AA Amyloid Research Articles

Pre-Clinical Characterization of a Novel Fusion Protein (AT-03), with Pan-Amyloid Binding and Removal

Background: Amyloidosis is characterized by extracellular deposition of protein fibrils that can involve any organ or tissue in the body. It is a severe, progressive and often lethal disorder. There are approximately seventeen different systemic amyloid diseases, each associated with the deposition of a specific precursor protein. Toxic amyloid deposits result in significant organ dysfunction and increased morbidity and mortality. Reduction and removal of tissue amyloid deposits could restore organ function, improve quality of life and increase life expectancy for patients. We have developed and characterized a fusion protein consisting of serum amyloid protein (SAP) linked to a single chain human IgG1 Fc domain, designated AT-03. SAP is a pentameric serum protein that is ubiquitously associated with amyloid deposits. The high affinity and specificity for amyloid resulted in the use of radio-iodinated SAP as an imaging agent for the non-invasive detection of systemic amyloid. The SAP domain of the fusion protein targets the amyloid deposits delivering Fc domains to stimulate amyloid removal via macrophage mediated phagocytosis.Methods: Binding of AT-03 to ATTR and AL fibrils and extracts was assessed by ELISA. Ex vivo phagocytosis of amyloid substrates was studied using activated human THP-1 cells. The biodistribution of AT-03 in murine models of AA, AApoA2 and AL amyloidosis was evaluated immunohistochemically or by SPECT imaging and microautoradiography. Clearance of AA amyloidosis in response to AT-03 therapy was accessed in a mouse model using histological scoring of amyloid burden.Results: AT-03 bound amyloid AL and ATTR substrates with sub nanomolar EC50 values. Systemic administration of AT-03 resulted in specific binding to diverse forms of amyloid in the heart, kidney, liver and/or spleen in multiple animal models. Opsonization of amyloid deposits with AT-03 in vitro resulted in a dose dependent phagocytosis by activated THP-1 cells. A single IV dose of AT-03 resulted in significant reduction of splenic AA amyloid within 14 days post-injection.Conclusions: We have developed a novel fusion protein with sub nanomolar pan amyloid reactivity that specifically binds diverse forms of amyloid in multiple organs and tissues in vivo and can effectuate amyloid removal. The data indicates that AT-03 may serve as a novel therapeutic for the removal of systemic amyloid deposits of diverse types. AT-03 is currently being developed for clinical evaluation. DisclosuresSirac: Attralus, Inc: Patents & Royalties, Research Funding. Jaccard: Janssen: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria; Abbvie: Honoraria. Bridoux: AstraZeneca: Consultancy, Speakers Bureau; Janssen: Consultancy. Bell: Attralus Inc: Current Employment. Guthrie: Attralus Inc: Current Employment. Selvarajah: Attralus Inc: Current Employment. Kennel: Attralus Inc: Current holder of stock options in a privately-held company, Patents & Royalties: Inventor and patent holder. Wall: Attralus Inc: Current holder of stock options in a privately-held company, Patents & Royalties: Inventor and patent holder, Research Funding.

AA amyloid in human food chain is a possible biohazard

AA amyloidosis can be transmitted experimentally in several mammalian and avian species as well as spontaneously between captive animals, even by oral intake of amyloid seeds. Amyloid seeding can cross species boundaries, and fibrils of one kind of amyloid protein may also seed other types. Here we show that meat from Swedish and Italian cattle for consumption by humans often contains AA amyloid and that bovine AA fibrils efficiently cross-seed human amyloid β peptide, associated with Alzheimer’s disease.

S2411 Secondary Amyloidosis Presenting as a Rare Complication of IBD

Introduction: 35% of patients with Inflammatory Bowel Disease (IBD) experience extraintestinal manifestations. However, amyloidosis is a rare complication of IBD;the incidence in the US is <1% for both Crohn's disease (CD) and Ulcerative Colitis (UC). We hope to shed some light in this underdiagnosed consequence with a clinical vignette. Case description/methods: A 75 year old man with recently diagnosed UC 6 weeks prior and history of thoracic laminectomy presented with bilateral lower extremity weakness that resulted in a fall in the shower and complaints of bloody diarrhea. Prior to his admission he was ambulating with a walker, he then developed loss of motor function of his lower extremities. He had been having several episodes of bloody diarrhea a day along with tenesmus and fecal incontinence for almost a year. He delayed getting medical aid until recently due to the COVID-19 pandemic. He had a colonoscopy which revealed pancolitis and he was started on aggressive steroids and mesalamine. CT and MRI imaging of the spine were inconclusive, but revealed swelling of the iliopsoas muscle with concern for polymyositis. However EMG, muscle enzymes and Immunological studies were all unremarkable. Muscle biopsy of the gastrocnemius revealed interstitial amyloid deposition. Mass spectrometry was indeterminate and could not isolate the type of amyloid protein. The patient's UC flare slowly improved after several weeks and he was transferred to acute rehab and later to a tertiary care center for further evaluation. Discussion: Primary amyloidosis is AL amyloid deposition associated with plasma cell dyscrasias such as multiple myeloma (MM). AA Amyloid can also build up as an acute phase reactant from chronic inflammatory conditions such as IBD and be deposited in extracellular tissue. Amyloidosis is more associated with CD than UC, more found in men and is often associated with renal involvement. One study found that only 15 out of 1709 (0.9%) patients with CD and 1 in 1341 (0.7%) patients with UC had amyloidosis. Our patient's long standing uncontrolled UC likely resulted in amyloid protein production and deposition. Although it is important to rule out MM in cases of amyloidosis, the timing of our patient's lower extremity weakness and diagnosis of amyloidosis in the setting of uncontrolled UC flare strongly suggests secondary amyloidosis. We hope this diagnostic walk through can guide clinicians to approach similar situations in the future.

Gastrointestinal AA amyloidosis secondary to chronic pyelonephritis presenting with refractory diarrhea and severe hypoalbuminemia

Secondary amyloidosis is a rare complication of chronic inflammatory diseases, such as collagen diseases, and is often difficult to treat. In addition, the gastrointestinal tract is frequently involved in amyloid deposition that often results in various disorders and symptoms. A 70-year-old woman was admitted to our hospital with refractory diarrhea and hypoalbuminemia. Abdominal computed tomography demonstrated extensive edematous wall thickening of the small intestine and colon. Video capsule endoscopy revealed multiple ulcerations with a white mossy appearance of the ileum. Double-balloon endoscopy showed severe circumferential ulcers in the entire ileum. Histological examination of ileum biopsy samples revealed severe amyloid deposition in the lamina propria and perivascular areas of the submucosa. The patient was diagnosed with gastrointestinal AA amyloidosis. The cause of AA amyloid deposition was presumed to be chronic pyelonephritis due to ureteral stones that had been left untreated for 35years. After treatment with ureteral drainage and antibiotics, the patient's symptoms and serological abnormalities improved dramatically. Here, we describe a case of severe gastrointestinal AA amyloidosis secondary to chronic pyelonephritis. Clinicians should thoroughly investigate the entire gastrointestinal tract in patients with refractory diarrhea and severe hypoalbuminemia considering the possibility of gastrointestinal amyloidosis.

MO868CLINICAL OUTCOMES FOR INTRAVENOUS DRUG USERS REQUIRING HAEMODIALYSIS

Abstract Background and Aims Intravenous drug users (IVDU) face significant challenges when requiring long-term therapies such as dialysis and pose management dilemma to clinicians. Many patients present late, complicated by erratic lifestyles and complex mental health needs, often requiring urgent renal replacement therapy (RRT). Decisions regarding modality can be difficult due to the lack of evidence for outcomes in this cohort. We investigated the clinical outcomes of patients with history of IVDU in our service who presented with ESRD. Method A single-centre retrospective analysis of ESRD patients with a background of IVDU. Incidence of hospital and ICU admission, length of stay and frequency of culture positive sepsis following the initiation of RRT were investigated. Primary outcome was days admitted versus days spent in the community, frequency of life-threatening sepsis and tunnelled catheter replacement. Data was collected from the date of first RRT (earliest April 2015 and latest November 2019) to last follow-up in September 2020 or patient death. An admission was included when the patient was admitted for at least an overnight stay in hospital. Admission days calculated do not include attendance for outpatient haemodialysis. Bacteraemia’s were included when a report confirming a positive culture associated with clinical features of infection; paired samples were counted as a single episode. Results Six patients initiated RRT during the study period and included four males and two females. Mean age of 46.6 years (32-54 years). Cause of ESRD was Amyloid AA in 5) and IgA nephropathy in 1). Mean follow-up was 677 days till censor (range 313 to 932 days). There was an average of nine inpatient admissions (range 3 to 17) averaging 280 inpatient days (range 29 to 637 days) across the cohort. At last follow-up, three patients died with an average time to death of 833 days from initiation of RRT (range 664 to 932 days). Four patients required at least one admission to the Intensive Care Unit (ITU) with an average length of stay of 10.3 days (range 1 to 47 days). All patients experienced at least two episodes of culture positive sepsis with a total of 72 bacteraemia’s across the cohort (range 2 to 41). Four patients required tunnelled catheter replacement ranging from 2 to 7 catheters. Results are summarised in Table 1. Conclusion IVDU patients represent a challenging patient population to manage with limited options available for RRT. This study highlights these difficulties particularly with the use of tunnelled catheters for haemodialysis. Our results indicate RRT in IVDUs is associated with frequent and prolonged hospital stays with multiple bacteraemia’s, ICU admissions and significant mortality. Clinicians are faced with a significant ethical dilemma as tunnelled catheters represent both a lifeline for continued survival and a perfect access to recreational drugs. If patients are to be offered haemodialysis via tunnelled access, more intensive and earlier multidisciplinary planning and counselling needs to be employed to ensure patients are aware of the significance of the associated risks. Psychological therapy and social care input would be essential to help reduce morbidity and mortality.

Characterization of G‐quadruplex Structures in Serum Amyloid A Gene as a Novel Approach for Systemic Amyloidosis Therapy

Transcriptional initiation is an important step in the regulation of transcription. When transcriptional initiation is dysfunctional, it will lead to abnormal gene expression. Overexpression of Serum Amyloid A (SAA) and self-assembly into fibrils have been associated with chronic inflammatory conditions and certain neoplasms, which lead to the deposition of AA amyloid in organs such as the liver, spleen, and kidney (systemic amyloidosis). For this reason, SAA is a highly significant molecular target. Insight into the structural biology of the promoter element that determines the combinatorial control of gene expression by different transcriptional factors is essential for understanding the dysfunction of SAA gene expression. The highly GC-rich region of the human SAA promoter is crucial for basal promoter activity and likely to assume a DNA secondary structure, such as G-quadruplex (GQ). GQs often serve as transcriptional silencer elements. Stabilization of GQ is possible with small molecule therapeutics to modulate gene expression. In the present study, G-quadruplex formation has been isolated from the GC-rich region of the 5’-untranslated region (5’UTR) of SAA2. An electrophoretic mobility shift and thioflavin T fluorescence assays were used to confirm the formation of a biologically relevant intramolecular structure. The structure of the G-quadruplex is currently under investigation by circular dichroism and DMS footprinting. These data characterizing the formation of a unique secondary structure in SAA gene are promising to develop novel anti-amyloid therapy for the treatment of systemic amyloidosis.

AA amyloid fibrils from diseased tissue are structurally different from in vitro formed SAA fibrils

Systemic AA amyloidosis is a world-wide occurring protein misfolding disease of humans and animals. It arises from the formation of amyloid fibrils from serum amyloid A (SAA) protein. Using cryo electron microscopy we here show that amyloid fibrils which were purified from AA amyloidotic mice are structurally different from fibrils formed from recombinant SAA protein in vitro. Ex vivo amyloid fibrils consist of fibril proteins that contain more residues within their ordered parts and possess a higher β-sheet content than in vitro fibril proteins. They are also more resistant to proteolysis than their in vitro formed counterparts. These data suggest that pathogenic amyloid fibrils may originate from proteolytic selection, allowing specific fibril morphologies to proliferate and to cause damage to the surrounding tissue.

Comparison of AA Amyloid Fibril Morphology and Serum Amyloid A Gene Sequence in 5 Animal Species.

Amyloid fibrils are characterized by a linear morphology and a cross-β structure. Polymorphic and multiple fibril morphologies can be found when amyloid fibrils are extracted from amyloid-laden tissue. In this study, we report on the purification and transmission electron microscopic analysis of amyloid fibrils from 5 different animal species (mouse, cow, goat, dog, and camel) with AA amyloidosis. The results show that amyloid fibrils had a linear morphology with a cross-structure and irregular length in vivo. Although the fibrils from these different species showed highly similar conformations, there were significant differences in fibril width and crossover distance. We analyzed the sequences of homologous amyloid proteins and serum amyloid A, an evolutionarily conserved protein and a major amyloid precursor. We found 78.23% homology between the most distant amyloid proteins. The findings suggested similar fibril width and crossover distance in different animal species that displayed high homology of amyloid protein sequences. Dog and camel, as well as goat and cow, showed high genetic homology and similar fibril morphology. These data indicate that the fibrils from different animal species have similar genetic homology and morphology, which may provide a better understanding of the pathogenesis of amyloidosis.

CARDIAC AA AMYLOIDOSIS SECONDARY TO FAMILIAL MEDITERRANEAN FEVER PRESENTING AS INTERMITENT COMPLETE HEART BLOCK: A RARE CASE WITH LITERATURE REVIEW

SESSION TITLE: Medical Student/Resident Cardiovascular Disease Posters SESSION TYPE: Med Student/Res Case Rep Postr PRESENTED ON: October 18-21, 2020 INTRODUCTION: Cardiac amyloidosis is rare but relatively more frequently seen with ATTR and AL types of amyloidosis. AA amyloidosis related cardiomyopathy or conduction abnormalities are rare owing to less frequent involvement of the myocardium in AA amyloidosis. We present a case of complete heart block in the setting of AA amyloidosis secondary to familial mediterranean fever. CASE PRESENTATION: A 50-year-old female with history of familial mediterranean fever (FMF) presented with syncopal episode. On presentation patient's vitals were stable, labs including TSH were within normal limits. Orthostatic vitals were positive. High-sensitivity troponins were negative with a normal EKG on presentation. Laterally displaced apical beat was noticed on examination. During hospitalization patient was noticed to have complete heart block that was not responsive to atropine and transcutaneous pacing however a response was noticed with epinephrine drip. TTE revealed heart failure with reduced ejection fraction of 41% with severe concentric left ventricular thickening typical for amyloid cardiomyopathy with a well-preserved E/A-wave, which is not usually seen in as thickened ventricle as patients. CRP and SAA were elevated. Patient had endomyocardial biopsy that confirmed amyloid deposition staining positive for amyloid AA and negative for TTR, kappa and lambda and a technetium pyrophosphate scan was also negative. A biventricular pacemaker was placed for complete heart block without adequate escape rhythm, which resulted in resolution of episodes of dizziness associated with bradycardia. Patient's FMF was managed with colchicine and anakinra with the help of rheumatology. Patient was started on diuresis during hospitalization and continued on discharge. Patient followed up with amyloidosis clinic after discharge. DISCUSSION: Systemic amyloidosis is rare and results from deposition of amyloid deposits in various organs and hence a wide range of effects. Prognosis may be vary with the type and extent of amyloidosis. More than 95% of cardiac amyloidosis is secondary to light chain/AL amyloidosis or transthyretin amyloidosis (ATTR), both genetic/hereditary and wild type.[1] Cardiac involvement from AA amyloidosis is very rare. Cardiac amyloidosis usually manifests with syncope or postural hypotension, which may be related with bradyarrhythmias.[2] Like the involvement of cardiovascular system, developments of arrhythmias are also common with ATTR type of amyloidosis as compared to other types and may require pacemaker placement. AA cardiac amyloidosis is rare and bradyarrhythmias or conduction system involvement has also been rarely reported. We report a rare case of complete heart block secondary to AA amyloidosis from familial Mediterranean fever requiring pacemaker placement. CONCLUSIONS: We present cardiac AA amyloidosis as a rare cause of syncope and orthostatic hypotension. Reference #1: Sipe, J.D., et al., Amyloid fibril proteins and amyloidosis: chemical identification and clinical classification International Society of Amyloidosis 2016 Nomenclature Guidelines. Amyloid, 2016. 23(4): p. 209-213. Reference #2: Chamarthi, B., et al., Features and prognosis of exertional syncope in light-chain associated AL cardiac amyloidosis. Am J Cardiol, 1997. 80(9): p. 1242-5 DISCLOSURES: No relevant relationships by Usama Talib, source=Web Response

AA Amyloid Deposition in the Central and Peripheral Nervous Systems in Flamingos.

AA amyloidosis is characterized by amyloid deposition in systemic organs, but amyloid deposition in the central nervous system (CNS) or peripheral nervous system (PNS) is rare. In this study, AA amyloidosis was observed in 31 of 48 flamingos that died at a Japanese zoo. Almost all cases developed AA amyloidosis secondary to inflammatory diseases such as enteritis. Affected flamingos had AA amyloid deposition around blood vessels in periventricular white matter of the brain and in peripheral nerves. In addition, cerebral Aβ amyloidosis was observed in one of the 31 cases with AA amyloidosis. In conclusion, flamingos in the zoo commonly developed systemic amyloidosis with frequent amyloid deposition in the CNS and PNS, which seems to be a unique distribution in this avian species. Comparative pathological analyses in flamingos may help elucidate the pathogenesis of amyloid neuropathy.

Bocio amiloide, una entidad benigna de rápido crecimiento

Amyloid goitre is an infrequent benign entity characterized by a rapid increase in the size of the thyroid gland due to amyloid deposit in the parenchyma. Such an increase in size, which takes place over only a few months, can cause symptoms such as dyspnea, dysphagia and dysphonia. We present three cases diagnosed in the same centre and estimated its incidence. All cases showed similar morphology, with varying proportions of thyroid follicles, mature adipose tissue and amyloid. AA Amyloid accumulation was verified and associated to previous pathologies (Crohn's disease, juvenile rheumatoid arthritis and chronic renal disease). One case showed a papillary microcarcinoma. Amyloid goitre is an infrequent entity which should be considered in the differential diagnosis of all patients with goitre, especially those with chronic underlying diseases.

Acute Coronary Syndrome Revealing Non-AA Amyloidosis: Case-Report and Review of Literature

Amyloidosis forms a set of diseases characterized histologically by extracellular deposition of insoluble proteins with fibrillar conformation in the tissues. In diffuse forms, heart, kidney and digestive tract are preferentially affected, more than the skin and the peripheral nervous system. Three types of amyloidosis predominate: AL that contains immunoglobulin light-chains, AA or serum amyloid A protein, and transthyretin amyloidosis (ATTR). We report the case of a 65-year-old male hospitalized for Acute Coronary Syndrome and in whom clinical investigations will find non-AA type amyloidosis. Amyloidosis AL is the commonest type, and is associated with cardiac involvement of variable extent in almost 70% of the cases. The diagnosis can be challenging since echocardiographic and cardiac MR findings are nonspecific. Coronary involvement may be due to the presence of infiltration of amyloid deposits at the vascular level. However, only a biopsy of a coronary vascular fragment can confirm the diagnosis with the contribution of histology but this can only be done in post mortem. Cardiac amyloidosis is a rare condition with a poor prognosis, the diagnosis of which should be made early. Coronary artery disease should be systematically sought by cardiac catheterization, in order to improve management.

P1503A MULTICENTER STUDY OF THE CLINICAL, LABORATORY CHARACTERISTICS AND POTENTIAL PROGNOSTIC FACTORS IN PATIENTS WITH AA AMYLOIDOSIS ON HEMODIALYSIS

Abstract Background and Aims While, AL amyloidosis is more common in western countries, the most common type of amyloidosis is AA amyloidosis in eastern Mediterranean region including Turkey. Although worse prognosis has been attributed to the AL amyloidosis, AA amyloidosis can also be related to higher mortality under renal replacement therapies. However, there are no sufficient data regarding etiology, clinical presentation and prognostic factors of AA amyloidosis. The objective of our study is to evaluate the clinical, laboratory characteristics and possible predictive factors related to mortality in patients with AA amyloidosis undergoing hemodialysis (HD). Method This multicenter, cross-sectional study was a retrospective analysis of 2100 patients on HD and carried out in 14 selected hemodialysis centers throughout Turkey. Thirty-two patients with biopsy proven AA amyloidosis and thirty-two control patients without AA amyloidosis undergoing HD were included between October 2018 and October 2019. There was no significant difference between the groups in terms of the age and dialysis vintage. Causes of AA amyloidosis, treatment (colchicine and/or anti-interleukin 1 (IL) treatment; canakinumab or anakinra) and number of Familial Mediterranean Fever (FMF) attacks in the last year in case of FMF, systolic and diastolic blood pressures, biochemical values such as mean CRP, hemoglobin, serum albumin, phosphorus, calcium, PTH, ferritin, transferrin saturation, total cholesterol levels and EPO dose, erythropoietin resistance index (ERI), interdialytic fluid intake, body mass indexes, heparin dosage, UF volume and Kt/V data in the last year were collected by retrospective review of medical records. Results Prevalence of AA amyloidosis was found 1.87% in HD centers. In amyloidosis and control groups, 56% and 53% were male, mean age was 54±11 and 53±11 years, mean dialysis vintage was 104±94 and 107±95 months, respectively. FMF was the most common cause of AA amyloidosis (59.5%). All FMF patients received colchicine and the mean colchicine dose was 0,70 ±0,30 mg/day. 26,3 % of FMF patients were unresponsive to colchicine and anti-IL-1 treatment was used in these patients. In AA amyloid and control groups, ERI were 7,88±3,78 and 5,41±3,06 IU/kg/week/g/dl, respectively, (p=0.008). Additionally, higher CRP values (18,78±18,74 and 10,61±10,47 mg/L, p=0.037), lower phosphorus (4,68±0,73 mg/dL vs 5,25±1,04, p=0.014), total cholesterol (135±42 vs 174±39 mg/dL, p&amp;lt;0.01) and serum albumin (3,67±0,49 mg/dL, 4,03±0,22, p&amp;lt;0.01) were observed in patients with AA amyloidosis compared to the control group. Conclusion In this study, we found that long term prognostic factors including higher inflammation, malnutritional parameters and higher ERI were more frequent in AA amyloidosis patients under hemodialysis treatment. Figure Demographic, clinical and laboratory characteristics of patients

Obesity-induced AA amyloidosis: A diagnosis of exclusion

A 47-year-old woman with morbid obesity (body mass index: 41 kg/m2) and a history of hypertension, pulmonary embolism and successfully treated gout (one year ago) presented with nephrotic syndrome (15 g/24 h) and loss of kidney function (endogenous creatinine clearance 27 ml/min/1.73 m2). A kidney biopsy revealed AA amyloid. An extensive investigation was performed to detect an underlying inflammatory disease process by testing blood and urine, imaging and genetic testing for autoinflammatory diseases. Serum levels of C-reactive protein (CRP) and serum amyloid A protein (SAA) were continuously elevated. Serum amyloid P component (SAP)- scintigraphy showed intense uptake in a massively enlarged liver and in the spleen. This extensive investigation did not reveal an underlying inflammatory process. Her gout became asymptomatic almost immediately after start of treatment. Therefore, we concluded that morbid obesity was the most probable cause of her AA amyloidosis. Treatment with colchicine and prednisolone did not substantially reduce the SAA and CRP levels. Also, treatment with anakinra (interleukin-1 receptor antagonist) and tocilizumab (interleukin-6 receptor antagonist) failed. The downhill course of the disease progressed to complete renal failure within three years and dialysis was started. This case indicates that the long-standing low-grade inflammation seen in morbid obesity may be a potential cause of systemic AA amyloidosis and may be difficult to treat. However, it is essentially a diagnosis of exclusion, since known underlying inflammatory conditions should be excluded first.

Amyloid in the Lung.

Amyloidosis is the term given to abnormal deposition of misfolded precursor proteins at single or multiple sites, leading to organ dysfunction or clinical signs and symptoms. Pulmonary manifestations are nonspecific and may be associated with several amyloid protein subtypes, commonly AL (light chain) and AA (autoimmune) amyloids. Signs or symptoms of amyloid disease may often involve more of the clinical abnormalities of other affected organs than the lungs themselves. Radiologic pulmonary findings include septal and parenchymal ground glass or nodular infiltrates, multiple nodules, cysts, and focal tracheobronchial abnormalities. Lymphadenopathy with or without calcification and pleural effusions has also been reported. Directed therapy is initiated in response to clinical signs or symptoms often as a result of systemic or secondary diseases or conditions. Long-term prognosis is more dependent on the extent of organ involvement where morbidity is often the highest in those with multisystemic disease.

Description of rare clinical case of AA-amyloidosis with involvement in pathological process of heart and lungs

Amyloidosis is a unique group of disorders caused by the insoluble protein fibers accumulation known as amyloid fibrils in extracellular tissue and organ spaces. The involvement of different organs and tissues in amyloidosis is often the cause of missed or delayed diagnosis, and amyloidosis remains a major clinical problem as it is associated with 1/1,000 deaths in developed countries. We present a case of a 59-year-old female patient with complaints of breath shortness while talking, a sense of air lack in the horizontal position, swelling of the lower limbs, reduction of blood pressure to a minimum of 70/50 mm Hg, weight reduction by 7 kg in 6 months, dizziness. The patient was hospitalized to the Cardiology Department of Scientific Research Institute – Ochapovsky Regional Clinical Hospital #1 with heart failure. The electrocardiogram revealed left ventricular hypertrophy. Echocardiography showed biventricular myocardial hypertrophy with a maximum interventricular septum thickness of 16 mm, nonuniform ventricular myocardial structure and reduction of global left ventricular comparability to 38%. Computer tomography of chest organs demostrated interstitial swelling of parenchyma of both lungs. The infection during the further examination. For the final morphological verification of the diagnosis, it was necessary to perform peripheral transbronchial biopsy S 3, 4, 5 of the left lung and myocardial biopsy with specific staining on amyloid-congo – red. In the lung and myocardial biopsy, the colour of the congo red is positive. An immunohistochemical study of the lung tissue and myocardial sample revealed Amyloid AA expression. This case represents a rare cause of heart failure in a woman. A feature of this observation is the rare involvement in the pathological process of both pulmonary tissue and myocardium with AA-amyloid deposition.

Pattern of renal amyloidosis in South Africa

BackgroundKidney disease is a serious manifestation of systemic amyloidosis and a major cause of morbidity and mortality. Tuberculosis (TB) occurs up to 27 times more commonly in human immunodeficiency virus (HIV) infected patients and is also an important cause of renal amyloid; there are however no reports of renal amyloidosis in South Africa in the HIV era.MethodsThis was a retrospective record review of cases of amyloidosis diagnosed on renal biopsies at our tertiary referral hospital between January 1985 and December 2016.ResultsForty-six cases of amyloidosis were identified over the study period. The calculated biopsy prevalence was 1.38 per 100 non-transplant renal biopsies (95% Confidence Interval 1.02–1.86). AL amyloidosis was identified in 26 (57%) cases and AA in 20 (43%). The median age at presentation was 51 years and 52% of cases were female. Patients with AA amyloidosis were significantly younger compared to their AL counterparts (age 42 years vs. 58 years, p = < 0.001) and were all significantly non-white. The main clinical presentation was nephrotic syndrome (85%) and 52% of cases also had a serum creatinine value of greater than 120 μmol/L. Of the 20 cases of AA amyloidosis, 12 (60%) were associated with tuberculosis. HIV infection was noted in only two (10%) of the 20 AA cases. Median survival after diagnosis was 2 months.ConclusionAmyloidosis is a rare cause of kidney disease and typically presents with nephrotic syndrome. A similar number of AA and AL types were observed, and outcomes are worse in cases of AA amyloid. While TB remains the major underlying disease in this type, HIV infection was infrequent in cases of AA renal amyloidosis.

Lipid membranes accelerate amyloid formation in the mouse model of AA amyloidosis

Introduction: AA amyloidosis develops as a result of prolonged inflammation and is characterized by deposits of N-terminal proteolytic fragments of the acute phase reactant serum amyloid A (SAA). Macrophages are usually found adjacent to amyloid, suggesting their involvement in the formation and/or degradation of the amyloid fibrils. Furthermore, accumulating evidence suggests that lipid membranes accelerate the fibrillation of different amyloid proteins.Methods: Using an experimental mouse model of AA amyloidosis, we compared the amyloidogenic effect of liposomes and/or amyloid-enhancing factor (AEF). Inflammation was induced by subcutaneous injection of silver nitrate followed by intravenous injection of liposomes and/or AEF to accelerate amyloid formation.Results: We showed that liposomes accelerate amyloid formation in inflamed mice, but the amyloidogenic effect of liposomes was weaker compared with AEF. Regardless of the induction method, amyloid deposits were mainly found in the marginal zones of the spleen and coincided with the depletion of marginal zone macrophages, while red pulp macrophages and metallophilic marginal zone macrophages proved insensitive to amyloid deposition.Conclusions: We conclude that increased intracellular lipid content facilitates AA amyloid fibril formation and show that the mouse model of AA amyloidosis is a suitable system for further mechanistic studies.

Cell assay for the identification of amyloid inhibitors in systemic AA amyloidosis

Systemic AA amyloidosis is still, up to this day, a life-threatening complication of chronic inflammatory diseases. Despite the success of anti-inflammatory treatment, the prognosis of some AA patients is still poor, which is why therapies directed at the amyloidogenic pathway in AA amyloidosis are being sought after. The cell culture model of amyloid formation from serum amyloid A1 (SAA1) protein remodels crucial features of AA amyloid deposit formation in vivo. We here demonstrate how the cell model can be utilized for the identification of compounds with amyloid inhibitory activity. Out of five compounds previously reported to inhibit self-assembly of various amyloidogenic proteins, we found that epigallocatechin gallate (EGCG) inhibited the formation of SAA1-derived fibrils in cell culture. From a series of compounds targeting the protein quality control machinery, the autophagy inhibitor wortmannin reduced amyloid formation, while the other tested compounds did not lead to a substantial reduction of the amyloid load. These data suggest that amyloid formation can be targeted not only via the protein self-assembly pathway directly, but also by treatment with compounds that impact the cellular protein machinery.

Synchronous Unicentric Castleman Disease and Inflammatory Hepatocellular Adenoma: a Case Report

Systemic symptoms such as fever and fatigue are non-specific manifestations spanning from inflammation to neoplasia. Here we report the case of a 34 year-old man who presented with systemic symptoms for four months. CT-scan and MRI revealed a 3.4 cm arterialized hepatic lesion and a 7 cm paraduodenal mass. Surgical resection of both lesions and histological examination revealed an inflammatory hepatocellular adenoma and a unicentric plasma cell type of Castleman disease. Moreover, a diffuse AA amyloid deposition in the liver was observed. Resection of both lesions was associated with an improvement of the symptoms. To our knowledge, this is the first report of a synchronous presentation of a unicentric plasma cell type of Castleman disease, inflammatory hepatocellular adenoma and AA amyloidosis.