Etiology

Amyloid material is composed of microscopic fibrils that are biochemically heterogeneous, with at least 20 different types of protein fibril composition. All amyloid deposits contain the same nonfibrillar component, serum amyloid P. Amyloid fibril deposition may have no apparent consequences or may ultimately interfere with organ function.

The traditional amyloidosis classification system uses the descriptive terms systemic and localized, which do not designate the etiology or associated clinical manifestations. The systemic, or multisystem, amyloidoses correspond to clinical patterns of primary, secondary, familial, and dialysis-related amyloidosis. The localized, or organ-limited, amyloidoses are associated with aging and diabetes and occur in isolated organs such as endocrine glands, without systemic involvement. The newer nomenclature for amyloidoses is based on biochemical analysis and uses A for amyloid followed by the abbreviation for the type of fibril protein. The most common type of amyloidosis in the USA has deposition of amyloid composed of pieces of monoclonal immunoglobulin light-chain (abbreviated as L) and is referred to as AL amyloidosis (formerly known as idiopathic amyloidosis or myeloma-associated amyloidosis). Amyloidosis in patients with the hereditary periodic fever syndromes (including familial Mediterranean fever [FMF], tumor necrosis factor receptor–associated periodic syndrome [TRAPS], CAPS, and hyperimmunoglobulinemia D syndrome [HIDS]), other autoinflammatory disorders, chronic infection, and chronic inflammatory diseases involving amyloid A protein is referred to as AA amyloidosis (formerly referred to as secondary or reactive amyloidosis). AA amyloidosis is the most common serious complication of FMF and TRAPS (Chapter 157). Amyloid conditions associated with aging (Alzheimer disease) as well as several rare autosomal dominant forms of amyloidoses have fibril protein composed of variants of the transport protein transthyretin (TTR) and are now referred to as TTR amyloidosis.

Epidemiology

AL amyloidosis is extremely rare in children, usually occurring in middle-aged or older individuals. It represents a plasma cell dyscrasia and can occur in isolation or along with multiple myeloma.

Only AA amyloidosis affects children in appreciable numbers, occurring in some individuals with hereditary periodic fever syndromes, chronic inflammatory diseases (such as juvenile idiopathic arthritis, ankylosing spondylitis, and inflammatory bowel disease), chronic infections (such as chronic osteomyelitis and tuberculosis), cystic fibrosis, and, less commonly, systemic lupus erythematosus and juvenile dermatomyositis. The factors that determine the risk for amyloidosis as a complication of inflammation are not clear, because many individuals with long-standing inflammatory disease do not demonstrate tissue amyloid deposition. AA amyloidosis affects approximately 10% of children with juvenile idiopathic arthritis in some European countries but is rarely seen as a complication of this condition in children in the USA and Canada. Additionally, Armenians with FMF living in Armenia are reported to have a significantly higher incidence of amyloidosis than their Armenian counterparts in North America. There is also ethnic variability in the frequency of amyloidosis, which occurs in up to 60% of Turks, 27% of Sephardic Jews, and 1-2% of Armenians with FMF living in the USA. Reasons for these differences are still unknown, although environmental and genetic factors in addition to the underlying inflammatory disease appear to have a role.

Pathogenesis

The AA protein isolated from AA amyloidosis is the 76–amino acid N-terminus fragment of serum amyloid A (SAA). SAA, a polymorphic protein synthesized in the liver, is an acute-phase reactant. Chronic inflammation results in elevation of SAA, which is the precursor to the fibril formation of AA amyloidosis. Three protein isoforms of SAA exist. SAA1 is the precursor of AA amyloidosis in the majority of cases and has 5 variants that differ from one another by amino acid substitutions. SAA is an apolipoprotein of high-density lipoprotein that is synthesized by hepatocytes under the transcriptional regulation of proinflammatory cytokines. Sustained overproduction of SAA (as occurs in autoinflammatory and chronic inflammatory diseases) is the major factor in the development of AA amyloidosis. Other factors, such as the environment, may also play a role. SAA protein undergoes a process of cleavage, misfolding, and aggregation and forms highly ordered abnormal β-sheets known as fibrils. AA amyloid fibrils associate with other fibrils such as aminoglycans and serum amyloid P forming deposits that disrupt the normal structure and function of tissues and organs.

The factors responsible for determining the site of amyloid deposition in any form of amyloidosis are unknown. Although the spleen, adrenals, liver, and gastrointestinal tract are frequent sites, renal involvement dominates the clinical course, causing the highest morbidity and mortality. AA amyloidosis fibrils have been generated in tissue culture through incubation of SAA with macrophages, possibly explaining amyloid depositions in tissues such as the liver and spleen. The increased deposition in the kidneys is related to a different mechanism, possibly the glyco-oxidative modification of the AA protein itself.

Clinical Manifestations

Different patterns of organ dysfunction result from deposition of different types of amyloid fibril protein material. Regardless of the cause of amyloidosis, clinical symptoms usually begin 10 yr after the onset of inflammatory disease. The diagnosis is not usually established until the disease is far advanced. The most common clinical presentation of AA amyloidosis is renal dysfunction, ranging from proteinuria to nephrotic syndrome and eventual renal failure. Involvement of the gastrointestinal system is also frequent and usually manifests as chronic diarrhea, gastrointestinal bleeding, abdominal pain, and malabsorption. Anemia, hepatomegaly, and splenomegaly may also be present.

Diagnosis

The diagnosis of amyloidosis is established by biopsy demonstrating amyloid fibril proteins in affected tissues. In the presence of amyloidosis, renal biopsies are contraindicated because of potential bleeding. The liver and spleen are often affected but are not suitable sites for biopsy either. Biopsy sites that are more accessible include the rectal mucosa, gingival tissue, and abdominal fat. A method of microradiographic scintigraphy using serum amyloid P component has been described as a useful tool for the diagnosis as well as for the monitoring of the status of amyloidosis. Amyloid deposits are composed of seemingly homogeneous eosinophilic material that stains with Congo red dye and demonstrates the pathognomonic apple-green birefringence in polarized light. Binding of thioflavine T to amyloid deposits produces an intense green-yellow fluorescence. Amyloid can also be recognized with routine hematoxylin and eosin (H&E) staining and electron microscopy.

Laboratory Findings

Patients with AA amyloidosis usually show elevated acute-phase reactants and high levels of immunoglobulins. Specific laboratory testing is possible only for AL amyloidosis, and most patients with this form of amyloidosis show increased plasma cells in the bone marrow and serum or urine monoclonal immunoglobulin (Ig) or free light chain. A biopsy showing amyloid deposition along with a monoclonal serum protein distinguishes AL amyloidosis from monoclonal gammopathy of uncertain significance (MGUS), which is common in older adults.

Treatment

The primary means of treatment of AA amyloidosis is aggressive management of the underlying inflammatory or infectious disease, which decreases levels of SAA protein. Colchicine is effective not only in controlling the attacks of FMF but also in preventing the development of amyloidosis associated with FMF. Children with FMF who are homozygous for the M694V mutation in the MEFV gene are at greater risk for development of amyloidosis and should receive colchicine for life.

Unlike AA amyloidosis associated with FMF, AA amyloidosis associated with other autoinflammatory conditions (including TRAPS, CPAPS, and HIDS) and chronic inflammatory conditions (juvenile idiopathic arthritis, rheumatoid arthritis, and ankylosing spondylitis) does not respond to colchicine. AA amyloidosis associated with juvenile idiopathic arthritis does respond to chlorambucil, which reverses renal findings and prolongs the life of treated patients. Chlorambucil is associated with chromosome breakage and an unknown risk of subsequent malignancy. There is little experience with other cytotoxic agents or with the therapy for AA amyloidosis associated with other conditions. Pulse cyclophosphamide therapy was shown to improve survival in patients with rheumatoid arthritis–associated AA amyloidosis. Increasing use of biologic medicines against proinflammatory cytokines to treat rheumatoid arthritis, juvenile idiopathic arthritis, and spondyloarthropathies seems to impact risk factors for the development of AA amyloidosis. Anti–tumor necrosis factor-α (TNF-α) therapy with etanercept or infliximab is well tolerated and effective in reducing proteinuria in patients with AA amyloidosis associated with colchicine resistant FMF, TRAPS, and chronic inflammatory arthritides. Cryopyrin-associated periodic syndromes (CAPSs) (Muckle-Wells syndrome [MWS], familial cold urticaria [FCU], familial cold autoinflammatory syndrome [FCAS]) and chronic infantile neurologic cutaneous and articular (CINCA) syndrome, also known as neonatal-onset multisystem inflammatory disease (NOMID), appear to respond to anakinra (IL-1 receptor antagonist). Dramatic resolution of amyloid depositions was seen via serum amyloid scintigraphy in patients with periodic fever syndromes and AA amyloidosis responding to biologic therapy. Tocilizumab, an anti–IL-6 receptor antibody, has been shown to attenuate experimental AA amyloid and to reverse AA amyloidosis complicating juvenile idiopathic arthritis. Drugs that specifically prevent fibril development are in development.

Complications and Prognosis

End-stage renal failure is the underlying cause of death in 40-60% of patients with amyloidosis, with a median survival time from diagnosis of 2-10 yr. According to a large-scale study of 374 patients with AA amyloidosis, the factors associated with a poor prognosis include older age, a lower albumin serum level, end-stage renal disease at baseline, and prolonged serum elevation of SAA. An elevated SAA value was the most powerful risk factor for end-stage renal disease and death from AA amyloidosis.

Prevention

The primary means of preventing AA amyloidosis is treatment of the underlying inflammatory or infectious disease, resulting in decreases in the level of SAA protein and the risk of amyloid deposition. Although the period of latency between the onset of inflammation (of the underlying disease) and the initial clinical signs of AA amyloidosis may vary and is often prolonged, progression of the amyloid depositions can be rapid.