AA (Inflammatory) Amyloidosis

Updated: Jan 08, 2021
  • Author: Jefferson R Roberts, MD; Chief Editor: Herbert S Diamond, MD  more...
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Overview

Practice Essentials

Amyloidosis comprises a heterogeneous group of diseases in which normally soluble plasma proteins are deposited in the extracellular space in an abnormal, insoluble, fibrillar form.

Amyloid A (AA) amyloidosis, previously known as secondary AA amyloidosis, is the most common form of systemic amyloidosis worldwide. [1]  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. SAA is created under the transciptional regulation of proinflammatory cytokines. [2] AA amyloidosis occurs in the course of chronic inflammatory diseases (infectious and noninfectious), hereditary periodic fevers, and with certain neoplasms, such as Hodgkin lymphoma and renal cell carcinoma. [3]  

Given the lack of currently available agents that directly target amyloid deposits, the major therapeutic strategy in AA amyloidosis is the use of agents that strongly suppress the inflammation caused by the primary disease. 

For information on other types of amyloidosis, see Amyloidosis.

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Background

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 the immunoglobulin-related amyloid light chain type (AL) of amyloidosis is more frequent than AA as the cause of systemic amyloid deposition. [4]

The major sites of involvement in AA amyloidosis are the kidney, liver, and spleen. Clinically overt disease typically develops when kidney damage occurs, manifesting as proteinuria, nephrotic syndrome, or derangement in renal function. These are clinically evaluated on basic laboratory tests, including a kidney function panel, complete metabolic panel, and/or urinaylsis. 

 

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Pathophysiology

The tissue fibril involved in AA amyloidosis consists of a 7500-dalton cleavage product of the SAA protein. SAA protein is an acute phase reactant,  like C-reactive protein (CRP), and is synthesized by hepatocytes under the transcriptional regulation of cytokines, including interleukin (IL)-1, IL-6 and tumor necrosis factor (TNF). [5, 6]  Under the influence of the inflammatory cytokine IL-6, hepatic transcription of the messenger ribonucleic acid (mRNA) for SAA may increase 1000-fold when exposed to an inflammatory stimulus. Elevated plasma concentrations of SAA lead to accumulations of amyloid in the form of cross--β-sheet fibrillar deposits. The mechanism of these cross--β-sheet fibrillar deposits is not completely understood at this time. [7]

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 sulfate (HS), a ubiquitously expressed glycosaminoglycan component of the extracellular matrix. SAA specifically binds to HS glycosaminoglycan, a common constituent of all types of amyloid deposits that has been shown to facilitate conformational transition of a precursor to β-pleated sheet structure. [8]

The protein has also 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 serum CRP levels 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.

Chronic or acute, recurrent, substantial elevations of SAA are necessary but not sufficient for the development of amyloidosis. The median plasma concentration of SAA in healthy persons is 3 mg/L, but the concentration can increase to more than 2000 mg/L during the acute-phase response. Many individuals with long-standing inflammatory disease, although severely compromised by their primary condition, do not develop tissue amyloid deposition. What determines a patient's risk for the development of this complication of inflammation is not understood. Therapy, genetic factors, and environmental factors have all been proposed as possible contributors to the response of the primary disease.

Genes and proteins involved

Three protein isoforms of SAA are described (ie, SAA 1, 2, 4). Each isoform is encoded by its own gene in a cluster on band 11p15.1 that also includes a pseudogene (SAA3P). SAA1 has 3 alleles (SAA1.1, SAA1.3, SAA1.5), defined by amino acid substitutions at positions 52 and 57 of the molecule. [9]

The frequency of these alleles varies between populations and may be associated with the occurrence of AA amyloidosis in diseases such as rheumatoid arthritis. Also, it may have a role in determining the level of SAA in blood, clearance, susceptibility to proteolytic cleavage, severity of disease, and response to treatment. Seventy-six percent of Caucasians have SAA1.1, whereas only 5% have SAA1.3. In the Japanese population, the 3 alleles occur at approximately the same rate. Patients with a 1.1/1.1 genotype have a 3-fold to 7-fold increased risk of amyloidosis. But overall, the actual significance of the SAA genotype remains undefined. [8]

Cellular and extracellular tissue factors

Mononuclear phagocytes might play a role in degradation of SAA and initiation of development of AA amyloidosis.

Polymorphisms of the mannose-binding lectin 2 (MBL-2) gene leading to decreased levels of functional MBL have been related to defective macrophage function. This suggests that genetic background may affect the ability of mononuclear phagocytes to effectively process and degrade SAA proteins.

Additional tissue factors, such as enzymes found in the extracellular matrix, are likely to be involved in the proteolytic processing of SAA. Matrix metalloproteinases (MMPs) are involved in generation of SAA N-terminal fragments. In vitro studies confirmed that human SAAs and AA amyloid fibrils are susceptible to proteolytic cleavage by MMPs, generating fragments of different sizes. Studies have demonstrated that susceptibility to MMP-1 degradation is highly dependent on SAA1 genotype. [10]

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 kidney biopsy specimens, have suggested that glycoxidative modification of proteins, probably the AA protein itself, may also play a role in AA deposition in kidneys.

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Etiology

A wide range of infectious and noninfectious diseases, hereditary periodic fevers, immune deficiencies, and neoplasms have been associated with AA amyloidosis. [11]  AA amyloidosis has also been found to be idiopathic; in some studies and reviews the rate of idiopathic cases is reported as high as 21%. [12]

Chronic infectious diseases that have been associated with AA amyloidosis include the following:

The precise frequencies of AA amyloidosis in those disorders are difficult to ascertain, but they may be as high as 10% in some chronic suppurative disorders (eg, osteomyelitis). The overall incidence in autopsies in Western countries is estimated at 0.5-0.86%, where the most frequent underlying diseases are RA (23-51%), juvenile idiopathic arthritis (7-48%), and ankylosing spondylitis (0-12%). [13, 14]

RA is the most common rheumatic cause of AA amyloidosis. However, most patients with RA do not develop AA amyloidosis. Prolonged duration of disease, continuous disease activity, and inadequate treatment are risk factors for AA amyloidosis. Renal failure due to amyloid deposition usually occurs in the fifth decade of life. In living patients with RA, the incidence of AA found on biopsies ranges from 7-29%.

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:

The most common cause of kidney involvement in ankylosing spondylitis is AA amyloidosis (62%), followed by IgA nephropathy (30%). [5]

AA amyloidosis is a rare complication of inflammatory bowel disease and occurs more commonly in Crohn disease and in males. The reason that Crohn disease is more readily complicated by AA amyloidosis than ulcerative colitis is not known but may be secondary to a greater degree of sustained inflammation in Crohn disease; in particular, the suppurative features of Crohn disease such as abscesses and fistulae may be risk factors. [16]

Chronic juvenile arthritis seems to be a special case, with a large geographic variance (7-48%) in the incidence of AA amyloidosis 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 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. More recently, AA amyloidosis associated with subcutaneous drug abuse was reported in 24 patients seen at a San Francisco hospital from 1998 to 2013. [17]

Familial Mediterranean fever (FMF) is characterized by recurrent attacks of fever, arthritis, pleuritis, peritonitis, or erysipelas-like erythema lasting 24–48 hours. FMF begins in childhood and usually affects persons of Mediterranean origin. AA amyloidosis develops in up to one-quarter of patients with FMF. 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 that may be complicated by AA amyloidosis include the following:

  • Tumor necrosis factor receptor–associated periodic syndrome (TRAPS)
  • Chronic infantile neurologic cutaneous articular syndrome (CINCA)
  • Muckle-Wells syndrome
  • Hyperimmunoglobulinemia D with periodic fever syndrome (HIDS)

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. [18, 19]

Among other noninfectious chronic inflammatory diseases, AA amyloidosis has been reported in systemic lupus erythematosuspolymyositis, 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.

There have been several rare cases suggesting that multiple sclerosis is a chronic inflammatory disease, in which AA amyloidosis can develop.  [15, 20]

SAA production is mediated through inflammatory cytokines, primarily IL-6, and AA deposition has been noted in other disorders associated with increased IL-6 production. Occasionally, patients with atrial myxomas, renal cell carcinomas, Hodgkin lymphoma, 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.

Few case reports have described patients with cyclic neutropenia developing AA amyloidosis. [21]

As many as 6% of patients with AA amyloidosis have no clinically overt inflammatory disease. However, a 2020 analysis of 40 patients with a primary immune deficiency found that secondary AA amyloidosis was a later complication. In this study, notable findings include the presence of bronchiectasis in as much as 52.5% in the population studied and an average time of ~16.18 +/- 7 years between initial symptoms of primary immune deficiency and AA amyloidosis onset. The immune disorders in the study included immunoglublin deficits, hyper IgM syndrome, hyper IgE syndrome, Chediak-Higashi syndrom, hereditary C4 deficiency, leukocyte adhesion deficiency type 1, and chronic granulomatous disease. This is a notable study in demonstrating that immune deficiencies often lead to chronic inflammation and can be complicated by AA amyloidosis. [22]

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Epidemiology

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.

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.

Most available data to approximate the epidemiology of AA amyloidosis are derived from autopsies. The overall autopsy incidence of AA amyloidosis in Western nations ranges from 0.50-0.86%. [23]

Currently, rheumatic diseases such as rheumatoid arthritis (RA), ankylosing spondylitis (AS), psoriatic arthritis, and juvenile idiopathic arthritis are the most frequent causes (70%) of AA amyloidosis. The reported prevalence of amyloidosis in RA ranges from 7%-26%. [24]  The rates vary by the diagnostic procedure used (that is, autopsy, kidney biopsy or subcutaneous fat aspiration), the clinical status (preclinical or symptomatic disease), and the type of study (case series or population-based study).

The most common cause of renal involvement in ankylosing spondylitis (AS) is AA amyloidosis (62%), followed by IgA nephropathy (30%). [25] Although its prevalence might be in decline, renal AA amyloidosis is a serious complication of AS, with a median survival time after onset of dialysis of 2.37 years, and with a 5-year survival rate of only 30%.

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. [26]

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 at onset of amyloidosis is related to the age at 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.

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Prognosis

The prognosis in patients with AA amyloidosis, regardless of the prognosis wi the primary disease, has generally been associated with the degree of renal compromise present at the time of diagnosis. 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. 

Patients with access to renal replacement therapy have improved survival to more than 4 years. In those cases, infection was the major cause of death. [27] 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.

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. The progression of amyloidosis is related to the production and concentration of the circulating amyloidogenic precursor protein. The concentration of the acute phase protein SAA during follow-up correlates with deterioration of renal function, amyloid burden, and mortality in AA amyloidosis.

In a study of 374 patients with AA amyloidosis who were followed for 15 years, the median survival after diagnosis of amyloidosis in those with a sustained acute phase response was 133 months. The risk of death was 17.7 times as high among patients with SAA concentrations in the highest eighth, or octile, (≥155 mg/L) as among those with concentrations in the lowest octile (< 4 mg/L). [28]

In general, amyloidosis shortened the median life span 7.7 years, and survival strongly depended on controlling the underlying inflammatory process. Amyloid deposits regressed in 60% of patients who had a median SAA concentration of less than 10 mg/L, and survival in these patients was superior to survival in those in whom amyloid deposits did not regress. Sustained increased concentration of SAA is the most significant risk factor in AA amyloidosis, whereas reduction of SAA concentration improves survival and is associated with arrest or even regression of amyloid deposits. [13, 29, 30]

A review of data from the Finnish Registry for Kidney Diseases identified 502 patients with amyloidosis entering renal replacement therapy from 1987-2002; 80% of those patients had amyloidosis associated with an underlying rheumatic disease. The 5-year survival rates among patients with the RA, AS, and juvenile idiopathic arthritis were 18%, 30%, and 27%, respectively. [31]

Cardiac amyloidosis appears to be a predictor of worse outcome, with a 5-year survival of 31% versus 63% for patients without cardiac involvement in a retrospective series of 42 patients from Japan. [32]  In patients with cardiac amyloidosis, the hypomotile and pathological heart wall and failing heart predispose the patient to mural thrombosis and embolic complications. Such right-sided heart involvement is a major prognostic determinant in AL amyloidosis, but is uncommon in AA amyloidosis. Amyloid in the conduction pathways can lead to high-grade blocks. [33]

The degree of renal involvement is important, with patients who have elevated creatinine concentrations doing worse compared with patients with a normal creatinine concentration. The pattern of renal involvement is also important. Specifically, glomerular involvement with amyloid and fibrosis appear to have clinical course characterized by deteriorating renal function compared to patients with other types of renal involvement. Generally, however, the median survival is longer than 5 years. [34]

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Patient Education

Patient education should include a discussion about the natural course of AA amyloidosis. Education should focus on the importance of early, aggressive anti-inflammatory management to prevent ultimate organ failure. Preparing the patient for either kidney transplantation or dialysis is another major educational goal. The manner in which this progressive disease is discussed depends on the relationship between the physician and the patient and the physician's assessment of the patient's emotional needs. Clinicians may consider earlier behavioral health or psychiatric assistance to help the patient cope with their diagnosis and understand their prognosis, treatment course, and disease progression. 

For patient education information, see Amyloidosis.

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