eMedicine Specialties > Rheumatology > Miscellaneous Inflammatory Arthritis

Amyloidosis, AA (Inflammatory)

Author: Richa Dhawan, MD, Faculty, Center of Excellence for Arthritis and Rheumatology, Louisiana State University Health Science Center at Shreveport
Coauthor(s): 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
Contributor Information and Disclosures

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.

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