AA (Inflammatory) Amyloidosis 

Updated: Dec 30, 2018
Author: Richa Dhawan, MD, CCD; Chief Editor: Herbert S Diamond, MD 

Overview

Practice Essentials

Amyloidosis comprises of 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 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. 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 lymphoma and renal cell carcinoma.[2]

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.

The major sites of involvement in AA amyloidosis are the kidney, liver, and spleen. Clinically overt disease typically develops when renal damage occurs, manifesting as proteinuria, nephrotic syndrome, or derangement in renal function.

The tissue fibril consists of a 7500-dalton cleavage product of the SAA protein, which is an acute phase reactant, and like C-reactive protein, is synthesized by hepatocytes under the transcriptional regulation of cytokines including interleukin (IL)-1, IL-6 and tumor necrosis factor (TNF).[3, 4]  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.

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. SAA specifically binds to heparan sulfate (HS) glycosaminoglycan, a common constituent of all types of amyloid deposits that has been shown to facilitate conformational transition of a precursor to beta-pleated sheet structure.[5]

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 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 Amyloidosis, Overview.

Pathophysiology

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, 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.

Genes and proteins involved:

Three protein isoforms of SAA are noted (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.[6]

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.[5]

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.[7]

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.

Etiology

Both infectious and noninfectious diseases have been associated with AA amyloidosis. 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 AS (0-12%).[8, 9]

RA is the most common rheumatic cause of AA amyloidosis. However, most patients with RA do not have development of 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:

  • Inflammatory bowel disease (0.4-2%)

  • Behçet syndrome in Turkey (1-2%)

  • Reactive arthritis in adults (0.3%)

  • Psoriatic arthritis (3-13%)

The most common cause of renal involvement in ankylosing spondylitis is AA amyloidosis (62%), followed by IgA nephropathy (30%).[3]

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 greater degree of sustained inflammation in association with the former and, in particular, the suppurative features of Crohn disease such as abscesses and fistulae may be risk factors.[10]

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.[11]

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.[12, 13]

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 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.[14]

As many as 6% of patients with AA amyloidosis have no clinically overt inflammatory disease.

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%.[15]

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%.[16]  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%).[17] 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.[18]

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.

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.

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. 

Patients with access to renal replacement therapy have improved survival to more than 4 years. In the latter cases, infection was the major cause of death.[19] 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. As per this study, 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).[20]

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 among these patients was superior to survival among 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.[8, 21, 22]

As per the Finnish Registry for Kidney Diseases, 502 patients with amyloidosis were identified entering RRT from 1987-2002. Eighty percent of these 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.[23]

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.[24]

The degree of renal involvement is important, with patients who have elevated creatinine levels doing worse compared with patients with a normal creatinine. 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 over 5 years.[25]

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.

 

Presentation

History

The most common presentation of amyloid A (AA) amyloidosis is renal. Renal involvement is found in as many as 90% of patients. Thus, signs and symptoms reflect the appearance of proteinuria, progressive development of renal insufficiency, or nephrotic syndrome.[26] Weakness, weight loss, and peripheral edema are the most common manifestations.

In patients with active rheumatoid arthritis (RA), some of those symptoms may be incorrectly attributed to progression of the inflammatory disease or to adverse effects of drugs. However, the development of proteinuria in patients with RA should always raise the suspicion of AA amyloidosis.

Amyloid deposits also occur in the spleen and liver, but even a significant splenic and hepatic load may remain asymptomatic for long periods. Splenic involvement might be suspected if Howell-Jolly bodies are found in a peripheral blood smear of a nonsplenectomized patient, or if frequent episodes of infection occur.

Rarely, evidence of bowel involvement dominates the presentation. GI involvement may lead to motility disorders and pseudo-obstruction. Amyloid accumulations in the small intestine can cause generalized malabsorption. The weakened bowel wall can rupture, leading to peritonitis. Blood vessel wall and tissue amyloid predispose to bleeding.[27]

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

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. Clinical evidence of cardiac involvement occurs in as many as 50% of patients with L chain–type (AL) amyloidosis compared with less than 5% with AA amyloidosis. Amyloid accumulation in the heart may be suggested by the following:

  • Decreased voltage in the electrocardiogram limb leads
  • Pseudoinfarction pattern in form of Q waves in the anterior chest leads
  • Thickening of the left ventricular wall disproportionate to the degree of current or prior hypertension

The hypomotile and pathological heart wall and failing heart predispose 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.[28]

Congestive heart failure, peripheral neuropathy, or carpal tunnel syndrome occasionally occurs during the course of AA amyloidosis. In contrast to AL amyloidosis and other amyloidoses, however, they are rarely, if ever, a presenting manifestation.

In patients with familial Mediterranean fever (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 Examination

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 major physical findings may be those associated with the primary inflammatory disease. 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.

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.

 

DDx

 

Workup

Approach Considerations

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 another associated condition should prompt a search for tissue AA deposition, most commonly in the kidney.

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.

Laboratory Studies

No specific tests for AA amyloidosis exist. While the serum amyloid A (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 exposure to contrast medium 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 in size in patients with renal amyloidosis.

Single-photon emission computed tomography (SPECT) may be useful because technetium occasionally binds to soft-tissue amyloid deposits. This was originally reported as an incidental finding. However, SPECT does not yield great sensitivity, and reports concerning its specificity of CT scanning have varied considerably. If results are positive, SPECT 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.

Iodine-123–labeled serum amyloid P (SAP) component scintigraphy 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. However, this method is not available in the United States because the SAP is of human origin and cannot tolerate stringent viral inactivation.[29]

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.[28]

Procedures

Biopsy

For the detection of amyloid, biopsy of a clinically affected organ is the most sensitive method and may also detect concomitant pathologies. However, such a biopsy is invasive and carries the risk of complications, in particular bleeding. Thus, if amyloidosis is clinically suspected, a less invasive procedure may be desirable.

In the early 1970s, Westermark and Stenkvist demonstrated that amyloid can be detected in subcutaneous fat. During the decades, subcutaneous fat pad biopsy, obtained via fine-needle aspiration, being safe, cheap, and rapid, has been introduced as a screening test for the detection of amyloidosis.[30]   Nevertheless, 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%.

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.

Congo red staining

Congo red stain continues to be the criterion standard for detection of amyloid deposits. In AL and AA amyloidosis, Congo red staining of aspirated subcutaneous abdominal fat has a sensitivity of 70-90% for the diagnosis. Kidney, heart, or liver samples have also been used for Congo red staining, but biopsy of rectal mucosa, skin, or subcutaneous fat is often sufficient, except in the cases of FMF, when it is rarely, if ever, positive.

The tissue is stained with an alkaline solution of Congo red, and examined 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 κ or λ 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).

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

Approach Considerations

The lack of currently available agents that directly target amyloid deposits mandates the use of agents that strongly suppress the inflammation caused by the primary disease. 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, serum amyloid A (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. Biologic agents including anti-TNFs, IL-1, and IL-6 blockers are the main therapeutic options used for this purpose.

The major consequence of renal amyloidosis is complete renal failure. Inpatient care may be necessary for intercurrent infections or deterioration in renal function, requiring acute dialysis or the initiation of chronic dialysis. 

Medical Care

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.

Colchicine

Colchicine is a plant-derived (colchicum autumnale) alkaloid that has been used for thousands of years to treat nonspecific arthritis. The use of colchicine (0.6 mg tid) by patients with familial Mediterranean fever (FMF) has been shown to reduce or eliminate the febrile episodes and to prevent the appearance of renal amyloidosis.[31]   When started early and used at sufficient doses with a good compliance, development of AA amyloidosis can be prevented but established AA renal amyloidosis is much less responsive to colchicine treatment. In addition,  beneficial effect in the other causes of AA amyloidosis has not been demonstrated.[32]

Alkylating agents

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.[33] The tradeoff for the aggressive use of alkylating agents is an increased incidence of leukemia.

Biologic agents

Biologic agents targeting proinflammatory cytokines such as tumor necrosis factor alpha (TNF-α), interleukin (IL)-1, and IL-6 have been tried in patients with AA amyloidosis. Treatment with tumor necrosis factor–α (TNF-α) inhibitors and interleukin-1 (IL-1) inhibitors has proved effective in controlling the progression of renal amyloid in patients with inflammatory arthritides and hereditary periodic fevers. The rationale for using TNF inhibitors in secondary amyloidosis comes from the fact that these medications lower levels of serum IL-6, which is an important mediator of the acute phase inflammatory response. By reducing IL-6, synthesis of acute-phase proteins is reduced, systemic inflammation suppressed, and SAA levels are lowered, leading to reduction of amyloid deposits.[34]

Anakinra, a recombinant form of IL-1 receptor antagonist, has shown favorable effects on dermatologic and rheumatic manifestations in patients with Muckle–Wells syndrome and familial cold autoinflammatory syndrome. This treatment also resulted in the resolution of AA amyloidosis in these patients.[35]

IL-6 is one of the pro-inflammatory cytokines playing a critical role in the induction of SAA genes, thus inhibition of IL-6 results in dramatic suppression of SAA. Tocilizumab (TCZ), a humanized monoclonal anti IL-6 receptor antibody, was effective in the treatment of amyloidosis secondary to various rheumatic diseases. It binds to soluble and membrane-bound IL-6 receptors and down regulates the synthesis of IL-6 with significant decrease in SAA levels.[36]  

A retrospective study that indirectly compared tocilizumab to anti-TNFs, with a median treatment duration of 2 years suggested a more favorable outcome with tocilizumab. Although IL-6 blockage seems to have the advantage of significantly reducing circulating SAA levels, its long-term impact on renal function is not known. Moreover, switching between these agents is frequently necessary in inflammatory conditions due to adverse events and primary or secondary inefficacy.[37]

Investigational therapies

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.

The plasma glycoprotein serum amyloid P component (SAP) is a universal constituent of all types of amyloid plaques, and potentiates the amyloidogenic process. A study by Bodin and colleagues tested a two-step therapeutic strategy for amyloidosis that targeted SAP by first pharmacologically depleting circulating levels of SAP with the bivalent crosslinker CPHPC, and then subsequently administering anti-human-SAP antibodies. In mice transgenic for human SAP, an experimental model of systemic AA amyloidosis, this treatment regimen produced almost complete regression of hepatic and splenic amyloid deposits 4 weeks after anti-SAP treatment.[38] In a phase I trial in 15 patients, this treatment safely triggered clearance of amyloid deposits from the liver and some other tissues.[39]

Interactions between heparan-sulfate and dermatan-sulfate glycosaminoglycan (GAG)-containing proteoglycans and the misfolded amyloid precursor protein are also considered important for amyloidogenesis and the stabilization of amyloid. This insight has been used in a clinical trial to destabilize amyloid deposits with eprodisate, a negatively charged, sulfonated GAG analog, which binds to GAG-binding sites of the amyloid fibrils.[40]  However, it was recently announced that in the Phase III trial, eprodisate did not meet the primary endpoint in slowing renal function decline.[41]

A study demonstrated the efficacy of pegylated INF-alpha once a week in FMF in the induction of a durable disease remission and the almost complete reversal of secondary renal AA amyloidosis.[42]

Surgical Care

Castelman disease, a rare IL-6–secreting tumor, can sometimes be completely excised. In those cases where surgery is not feasible or curative, evidence suggests benefit with anti-IL-6 therapies.[12]

Although kidney transplantation is widely used for treating renal amyloidosis secondary to familial Mediterranean fever (FMF), some data suggest that patients who have amyloidosis do not have as favorable a prognosis as patients transplanted for other forms of renal failure.[43] Nonetheless, there have been reports of improving results and transplantation is a reasonable option.[44]

Recurrence of amyloidosis in the allograft, gastrointestinal intolerance, and fatal infections remain as major complications during the post-transplant period. Severe sepsis is the cause of 60% to 100% of all deaths with a functioning graft in kidney recipients with AA amyloidosis.[45]

In a multicentric retrospective survey to assess the graft and patient survival in 59 renal transplant recipients with AA amyloidosis, the recurrence rate of AA amyloidosis nephropathy was estimated at 14%. There was significant decrease in the 5-year and 10-year survival of patients in the AA amyloidosis group compared with the control group.[46]  

 

Consultations

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

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.

Diet

No specific dietary recommendations for patients with amyloid disease exist. Patients with chronic kidney disease 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 symptoms. In these cases, attention should be paid to maintaining caloric intake with minimal gastrointestinal distress.

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.

Long-Term Monitoring

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

 

Medication

Medication Summary

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. Use medications 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.[32]

Anti-inflammatory agents

Class Summary

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.

 

Questions & Answers

Overview

What is AA (inflammatory) amyloidosis?

What is the pathophysiology of AA (inflammatory) amyloidosis?

What is the role of genetics in the pathophysiology of AA (inflammatory) amyloidosis?

What are the cellular and extracellular tissue factors in the pathophysiology of AA (inflammatory) amyloidosis?

What causes AA (inflammatory) amyloidosis?

What is the prevalence of AA (inflammatory) amyloidosis?

What is the prognosis of AA (inflammatory) amyloidosis?

What is included in patient education about AA (inflammatory) amyloidosis?

Presentation

Which clinical history findings are characteristic of AA (inflammatory) amyloidosis?

Which physical findings are characteristic of AA (inflammatory) amyloidosis?

DDX

What are the differential diagnoses for AA (Inflammatory) Amyloidosis?

Workup

How is AA (inflammatory) amyloidosis diagnosed?

What is the role of lab tests in the workup of AA (inflammatory) amyloidosis?

What is the role of imaging studies in the workup of AA (inflammatory) amyloidosis?

What is included in the workup of AA (inflammatory) amyloidosis with cardiac involvement?

What is the role of biopsy in the workup of AA (inflammatory) amyloidosis?

Which histologic findings are characteristic of AA (inflammatory) amyloidosis?

How is AA (inflammatory) amyloidosis staged?

Treatment

How is AA (inflammatory) amyloidosis treated?

When is AA (inflammatory) amyloidosis managed by treatment of the underlying etiology?

What is the role of colchicine in the treatment of AA (inflammatory) amyloidosis?

What is the role of alkylating agents in the treatment of AA (inflammatory) amyloidosis?

What is the role of targeted biological agents in the treatment of AA (inflammatory) amyloidosis?

Which treatments for AA (inflammatory) amyloidosis are currently being investigated?

What is the role of surgery in the treatment of AA (inflammatory) amyloidosis?

Which specialist consultations are beneficial to patients with AA (inflammatory) amyloidosis?

Which dietary modifications are used in the treatment of AA (inflammatory) amyloidosis?

How is AA (inflammatory) amyloidosis prevented?

What is included in the long-term monitoring of AA (inflammatory) amyloidosis?

Medications

What is the role of medications in the treatment of AA (inflammatory) amyloidosis?

Which medications in the drug class Anti-inflammatory agents are used in the treatment of AA (Inflammatory) Amyloidosis?