deposits. Another protein, lactoferrin, is also reported as the major fibril protein in familial subepithelial corneal amyloidosis. The relationship between keratoepithelin and lactoferrin in familial corneal amyloidosis is not yet clear. Calcitonin amyloid In calcitonin amyloid (ACal), the precursor protein is calcitonin, a calcium regulatory hormone synthesized by the thyroid. Patients with medullary carcinoma of the thyroid may develop localized amyloid deposition in the tumors, consisting of normal-sequence procalcitonin (ACal). The presumed pathogenesis is increased local calcitonin production, leading to a sufficiently high local concentration of the peptide and causing polymerization and fibril formation. Islet amyloid polypeptide amyloidosis In islet amyloid polypeptide amyloidosis (AIAPP), the precursor protein is an islet amyloid polypeptide (IAPP), also known as amylin. IAPP is a protein secreted by the islet beta cells that are stored with insulin in the secretory granules and released in concert with insulin. Normally, IAPP modulates insulin activity in skeletal muscle. IAPP amyloid is found in insulinomas and in the pancreas of many patients with diabetes mellitus type 2. Prolactin amyloid In prolactin amyloid (Apro), prolactin or prolactin fragments are found in the pituitary amyloid. This condition is often observed in elderly people and has also been reported in an amyloidoma in a patient with a prolactin-producing pituitary tumor. Keratin amyloid Some forms of cutaneous amyloid react with antikeratin antibodies. The identity of the fibrils is not chemically confirmed in keratin amyloid (Aker). Medin amyloid Aortic medial amyloid occurs in most people older than 60 years. Medin amyloid (AMed) is derived from a proteolytic fragment of lactadherin, a glycoprotein expressed by mammary epithelium. NONFIBRILLAR COMPONENTS OF AMYLOIDSection 7 of 11
All types of amyloid deposits contain not only the major fibrillar component (solubility in water, buffers of low ionic strength) but also nonfibrillar components that are soluble in conventional ionic strength buffers. The role of the minor components in amyloid deposition is not clear. These components do not appear to be absolutely required for fibril formation, but they may enhance fibril formation or stabilize formed fibrils. The nonfibrillar components, contained in all types of amyloid, include the following:
MECHANISMS OF AMYLOID FORMATIONSection 8 of 11
Amyloid protein structures In all forms of amyloidosis, the cell secretes the precursor protein in a soluble form that becomes insoluble at some tissue site, compromising organ function. All the amyloid precursor proteins are relatively small (ie, molecular weights 4000-25,000) and do not share any amino acid sequence homology. The secondary protein structures of most soluble precursor proteins (except for SAA and chromosomal prion protein [Prpc]) have substantial beta pleated sheet structure, while extensive beta sheet structure occurs in all of the deposited fibrils. In some cases, hereditary abnormalities (primarily point mutations) in the precursor proteins are always present (eg, lysozyme, fibrinogen, cystatin C, gelsolin). In other cases, fibrils form from normal-sequence molecules (eg, AL, b2M). In other cases, normal-sequence proteins can form amyloid, but mutations accelerate the process (eg, TTR, beta protein precursor). Deposition location In localized amyloidoses, the deposits form close to the precursor synthesis site; however, in systemic amyloidoses, the deposits may form either locally or at a distance from the precursor-producing cells. Amyloid deposits primarily are extracellular, but reports exist of fibrillar structures within macrophages and plasma cells. Proteolysis and protein fragments In some types of amyloidosis (eg, always in AA, often in AL, ATTR), the amyloid precursors undergo proteolysis, which may enhance folding into an amyloidogenic structural intermediate. Also, some of the amyloidoses may have a normal proteolytic process that is disturbed, yielding a high concentration of an amyloidogenic intermediate. The factors that lead to different organ tropism for the different amyloidoses are unknown. Whether the proteolysis occurs before or after tissue deposition is unclear in patients in whom protein fragments are observed in tissue deposits. In some types of amyloid (eg, AL, Ab, ATTR), nonfibrillar forms of the same molecules can accumulate before fibril formation; thus, nonfibrillar deposits, in some cases, may represent intermediate deposition. APPROACH TO DIAGNOSING AMYLOIDOSISSection 9 of 11
Pathologic diagnosis (Congo red staining and immunohistochemistry) Amyloidosis is diagnosed when Congo red–binding material is demonstrated in a biopsy specimen. Because different types of amyloidosis require different approaches to treatment, determining only that a patient has a diagnosis of amyloidosis is no longer adequate. A clinical situation may suggest the type of amyloidosis, but the diagnosis generally must be confirmed by immunostaining a biopsy specimen. Antibodies against the major amyloid fibril precursors are commercially available. For example, AL, ATTR, and Ab2M can present as carpal tunnel syndrome or gastrointestinal amyloidosis, but each has a different etiology and requires a different treatment approach. Similarly, determining whether the amyloid is of the AL or ATTR type is often difficult in patients with cardiac amyloidosis, because the clinical picture is usually similar. Without immunostaining to identify the type of deposited protein, an incorrect diagnosis can lead to ineffective and, perhaps, harmful treatment. Be wary of drawing diagnostic conclusions from indirect tests (eg, monoclonal serum proteins) because the results of these presumptive diagnostic tests can be misleading; for example, monoclonal serum immunoglobulins are common in patients older than 70 years, but the most common form of cardiac amyloidosis is derived from TTR. Diagnosis by subcutaneous fat aspiration For many years, rectal biopsy was the first procedure of choice. An important clinical advance was the recognition that the capillaries in the subcutaneous fat are often involved in patients with systemic amyloidosis and can often provide sufficient tissue for the diagnosis of amyloid, immunostaining, and, in some cases, amino acid sequence analysis; thus, biopsy of the organ with the most severe clinical involvement is often unnecessary. For example, in cardiac amyloidosis, the definitive diagnosis of the type of amyloid can be made using an endomyocardial biopsy specimen, with Congo red and immunologic staining of the tissue sample. Alternatively, when noninvasive testing suggests cardiac amyloidosis, a specific diagnosis is often made by studying a subcutaneous fat aspiration instead of endomyocardial biopsy, thereby avoiding an invasive procedure. Organ biopsies When the subcutaneous fat aspiration biopsy does not provide information to reach a firm diagnosis, biopsies can be obtained from other organs. In addition, an advantage to performing a biopsy of an involved organ (eg, kidney, heart) is that it definitively establishes a cause-and-effect relationship between the organ dysfunction and amyloid deposition. Other sites that are often sampled include the salivary glands, stomach, and bone marrow. MULTIMEDIASection 10 of 11
REFERENCESSection 11 of 11
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