eMedicine Specialties > Rheumatology > Miscellaneous Inflammatory Arthritis

Amyloidosis, AA (Inflammatory)

Richa Dhawan, MD, Faculty, Center of Excellence for Arthritis and Rheumatology, Louisiana State University Health Science Center at Shreveport
Mohammed Mubashir Ahmed, MD, Associate Professor, Department of Medicine, Division of Rheumatology, University of Toledo College of Medicine; Eisha Mubashir, MD, Fellow in Rheumatology, Department of Medicine, Fellow, Center of Excellence for Arthritis and Rheumatology, Louisiana State University Health Sciences Center, Shreveport; Joel Buxbaum, MD, Professor, Department of Molecular and Experimental Medicine, The Scripps Research Institute

Updated: Nov 21, 2008

Introduction

Background

Amyloid A (AA) amyloidosis is the most common form of systemic amyloidosis worldwide. It is characterized by extracellular tissue deposition of fibrils that are composed of fragments of serum amyloid A (SAA) protein, a major acute-phase reactant protein, produced predominantly by hepatocytes. AA amyloidosis occurs in the course of a chronic inflammatory disease of either infectious or noninfectious etiology, hereditary periodic fevers, and with certain neoplasms such as Hodgkin disease and renal cell carcinoma.

In developing countries, the most common instigator of AA amyloidosis is chronic infection; in industrialized societies, rheumatic diseases, such as rheumatoid arthritis (RA), are the usual stimuli. The United States is a major exception to this in that immunoglobulin-related amyloid light chain type (AL) of amyloidosis is more frequent than AA as the cause of systemic amyloid deposition.

In AA amyloidosis, the kidney, liver, and spleen are the major sites of involvement. The tissue fibril consists of a 7500-dalton cleavage product of the SAA protein, an acute-phase protein produced in numerous tissues. The major source of the circulating protein is the hepatocyte. Under the influence of the inflammatory cytokine interleukin (IL)-6, hepatic transcription of the messenger ribonucleic acid (mRNA) for SAA may increase 1000-fold when exposed to an inflammatory stimulus.

Intact circulating SAA (molecular weight 12,500 dalton) is complexed with high-density lipoproteins (HDL). During the course of inflammation, the apolipoprotein SAA (apoSAA) apparently displaces apolipoprotein A1 (apoA1) from the HDL particles and facilitates HDL-cholesterol uptake by macrophages.

Several lines of evidence have indicated that the conversion of SAA into amyloid fibrils occurs through its specific interaction with heparan sulphate, a ubiquitously expressed glycosaminoglycan component of the extracellular matrix.

The protein also has been shown to be chemotactic for neutrophils, and it stimulates degranulation, phagocytosis, and cytokine release in these cells.

Until relatively recently, the erythrocyte sedimentation rate (ESR) and the serum C-reactive protein (CRP) level were used to monitor inflammation clinically. Current data suggest that, under some circumstances, changes in SAA may be a better measure. Increases in both CRP and SAA have been associated with active atherosclerotic coronary artery disease and cited as evidence for the inflammatory nature of that disease process. SAA also has been used to monitor the dissemination of malignancy.

For information on other types of amyloidosis, see the article Amyloidosis, Overview in eMedicine’s Rheumatology volume.

Pathophysiology

Chronic or acute, recurrent, substantial elevations of SAA are necessary but not sufficient for the development of amyloidosis. Many individuals with long-standing inflammatory disease, while severely compromised by their primary condition, clearly do not develop tissue amyloid deposition. What determines any patient's risk for the development of this complication of inflammation is not known. Therapy, genetic factors, and environmental factors have all been proposed as possible contributors to the response of the primary disease.

Three protein isoforms of SAA exist (ie, SAA 1, 2, and 4). Each isoform is encoded by its own gene in a cluster on band 11p15.1 that also includes a pseudogene (SAA3P). SAA1 has 5 alleles that vary from each other by amino acid substitutions at 1, 2, or 3 positions. The SAA2 alleles differ from SAA1 at 7 positions and from each other at a single residue. SAA4 has a single allele, and the protein varies considerably from isoforms 1 and 2. The distribution of SAA1 alleles varies in different populations. SAA2 allele frequencies seem similar across populations, though the data are less consistent.

SAA 1 is the fibril precursor in most cases of AA amyloidosis, although SAA 2 has also been found in some cases. Frequently, heterogeneity exists at the amino terminus of the deposited AA fibrils, and truncated forms of the protein have also been described, suggesting that the fibril protein is generated by proteolysis of the SAA precursor, with further digestion occurring at the site of deposition. The degree of digestion may vary in different tissue sites.

The factors responsible for determining the site of deposition in any form of amyloidosis have not been identified. AA fibrils have been generated in tissue cultures by incubating SAA with macrophages. Deposits are frequently found in tissues with large numbers of phagocytic cells, notably the liver and spleen, but other affected organs, such as the kidneys, do not have the same cellular composition. Some data, derived from analysis of renal biopsy specimens, have suggested that glycoxidative modification of proteins, probably the AA protein itself, may also play a role in AA deposition in kidneys.

Frequency

United States

The absolute prevalence of AA amyloidosis is difficult to ascertain because it depends on both the occurrence of predisposing inflammatory disorders and the proportion of individuals with those conditions who develop tissue amyloid deposition. The diseases in which AA amyloidosis has been reported are noted below, as are the frequencies (when such data are available). AA amyloidosis is far less common in the United States than in other countries, even in the setting of the same inflammatory disease. The variation in the occurrence of amyloid in a particular disease in different geographic locales may reflect genetic background, differences in treatment of the primary disease, or factors that are not currently understood.

International

As in the United States, the frequency of AA amyloidosis is determined by the prevalence of the associated diseases, as well as the incidence of amyloid deposition in those conditions. For instance, in some Middle Eastern countries, the prevalence of familial Mediterranean fever (FMF) is higher than anywhere else in the world. The frequency of renal amyloidosis in some populations with untreated FMF is almost 100%. In those countries, amyloidosis represents a significant proportion of all renal disease.

In contrast, autopsy studies from the Netherlands have suggested a minimal prevalence of amyloidosis of approximately 1 per 75,000 population. Because 30-40% of amyloidosis cases in Western Europe is of the AL type, the estimated prevalence of AA amyloidosis is 1 per 100,000 population. Both the duration and severity of the inflammatory disease correlate with the frequency of amyloidosis as a complication.

The occurrence of multiple alleles encoding the predominant fibril precursor raised the issue of whether each allele had the same propensity to form amyloid. If an amyloidogenic allele were more common in a particular population, then the frequency of amyloidosis in inflammatory disease would be expected to be higher.

Three studies have indicated that a particular inherited form of SAA1 is associated with an increased frequency of amyloidosis in the course of a single inflammatory disease. In Japanese people, in whom the SAA 1.5 allele is far more common than in whites (37.4% vs 5.3%), the 1.5 allele is enriched among patients with RA and amyloidosis. Individuals with RA and a single 1.5 gene have twice the risk for developing amyloid as those with no 1.5 alleles. People who are homozygous for the 1.5 allele have a relative risk of 4.48 compared with those with RA who lack any 1.5 alleles. The mechanism of the association may reside in the fact that the SAA 1.5 allele is associated with higher SAA levels in Japanese patients. The duration of the inflammatory disease prior to the development of amyloidosis appeared to be inversely related to the dose of the allele.

In the United Kingdom, heterozygosity or homozygosity for the SAA 1.1 allele is associated with a greater risk for amyloidosis in whites with juvenile chronic arthritis; however, in patients with adult RA, the increase was not statistically significant.

Mortality/Morbidity

In some cases, usually of infectious origin, the clinical consequences of amyloid deposition may dissipate with reduction or disappearance of the tissue deposits if the inflammatory disease can be suppressed totally or eliminated. If treatment of the primary disease is unsuccessful, death of organ failure secondary to the amyloid deposition is the rule. In patients treated at centers in the United States, the United Kingdom, and Europe from 1956-1992, renal failure or sepsis was the mode of exitus in one half to three quarters of AA amyloidosis cases, with a median survival of 24-36 months. Series that are more current show a longer survival, which is based largely on the increased availability of renal replacement therapy.

Race

Very few appropriately controlled data address the question of racial prevalence of AA amyloidosis, other than observations suggesting that an increased frequency of AA amyloidosis occurs in the course of RA, which is related to variation in the distribution of particularly amyloidogenic SAA1 alleles among different ethnic groups. Within a single medical center in California, autopsies of patients of similar economic status with different ethnic origins displayed differences in the frequency of AA amyloidosis. In that series, AA amyloidosis was more common in Hispanic patients of Mexican origin than in either whites or African Americans.

Sex

In the United States, AA amyloidosis is more common in females, reflecting the fact that the major predisposing disease, RA, is predominantly a disorder of younger women and middle-aged men; hence, women are apt to have the disease for a longer period than men.

• Despite the statistical female predominance in terms of overall numbers of AA amyloidosis cases, males seem to have an earlier average age of onset.
• FMF is more common in males than in females (male-to-female ratio, 60:40), but the frequency of renal amyloidosis in people who are affected appears to be similar.

Age

The age of onset of amyloidosis is related to the age of onset of the inflammatory disease, its severity, and the duration of the disease within the constraints imposed by the alleles of SAA carried by the patient. Thus, in the course of juvenile rheumatoid arthritis (JRA), amyloidosis occurs in teenagers. When it is a consequence of adult RA, it develops in late middle age. In the course of inadequately treated FMF, the renal amyloidosis is also of relatively early onset.

Clinical

History

The most common presentation of amyloid A (AA) amyloidosis is renal; thus, symptoms reflect the appearance of proteinuria, progressive development of renal insufficiency, or nephrotic syndrome.

• Weakness, weight loss, and peripheral edema are the most common symptoms.
  • In patients with active RA, these symptoms may be attributed incorrectly to progression of the inflammatory disease or to adverse effects of drugs.
  • The amyloid deposits first occur in the spleen and liver. However, even a significant splenic and hepatic load may remain asymptomatic for long periods. Rarely, evidence of bowel involvement (associated with constipation, diarrhea, gastrointestinal bleeding) dominates the presentation. Goiter has also been reported as a possible feature of symptomatic AA amyloidosis. Cardiac AA deposits may be revealed with echocardiography in about 10% of patients.
  • Again, in patients with inflammatory joint disease, the gastrointestinal symptoms can also be secondary to treatment, particularly with nonsteroidal anti-inflammatory drugs.
• In contrast to AL amyloidosis and other amyloidoses, congestive heart failure, peripheral neuropathy, or carpal tunnel syndrome occasionally occurs during the course of AA amyloidosis, but they are rarely, if ever, a presenting manifestation.
• In patients with FMF, the history of periodic fever, arthritis, serositis, and the presence of the same disorder in other family members are characteristic. Some instances have been reported in which febrile episodes are not apparent, and renal amyloid is the first manifestation of disease.
• In patients with atrial myxoma or renal carcinoma, the appearance of symptoms consistent with nephrotic syndrome or renal failure due to amyloidosis may be the first evidence of the primary neoplastic disease.
  • In general, the appearance of symptoms suggesting renal disease in a patient with chronic infectious or noninfectious inflammation should raise a warning flag with respect to the presence of AA amyloidosis as a complication.
  • Rarely, a more specific symptom, such as abdominal fullness or right upper quadrant discomfort (reflecting hepatomegaly), might bring the patient to the physician.

Physical

• Patients with amyloid renal disease are commonly hypertensive, although whether the hypertension is associated with the renal amyloidosis or is a coincidental finding is not always clear.
• Sallow complexion and peripheral edema are the main physical findings in individuals with either renal failure or nephrotic syndrome.
• The purpura and macroglossia observed in AL amyloidosis are not features of AA amyloidosis, nor is the orthostatic hypotension associated with AL amyloidosis or the familial amyloidoses, unless gastrointestinal bleeding or other forms of hypovolemia associated with renal dysfunction are present.
• The major physical findings may be those associated with the primary inflammatory disease, notably deforming arthritis.
• The appearance of hepatosplenomegaly in a patient with ongoing inflammation should prompt investigation for amyloidosis, although some patients with severe RA develop splenomegaly with subsequent Felty syndrome (splenomegaly and neutropenia or pancytopenia in the course of RA). These patients with Felty syndrome generally have normal renal function, although they might have a renal disease other than AA deposition.

Causes

• Chronic infectious diseases, including tuberculosis, leprosy, bronchiectasis, chronic osteomyelitis, and chronic pyelonephritis, have been associated with AA amyloidosis. The precise frequencies are difficult to ascertain, but they may be as high as 10% in some chronic suppurative disorders, eg, osteomyelitis.
• In industrialized countries, chronic noninfectious inflammatory diseases are more commonly the cause of AA amyloidosis. In RA, the incidence is 5-26%, being found more often on autopsy than biopsy. The frequency of AA amyloidosis may be lower in patients treated earlier and more aggressively. Other inflammatory disorders associated with AA amyloidosis include the following:
  • Inflammatory bowel disease (0.4-2%)
  • Behçet syndrome in Turkey (1-2%)
  • Reactive arthritis in adults (0.3%)
  • Ankylosing spondylitis in children (4-5%)
  • Psoriatic arthritis (3-13%)
  • Chronic juvenile arthritis: This seems to be a special case, with a large geographic variance (0.14-17%) in the incidence of AA amyloidosis depending on whether the analysis was performed in the United States (low) or Eastern Europe (high).
  • Subcutaneous drug abuse: In the 1980s, a high frequency of renal AA amyloidosis was observed among subcutaneous drug abusers in some cities in the United States. Whether this was related to the drug or to some contaminating substance that elicited chronic inflammation when injected subcutaneously is not clear.
  • FMF and other fever syndromes: Renal AA amyloidosis is virtually a universal complication of FMF in some populations if the patients are not compliant with colchicine prophylaxis. Other hereditary fever syndromes, such as tumor necrosis factor receptor–associated periodic syndrome (TRAPS), chronic infantile neurologic cutaneous articular syndrome (CINCA), Muckle-Wells syndrome, and hyperimmunoglobulinemia D with periodic fever syndrome (HIDS), may be complicated by AA amyloidosis.
  • Tumors: Among tumors, hypernephroma has been associated with AA amyloidosis. More recently, Castleman disease (angiofollicular lymph node hyperplasia) has been recognized as a cause of amyloidosis. Resection of the tumor can lead to the regression of clinical signs of amyloid nephropathy.¹
• Among other noninfectious chronic inflammatory diseases, AA amyloidosis has been reported in systemic lupus erythematosus, polymyositis, and polymyalgia rheumatica and has been observed in temporal artery biopsy samples of such patients. AA amyloidosis has also been noted in patients with gout, pseudogout, and some cases of apparently noninflammatory sarcoidosis.
• Because SAA production is mediated through inflammatory cytokines, primarily IL-6, AA deposition has been noted in other disorders associated with increased IL-6 production. Occasionally, patients with atrial myxomas, renal cell carcinomas, Hodgkin disease, hairy cell leukemia, and carcinomas of the lung and stomach have been found to have renal AA amyloidosis, presumably because of production of the cytokine by the tumor cells. Paradoxically, some patients with agammaglobulinemia also have developed AA amyloidosis, demonstrating the dissociation between cytokine production and the synthesis of its normal downstream effector molecules, immunoglobulins.

Differential Diagnoses

Amyloidosis, Familial Renal
Amyloidosis, Immunoglobulin-Related
Glomerulonephritis, Membranous
Renal Vein Thrombosis

Workup

Laboratory Studies

• The overwhelming factor in diagnosing amyloid A (AA) amyloidosis is considering the possibility that it is present. The development of proteinuria in any individual with chronic inflammatory disease or any of the associated conditions listed in Causes should prompt a search for tissue AA deposition, most commonly in the kidney.
• No specific tests for AA amyloidosis exist.
  • While the SAA precursor is usually elevated, prolonged elevation does not necessarily indicate tissue deposition because many patients with inflammatory disease have very high levels of SAA without developing amyloidosis.
  • Serum immunoglobulins should be evaluated because the presence of a monoclonal serum or urine protein suggests AL amyloidosis as a more likely diagnosis.
  • Patients with AA amyloidosis tend to show polyclonal hypergammaglobulinemia, reflecting their underlying inflammatory condition.
• Evaluate the parameters of renal function to monitor the course of the nephrotic syndrome or renal failure.
  • Occasionally, patients show renal tubular acidosis as an early manifestation of renal involvement.
  • Deterioration of a patient with the nephrotic syndrome may indicate progression of the amyloid renal disease, but consider the possibility of renal vein thrombosis because this complication can be observed in nephrotic syndrome due to any cause.
  • A serum creatinine level greater than 2 mg/dL and/or a serum albumin level less than 2.5 g/dL have been associated with diminished survival rates, including renal survival.

Imaging Studies

• Avoid intravenous pyelography in patients with suspected amyloidosis because dye exposure has been associated with more frequent renal failure in individuals with substantial proteinuria.
• Ultrasonography is useful in establishing renal size; however, kidneys may be large, small, or normal size in patients with renal amyloidosis.
• CT scanning may be useful because technetium occasionally binds to soft-tissue amyloid deposits. This was originally reported as an incidental finding. However, CT scanning does not yield great sensitivity, and reports concerning the specificity of CT scanning have varied considerably. If results are positive, CT scanning can be used to monitor gross progression of the deposition in a given organ.
• MRI may have a role in amyloidosis diagnosis in the future, but, currently, no formal studies have reported its use in a large series of patients.
• Radiolabeled P-component gamma scanning has been used in centers in London and France to demonstrate the total body burden of amyloid and its disappearance after successful treatment of the primary disease. This test has been most useful in AA amyloidosis because the major sites of deposition, ie, liver, kidneys, spleen, and adrenal glands, are readily accessible to the imaging agent.

Other Tests

• In the 10% of cases of AA amyloidosis in showing cardiac involvement, conventional parameters of cardiac dysfunction, measured using electrocardiography, echocardiography, and cardiac catheterization with endomyocardial biopsy, provide the appropriate diagnostic information and tissue for the demonstration of AA (or other amyloid) deposition in the myocardium or coronary vessels.

Procedures

• Biopsy with Congo red staining and immunostaining: The tissue with the highest yield, particularly in the presence of proteinuria or renal failure, is the kidney. Technically adequate samples have a diagnostic yield close to 100%. Stain the tissue with an alkaline solution of Congo red, and examine it under polarized light, where positive (green) birefringence is detectable in the presence of amyloidosis of any type. The nature of the fibril precursor can be established by immunohistochemical staining with antibodies specific for the major amyloid precursors (AA, immunoglobulin L chains of k or l type, antitransthyretin). In AA amyloidosis, only the AA is positive. The amyloid nature of the deposit can by confirmed by staining with an antiserum specific for serum amyloid P-component (SAP).
• If renal biopsy is deemed too risky for a specific patient or if amyloidosis without renal disease is suspected, 2 sites have been shown to be useful in obtaining tissue for histologic and immunochemical analysis. Subcutaneous fat aspiration is positive in approximately 60% of individuals with AA amyloidosis, except in the case of FMF, when it is rarely, if ever, positive.
• Rectal biopsy is more useful than subcutaneous fat aspiration in AA amyloidosis. It has been found to produce positive results (assuming that submucosa is included in the biopsy specimen) in 80-85% of patients ultimately found to have tissue amyloid at a clinically relevant site. Samples from either the subcutaneous fat aspirate or the rectal biopsy can be stained as conventional tissue biopsies to determine the presence and nature of the amyloid precursor. Occasionally, patients have positive results on subcutaneous fat aspirates in the presence of a negative result on rectal biopsy, while others may have deposits in the rectal tissue and not in the aspirate. Use of both procedures may increase the yield to 90%. Abdominal subcutaneous fat biopsy results are not very sensitive in AA amyloidosis caused by FMF and in dialysis-related amyloidosis. The results are usually negative, probably because beta2-microglobulin does not accumulate in this tissue.
• Series from individual centers have shown that the labial gland or gastric mucosal biopsies can also be high-yield procedures, but these have not been used widely for amyloidosis, and their general utility remains to be definitively established.
• In the past, liver biopsy was a common procedure in the investigation of AA amyloidosis. Several reports of fatal liver rupture or bleeding, as well as the availability of sampling procedures with little or no morbidity and mortality, have resulted in its decreased use.
• Once histological diagnosis of amyloidosis has been established, the amyloid type should be defined based on immunohistochemical analysis and genetic testing. Immunoelectron microscopy characterizes the amyloid deposits by co-localizing the specific proteins with the fibrils and can be performed on abdominal fat samples.

Histologic Findings

Infiltrated tissues show homogeneous eosinophilic staining with hematoxylin and eosin. The earliest deposits are usually vascular. In the kidney, early deposits may be mesangial, but, late in the course, entire glomeruli may be obliterated. Distinguishing these from glomerulosclerosis and from other causes is difficult prior to Congo red staining. Congo red binding by itself may be observed in other states, particularly in collagen-rich tissues, but the green birefringence is characteristic on examination with polarized light and the amyloid nature of the deposit can be demonstrated by observing the characteristic beta pleated sheet on electron microscopy. The nature of the precursor can be established with certainty using antisera specific for various amyloid precursors. In this case, staining with anti-AA serum is positive, as described above.

Staging

No formal staging system has been proposed for any of the amyloidoses.

Treatment

Medical Care

At present, the major therapeutic strategy in amyloid A (AA) amyloidosis is treatment of the primary inflammatory disease in order to reduce the circulating levels of the amyloid precursor protein SAA. Intensive treatment that lowers SAA levels to less than 10 mg/L may halt disease progression and induce a slow progressive recovery of renal function. Accounts exist of the disappearance of the amyloid deposits associated with tuberculosis or chronically infected burns with appropriate treatment of the infection. Similarly, case reports exist of the disappearance of amyloid deposition associated with chronic inflammatory bowel disease after resection of the affected section of bowel.

Data from a randomized prospective series of patients with juvenile chronic arthritis who were treated with chlorambucil or cyclophosphamide show that the occurrence of amyloidosis is markedly reduced.² The tradeoff for the aggressive use of alkylating agents is an increased incidence of leukemia.

Treatment with tumor necrosis factor-a inhibitors and interleukin-1 inhibitors has recently proved effective in controlling the progression of renal amyloid in patients with inflammatory arthritides and hereditary periodic fevers. The application of these agents will possibly achieve similar therapeutic effects without the additional risk, thus lowering the incidence of amyloidosis without increasing mortality.

• The use of colchicine (0.6 mg tid) by patients with FMF has been shown to reduce or eliminate the febrile episodes and to prevent the appearance of renal amyloidosis. The mechanism of action is not clear, although the elimination of AA deposition is likely mediated through the suppression of the inflammatory response and SAA production, rather than having a primary effect on amyloidogenesis.
  • Based on observations of people with FMF and mice with experimental AA amyloidosis, individual patients with the nephrotic syndrome secondary to renal AA amyloidosis in the course of inflammatory bowel disease, ankylosing spondylitis, and psoriatic arthritis were treated with colchicine and had clinical pictures consistent with the resolution of the nephrotic syndrome.
  • While none of these reports contained follow-up renal biopsies, the clinical information supports the conclusion; however, many unreported instances in which colchicine has been used unsuccessfully in similar circumstances also are likely to exist. The only attempt at a randomized prospective trial of colchicine has been carried out in AL disease, and it showed no effect on that process.
• The following are new approaches to the treatment of AA amyloidosis that are currently undergoing clinical trials:
  • A low–molecular-weight sulfonated molecule has been developed that interferes with fibril formation and deposition of amyloid by inhibiting interaction of SAA with glycosaminoglycans. In experimentally induced murine AA amyloidosis, this drug (NC-503) has been shown to reduce the amount of amyloid deposits.
  • Dimerization of human SAP molecules in vivo with a palindromic compound (CPHPC) triggers very rapid clearance of the complexed protein by the liver, depleting SAP from the circulation within a few hours of drug administration.
  • Anti–IL-6R therapy appears promising for the treatment of AA amyloidosis.³
  • A case report exists of severe protein-losing enteropathy with intractable diarrhea due to systemic AA amyloidosis successfully treated with corticosteroids and octreotide⁴ .
  • A single patient with AA amyloidosis secondary to Hodgkin disease was administered 4'-iodo-4'deoxydoxorubicin as antitumor therapy (see the treatment section in Amyloidosis, Immunoglobulin-Related); this patient has been reported to show a reduction in proteinuria and the liver amyloid burden on biopsy. The response was not complete and the resolution on liver biopsy may have been the result of sampling differentially infiltrated portions of tissue; nonetheless, the result is potentially exciting.⁵
  • A more experimentally and theoretically based approach uses the observation that anionic sulphonates interfere with the deposition of AA fibrils in a murine model of inflammatory amyloidosis. One of these compounds is in clinical trials, the results of which should be available over the next 2 years. Little or no toxicity was shown in the preclinical testing.
• In patients with AA amyloidosis who were treated before 1990, the major cause of death was renal failure, generally accounting for 35-70% of mortality, with infection responsible for an additional 10-20%. The mean survival was 2-4 years, with the degree of renal insufficiency present at the time of diagnosis correlating with longevity. In a series of patients with AA amyloidosis presenting from 1985-1999, the median survival was 53 months, and the median renal survival (time alive and independent of renal replacement) was 18 months.⁶ Because of the increased availability of renal replacement, renal failure was the cause of death in only 12.5% of people, and infection became dominant (42%). Nonetheless, the results of dialysis in patients with renal amyloid and an underlying inflammatory disease are worse than the results in those undergoing dialysis for other chronic renal diseases.

Surgical Care

Renal transplantation is an option in these patients, with some successes reported; however, data suggest that patients who have amyloidosis do not have as favorable a prognosis as patients transplanted for other forms of renal failure. Nonetheless, results have been improving, and transplantation is a reasonable option, particularly if the primary inflammatory disease has been treated successfully.

Consultations

• Because AA amyloidosis is usually a complication of a primary chronic infectious or inflammatory disease, consultations with specialists in infectious diseases concerning antibiotics, surgical resection, and other diagnostic and therapeutic modalities are appropriate.
  • Consult a rheumatologist with regard to newer modes of anti-inflammatory treatment before assuming that the patient will inevitably follow a downhill course.
  • Nephrologic and surgical management of the chronic renal failure also requires a coordinated team approach for an optimal outcome.
  • Cardiac complications at the time of transplantation seem to be more common in patients with amyloidosis than in those with other forms of renal failure.

Diet

No specific dietary recommendations for patients with amyloid disease exist.

• Patients with chronic renal failure should be managed by a nutritionist who has experience with such patients, maintaining appropriate levels of sodium and protein intake.
• Occasionally, patients have significant gastrointestinal symptomatology, and attention should be paid to maintaining caloric intake with minimal gastrointestinal distress.

Activity

Encourage as much activity as the patient can tolerate in order to maintain muscle mass and a positive outlook.

Medication

No specific therapeutic agents are recommended for the treatment of amyloid A (AA) amyloidosis. Therapy for the underlying inflammatory disorders should be as aggressive as possible.

Anti-inflammatory agents

Colchicine is a disaggregator of microtubules, not a member of any of the traditional categories of anti-inflammatory agents.

Colchicine

Decreases leukocyte motility and phagocytosis in inflammatory responses. Effective in the treatment of acute gout, pseudogout, and the prophylaxis of acute febrile episodes of FMF. The latter effect probably is responsible for the reduced frequency of renal amyloidosis when treatment is adequate.

Dosing

Adult

0.6 mg bid PO unless not tolerated or renal insufficiency occurs; in these cases, lower doses will be used

Pediatric

Not established

Interactions

Sympathomimetic agent toxicity and effect of CNS depressants are significantly increased with colchicine

Contraindications

Documented hypersensitivity; severe renal, hepatic, GI, or cardiac disorders; blood dyscrasias

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Risk of renal failure, hepatic failure, permanent hair loss, bone marrow suppression, numbness or tingling in hands and feet, disseminated intravascular coagulopathy, and decreased sperm count; associated with idiosyncratic reactions; overdose results in bone marrow and gastrointestinal toxicity and death from overwhelming sepsis secondary to intestinal ulceration; decrease dose in patients with renal impairment

Follow-up

Further Inpatient Care

• Inpatient care may be necessary for intercurrent infections or deterioration in renal function, requiring acute dialysis or the initiation of chronic dialysis.

Further Outpatient Care

• Monitor renal function to assess progress and the ultimate need for dialysis or transplantation.

Inpatient & Outpatient Medications

• Use medications effective in the treatment of the primary inflammatory diseases to completely suppress the inflammatory process, if possible.
• Colchicine may be administered concurrently with these agents, although no controlled studies indicate that it is effective in amyloid A (AA) amyloidosis, other than in cases associated with FMF.

Transfer

• Diminishing renal function demands management by an experienced nephrologist, with particular emphasis placed on the need for dialysis and the availability of transplantation.

Deterrence/Prevention

• The use of colchicine prophylaxis in FMF has been previously mentioned, as has the need for aggressive anti-inflammatory treatment for the predisposing inflammatory disorders (see Treatment).
• The recent introduction of anti-inflammatory biological agents for the treatment of rheumatologic disorders may decrease the current rate of appearance of tissue AA deposition.

Complications

• The major consequence of renal amyloidosis is complete renal failure. Because it occurs in the natural course of AA amyloidosis, it may not be considered a complication but certainly requires aggressive management, with transplantation or maintenance with dialysis.

Prognosis

• The prognosis of the AA amyloidosis, regardless of the prognosis of the primary disease, has generally been associated with the degree of renal compromise present at the time of diagnosis, ie, poor prognosis is associated with a serum creatinine level greater than 2 mg/dL or a serum albumin level of less than 2.5 g/dL. Mean survival is 2-3 years.
• More recent studies in which patients had access to renal replacement therapy suggest improved survival to more than 4 years. In the latter cases, infection was the major cause of death. With improved aggressive anti-infectious treatment, further enhanced survival likely is possible, even without specific treatment that allows resorption of the deposited fibrils or inhibits further deposition.
• The idea has been suggested that, even with fibril resorption and no further deposition, residual tissue damage will persist or fibrillar material will redistribute, primarily to the kidney. At present, these speculations remain to be tested.

Patient Education

• Inform patients about the natural course of AA amyloidosis and the fact that aggressive anti-inflammatory management could prevent ultimate organ failure.
• Preparing the patient for either renal transplant or dialysis is the major educational goal. Clearly, the manner in which this is presented depends on the relationship between the physician and the patient and the physician's assessment of the patient's emotional needs.

Miscellaneous

Medicolegal Pitfalls

• Misdiagnosis of amyloid A (AA) amyloidosis as AL amyloidosis and the institution of cytotoxic therapy appropriate for AL amyloidosis cause needless risk for the complications of chemotherapy. Competent immunohistologic diagnosis of biopsy samples is critical to avoid this pitfall.
• Failure to diagnosis and appropriately treat a treatable primary cause of AA amyloidosis puts the patient at risk for continuing deposition of amyloid, when it could be reduced or eliminated by appropriate antibiotic, surgical, or aggressive anti-inflammatory therapy.

Special Concerns

• The major special concern with AA amyloidosis is the accuracy of the diagnosis, and the managing physician must be aware that ongoing research in the therapy of the predisposing inflammatory disorders and amyloid itself may result in advances that should be implemented immediately in the therapeutic regimen.
• Participation of patients with amyloidosis in clinical trials is critical to the evaluation of new therapeutic modalities.

References

1. Lachmann HJ, Gilbertson JA, Gillmore JD, et al. Unicentric Castleman's disease complicated by systemic AA amyloidosis: a curable disease. QJM. Apr 2002;95(4):211-8. [Medline].

2. Ahlmen M, Ahlmen J, Svalander C, et al. Cytotoxic drug treatment of reactive amyloidosis in rheumatoid arthritis with special reference to renal insufficiency. Clin Rheumatol. Mar 1987;6(1):27-38. [Medline].

3. Mihara M, Shiina M, Nishimoto N, et al. Anti-interleukin 6 receptor antibody inhibits murine AA-amyloidosis. J Rheumatol. Jun 2004;31(6):1132-8. [Medline].

4. Fushimi T, Takahashi Y, Kashima Y, et al. Severe protein losing enteropathy with intractable diarrhea due to systemic AA amyloidosis, successfully treated with corticosteroid and octreotide. Amyloid. Mar 2005;12(1):48-53. [Medline].

5. Perez Equiza E, Arguinano JM, Gastearena J. Successful treatment of AA amyloidosis secondary to Hodgkin's disease with 4'-iodo-4'-deoxydoxorubicin. Haematologica. Jan 1999;84(1):93-4. [Medline].

6. Joss N, McLaughlin K, Simpson K, et al. Presentation, survival and prognostic markers in AA amyloidosis. QJM. Aug 2000;93(8):535-42. [Medline].

7. Akar N, Yalcinkaya F, Akar E, et al. MEFV mutation analysis in Turkish familial Mediterranean fever patients with amyloidosis. Amyloid. Dec 1999;6(4):301-2. [Medline].

8. Berglund K, Thysell H, Keller C. Results, principles and pitfalls in the management of renal AA-amyloidosis; a 10-21 year followup of 16 patients with rheumatic disease treated with alkylating cytostatics. J Rheumatol. Dec 1993;20(12):2051-7. [Medline].

9. Bohle A, Wehrmann M, Eissele R, et al. The long-term prognosis of AA and AL renal amyloidosis and the pathogenesis of chronic renal failure in renal amyloidosis. Pathol Res Pract. Apr 1993;189(3):316-31. [Medline].

10. Booth DR, Booth SE, Gillmore JD, et al. SAA1 alleles as risk factors in reactive systemic AA amyloidosis. Amyloid. Dec 1998;5(4):262-5. [Medline].

11. Buck FS, Koss MN, Sherrod AE, et al. Ethnic distribution of amyloidosis: an autopsy study. Mod Pathol. Jul 1989;2(4):372-7. [Medline].

12. Buxbaum J. The amyloidoses. In: Dieppe PA, Klippel JH, eds. Rheumatology. 2^nd ed. St. Louis, Mo: Mosby; 1998:1-10.

13. Cunnane G, Whitehead AS. Amyloid precursors and amyloidosis in rheumatoid arthritis. Baillieres Best Pract Res Clin Rheumatol. Dec 1999;13(4):615-28. [Medline].

14. Drewe E, Huggins ML, Morgan AG, et al. Treatment of renal amyloidosis with etanercept in tumour necrosis factor receptor-associated periodic syndrome. Rheumatology (Oxford). Nov 2004;43(11):1405-8. [Medline].

15. Gabay C, Kushner I. Acute-phase proteins and other systemic responses to inflammation. N Engl J Med. Feb 11 1999;340(6):448-54. [Medline].

16. Gallo GR, Feiner HD, Chuba JV, et al. Characterization of tissue amyloid by immunofluorescence microscopy. Clin Immunol Immunopathol. Jun 1986;39(3):479-90. [Medline].

17. Gertz MA, Kyle RA. Secondary systemic amyloidosis: response and survival in 64 patients. Medicine (Baltimore). Jul 1991;70(4):246-56. [Medline].

18. Heering P, Hetzel R, Grabensee B, et al. Renal transplantation in secondary systemic amyloidosis. Clin Transplant. Jun 1998;12(3):159-64. [Medline].

19. Helin HJ, Korpela MM, Mustonen JT, et al. Renal biopsy findings and clinicopathologic correlations in rheumatoid arthritis. Arthritis Rheum. Feb 1995;38(2):242-7. [Medline].

20. Hirschfield GM. Amyloidosis: a clinico-pathophysiological synopsis. Semin Cell Dev Biol. Feb 2004;15(1):39-44. [Medline].

21. Janssen S, Van Rijswijk MH, Meijer S, et al. Systemic amyloidosis: a clinical survey of 144 cases. Neth J Med. 1986;29(11):376-85. [Medline].

22. Kisilevsky R, Young ID. Pathogenesis of amyloidosis. Baillieres Clin Rheumatol. Aug 1994;8(3):613-26. [Medline].

23. Lam SKL, Ngian GS, Travers R, Lim KKT. Amyloidosis: a rheumatological perspective on diagnosis, further investigation and treatment. International Journal of Rheumatic Diseases. Jun 2008;11(1):55-9.

24. Livneh A, Langevitz P, Shinar Y, et al. MEFV mutation analysis in patients suffering from amyloidosis of familial Mediterranean fever. Amyloid. Mar 1999;6(1):1-6. [Medline].

25. Livneh A, Zemer D, Langevitz P, et al. Colchicine treatment of AA amyloidosis of familial Mediterranean fever. An analysis of factors affecting outcome. Arthritis Rheum. Dec 1994;37(12):1804-11. [Medline].

26. Lofberg H, Thysell H, Westman K, et al. Demonstration and classification of amyloidosis in needle biopsies of the kidneys, with special reference to amyloidosis of the AA-type. Acta Pathol Microbiol Immunol Scand [A]. Nov 1987;95(6):357-63. [Medline].

27. Moriguchi M, Terai C, Koseki Y, et al. Influence of genotypes at SAA1 and SAA2 loci on the development and the length of latent period of secondary AA-amyloidosis in patients with rheumatoid arthritis. Hum Genet. Oct 1999;105(4):360-6. [Medline].

28. Nakamura T. Clinical strategies for amyloid A amyloidosis secondary to rheumatoid arthritis. Mod Rheumatol. 2008;18(2):109-18. [Medline].

29. Obici L, Perfetti V, Palladini G, et al. Clinical aspects of systemic amyloid diseases. Biochim Biophys Acta. Nov 10 2005;1753(1):11-22. [Medline].

30. Sipe J. Revised nomenclature for serum amyloid A (SAA). Nomenclature Committee of the International Society of Amyloidosis. Part 2. Amyloid. Mar 1999;6(1):67-70. [Medline].

Keywords

amyloidosis, secondary amyloidosis, amyloid A amyloidosis, AA amyloidosis, inflammatory amyloidosis, systemic amyloidosis, inflammation-associated amyloidosis, tissue amyloid deposition, AA deposition, renal amyloidosis, amyloid renal disease, amyloid nephropathy, rheumatoid arthritis, RA, familial Mediterranean fever, FMF, serum amyloid A protein, SAA protein

Contributor Information and Disclosures

Author

Richa Dhawan, MD, Faculty, Center of Excellence for Arthritis and Rheumatology, Louisiana State University Health Science Center at Shreveport
Richa Dhawan, MD is a member of the following medical societies: American Association of Physicians of Indian Origin, American College of Physicians-American Society of Internal Medicine, and American College of Rheumatology
Disclosure: Nothing to disclose.

Coauthor(s)

Mohammed Mubashir Ahmed, MD, Associate Professor, Department of Medicine, Division of Rheumatology, University of Toledo College of Medicine
Mohammed Mubashir Ahmed, MD is a member of the following medical societies: American College of Physicians, American College of Rheumatology, and American Federation for Medical Research
Disclosure: Nothing to disclose.

Eisha Mubashir, MD, Fellow in Rheumatology, Department of Medicine, Fellow, Center of Excellence for Arthritis and Rheumatology, Louisiana State University Health Sciences Center, Shreveport
Disclosure: Nothing to disclose.

Joel Buxbaum, MD, Professor, Department of Molecular and Experimental Medicine, The Scripps Research Institute
Joel Buxbaum, MD is a member of the following medical societies: American Society for Clinical Investigation, American Society of Human Genetics, and Association of American Physicians
Disclosure: Nothing to disclose.

Medical Editor

Robert E Wolf, MD, PhD, Professor Emeritus, Department of Medicine, Louisiana State University Health Sciences Center at Shreveport; Chief, Rheumatology Section, Medical Service, Overton Brooks Veterans Administration Medical Center of Shreveport
Robert E Wolf, MD, PhD is a member of the following medical societies: American College of Rheumatology, Arthritis Foundation, and Society for Leukocyte Biology
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: Nothing to disclose.

Managing Editor

Elliot Goldberg, MD, Dean of the Western Pennsylvania Clinical Campus, Professor, Department of Medicine, Temple University School of Medicine
Elliot Goldberg, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians, and American College of Rheumatology
Disclosure: Nothing to disclose.

CME Editor

Alex J Mechaber, MD, FACP, Associate Dean for Undergraduate Medical Education, Associate Professor of Medicine, University of Miami Miller School of Medicine
Alex J Mechaber, MD, FACP is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians-American Society of Internal Medicine, and Society of General Internal Medicine
Disclosure: Nothing to disclose.

Chief Editor

Herbert S Diamond, MD, Professor of Medicine, Temple University School of Medicine; Chairman Emeritus, Department of Internal Medicine, Western Pennsylvania Hospital
Herbert S Diamond, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians, American College of Rheumatology, American Medical Association, and Phi Beta Kappa
Disclosure: medifocus Honoraria Review panel membership; health dialogs Honoraria Consulting; Merck, Amgen, Biogen, Zimmer, Wyeth, Johnson&Johnson, Stryker, Medtronic, Zimmer.Abbott,  Ownership interest Other; West Penn Allegheny Health System Consulting fee Consulting; Alpharma Honoraria Consulting; Proctor&Gamble Grant/research funds Independent contractor

© 1994- by Medscape.
All Rights Reserved
(http://www.medscape.com/public/copyright)