CHAPTER 107 THE AMYLOIDOSES
CHAPTER 107 THE AMYLOIDOSES
JOEL N. BUXBAUM
DANIEL R. JACOBSON
Definition and History
Etiology and Pathogenesis
Mechanisms of Amyloid Formation
Structure of Immunoglobulin-Related Amyloid Fibrils
Carpal Tunnel Syndrome
Respiratory Tract Involvement
Clinical Findings in MIDD
Coagulation System Abnormalities
Transthyretin (TTR) Amyloidosis
b2 Microglobulin Amyloid
Other Forms of Amyloidosis
Therapy, Course, and Prognosis
Therapy of Localized AL
Pharmacologic Agents Designed to Break Down Amyloid Fibrils
Treatment of Nonamyloid Midd
Supportive Measures for AL
The amyloidoses are disorders of secondary structure, in which a protein, synthesized and secreted from the cell as a soluble molecule, forms insoluble, fibrillar tissue deposits, leading to organ dysfunction. The site and rate of deposition determine the clinical presentation. All amyloid deposits contain a single major fibrillar component and minor nonfibrillar components. To date, 19 fibril proteins have been isolated from different forms of human amyloidosis; one of these is immunoglobulin light chain. Light-chain amyloidosis (AL) is a monoclonal plasma cell disease in which the secreted immunoglobulin, because of its amino acid sequence, is predisposed to fibrillogenesis under physiologic conditions. AL is characterized by fatigue, weight loss, purpura, heart failure, proteinuria, renal failure, gastrointestinal dysfunction, neuropathy, and various other symptoms, depending upon the organ involved. Diagnosis is made by biopsy of an affected organ or subcutaneous fat aspiration followed by Congo red staining and immunohistochemistry of the specimen, to determine the type of amyloid. In the face of similar clinical features, immunohistochemistry distinguishes AL tissue deposition from that of other systemic amyloidoses in which AL-specific treatment would be inappropriate. Chemotherapy with melphalan and prednisone reduces the size of the plasma cell clone producing the amyloidogenic light chain and prolongs survival.
Acronyms and abbreviations that appear in this chapter include: AA, acquired amyloid; AL, light-chain amyloidosis; CJD, Creutzfeldt-Jakob disease;, FAC, familial amyloidotic cardiomyopathy; FFI, fatal familial insomnia; FMF, familial mediterranean fever; GSS, Gerstmann-Straüssler-Scheinker disease; Idox, 4-iododoxorubicin; MIDD, monoclonal immunoglobulin deposition disease; SAA, serum amyloid A–related protein; SAP, serum amyloid P; SCA, senile cardiac amyloid; SSA, senile systemic amyloidosis; TTR, transthyretin.
DEFINITION AND HISTORY
The amyloidoses are characterized by the extracellular accumulation of insoluble protein fibrils. Deposits were first identified in autopsy specimens by their homogeneous, eosinophilic appearance in conventional histologic sections stained with hematoxylin and eosin. Subsequently they were shown to bind metachromatic dyes and to possess the property of Congophilia, i.e., binding the dye Congo red, with a characteristic apple-green-appearing birefringence when the stained tissues were examined under polarized light. Electron microscopy and x-ray diffraction revealed a fibrillar ultrastructure, with extensive b-pleated sheet secondary structure. All the amyloidoses, regardless of the clinical setting or chemical composition, possess these staining and ultrastructural properties.
Historically, the amyloidoses were classified according to the clinical or pathologic features of the associated diseases. Secondary amyloidosis accompanied chronic inflammatory processes. Familial amyloidosis was recognized by distinctive clinical manifestations within a kindred. All other types, except that occurring with myeloma, were termed primary, in the sense of idiopathic, although some investigators had drawn attention to similarities between primary amyloidosis and the myeloma-related form. The development of methods for dissolving and fractionating amyloid fibrils extracted from tissues permitted the identification of nineteen different proteins as amyloid precursors to date (Table 107-1). Classification is now based on the chemical nature of the fibrillar component of the deposits. Terms such as primary and secondary amyloidosis, and descriptive clinical diagnoses, such as senile, dialysis-associated, and myeloma-associated, have been abandoned in favor of the etiologically based, chemical terminology.1
TABLE 107-1 THE MODERN (CHEMICAL) CLASSIFICATION OF HUMAN AMYLOIDOSIS
All amyloid deposits contain a major (85 to 95 percent) fibrillar component, which is soluble in water and buffers of low ionic strength, and nonfibrillar components that are extractable with conventional ionic strength buffers. The nonfibrillar components include P (pentagonal) component, apolipoprotein E, and heparan sulfate proteoglycans, which are found in all types of amyloid. Complement components, proteases, and membrane constituents have been demonstrated in some, but not all, tissue deposits. P component comprises 5 to 10 percent of the total deposited protein. It is derived from circulating serum amyloid P (SAP) component, which behaves as a typical acute phase reactant in the mouse, but not in humans. P component has structural homology to C-reactive protein and belongs to the pentraxin group of proteins.2
ETIOLOGY AND PATHOGENESIS
MECHANISMS OF AMYLOID FORMATION
The amyloid precursor proteins are relatively small, with molecular weights between 4000 and 25,000. They do not share any detectable amino acid sequence homology, although the secondary structures of most have substantial b-pleated sheet structure. The known exceptions are serum amyloid A-related protein (SAA) and Prpc, which contain little or no b-folding in the precursor despite extensive b-sheet in the deposited fibrils. The clinical amyloidoses are in vivo disorders of secondary protein structure in which the precursor proteins are secreted from the cell in a soluble form, only to become insoluble at some tissue site, ultimately compromising organ function. They represent an extracellular subset of a spectrum of disorders of secondary protein structure. The protein aggregates in the intracellular forms, Parkinson’s disease (cytoplasmic) and Huntington’s disease (intranuclear), lack the amyloid-defining properties.3,4
In some cases, the aberrant secondary structure seen in amyloid formation reflects a hereditary alteration in sequence that predisposes to fibril formation, e.g., transthyretin (TTR), lysozyme, fibrinogen, cystatin c, gelsolin, AbPP, ApoA1. In other cases wild-type molecules are the fibril precursor (TTR, AbPP, b2M, ApoA1). The deposits are primarily extracellular, but there have been reports of fibrillar structures within lysosomes of macrophages and the cisternae of plasma cells in AL marrow.5 In the localized forms of amyloidosis, the deposits are found close to the site of synthesis of the precursor, while in the systemic amyloidoses the deposits may form either locally or at a distance from the precursor-producing cells. AL is usually a systemic disorder, but localized AL may occur in the setting of an apparently confined plasma cell proliferation.
The role of P component and that of the other accessory molecules in amyloid deposition is not clear. While they do not appear to be an absolute requirement for fibril formation, they may stabilize the fibril, protecting it from proteolysis once it is formed, or enhance the transition from prefibril to fibril. In experimental systems, the rate of amyloid deposition is slower in the absence of P component.6 Intravenously injected purified P component will preferentially bind to amyloid deposits; this property has been exploited clinically, using radiolabeled P component, to localize and quantify the total body burden of amyloid.7
Apolipoprotein E has been found in all types of amyloid deposits.8 One Apo E allele (Apo E4) is strongly associated with Alzheimer’s disease. Apo E4 also may be a genetic risk factor for other forms of amyloidosis; however, its association with other amyloidoses is less well supported by the epidemiological evidence.9,10,11,12 and 13 The mechanism of Apo E involvement is not known.
Heparan sulfate proteoglycans are basement membrane components that are intimately associated with all types of tissue amyloid deposits.14 As with P component and Apo E, their role in amyloidogenesis remains undefined. Compounds known to bind to heparan sulfate proteoglycans, such as anionic sulphonates, have been shown to decrease fibril deposition in murine models of acquired amyloid (AA) disease and have been suggested as potential therapeutic agents.15
In some instances (e.g., uniformly in AA, frequently in AL, and inconsistently, perhaps in a tissue-related manner, in TTR) the amyloid precursors undergo proteolysis which may enhance the kinetics of folding into a profibrillar structural intermediate. It is also possible that in some of the amyloidoses (e.g., Ab or AA), a normal proteolytic process is disturbed, yielding a higher than normal concentration of a profibrillar molecule. Whether tissue deposition is purely physicochemical, or depends upon an interaction equivalent to that between ligand and receptor in which some component of tissue ground substance is the binding target, is unknown. In cases in which proteolysis is seen, it is unclear when cleavage takes place relative to deposition. In AL, Ab, and A-TTR, there is both clinicopathological and experimental evidence for deposition of nonfibrillar, non–Congo-red–binding forms of the same molecules as found in the fibrils.16,17 and 18 Nonfibrillar deposits probably represent a processing or deposition intermediate but may represent an alternative form of deposition.
STRUCTURE OF IMMUNOGLOBULIN-RELATED AMYLOID FIBRILS
When examined by immunofluorescent and immunohistologic techniques or immunogold electron microscopy, tissue AL amyloid deposits show binding of antibodies to a single Ig polypeptide chain class. In nearly all cases, the deposits consist of monoclonal L-chains and/or their derived peptides.19 Rarely, the deposits contained only H-chain determinants and were classified as AH rather than AL.20
Extraction of L-chain–related amyloid deposits using either distilled water or low ionic strength buffers has yielded fibril subunits comprised of L-chain fragments, whole chains, or both. The fragments include the amino terminus of the chain and extend into the constant region. They are usually about 16,000 Da in molecular mass but may be as small as 5000 Da.19 In 90 percent of patients the deposited peptides include constant region sequence, accounting for the property of staining with commercially available anti–L-chain sera which are specific for constant region determinants. These observations are consistent with the failure, even in experienced laboratories, of 10 percent of deposits to bind either anti-k or anti-l antisera. In most cases, the deposits contain complete L-chains and L-chain fragments. In a minority of cases only complete chains are deposited. Molecules larger than conventionally sized L-chains, representing enzymatically glycosylated L-chains, have also been found.
The prominence of fragments in the deposits has suggested a proteolytic origin of the fibril precursor from an intact amyloidogenic L-chain; however, direct in vivo evidence for this hypothesis is lacking. Occasional ultrastructural demonstration of L-chain fibrils within the cisternae of malignant plasma cells or within macrophages have been used to support the role of lysosomal digestion of the precursor to yield fibril.5 It has been argued, however, that such findings could also be explained by phagocytic ingestion of preformed fibrils. A single cell culture experiment suggested plasma cell-macrophage interaction in the production of AL fibrils.21 In vitro experiments have shown that lysosomal enzymes can digest L-chains to molecules that form fibrils in the test tube.22 In other studies, the propensity of a light chain to form amyloid fibrils in vitro following protease digestion did not correlate with in vivo amyloid formation.23 Marrow cells, obtained from all patients with well-documented tissue AL deposition, synthesize excess L-chains, regardless of whether free L-chains are detected in the patients’ serum or urine. In some instances the cells contained L-chain fragments, but the synthetic or degradative origin of the fragments was not definitively established.24
In addition to the chemical analysis of deposited AL fibrils, considerable information has been obtained from the study of light chains isolated from the serum and/or urine of patients with AL. In some instances, the fibrils were also available, but in others the L-chains were assumed, but not proved, to be identical with the deposited proteins based on the immunohistochemistry. The most common AL precursor proteins are L-chains of the l class: l AL is about twice as prevalent as k AL.19 In contrast, in nonamyloid monoclonal immunoglobulin deposition disease (MIDD), k chains are the predominant precursor. In the instances in which H-chains were the major amyloid component, chemical analysis revealed that the precursor H-chain displayed domain deletions resulting in polypeptides the size of L-chains.20 In studies of nonamyloid MIDD containing both H- and L-chain deposition, the heavy chains are also smaller than normal.25
Within L-chain classes, not all variable regions have the same fibrillogenic potential. L-chains of the Vlvi class appear to be the most amyloidogenic: Clonal plasma cell proliferative diseases in which the Vlvi gene is expressed are always associated with amyloid deposition.26,27 Recent data, using molecular probes specific for germline V-region genes, have suggested that monoclonal Igs of the Vlvi class are more likely to be associated with renal disease than with other organ involvement and are less likely to be associated with myeloma. To date no such pattern has been demonstrated for other germline V-genes expressed in amyloid proteins. Among k V-genes, the Vk1 subgroup is overrepresented among amyloid forming L-chains, while some other subclasses appear underrepresented in amyloidosis in comparison to plasma cell disorders without amyloidosis.28
Within the V-region families certain amino acid residues occurring at particular positions in the L-chain sequence seem to render those chains more amyloidogenic. When a combination of such residues is present the chances of a L-chain being associated with tissue amyloid deposition is increased.29 Other substitutions seem more likely to be associated with the nonfibrillar deposits of MIDD.30 Another structural feature that appears to predispose to AL deposition is enzymatic glycosylation of the L-chain. While approximately 15 percent of human L-chains bear sugar residues, almost one-third of amyloidogenic L-chains are glycosylated.31 The nature of the contribution of glycosylation to the process is unknown.
AL is the most common form of systemic amyloidosis in the United States. In Olmstead County, Minnesota, AL prevalence is about 1 case per 100,000 people.32 It is not clear if the estimate, obtained in a relatively homogeneous northern European–derived population, would apply in an ethnically diverse setting.
The clinical picture of patients with AL varies widely. The median age at diagnosis in one large series of AL patients was 64 years. The most common presenting symptoms are weakness and weight loss, followed by purpura, particularly in loose facial tissue. Prognosis depends upon the pattern of tissue deposition. The kidneys are the most frequent sites of AL deposits; the heart, peripheral nerves, gastrointestinal tract, and liver are also affected. Any organ can be involved, with symptoms and physical findings reflecting the extent of anatomic compromise. Patients with clinical cardiac involvement have the worst prognosis, while patients with signs and symptoms limited to peripheral nerves have the longest survival.33 Other favorable prognostic features include a small number of clonal plasma cells in the marrow and normal renal function.34,35
Initial physical findings include peripheral edema, hepatomegaly, purpura, orthostatic hypotension, peripheral neuropathy, carpal tunnel syndrome, and macroglossia.32,36,37 Peripheral edema and hypotension may be related to congestive heart failure and/or the nephrotic syndrome. Purpura results from vascular fragility produced by amyloid deposition in the subendothelium of the small blood vessels. It may be very prominent in patients with coagulopathy.38,39 In recent series, macroglossia has been less common at the time of initial presentation than in older studies, perhaps because of earlier diagnosis. When it does occur, it is highly suggestive that the amyloid is of the AL type, as it has only been seen in AL and occasionally in b2M amyloid.40
It is not known what leads to the pattern of tissue deposition in a given patient. Amyloid in a particular organ leads to similar clinical consequences regardless of the chemical type. For example, cardiac AL and cardiac TTR amyloidosis produce similar symptoms and findings on electrocardiography and echocardiography, although AL cardiomyopathy typically runs a more rapid clinical course.41,42 In recent analyses, the median survival following diagnosis of AL was slightly longer than 1 year, with fewer than 10 percent surviving 5 years.32 Patients with cardiac presentation had a median survival of about 6 months.33 Renal and cardiac involvement were the most common causes of death before aggressive dialysis was used in patients with renal amyloid; more recently, cardiac deaths predominate.
The most common renal manifestation of AL disease is proteinuria; 30 percent to 50 percent of AL patients excrete at least a gram of predominantly non–L-chain protein per day in the urine.43,44 and 45 AL can also cause hematuria. Azotemia is a late manifestation of renal AL, but dialysis can stabilize the course of patients with extensive kidney involvement and is an option in patients developing renal failure.46 Renal biopsy reveals deposits in the glomerular mesangium and, later, along the basement membrane. Nonamyloid immunoglobulin deposits will also be detected by immunohistochemical staining.47
AL deposits in the heart occur in the ventricular interstitium and along the conduction system.48,49 The amyloid causes diastolic dysfunction, congestive heart failure, and arrhythmias, including heart block, premature ventricular contractions, and various tachyarrhythmias.50 Deposits in the coronary arteries, usually the smaller intracardiac arterioles, may cause a clinical picture similar to atherosclerotic coronary artery disease.51 The interstitial deposition leads to thickening of the ventricular walls without the increase in chamber volume that occurs in heart failure arising from long-standing hypertension. Late in the course, the stiff myocardium can yield cardiac catheterization data similar to constrictive pericarditis. Cardiac involvement eventually occurs in over 75 percent of patients with AL.32,52 Death is due to cardiac deposition with congestive heart failure or arrhythmias in about half of AL patients. The actual number may be higher because some patients have undiagnosed terminal arrhythmias.
No noninvasive test is sufficiently sensitive or specific for diagnosing cardiac amyloidosis. Electrocardiography often shows a low voltage QRS complex in the limb leads.53 In some cases, loss of anterior forces suggests anteroseptal infarction that is not confirmed at autopsy.54 The most useful diagnostic test for cardiac amyloidosis, apart from endomyocardial biopsy, is echocardiography, which reveals increased ventricular wall thickness, increased septal thickness, and the appearance of granular “sparkling.” The latter finding is neither sensitive nor specific enough to be diagnostic but is suggestive when present. Evaluation of diastolic function by Doppler echocardiography shows impaired ventricular relaxation early with shortened deceleration times later, ultimately showing a pattern much like that of constrictive pericarditis. The ejection fraction is preserved until late in disease. Other echocardiographic findings include valvular thickening and insufficiency, atrial enlargement, and rare atrial thrombosis.55,56 and 57 Scanning with radiolabeled P component (available only in Europe as of 1999) is a sensitive noninvasive means of detecting and monitoring the amount of amyloid in many organs.6 It is not useful for diagnosing cardiac amyloid because the myocardial signal does not stand out from the background created by the label in the intracardiac blood. The combined use of electrocardiography plus echocardiography appears to have the most diagnostic value.53,58
AL (and other systemic amyloidoses) can lead to severe orthostatic hypotension with restriction of normal activity and syncope.32 Poor cardiac contractility resulting from myocardial deposition, autonomic neuropathy secondary to amyloid deposits in the peripheral nerves, and impaired arteriolar responsiveness resulting from endothelial deposition all may contribute. Diuretic treatment of heart failure or the nephrotic syndrome with reduction of intravascular volume also predisposes to symptomatic hypotension.
Sensorimotor neuropathy, consequent to deposition in peripheral nerves with axonal degeneration of the small nerve fibers, occurs in about 20 percent of AL cases. The symmetric sensory impairment and weakness, sometimes accompanied by painless ulcers, is similar to that of diabetic neuropathy.32 The lower extremities are usually affected more severely than the upper. Diagnosis can be made by sural nerve biopsy, although the actual deposits may be proximal to the sural nerve and not in the biopsy specimen.60 Cranial neuropathy is occasionally seen.61 Autonomic neuropathy, leading to orthostatic hypotension, diarrhea, or impotence, may be incapacitating.62 The combination of severe peripheral and autonomic neuropathy is also a common presentation of familial transthyretin-amyloidosis, but the patient’s age, absence of other organ involvement, and family history should be discriminated.
CARPAL TUNNEL SYNDROME
Carpal tunnel syndrome was the initial presenting finding in one-fifth of AL patients evaluated in a large referral center.32 Involvement of the carpal ligament is also seen in b2M amyloid in patients undergoing dialysis, and in TTR amyloidosis, with or without a TTR variant.63 Treatment is surgical. At the time of carpal tunnel release, the tissue specimen can be stained with Congo red and immunohistochemistry performed if a definitive diagnosis has not been previously established. Amyloidosis is responsible for only a small fraction of symptomatic individuals undergoing surgery for relief of median nerve compression.
All forms of systemic amyloidosis involve the gastrointestinal tract. Most patients with AL have histologic evidence of infiltration of the gut, particularly in the blood vessels, but the deposition is symptomatic in only a minority.32,64 Macroglossia can become severe enough to interfere with swallowing and breathing. Gastric AL can cause hematemesis, nausea, and vomiting.65 Intestinal AL can impair motility and cause hemorrhage, obstruction, constipation, and diarrhea, or alternating constipation and diarrhea.66,67,68,69 and 70 Malabsorption from AL is rare. AL autonomic neuropathy also contributes to impaired gastrointestinal motility.
Hepatic AL, causing hepatomegaly, is common, although liver function abnormalities are rare even in cases with massive deposition.39,71 Splenomegaly may also develop and is usually asymptomatic, but functional asplenism may produce Howell-Jolly bodies in the peripheral blood. Spontaneous rupture of a massively infiltrated liver or spleen is a surgical emergency.72
RESPIRATORY TRACT INVOLVEMENT
Systemic AL commonly deposits in the respiratory tract, in a nodular or diffuse pattern. Any part of the respiratory tree, from nasopharynx to pulmonary alveoli, may be involved. Involvement is often asymptomatic, although alveolar or diffuse interstitial involvement can cause dyspnea. Chest radiography reveals a reticular nodular pattern or interstitial infiltration.73,74 and 75
AL deposits in the joints may resemble seronegative rheumatoid arthritis.76 Deposits in the glenohumeral articulation may cause localized pain and swelling, the “shoulder pad sign,”77 while deposits in skeletal muscle may produce pseudohypertrophy.78,79 Congophilic fibrils may be seen in the synovial fluid.
Localized amyloid deposits, including amyloid masses termed amyloidomas, may be found in various sites even in the absence of systemic disease. In some cases, plasma cells have been demonstrated histologically surrounding the deposits; in one case DNA sequencing revealed that the local plasma cells were producing the deposited L-chains.80 For unknown reasons, the respiratory tract is the most common site of localized AL. It often remains confined, without progression to systemic disease.81,82 Similar AL deposits involving the lower urinary tract, the mediastinum, retroperitoneum and skin, as either plaques or nodules, have been described.83,84
Bleeding may be a severe manifestation of AL, or indeed of any of the systemic amyloidoses. Subendothelial deposition results in capillary fragility and mucocutaneous hemorrhage.85 A deficiency in coagulation factor X, secondary to its binding to AL amyloid fibrils, can produce life-threatening bleeding.38 Less often, extensive liver involvement can lead to decreased levels of other vitamin K–depending clotting factors.39
CLINICAL FINDINGS IN MIDD
Patients with MIDD, without myeloma, usually present with proteinuria or the full nephrotic syndrome with nodular glomerulosclerosis and slowly developing renal failure. When MIDD accompanies myeloma the histology is characterized by tubular deposits and Bence-Jones cast nephropathy with rapidly developing renal failure.47 As in AL, cardiac involvement can occur in either group. Despite the differences in the intramyocardial distribution of amyloid and MIDD deposits, the physiologic consequences of alterations in relaxation and compliance, distortions in the voltage/mass relationship, diastolic dysfunction, arrhythmias, and congestive heart failure are similar.86
Amyloidosis is diagnosed by demonstration of Congo red–binding material with the characteristic apple-green fluorescence under polarized light in a biopsy specimen. Sampling of relatively accessible tissues under direct vision provides a reliable means for determining the presence of amyloid deposition. For many years, rectal biopsy was the procedure of choice. Currently subcutaneous fat aspiration is the first approach to obtaining material for Congo red and immunohistochemical staining.87,88 The combination of fat aspiration and rectal biopsy will identify 80 to 90 percent of patients later found to have amyloid elsewhere. Other sampling sites include salivary glands, stomach, and marrow (Table 107-2). Biopsy of an organ with impaired function, such as kidney or heart, is a high-yield procedure that definitively establishes the relationship between organ dysfunction and amyloid deposition.
TABLE 107-2 BIOPSY DIAGNOSIS OF AMYLOIDOSIS
Because different types of amyloidosis require different approaches to treatment, it is no longer adequate to determine only that a patient has amyloidosis. Although the clinical situation may suggest the type of amyloidosis, the diagnosis must be established by immunohistochemistry of a biopsy specimen using antibodies against the major amyloid fibril precursors. AL, TTR, and b2M amyloidoses can all present as carpal tunnel syndrome or gastrointestinal amyloidosis, but each has a different etiology, requiring different approaches to treatment. Distinguishing between AL and TTR cardiac amyloidosis on clinical grounds alone is particularly difficult, as the age of the patient, the patterns of organ involvement, and the clinical consequences of deposition are often similar. For instance, in individuals over age 70, a group in which serum M-proteins are common, the most prevalent form of cardiac amyloidosis is TTR-derived.41,92 When cardiac amyloidosis is suspected because of the results of noninvasive cardiac testing, the definitive distinction between AL and A-TTR can be made by endomyocardial biopsy, with Congo red and immunohistochemical staining of the tissue sample. In a patient with congestive heart failure and noninvasive testing suggestive of amyloidosis, subcutaneous fat aspiration can provide material for definitive diagnosis, avoiding the more invasive endomyocardial biopsy. Without immunohistologic identification of the deposited protein, an incorrect presumptive diagnosis of AL could lead to ineffective and perhaps harmful treatment.
The cardinal laboratory finding in AL and MIDD, a monoclonal immunoglobulin light chain, is detected on clinical laboratory testing in the serum or concentrated urine of 80 to 90 percent of patients.19,32,36 It is likely that a monoclonal protein would be detected in all patients with systemic deposition disease if a sufficiently sensitive assay were available.93 The concentration of normal immunoglobulins is often decreased, as in myeloma.36,94 The combination of hypogammaglobulinemia and proteinuria should suggest a diagnosis of AL or MIDD. In contrast, systemic AA is usually associated with polyclonal hyperglobulinemia related to the persistent inflammation and increase in cytokine (Il-6) production.
About 40 percent of patients have more than 10 percent plasma cells in the marrow.32,89 Light-chain immunophenotyping of the marrow, even in the absence of increased numbers of plasma cells, will usually reveal the distortion in the k/l ratio reflecting the L-chain type of the amyloid precursor.
COAGULATION SYSTEM ABNORMALITIES
Many clotting system abnormalities have been described in AL. Factor X may bind to amyloid fibrils, leading to its rapid clearance from the blood, with consequent prolongation of the prothrombin and partial thromboplastin times.38 Elevation in tissue and urine plasminogen activators and decrease in tissue plasminogen activator inhibitor, leading to hyperfibrinolytic states, have also been reported.97
The differential diagnosis of AL includes MIDD, or, if a diagnosis of amyloidosis has already been made, nonimmunoglobulin forms of systemic amyloidosis. Diagnostic confusion in the evaluation of biopsies can be created by the binding of Congo red to collagen. The nonspecific nature of the binding can usually be clarified by immunohistochemical analysis and electron microscopy.
TRANSTHYRETIN (TTR) AMYLOIDOSIS
Transthyretin (formerly known as thyroxine binding prealbumin) is a normal serum protein that transports thyroxine and retinol binding protein. It is synthesized in the liver, choroid plexus, and retina being regulated independently in the liver and choroid.98 Hepatic, but not choroid plexus, synthesis is decreased during inflammation and malnutrition. The protein consists of 4 identical subunits of 127 amino acids, and contains considerable b-pleated sheet structure.
TTR amyloidosis resembles AL in affecting the peripheral and autonomic nervous systems, heart, and gastrointestinal tract. It differs in that renal disease is rarely a dominant manifestation. TTR amyloid occurs in two molecular contexts. Normal-sequence TTR commonly forms amyloid deposits in the cardiac ventricles, gastrointestinal tract, carpal ligament, and other organs of elderly people.41,54,63,99,100 and 101 It may be confused with AL, since monoclonal serum or urine proteins may occur coincidentally in such patients. The variant forms of TTR, containing point mutations, form systemic deposits, usually involving the heart and/or peripheral nerves, but usually at an earlier age.102
In clinical practice normal TTR was utilized as an indicator of malnutrition.103 It was first noted to be involved in disease pathogenesis when a mutant molecule (TTR Met30) was found to be the fibril precursor of the amyloid found in the systemic and peripheral nerve deposits in Portuguese patients with familial amyloidotic polyneuropathy (FAP). FAP is characterized by predominant peripheral and autonomic neuropathy, as well as involvement of the heart, gastrointestinal tract, and vitreous.104 The pattern of organ involvement varies among kindreds. The age of onset varies from the teens to beyond age 60. In the advanced stage of disease, proteinuria, renal failure, lower cranial nerve involvement, decreased salivation, macroglossia, goiter, and neuropathic knee or ankle damage may occur. It is in the latter stages when, in the absence of a positive family history, the disorder is most apt to be confused with AL, but the long clinical course distinguishes TTR amyloid from AL.
Other familial amyloid syndromes with different clinical patterns of involvement (predominant upper or lower extremity neuropathy, varying involvement of the heart, kidneys, GI tract, and eye) have been reported. Often the clinical phenotype is specific for a particular TTR mutation, but even with the same mutation phenotypic variation is seen.105,108 When TTR primarily affects the heart, without significant neuropathy, and a TTR mutation is present, the disease is termed familial amyloidotic cardiomyopathy (FAC). As of June 1999, 71 different amyloid-associated amino acid substitutions had been discovered at 55 of the 127 positions in the TTR molecule.106 TTR Met30 FAP has been treated with liver transplantation to replace the gene encoding the variant TTR with a wild type gene. This form of gene therapy has resulted in some clinical improvement, particularly in autonomic neuropathy. It is not clear if it is effective in patients with other mutations, especially those with predominant cardiac involvement.104,107
Isolated ventricular amyloid in elderly people, generally without a family history of amyloidosis, was originally called senile cardiac amyloid (SCA). While the deposition was originally thought to be incidental, it now appears that in half the cases the deposits are the cause of death.101,108 Detailed autopsy studies indicated that many patients with SCA also had deposits in the lungs and blood vessels, and the alternative name senile systemic amyloidosis (SSA) was proposed. Ventricular TTR deposition has been found at autopsy in 10 to 25 percent of people over age 80. Functional abnormalities, including atrial fibrillation and congestive heart failure, occur in the absence of any anatomically definable cardiac disease other than the amyloid deposits. In several patients the TTR deposits in SCA/SSA have been shown to be of wild-type sequence.109
Occasional patients present in the sixth to eighth decades with severe cardiac TTR-amyloidosis and no known family history. Despite the negative family history, some have been found to have a TTR mutation; thus, they have FAC, not SCA/SSA.110,111 and 112 The most common mutation in this age group is a substitution of Ile for Val at position 122, which is carried by 3 to 4 percent of African Americans.113 Thus, there are 1.3 million gene carriers in the United States, with approximately 150,000 over the age of 60 at risk for cardiac deposition.110 None of the patients with TTR Ile122 cardiomyopathy has been noted to be associated with neuropathy. Patients presenting in this manner might be incorrectly assumed to have AL with predominant cardiac manifestations.
Worldwide, AA amyloid is the most common of the systemic amyloidoses.114 The AA protein comprises the fibril in the amyloid deposition accompanying chronic inflammatory diseases of either infectious (e.g., leprosy, osteomyelitis, tuberculosis) or noninfectious (e.g., rheumatoid arthritis, familial mediterranean fever, or FMF,) etiologies. In emerging nations, AA is more likely to occur subsequent to untreated or long-standing infections. In contrast, most patients in the United States and Western Europe with AA have an underlying rheumatic disorder such as long-standing rheumatoid arthritis. Even in association with noninfectious inflammatory disease, the incidence of AA varies considerably among countries with apparently similar levels of economic development, suggesting that factors other than the degree of industrialization play a significant role.
About 70 percent of patients with AA have renal disease (tubular disorders, nephrotic syndrome, and/or renal insufficiency) at the time of diagnosis.37,115 Renal vein thrombosis may occur, although it is not clear if it is more frequent in amyloidosis than it is in nephrotic syndrome from other causes.116 Gastrointestinal involvement, hepatomegaly, and splenomegaly are common. Adrenal deposits can be seen, but clinical adrenal insufficiency is rare. Peripheral neuropathy and clinically significant cardiac involvement are rare. For unclear reasons, subcutaneous fat aspiration is not usually useful in patients with AA associated with FMF.117
The precursor molecule apo-SAA circulates in the serum bound to high-density lipoprotein and behaves as an acute phase reactant. The concentration of SAA in normal serum is barely detectable, but with inflammation it may increase by 2 to 3 orders of magnitude. SAA is involved in the intracellular metabolism of cholesterol by inflammatory cells; the production of apo-SAA, but not its tissue deposition, is part of the normal inflammatory response.118 Three SAA genes, two of which have multiple alleles, encode the expressed isoforms of the protein; there is also an SAA pseudogene.119 SAA1 is the predominantly deposited protein in human AA disease. SAA1 allele frequencies vary in different ethnic groups. The differences may be responsible for the variation in the incidence of AA in the course of inflammatory diseases, some populations having alleles of greater amyloidogenicity.120
Renal AA has also been found in association with some tumors, most commonly renal cell carcinoma, Hodgkin’s lymphoma, and rarely atrial myxomas.121,122 The relationship may be secondary to cytokine production by the tumor or by inflammatory cells responding to the tumor.
Differences in the frequency of AA disease have been seen in different ethnic groups with the autosomal recessive disease familial Mediterranean fever, a periodic febrile disorder with serositis, arthritis, and skin rashes, associated with high levels of SAA production.123 The febrile disease is associated with mutations in the pyrin/marenostrin gene, which is expressed in granulocytes. The normal function of the pyrin/marenostrin protein may be to inhibit, or turn off, the inflammatory response. In Armenian kindreds the frequency of renal amyloidosis is quite low, while in Sephardic Jews renal involvement, ultimately fatal, is common by age 30.124 It has been suggested that the ethnic discrepancy may be related to differences in the spectrum of mutations in each group, variation in other genes controlling the process of amyloidogenesis, or differences in environmental influences in the different populations.125
In AA associated with FMF, colchicine prophylaxis reduces the frequency and severity of the febrile episodes.126 It is likely that the elimination of renal amyloidosis in patients who adhere to the thrice-daily regimen results from a reduction in inflammation, rather than an amyloid-specific effect. Colchicine has also been reported to inhibit experimental AA formation in murine inflammatory models.127 Because of these two sets of observations, colchicine has also been used empirically in patients with AA unrelated to FMF. The evidence for its benefit in these is largely anecdotal.128
Other hereditary periodic febrile disorders have been described in association with AA. In the Muckle-Wells syndrome, AA deposition accompanies deafness, urticaria, and febrile episodes. It appears to display autosomal dominant inheritance. The responsible gene is unknown, although a candidate region for the gene has recently been localized to chromosome 1q44.129
b2 MICROGLOBULIN AMYLOID
Patients undergoing long-term hemodialysis develop carpal tunnel amyloid consisting of b2 microglobulin (b2M)–derived fibrils. This type of amyloid primarily involves synovial membranes, causing trigger finger, bone cysts, and destructive spondyloarthropathy. The heart, GI tract, liver lung, prostate, adrenals, and tongue may also be involved.130,131 b2M amyloidosis increases with the duration of hemodialysis: It first appears after about 5 years and increases to 20 percent at 10 years, 30 to 50 percent at 15 years, and 80 to 100 percent at 20 years.132 Deposits also occur in patients treated with continuous ambulatory peritoneal dialysis and have been reported in patients with renal failure who have not undergone dialysis.133,134 Diagnosis is made in the clinical setting of long-standing renal failure treated by dialysis, the characteristic x-ray lesions, which resemble the punched-out lytic bone lesions of myeloma, and biopsy demonstration of amyloid staining with anti-b2M antiserum. Subcutaneous fat aspiration is not usually helpful.135 The long history of renal failure and dialysis in a patient with carpal tunnel syndrome should allow the distinction between AL and b2M amyloid to be made easily on clinical grounds and confirmed by biopsy. Kidney transplantation may arrest amyloid progression in these patients.
b2M, the light-chain component of the major histocompatibility complex, is both excreted and catabolized in the kidney. In renal failure, it accumulates in the serum. Because of its size b2M is not removed by conventional dialysis membranes and serum levels may reach 30 to 60 times normal in dialysis patients. Originally it was believed that the mass-action effect was responsible for this form of amyloid deposition, so more permeable dialysis membranes with larger pore sizes were developed to reduce this debilitating complication of dialysis. Current data suggest that the pathogenesis is more complicated, involving macrophage activation by dialysis membranes with increased b2M production, nonenzymatic glycation of the protein and additional activation via the receptor for advanced glycation end-products.136
OTHER FORMS OF AMYLOIDOSIS
HEREDITARY RENAL AMYLOIDOSES
Each of the hereditary amyloidoses (AApoAI, Afib, Alys) should be considered when a renal biopsy is reported to show amyloid deposition.137,138,139,140 and 141 The clinical differentiation between the hereditary renal amyloidoses and AL with a dominant renal presentation should be easily established on the basis of family history and immunoglobulin studies. The definitive diagnosis is made by immunohistologic staining of the biopsy material with antibodies specific for the candidate amyloid precursor proteins.
AMYLOIDOSES LOCALIZED TO THE CENTRAL NERVOUS SYSTEM
There should be little clinical confusion between AL disease and any of the primarily CNS amyloidoses, as AL deposits are rarely found in the central nervous system, though they may be found in the cerebral vessels. The authors have seen one case of a cerebral AL amyloidoma in a patient with a circulating monoclonal IgM protein. The primary CNS amyloidoses include Acys, hereditary cerebral hemorrhage with amyloidosis-Icelandic type, in which the precursor is the protease inhibitor cystatin c142; the Ab amyloidoses, including Dutch-type hereditary cerebral hemorrhage with amyloidosis, Alzheimer’s disease, and Down’s syndrome143,144; APrp, the prionoses including Creutzfeldt-Jakob disease (CJD), Gerstmann-Straüssler-Scheinker (GSS) disease, fatal familial insomnia (FFI), bovine spongioform encephalopathy, kuru, and scrapie in goats and sheep.145,146
Three proteins, gelsolin (Agel),147 kerato-epithelin (AKE),148 and lactoferrin (Alac),149 have been found in fibrils from patients with autosomal dominant corneal amyloidosis. Whether there is a pathophysiologic relationship among these disorders is not yet clear.
OTHER LOCALIZED AMYLOIDOSES
Four polypeptide hormones have been defined as the fibril precursors in tissue-specific localized amyloidoses: AANF in isolated atrial amyloid150; Acal in medullary carcinoma of the thyroid151; AIAPP seen in the pancreatic islets of the elderly, putatively involved in the pathogenesis of type II diabetes mellitus152; APro from pituitary adenomas153; and Aker localized to the skin.154,155
THERAPY, COURSE, AND PROGNOSIS
Potential treatments of any of the amyloidoses can be directed at interfering with any or all of several pathogenetic processes. Production of the precursor can be reduced or its catabolism enhanced; generation of the profibrillar intermediate can be blocked; interactions between profibrillar molecules to yield the fibril can be inhibited; deposition can be slowed; or deposits can be actively mobilized. At present, standard treatment for AL involves only one of these strategies, i.e., that of reducing production of the monoclonal immunoglobulin precursor via chemotherapy, or occasionally via radiotherapy or surgery of a localized amyloidogenic plasmacytoma. Equally important are supportive measures that maintain organ function in the absence of specific treatment or while specific therapy is being administered.
The rationale for chemotherapy assumes that AL, like myeloma, is caused by proliferation of a plasma cell clone; therefore, drugs likely to benefit AL patients are the same as those that are useful for myeloma. It is more difficult to assess the response to therapy in AL than in myeloma, since it requires indirect measurements of end-organ damage, serial biopsies, or serial P-component scans where available. In addition, studies of AL therapy require that all cases have a tissue diagnosis of the type of amyloid (e.g., AL versus ATTR). The recognition that there are different amyloid precursor proteins, which can be distinguished using readily available antisera, has made histologic diagnosis unequivocal.
The first effective regimen for myeloma was melphalan and prednisone. After the combination was shown to be of use in myeloma, it was tried in AL, with several case reports suggesting occasional benefit. In the initial randomized studies of melphalan and prednisone versus placebo or colchicine, several patients demonstrated objective responses to chemotherapy. In one study, a trend toward improved survival was seen with chemotherapy; however, statistical significance was not attained.156,157 In a subsequent trial,158 patients were randomized to one of three arms: (1) melphalan and prednisone; (2) melphalan, prednisone, and colchicine; or (3) colchicine alone. Median survival was greater in the melphalan-prednisone-colchicine and melphalan-prednisone arms (18 and 17 months, respectively) than in the colchicine alone arm (8.5 months). In a second trial, 100 patients were randomized to receive oral melphalan, prednisone, and colchicine, or colchicine alone.159 Overall survival in the melphalan-prednisone-colchicine group was 12.2 months, as compared with 6.7 months in the colchicine alone group. The difference did not reach statistical significance (P = .087), because of the small sample size and early deaths of patients with severe cardiac or renal disease in both treatment arms. Taken together, these studies demonstrate a survival benefit of melphalan and prednisone, as compared with placebo, in AL. Patients most likely to respond to chemotherapy with objective improvement in end-organ damage are those with the renal involvement and the nephrotic syndrome. Approximately a quarter of this group will have at least a 50 percent decrease in proteinuria, with most showing its complete disappearance. Functional improvement can occur in nearly any affected organ but is least common in neuropathy.33,59
Other regimens used for myeloma have also been explored in AL. In one study, patients were randomized to either melphalan and prednisone or a 5-drug regimen, i.e., vincristine, carmustine, melphalan, cyclophosphamide, and prednisone; response rates and survival were not different between the two groups.160 In a phase II trial, high-dose dexamethasone also produced responses in some AL patients, but survival was not superior to what would have been expected from melphalan and prednisone based on historic controls.161 High-dose dexamethasone also gave objective organ responses in 3 of 19 patients who had previously received chemotherapy.162 Melphalan plus prednisone can now be considered standard therapy for AL, with any other regimen shown to be effective in myeloma being a reasonable second choice.
For patients who respond to chemotherapy, there are no data defining the optimal duration of treatment. In those with objective improvement in organ function who do not develop toxicity, some investigators have continued chemotherapy for 1 or 2 years. When disease initially responds and then progresses off treatment, chemotherapy—the same or a different regimen—can be resumed. There is little information whether any maintenance therapy such as a interferon is of use, mirroring the situation in myeloma.
Melphalan has considerable leukemogenic potential: The actuarial risk for acute myelogenous leukemia (AML) in one study of patients with myeloma treated with melphalan was 17 percent at 50 months.163 In two other studies 5 percent of patients developed myelodysplasia (including several with chromosomal abnormalities and/or progression to AML) in 3 years of follow-up.
In order to obtain better survival in myeloma, protocols using “high-dose” chemotherapy, followed by autologous marrow or peripheral blood stem cell rescue, have been instituted. Several phase II trials of high-dose therapy in selected patients have demonstrated favorable response and survival rates as compared with historical controls.164 A panel of myeloma experts, reviewing the data available in 1998, concluded that high-dose therapy was appropriate in myeloma patients under age 55 with stage 3 disease and a complete or partial response or stable disease after initial chemotherapy. It is possible that further trials will justify extension of the procedure to other groups.165
Following the myeloma model, several centers have reported phase II trials of high-dose chemotherapy followed by rescue with autologous marrow or peripheral blood stem cells in AL.166,167 In one highly selected group of patients (median age 48, exclusion of patients with severely impaired cardiac, pulmonary, or renal function), a response, as assessed by objective improvement in end-organ function, was reported in 11 of 17 patients (65 percent). Based on these data, some centers now employ high-dose chemotherapy regimens for all patients able to tolerate the conditioning regimen. In the initial studies of high-dose therapy with peripheral blood stem cell rescue, patients with severe cardiac involvement experienced very high early mortality.168 The risk has been attributed to intolerance of the fluid shifts that accompany peripheral blood stem cell harvesting. Patients with severe cardiac involvement, i.e., those with the worst prognosis of any AL subgroup, have been excluded from high-dose therapy trials. Another concern with high-dose therapy followed by stem cell rescue is that autologous stem cells collected for reinfusion will generally contain clonal cells producing the amyloidogenic light chain.169
Until the results of phase III randomized trials comparing standard to high-dose chemotherapy are available, the choice in individual patients will remain difficult and will require discussion of the risks and possible benefits with the patient.170 In view of the limited numbers of patients diagnosed with AL and the large numbers of patients required to perform such studies in a timely manner, referral of patients to specialized centers performing such randomized phase III trials is essential.
THERAPY OF LOCALIZED AL
The treatment of localized AL (most often in the pulmonary tract) has not been systematically studied. Since progression to systemic disease does not occur often, chemotherapy may not be indicated. Localized radiotherapy, aimed at destroying the local collection of plasma cells producing the AL precursor, is a reasonable therapeutic approach.171 In patients with massive macroglossia, conventional surgical resection has not been effective. Relief can sometimes be achieved with laser techniques, although formal studies of efficacy have not been reported.
PHARMACOLOGIC AGENTS DESIGNED TO BREAK DOWN AMYLOID FIBRILS
The antiamyloid activity of 4-iododoxorubicin (Idox), an anthracycline analogue of doxorubicin was discovered serendipitously when it was being studied as a cytotoxic chemotherapeutic agent for myeloma. One patient with myeloma and AL began excreting a large amount of light chains into the urine, and dramatically improved clinically within days.172 Subsequently, five of eight patients treated in a pilot trial responded with clinical improvement, which appeared unrelated to any cytotoxic effect on the plasma cell clone. From 1995 to 1997 Idox was given to a further 14 patients in a single-institution study and to 28 patients at other institutions on a compassionate basis. Of these 42 patients, 13 had disease responses, and 15 showed stabilized disease. Responses were transient, however, and disease typically progressed after a period of months. In mid-1999, a phase II trial of Idox for AL was begun at two centers in the United States.
Laboratory studies demonstrated that Idox binds to various types of amyloid. It is possible that its most effective use may be in combination with cytotoxic chemotherapy, in an effort to simultaneously decrease clonal light-chain production and enhance mobilization of deposited light chains. Other small molecules that may bind to amyloid fibrils, of the AL and other types, are under investigation.
TREATMENT OF NONAMYLOID MIDD
As in AL, once a diagnosis of MIDD is established, it should be determined whether the patient has myeloma (e.g., serum and urine evaluation for monoclonal protein, marrow aspiration and biopsy, skeletal survey). Regimens effective in myeloma and AL should be utilized to reduce end organ damage, as MIDD is a similar monoclonal plasma cell disorder. However, no published studies have addressed chemotherapeutic treatment of nonamyloid MIDD in a systematic fashion.
SUPPORTIVE MEASURES FOR AL
Diuretics and angiotensin-converting inhibitors are the mainstay of therapy for congestive heart failure resulting from amyloidosis. Hypotension, resulting from a low ejection fraction and/or autonomic neuropathy, may limit diuretic use. On the other hand, if edema is troubling and hypotension is asymptomatic, diuretics can be increased. The use of digoxin and calcium channel blockers must be avoided in both AL and TTR cardiac amyloidosis because these compounds bind to amyloid fibrils and have been reported to increase congestive heart failure and produce arrhythmias.173,174 and 175 Pacemakers are of use in some patients with symptomatic bradycardia.176,177 Cardiac transplants have been performed in a small number of AL patients. This therapy may be lifesaving for patients with severe disease, but in the absence of effective systemic therapy to eliminate production of the amyloidogenic light chain, amyloid recurs in the transplanted organ.178,179 For young patients with severe cardiac involvement, cardiac transplantation followed by high-dose therapy and autologous stem cell reinfusion has been utilized, but its efficacy has not been established.
Hemodialysis and peritoneal dialysis are indicated in patients with AL and renal failure.46 Renal transplantation has been utilized in patients with amyloidosis, but most have not been of the AL type. Since AL is a systemic disease and hemodialysis is generally effective, renal transplantation is rarely indicated, except perhaps in occasional patients who have had particularly good responses to chemotherapy, where long survival may be expected. In the absence of effective chemotherapy, reaccumulation of amyloid in the transplanted kidney has been reported.
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Ernest Beutler, Marshall A. Lichtman, Barry S. Coller, Thomas J. Kipps, and Uri Seligsohn