Amyloidosis amyloid deposits

The term amyloidosis is associated with a heterogeneous group of protein-folding disorders. These diseases, like type 2 diabetes and Alzheimer s disease, are characterized by the presence of macroscopic abnormalities, amyloid deposits, in one or more organs of the patients. The proteins or protein fragments accumulated in these deposits belong to three main... 

ApoSAA, normally a trace component of plasma, is an acute-phase plasma protein, that is, one that is elevated in a variety of disease states (R18). Its identification is interesting. A small protein of 76 residues, now called protein AA, was identified during the study of the proteins present in extracellular amyloid deposits in the type of amyloidosis particularly associated with inflammation (B24, H36, Lll, S38), Antibodies to protein AA reacted with two AA-related proteins in plasma, one of approximate Mr 180,000 (SAA) and the other found in HDL of Mr 14,000-15,000 or 12,000 (apoSAA) (A19, B25, B26, L12, L15). The N-terminal 76-amino-acid portion of apoSAA is identical to that of amyloid protein AA (E8). Human apoSAA has now been sequenced and has been shown to consist of 104 amino acid residues (B27). Further studies in man have demonstrated microheterogeneity in apoSAA (B18, B19, M30) and Benditt et al. describe specific amino acid substitutions (B27, P6). Shore et al. have described a second similar threonine-poor apolipoprotein, apparently a dimer of Mr 40,000... 

L13. Lofberg, H., Grubb, A. O., Nilsson, E. K., Jensson, O., Gudmundsson, G., et al., Immunohis-tochemical characterization of the amyloid deposits and quantitation of pertinent cerebrospinal fluid proteins in hereditary cerebral hemorrhage with amyloidosis. Stroke 18(2), 431-440 (1987). 

The formation of this insoluble variety of protein, resistant to normal proteolysis due to its P-conformation, is the one characteristic common to aU types of amyloid, whatever their composition. Amyloid fibrils may have multiple soluble plasma protein precursors that are either increased in quantity or modified by proteolysis to make them insoluble. The result is a disease group with diverse etiologies, called amyloidosis. The deposits can be local or systemic. They exert pressure on vital structures and eventually cause death. No details are known about the local mechanism of formation of these deposits or the determinant for the site of deposition. 

Senile Amyloidosis. Senile amyloid protein is found most often in the heart (senile cardiac amyloid), but also in the pancreas and brain. There seems to be an independent pathogenesis for these three forms. Nodular or infiltrative amyloid deposits may also be seen in the skin, lungs, and trachea and may involve endocrine organs such as the pancreas (in long-standing diabetes) or the thyroid (in medullary carcinoma). These forms usually are asymptomatic, except for the cardiac form. 

When tested, the amyloid is of the secondary type, amyloid A protein. Serum amyloid A, an acute phase reactant produced by hepatocy tes, circulates complexes to high density lipoprotein and is cleaved into smaller fragments which subsequently polymerize into the P pleated sheet configuration of amyloid [23, 35]. In heroin related amyloidosis, the amyloid is heavily distributed in the tubular basement membranes, vessel walls, and interstitium as well as the glomeruli. There is greater tubular basement membrane and interstitial amyloid deposition in drug related renal amyloid than in secondary renal amyloid unrelated to heroin abuse... 

In AL amyloidosis, amyloid is formed from degradation products of the X or k light chains that deposit most frequently in the extracellular matrix of the kidney and the heart but also may deposit in the tongue. In other types of amyloidosis, the amyloid arises from other proteins and deposits in a characteristic organ. For example, the amyloid associated with chronic inflammatory conditions, such as tuberculosis or rheumatoid arthritis, is derived from an acute phase serum protein called serum amyloid Athat is produced by the liver in response to inflammation. It deposits most frequently in the kidney, and cardiac involvement is rare. 

Bergstrom J, Mur[4iy CL, Weiss DT, Solomon A, Sletten K, Heilman U, Westermark P (2004) Two different types of amyloid deposits— apolipoprotein A-IV and transthyretin— in a patient with systemic amyloidosis. Lab Invest 84 981-988... 

The nature of the protein, or more precisely, proteins associated with amyloidosis has been the subject of many investigations and considerable controversy. A number of factors are responsible for the difficulties encountered. One is the insolubility of amyloid in neutral salt solution the protein can ordinarily be solubilized only by methods which lead to at least partial denaturation. Another problem is contamination of the fibrillar amyloid deposits in extracellular compartments by various substances, including serum proteins. Attempts to identify amyloid by immunofluorescent methods have therefore yielded contradictory results. Serum immunoglobulin, complement, etc., have been associated with amyloid by various investigators. 

Levin et al. were unable to find any amyloid of nonimmunoglobulin nature in the deposits of three patients with multiple myeloma or mac-roglobulinemia. However, the converse was not true, since some material related to L chain was found in patients with secondary amyloidosis, whose deposits were mainly nonimmunoglobulin in nature. This immunoglobulin-like material appeared heterogeneous, in contrast to that seen in myeloma patients. Relatively few individuals with secondary amyloidosis have been examined at this writing for the presence of amyloid related to immunoglobulin. 

Among the 29 case reports over the past 30 years (17-19), 19 cases provide sufficient data to establish the diagnosis of AL amyloidosis. Pleural biopsies documented amyloid deposits in 13 (68%) of these cases. Although 16 of 19 cases (84%) had concomitant congestive heart failure (CHF), 56% expressed exudative pleural fluid chemistries, suggesting disruption of pleural membrane mechanics. 

Taken together, these data indicate that left ventricular dysfunction and elevated cardiac filling pressures, hypothyroidism, and nephrotic syndrome/ hypoalbuminemia may all contribute but are not sufficient for the formation and maintenance of large persistent pleural effusion in AL amyloidosis. The incidence of exudative chemistries and the presence of amyloid deposits on pleural biopsies suggest that amyloid infiltrates and disrupts pleural mechanics, inducing fluid secretion and impairing parietal membrane drainage from the pleural space. 

The literature includes eight case reports of pulmonary hypertension in AL amyloidosis attributed to pulmonary vascular amyloid deposition (Table 2). Autopsies confirmed pulmonary artery amyloid deposits in four out of four cases. The prevalence of restrictive cardiomyopathy and diastolic dysfunction in AL patients predisposes them to secondary forms of pulmonary vascular disease. Direct measurements of pulmonary artery pressures (PAP) were obtained in five cases (3 pulmonary arteriograms, 2 right heart catheterizations) however, only two reports include direct measures of left atrial filling pressures. Echocardio-graphic estimates of elevated right ventricular systolic pressures and normal diastolic function were reported in all cases. 

An autopsy series of 15 individuals with AL amyloidosis or multiple myeloma/AL amyloid found mild-to-severe pulmonary vessel amyloid deposition in >90% of cases (13). The ubiquity of pulmonary vascular amyloid in AL patients is in stark contrast to the small number of clinically recognized cases of amyloid-mediated pulmonary hypertension. It appears, therefore, pulmonary vascular amyloid deposition is required, but not sufficient, for inducing pulmonary hypertension in AL patients. 

Pathology series confirm the clinical scarcity of lung disease in AA amyloidosis. Celli et al. (13) reported autopsy findings in seven patients with AA amyloid, none of who had signs or symptoms of lung disease. Amyloid deposits were identified in only three out of seven cases, limited to either lung vessels or airway walls. No interstitial amyloid was detected. An 88-year autopsy experience at Johns Hopkins included 113 cases of A A amyloid, with interstitial disease in one case (14). 

Four cases of pleural effusion and biopsy-proven pleural amyloid infiltration in patients with AA amyloidosis have been reported in the past 30 years (17-19). Three cases occurred in patients with long-standing rheumatoid arthritis and the remaining patient had cystic fibrosis. No amyloid-related pleural effusions have been reported in FMF. The rarity of pleural effusions in AA amyloidosis is further evidenced by the absence of pleural disease at autopsy in 113 A A patients (14), a registry of 287 Turkish AA patients (36), or autopsies of 7 patients— despite bronchial waU or pulmonary vessel amyloid deposition in over 70% (13). 

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