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PubMed2002

Primary systemic amyloidosis.

Primary amyloidosis is a plasma cell dyscrasia in which insoluble immunoglobulin light chain fragments are produced and polymerize into fibrils that deposit extracellularly, causing visceral organ dysfunction and death. The disorder is rare. Its recognition requires understanding the association between nephrotic syndrome, cardiomyopathy, peripheral neuropathy, and hepatomegaly with amyloidosis. The most important screening test for amyloidosis is immunofixation of the serum and urine to detect a monoclonal immunoglobulin light chain. All patients need the diagnosis confirmed histologically. The least invasive source of tissue for amyloid detection is the subcutaneous fat. The most important prognostic factor is whether there is cardiac involvement, which is best assessed by echocardiography with Doppler studies. Therapies used include oral melphalan/prednisone and high-dose corticosteroids. High-dose chemotherapy followed by stem cell reconstitution seems to provide the highest reported response rates. Transplant is associated with unique morbidities not seen in the transplantation of patients with other hematologic malignancies.

Amyloidosis↗
PubMed1987

Sensitivity and specificity of the echocardiographic features of cardiac amyloidosis.

Thirty-one patients with documented cardiac amyloidosis were compared to 39 control subjects with left ventricular hypertrophy to determine specific 2-dimensional echocardiographic features of amyloid. In 16 patients, increased myocardial echogenicity was present when a single short-axis view was examined, and had a sensitivity of 63% and a specificity of 74% for the diagnosis of amyloidosis. When complete echocardiograms were reviewed (15 patients), an improved sensitivity of 87% and specificity of 81% based on increased echogenicity was seen. Increased atrial septal thickness was present in 60% of amyloid patients and no controls. The combination of increased myocardial echogenicity and increased atrial thickness was 60% sensitive and 100% specific for the diagnosis of amyloidosis. The ratio of electrocardiographic voltage (S in V1 + R in V5 or V6) to left ventricular cross-sectional area also was examined. A ratio of less than 1.5 was 82% sensitive and 83% specific for amyloid (excluding the 2 patients with left bundle branch block), but added little to the diagnosis as determined from the 2-dimensional echocardiogram.

Amyloidosis↗
PubMed1975

The clinical spectrum of light chain myeloma. A study of 35 patients with special reference to the occurrence of amyloidosis.

During a 40 month interval, 35 patients were seen with a plasma cell dyscrasia in which the only detectable monoclonal immunoglobulin abnormality consisted of excess production of either type kappa or type lambda light chains (Bence Jones protein). This group constituted 17.3 per cent of the total number of patients with plasma cell dyscrasias and 25.7 per cent of the patients with myeloma identified during the same period. Variable initial clinical presentation, the absence of a typical monoclonal serum spike and the unreliability of commonly used urine protein tests made recognition of the disorder difficult in many patients. Sulfosalicylic acid and p-toluene sulfonic acid proved valuable in screening for ueine protein. Definition of "proteinuria" by quantitative, electrophoretic and immunochemical studies was essential for diagnosis. Bence Jones proteinemia was present in 80 per cent of the patients; panhypogammaglobulinemia and lytic bone lesions were demonstrable in more than 60 per cent. Although no specific morphologic abnormality of marrow plasma cells was evident by light microscopy, the absence of rouleau on peripheral blood smear was a helpful diagnostic clue. Although patients with lambda light chains presented with more Bence Jones proteinuria, this did not correlate with the severity of initial renal functional impairment or with survival when compared to patients with kappa light chains. No other clinical or laboratory observation differentiated the groups with kappa light chains from those with lambda light chains. Amyloid was identified in seven patients. Their course was dominated by the features of primary systemic amyloidosis instead of the usual findings of classic myeloma. Patients with amyloidosis had lower initial serum albumin levels, fewer lytic bone lesions and reduced survival compared to patients without amyloidosis.

Acute Kidney Injury↗
PubMed1977

The conduction system in cardiac amyloidosis. Clinical and pathologic features of 23 patients.

Cardiac amyliodosis is frequently associated with major electrocardiographic conduction disturbances; but that these disturbances are due to infiltrative destruction of the conduction system by amyloid is unclear. We studied the conduction systems in 23 autopsy patients with cardiac amyloidosis (group 1) (mild in seven, moderate in five and severe in 11), 21 (91 per cent) of whom had had abnormalities of conduction or rhythm during life. For comparison, we examined the conduction system in 23 control subjects matched in age and heart weight (group 2). Of the 23 patients in group 1, only three had extensive amyloidosis of the conduction system; in all three, electrocardiograms showed first degree atrioventricular block and left anterior hemiblock. A more common morphologic abnormality of the conduction system was severe sinoatrial node fibrosis present in seven (30 per cent) patients, and idiopathic atrophy and fibrosis of the bundle branches present in six (26 per cent) patients. None of the patients in group 2 had severe sinoatrial node fibrosis, but two (9 per cent) had idiopathic atrophy and fibrosis of the left bundle branch. Marked fibrosis of the sinus node was more frequent in patients with severe or moderate amyloid, but fibrosis of the bundle branch did not appear to be related to the amount of amyloid elsewhere in the heart. Varying degrees of atrioventricular and bundle branch block were also present in six patients with no morphologic abnormalities of the conduction system. Thus, conduction and rhythm disturbances are frequent in cardiac amyloidosis, but direct amyloid infiltration of the specialized conduction tissue of the heart does not account for the majority of these disturbances. Whether the increased incidence of fibrosis of the conduction system in group 1 compared to that in group 2 relates to the infiltrative myocardiopathy is uncertain.

Adult↗
PubMed1980

AA protein in a case of "primary" or "idiopathic" amyloidosis.

Amyloidosis constitutes a group of diseases in which extracellular fibrils with a characteristic appearance are deposited in a variety of tissues. Several different proteins have been identified as the major subunits of the fibrils. In the primary and myeloma-associated type, the amyloid fibrils consist of immunoglobulin light chain fragments, whereas in the secondary type and the amyloid associated with familial Mediterranean fever the major component is the AA protein. In this report a 21 year old man of Yemenite extraction with no underlying disease and no family history of amyloidosis was found to have amyloid deposits composed of AA protein. Although clinically this might be classified as primary amyloidosis, the absence of light chain fragments makes that diagnosis unlikely. Therefore, it is suggested that whenever possible the clinical classification be supplemented by a description of the biochemical nature of the fibrils.

Adult↗
PubMed1984

Primary (AL) amyloidosis as a cause of breast masses.

Amyloidosis is rarely considered in the differential diagnosis of breast masses. During the past six years, 27 women with primary (24) and multiple myeloma-associated (three) amyloidosis (AL amyloid) were evaluated at our center. In five of these patients, amyloid was demonstrated on microscopic examination of breast tissue. The clinical presentations were similar to fibrocystic breast disease in two cases and malignancy in two others. Amyloidosis of the breast may be more common than previously recognized, especially considering the predilection of amyloid for depositing around fat cells. Therefore, pathologic examination of nonmalignant breast tissue should include Congo red staining and viewing under polarized light.

Amyloid↗
PubMed1986

Primary amyloidosis associated with multiple myeloma. Predictors of successful therapy.

Of 34 patients with primary amyloidosis seen at the University of Arizona between 1973 and 1984, 25 had amyloidosis in association with overt multiple myeloma. Response to treatment was evaluable in 16 of the 25 patients. Median survival in the seven patients (44 percent) with response to treatment was 28 months versus a median of seven and a half months for the nine patients without response (p less than 0.001). Although there were no absolute predictors of response, patients with response were much less likely to have cardiac amyloid (14 percent versus 78 percent, p = 0.02), but more likely to have unusually high serum beta 2-microglobulin (above 15 micrograms/dl in three of four with response versus in neither of two without response) and kappa subtype monoclonal protein (57 percent versus 33 percent). Renal amyloid and/or serum creatinine levels above 2 mg/dl in three of seven (43 percent) patients with response did not preclude a good outcome. It is concluded that a chemotherapy induction trial is worthwhile in primary amyloidosis associated with myeloma since a subset of patients can have prolonged survival (more than two years).

Aged↗
PubMed1987

Survival of patients with primary (AL) amyloidosis. Colchicine-treated cases from 1976 to 1983 compared with cases seen in previous years (1961 to 1973).

Primary amyloidosis has a variable course, but is generally associated with a short life expectancy. To date, no specific therapy has been available. Fifty-three patients with AL amyloidosis seen between 1976 and 1983 were treated with colchicine, and their clinical course and survival were compared with that in 29 other patients seen between 1961 and 1973. Of the variables measured, the treatment, the patient's sex, and the time interval from diagnosis to referral of treatment were significantly associated with length of survival. Median survival for the colchicine-treated patients was 17 months, compared with six months for the non-colchicine-treated patients. A surprising finding was the longer life span in female patients (median eight months versus four and a half months in the non-colchicine-treated group, and 25.5 months versus 10 month in the colchicine-treated group). The study suggests that colchicine has improved the life expectancy in AL amyloidosis. Although it is not a specific therapy, it may be a reasonable form of adjunctive treatment in this complex disorder.

Amyloidosis↗
PubMed1988

Hepatic amyloidosis (primary [AL], immunoglobulin light chain): the natural history in 80 patients.

PURPOSE: We wished to study patients with a premortem diagnosis of primary hepatic amyloidosis to determine what clinical and laboratory features might assist in recognizing the disease and assessing prognosis. PATIENTS AND METHODS: A group of 80 patients with liver biopsy proven primary hepatic amyloidosis was followed from diagnosis to death. RESULTS: At presentation, 77 percent of the group had an associated nephrotic syndrome, congestive heart failure, peripheral neuropathy, or orthostatic hypotension. Certain clues suggested the diagnosis of hepatic amyloidosis in patients with liver disease, including the following: (1) proteinuria (88 percent); (2) abnormal serum protein electrophoresis (monoclonal protein or hypogammaglobulinemia, 64 percent); (3) hyposplenism on the peripheral blood smear (62 percent), defined by the presence of Howell-Jolly bodies; and (4) hepatomegaly disproportional to the liver enzyme abnormalities. Liver function tests were not sensitive or specific. Hepatomegaly from amyloid was frequently seen, with normal levels of alkaline phosphatase, aspartate aminotransferase, and bilirubin (32 percent). Myeloma was diagnosed in 11 patients but had no effect on the clinical course. In vitro coagulation abnormalities were common, bleeding was infrequent, and liver biopsy carried a slightly increased risk. The median survival of the entire group was nine months, and projected five- and 10-year survival rates were 13 and 1 percent, respectively. CONCLUSION: Because survival is poor and no clinical features permit prospective recognition of those patients in whom the disease is likely to have an indolent course, a trial of therapy is warranted in all patients.

Amyloidosis↗
PubMed1990

Beta 2-microglobulin predicts survival in primary systemic amyloidosis.

PURPOSE: The study assessed whether beta 2-microglobulin levels predict survival or response in patients with primary systemic amyloidosis without associated multiple myeloma. PATIENTS AND METHODS: The study group consisted of 131 untreated patients with biopsy-proven primary systemic amyloidosis diagnosed and evaluated at the Mayo Clinic. No patient had multiple myeloma. The minimum follow-up of surviving patients is 8 years. No patient was lost to follow-up. RESULTS: The median survival of patients with an increased beta 2-microglobulin level was 10.8 months, compared with patients with a normal beta 2-microglobulin level (less than or equal to 2.7 micrograms/mL, 0.23 mumol/L) of 32.9 months (p less than 0.001). In a multivariate proportional-hazards model, the best model included congestive heart failure (p less than 0.0001) and increased beta 2-microglobulin levels (p less than 0.05). After adjustment for the presence of congestive heart failure, beta 2-microglobulin level remained significant. When the analysis was restricted to those patients with normal renal function, the median survival of those with an elevated beta 2-microglobulin level was 9.1 months versus 39.4 months for those with a normal level (p less than 0.001). The serum level of beta 2-microglobulin was increased in patients with nephrotic-range proteinuria with or without renal insufficiency (p = 0.05). CONCLUSION: The serum beta 2-microglobulin level should be measured routinely in all patients with primary systemic amyloidosis because it provides a useful objective factor to identify subsets of patients with this disease who have unfavorable outcomes.

Adult↗
PubMed1996

Subpopulation of dogs with severe brain parenchymal beta amyloidosis distinguished with cluster analysis.

A study of the brains of 30 dogs, mongrels from 6.5 to 26.5 years of age, revealed that all dogs older than 13 years of age develop amyloid-beta-positive plaques. Cluster analysis based on the age of the dogs and the numerical density of amyloid-positive plaques stained with monoclonal antibody 4G8 (17-24aa) revealed that the population of old dogs consists of two subpopulations: one with a very low (0.8/mm2 on average) and other with a high (19.2/mm2 on average) numerical density of plaques. These two groups (19.5 and 19.1 years of age, respectively) appear to emerge from the younger group (12.2 years of age on average), with moderate (2.2/mm2 on average) numerical density of 4G8-positive plaques. These data may indicate that only a portion of the mongrel population (43%) is susceptible to amyloidosis beta or that only this severely affected subpopulation was exposed to a factor or factors inducing this pathology and developed severe cortical amyloidosis that correlates with age. Dog plaques are only of the diffuse type, with nonfibrillar, thioflavin S-, and Congo red-negative amyloid in all groups distinguished by cluster analysis. Only from 10% of 4G8-positive plaques in the mildly affected group to 29% in the severely and 37% in the moderately affected group are Bielschowsky positive. In the younger, moderately affected group, 6E10 (1-17aa)-positive plaques prevail. In the two old groups with severe and weak changes, almost all 4G8-positive plaques are also 6E10-positive. Carboxy-terminal region immunocytochemistry reveals that BC42-positive plaques are numerous, whereas BC40-positive plaques are few or absent. The differences in the silver-positivity of plaques and their immunoreactivity in both the amino- and carboxy-terminal regions may reflect differences in amyloid-beta deposition and resolution. Dog parenchymal amyloidosis beta appears to be a model for the study of diffuse plaques.

Amyloid beta-Peptides↗
PubMed1986

Secondary amyloidosis in association with Aspergillus lung disease.

Three patients with amyloidosis secondary to bronchiectasis are described: in two patients bronchiectasis was secondary to allergic bronchopulmonary aspergillosis and in the third, post-tuberculous bronchiectasis was complicated by asthma and allergy to Aspergillus. We suggest that chronic Aspergillus allergy may cause amyloidosis and that some cases of amyloidosis ascribed to tuberculosis in the past may in fact have been secondary to Aspergillus allergy.

Amyloidosis↗
PubMed1993

Increase in plasma concentration of ubiquitin in dialysis patients: possible involvement in beta 2-microglobulin amyloidosis.

beta 2-Microglobulin(beta 2-M) amyloidosis is a serious complication of dialysis therapy; however, its pathogenesis is still unclear. Recent studies have indicated that ubiquitin has amyloid enhancing factor activity, raising the possibility that ubiquitin plays a role in beta 2-M amyloidogenesis. In this study, synovial tissue from patients with long-term dialysis was examined immunohistochemically. The synovial tissue was labeled with anti-ubiquitin antibody, indicating co-deposition of ubiquitin with beta 2-M amyloid. To elucidate the involvement of plasma ubiquitin, we established a specific radioimmunoassay for ubiquitin. Using this method, we observed that the plasma concentration of ubiquitin-like immunoreactivity in dialysis patients was significantly higher than that in normal subjects. In chronic renal failure patients, the plasma concentration of ubiquitin-like immunoreactivity was also significantly higher than that in normal controls, which finding suggests that a reduction in renal clearance is, at least in part, responsible for the increased plasma concentration of ubiquitin. In dialysis patients, plasma concentrations of ubiquitin-like immunoreactivity in patients with carpal tunnel syndrome, one of the major symptoms of beta 2-M amyloidosis, were significantly higher than those in patients not exhibiting this syndrome. These results suggest a possible involvement of plasma ubiquitin in beta 2-M amyloidosis.

Amyloidosis↗
PubMed1991

The transthyretin cDNA sequence is normal in transthyretin-derived senile systemic amyloidosis.

A variety of mutations leading to amino acid substitutions have been described in the transthyretin gene in association with different familial amyloidoses and have been implicated to be involved in the pathogenesis of amyloid deposits. However, there has been disagreement whether or not a transthyretin mutation is present in the most common form of transthyretin-derived amyloid, namely senile systemic amyloidosis. Therefore, the cDNA sequence of liver transthyretin was determined in a 91-year-old patient with typical senile systemic amyloidosis. This sequence was completely normal and lacked any variation. We conclude that in senile systemic amyloidosis factors other than the presence of a sequentially variant transthyretin must determine the amyloid fibril formation.

Aged↗
PubMed1989

Severe secondary amyloidosis in a dog with dermatomyositis.

A male collie aged 5 years 10 months, which developed dermatomyositis at 2 months of age, died from severe secondary amyloidosis. Amyloid deposition was most severe in renal glomeruli and produced renal failure. Amyloidosis has been reported in man with immune-mediated disorders including rheumatoid arthritis, systemic lupus erythematosus and dermatomyositis. It is possible that the inflammation in this case of familial canine dermatomyositis may have predisposed to the development of amyloidosis.

Amyloidosis↗
PubMed1994

Autonomic nervous system and cardiac involvement in familial amyloidosis, Finnish type (FAF).

Familial amyloidosis, Finnish type (FAF), is a gelsolin-related inherited systemic amyloidosis. We report autonomic nervous system and cardiac findings in a study of 30 FAF patients (18 females, 12 males aged 27-74 years; mean 53.9 years). Cardiovascular reflex tests showed a significant decrease in heart rate variation in FAF patients compared with healthy controls. Orthostatic hypotension was found in 9 of 28 FAF patients, but only in 3 of 69 controls. Signs of amyloid cardiopathy were rare at clinical examination and in radio-, echocardio- and electrocardiographic examinations. Histological and immunohistochemical studies revealed amyloid deposition and immunoreactivity against the gelsolin-related FAF amyloid subunit in autonomic nervous system structures and in cardiac tissue in 3 autopsied FAF patients. The results show that minor autonomic nervous system dysfunction can be found in FAF, while clinically significant amyloid cardiopathy or autonomic neuropathy is not characteristic of this type of amyloidosis.

Adult↗
PubMed1983

Oral amyloidosis: a late complication of multiple myeloma.

Amyloidosis as a complication of multiple myeloma carries with it grave prognostic implications, and the median survival of myeloma patients following a diagnosis of amyloidosis is only 4 months. This article describes a patient who survived 6 years with kappa light chain myeloma, but only 4 months after the development of oral amyloid deposits. Oral amyloidosis may be clinically difficult to distinguish from fibrous, neurogenous, or salivary gland pathosis; however, histologic specimens stained with Congo red have a characteristic "apple green" appearance when examined microscopically with polarized light.

Amyloidosis↗
PubMed1993

Tracheobronchial AL amyloidosis: histologic, immunohistochemical, ultrastructural, and immunoelectron microscopic observations.

We have studied three cases of localized amyloidosis in the lower respiratory tract. Amyloid was nodularly or diffusely deposited in the lamina propria of the tracheobronchial mucosa. Its nature was confirmed by Congo red staining with green birefringence on polarized microscopy. "Tracheobronchopathia osteoplastica" also was demonstrated. Plasma cells and lymphocytes were scant in the amyloid mass. Few fibroblasts and even fewer macrophages were seen. The number of plasma cells was not increased in the bone marrow in any of our cases. Amyloid fibrils were demonstrated by electron microscopic examination. The amyloid P component was detected by immunohistochemical methods. The precursor protein of amyloidosis was shown to be amyloid L protein by the postembedding protein-A gold technique with anti-light chain antisera. The role of the plasma cells in amyloid formation, however, could not be ascertained. Based on these observations, amyloid fibril formation in tracheobronchial amyloidosis appears to be related to light chains secreted by local plasma cells, combined with amyloid P, calcium, and other factors.

Adult↗