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PubMed2005

Protein fibrils in nature can enhance amyloid protein A amyloidosis in mice: Cross-seeding as a disease mechanism.

Secondary, or amyloid protein A (AA), amyloidosis is a complication of chronic inflammatory diseases, both infectious and noninfectious. AA constitutes the insoluble fibrils, which are deposited in different organs, and is a major N-terminal part of the acute phase protein serum AA. It is not known why only some patients with chronic inflammation develop AA amyloidosis. Nucleation is a widely accepted mechanism in amyloidogenesis. Preformed amyloid-like fibrils act as nuclei in amyloid fibril formation in vitro, and AA amyloid fibrils and synthetic amyloid-like fibrils also may serve as seed for fibril formation in vivo. In addition to amyloid fibrils, there is a variety of similar nonmammalian protein fibrils with beta-pleated structure in nature. We studied three such naturally occurring protein fibrils: silk from Bombyx mori, Sup35 from Saccharomyces cerevisiae, and curli from Escherichia coli. Our results show that these protein fibrils exert amyloid-accelerating properties in the murine experimental AA amyloidosis, suggesting that such environment factors may be important risk factors in amyloidogenesis.

Actins↗
PubMed2002

Transmissibility of systemic amyloidosis by a prion-like mechanism.

The generation of amyloid fibrils from an amyloidogenic polypeptide occurs by a nucleation-dependent process initiated in vitro by seeding the protein solution with preformed fibrils. This phenomenon is evidenced in vivo by the fact that amyloid protein A (AA) amyloidosis in mice is markedly accelerated when the animals are given, in addition to an inflammatory stimulus, an i.v. injection of protein extracted from AA amyloid-laden mouse tissue. Heretofore, the chemical nature of this "amyloid enhancing factor" (AEF) has not been definitively identified. Here we report that the active principle of AEF extracted from the spleen of mice with silver nitrate-induced AA amyloidosis was identified unequivocally as the AA fibril itself. Further, we demonstrated that this material was extremely potent, being active in doses <1 ng, and that it retained its biologic activity over a considerable length of time. Notably, the AEF was also effective when administered orally. Our studies have provided evidence that AA and perhaps other forms of amyloidosis are transmissible diseases, akin to the prion-associated disorders.

Administration, Oral↗
PubMed1986

Polymerization of intact beta 2-microglobulin in tissue causes amyloidosis in patients on chronic hemodialysis.

Systemic amyloidosis with a predilection for bone and synovium may complicate the course of patients on long-term hemodialysis. This form of amyloidosis can be typed as distinct from other amyloid diseases by using small tissue samples obtained by bone biopsy and at postmortem. Immunoblot analysis of two-dimensional gels of partially solubilized amyloid fibrils established that tissue deposits are composed of monomers, dimers, and higher polymers of beta 2-microglobulin (beta 2m) and that amyloid P component was also present. Anti-beta 2m antiserum recognized fibrils, as shown by immunoelectron microscopy. Purified monomer isolated from dissociated fibrils yielded peptides corresponding to the entire known sequence of beta 2m. Virtually all serum beta 2m, as well as that present in tissue fluid bathing amyloid fibrils, was monomeric. Hemodialysis-related amyloidosis is an example of a deposition disease occurring in hemodialysis patients. We have shown conclusively that, in this amyloid disease, polymerization of an intact normal serum protein to a fibrillar configuration may occur without proteolysis. We propose the designation A beta 2m for this form of amyloid fibril subunit protein.

Amino Acid Sequence↗
PubMed1987

Hereditary cerebral hemorrhage with amyloidosis in patients of Dutch origin is related to Alzheimer disease.

Hereditary cerebral hemorrhage with amyloidosis in Dutch patients is an autosomal dominant form of vascular amyloidosis restricted to the leptomeninges and cerebral cortex. Clinically the disease is characterized by cerebral hemorrhages leading to an early death. Immunohistochemical studies of five patients revealed that the vascular amyloid deposits reacted intensely with an antiserum raised against a synthetic peptide homologous to the Alzheimer disease-related beta-protein. Silver stain-positive, "senile plaque-like" structures were also labeled by the antiserum, yet these lesions lacked the dense amyloid cores present in typical plaques of Alzheimer disease. No neurofibrillary tangles were present. Amyloid fibrils were purified from the leptomeningeal vessels of one patient who clinically had no signs of dementia. The protein had a molecular weight of approximately equal to 4000 and its partial amino acid sequence to position 21 showed homology to the beta-protein of Alzheimer disease and Down syndrome. These results suggest that hereditary cerebral hemorrhage with amyloidosis of Dutch origin is pathogenetically related to Alzheimer disease and support the concept that the initial amyloid deposition in this disorder occurs in the vessel walls before damaging the brain parenchyma. Thus, deposition of beta-protein in brain tissue seems to be related to a spectrum of diseases involving vascular syndromes, progressive dementia, or both.

Alzheimer Disease↗
PubMed1994

A role for destabilizing amino acid replacements in light-chain amyloidosis.

Light-chain (L-chain) amyloidosis is characterized by deposition of fibrillar aggregates composed of the N-terminal L-chain variable region (VL) domain of an immunoglobulin, generally in individuals overproducing a monoclonal L chain. In addition to proteolytic fragmentation and high protein concentration, particular amino acid substitutions may also contribute to the tendency of an L chain to aggregate in L-chain amyloidosis, although evidence in support of this has been limited and difficult to interpret. In this paper we identify particular amino acid replacements at specific positions in the VL domain that are occupied at frequencies significantly higher in those L chains associated with amyloidosis. Analysis of the structural model for the VL domain of the Bence-Jones protein REI suggests that these positions play important roles in maintaining domain structure and stability. Using an Escherichia coli expression system, we prepared single-point mutants of REI VL incorporating amyloid-associated amino acid replacements that are both rare and located at structurally important positions. These mutants support ordered aggregate formation in an in vitro L-chain fibril formation model in which wild-type REI VL remains soluble. Moreover, the ability of these sequences to aggregate in vitro correlates well with the extent to which domain stability is decreased in denaturant-induced unfolding. The results are consistent with a mechanism for the disease process in which the VL domain, either before or after proteolytic cleavage from the L-chain constant region domain, unfolds by virtue of one or more destabilizing amino acid replacements to generate an aggregation-prone nonnative state.

Amino Acid Sequence↗
PubMed1998

Acceleration of amyloid protein A amyloidosis by amyloid-like synthetic fibrils.

Amyloid protein A (AA) amyloidosis is a consequence of some long-standing inflammatory conditions, and subsequently, an N-terminal fragment of the acute phase protein serum AA forms beta-sheet fibrils that are deposited in different tissues. It is unknown why only some individuals develop AA amyloidosis. In the mouse model, AA amyloidosis develops after approximately 25 days of inflammatory challenge. This lag phase can be shortened dramatically by administration of a small amount of amyloid extract containing an as yet undefined amyloid-enhancing factor. In the present study, we show that preformed amyloid-like fibrils made from short synthetic peptides corresponding to parts of several different amyloid fibril proteins exert amyloidogenic enhancing activity when given i.v. to mice at the induction of inflammation. We followed i.v. administered, radiolabeled, heterologous, synthetic fibrils to the lung and to the perifollicular area in the spleen and found that new AA-amyloid fibrils developed on these preformed fibrils. Our findings thus show that preformed, synthetic, amyloid-like fibrils have an in vivo nidus activity and that amyloid-enhancing activity may occur, at least in part, through this mechanism. Our findings also show that fibrils of a heterologous chemical nature exert amyloid-enhancing activity.

Amino Acid Sequence↗
PubMed2002

Primary localized bilateral conjunctival amyloidosis and epiphora.

BACKGROUND: Conjunctival amyloidosis is a rare entity, which can present with epiphora. The management options, including the surgical treatment of this disease, are illustrated with a case study. METHODS: A combination of retrospective and prospective review of a patient's clinical findings, course and treatment outcome. RESULTS: A middle-aged patient with epiphora due to localized conjunctival amyloidosis is described. The clinical course of the epiphora during a 10-year period revealed a decrease on the initially symptomatic side and involvement of the opposite side despite bilateral progressive lacrimal drainage stenosis. The pathophysiology of this phenomenon is discussed. The progressive conjunctival deposits in this patient eventually required operative debulking through a conjunctival approach. Medial ectropion and punctal stenoses were also simultaneously corrected. The patient became symptom free one week after these operative interventions. CONCLUSIONS: Localized conjunctival amyloidosis is a chronic, slowly progressive disease, which is frequently bilateral. Associated ocular involvement does not seem to be a part of this disease, even with long-term follow-up. The treatment of associated epiphora requires an organized approach to the underlying cause(s). The epiphora may be managed by a staged correction of its pathogenic mechanisms.

Aged↗
PubMed1998

Localised primary amyloidosis of inguinal lymph node with superimposed bone metaplasia.

We present here a case of localised primary amyloidosis of the right inguinal lymph node in a 42 year old female. On gross examination the specimen was 4.0 x 4.0 x 3.2 cm in size with a tan-pink color and two whitish-yellow areas of hard consistency. Histologically the lymph node was replaced by an eosinophilic amorphous material, alkaline Congo red, crystal violet, thioflavine T and sodium sulphate-alcian blue (SAB). We observed areas of mature bone metaplasia alternating with sheets of plasma cells and clusters of foreign body giant cell reaction. Immunohistochemical study showed anti-lambda chain staining within the amorphous material. The negative clinical history, physical examination, normal serum electrophoresis and bone marrow and rectal biopsy allowed us to make the diagnosis of localised primary amyloidosis of lymph node. The patient is alive and without evidence of disease progression to systemic amyloidosis or plasma cell dyscrasia, after clinical follow-up of seven years.

Adult↗
PubMed2002

Long-term effects of losartan on proteinuria and renal function in patients with renal amyloidosis.

OBJECTIVE: To investigate the effect of the angiotensin II receptor antagonist losartan on proteinuria in secondary amyloidosis cases. MATERIAL AND METHODS: Sixteen patients with renal biopsy-proven AA amyloidosis with proteinuria were included in the study. All the patients had received colchicine treatment for at least 18 months. The patients were divided into two groups with similar age and gender distributions. Eight patients were given losartan at a dose of 50 mg/day for 12 months and the other 8 patients served as controls. Mean arterial blood pressure, proteinuria, serum albumin level and renal function were determined at the initiation of the study and after 1 and 12 months. RESULTS: There were no significant differences in proteinuria, serum albumin level, renal function or mean arterial blood pressure at the initiation of the study. In the losartan group daily proteinuria decreased significantly from 5.2 +/- 0.7 g at the initiation of the study to 3.9 +/- 1.2 g at 1 month and 3.6 +/- 0.8 g at 12 months, while in the control group it changed from 4.6 +/- 1.0 g to 4.7 +/- 1.0 g and 6.1 +/- 1.2 g, respectively. The increment at 12 months was significant. After 12 months of treatment with losartan, proteinuria was significantly lower in comparison to the degree of proteinuria in the control group. Serum albumin level increased significantly in the losartan group but was unchanged in the control group. In the control group, creatinine clearance showed a significant decrease. There was no significant difference in mean arterial blood pressure measurements, serum creatinine levels, total protein, albumin and creatinine clearance levels between the two groups. CONCLUSIONS: Losartan seemed to prevent an increase in proteinuria without altering the creatinine clearance level in patients with amyloidosis type AA during a 12-month period. This indicates that losartan may be used to decrease proteinuria in this patient group. However, our results are only preliminary and need to be confirmed by larger studies.

Adult↗
PubMed2003

Amyloidosis of the seminal vesicle--a case report and review of the literature.

The finding of amyloid deposits in the seminal vesicles has been known for many years. The deposits are usually localized and asymptomatic. In recent years seminal vesicle amyloidosis has been reported to simulate prostate and bladder cancer invasion on MRI. We therefore feel that knowledge of the entity is important and present herein a typical case confirming the previous findings that amyloidosis of the seminal vesicles is a unique form of amyloidosis, a relatively common incidental finding and one that may be related to prostate cancer.

Amyloidosis↗
PubMedDate not supplied

Atypical amyloidosis: diagnostic challenges and the role of immunoelectron microscopy in diagnosis.

Renal AL-amyloidosis is usually lambda-light-chain-related, particularly lambda type 6. Kappa-light-chain-related renal amyloidosis is a rare entity. Relatively few cases have been reported in the literature. The pathologic findings in some of these cases may mimic other disease processes. It is important to recognize the different morphologic expressions of this entity in order to render the right diagnosis. The authors discuss one such case in which the initial pathologic impression was erroneous and, upon further studies, including ultrastructural immunogold labeling, the diagnosis of kappa-light-chain-related renal amyloidosis was established.

Aged↗
PubMed2004

Addison's disease associated with widespread abdomino-pelvic visceral calcification due to secondary amyloidosis: a case report.

We report the case of a 42-year-old woman who presented with Addison's disease with widespread abdomino-pelvic visceral calcifications due to secondary amyloidosis. AA amyloidosis and calcification were supported by histological evidence of liver tissue. To our knowledge, no other case with such extensive visceral calcification involving the adrenals, liver, ovaries, and renal secondary to amyloidosis has been published.

Abdomen↗
PubMed2002

Primary amyloidosis presenting with massive generalized lymphadenopathy.

Systemic amyloidosis is an unusual cause of generalized massive lymphadenopathy. In such cases the clinical picture may mimic lymphoma. We report a case of generalized massive lymphadenopathy caused by amyloidosis. The 55-year old female patient was admitted to our hospital with dyspnea and edema in the lower extremities. These were diminished breath sounds with bilateral basal congestion hepatosplenomegaly and generalized massive lymphadenopathy in axillary, cervical, and inguinal areas. The diagnosis was made by excisional biopsy of one of the involved lymph nodes. Amyloidosis (AL type) was shown and treatment with melphalan and prednisone was initiated. Unfortunately the patient died after 51 days in hospital.

Amyloidosis↗
PubMed2004

Mutant fibrinogen A-alpha-chain associated with hereditary renal amyloidosis and peripheral neuropathy.

A middle age Portuguese woman was investigated for renal amyloidosis. She presented with progressive renal failure, proteinuria, hypertension, and sensory symptoms in the feet. Clinical and neurophysiological evaluation disclosed sensory-autonomic neuropathy. Cardiovascular tests and 123-MIBG investigation showed parasympathetic dysfunction and decrease of myocardial innervation, in accordance with small fiber neuropathy, as usually observed in amyloidosis. Immunohistochemical studies revealed AFib amyloidosis and genetic studies the amino acid exchange Glu526Val of the fibrinogen Aalpha-chain mutation, which was also present in one of her sons. The mutant gene in this patient was associated with the same haplotype as all other reported cases of Glu526Val mutations. This is the first reported AFibamyloidosis in Portugal, and the first case of AFib in which sensory and autonomic nerve fiber dysfunction is described, indicating that small nerve fiber lesion can occur in the fibrinogen Aalpha chain mutation. This can be important for prognosis, in particular when liver transplantation is considered for treatment.

Amino Acid Substitution↗
PubMed2004

VAD with or without subsequent high-dose melphalan followed by autologous stem cell support in AL amyloidosis: Japanese experience and criteria for patient selection.

Patients with AL amyloidosis were treated with VAD (vincristine, doxorubicin and dexamethasone) with or without high-dose melphalan followed by auto-PBSCT according to eligibility criteria based on disease severity, and prospectively investigated the therapeutic benefits and complications. Thirty-one patients were enrolled in this study. VAD and subsequent high-dose melphalan with auto-PBSCT were performed only in patients who met all of the eligibility criteria. Among patients ineligible for this treatment, VAD alone was performed in those with satisfactory general status. Eleven patients met the eligibility criteria, and of these, 7 were treated with VAD and subsequent high-dose melphalan with auto-PBSCT. Seven patients received VAD alone, and the remaining 17 were treated with the supportive therapy. Among the 14 patients treated with chemotherapy, 9 (5 of the 7 treated with VAD and high-dose melphalan, and 4 of the 7 treated with VAD alone) showed complete hematological response with apparent improvement of amyloidosis-related clinical symptoms. Serious complications of chemotherapy were cytomegalovirus infection and pneumocystis carinii pneumonia seen in 1 and 2 patients, respectively. These chemotherapies may be effective for reduction of M-protein and are also useful in improving of amyloidosis-induced organ dysfunction. In patients who cannot tolerate high-dose melphalan, VAD alone is a potent therapeutic option, although there are possible harmful effects on the heart and peripheral nerve.

Adult↗
PubMed2005

Multicentre versus single centre approach to rare diseases: the model of systemic light chain amyloidosis.

BACKGROUND: Early diagnosis and supportive therapy are important in primary systemic amyloidosis (AL). In 1986, a national network was started in Italy to increase the awareness of medical professionals, achieve early diagnoses, and provide locally qualified care. We compared the AL patient population observed at a referral center, Mayo Clinic, with that recruited through the Italian network. METHODS: All the patients diagnosed with AL between 1988 and 1998 at Mayo Clinic or in any of the centers of the Italian Amyloidosis Study Group were included. FINDINGS: The median survival of Italian patients was 30 months versus 12 months in the Mayo cohort (P<0.001). Mayo Clinic patients were older (66.4 vs. 60.1 y, P<0.001). In the Italian cohort, dominant kidney involvement was more frequent (49.3% vs. 27.8%, P<0.001), while in the Mayo group more patients had dominant cardiac amyloidosis (37.4% vs. 27.8%, P=0.03). Italian patients were more likely to have kidney involvement without heart involvement (43.7% vs. 19.6%, P<0.001). Among Italian patients, 78.9% received alkylating agents versus 60.9% in the Mayo cohort (P<0.001). The multivariate analysis showed that age, performance status, dominant heart involvement, >or=2 organs involved, and treatment with alkylating agents independently predicted survival. This study shows that AL patient populations may differ significantly between centers according to their accrual systems, with possible impact on treatment trials.

Amyloidosis↗
PubMed2005

Localized amyloidosis: a survey of 35 French cases.

Since the prognosis of localized amyloidosis remains unclear, we conducted a survey to define the characteristics and the course of this disease. The charts of 35 patients with either laryngeal (14 patients), tracheobronchial (10 patients), colonic (1 patient), or lower urinary tract amyloidosis (10 patients) were analyzed. The average age at diagnosis was 52.7+/-12 years (range 33-73 years). The amyloid protein type was specified to be amyloid light chain (AL) in 15 cases. All patients had undergone additional biopsies (accessory salivary glands, rectal, fat pad and bone marrow aspirates) to rule out a systemic disease. Symptomatic treatments included endoscopic excision and laser therapy. Colchicine and chemotherapy with prednisone and melphalan were prescribed with limited success. During a mean follow-up period of 6.1+/-5.3 years no patient developed a systemic form of amyloidosis. Six deaths were reported, one related to the disease because of a fatal airway hemorrhage. We suggest that immunolabeling studies should be more routinely performed. There was no risk of developing a systemic disease from local amyloid deposits in our survey. However, local evolution can be life-threatening. Such patients should be referred to specialist centers for further evaluation. Management requires close follow-up to exclude recurrence and to determine the appropriate symptomatic treatment.

Adult↗
PubMed2006

Natural history of thromboembolism in AL amyloidosis.

To determine the natural history of thromboembolism in patients with biopsy-proven AL amyloidosis, medical records of 2,132 patients evaluated at Mayo Clinic between 1975 and 2000 were reviewed. Forty patients (21 male) were found to have objectively documented thromboembolism. The median age was 65 years. Four patients had a monoclonal gammopathy of undetermined significance, 20 had an unspecified plasma cell proliferative disorder, 11 had multiple myeloma, and 1 had Waldenström macroglobulinemia. Twelve patients had cardiac amyloid, and 20 had renal amyloid. Neither the extent of the amyloid nor the type of monoclonal protein was predictive of the development of thromboembolic events. Thromboembolism preceded the diagnosis of AL amyloidosis in 11 patients, occurred at the time of diagnosis or within 1 month after diagnosis in 11 patients, and occurred 1 month or more after diagnosis in 18 patients. Twenty-nine patients (73%) had venous thrombosis and 11 (28%) had arterial thrombosis. Eight patients (20%) died within 1 month after the thrombotic event, and 18 (45%) died within 1 year. The development of thrombosis in patients with AL amyloidosis appears to predict significant mortality within the first month and year after the event.

Aged↗