PRODUCTION OF NORMAL AMOUNTS OF MUTANT PROTEIN (e.g., transthyretin)
Fig. 5.42 Pathogenesisofamyloidosis.(A)Generalmechanismofformationofamyloidfibrils.(B)Formationofamyloidfromexcessiveproductionofproteins pronetomisfolding.(C)Formationofamyloidfrommutantprotein.
modest increase in the number of plasma cells in the bone marrow, which presumably secrete the precursors of AL protein.
Reactive Systemic Amyloidosis. The amyloid deposits in this pattern are systemic in distribution and are composed of AA protein. This category was previously referred to as secondary amyloidosis because it is secondary to an
Table 5.16 Classification of Amyloidosis associated inflammatory condition. At one time, tuberculosis, bronchiectasis, and chronic osteomyelitis were the most important underlying conditions, but currently, these conditions frequently resolve with antibiotic treatment and less often lead to amyloidosis. More commonly now, reactive systemic amyloidosis complicates rheumatoid arthritis, other connective tissue disorders such as ankylosing spondylitis, and inflammatory bowel disease, particularly
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Crohn disease and ulcerative colitis. Among these, the most frequent associated condition is rheumatoid arthritis. Amyloidosis is reported to occur in approximately 3% of patients with rheumatoid arthritis and is clinically significant in one half of those affected. Heroin abusers who inject the drug subcutaneously also have a high occurrence rate of generalized AA amyloidosis. The chronic skin infections, which cause the “skin-popping” associated with injection of narcotics, seem to be responsible for the amyloidosis. Reactive systemic amyloidosis also may occur in association with certain cancers, the most common being renal cell carcinoma and Hodgkin lymphoma.
In AA amyloidosis, SAA synthesis by liver cells is stimulated by cytokines such as IL-6 and IL-1 that are produced during inflammation; thus, long-standing inflammation leads to a sustained elevation of SAA levels. While SAA levels are increased in all cases of inflammation, only a small subset get amyloidosis. It seems that in some patients SAA breakdown produces intermediates that are prone to forming fibrils.
Heredofamilial Amyloidosis. A variety of familial forms of amyloidosis have been described. Most are rare and occur in limited geographic areas. The most common and best studied is an autosomal recessive condition called familial Mediterranean fever, which is encountered largely in individuals of Armenian, Sephardic Jewish, and Arabic origins. This is an “autoinflammatory” syndrome associated with excessive production of the cytokine IL-1 in response to inflammatory stimuli. It is characterized by attacks of fever accompanied by inflammation of serosal surfaces that manifests as peritonitis, pleuritis, and synovitis. The gene for familial Mediterranean fever encodes a protein called pyrin that is important in dampening the response of innate immune cells, particularly neutrophils, to inflammatory mediators. The amyloid seen in this disorder is of the AA type, suggesting that it is related to the recurrent bouts of inflammation.