Splenic amyloidosis: correlations between chemical types of amyloid protein and morphological features

Sixty-one autopsy cases of splenic amyloidosis were reviewed to assess the relationship between the morphological patterns and chemical types of amyloid protein. On the basis of immunohistochemical reactions of amyloid protein, the cases were classified into 34 cases of AA and 27 of AL amyloidosis. Amyloid deposition in the spleen was divided into three major sites: the red pulp, the white pulp, and blood vessels. Red pulp involvement by amyloid was noted in 52% of the AL cases but in none of the AA cases. White pulp amyloid deposition was found in 70% of the AL and 35% of the AA cases. This difference was statistically significant (P less than 0.001). On the other hand, vascular deposition of amyloid was invariably noted in all cases with AA or AL amyloidosis, affecting the AA cases rather severely. These results strongly suggest that the widely held concept of deposition of amyloid as predominantly vascular in AL amyloidosis and parenchymal in AA amyloidosis requires revision. Our findings indicate that parenchymal, especially the red pulp, involvement is a consistent feature of AL amyloidosis, whereas vascular involvement is a finding common to both types of systemic amyloidosis.     

Hepatic amyloidosis: morphologic differences between systemic AL and AA types

The liver is almost universally involved in systemic amyloidosis. Patterns of topographic distribution of amyloid within the liver lobule have been recognized, but the reliability of using these for classification of amyloid type is in question. We examined 286 livers from cases of systemic amyloidosis obtained from autopsies at Los Angeles County-University of Southern California Medical Center, classifying them as AL or AA type by means of the potassium permanganate Congo red-staining method along with a specific anti-AA antiserum. Prior publications have asserted that deposition of secondary (AA) amyloidosis is limited to the vessels in the portal tract, constituting a "vascular" pattern, and that in primary (AL) amyloidosis the deposits exhibit a "sinusoidal" pattern in that they are seen along hepatic sinusoids as well as in portal vessels. We confirmed that AL amyloid involves the portal vessels as frequently as AA amyloid and that deposition occurred significantly more frequently in the portal stroma, the central vein, and the "sinusoidal" areas. However, we also found a "sinusoidal" pattern in 29 of 78 cases of secondary (AA) amyloidosis; in 14 of these, more than half of the sinusoidal spaces were replaced by amyloid deposits. We also noted that in 23 of the 29 AA amyloidosis cases with "sinusoidal" involvement, a "sago" pattern of distribution of amyloid in the spleen was present. No consistent association of a specific chronic inflammatory disease with "sago" spleen and "sinusoidal" deposits could be documented. We conclude that topographic distribution of amyloid within the liver lobule is not a reliable method of distinguishing AA from AL amyloidosis and that specific staining methods must be used if the physician is to be able to attempt modern therapeutic modalities.     

Hepatic amyloidosis. A histopathologic analysis of primary (AL) and secondary (AA) forms.

The liver is a major site of amyloid deposition. The spectrum of histopathologic changes in the liver was studied in 38 patients with systemic amyloidosis (25 with primary or myeloma-associated amyloidosis [AL] and 13 with secondary, reactive [AA] amyloidosis). Overall architectural distortion, alterations of portal triads, as well as predilection for topographic deposition in the parenchyma and/or blood vessel walls were noted. Significant histopathologic differences in AL or AA amyloid liver involvement included 1) portal fibrosis, seen in 7 of 25 (28%) AL patients and 8 of 13 (62%) AA patients (P = 0.05), 2) parenchymal amyloid deposition in 25 of 25 (100%) AL amyloid and 10 of 13 (77%) AA amyloid patients (P = 0.04), and 3) vascular amyloid deposition found in 17 of 25 (68%) with AL amyloid and 13 of 13 (100%) patients with AA amyloid (P = 0.02). These data vary from the widely held concept that deposition of amyloid is predominantly vascular in the AL form and parenchymal in amyloid AA. Clearly, however, in individual cases significant overlap occurred, and characterization of amyloid types based on morphologic distribution of amyloid deposits may be possible in only a minority of cases. In most cases, differentiation of amyloid AL and amyloid AA forms requires clinical, histochemical, immunochemical, and sometimes more elaborate laboratory amino acid sequence studies for accurate identification.     

Morphologic differences in the pattern of liver infiltration between systemic AL and AA amyloidosis

Biopsy and necropsy tissue from 31 unselected patients with systemic amyloidosis, in which there was histologic evidence of liver involvement, were reviewed with reference to the location and pattern of amyloid deposition in the liver. Amyloidosis was classified into AA and AL types on the basis of immunohistochemistry and permanganate reaction of the amyloid deposits. Nineteen were categorized as AA (secondary) and 12 as AL (primary) amyloidosis. Deposition of AA amyloid was limited to the walls of vessels in the portal tract, constituting a "vascular" pattern. In AL amyloidosis, the deposits exhibited a "sinusoidal" pattern in that they were seen along hepatic sinusoids as well as in vessel walls. This difference was statistically significant (P less than .001). The histologic pattern of liver infiltration offers a valuable clue in the classification of systemic amyloidosis and provides information that may be useful in the selection of patients for therapy.     

AA Amyloidosis Induced in Sheep Principally Affects the Gastrointestinal Tract

AA amyloidosis was initiated experimentally in adult sheep by induction of gangrenous pneumonia, an inflammatory process known to be associated with amyloid formation. A vegetable fragment contaminated with rumen content was instilled into the lungs of 4 experimental animals. A fifth animal was not inoculated and served as control. The animals were examined daily and blood and urine were sampled biweekly post-inoculation. One sheep was killed 18 days post-inoculation (dpi), another 49 dpi, and the remaining two (as well as the control animal) 63 dpi. Respiratory signs, diarrhoea and/or soft, unformed stool were observed in all inoculated sheep. All experimental animals developed gangrenous pneumonia with hypoalbuminaemia and hypergammaglobulinaemia, and elevated urinary protein, creatinine, gamma glutamyl transferase and ß-glucuronidase. Amyloid deposition was most pronounced in the gastrointestinal tract and was evident from 18 dpi. Amyloid was present from the tongue to the rectum, but was most prominent in the duodenum where the deposits disrupted the normal mucosal architecture. Other body organs had only mild amyloid deposition. Immunohistochemistry confirmed that the deposits were AA amyloid. These findings suggest that the gastrointestinal tract is the main target organ for AA amyloid deposition in sheep. The observations in this experimental model must now be confirmed in animals with spontaneously arising AA amyloidosis.     

Clinical and histological characteristics of renal AA amyloidosis: a retrospective study of 68 cases with a special interest to amyloid-associated inflammatory response

We retrospectively reviewed the clinicopathological features of a series of 68 renal AA amyloidosis observations collected between 1990 and 2005. The amyloidogenic disease was a chronic infection (40.8%), a chronic inflammation (38%), a tumor (9.9%), a hereditary disease (9.9%), or was undetermined in 1.4% of cases. Nephrotic syndrome and renal insufficiency were noted in 63.1% and 75% of patients, respectively. The distribution pattern of glomerular amyloid deposits was mesangial segmental (14.7%), mesangial nodular (26.5%), mesangiocapillary (32.3%), and hilar (26.5%). Glomerular form was observed in 80.9% of cases and vascular form in 19.1%. AA amyloidosis-related inflammation was noted in 30 patients (44.1%) and appeared as a multinucleated giant cell reaction (27.9%) or a glomerular inflammatory infiltrate (25%), including glomerular crescents (17.6%). At the end of follow-up, 26 patients (38.2%) showed end-stage renal disease. The clinical presentation of glomerular and vascular forms was distinct with a clear predominance of proteinuria in glomerular form. Inflammatory reaction was preferentially observed in biopsies with a codeposition of immunoglobulin chains and/or complement factors in AA amyloid deposits. The distribution pattern of glomerular amyloid deposits and glomerular inflammatory reaction were independent factors influencing proteinuria level. Tubular atrophy, abundance, and distribution pattern of glomerular amyloid deposits at the time of biopsy were independent predictors of renal outcome. In conclusion, the glomerular involvement appeared as the determining histological factor for clinical manifestations and outcome of renal AA amyloidosis. AA amyloidosis-related inflammation could partly result from an immune response directed against AA fibrils and could induce amyloid resolution and crescents.     

The pattern of amyloidosis in Malaysia

Congo red screening of routine biopsies at the University Hospital Kuala Lumpur revealed the following categories of amyloidosis: systemic AL (5.9%); systemic AA (3.2%); isolated atrial (14%); primary localized cutaneous (7.5%); other primary localized deposits (3.2%); localized intratumour (58%); and dystrophic (8.6%). Unlike in the West, AA amyloidosis in this population was usually secondary to leprosy or tuberculosis. Liver involvement in AL amyloidosis was shown to exhibit a sinusoidal pattern and differed from the vascular pattern of AA amyloidosis. Within the category of AA amyloidosis, there were two patterns of renal involvement--glomerular and vascular, with the glomerular pattern carrying a more ominous clinical picture. Notable among the localized amyloidoses were isolated atrial amyloidosis complicating chronic rheumatic heart disease, intratumour amyloidosis within nasopharyngeal carcinomas and dystrophic amyloidosis which occurred in fibrotic tissues.     

Ubiquitin: its potential significance in murine AA amyloidogenesis.

Amyloid enhancing factor (AEF), which has recently been shown to have identity with ubiquitin (Ub), is believed to play a causative role in experimentally induced AA amyloidosis in mice. We have examined the profile of Ub in activated leukocytes and splenic reticulo-endothelial (RE) cells and its relationship with serum amyloid A protein (SAA) and AA amyloid deposits in an alveolar hydatid cyst (AHC)-infected mouse model of AA amyloidosis. Two monospecific antibodies, anti-ubiquitin (RABU) and anti-mouse AA amyloid, were used as immunological probes to localize Ub, SAA, and AA amyloid. In response to AHC infection, the dull and diffuse Ub immunoreactivity in normal mouse leukocytes and RE cells promptly changed to a discrete granular pattern suggesting an increase in the intracellular concentration of Ub and the formation of Ub-protein conjugates. This corresponded to an elevation in SAA levels, SAA uptake by RABU-positive phagocytic cells, co-localization of Ub-SAA immunoreactive splenocytes in the perifollicular areas, and deposition of Ub-bound AA amyloid in the splenic and hepatic tissues. These results suggest that Ub-loaded monocytoid cells may play an important role in the physiological processing of the sequestered SAA into AA amyloid. Aspects of AA amyloidogenesis are discussed in relation to other experimental models in which stress-induced Ub-protein conjugate formation and its transport to lysosomal vesicles have been studied.     

Cerebrovascular involvement in systemic AA and AL amyloidosis: a clear haematogenic pattern

 Amyloid deposits in cerebral vessels are common in β-amyloid diseases (Alzheimer’s disease, congophilic amyloid angiopathy, Down’s syndrome and hereditary cerebral amyloidosis with haemorrhage of the Dutch type). We report of 20 autopsies on patients who had died with systemic amyloidosis of the AA, Aλ and Aκ types: the brains were examined for the occurrence of amyloid. Vascular amyloid was detected in choroid plexus (in 17 of 20 cases), infundibulum (5 of 8), area postrema (6 of 11), pineal body (3 of 7) and subfornical organ (2 of 3), but not in cortical and leptomeningeal vessels. Immunohistochemical classification of the cerebral amyloid and the systemic amyloid syndrome showed identity proving the same origin of both. The distribution is indicative of a haematogenic pattern of amyloid deposition in systemic amyloidosis and is different from that in Alzheimer’s, prion, ATTR and cystatin C diseases. It corresponds to areas of the brain with a ”leaky” blood–brain barrier. Additionally, all the cases with AA amyloidosis exhibited an Aβ coreactivity in choroid plexus vessels. In one exceptional case, Aβ reactivity of AA amyloid also occurred outside of the brain. Received: 2 November 1998 / Accepted: 25 January 1999     

Amyloid fibril composition is related to the phenotype of hereditary transthyretin V30M amyloidosis

Swedish familial systemic amyloidosis with polyneuropathy (FAP) depends on a mutation leading to a methionine-for-valine substitution in transthyretin. The disease appears with different clinical manifestations, including age of onset and involvement of the heart. Liver transplantation is currently the only curative treatment, but progressive cardiomyopathy may occur post-transplant. Two amyloid deposition patterns have previously been described in the heart. In one, the amyloid consists partially of transthyretin fragments and is weakly stainable by Congo red, while in the other, only full-length molecules are found and the fibrils have a strong affinity for Congo red. The present study aimed to see whether these morphological and biochemical variations have clinical implications. Subcutaneous adipose tissue biopsies were taken from 33 patients with Val30Met FAP and examined by microscopy, electrophoresis and western blot. Clinical data included age, sex, duration of disease and echocardiographic determination of the interventricular septum (IVS) thickness. It was found that fibrils composed of only full-length transthyretin were associated with early age of onset (44.8 +/- 12.9 years), no clinical cardiac involvement and a strong affinity for Congo red. In contrast, presence of transthyretin fragments in the amyloid was associated with late age of onset (67.3 +/- 7.0 years), signs of cardiac involvement and weak Congo red staining. For each individual, the same molecular type of amyloid was found in different organs. This is the first report showing that variations in clinical appearance of familial ATTR amyloidosis are associated with specific structural differences in the amyloid fibrils, and therefore may have a molecular cause. The molecular type of amyloid can be determined from a subcutaneous fat tissue biopsy. Copyright (c) 2008 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

Secondary (AA) amyloidosis in Crohn's disease

Amyloidosis is a clinical entity that results from deposition of an extracellular protein material that causes disruption in normal architecture and impairs function of multiple organs and tissues. Secondary amyloidosis (AA) is a rare but serious complication that occurs in the context of cancer, chronic inflammation and chronic infectious diseases, including inflammatory bowel disease, mainly long-standing Crohn's disease. Renal failure is the most common clinical presentation of AA, ranging from nephrotic syndrome and impaired renal function to renal failure, with a potential for high morbidity. The incidence of the association of secondary amyloidosis in patients with Crohn's disease has been reported to be 0.5%-8%. We present a case of a 39-year-old male patient diagnosed with Crohn's disease at age 21 and submitted to right hemicolectomy because of ileus 17 years before. Thereafter, he was treated with corticosteroids for 15 years and with azathioprine for a short period; in the last three years he was on therapy with mesalazine alone. He was hospitalized due to worsening clinical condition and re-evaluation of the underlying disease. Physical examination revealed marked peripheral edema in both lower extremities. Endoscopic and radiographic examinations confirmed the underlying disease activity. Laboratory tests showed an increase of inflammatory reactants, anemia, hypocalcemia, and severe hypoalbuminemia and hypoproteinemia. He had proteinuria over 24 g/L and creatinine clearance of 66 mL/min, falling within second grade of chronic kidney disease. Renal biopsy was performed for evaluation of renal insufficiency with nephrotic range proteinuria. Congo red staining showed the presence of characteristic amyloid deposition; deposits immunoreacted with the antibody against amyloid A protein, confirming the diagnosis of secondary amyloidosis. The patient was suggested active induction treatment with corticosteroids and azathioprine to achieve remission of Crohn's disease, thereafter treatment with infliximab, but he did not consent with this therapy at that time. Studies with infliximab have demonstrated a decrease in SAA circulating levels and proteinuria, as well as stabilization of renal function. Amyloidosis is frequently described as a major cause of death in patients with Crohn's disease, with long-term mortality between 40% and 60%. Various therapeutic attempts such as azathioprine, colchicine, dimethyl sulfoxide, infliximab, and elemental diets have been tried but there is no definite treatment for secondary amyloidosis in Crohn's disease. Kidney transplantation may offer the best prospects for patients with Crohn's disease who develop amyloidosis and end-stage renal failure.     

The pattern of amyloid deposition in the lung

A review of routine histopathological samples and autopsies examined at the Department of Pathology, University of Malaya revealed 15 cases of amyloidosis of the lung. Two were localized depositions limited to the lung while in the remainder, lung involvement was part of the picture of systemic amyloidosis. Both cases of localized amyloidosis presented with symptomatic lung/bronchial masses and a clinical diagnosis of tumour. Histology revealed "amyloidomas" associated with heavy plasma cell and lymphocytic infiltration and the presence of multinucleated giant cells. In both cases, the amyloid deposits were immunopositive for lambda light chains and negative for kappa chains and AA protein. One was a known systemic lupus erythematosus patient with polyclonal hypergammaglobulinaemia. The other patient was found to have plasma cell dyscrasia with monoclonal IgG lambda gammopathy. Both patients did not develop systemic amyloidosis. In contrast, lung involvement in systemic AA amyloidosis was not obvious clinically or macroscopically but was histologically evident in 75% of cases subjected to autopsy. Amyloid was detected mainly in the walls of arterioles and small vessels, and along the alveolar septa. It was less frequently detected in the pleura, along the basement membrane of the bronchial epithelium and around bronchial glands. In one case of systemic AL amyloidosis associated with multiple myeloma, an "amyloidoma" occurred in the subpleural region reminiscent of localized amyloidosis. These cases pose questions on (1) whether localized "tumour-like" amyloidosis is a forme fruste of systemic AL amyloidosis and (2) the differing pattern of tissue deposition of different chemical types of amyloid fibrils, with the suggestion that light chain amyloid has a greater tendency to nodular deposition than AA amyloid.     

Long‐term kinetics of AA amyloidosis and effects of inflammatory restimulation after disappearance of amyloid depositions in mice

Amyloid A (AA) amyloidosis is characterized by extracellular pathogenic deposition of insoluble fibril protein in various body organs. Deposited amyloid generally remains in a variety of organs for long periods, but its disappearance has been reported after the precursor protein is diminished. The kinetics of AA deposition are not completely understood and, in particular, the roles of cells and cytokines in the deposition and clearance of amyloid remain unclear. In this study, we investigated the disappearance of amyloid depositions in mice over a 1‐year period. AA amyloidosis was induced experimentally in mice by injecting amyloid‐enhancing factor (AEF) and silver nitrate. Mice were killed at different time‐points to examine the occurrence and disappearance of amyloid depositions. Maximum levels of amyloid depositions were observed at 20 days after inoculation. Clearance of amyloid depositions was observed from the 40th day onwards, with only minute traces of amyloid present by 240 days. A second inflammatory stimulus consisting of AEF and silver nitrate was given at 330 or 430 days, after amyloid depositions had disappeared almost completely. After that, serum amyloid A was overproduced and redeposition of amyloid was observed, indicating that all mice were primed for aggressive amyloid depositions. After administration of the inflammatory stimuli, the proinflammatory environment was found to have increased levels of interleukin (IL)‐6, while anti‐inflammatory conditions were established by IL‐10 as regression of amyloid deposition occurred. These results suggest that the proinflammatory and anti‐inflammatory status have key roles in both amyloid deposition and clearance.     

Idiopathic Amyloidosis Due to AA Protein: A Report of 2 Cases

Abstract

Two cases of idiopathic amyloidosis are described. AA protein was found to be the major constituent of tissue amyloid in both, based on sensitivity of Congo red birefringence to pretreatment of slides with potassium permanganate and immunoperoxidase staining with a monospecific antiserum. However, an underlying inflammatory, infectious or neoplastic disorder was not identified. The occurrence of AA amyloidosis without clearcut underlying disease is rare, having been described in only thirteen previous instances. Recent clinical series suggest that such cases may have a different course and response to therapy from “primary” amyloidosis due to systemic light chain deposition. Such cases may also underscore the importance of genetic factors in the pathogenesis of AA amyloid and the importance of characterizing the amyloidoses biochemically, as well as clinically. (The J Histotechnol 12:137, 1989.)     

Amyloid deposits in lymph nodes: A morphologic and immunohistochemical study

In a series of approximately 80,000 lymph nodes, amyloid deposition was found in 18; 12 of those nodes were selected, on the basis of availability of specimens, for investigation by immunohistochemical typing to identify the protein of origin and by correlation with morphologic criteria and clinical information. Four patterns of amyloid deposition were identified: lymph node vessel involvement, follicular deposition, diffuse deposition, and a combination of follicular and diffuse deposition. All cases were classified immunohistochemically with the amyloid type-specific antisera anti-AA, anti-A lambda, anti-A kappa, anti-ASc1, and anti-AF. Immunoglobulin-derived protein (AL) in lymph nodes was found in every case of isolated amyloidosis, lymphoplasmacytic/lymphoplasmacytoid immunocytoma, plasmacytoma, and idiopathic amyloidosis. Among the cases of AL amyloidosis were nine of A lambda and one of the A kappa type. AA protein was present in two cases of reactive systemic amyloidosis. There was no useful morphologic correlation with the immunohistochemically identified amyloid types.     

Morphologic and chemical variation of the kidney lesions in amyloidosis secondary to rheumatoid arthritis

The kidneys of 20 patients who died of secondary systemic amyloidosis due to rheumatoid arthritis were studied histologically, and four of these were shown to have an uncommon pattern of deposition with almost no glomerular involvement but heavy deposits in the outer zone of the medulla. In three of the four patients frozen tissue was available. Immunochemical characterization of amyloid fibrils from these three cases showed that the major subunit amyloid fibril protein was protein AA, typical of secondary amyloidosis. Gel chromatography of fibrils revealed an uncommon elution pattern with two retarded major protein peaks. Both these proteins showed immunologic identity with protein AA and had N-terminal amino acid sequences identical with that protein but differed in size obviously due to a shortening of the C-terminal in one of the proteins. The reason for the correlation between the pattern of deposition of amyloid and alterations in protein AA is unclear but might be due to variations in enzymes responsible for the cleavage of the amyloid fibril subunit precursor protein SAA.     

Classical and alternative pathway complement activation are not required for reactive systemic AA amyloid deposition in mice

During induction of reactive systemic amyloid A protein (AA) amyloidosis in mice, either by chronic inflammation or by severe acute inflammation following injection of amyloid enhancing factor, the earliest deposits form in a perifollicular distribution in the spleen. Because the splenic follicular localization of immune complexes and of the scrapie agent are both complement dependent in mice, we investigated the possible complement dependence of AA amyloid deposition. In preliminary experiments, substantial depletion of circulating C3 by cobra venom factor had little effect on experimental amyloid deposition. More importantly, mice with targeted deletion of the genes for C1q or for both factor B and C2, and therefore unable to sustain activation, respectively, of either the classical complement pathway or both the classical and alternative pathways, showed amyloid deposition similar to wild type controls. Complement activation by either the classical or alternative pathways is thus not apparently necessary for the experimental induction of systemic AA amyloid in mice.     

Gastrointestinal amyloid deposition in AL (primary or myeloma-associated) and AA (secondary) amyloidosis: Diagnostic value of gastric biopsy

Gastrointestinal amyloid deposition was investigated in 21 autopsy cases of nonhereditary systemic amyloidosis, 18 of the AL (primary or myeloma-associated) type and three of the AA (secondary) type. Vascular deposition of amyloid, most apparent in the submucosa, was found in all cases. Parenchymal deposition was observed mainly in the muscularis mucosae and muscularis externa in the AL type, and in the lamina propria mucosae in the AA type. Comparison of amyloid deposition in the stomach and rectum revealed no differences for the AA type. In the AL type, however, deposition in the lamina propria mucosae and muscularis mucosae was more frequent and marked in the wall of the stomach than in the rectum. Thus, gastric biopsy would be more valuable than rectal biopsy in the diagnosis of AL amyloidosis.     

Experimental model of oral transmissible AA amyloidosis in quails

ABSTRACT

In poultry and zoo birds, mass outbreaks of amyloid A (AA) amyloidosis are often reported, and horizontal transmission is considered as one of the causes. However, oral transmission of avian AA amyloidosis in nature has been unclear. In order to clarify the horizontal transmission of avian AA amyloidosis, basic research using an appropriate oral transmission model is necessary. In this study, we developed an oral transmission model of AA amyloidosis using quails, and assessed the oral transmission efficiency of AA amyloidosis in quails and mice. Young quails, adult quails, and young mice received inflammatory stimulation with lipopolysaccharide; simultaneously, homogeneous amyloid fibrils were orally or intravenously administered. By histological examination, induction of amyloidosis by oral or intravenous administration of amyloid was confirmed in all species. Furthermore, both quail and murine AA amyloidosis were orally transmitted in a dose-dependent manner. These results support the possibility of horizontal transmission of avian AA amyloidosis in nature. This model will be able to contribute to the elucidation of spontaneous horizontal transmission of avian AA amyloidosis in the future.

RESEARCH HIGHLIGHTS

• Quail AA amyloidosis was orally transmitted in a dose-dependent manner.

• Oral transmission was less efficient than intravenous transmission.

• In-cage horizontal transmission did not occur during 4-week cohabitation.

• Amyloid deposition in tissues of quail was grossly visible.

     

AA protein-related renal amyloidosis in drug addicts.

Reports of renal amyloidosis occurring among narcotic addicts have been limited, for the most part, to case reports. In a prospective survey of 150 addicts examined at autopsy in the Office of the Chief Medical Examiner of the City of New York, 7 cases of renal amyloidosis were found. Immunohistologic examination demonstrated that in all of the 7 cases, the amyloid was AA protein-related. The amyloid extracted from the kidneys of two addicts and analyzed biochemically did not differ from the AA amyloid secondary to chronic infectious and inflammatory diseases. The combined data of previous reports and the present survey demonstrate that addicts who are subcutaneous users with skin infections most frequently develop amyloidosis. Our data demonstrating renal amyloidosis in 26% of addicts with chronic suppurative skin infections suggest that such addicts are at high risk for the development of amyloidosis.