AA (Inflammatory) Amyloidosis 

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

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.

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. 

 

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.

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 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.

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]

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.

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]

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.

 

Presentation

History

The most common presentation of amyloid A (AA) amyloidosis is renal. Renal involvement is found in as many as 90% of patients. Signs and symptoms reflect the appearance of proteinuria, progressive development of renal insufficiency, or nephrotic syndrome.[35]  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 for underlying AA amyloidosis.

Amyloid deposits also occur in the spleen and liver, but even a significant splenic and hepatic load may remain clinically asymptomatic for long periods of time. Rarely, abdominal fullness or right upper quadrant discomfort (reflecting hepatomegaly), might bring the patient to the physician. Hepatic dysfunction will eventually present itself on physican examination, but may also not be evident on laboratory analysis for long periods of time. Splenic involvement might be suspected if Howell-Jolly bodies are found on a peripheral blood smear of a nonsplenectomized patient, or if frequent episodes of infection occur.

Rarely, evidence of bowel involvement dominates the presentation. Gastrointestinal (GI) involvement may lead to motility disorders and pseudo-obstruction. Amyloid accumulations in the small intestine can cause generalized malabsorption, manifesting as a variety of nutrient deficiencies and the complications associated with specific nutrients (eg, iron deficiency anemia, macrocytic anemia in vitamin B12/folate deficiency). GI involvement can result in weakening of the intestinal wall, which can rupture and lead to peritonitis. Amyloid deposition in blood vessel walls and tissue  predispose patients to bleeding.[36]

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.[37]

 Clinical evidence of cardiac involvement occurs in less than 5% with AA amyloidosis, compared with as many as 50% of patients with L chain–type (AL) amyloidosis. 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. [38]

In general, the appearance of symptoms suggesting kidney disease in a patient with chronic infectious or noninfectious inflammation should raise a warning flag for possible underlying AA amyloidosis.

Physical Examination

Patients with amyloid renal disease are commonly hypertensive, although whether the hypertension is associated with the renal amyloidosis or if it 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. 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 kidney function, although they might have a renal disease other than AA deposition.[39]

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.  In summary, the physical examination manifestations that will appear in a patient with AA amyloidosis depend on the organ system involved. The following are possible patient presentations depending on the organ system involved:

  • Renal involvement: edema of extremities (due to proteinuria)
  • Hepatic involvement: hepatomegaly
  • Gastrointestinal involvement: diarrhea or constipation, bleeding
  • Splenic involvement: splenomegaly
  • Cardiac involvement: chest pain, edema, shortness of breath, palpitations

Complications

Complications of AA amyloidosis focus on the organ system involved. Renal dysfunction and consequently the progression to end-stage-renal-disease and dialysis are the most common complications. Hepatic dysfunction manifesting as liver failure, splenic dysfunction with more frequent infections, gastrointestinal dysfunction with malabsoprtion and possible bowel rupture, and cardiac dysfunction with heart failure are all possible outcomes, but less common than the renal disease progression. 

 

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.

The diagnosis of all forms of amyloidosis is confirmed by Congo red staining in a biopsy specimen. AA amyloidosis is then identified through immunohistochemical analysis and genetic testing. With respect to site selection, rectal biopsy is more useful than subcutaneous fat aspiration in AA amyloidosis. Biopsy of a clinically affected organ is the most sensitive method and may also detect concomitant pathologies, but is invasive and carries the risk of complications. 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 kidney 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.

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.[40]  During the subsequent decades, subcutaneous fat pad biopsy, obtained via fine-needle aspiration, was introduced as a screening test for the detection of amyloidosis, as it is safe, cheap, and rapid.[41]  Nevertheless, the tissue with the highest yield, particularly in the patients with 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 in the same manner 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.

Imaging Studies

Avoid intravenous pyelography in patients with suspected amyloidosis because exposure to contrast medium has been associated with more frequent acute kidney injury in individuals with substantial proteinuria.

Ultrasonography is useful in determining kidney 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.

Magnetic resonance imaging 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.[42]

Other Tests

In patients with AA amyloidosis who have 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.[33]  Amyloid accumulation in the heart may be suggested by the following:

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

 

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 later in the course, entire glomeruli may be obliterated. Distinguishing these from glomerulosclerosis and from other causes was 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.

 

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 kidney function. Biologic agents, including tumor necrosis factor (TNF) inhibitors and interleukin-1 (IL-1) and IL-6 antagonists, are the main therapeutic options used for this purpose.,

The major consequence of renal amyloidosis is complete renal failure. Hospitalized inpatient care may be necessary for intercurrent infections or deterioration in kidney 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. In general, early and aggressive therapy and treatment of the underlying inflammatory disease causing secondary AA amyloidosis helps treat and slow the progression of AA amyloidosis complications. 

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.[43] When started early and used at sufficient doses with 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.[44]

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.[45] 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  tumor necrosis factor–αnecrosis factor alpha (TNF-α), interleukin (IL)-1, and IL-6 have been tried in patients with AA amyloidosis. Treatment with TNF-α inhibitors and 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, which can be measured through serum C-reactive protein (CRP) levels. Lowering of IL-6 levels results in reduced synthesis of acute-phase proteins, suppression of systemic inflammation, and lower SAA levels, leading to reduction of amyloid deposits.[46]

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.[47]

IL-6 is one of the pro-inflammatory cytokines playing a critical role in the induction of SAA genes, and inhibition of IL-6 results in dramatic suppression of SAA. Tocilizumab, a humanized monoclonal anti–IL-6 receptor antibody, has proved 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.[48]  A case report of a patient with AA amyloidosis secondary to rheumatoid arthritis describes reduction in inflammatory parameters and improvement in kidney function with tocilizumab treatment.[49]

A retrospective study that indirectly compared tocilizumab to TNF inhibitors, 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 kidney function is not known. Moreover, switching between these agents is frequently necessary in inflammatory conditions due to adverse events and primary or secondary inefficacy.[50]

Surgical Care

Castleman disease, a rare group of lymphoproliferative disorders in which IL-6 is often the pathologic driver, can be complicated by AA amyloidosis. Surgical resection is effective for cases that involve a single region of enlarged lymph nodes (unicentric Castleman disease). In certain cases where surgery is not feasible or curative, the anti–IL-6 agent siltuximab may be effective.[18]

Although kidney transplantation is widely used for treating renal amyloidosis secondary to familial Mediterranean fever (FMF), some data suggest that patients with amyloidosis do not have as favorable a prognosis as patients transplanted for other forms of end-stage kidney disease.[51] Nonetheless, there have been reports of improving results and transplantation is a reasonable option.[52]

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.[53]

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.[54]  

 

Consultations

Worsening kidney function demands management by an experienced nephrologist, with particular emphasis placed on the eventual need for dialysis and the availability of transplantation. Nephrologic and surgical management of the chronic kidney disease 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 kidney disease.

In AA amyloidosis that develops as a complication of a primary chronic infectious disease, consultations with an infectious diseases specialist concerning antibiotics, surgical services to discuss resection, and other diagnostic and therapeutic modalities are appropriate. For cases related to rheumatologic disease, consultation with a rheumatologist may be beneficial in guidance for choices for newer modes of anti-inflammatory treatment.

Diet

No specific dietary recommendations for patients with amyloid disease exist. Patients with chronic kidney disease should be managed by both a nephrologist and a nutritionist who has experience with such patients. Both will be able to guide the patient in maintaining appropriate levels of sodium and protein intake. As the kidney disease progresses, lower-potassium diets will often be recommended. 

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. The 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

Clinicians managing a patient with AA amyloidosis should take into account the organ systems involved. As with any patient with chronic kidney disease, kidney function should be monitored perioidically to assess progress and the possible ultimate need for dialysis or transplantation. Anemia of chronic disease often goes hand-in-hand with chronic kidney disease, and routine monitoring of hemoglobin, hematocrit, and iron studies should be performed. Overall, laboratory values to follow include a complete blood count, complete metabolic panel, and urinalysis (to monitor proteinuria). Other laboratory values that may be affected in chronic kidney disease, vitamin D and parathyroid hormone, should be followed by an experienced nephrologist.[55]

 

Medication

Medication Summary

No specific therapeutic agents are recommended for the treatment of amyloid A (AA) amyloidosis. Medical therapy for the underlying inflammatory disorders should be as aggressive as possible to completely suppress the inflammatory process. 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 amilial Mediterranean fever.[44]

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?