eMedicine - Amyloidosis, AA (Inflammatory) : Article by Joel Buxbaum, MD

Amyloidosis, AA (Inflammatory)

Last Updated: September 18, 2003

Synonyms and related keywords: secondary amyloidosis, amyloid A amyloidosis, AA amyloidosis, inflammation-associated amyloidosis, rheumatoid arthritis, RA, serum amyloid A protein, SAA protein

AUTHOR INFORMATION

Author: 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 Association for Advancement of Science, American Society for Clinical Investigation, American Society of Human Genetics, and Association of American Physicians

Editor(s): Robert E Wolf, MD, PhD, Chief, Professor, Department of Internal Medicine, Section of Rheumatology, Louisiana State University Health Sciences Center; Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, Pharmacy, eMedicine; Herbert S Diamond, MD, Chairman, Department of Internal Medicine, Professor of Medicine, Temple University School of Medicine, Department of Internal Medicine, Western Pennsylvania Hospital; Alex J Mechaber, MD, FACP, Director of Clinical Skills Program, Assistant Professor, Department of Internal Medicine, Division of General Internal Medicine, University of Miami School of Medicine; and Arthur Weinstein, MD, Professor of Medicine, Georgetown University; Associate Chairman, Department of Medicine, Director, Section of Rheumatology, Washington Hospital Center

INTRODUCTION

Background: Amyloid A (AA) amyloidosis is the most common form of systemic amyloidosis worldwide. It occurs in the course of a chronic inflammatory disease of either infectious or noninfectious etiology. In developing countries, the most common instigator 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, the kidney, liver, and spleen are the major sites of involvement. The tissue fibril consists of a 7500-dalton cleavage product of the serum amyloid A (SAA) protein, an acute phase protein produced in a number of 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.

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.

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 the majority of cases of AA amyloidosis, though SAA 2 also has been found in some cases. Frequently, heterogeneity exists at the amino terminus of the deposited AA fibrils, and truncated forms of the protein also have 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 frequently are 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, also may play a role in AA deposition in kidneys.

Frequency:

In the US: The absolute prevalence of AA amyloidosis is difficult to ascertain because it depends upon 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). It 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.

Internationally: 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 out of 75,000 population. Because 30-40% of amyloidosis in Western Europe is of the AL type, the estimated AA amyloidosis prevalence is 1 out of 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% versus 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 to 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 the 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 from 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 the 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 addressing this question exist, 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 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 numbers of cases, males seem to have an earlier average age of onset.

In FMF, males are affected more commonly than 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 also is of relatively early onset.

CLINICAL

History: The most common presentation of AA amyloidosis is renal; thus, symptoms reflect either the appearance of renal failure or nephrotic syndrome.

Weakness, weight loss, and peripheral edema are the most common symptoms.

In patients with active RA, these complaints may be attributed incorrectly to progression of the inflammatory disease or to adverse effects of drugs.

Rarely, evidence of bowel involvement (with complaints of constipation, diarrhea, or gastrointestinal bleeding) dominates the presentation.

Again, in patients with inflammatory joint disease, these symptoms also can be secondary to treatment, particularly with nonsteroidal anti-inflammatory drugs.

In contrast to AL and other amyloidoses, congestive heart failure, peripheral neuropathy, or carpal tunnel syndrome occasionally may occur 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 complaint, such as abdominal fullness or right upper quadrant discomfort (reflecting hepatomegaly), might bring the patient to the physician.

Physical:

Patients with amyloid renal disease commonly are hypertensive, though 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 the nephrotic syndrome.

The purpura and macroglossia observed in AL are not features of AA amyloidosis, nor is the orthostatic hypotension associated with AL 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 indicate investigation for amyloidosis, though 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, though they might have a renal disease other than AA amyloid deposition.

Causes:

Chronic infectious diseases, including tuberculosis, leprosy, bronchiectasis, chronic osteomyelitis, and chronic pyelonephritis, have been associated with the occurrence of AA. 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. In rheumatoid arthritis, the incidence is 5-26%, being found more often on autopsy than biopsy. The frequency may be lower in patients treated earlier and more aggressively. Other inflammatory disorders associated with AA include the following:

Inflammatory bowel disease (0.4-2%)

Behçet syndrome in Turkey (1-2%)

Reiter syndrome in adults (0.3%)

Ankylosing spondylitis children (4-5%)

Psoriatic arthritis (3-13%)

Chronic juvenile arthritis seems to be a special case, with a large geographic variance (0.14-17%) in the incidence of AA depending on whether the analysis was performed in the United States (low) or Eastern Europe (high).

In the 1980s, a high frequency of renal AA was observed among people who were 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.

Kidney AA is virtually a universal complication of FMF in some populations if the patients are not compliant with colchicine prophylaxis.

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 biopsies of such patients. AA amyloidosis also has 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, presumably because of production of the cytokine by the tumor cells. Paradoxically, some patients with agammaglobulinemia also have developed AA, demonstrating the dissociation between cytokine production and the synthesis of its normal downstream effector molecules, immunoglobulins.

DIFFERENTIALS

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

WORKUP

Lab Studies:

The overwhelming factor in making the diagnosis of 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 cited in Causes should provoke the physician to search for tissue AA amyloid deposition, most commonly in the kidney.

No specific tests for AA amyloidosis exist.

While the SAA precursor usually is elevated, prolonged elevation does not necessarily indicate tissue deposition because many patients with inflammatory disease may 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 may 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 from 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.

Sonography is useful in establishing renal size; however, kidneys may be of 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 originally was reported as an incidental finding. However, CT scan does not have great sensitivity, and reports concerning the specificity of CT scan have varied considerably. If results are positive, CT scan can be used to monitor gross progression of the deposition in a given organ.

Magnetic resonance imaging may have a role in amyloid 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 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 rarely, if ever, is 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%.

Series from individual centers have shown that the labial gland or gastric mucosal biopsies also can 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.

Histologic Findings: Infiltrated tissues show homogeneous eosinophilic staining with hematoxylin and eosin. The earliest deposits usually are vascular. In the kidney, early deposits may be mesangial, but, late in the course, entire glomeruli may be obliterated. Distinguishing these from glomerulosclerosis 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 fibrils 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, treatment of AA amyloidosis consists of treatment of the primary inflammatory disease. 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 (Ahlmen, 1987). The trade off for the aggressive use of alkylating agents is an increased incidence of leukemia. The application of the newer anti-inflammatory biologicals, such as the inhibitors of tumor necrosis factor (TNF) and IL-1, possibly will 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, though the elimination of AA amyloid deposition is likely to be 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.

Two new approaches to AA amyloidosis treatment currently are undergoing clinical trials.

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.
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 (Joss, 2000). 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 usually is 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 AA amyloidosis. Therapy for the underlying inflammatory disorders should be as aggressive as possible.

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

Drug Name
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.
Adult Dose 0.6 mg bid PO unless not tolerated or renal insufficiency occurs; in these cases, lower doses will be used
Pediatric Dose Not established
Contraindications Documented hypersensitivity; severe renal, hepatic, GI, or cardiac disorders; blood dyscrasias
Interactions Sympathomimetic agent toxicity and effect of CNS depressants are significantly increased with colchicine
Pregnancy C - Safety for use during pregnancy has not been established.
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.

In/Out Patient Meds:

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, though no controlled studies indicate that it is effective in 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 mentioned previously, 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 amyloid deposition.

Complications:

The major consequence of renal amyloidosis is complete renal failure. Because it occurs in the natural course of the disorder, 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, generally has been associated with the degree of renal compromise present at the time of diagnosis, ie, poor prognosis is associated with a serum creatinine greater than 2 mg/dL or a serum albumin 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 the disorder 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 upon the relationship between the physician and the patient and the physician's assessment of the patient's emotional needs.

MISCELLANEOUS

Medical/Legal Pitfalls:

Misdiagnosis of 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.

BIBLIOGRAPHY

Ahlmen M, Ahlmen J, Svalander C, Bucht H: Cytotoxic drug treatment of reactive amyloidosis in rheumatoid arthritis with special reference to renal insufficiency. Clin Rheumatol 1987 Mar; 6(1): 27-38.
Akar N, Yalcinkaya F, Akar E, Cakar N: MEFV mutation analysis in Turkish familial Mediterranean fever patients with amyloidosis. Amyloid 1999 Dec; 6(4): 301-2.
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 1993 Dec; 20(12): 2051-7.
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 1993 Apr; 189(3): 316-31.
Booth DR, Booth SE, Gillmore JD, et al: SAA1 alleles as risk factors in reactive systemic AA amyloidosis. Amyloid 1998 Dec; 5(4): 262-5.
Buck FS, Koss MN, Sherrod AE, et al: Ethnic distribution of amyloidosis: an autopsy study. Mod Pathol 1989 Jul; 2(4): 372-7.
Buxbaum J: The amyloidoses. In: Dieppe PA, Klippel JH, eds. Rheumatology. 2nd ed. St. Louis, Mo: Mosby; 1998:1-10.
Cunnane G, Whitehead AS: Amyloid precursors and amyloidosis in rheumatoid arthritis. Baillieres Best Pract Res Clin Rheumatol 1999 Dec; 13(4): 615-28.
Gabay C, Kushner I: Acute-phase proteins and other systemic responses to inflammation. N Engl J Med 1999 Feb 11; 340(6): 448-54.
Gallo GR, Feiner HD, Chuba JV, et al: Characterization of tissue amyloid by immunofluorescence microscopy. Clin Immunol Immunopathol 1986 Jun; 39(3): 479-90.
Gertz MA, Kyle RA: Secondary systemic amyloidosis: response and survival in 64 patients. Medicine (Baltimore) 1991 Jul; 70(4): 246-56.
Heering P, Hetzel R, Grabensee B, Opelz G: Renal transplantation in secondary systemic amyloidosis. Clin Transplant 1998 Jun; 12(3): 159-64.
Helin HJ, Korpela MM, Mustonen JT, Pasternack AI: Renal biopsy findings and clinicopathologic correlations in rheumatoid arthritis. Arthritis Rheum 1995 Feb; 38(2): 242-7.
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.
Joss N, McLaughlin K, Simpson K, Boulton-Jones JM: Presentation, survival and prognostic markers in AA amyloidosis. QJM 2000 Aug; 93(8): 535-42.
Kisilevsky R, Young ID: Pathogenesis of amyloidosis. Baillieres Clin Rheumatol 1994 Aug; 8(3): 613-26.
Livneh A, Langevitz P, Shinar Y, et al: MEFV mutation analysis in patients suffering from amyloidosis of familial Mediterranean fever. Amyloid 1999 Mar; 6(1): 1-6.
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 1994 Dec; 37(12): 1804-11.
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] 1987 Nov; 95(6): 357-63.
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 1999 Oct; 105(4): 360-6.
Perez Equiza E, Arguinano JM, Gastearena J: Successful treatment of AA amyloidosis secondary to Hodgkin's disease with 4'-iodo-4'-deoxydoxorubicin. Haematologica 1999 Jan; 84(1): 93-4.
Sipe J: Revised nomenclature for serum amyloid A (SAA). Nomenclature Committee of the International Society of Amyloidosis. Part 2. Amyloid 1999 Mar; 6(1): 67-70.