Amyloidosis AA

Amyloidosis AAIntroduction:

Amyloidosis (amyloid associated) or inflammatory amyloidosis is one of the major varieties of generalized amyloidosis, in the same way as AL (immunoglobulin) amyloidosis and hereditary amyloidosis. In AA amyloidosis, the amyloid protein is the AA protein, which is derived by cleavage of the serum amyloid associated protein (SAA), one of the major proteins of the inflammatory reaction. As a result, almost all diseases with chronic inflammation, regardless of the cause – infectious, tumorous or “inflammatory” – may be complicated by amyloidosis. The scarcity of chronic infectious diseases and the better control of many chronic inflammatory diseases have led, at least in developed countries, to a change in the epidemiology of this complication of inflammation which seems less frequent but which remains, once installed , poor prognosis. Current treatments are essentially based on the control of inflammation, which rarely relies on etiological treatment.


Most epidemiological data do not distinguish AA amylose from AL amyloidosis. Many are biased because they were obtained from autopsies, or from specialized centers. An estimate of the annual incidence, based on mortality data, is 4.5 per million per year. In Holland, the incidence of generalized amyloidosis (AA and AL) based on death certificates would be 13.3 per million per year. The amylose AL / amylose AA ratio varies considerably from one study to another, directly depending on the recruitment of the centers where these studies took place. centers of inflammatory diseases recruiting more AA amyloses and hematology centers more AL amyloidosis. A prospective French study in Franche-Comté suggests that the annual incidence of AA amyloidosis is rock of that of AL amyloidosis (Nadine Magy, personal communication).

Etiology: Chronic inflammatory diseases have replaced infections

Rheumatoid arthritis is now the most common cause, followed by ankylosing spondylitis, juvenile chronic arthritis, inflammatory bowel disease and familial Mediterranean fever, to which other hereditary diseases of inflammation can be linked. Pulmonary infections and bronchiectasis to which cystic fibrosis can be linked remain the most common infectious causes of tuberculosis. Human immunodeficiency virus infection is a rare cause of AA amyloidosis.

Among the tumors, kidney cancer, hepatoma and lymphomas are the most frequent causes. Castleman’s disease is one of the most recently recognized causes and deserves to be sought before AA amyloidosis without obvious cause, because the removal of the tumor allows in some cases a regression of the clinical kidney disease. In some patients, AA amyloidosis may be considered as the result of a combination of several inflammatory diseases, for example, when tuberculosis complicates rheumatoid arthritis.

The prevalence of AA amyloidosis varies with the modes of diagnosis: autopsy, digestive biopsy, renal biopsy, aspiration of the subcutaneous fat of the abdomen for the most part, but also depending on the presence of clinical signs and the nature of the underlying disease. The prevalence of AA amyloidosis in rheumatoid arthritis ranges from 3% to 23%. In ankylosing spondylitis, the prevalence of amyloidosis in patients is around 5%.

Clinical aspects:

Preclinical phase:

There is a so-called “preclinical” or “lag-phase” phase, during which amyloid deposits form, without clinical repercussion. This phase was observed in experimental amyloid AA models. In humans, it is known that in certain subjects, the clinical phase is never reached, the deposits being discovered only at autopsy. The existence of this preclinical phase is shown by two types of data, histological and scintigraphic. Thus, in patients with rheumatoid arthritis, subcutaneous aspiration puncture of the abdomen can detect amyloid deposits which remain asymptomatic in 75% of them with a 7-year follow-up. On the other hand, amyloid P-scintigraphy, which marks the amyloid deposits of multisystemic amyloidosis, reveals splenic, hepatic and renal deposition before the onset of clinical signs and biochemical or hematological abnormalities. This preclinical phase takes place over several years and the median duration of the course of the inflammatory disease preceding the onset of clinical signs is 15 to 18 years.


This preclinical phase is followed by a clinical phase, the main sign of which is proteinuria, which reflects renal involvement, which is essentially glomerular. Amyloid nephropathy should be detected by the search for proteinuria during any chronic inflammatory disease, as diabetic nephropathy is detected by the search for microalbuminuria.

Amyloid nephropathy evolves naturally towards nephrotic syndrome and chronic renal failure, within 2 to 10 years. It can be complicated by venous thrombosis, especially renal veins, acute renal failure, and nephrotic syndrome can persist with advanced renal insufficiency, with an increased risk of protein loss and undernutrition. More rarely, renal involvement is manifested by the appearance of renal insufficiency without proteinuria, in relation to the vascular predominance of amyloid deposits.

Impairment of other organs:

The digestive manifestations are varied: abdominal pain, chronic diarrhea, nausea, vomiting, malabsorption can be disabling. Spleen involvement is early, as shown by experimental data and P-component scintigraphy, but most often without splenomegaly or clinical consequences. The haematological signs of hypersplenism are unusual in AA amyloidosis. Liver involvement is later and results in hepatomegaly with cholestasis, usually without clinical consequences. Infiltrative heart disease is rare in AA amyloidosis (less than 10%) and is mainly found in patients with prolonged disease in patients treated for end-stage renal disease. Thyroid deposits can form a goiter with sometimes hypothyroidism. Adrenal gland involvement may be accompanied by adrenal insufficiency and should be investigated.

Diagnostic :

Diagnosis of amyloidosis:

The histological evidence for AA amyloidosis can be obtained by rectal biopsy, aspiration of subcutaneous fat, gastric biopsy, accessory salivary gland biopsy, or by a directed, usually renal, biopsy, which is positive in 90% of cases. The salivary gland biopsy simple labial accessories has less risk of haemorrhage than rectal biopsy, and provides a material easier to analyze routinely than suction of subcutaneous fat. It became the first-line examination for the diagnosis of the three major forms of generalized amyloidosis, AA, AL and ATTR.

The Congo coloration of amyloid deposits and their specific appearance (yellowish-green dichroism) in polarized light remains the most widely used.

Diagnosis of amyloidosis AA:

The diagnosis of AA amyloidosis is discussed in the presence of an amyloidosis affecting certain organs – kidney, gastrointestinal tract, liver, spleen, thyroid – and associated with an inflammatory disease likely to cause this complication and which has generally been known for a long time. It is then necessary to prove that the amyloid deposits are formed of AA protein. Treatment of tissues with potassium permanganate (KMnO 4 ) prior to Congo red staining has been widely used to distinguish AL amylose (resistant to permanganate) from AA (sensitive) amylose.This test does not always make it possible to distinguish these two types of amylose, in particular of thick amyloid AA deposits, can partially persist after impregnation with permanganate. Immunohistochemistry is now the best way to classify various types of amyloidosis. The use of specific antibodies improves techniques and simplifies recognition of different biochemical varieties of amylose. AA amyloid deposits are thus specifically recognized by antibodies specific to AA protein and are not recognized by antibodies directed against other amyloid proteins, the first of which is the immunoglobulin light chains.

The diagnosis is sometimes delicate:

In many situations the diagnosis can be difficult or difficult in various ways. We will discuss the main difficulties.

• Amylose is certain, the histology is in favor of AA type amyloidosis and there is a chronic inflammatory disease recognized for a long time with focal clinical signs, biochemical and hematologic signs characteristic of inflammation but without diagnosis etiology.

It is necessary to mention in particular certain genetic inflammatory diseases whose main complication remains the amylose. Not so much the familial Mediterranean fever (FMF, OMIM 249100), which is most often diagnosed because known, but rather one of the three other entities that are close to it: the intermittent fever related to the tumor necrosis factor 1A receptor type (TNFRSF1A for TNF receptor superfamily 1A), known as TRAPS (OMIM 142680), TNF receptor associated periodic syndrome, periodic fever syndrome with hyperimmunoglobulinemia D or hyperimmunoglobulinemia D periodic fever syndrome (HIDS, OMIM 260920), and Muckle-Wells syndrome 191900) and its variants: cold family urticaria cold urticaria (FCU), called familial cold autoinflammatory syndrome (FCAS, OMIM 120100) and CINCA (chronic infantile neurological cutaneous and articular syndrome, OMIM 607115).

Another difficult situation may arise when AA amylosis is highly probable due to clinical and histological data but there is no history of inflammatory disease in the long term. It is necessary to look for a disease of Castleman or a malignant tumor, a disease of Hodgkin, even some benign tumors.

The diagnosis of idiopathic AA amyloidosis should be made only after all possible causes, or at least treatable, of AA amyloidosis have been eliminated and other amyloidosis should be investigated. In the first place AL amyloidosis, as it affects in some cases only the organs affected by AA amylosis. Diagnosis should be made if there is an immunoglobulin or circulating monoclonal light chains in the blood and urine. The development of the dosage

serum monoclonal light chains now makes it possible to detect a monoclonal component circulating in virtually all cases of AL amyloidosis. In the absence of an argument for AL amyloidosis, hereditary amyloidosis with predominant renal presentation should be evoked. Diagnosis is based on the family survey – in the knowledge that many cases occur in isolation – on clinical signs, on the precise topography of renal involvement, and on the immunohistochemical study of antibody deposits amyloid proteins involved in these varieties and on the search for mutations.

In the absence of a definitive conclusion after all these steps, the direct determination of the amyloid protein present in the deposits by proteomic techniques can be proposed.


The amyloid AA protein, present in amyloid deposits, is derived from a serum precursor, the SAA protein. It is an apolipoprotein associated with high density lipids which belongs to the family of proteins of inflammation, during which its serum concentration is multiplied by 100 to 1000, under the influence mainly of interleukin (IL) 6 IL1 and TNF.Chronic elevation of serum SAA is the major factor contributing to the formation of amyloidosis in chronic inflammatory diseases. However, all patients who have a chronic inflammatory disease and a prolonged increase in serum SAA do not develop amyloidosis. There are therefore additional genetic and environmental factors that favor this complication.

Among the modifying genes that could influence the risk of amyloidosis are the genes encoding the SAA (serum amyloid A) proteins. There are two genes encoding these proteins and several polymorphic variants (characterized by different protein sequences) circulate in the blood of the same individual. A British study of patients with rheumatoid arthritis or chronic juvenile polyarthritis – two multifactorial disorders with a genetic component and characterized by chronic inflammatory syndrome – has shown that homozygous SAA1.1 genotype is more common in patients with amyloidosis secondary than in those who do not have this complication.

Similarly, in FMF patients belonging to different populations, homozygosity for the SAA1.1 variant significantly increases the risk of amyloidosis compared to other genotypes at the SAA1 locus. As often, the respective influence of the different alleles varies according to the population. Thus, in the Japanese population of patients with rheumatoid arthritis, the risk of developing amyloidosis is associated with homozygous SAA1.3 genotype.

Moreover, a polymorphism of the promoter region of the SAA1 gene (T in position -13) is also associated with the risk of developing amylosis in Japanese patients with rheumatoid arthritis. This polymorphism could influence the level of transcription of the SAA1 gene. Thus, while it is well established that the region of the SAA1 gene plays a major role in the susceptibility to developing amyloidosis, the precise mechanism responsible for this increased susceptibility remains to be elucidated.


Treatment of inflammation:

The treatment of AA amyloidosis includes several aspects and steps. The eradication of infectious diseases, such as tuberculosis and leprosy, is a “preventive” treatment for AA amyloidosis. Although eradication of chronic inflammatory diseases can not be discussed at present, the use of more potent anti-inflammatory treatments for several years has certainly contributed to the decrease in the incidence of amyloidosis in these diseases. The FMF is a case in point as spectacular as it is established that the long-term treatment of this disease by colchicine prevents both inflammatory attacks and amylosis. Treatment with colchicine can still remove the clinical signs of renal involvement, even when there is a nephrotic syndrome. A dose of 1 mg / d is often sufficient to prevent access, but higher doses are sometimes necessary (up to 2.5 mg / d). It is currently impossible to determine for each individual the dose needed to prevent amyloidosis. Regular measurement of serum AAS concentration could help determine the dose of colchicine needed to control inflammation and better prevent amyloidosis.

Once the amyloidosis is established, treatment of the underlying disease remains essential.

A reduction in the availability of amyloid precursor is currently the most logical therapeutic approach for all forms of amylose with the theoretical objective of stopping the progression of the deposits. In the case of AA amyloidosis, this concept should lead to lowering as much as possible the serum level of SAA protein, or C-reactive protein when SAA dosage is not available, which is the case in France .

Thus, in case of infectious disease, an adapted antibiotic or anti-tuberculosis treatment must be started. When amyloidosis is associated with a tumor, effective treatment of the tumor can lead to regression of the deposits.

The most frequent situation is that of amyloidosis complicating a chronic inflammatory disease. In these diseases, amyloidosis must be combated by strengthening the treatment of inflammatory disease, as the development appears to be directly related to the control of inflammation and serum concentration of the SAA protein. However, data on the efficacy of different medications that are most effective in treating inflammatory amyloidosis remain modest.

The value of chlorambucil treatment appears to be established in the amyloidosis of juvenile chronic arthritis, but the leukemogenic risk should be taken into account. There is little data available in rheumatoid arthritis, which remains the leading cause of AA amyloidosis in developed countries in all recent series. Several studies suggest the value of chlorambucil and cyclophosphamide in this indication.

New treatments have transformed the management of several chronic inflammatory diseases: TNF inhibitors. At present, there are only a few studies that report isolated cases or short series of patients with amyloidosis complicating chronic inflammatory diseases treated with etanercept and / or infliximab, often associated with other immunosuppressive drugs. The responses are always evaluated in the short term, and relate mainly to markers of kidney damage, proteinuria and renal insufficiency. The results can be considered encouraging, always spectacular in isolated cases, much less convincing in the even short series, where some patients do not respond to treatment.

These rather favorable results are to be weighed against serious side effects, especially infections. No work compares an immunosuppressive drug (cyclophosphamide or chlorambucil) to an anti-TNF drug for the treatment of AA amyloidosis.

It should be added that in all patients with chronic inflammatory disease, especially those with amyloidosis, active treatment of infections is necessary. Particular care should be taken during surgery and postoperative periods. Renal amyloidosis in particular may be suddenly worsened during this period, mainly for haemodynamic reasons.

Underlying, undiagnosed amyloidosis may also be revealed in this context.

Supplementary treatment:

This is basically the treatment of terminal renal insufficiency. Renal transplantation is not contraindicated in cases of AA amyloidosis and exposes to less complications than chronic hemodialysis.

In all cases, patients with AA amyloidosis are fragile, and all episodes of inflammation must be combated because they expose to an acceleration of the formation of deposits. Particular vigilance must be maintained during the postoperative period, when several factors combine (hypovolemia, decreased renal perfusion, inflammation) to sometimes aggravate the renal state permanently.

Upcoming treatments:

Specific anti-amyloid molecules are being tested.

They target glycoproteins which are involved in in vivo amylogenesis: proteoglycans and the amyloid component P.


AA amyloidosis is a serious complication of chronic inflammation, the incidence of which has diminished due to the scarcity of certain chronic infectious diseases and the earlier and more potent treatment of chronic inflammatory diseases. Once installed, its prognosis remains worrying. Therapeutic advances are needed, especially the development of targeted drugs on the intimate phases of amylogenesis.