Reactive Amyloidosis Research Articles

Expert Center for cardiac amyloidosis: reality and perspectives

Aim. To evaluate the features of diagnosis of amyloid cardiomyopathy (ACMP), differential diagnosis of different types of amyloidosis and its clinical manifestations. Materials and methods. Were analyzed 150 cases of patients who consulted at the Expert Center for Amyloidosis with suspicion of the presence of ACMP. 63 patients were diagnosed with ACMP: 25 (39.7%) – women, 38 (60.3%) – men, with an average age of 64.1±1.5. 36 (57.1%) patients had AL-amyloidosis (immunoglobulin amyloid light-chain amyloidosis), 25 (39.7%) – ATTR-amyloidosis (transthyretin amyloidosis), 2 (3.2%) – AA-amyloidosis with heart failure (reactive systemic amyloidosis caused by hypersecretion of á-globulin). The analysis of clinical manifestations depending on the type of amyloidosis, data of laboratory and instrumental methods of diagnosis is carried out. Results. In most cases, 53 (84.1%) patients, amyloidosis manifested as signs of heart failure. Among cardiac manifestations, shortness of breath (95.2%), general weakness (93.7%), lower limb edema (76.2%) were the most common. To confirm the diagnosis, despite the high accuracy of the speckle-tracking echocardiography and magnetic resonance imaging of the heart with gadolinium, in rare cases a biopsy is required (e.g. there is a combination of clinical signs of several types of amyloidosis). Biopsy of the affected organ was performed in 31 (49.2%) patients. The strategy for further pathogenetic treatment depends on the determination of the type of amyloidosis. Free light chains of immunoglobulins were detected in 57.1% of cases, which allowed diagnosis of AL-amyloidosis. In 17 (38.6%) patients myocardial scintigraphy with 99mTc-pyrophosphate showed signs of ATTR-amyloidosis, which with a negative result of immunochemical studies allows non-invasive diagnosis of it. Conclusion. ACMP is a disease with an extremely adverse prognosis. Raising the awareness of specialists about ACMP is an important goal. With timely diagnosis, pathogenetic therapy can be started early, which will improve the quality of life and prognosis of patients with ACMP.

A reactive systemic amyloidosis with fibrosis in a Vigova duck : A case report

A reactive systemic amyloidosis with fibrosis in a Vigova duck : A case report

Systemic and Cardiac Amyloidosis in Captive Celebes Crested Macaques (Macacanigra)

Systemic amyloidosis has been described in many animals and the most common form is reactive systemic AA amyloidosis. However, cardiac amyloidosis leading to heart failure is rare in animals. We now describe systemic and cardiac amyloidosis in two captive endangered Celebes crested macaques (Macaca nigra) at the Singapore Zoo. Both animals were geriatric and had chronic morbidities. Physical examination, radiography and ultrasonography revealed cardiac arrhythmia, pleural effusion, pulmonary oedema and ascites, consistent with cardiac failure. Amyloidosis was suspected and confirmed as type AA by immunohistochemistry.

When All Is Not as It Seems: Recurrent Fever and New-onset Joint Pain in a 17-Month-old Girl.

When All Is Not as It Seems: Recurrent Fever and New-onset Joint Pain in a 17-Month-old Girl.

In vitro exposure of human lens epithelial cells to X-rays at varied dose-rates leads to protein-level changes relevant to cataractogenesis

Background Accumulated body of evidence shows that ionizing radiation increases the risk of cataracts. The mechanisms are not clear and the International Commission on Radiological Protection indicates a need for research into understanding the process, particularly at low doses and low dose rates of exposure. Purpose This study was designed to examine protein-level modifications in a human lens epithelial (HLE) cell-line following radiation exposures. Materials and methods HLE cell-line was subjected to X-irradiation at varied doses (0-5 Gy) and dose-rates (1.62 cGy/min and 38.2 cGy/min). Cells were collected 20 h post-exposure, lysed and proteins were clarified following fractionation by a molecular weight cut-off filtration method. Fractionated cellular proteins were enzymatically digested and subjected to mass spectrometry analysis. Results Statistically significant radiation dose-related protein changes compared to the control group were identified. Heatmap and hierarchical clustering analysis showed dose-rate dependant responses. Pathway analysis mapped the proteins to biological functions of mitochondrial dysfunction, reactive oxygen species generation, cell death, cancer, organismal injury and amyloidosis. Conclusion Overall findings suggest that ionizing radiation exposure of HLE cells by mediating dose rate-dependant oxidative stress and cell death-related mechanisms, can be relevant to cataractogenesis.

Role of Colchicine Treatment in Tumor Necrosis Factor Receptor Associated Periodic Syndrome (TRAPS): Real-Life Data from the AIDA Network.

Objective To analyze the potential role of colchicine monotherapy in patients with tumor necrosis factor receptor associated periodic syndrome (TRAPS) in terms of control of clinical and laboratory manifestations. Methods Patients with TRAPS treated with colchicine monotherapy were retrospectively enrolled; demographic, clinical and therapeutic data were collected and statistically analysed after having clustered patients according to different times at disease onset, penetrance of mutations, dosage of colchicine, and different disease manifestations. Results 24 patients (14 males; 15 with pediatric disease onset) treated with colchicine monotherapy were enrolled. Colchicine resulted in a complete response in 3 (12.5%) cases, partial response in 14 (58.3%) patients, and lack of response in 7 (29.2%) patients. There were not significant differences in colchicine response between pediatric and adult disease onset (p = 0.42), between low- and high-penetrance mutations (p = 0.62), and according to different dosages (p = 0.66). No significant differences were identified in the frequency of specific disease manifestations between patients experiencing any response to colchicine and patients with lack of response. Conclusions Colchicine monotherapy is useful in a low percentage of TRAPS patients; nevertheless, it could be attempted in patients with milder phenotypes and at a lower risk of developing reactive amyloidosis.

Role of Serum Amyloid A Protein in the Early Detection of Late Onset Sepsis in Neonate

Background: Late onset sepsis (LOS) is an important cause of serious illness and deaths among neonates. Diagnosis of neonatal sepsis remains a challenge owing to nonspecific early clinical signs and the non-availability of a reliable biomarker. Serum amyloid A (SAA), the precursor protein in inflammation-associated reactive amyloidosis, whose level in the blood increases up to 1000 fold in response to inflammation and it is also an acute phase reactant like PCT and CRP. Objectives: assessing the accuracy and rapidity of SAA in detection of LOS in neonates. Method: This is a case-control study which was carried out on neonates admitted in (NICU) of Benha University Hospital and Benha Teaching Hospital during the period (from June 2018 to November 2019). Group 1 (patients group): 45 neonates with neonatal sepsis, group 2 (control group): 40 healthy neonates age and sex matched. SAA was measured. Results: mean value of SAA in septic group was 38.8 µg/ml compared to 1.26 µg/ml in control group , with statistically significant increase in patients than controls (p 2.8 µg/ml, SAA had a sensitivity 86.7%, specificity 85%, PPV 86.7%, and NPV 85% for early diagnosis of LOS. At a cut-off value of SAA>45.2 µg/ml, SAA had a sensitivity 83.3%, specificity 69.7%, PPV 50%, and NPV 92% for the prediction of mortality among LOS patients. Conclusion: The high sensitivity, specificity, positive predictive value and negative predictive value of SAA protein could help the clinicians for early diagnosis of LOS.

Hints for Genetic and Clinical Differentiation of Adult-Onset Monogenic Autoinflammatory Diseases.

Monogenic autoinflammatory diseases (mAIDs) are inherited errors of innate immunity characterized by systemic inflammation recurring with variable frequency and involving the skin, serosal membranes, synovial membranes, joints, the gastrointestinal tube, and/or the central nervous system, with reactive amyloidosis as a potential severe long-term consequence. Although individually uncommon, all mAIDs set up an emerging chapter of internal medicine: recent findings have modified our knowledge regarding mAID pathophysiology and clarified that protean inflammatory symptoms can be variably associated with periodic fevers, depicting multiple specific conditions which usually start in childhood, such as familial Mediterranean fever, tumor necrosis factor receptor-associated periodic syndrome, cryopyrin-associated periodic syndrome, and mevalonate kinase deficiency. There are no evidence-based studies to establish which potential genotype analysis is the most appropriate in adult patients with clinical phenotypes suggestive of mAIDs. This review discusses genetic and clinical hints for an ideal diagnostic approach to mAIDs in adult patients, as their early identification is essential to prompt effective treatment and improve quality of life, and also highlights the most recent developments in the diagnostic work-up for the most frequent hereditary periodic febrile syndromes worldwide.

A 62-Year-Old African American Woman With Stable Lymphadenopathy Over 5 Years

Abstract The patient is a 62-year-old African American female with medical history of Plummer Vinson syndrome and CT scan in 2014 showing lymphadenopathy of the porta hepatis. Needle core biopsy of enlarged lymph nodes revealed sheets of polytypic plasma cells with no aberrant B or T cells or granulomas or hyaline-like depositions identified. The findings were suspicious for unicentric Castleman disease. In 2019, the patient presented with chronic fatigue without other systemic symptoms. Contrast CT revealed persistent retroperitoneal lymphadenopathy and calcified granulomas in the liver, spleen, and lung. Excision of portal and celiac nodes showed preserved nodal architecture with mild mantle zone expansion and marked hyaline-like deposition in the follicles. Sheets of mature plasma cells and focally increased vasculatures were seen in the interfollicular areas. Focally frequent nonnecrotizing granulomas were noted. Occasional giant cells and rare asteroid bodies were identified in the granulomas. Immunohistochemistry stain workup revealed normal distribution of the B and T lymphocytes. CD138 stain highlighted marked increased plasma cells and HHV8 was negative. Immunofluorescence microscopy for kappa and lambda did not show monoclonality; IgA was positive in <10% of plasma cells; special stain for Congo red and serum amyloid associated protein (SSA) IHC stain were strongly positive in the follicles. The overall findings are consistent with reactive lymphadenopathy with interfollicular polytypic plasmacytosis, noncaseating granuloma formation, and reactive amyloidosis. The features of mantle zone hyperplasia and polytypic plasmacytosis are suggestive of HHV8-negative/idiopathic unicentric Castleman disease. This case possibly represents an example of concurrent amyloidosis, sarcoidosis, and idiopathic unicentric Castleman disease. Given that SSA was recently reported to have a pathogenic role in granulomatous inflammation of sarcoidosis through sustained inflammatory reaction, the possibility of increased SSA triggering sarcoidoisis in this patient can be considered. However, the exact pathogenesis of these concurrent findings needs further investigation and clarification.

Mucocutaneous manifestations in systemic amyloidosis A retrospective analytical study in a tertiary care center.

The mucocutaneous clinical profile of patients with amyloidosis in Latin America has been scarcely reported. To describe clinical characteristics of skin and mucosal manifestations in systemic amyloidosis in a tertiary care center in Mexico City. A cross sectional, retrospective analytical study was performed in patients with systemic amyloidosis over a 15-year period. Statistical analysis was done. A total of 98 patients were included (53 [54%] men; overall median age=49years old). Acquired systemic immunoglobulin light chain amyloidosis (AL) was the most common (49%) type, followed by (24.5%) wild-type transthyretin amyloidosis (H-TTR) (24.5%), undetermined cases (21%), and reactive systemic amyloidosis (AA) (6.1%). There were mucocutaneous manifestations in 34.7% of cases, mostly multiple myeloma-related AL (ALMM). Head and neck was the most often affected site (38.2%), and purpuric macules were the most common morphology (44.1%). Mucocutaneous affectation was predominantly observed in AL (50.0%) compared to other types (20.0%) of amyloidosis (P=0.01). Likewise, involvement of organs was also significantly different among the diverse amyloidosis types (P<0.05). The most frequent comorbidities were hypertension (18.3%) and hypothyroidism (18.3%). The clinical spectrum of manifestations in amyloidosis is wide. Involvement of skin and mucosa in amyloidosis is common; significant differences were observed concerning distribution of mucocutaneous amyloid manifestations among the different types of amyloidosis.

Predictive Factors for Inaccurate Diagnosis of Swollen Lymph Nodes in Endoscopic Ultrasound-Guided Fine Needle Aspiration.

Background/AimsThis study aimed to identify the predictive factors for inaccurate endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) diagnosis of swollen lymph nodes without rapid on-site cytopathological evaluation. MethodsEighty-three consecutive patients who underwent EUS-FNA for abdominal or mediastinal lymph nodes from January 2008 to June 2017 were included from a prospectively maintained EUS-FNA database and retrospectively reviewed. The sensitivity, specificity, and accuracy of EUS-FNA for the detection of neoplastic diseases were calculated. Candidate factors for inaccurate diagnosis (lymph node size and location, needle type, puncture route, number of passes, and causative disease) were evaluated by comparison between accurately diagnosed cases and others. ResultsThe final diagnosis of the punctured lymph node was classified as neoplastic (65 cases: a metastatic lymph node, malignant lymphoma, or Crow-Fukase syndrome) or non-neoplastic (18 cases: a reactive node or amyloidosis). The sensitivity, specificity, and accuracy were 83%, 94%, and 86%, respectively. On multivariate analyses, small size of the lymph node was the sole predictive factor for inaccurate EUS-FNA diagnosis with a significant difference (odds ratios, 19.8; 95% confidence intervals, 3.15–124; p=0.0015). ConclusionsThe lymph node size of <16 mm was the only independent factor associated with inaccurate EUS-FNA diagnosis of swollen lymph nodes.

The Broad-Ranging Panorama of Systemic Autoinflammatory Disorders with Specific Focus on Acute Painful Symptoms and Hematologic Manifestations in Children.

Systemic autoinflammatory disorders (SAIDs) are inherited defects of innate immunity characterized by recurrent sterile inflammatory attacks involving skin, joints, serosal membranes, gastrointestinal tube, and other tissues, which recur with variable rhythmicity and display reactive amyloidosis as a potential long-term complication. Dysregulated inflammasome activity leading to overproduction of many proinflammatory cytokines, such as interleukin-1 (IL-1), and delayed shutdown of inflammation are considered crucial pathogenic keys in the vast majority of SAIDs. Progress of cellular biology has partially clarified the mechanisms behind monogenic SAIDs, such as familial Mediterranean fever, tumor necrosis factor receptor-associated periodic syndrome, cryopyrin-associated periodic syndrome, mevalonate kinase deficiency, hereditary pyogenic diseases, idiopathic granulomatous diseases and defects of the ubiquitin-proteasome pathway. Whereas, little is clarified for the polygenic SAIDs, such as periodic fever, aphthous stomatitis, pharyngitis, and cervical adenopathy (PFAPA) syndrome. The puzzle of symptomatic febrile attacks recurring over time in children requires evaluating the mixture of clinical data, inflammatory parameters in different disease phases, the therapeutic efficacy of specific drugs such as colchicine, corticosteroids or IL-1 antagonists, and genotype analysis in selected cases. The long-term history of periodic fevers should also need to rule out chronic infections and malignancies. This review is conceived as a practical template for proper classification of children with recurring fevers and includes tips useful for the diagnostic approach to SAIDs, focusing on the specific acute painful symptoms and hematologic manifestations encountered in childhood.

Apolipoprotein A-II induces acute-phase response associated AA amyloidosis in mice through conformational changes of plasma lipoprotein structure

During acute-phase response (APR), there is a dramatic increase in serum amyloid A (SAA) in plasma high density lipoproteins (HDL). Elevated SAA leads to reactive AA amyloidosis in animals and humans. Herein, we employed apolipoprotein A-II (ApoA-II) deficient (Apoa2−/−) and transgenic (Apoa2Tg) mice to investigate the potential roles of ApoA-II in lipoprotein particle formation and progression of AA amyloidosis during APR. AA amyloid deposition was suppressed in Apoa2−/− mice compared with wild type (WT) mice. During APR, Apoa2−/− mice exhibited significant suppression of serum SAA levels and hepatic Saa1 and Saa2 mRNA levels. Pathological investigation showed Apoa2−/− mice had less tissue damage and less inflammatory cell infiltration during APR. Total lipoproteins were markedly decreased in Apoa2−/− mice, while the ratio of HDL to low density lipoprotein (LDL) was also decreased. Both WT and Apoa2−/− mice showed increases in LDL and very large HDL during APR. SAA was distributed more widely in lipoprotein particles ranging from chylomicrons to very small HDL in Apoa2−/− mice. Our observations uncovered the critical roles of ApoA-II in inflammation, serum lipoprotein stability and AA amyloidosis morbidity, and prompt consideration of therapies for AA and other amyloidoses, whose precursor proteins are associated with circulating HDL particles.

Familial Mediterranean Fever Is Associated With Increased Mortality After Kidney Transplantation—A 19 Years' Single Center Experience

Current data regarding the outcome of kidney transplantation in patients with familial Mediterranean fever (FMF) who reach end-stage renal disease (ESRD) due to reactive amyloidosis A (AA) are scarce and inconclusive. The outcomes of 20 patients with FMF and biopsy-proven AA amyloidosis that were transplanted between 1995 and 2014 were compared with 82 control patients (32 with diabetes mellitus and 50 with nondiabetic kidney disease). Major outcome data included overall patient and graft survivals. During a mean overall follow-up of 116.6 ± 67.5 months 11 patients (55%) with FMF died versus 26 patients (31%) in the control group. Median time of death for patients with FMF was 61 months (range, 16-81) after transplantation. Estimated 5-year, 10-year, and actuarial 15-year overall patients survival rates were 73%, 45%, and 39%, respectively, for patients with FMF, versus 84%, 68% and 63%, respectively, for the control group (P = 0.028). FMF was associated with more than twofold increased risk for death after transplantation, and with a threefold increased risk for hospitalization because of infections during the first year. Infections and cardiovascular disease were the cause of death in the majority of patients with FMF. Overall graft survival was similar between the groups. Recurrence of AA amyloidosis was diagnosed in 2 patients during the first year after transplantation. FMF is associated with increased risk of mortality after kidney transplantation.

Living kidney transplantation between brothers with unrecognized renal amyloidosis as the first manifestation of familial Mediterranean fever: a case report

BackgroundFamilial Mediterranean fever is an autosomal recessive disease characterized by recurrent episodes of fever and polyserositis and by the onset of reactive amyloid-associated amyloidosis. Amyloidosis due to familial Mediterranean fever can lead to end-stage renal disease, culminating in kidney transplantation for some patients. In this study, we report the clinical outcome of two brothers with familial Mediterranean fever who were the inadvertent donor and recipient, respectively, of a kidney. Subsequently, they were diagnosed with renal amyloidosis secondary to familial Mediterranean fever and were successfully treated with anakinra and colchicine.Case presentationTwo brothers with familial Mediterranean fever and renal amyloidosis were the inadvertent donor and recipient, respectively, of a kidney. The recipient had presented recurrent acute febrile episodes of familial Mediterranean fever, developed nephrotic syndrome secondary to amyloidosis and needed bilateral nephrectomy and chronic dialysis. His elder brother, in apparent good health, donated his left kidney to his brother. Immediately after the kidney transplantation, both the donor and recipient presented massive proteinuria, impaired renal function and elevated serum amyloid A levels. Biopsies of the brothers’ kidneys showed amyloidosis. Genetic studies thereafter revealed a homozygous variant for the MEFV gene (NM_000243.2.c.2082G > A; p.M694I) in both brothers. At this point, both the donor and recipient were treated with colchicine and anakinra, resulting in improved renal function, decreased proteinuria, undetectable serum amyloid A levels and stable renal function at 62 months of follow-up and no major adverse effects.ConclusionsIn familial Mediterranean fever, analyses of the MEFV gene should be performed in potential live kidney donors from a direct family member (either between siblings or between parents and children). In addition, genetic studies are required when consanguinity is suspected between members involved in the living transplant. Finally, anakinra could be a safe adjuvant therapy combined with colchicine for patients with familial Mediterranean fever and amyloidosis, including those with successful kidney transplantation.

Reactive Amyloidosis in a middle aged female with Behcet’s disease – Case report

Reactive Amyloidosis in a middle aged female with Behcet’s disease – Case report

Serum amyloid A forms stable oligomers that disrupt vesicles at lysosomal pH and contribute to the pathogenesis of reactive amyloidosis

Serum amyloid A (SAA) is an acute-phase plasma protein that functions in innate immunity and lipid homeostasis. SAA is a protein precursor of reactive AA amyloidosis, the major complication of chronic inflammation and one of the most common human systemic amyloid diseases worldwide. Most circulating SAA is protected from proteolysis and misfolding by binding to plasma high-density lipoproteins. However, unbound soluble SAA is intrinsically disordered and is either rapidly degraded or forms amyloid in a lysosome-initiated process. Although acidic pH promotes amyloid fibril formation by this and many other proteins, the molecular underpinnings are unclear. We used an array of spectroscopic, biochemical, and structural methods to uncover that at pH 3.5-4.5, murine SAA1 forms stable soluble oligomers that are maximally folded at pH 4.3 with ∼35% α-helix and are unusually resistant to proteolysis. In solution, these oligomers neither readily convert into mature fibrils nor bind lipid surfaces via their amphipathic α-helices in a manner typical of apolipoproteins. Rather, these oligomers undergo an α-helix to β-sheet conversion catalyzed by lipid vesicles and disrupt these vesicles, suggesting a membranolytic potential. Our results provide an explanation for the lysosomal origin of AA amyloidosis. They suggest that high structural stability and resistance to proteolysis of SAA oligomers at pH 3.5-4.5 help them escape lysosomal degradation, promote SAA accumulation in lysosomes, and ultimately damage cellular membranes and liberate intracellular amyloid. We posit that these soluble prefibrillar oligomers provide a missing link in our understanding of the development of AA amyloidosis.

Muckle–Wells Syndrome in a Child With Recurrent Urticaria

Cryopyrin associated periodic syndromes (CAPS) are rare monogenic autoinflammatory diseases from the group of hereditary periodic syndromes caused by a regulation defect of inflammatory cytokines, in particular interleukin 1 β . They include familial cold autoinflammatory syndrome (FCAS), Muckle–Wells syndrome (MWS), and neonatal-onset multisystem inflammatory disease (CINCA/NOMID). Previously, Muckle–Wells syndrome was considered as a triad of symptoms — urticaria, deafness, and reactive amyloidosis. Today, the spectrum of symptoms is constantly expanding: it includes fever, fatigue, conjunctivitis, arthralgia, arthritis, myalgia, irritability, headache, abdominal pain, mouth ulcers, pericarditis, which involves doctors of different specialties in the diagnostic and treatment process, who are not always familiar with this disease. In Russia, single observations of this disease have been described. We present the clinical case of Muckle–Wells syndrome in a 5-year-old child, whose first symptoms appeared at the age of 2 months. This observation underscores the complexity of diagnosing the syndrome in children.

Rheumatoid Arthritis Complicated by Reactive AA Amyloidosis Treated with Anti-IL-6 Receptor Antibody Tocilizumab

Rheumatoid Arthritis Complicated by Reactive AA Amyloidosis Treated with Anti-IL-6 Receptor Antibody Tocilizumab

Systemic amyloidosis: novel therapies and role of biomarkers.

Systemic amyloidosis is caused by misfolding and extracellular deposition of one of an ever-growing list of circulating proteins, resulting in vital organ dysfunction and eventually death. Despite different predisposing conditions, including plasma cell dyscrasias [immunoglobulin light chain (AL) amyloidosis], long-lasting inflammation [reactive (AA) amyloidosis] or mutations (hereditary amyloidoses), clinical manifestations are conspicuously overlapping and mimic more prevalent conditions, significantly complicating and often delaying the recognition of these rare, complex diseases. However, refined diagnostic and imaging approaches and the increasing role of biomarkers, which help in establishing the diagnosis, assessing the prognosis and evaluating the response to therapy, have considerably improved the management of these conditions. The pillar of anti-amyloid therapy remains the prompt reduction or elimination of the amyloidogenic precursor. This is accomplished by targeting the underlying condition, and recent improvements in the treatment of plasma cell disorders and chronic inflammatory conditions have positively reverberated onto the management of AL and AA amyloidosis, respectively. Moreover, recent, substantial improvements in the understanding of the molecular underpinnings of systemic amyloidosis have unveiled different key steps in the amyloidogenic cascade which can be valid therapeutic targets. These include stabilizers of the native conformation of the amyloidogenic precursor, inhibitors of fibrillogenesis, amyloid fibril disruptors and promoters of amyloid clearance. Innovative pharmacological strategies, including rational, structure-based drug design, gene knockdown and immunotherapy, but also repurposing of old, safe drugs with newly recognized anti-amyloid properties, are currently being pursued already in the clinical setting, holding the promise of dramatically improving the outcome of these dismal conditions in the near future.