AA amyloidosis (ORPHA:85445)
A rare amyloidosis that complicates chronic inflammatory disorders and is characterized by the aggregation and deposition of amyloid fibrils composed of serum amyloid A protein, an acute phase reactant. The kidney is involved in virtually all patients and dominates the clinical picture. Other frequently involved sites are the liver, the spleen, suprarenal gland, gut and less frequently the heart.
Epidemiology
The exact prevalence is not known. AA amyloidosis occurs in less than 5% of patients with chronic inflammatory disorders. The disease is more frequent in certain countries like Finland, Japan, Turkey and the Middle East.
Clinical description
The predominant feature of AA amyloidosis at diagnosis is renal dysfunction, proteinuria and nephrotic syndrome. AA amyloidosis complicates chronic inflammatory disorders and is typically preceded by many years of active inflammatory disease. These may include chronic inflammatory arthritis, (rheumatoid arthritis, juvenile idiopathic arthritis), chronic infections (bronchiectasis, osteomyelitis, tuberculosis), auto-inflammatory diseases (familial mediterranean fever (FMF), TRAPS syndrome), Crohn's disease and less commonly Castleman's disease, Schnitzler syndrome, vasculitis or neoplasias (lymphoma, mesothelioma). In almost 25% of cases with AA, the cause of inflammation remains unclear (idiopathic AA amyloidosis) and it has been proposed that obesity may have a role in these cases. In the last decades, the progressive improvement of treatment for rheumatic diseases has reduced the number of cases driven by inflammatory arthritis and, in parallel, increased the number of patients with an underlying chronic infectious disease or idiopathic AA amyloidosis.
Etiology
Chronic inflammatory disorders are associated with elevated levels of the acute-phase reactant, serum amyloid A protein (SAA) protein. AA amyloid fibrils are derived from SAA through a process of cleavage, misfolding, and aggregation. Amyloid fibrils associate with other moieties, including glycosaminoglycans and serum amyloid P component (SAP), forming deposits that disrupt structure and function of tissues and organs.
Diagnostic methods
Diagnosis of AA amyloidosis requires the demonstration of amyloid deposits on tissue biopsy revealed by Congo red staining on light microscopy and apple green birefringence on polarized light microscopy and amyloid typing by light microscopy, immunoelectron microscopy or proteomic analysis. Amyloidosis is suspected when signs of renal dysfunction (renal failure and proteinuria) are noted in the background of a chronic inflammatory disease with persistent elevated SAA concentration.
Differential diagnosis
Differential diagnoses include AL amyloidosis, familial renal amyloidosis and other causes of renal dysfunction like membranous glomerulonephritis and renal vein thrombosis.
Management and treatment
Treatment of AA amyloidosis relies on treating the underlying inflammatory disease (antimicrobial therapy in chronic infections, colchicine in FMF, immunosuppressive agents in chronic arthritis). The aim of therapy is the reduction of SAA concentration (ideally <10 mg/L) in order to minimize the risk of disease progression and possibly to reverse organ dysfunction. Successful treatment of the underlying inflammatory disorders reduces SAA concentrations. In patients with end stage renal disease and controlled underlying disease, renal transplantation could be considered as a valuable treatment option.
Prognosis
Factors associated with a poor prognosis are older age, a reduced serum albumin concentration, end-stage renal failure at baseline, and the degree by which the SAA concentration is elevated during follow-up. Patients with underlying chronic infectious diseases have a worse outcome. Twenty-four hour proteinuria and estimated glomerular filtration rate (eGFR) can identify patients with higher risk of end-stage renal failure at diagnosis.

                            Last update: 
                            September 2021


                            - Expert reviewer(s): 
                            Pr Giovanni PALLADINI | EuroBloodNet*


                                * European Reference Network