[Interdisciplinary guidelines for the diagnosis and therapy of extracerebral amyloidosis].
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Amyloidosis↗
Biomedical subjects
Reinhold P Linke
Publications and source records attributed to Reinhold P Linke.
Classification of amyloidosis: misdiagnosing by way of incomplete immunohistochemistry and how to prevent it.
Classification of every individual case of amyloid disease is necessary in order to recognize its origin and its possible pathogenesis for therapeutic consideration. Classification of the amyloids can be performed in different ways. One method primarily exploits serum proteins-but these are risk factors only, and therefore render only ancillary information. In principle, one cannot establish the diagnosis alone through their use. Another approach analyzes the origin of the deposited amyloids, either by extracting the amyloid proteins followed by immunochemical or chemical analysis, or by using immunohistochemistry. Based on chemical analysis of prototypes of amyloid fibril proteins, we have developed a profile of antibodies over the years that specifically identify amyloid in tissue sections. These antibodies have been used for years as a routine service for clinicians and pathologists in immunohistochemically classifying amyloid found in formalin-fixed tissue sections. The typing is always controlled by established amyloid classes. In several cases, we have been asked for a second opinion on a diagnosed amyloid class. Our own immunohistochemical data were then compared with those submitted. These submitted immunohistochemical results represented misdiagnoses of amyloid classes in most patients, since the technique performed was usually incomplete. It is the purpose of this report to analyze such cases and to document some of the typical mistakes. Here, we show how to avoid common pitfalls and how one can arrive at a correct diagnosis using immunohistochemistry appropriately.
Amyloid↗
Indications for high-dose chemotherapy with autologous stem cell support in patients with systemic amyloid light chain amyloidosis.
Systemic amyloid light chain amyloidosis is a protein conformation disorder caused by a clonal plasma cell dyscrasia. Symptoms result from fibrillar extracellular deposits in kidney, heart, liver, gut, peripheral nervous system and other tissues. The deposits disrupt organ function and ultimately lead to death. The prognosis of systemic amyloid light chain (AL) amyloidosis is poor; less than 5% of all patients survive 10 years or longer. Using conventional chemotherapy, the median survival could be prolonged by 4 months. Treatment with high-dose melphalm (HDM) and autologous stem cell transplantation (ASCT) of selected patients has been shown to arrest and even to reverse the disease course. This procedure however remains controversial because treatment related mortality (TRM) in AL amyloidosis is substantially higher (15-40%) than in multiple myeloma (<5%). Here we review recent results of ASCT, eligibility criteria for HDM and report our own treatment results in 41 patients.
Adult↗
Expression of serum amyloid A, in normal, dysplastic, and neoplastic human colonic mucosa: implication for a role in colonic tumorigenesis.
Serum amyloid A (SAA) is an acute phase reactant, whose level in the blood is elevated in response to trauma, infection, inflammation, and neoplasia. Elevated levels of SAA in the serum of cancer patients were suggested to be of liver origin rather than a tumor cell product. The role of SAA in human malignancies has not been elucidated. We investigated the expression of SAA at various stages of human colon carcinoma progression. Nonradioactive in situ hybridization applied on paraffin tissue sections from 26 colon cancer patients revealed barely detected SAA mRNA expression in normal looking colonic epithelium. Expression was increased gradually as epithelial cells progressed through dysplasia to neoplasia. Deeply invading colon carcinoma cells showed the highest levels of SAA. Expression was also found in colon carcinoma metastases. Cells of lymphoid follicles of the intestinal wall, inflammatory cells, ganglion cells, and endothelial cells, also expressed SAA mRNA. Immunohistochemical staining revealed SAA protein expression that colocalized with SAA mRNA expression. RT-PCR analysis confirmed the expression of the SAA1 and SAA4 genes in colon carcinomas, expression that was barely detectable in normal colon tissues. These findings indicate local and differential expression of SAA in human colon cancer tissues and suggest its role in colonic tumorigenesis.
Adenocarcinoma↗
Raft lipids as common components of human extracellular amyloid fibrils.
Amyloid fibrils are fibrillar polypeptide aggregates from several degenerative human conditions, including Alzheimer's and Creutzfeldt-Jakob diseases. Analysis of amyloid fibrils derived from various human diseases (AA, ATTR, Abeta2M, ALlambda, and ALkappa amyloidosis) shows that these are associated with a common lipid component that has a conserved chemical composition and that is specifically rich in cholesterol and sphingolipids, the major components of cellular lipid rafts. This pattern is not notably affected by the purification procedure, and no tight lipid interactions can be detected when preformed fibrils are mixed with lipids. By contrast, the early and prefibrillar aggregates formed in an AA amyloid-producing cell system interact with the raft marker ganglioside-1, and amyloid formation is impaired by addition of cholesterol-reducing agents. These data suggest the existence of common cellular mechanisms in the generation of different types of clinical amyloid deposits.
Amyloid↗
Senile seminal vesicle amyloid is derived from semenogelin I.
Senile seminal vesicle amyloid (SSVA), one of the most common forms of localized amyloidosis, is associated with the male aging process. Although it had been posited that the amyloidogenic component originated from exocrine cells and that, on the basis of immunohistochemistry, that the amyloid was composed of lactoferrin, the nature of SSVA was never established definitively. To address this issue, we have used our microanalytic techniques to characterize the structure of the congophilic green birefringent protein extracted from 5 such amyloid-containing specimens. Mass spectrometric analysis revealed that in all cases, the fibrils were composed mainly of polypeptide fragments identical in sequence to the N-terminal portion of the major secretory product of seminal vesicles, namely semenogelin I (SgI). Although lactoferrin was detected in 3 instances, the trace amount and seemingly intact form of this molecule indicated that it was not the amyloidogenic molecule. The SgI nature of the amyloid was confirmed through demonstration that the deposits were immunostained specifically with Sgl-reactive antibodies. The results of our research provide unequivocal evidence that SSVA is derived from SgI, and we provisionally designate this form of amyloidosis as ASgI.
Aged↗
Histochemical and topo-optical investigations on tissue-isolated and in vitro amyloid fibrils.
An improved microscopic slide preparation for staining of tissue-isolated and in vitro amyloid fibrils is described in detail. Specimens were prepared by slow drying of an amyloid fibril suspension on aminoalkyl-silanised glass slides underneath a coverglass. The purpose of this method is to obtain microscopically visible fibers. Polarization microscopy was performed on unstained fibers in different embedding media, on fibers stained with Congo red, toluidine blue, 1,9-dimethylmethylene blue, anisotropic PAS reaction and Sudan black. Results were identical in 8 tissue-isolated amyloid fibril preparations. The refractive index of amyloid was about 1.5, as expected for protein fibrils. Congo red-stained fibrils showed yellow or blue-green polarization colors, while staining with toluidine blue or 1,9-dimethylmethylene blue induced green or orange polarization colors. The latter dyes stained the fibrils even in buffers with low pH or high ionic strength, pointing to strong acidic groups like sulphates in amyloid. The anisotropic PAS reaction for selective demonstration of periodate reactive carbohydrates in tissue-isolated amyloid fibrils was positive. Thus, linearly ordered acidic groups and carbohydrate residues could be detected for the first time in tissue-isolated amyloid fibrils using an improved technique for microscopic slide preparation on one side and topo-optical reactions on the other.
Amyloid↗
Ptosis from localized A-lambda-amyloid deposits in the levator palpebrae muscle.
PURPOSE: To describe a patient with unilateral ptosis caused by localized amyloid deposits of immunoglobulin lambda-light chains (A-lambda-amyloid) in the levator palpebrae muscle. STUDY DESIGN: Case report and literature review. PARTICIPANT: A 32-year-old otherwise healthy female with right-sided unilateral ptosis. METHODS: The patient presented with right-sided unilateral ptosis without other ocular abnormalities. Palpebral fissures measured 5 mm on the right side and 8 mm on the left. Systemic evaluation, including neurologic and neuroradiologic examinations, was normal. RESULTS: Several years after initial presentation, conjunctival amyloid deposits appeared. Ptosis surgery with resection of the levator muscle was performed, revealing massive deposits of A-lambda-amyloid in the excised tissue. CONCLUSIONS: Our patient had unilateral ptosis due to localized A-lambda-amyloid deposits in the levator muscle. No other amyloid deposits were initially found. Visible conjunctival deposits developed only years later. Ocular amyloidosis with isolated initial involvement of the levator muscle is a rare condition. Localized monoclonal gammopathy may have been the cause of this unique presentation.
Adult↗
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↗
High-dose melphalan with autologous stem cell transplantation after VAD induction chemotherapy for treatment of amyloid light chain amyloidosis: a single centre prospective phase II study.
Amyloid light chain (AL) amyloidosis is the result of a clonal plasma cell expansion, in which monoclonal light chains transform to amyloid deposit in various tissues and can lead to organ dysfunction and organ failure. The median survival of patients with AL amyloidosis without therapy is 10-14 months. With high-dose melphalan (HDM) and autologous stem cell transplantation (ASCT), haematological and clinical remission rates of up to 50% of treated patients have been reported from phase II studies. HDM followed by ASCT appears to prolong survival in patients, if haematological remission can be reached. In this phase II study, we evaluated vincristine, adriamycin and dexamethasone (VAD) as induction chemotherapy prior to stem cell mobilization and HDM with ASCT. The regimen was, in general, feasible in patients with AL amyloidosis, but VAD chemotherapy had a considerable World Health Organization (WHO) grade III-IV toxicity (25%) and mortality (7%) rate. VAD pretreatment did not interfere with stem cell mobilization and HDM with ASCT was possible in 86% of patients. The overall treatment efficacy was comparable with reported results of HDM and ASCT without preceding chemotherapy. We could not show an additional benefit of VAD induction in terms of increasing haematological response rate; however the 13% mortality rate after HDM and ASCT in our series was lower than the previous report.
Adult↗
[Systemic ALlambda amyloidosis associated with vascular fragility].
A 63-year-old patient had experienced bilateral spontaneous periorbital hemorrhage for one year. After hospitalization because of recurring hemoptysis, biopsies of skin and colon revealed systemic ALlambda amyloidosis. In addition, the heart and lungs appeared to be involved. Monoclonal gammopathy was excluded by a normal plasma cell count and a polyclonal expression pattern in a bone marrow sample and by radiographic examination. The patient was treated with a relatively non-aggressive regimen of melphalan and prednisolone monthly with careful hematologic monitoring. This approach led to a significant improvement in relevant parameters. Recent advances in diagnosis, monitoring and therapy have made it easier to manage patients with amyloidosis with their poor prognosis.
Amyloidosis↗
Selection of D-amino-acid peptides that bind to Alzheimer's disease amyloid peptide abeta1-42 by mirror image phage display.
A mirror image phage display approach was used to identify novel and highly specific ligands for Alzheimer's disease amyloid peptide Abeta(1-42). A randomized 12-mer peptide library presented on M13 phages was screened for peptides with binding affinity for the mirror image of Abeta(1-42). After four rounds of selection and amplification the peptides were enriched with a dominating consensus sequence. The mirror image of the most representative peptide (D-pep) was shown to bind Abeta(1-42) with a dissociation constant in the submicromolar range. Furthermore, in brain tissue sections derived from patients that suffered from Alzheimer's disease, amyloid plaques and leptomeningeal vessels containing Abeta amyloid were stained specifically with a fluorescence-labeled derivative of D-pep. Fibrillar deposits derived from other amyloidosis were not labeled by D-pep. Possible applications of this novel and highly specific Abeta ligand in diagnosis and therapy of Alzheimer's disease are discussed.
Alzheimer Disease↗
Severe problems in diagnosing amyloid diseases.
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Amyloid↗
Diarrhea, nephrotic syndrome and hidradenitis suppurativa: an unusual case.
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Albuminuria↗
No regression of renal AL amyloid in monoclonal gammopathy after successful autologous blood stem cell transplantation and significant clinical improvement.
BACKGROUND: High-dose chemotherapy followed by autologous blood stem cell transplantation induces remission of plasma cell dyscrasia in patients with AL amyloidosis. The impact of this treatment on the glomerular amyloid mass is still unknown. METHODS: In the present study, the quantity of the renal amyloid mass before and more than 3 years after high-dose melphalan treatment and autologous blood stem cell transplantation was assessed in two patients. At the time of the second renal biopsy, both patients were in complete remission without detectable serum and urinary monoclonal IgA-lambda and a normal percentage of plasma cells in the bone marrow. RESULTS: In both patients with biopsy-proven AL amyloidosis, urinary protein excretion decreased from 7 g/24 h to <2 g/24 h more than 3 years after autologous blood stem cell transplantation. In contrast, glomerular amyloid deposits persisted, as shown in the second biopsy. CONCLUSION: Despite complete remission of the plasma cell dyscrasia and improvement of glomerular permeability, the amount of glomerular amyloid mass did not regress.
Amyloid↗
Adhesion of human platelets to serum amyloid A.
Serum amyloid A (SAA) is an acute phase reactant, and its level in the blood is elevated to 1000-fold in response of the body to trauma, infection, inflammation, and neoplasia. SAA was reported to inhibit platelet aggregation and to induce adhesion of leukocytes. This study looked at adhesion of human platelets to SAA. Immobilized SAA supported the adhesion of human washed platelets; level of adhesion to SAA was comparable to fibronectin and lower than to fibrinogen. Adhesion to SAA was further enhanced by Mn(2+) and the physiological agonist, thrombin. Platelet adhesion to SAA was completely abolished by anti-SAA antibody. SAA-induced adhesion was inhibited by antibodies against the integrin receptor alphaIIbbeta3, by the peptide GRGDSP and by SAA-derived peptide containing YIGSR-like and RGD-like adhesion motifs (amino acids 29 to 42). Adhesion was not inhibited by control immunoglobulin G, by antibody against the integrin receptor alphaVbeta3, by the peptide GRGESP, and by SAA-derived peptide that includes incomplete RGD motif. SAA-derived peptide 29 to 42 also inhibited platelet adhesion to fibronectin. Transfected human melanoma cells expressing alphaIIbbeta3 adhered to SAA, whereas transfected cells expressing alphaVbeta3 did not. By using flow cytometry, the alphaIIbbeta3 cells displayed significantly higher levels of binding of soluble SAA than the alphaVbeta3 cells. These data indicate that human platelets specifically adhere to SAA in an RGD- and alphaIIbbeta3-dependent manner. Thus, SAA may play a role in modulating platelet adhesion at vascular injury sites by sharing platelet receptors with other platelet-adhesive proteins.
Adult↗
99mTc-DPD scintigraphy in transthyretin-related familial amyloidotic polyneuropathy.
Familial amyloidotic polyneuropathy (FAP) caused by amyloidogenic transthyretin (ATTR) mutations is the most common form of hereditary amyloidosis. We investigated the diagnostic value of the bone scanning agent technetium-99m 3,3-diphosphono-1,2-propanodicarboxylic acid (99mTc-DPD) in this disease. Eight patients (four males, four females; age 54.4+/-8.3 years, range 43-67 years) with ATTR-FAP proven by immunohistochemistry and molecular analysis and a control group comprising ten oncological out-patients (five males, five females; age 53.4+/-8.5 years, range 34-66 years) without evidence of bony metastases were studied using 99mTc-DPD. Whole body tracer retention was 80.1%+/-10.3% (range 65.1%-94.8%) in FAP patients and 55.7%+/-8.1% (range 40.2%-66.7%) in controls at 3 h p.i. (P<0.001), and cardiac uptake was 7.3%+/-2.2% (range 4.2%-10.1%) in FAP patients and 3.1%+/-0.5% (range 2.3%-4.0%) in controls (P<0.001). The heart/whole body uptake ratio was 8.9%+/-1.7% (range 6.5%-11.0%) in FAP patients and 5.6%+/-0.5% (range 5.1%-6.8%) in controls (P<0.001). The three FAP patients with the highest cardiac tracer uptake had cardiomyopathy or arrhythmia. 99mTc-DPD scintigraphy is proposed as a simple and valuable diagnostic aid to evaluate the severity of the disease and the risk of concomitant heart problems.
Adult↗