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PubMed2001

A putative role for cathepsin K in degradation of AA and AL amyloidosis.

The aims of this study were to investigate the role of cathepsin K in the pathology of amyloidosis by demonstrating its presence in multinucleated giant cells (MGCs) adjacent to amyloid deposits, and determining its ability to degrade amyloid fibril proteins in vitro. The study was performed using autopsy and biopsy specimens from patients with AA or AL amyloidosis. In six (55%) patients with AA amyloidosis and seven (58%) patients with AL amyloidosis, variable numbers of CD68-immunoreactive MGCs were found adjacent to amyloid deposits. In each case strong cytoplasmic immunostaining for cathepsin K was found in MGCs; immunostaining of amyloid deposits was present in five (45%) patients with AA amyloidosis and three (25%) patients with AL amyloidosis. In vitro degradation experiments showed that recombinant cathepsin K completely degraded AA amyloid fibril proteins at pH 5.5 as shown by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and Western blotting. Less effective degradation took place at pH 7.4 and there was no degradation in the presence of a general cysteine protease inhibitor (E64) or in the absence of cathepsin K. This is the first study to show that cathepsin K is expressed in MGCs adjacent to amyloid deposits and to demonstrate its ability to degrade amyloid fibril proteins.

Adult↗
PubMed1992

Familial amyloidosis: a study of 52 North American-born patients examined during a 30-year period.

Between 1961 and 1990, 52 patients with biopsy-proven familial amyloidosis born in North America were examined at the Mayo Clinic. At the time of diagnosis of familial amyloidosis, 83% of these patients had peripheral neuropathy, 33% had autonomic neuropathy, and 27% had cardiomyopathy. Renal disease was noted in fewer than 10%, and liver involvement was rare. The median age at diagnosis was 64 years. The sensitivity of various diagnostic biopsies was similar to that for primary amyloidosis: deposits of amyloid were found in 77 and 78% of the subcutaneous fat aspirates or rectal biopsy specimens, respectively, and in 41% of specimens of bone marrow. The median duration of survival of 5.8 years for patients with inherited amyloidosis was superior to that for patients with primary amyloidosis. When patients were stratified by organ involvement, the survival of patients with familial amyloidosis remained superior. The presence of cardiomyopathy and an interactive variable of age and the presence of autonomic neuropathy were powerful predictors of survival. Of the 52 patients, 22 died, 12 (55%) of cardiac failure or cardiac arrhythmia. Nine patients (41%) died of inanition in conjunction with progressive peripheral or autonomic neuropathy. Transthyretin was identified by immunohistochemical studies in 31 of the 34 tissue specimens tested. A transthyretin mutation was identified in 24 of the 31. A transthyretin mutation was found in five additional patients for whom tissue was unavailable for immunostaining.

Adult↗
PubMed1982

Mechanism of reduced amyloid-A-degrading activity in serum of patients with secondary amyloidosis.

Human serum contains amyloid-A-degrading (AADP) activity. This activity is reduced in amyloidosis associated with rheumatoid arthritis. Since AADP co-migrates with albumin on agarose-gel electrophoresis, the relationship between these serum factors was studied in patients with amyloidosis and patients with amyloidosis and patients with altered albumin synthesis and/or distribution. AADP activity correlated positively with albumin levels in patients with rheumatoid arthritis complicated by amyloidosis. A weaker association was noted between serum activity and prealbumin levels. The AADP activity in patients with rheumatoid arthritis without signs of amyloidosis and patients with liver cirrhosis was also positively associated with serum albumin level. During the acute-phase reaction after surgery serum AADP activity fell in parallel with serum albumin level. Purified albumin preparations displayed AADP activity. The results show that serum albumin level reflects AADP activity. It is suggested that the development of hypoalbuminaemia in patients with amyloidosis may give rise to a vicious circle which leads to an accelerated reduction in AADP activity and accelerated amyloidogenesis.

Adult↗
PubMed2004

[Secondary vesical amyloidosis].

The bladder involvement is a very unusual fact in systemic amyloidosis. The distinction of primary and systemic amyloidosis disease with bladder involvement (secondary bladder amyloidosis) is important to the urologist. Secondary amyloidosis of the bladder is a rare disease entity (approximately 20 cases published). We document a case of a woman with a large history of rheumatoid arthritis who developed severe macrohematuria. Diagnosis was done by biopsy that revealed amyloidosis, and it was confirmed with an immunohistochemical staining of the specimens that defined the process as amyloid AA (secondary amyloidosis).

Aged↗
PubMed1994

The epidemiology of AL and AA amyloidosis.

The limited available epidemiological information on AL amyloidosis suggests that there may be differences between population-based studies and case series data with respect to variables such as age and racial patterns. Much more work in this area is required before specific aetiologic hypotheses can be tested. Most available data to approximate the epidemiology of AA amyloidosis are derived from autopsies. Most patients with AA amyloidosis die from causes other than amyloidosis, therefore mortality data based on death certificates is of limited value in AA amyloidosis. Case ascertainment in autopsy studies may be difficult due to the frequent lack of adequate histological controls. Establishment of registries for both AL and AA amyloidosis would facilitate epidemiological research in these disorders.

Age Factors↗
PubMed2002

Diagnostic tools for amyloidosis.

Demonstration of amyloid deposits in biopsy specimens is the only means of confirming the diagnosis of amyloidosis. In experienced hands, nonsurgical biopsies of the rectal mucosa or, preferably, of the abdominal fat pad or labial salivary glands provide the diagnosis in 80 to 85% of cases. Immunolabeling studies help to determine the histological type of amyloidosis but are not performed routinely in everyday practice. In patients with a family history of amyloidosis, studies of the genome and amyloid protein can identify the protein variants capable of causing systemic amyloidosis. Once the diagnosis of amyloidosis is established, the extent of systemic involvement with amyloid should be evaluated by performing renal and hepatic function tests, a proteinuria assay, and an echocardiogram. Scintigraphy with radiolabeled serum amyloid P (SAP) component is a rapid and specific investigation that provides a map of the amyloid deposits. Deposits are usually seen in the liver and spleen. SAP component scintigraphy can provide support for the diagnosis of amyloidosis in patients with negative histological studies. Tissue retention of radioactivity predicts survival.

Amyloidosis↗
PubMed1999

Report on 59 patients with renal amyloidosis.

We studied a group of 59 patients with renal amyloidosis. Mean age (45 male, 14 female) was 33.05+/-13.04 years. All of the cases had secondary amyloidosis. The causes of secondary amyloidosis were as follows: familial Mediterranean fever (FMF) 18 (30.5%), pulmonary tuberculosis 12 (20.33%), chronic oseomyelitis 8 (13.55%), bronchiectasia 9 (15.25%), rheumatic diseases 4 (6.4%), Castleman's disease 1 (1.6%), unknown aetiology 7 (11.86%). Hypertension was detected in 15.3% of the cases. In patients with less than 20 ml/min creatinine clearance (Ccr) hypertension was found in 20%. Hypotension was detected in 6 patients and all of these cases had severe hypoalbuminaemia (<2.1 g/dl). Nephrotic range proteinuria (>3.5 g/day) was found in 75% of cases. Daily proteinuria was correlated with serum levels of albumin, total lipid and cholesterol, haematocrit and duration of disease. The mean Ccr was 51.03+/-40.60 ml/min. Twenty-nine per cent of patients had Ccr less than 20 ml/min. Renal, subcutaneous fat and rectal biopsies demonstrated amyloid in 100%, 20% and 57.6%, respectively, of patients tested. Patients with secondary amyloidosis were treated with colchicine in addition to the therapy of primary disease (in 6 patients). Nine patients died, and end-stage renal disease developed in 12 patients during four years of follow-up. Proteinuria disappeared or decreased in patients with secondary amyloidosis except secondary to collagen tissue disease, without advanced renal failure. Colchicine did not affect amyloid deposition in 2 patients with normal renal function and negative proteinuria, who were rebiopsied. It can be questioned that "Colchicine may have effect(s) for decrement on proteinuria". At least colchicine can be of use in secondary amyloidosis.

Adolescent↗
PubMed2002

Spontaneous pancreatic islet amyloidosis in 40 baboons.

Spontaneous amyloidosis occurs in many nonhuman primate species but remains difficult to diagnose and treat. Nonhuman primates continue to offer promise as animal models in which to study amyloidosis in humans. Amyloidosis was not diagnosed clinically but was found histologically in four male and 36 female baboons. The baboons averaged 18 years of age at death (range, 7-28 years). Clinical signs, if present, were hyperglycemia and cachexia. Blood glucose values were elevated in 12 of 30 baboons with available clinical pathology data. Four baboons had been clinically diagnosed as diabetic and three were treated with insulin. Amyloid was found in the islets of Langerhans of the pancreas in 40 baboons; 35 baboons had amyloid only in the islets of Langerhans. Amyloid was found in nonislet tissue of baboons as follows: five, nonislet pancreas; four, intestine and adrenal; three, kidney; two, prostate and spleen; and one each, lymph node, liver, gall bladder, stomach, tongue, urinary bladder, and salivary gland. Sections of paraffin-embedded tissues were evaluated for amyloid with hematoxylin and eosin (HE) and congo red (CR) staining, and using immunohistochemistry for human islet amyloid polypeptide (IAPP), calcitonin gene-related peptide (CGRP), glucagon, pancreatic polypeptide (PP), somatostatin (SS), and porcine insulin. Islet amyloid was positive with HE in 40 baboons, with CR in 39 baboons, and with IAPP and CGRP in 35 baboons. IAPP and CGRP only stained islet amyloid. PP, SS, glucagon, and porcine insulin did not stain amyloid. Islet amyloidosis in the baboon appears to be difficult to diagnose clinically, age-related, and similar to islet amyloidosis in other species. The baboon may be a good model for the study of islet amyloidosis in humans.

Amyloid↗
PubMed1997

Dialysis-related amyloidosis of the tongue in long-term hemodialysis patients.

Dialysis-related amyloidosis (DRA) predominantly occurs in the osteoarticular structures. However, according to studies in the increasing number of long-term hemodialysis patients, DRA has also been systemically found to appear in the other tissues and organs as well. In this study, we investigated lingual amyloidosis in relation to systemic DRA. A total of 472 patients were studied who were on regular hemodialysis for more than 10 years, including 103 patients for more than 20 years. Eight of these patients (7 males and 1 female, mean age 59 +/- 8 years, range 46 to 68 years) developed lingual amyloidosis, seemingly as a result of beta2-microglobulin (beta2m) deposits. All patients demonstrating lingual amyloidosis had been treated with regular hemodialysis for more than 20 years (mean HD duration 23.6 +/- 1.4 years), and its morbidity was 7.8% in the 103 patients and 20% (6 patients) in the 30 patients treated for more than 23 years with hemodialysis. Hemodialysis (HD) duration with bioincompatible unsubstituted cellulose membranes in the 8 patients was longer than that in the control group without lingual amyloidosis (P < 0.05). Lingual amyloid nodules were whitish-yellow in color and varied in size, at least over 1 mm in diameter. Their consistency was firmer than the intact tongue. The location of the amyloid nodules could be classified into two types: (1) diffuse type (diffusely distributed over the tongue), and (2) lateral type (localized only in the lateral side of the tongue). Five of the eight patients with lingual amyloidosis complained of functional disturbances in the tongue, such as abnormal taste, or difficulty in mobility and articulation. No macroglossia was observed in any of these cases. It was thus concluded that DRA of the tongue is a very rare complication, occurring in the late stage of long-term hemodialysis patients, that disturbs their quality of life.

Adult↗
PubMed2001

An overview of the use of high-dose melphalan with autologous stem cell transplantation for the treatment of AL amyloidosis.

Primary or AL amyloidosis results from a plasma cell dyscrasia in which fibrillar light chain protein deposition leads to organ failure and death. Standard treatment for AL amyloidosis has been oral melphalan and prednisone. However, this form of treatment modifies the natural history of this lethal disease only marginally, extending median survival from 13 months following diagnosis to 17 months. At Boston University Medical Center, we have developed treatment protocols using high-dose intravenous melphalan with autologous peripheral blood stem cell transplantation (HDM/SCT) to treat AL amyloidosis, and we have treated over 200 patients with HDM/SCT during the past six years. This extensive experience has shown that patients with AL amyloidosis, despite multisystem involvement and compromised organ function can tolerate this aggressive form of treatment. Furthermore, HDM/SCT results in durable hematologic responses in a substantial proportion of patients, and such responses are associated with clinical improvement, decreased amyloid-related organ dysfunction, and prolonged survival. However, toxicity from treatment is high (overall peri-transplant mortality, 14%), particularly for those patients with clinically significant cardiac involvement. For this reason, we believe a multidisciplinary management approach is essential when using HDM/SCT for treatment of AL amyloidosis. Based on our experience, we believe that HDM/SCT is the treatment of choice for patients with AL amyloidosis who have a good performance status and limited cardiac involvement at the time of diagnosis. HDM/SCT offers the best chance for hematologic remission, prolongation of survival, and reversal of amyloid-related disease. At the same time, we believe that HDM/SCT should continue to be examined in the context of clinical trials, directed at developing approaches to broaden the applicability of this therapy by minimizing toxicity and to increase the likelihood of complete hematologic responses.

Academic Medical Centers↗
PubMed1999

Phenotype-genotype correlation in familial Mediterranean fever: evidence for an association between Met694Val and amyloidosis.

Familial Mediterranean fever (FMF) is an autosomal recessive disease characterised by recurrent attacks of inflammation of serosal membranes. Amyloidosis is the most severe complication of the disease. The aim of this study was to investigate the genotype-phenotype correlation and specifically the association between amyloidosis and the four common mutations in exon 10 of the gene causing FMF (MEFV) in a total of 83 FMF families from three ethnic groups: North African Jews, Armenians and Turks. A significant association was found between amyloidosis and the specific mutation at the MEFV gene: Met694Val (RR = 1.41, P = 0.02). Amyloidosis was present in 18 out of 87 homozygous FMF patients (20.7%) and in only two out of the 41 compound heterozygous FMF patients (4.9%). No patients carrying other mutations had amyloidosis. There was no significant association between the various mutations and the type or severity of the FMF symptoms. This finding underscores the importance of performing molecular studies on all suspect FMF patients. In addition to providing accurate diagnosis, these tests allow identification of presymptomatic genetically affected individuals, detection of carriers and assessment of the risk for amyloidosis in later life.

Adolescent↗
PubMed2003

High-dose intravenous melphalan with autologous stem cell transplantation in AL amyloidosis-associated end-stage renal disease.

BACKGROUND: The development of end-stage renal disease (ESRD) is common among patients with amyloid light-chain AL amyloidosis-associated renal disease and survival of these patients is poor. High-dose intravenous melphalan and autologous stem cell transplantation induce remission of the plasma cell dyscrasia in a significant proportion of patients with AL amyloidosis. The efficacy and tolerability of such treatment for patients with AL amyloidosis-associated ESRD are unknown. METHODS: Between June 1994 and June 2000, 15 patients with AL amyloidosis-associated ESRD were treated with intravenous melphalan (70 to 200 mg/m2) and autologous peripheral blood stem cell transplantation. Clinical and laboratory data were prospectively collected prior to treatment, during the peritransplant period, and at 3 months, 12 months, and annually thereafter. Treatment outcomes and toxicities were compared with 180 non-ESRD patients treated during the study period. RESULTS: Eight of 15 patients (53%) had a hematologic complete response following treatment. Two patients (13%) died during the peritransplant period. Transfusion requirements were greater and there was a trend toward increased severity of mucositis in the ESRD patients compared with the non-ESRD patients. Median survival for the ESRD patients with a hematologic complete response was 4.5 years. Five patients with hematologic complete response have either undergone or are awaiting renal transplantation. CONCLUSION: High-dose intravenous melphalan with stem cell transplantation is an effective treatment in selected patients with AL amyloidosis-associated ESRD. Although the toxicity profile is greater in ESRD patients, the treatment offers the possibility of successful renal transplantation if hematologic remission is achieved. This treatment should be considered for patients with AL amyloidosis-associated ESRD.

Adult↗
PubMed2002

Systemic amyloidosis associated with pleomorphic sarcoma of the spleen and remission of nephrotic syndrome after removal of the tumor.

We report a case of a 57-year-old woman who was diagnosed with a systemic AA amyloidosis associated with a pleomorphic sarcoma of the spleen. Although the association and causality between chronic inflammatory states and systemic AA amyloidosis have been well established, the evidence linking solid malignancies to reactive AA amyloidosis is scarce. Our patient had a significant systemic amyloid deposition including biopsy-proven renal and cardiac AA amyloidosis. Subsequent evaluation uncovered the presence of a large splenic mass, which was treated by splenectomy. Histologically the splenic tumor was classified as pleomorphic sarcoma. The removal of the tumor resulted in a marked decline in proteinuria, stable renal and cardiac functions, and symptomatic improvement at 1-year follow-up. Based on the noted improvements, we speculate that the pleomorphic sarcoma of the spleen caused secondary amyloidosis in our case. Stromal tumors, although rare, may be associated with and should be considered in the differential diagnosis of the cause of AA amyloidosis.

Amyloidosis↗
PubMed2002

Heart rate variability as a predictor of mortality in patients with AA and AL amyloidosis.

AIMS: Patients with AA and AL amyloidosis have a limited life-expectancy. The aim of this study was to investigate whether heart rate variability can predict mortality in these patients. METHODS AND RESULTS: Twenty-two recently diagnosed patients with AA and 23 patients with AL amyloidosis were included. Fifteen patients (5 AA, 10 AL) died within 1 year. Twenty-four hour Holter recording was performed to quantify the mean of all normal to normal RR-intervals (mean NN) and the standard deviation of all normal to normal RR-intervals (SDNN). The SDNN predicted 1-year mortality in the total group of patients with amyloidosis. The median SDNN was 73 ms. In patients with an SDNN < or =73 ms, the risk of dying within 1 year was found to have increased 3.5-fold (P=0.0036; 95% CI 1.1-11.0). An SDNN < or =50 ms, a predictor of mortality in other patient groups, increased the risk of dying within 1 year 22-fold (P=0.0001; 95% CI 5.4-90.4). In contrast to patients with AA amyloidosis, in the subgroup analysis of patients with AL amyloidosis the SDNN remained a predictive parameter (SDNN < or =50 ms: risk ratio 11.5, 95% CI 2.4-56.2, P=0.0025). CONCLUSION: The SDNN is a strong predictor of short-term mortality in patients with AL amyloidosis.

Adult↗
PubMed1981

[Amyloidosis-a dreaded complication of juvenile chronic arthritis (JCA). (author's transl)].

Our studies describe symptoms, clinical course and prognosis of 60 children (out of a total of 2063 patients) suffering from chronic arthritis complicated with amyloidosis. Amyloidosis is predominantly caused by the systemic subgroup of juvenile chronic arthritis, which is characterized by high inflammation activity. The amyloidosis and the sequelae are one of the main causes of death in JCA (27 of the 90 lethal cases in our juvenile chronic arthritis unit were connected with amyloidosis). Proteinuria is the most frequent sign in the early stage of the amyloidosis. Early diagnose and treatment by cytostatic drugs like chlorambucil seems to improve the prognosis. The cumulative survival results in the existence of two different subgroup of amyloidosis.

Adolescent↗
PubMed1997

Variant-sequence transthyretin (isoleucine 122) in late-onset cardiac amyloidosis in black Americans.

BACKGROUND: After the age of 60, isolated cardiac amyloidosis is four times more common among blacks than whites in the United States; 3.9 percent of blacks are heterozygous for an amyloidogenic allele of the normal serum carrier protein transthyretin in which isoleucine is substituted for valine at position 122 (Ile 122). We hypothesized that the high prevalence of transthyretin Ile 122 is at least partially responsible for the increased frequency of senile cardiac amyloidosis among blacks. METHODS: Paraffin blocks of cardiac tissue were obtained from an earlier study of 52,370 autopsies in Los Angeles and were examined by immunohistochemical and DNA analyses. Samples were available from 32 of 55 blacks and 20 of 78 whites over 60 years of age with isolated cardiac amyloidosis and from two control groups (228 cases). RESULTS: Transthyretin amyloidosis was identified in 31 of the 32 cardiac-tissue samples from the black patients and in 19 of the 20 samples from the white patients. Six of the 26 analyzable DNA samples (23 percent) from the black patients and none of the 19 samples from the white patients were heterozygous for the Ile 122 variant. Four of 125 DNA samples obtained at autopsy (3.2 percent) from a second, more recent, age-matched cohort of blacks without amyloidosis at the same institution were heterozygous for the transthyretin Ile 122 allele. On reexamination the cardiac tissue from these four patients contained small amounts of amyloid not detected at the initial autopsies. All subjects with the Ile 122 variant had ventricular amyloid. CONCLUSIONS: The assessment of elderly black patients with unexplained heart disease should include a consideration of transthyretin amyloidosis, particularly that related to the Ile 122 allele.

Aged↗
PubMed2002

Lack of effect of dimethylsulphoxide in cutaneous amyloidosis.

OBJECTIVE: To evaluate dimethylsulphoxide (DMSO) as a topical therapeutic agent for the treatment of two major variants of primary, localized, cutaneous amyloidosis -- macular amyloidosis (MA) and papular/lichen amyloidosis (LA) -- using a monocentric, open, prospective trial. METHODS: A total of 25 patients with histopathologically proven cutaneous amyloidosis - MA, LA and BA (biphasic amyloidosis) (13 MA, seven LA, five BA) were requested to undertake a once daily application of either 50% or 100% DMSO for 12 weeks. Progress was regularly assessed with a scoring system for pruritus, pigmentation and papules. RESULTS: In 17 (68%) cases, the scores for pruritus decreased but never completely disappeared in any of the patients. Lightening of the pigmentation was noted in only six (24%) cases and the scores for the papules were decreased in only two out of 12 (16.6%) patients. Post-treatment skin biopsies did not reveal a reduction/disappearance of the amyloid deposits. In the follow-up period, the relapse rate was 100%. CONCLUSION: DMSO does not have an anti-pruritic effect or amyloid-dissolving properties. As the results are partial and transient, it is concluded that DMSO is not a satisfactory treatment for cutaneous amyloidosis.

Adolescent↗
PubMed2005

Unexpectedly high incidence of visceral AA-amyloidosis in slaughtered cattle in Japan.

Experimental mouse AA amyloidosis can be transmissible by dietary ingestion of amyloid fibrils and it is well known that AA amyloidosis occasionally develops in aged cattle. Bovine liver and intestine have conventionally been used in Oriental foods, and the incidence of visceral AA amyloidosis in slaughtered cattle was evaluated. Renal tissues from 302 aged cattle older than 4 years were obtained from a local abattoir. Amyloid deposition was microscopically examined and amyloid protein was immunochemically determined. Renal amyloid deposition was seen in 15 out of 302 cattle with no previous history of diseas, an incidence of 5.0%. Amyloid protein in these cattle was AA and they had pathological findings in their visceral organs on gross examination. The incidence of visceral AA amyloidosis in slaughtered cattle in this study was disturbingly high compared with those (0.4-2.7%) previously reported from Japan and other foreign countries. AA amyloidosis is a life-threatening complication in patients with chronic inflammatory diseases and these patients at risk should avoid ingesting food that may possibly contain AA amyloid fibrils. More detailed information on cattle amyloidosis is required to guarantee the safety of our food.

Amino Acid Sequence↗