Amyloid A Research Articles

Serum proteomic changes related to residual impairment in remittent depression are associated with immune and inflammatory processes.

In patients with major depressive disorder, various functional areas are impaired, negatively impacting the quality of life. Remission can restore pre-depression functions; however, some patients may still have residual impairments. Distinguishing between near-normal recovery and residual impairment helps identify those at a high risk of relapse risk and helps tailor treatment. Accordingly, we aimed to discover and validate biomarkers that distinguish between near-normal recovery and residual impairment in remission states through serum proteome analysis. Pooled serum and individual serum samples from three groups (depression status, remission status with residual impairment, and remission status with normal recovery) were analyzed using liquid chromatography-tandem mass spectrometry. The combination of four proteins-antithrombin-III, serum amyloid A4 protein, C1q subcomponent subunit B, and serum amyloid P-component-was selected as a candidate biomarker. The trend of protein changes suggests complement C1q subcomponent subunit B and serum amyloid P-component as potential biomarkers for distinguishing remission from residual impairment. Changes in complement C1q subcomponent subunit B and serum amyloid P-component suggest that the complement system and inflammation-related immune mechanisms are associated with residual impairment in remittent major depressive disorder.

Secondary amyloidosis treated with tocilizumab as a complication of temporal arteritis

Background: Temporal arteritis is a large-vessel vasculitis mostly seen in the elderly. Amyloidosis may be secondary to a chronic inflammation of body organs. Here, we present the second case report of temporal arteritis complicated by amyloidosis that was successfully treated by tocilizumab. Case presentation: A 64-year-old female presented complaining of fatigue, fever, and diarrhea accompanied by abdominal pain. One year before presentation, she was diagnosed with temporal arteritis. She was treated with 15 mg/day oral prednisone for the last 6 months, with partial remission, but persistence of the fatigue and an elevated erythrocyte sedimentation rate (ESR, 56 mm/h). Physical examination showed tenderness of both temporal arteries and a soft abdomen. Colon tissue biopsy showed amyloid depositions in the vessels and stroma that were positive for Congo red staining. Tocilizumab was started with 8 mg/kg intravenous, the diarrhea resolved, and the arthralgia improved within 1 month, with a decrease in the ESR to 8 mm/h, and a C-reactive protein (CRP) level of 0.98 mg/dl. Monthly tocilizumab therapy remains efficacious 12 months later and was stopped due to lack of tocilizumab from the hospital. No side effects of tocilizumab were registered. Conclusion: Chronic inflammation may be complicated by amyloidosis in patients with rheumatic diseases and genetic predisposition. Therefore, it is important to screen for intestinal Amyloid A (AA) amyloidosis in individuals with gastrointestinal disorders complicated by rheumatic disorders. AA amyloidosis may be complicated by temporal arteritis and presented with gastrointestinal symptoms such as diarrhea.

Classification of amyloidosis and protein misfolding disorders in animals 2024: A review on pathology and diagnosis.

Amyloidosis is a group of diseases in which proteins become amyloid, an insoluble fibrillar aggregate, resulting in organ dysfunction. Amyloid deposition has been reported in various animal species. To diagnose and understand the pathogenesis of amyloidosis, it is important to identify the amyloid precursor protein involved in each disease. Although 42 amyloid precursor proteins have been reported in humans, little is known about amyloidosis in animals, except for a few well-described amyloid proteins, including amyloid A (AA), amyloid light chain (AL), amyloid β (Aβ), and islet amyloid polypeptide-derived amyloid. Recently, several types of novel amyloidosis have been identified in animals using immunohistochemistry and mass spectrometry-based proteomic analysis. Certain species are predisposed to specific types of amyloidosis, suggesting a genetic background for its pathogenesis. Age-related amyloidosis has also emerged due to the increased longevity of captive animals. In addition, experimental studies have shown that some amyloids may be transmissible. Accurate diagnosis and understanding of animal amyloidosis are necessary for appropriate therapeutic intervention and comparative pathological studies. This review provides an updated classification of animal amyloidosis, including associated protein misfolding disorders of the central nervous system, and the current understanding of their pathogenesis. Pathologic features are presented together with state-of-the-art diagnostic methods that can be applied for routine diagnosis and identification of novel amyloid proteins in animals.

An evaluation of serum blood parameters and amyloid-A levels in women with hyperemesis gravidarum; A prospective observational study.

This study aimed to investigate whether serum amyloid A (AA) level can be used as a biomarker in women with hyperemesis gravidarum (HEG). This prospective observational study was conducted at the Antalya Training and Research Hospital Gynecology and Obstetrics Clinic, Türkiye, between July and December 2023. Forty women diagnosed with HEG and 40 healthy women were included. No statistically significant differences were observed between the groups in terms of sociodemographic data such as age, body mass index, family history, educational status, economic level, place of residence, occupation, smoking and alcohol use, or drug habits. However, obstetric characteristics such as number of miscarriages, number of dilatation curettages, and gestational age and laboratory values including complete blood count, hematocrit, leukocyte, neutrophil, lymphocyte, platelet, free T4, albumin, alanine aminotransferase, aspartate aminotransferase, urea, creatinine, hs-C-reactive protein, and sodium (P > .05) all differed significantly. In addition, significant differences were observed between the HEG and healthy groups in terms of numbers of gravidities (2 [1-3] vs 1 [0-1], respectively, P < .001), numbers of parities (1 [0-1] vs 1 [0-1], P < .001), numbers of living children (1 [0-2] vs 1 [0-1], P < .001), presenting complaints (nausea 0 [0%], nausea + vomiting 0 [0%], none 40 [100.0%] vs nausea 27 [67.5%], nausea + vomiting 13 [32.5%], none 0 [0%], P < .001), serum thyroid-stimulating hormone (1.16 ± 0.56 vs 1.81 ± 0.624, P = .004), potassium (4.1 ± 0.7 vs 3.8 ± 0.2, P = .001), and AA values (7.29 ± 2.61 vs 10.74 ± 3.04, P < .001). At receiver operating characteristic analysis, the area under the curve (AUC: 0.881) was statistically significant for serum AA (P: <.001), with a cutoff value of ≥ 8.79 ([95% confidence interval] 0.743-0.919, sensitivity 87.4%, specificity 80.2%). The positive predictive value of serum AA was 81.1% and the negative predictive value was 80.4%. The study results showed that serum AA can be used as a diagnostic biomarker in HEG. Prospective studies involving more participants are now required to confirm our results.

Beyond the spine: a case of ankylosing spondylitis complicated by secondary amyloidosis

BackgroundAnkylosing spondylitis (AS) is a chronic inflammatory condition primarily affecting the spine and sacroiliac joints, often associated with human leukocyte antigen B27 (HLA-B27) positivity. While musculoskeletal symptoms are typical manifestations, AS can also lead to systemic complications, including secondary systemic amyloidosis (SSA), also known as Amyloid A (AA) amyloidosis, involving multiple organs.Case presentationWe present a case of a 45-year-old Asian male with a complex medical history, including diabetes and hypertension, who developed AS complicated by SSA. The patient exhibited a diverse range of symptoms, including cardiac, renal, gastrointestinal, and musculoskeletal manifestations. He reported shortness of breath on exertion, orthopnea, pedal edema, generalized weakness, back pain, neck pain, low-grade fever, decreased appetite, frothy urine, and significant weight loss over the past year. Diagnostic evaluations revealed HLA-B27 positivity and histologically confirmed AA amyloidosis, providing a comprehensive understanding of the systemic involvement.ConclusionThis case report highlights the intricate interplay between AS and SSA, particularly AA amyloidosis, with a focus on its systemic impact beyond musculoskeletal symptoms. The tragic outcome, marked by severe cardiac involvement, underscores the challenges in managing such complex cases. This report emphasizes the importance of early diagnosis and treatment of AS to prevent severe complications, along with vigilant monitoring and individualized treatment plans, as well as the need for further research to enhance our understanding and improve management strategies for AS-related amyloidosis.

Unveiling novel serum biomarkers in intrahepatic cholangiocarcinoma: a pilot proteomic exploration.

Recent advancements in proteomics have shown promise in identifying biomarkers for various cancers. Our study is the first to compare the serum proteomes of intrahepatic cholangiocarcinoma (iCCA) with cirrhosis (CIR), primary sclerosing cholangitis (PSC), and hepatocellular carcinoma (HCC), aiming to identify a proteomic signature that can effectively distinguish among these conditions. Utilizing high-throughput mass spectrometry on serum samples, we identified 845 proteins, of which 646 were suitable for further analysis. Unique clustering patterns were observed among the five groups, with significant proteomic differences. Our key findings include: S100 calcium-binding protein A9 (S100A9) and haptoglobin (HP) were more abundant in iCCA, while intercellular adhesion molecule 2 (ICAM2) was higher in HCC. Serum amyloid A1 (SAA1) and A4 (SAA4) emerged as potential biomarkers, with SAA1 significantly different in the iCCA vs healthy controls (HC) comparison, and SAA4 in the HCC vs HC comparison. Elevated levels of vascular cell adhesion molecule 1 (VCAM-1) in HCC suggested its potential as a differentiation and diagnostic marker. Angiopoietin-1 receptor (TEK) also showed discriminatory and diagnostic potential in HCC. ELISA validation corroborated mass spectrometry findings. Our study underscores the potential of proteomic profiling in distinguishing iCCA from other liver conditions and highlights the need for further validation to establish robust diagnostic biomarkers.

The ASC inflammasome adapter governs SAA-derived protein aggregation in inflammatory amyloidosis

Extracellularly released molecular inflammasome assemblies -ASC specks- cross-seed Aβ amyloid in Alzheimer’s disease. Here we show that ASC governs the extent of inflammation-induced amyloid A (AA) amyloidosis, a systemic disease caused by the aggregation and peripheral deposition of the acute-phase reactant serum amyloid A (SAA) in chronic inflammatory conditions. Using super-resolution microscopy, we found that ASC colocalized tightly with SAA in human AA amyloidosis. Recombinant ASC specks accelerated SAA fibril formation and mass spectrometry after limited proteolysis showed that ASC interacts with SAA via its pyrin domain (PYD). In a murine model of inflammatory AA amyloidosis, splenic amyloid load was conspicuously decreased in Pycard−/− mice which lack ASC. Treatment with anti-ASCPYD antibodies decreased amyloid loads in wild-type mice suffering from AA amyloidosis. The prevalence of natural anti-ASC IgG (−logEC50 ≥ 2) in 19,334 hospital patients was <0.01%, suggesting that anti-ASC antibody treatment modalities would not be confounded by natural autoimmunity. These findings expand the role played by ASC and IL-1 independent inflammasome employments to extraneural proteinopathies and suggest that anti-ASC immunotherapy may contribute to resolving such diseases.

Studies on the potential risk of amyloidosis from exposure to cultured fibril from silk fibroin

Amyloid A (AA) amyloidosis is induced by administering amyloid fibrils to animals under inflammatory conditions. Silk fibroin (SF), the main component of silk threads, forms amyloid-like fibrils and has been previously reported to induce AA amyloidosis in mice. In this study, SF was cultured in ethanol solution, and after confirming fibril formation through thioflavin T assay, Congo red assay, and observation under electron microscopy, cultured SF ethanol solutions were administered to mice via various routes to investigate the induction of target organs and amyloidosis. As a result, cultured SF ethanol solutions were confirmed to reach the lungs and spleen, but no amyloid deposition was observed. While SF forms amyloid-like fibril structures through cultivation in ethanol solution, its amyloid-enhancing factor (AEF) activity is considered low in mice.

Deactivation of the Unfolded Protein Response Aggravated Renal AA Amyloidosis in HSF1 Deficiency Mice.

Systemic amyloid A (AA) amyloidosis, which is considered the second most common form of systemic amyloidosis usually takes place several years prior to the occurrence of chronic inflammation, generally involving the kidney. Activated HSF1, which alleviated unfolded protein response (UPR) or enhanced HSR, is the potential therapeutic target of many diseases. However, the effect of HSF1 on AA amyloidosis remains unclear. This study focused on evaluating effect of HSF1 on AA amyloidosis based on HSF1 knockout mice. As a result, aggravated amyloid deposits and renal dysfunction have been found in HSF1 knockout mice. In progressive AA amyloidosis, HSF1 deficiency enhances serum amyloid A production might to lead to severe AA amyloid deposition in mice, which may be related to deactivated unfolded protein response as well as enhanced inflammation. Thus, HSF1 plays a significant role on UPR related pathway impacting AA amyloid deposition, which can mitigate amyloidogenic proteins from aggregation pathologically and is the possible way for intervening with the pathology of systemic amyloid disorder. In conclusion, HSF1 could not only serve as a new target for AA amyloidosis treatment in the future, but HSF1 knockout mice also can be considered as a valuable novel animal model for renal AA amyloidosis.

Evaluation of Serum Amyloid A and some Biochemical markers in Iraqi patients with systemic lupus erythematosus

An autoimmune condition called systemic lupus erythematosus (SLE) is caused by long-term inflammation. Amyloid A (AA) amyloidosis results in nephropathy and other internal symptoms, including death. The current study set out to look at the relationship between serum amyloid A (SAA) levels in circulation and SLE patients. Methods: Sixty SLE patients and 30 healthy with age range (19-55) yearswere involved in this study. A SLE patient wasidentified in the teaching hospital in Baghdad. In this study, laboratory indicators such as blood lipid, kidney function, test results, and total cholesterol (TC), triglyceride (TG), SAA, and ALB were assessed using an automated biochemical analyzer. Results: Patients with active SLE had serum amyloid A (SAA) values 5.83 mg/L [IQR: 2.08–10.87], 4.92 mg/L [IQR: 1.57–11.43], and 1.33 mg/L [IQR: 0.13–3.12], respectively, substantially upper than personswith inactive SLE or healthy control subjects (P &lt; 0.001). ESR values in healthy control subjects, patients with inactive SLE, and patients with active SLE. In conclusion, the current study's findings offered more proof of SAA's potential involvement in SLE and suggested that it might be valuable biomarkers that could reveal more details about the disease's activity.

An evaluation of serum blood parameters and amyloid A levels in pregnant women with threatened miscarriage.

This study investigated whether serum amyloid A (AA) levels can be used as a biomarker in patients with threatened abortion. This prospective cohort study was conducted at the Antalya Training and Research Hospital, Department of Obstetrics and Gynecology, Türkiye, between April and October 2023. Eighty-eight pregnant women, 44 diagnosed with threatenedmiscarriage (Group 1) and 44 healthy individuals (Group 2), were included in the study. Sociodemographic, obstetric, and laboratory parameters were compared between the groups. No statistically significant differences were observed between the groups in terms of sociodemographic data (age, body mass index, education level, economic status, occupation status, smoking, and alcohol consumption). However, obstetric characteristics (number of pregnancies, living children, miscarriages, dilatation and curettage, gestational age on admission, and fetal crown-rump length) and laboratory values including complete blood count, hematocrit, leukocyte, neutrophil, lymphocytes, platelet, hs-C-reactive protein, neutrophil-lymphocyte and platelet-lymphocyte ratio (p>.05), and serum AA values (7.49±3.07 in Group1 vs. 9.46±4.80 in Group 2, p=.024) differed significantly. Receiver operating characteristic analysis showed that the area under the curve (AUC: 0.662) was statistically significant for serum AA (p=.032), with a cut-off value of ≥7.51 (95% [confidence interval] 0.516-0.749, sensitivity 65%, specificity 51%). The positive predictive value of serum AA for threatened miscarriage was 56.8%, and the negative predictive value 59.4%. This study shows that serum AA can be used as a biomarker in the diagnosis of threatened miscarriage. Prospective studies involving more participants are now needed to confirm our results.

Mass Spectrometry Proteomics Characterization of Plasma Biomarkers for Colorectal Cancer Associated With Inflammation.

Colorectal cancer (CRC) prognosis is determined by the disease stage with low survival rates for advanced stages. Current CRC screening programs are mainly using colonoscopy, limited by its invasiveness and high cost. Therefore, non-invasive, cost-effective, and accurate alternatives are urgently needed. This retrospective multi-center plasma proteomics study was performed to identify potential blood-based biomarkers in 36 CRC patients and 26 healthy volunteers by high-resolution mass spectrometry proteomics followed by the validation in an independent CRC cohort (60 CRC patients and 44 healthy subjects) of identified selected biomarkers. Among the 322 identified plasma proteins, 37 were changed between CRC patients and healthy volunteers and were associated with the complement cascade, cholesterol metabolism, and SERPIN family members. Increased levels in CRC patients of the complement proteins C1QB, C4B, and C5 as well as pro-inflammatory proteins, lipopolysaccharide-binding protein (LBP) and serum amyloid A4, constitutive (SAA4) were revealed for first time. Importantly, increased level of C5 was verified in an independent validation CRC cohort. Increased C4B and C8A levels were correlated with cancer-associated inflammation and CRC progression, while cancer-associated inflammation was linked to the acute-phase reactant leucine-rich alpha-2-glycoprotein 1 (LRG1) and ceruloplasmin. Moreover, a 4-protein signature including C4B, C8A, apolipoprotein C2 (APO) C2, and immunoglobulin heavy constant gamma 2 was changed between early and late CRC stages. Our results suggest that C5 could be a potential biomarker for CRC diagnosis. Further validation studies will aid the application of these new potential biomarkers to improve CRC diagnosis and patient care.

Clinical, Endoscopic, and Histopathologic Observations in Gastrointestinal Amyloidosis.

Amyloidosis is a group of systemic disorders caused by extracellular deposition of misfolded serum proteins. Gastrointestinal (GI) involvement is associated with a higher risk of GI bleeding, especially if mucosal lesions are present. Our study aims to evaluate the frequency of GI manifestations in patients with amyloidosis, to clinically characterize these patients and to describe the endoscopic and histopathologic findings in GI amyloidosis. A retrospective, single-center study of all patients admitted with amyloidosis and GI manifestations was conducted at a German University Hospital between July 2003 and June 2023. Clinical, endoscopic, and histopathological data was retrieved from medical records. Between July 2003 and June 2023, 63 patients with different types of amyloidosis were included into the study. Twenty-three (36,5%) were diagnosed with GI involvement of amyloidosis (60.9% male, median age 62 ± 18.28 years). The distribution of the types of amyloidosis were amyloid light chain (AL) at 52.5%, transthyretin (ATTR) at 21.7%, amyloid A (AA) at 13.0%, and unknown at 18%. Initial GI symptoms were present in 78.3% of the patients and included mainly diarrhea (34.8%), and abdominal pain (30.4%) Affected GI organs were primarily the colon (60,8%) and the stomach (39.1%). Endoscopic findings were ulcerations (47.8%), mucosal inflammation (43.5%), polyps (26.1%), erosions (13.0%), vascular malformation, polypoid protrusion, submucosal hematoma, erythema, metaplasia, and diverticulum. Histopathological findings included vascular wall thickening, (peri-)vascular and interstitial amyloid deposition. Gastrointestinal bleeding occurred in 39.1% of the patients. The mortality rate 5 years after diagnosis was 47.8%. Gastrointestinal amyloidosis can present with multiple symptoms and endoscopic findings, rendering diagnosis a challenge. Of clinical relevance, GI bleeding was a frequent event in our patient cohort. Therefore, clinicians must be aware of GI bleeding as a manifestation of amyloidosis and definite diagnosis should be achieved based on biopsy results.

Renal Amyloid A (AA) Amyloidosis in a 24-Year-Old Drug User

Renal Amyloid A (AA) Amyloidosis in a 24-Year-Old Drug User

Molecular and translational biology of the blood-based VeriStrat® proteomic test used in cancer immunotherapy treatment guidance

IntroductionThe VeriStrat® test (VS) is a blood-based assay that predicts a patient's response to therapy by analyzing eight features in a spectrum obtained from matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) analysis of human serum and plasma. In a recent analysis of the INSIGHT clinical trial (NCT03289780), it was found that the VS labels, VS Good and VS Poor, can effectively predict the responsiveness of non-small cell lung cancer (NSCLC) patients to immune checkpoint inhibitor (ICI) therapy. However, while VS measures the intensities of spectral features using MALDI-TOF analysis, the specific proteoforms underlying these features have not been comprehensively identified. ObjectivesThe objective of this study was to identify the proteoforms that are measured by VS. MethodsTo resolve the features obtained from the low-resolution MALDI-TOF procedure used to acquire mass spectra for VS DeepMALDI® analysis of serum was employed. This technique allowed for the identification of finer peaks within these features. Additionally, a combination of reversed-phase fractionation and liquid chromatography-tandem mass spectrometry (LC-MS/MS) was then used to identify the proteoforms associated with these peaks. ResultsThe analysis revealed that the primary constituents of the spectrum measured by VS are serum amyloid A1, serum amyloid A2, serum amyloid A4, C-reactive protein, and beta-2 microglobulin. ConclusionProteoforms involved in host immunity were identified as significant components of these features. This newly acquired information improves our understanding of how VS can accurately predict patient response to therapy. It opens up additional studies that can expand our understanding even further.

Pathomorphological Features of the Novel Coronavirus Disease in Patients with Systemic Amyloidosis.

Amyloidosis is one of the rare systemic illnesses characterized by the deposition of amyloid fibrils in various organs and tissues. There is a common point between COVID-19 and systemic amyloidosis regarding the multiorgan involvement in the pathological process which leads to a heightened risk for severe morbidity and mortality in amyloidosis patients who contracted COVID-19. We performed a pathomorphological analysis of the autopsy records of 22 patients who had COVID-19 and pre-existing systemic amyloidosis. The premortem diagnosis of systemic amyloidosis was established in 55% of patients, and in other 45% of cases, amyloidosis was found at autopsy. Based on the results of immunohistochemical amyloid typing, amyloid A (AA) amyloidosis was detected in 23%, amyloid light chain (AL) lambda in 32%, AL kappa-in 9%, and transthyretin (ATTR) amyloidosis-in 36% of observations. Immunohistochemical staining with an antibody against SARS-CoV-2 Spike (S) protein revealed positive immune reactions in type II alveolocytes in 59% of deceased persons. The analysis of autopsy findings indicates that patients with systemic amyloidosis are more likely to experience an aggressive clinical course of COVID-19 which leads to a multiorgan failure and a higher risk of fatal outcome.

Hyperspectral Raman Imaging for Automated Recognition of Human Renal Amyloid.

In the clinical setting, routine identification of the main types of tissue amyloid deposits, light-chain amyloid (AL) and serum amyloid A (AA), is based on histochemical staining; rarer types of amyloid require mass spectrometry analysis. Raman spectroscopic imaging is an analytical tool, which can be used to chemically map, and thus characterize, the molecular composition of fluid and solid tissue. In this proof-of-concept study, we tested the feasibility of applying Raman spectroscopy combined with artificial intelligence to detect and characterize amyloid deposits in unstained frozen tissue sections from kidney biopsies with pathologic diagnosis of AL and AA amyloidosis and control biopsies with no amyloidosis (NA). Raman hyperspectral images, mapped in a 2D grid-like fashion over the tissue sections, were obtained. Three machine learning-assisted analysis models of the hyperspectral images could accurately distinguish AL (types λ and κ), AA, and NA 93-100% of the time. Although very preliminary, these findings illustrate the potential of Raman spectroscopy as a technique to identify, and possibly, subtype renal amyloidosis.

Chemical design of radioiodinated probes with a metabolizable linkage for target-selective imaging of systemic amyloidosis

IntroductionSystemic amyloidosis is a rare disease caused by the deposition of amyloid fibrils in various organs. Amyloid-targeted radiopharmaceuticals have been developed and applied to diagnose systemic amyloidosis peripherally; however, high-contrast imaging has not been achieved because of the high background signals in normal organs. To overcome this problem, we designed an amyloid-targeted radioiodinated probe 1 with a metabolizable linkage (ester bond) to release of radiolabeled metabolites (m-iodohippuric acid) in normal organs that could be rapidly excreted in the urine. MethodsCompound 1 was synthesized by conjugating 2-(4-(methylamino)phenyl)benzo[d]thiazol-6-ol, an amyloid-targeting compound, with m-iodohippuric acid. [125I]1 was synthesized via iododestannylation using a tributyltin precursor. Mouse models of amyloid A (AA) amyloidosis, a type of systemic amyloidosis, were prepared by administering amyloid-enhancing factor to mice and used for in vitro autoradiography using organ sections and in vivo evaluation. Results[125I]1 was obtained with a radiochemical yield of 59% and radiochemical purity of over 95%. An in vitro autoradiographic study demonstrated that [125I]1 specifically binds to amyloid in the splenic tissue. Upon administration to normal mice, [125I]1 was distributed to organs throughout the body, followed by the rapid excretion of radioactivity in the urine as m-[125I]iodohippuric acid. Furthermore, ex vivo autoradiography showed that [125I]1 bound to the amyloid formed around the follicles in the spleens of AA amyloidosis model mice. ConclusionThese results suggest that the interposition of a metabolizable linkage between an amyloid-targeting moiety and a radiolabeled hippuric acid would be useful in the design of radiopharmaceuticals for high-contrast imaging of systemic amyloidosis.

Elucidation of the mechanism of amyloid A and transthyretin formation using mass spectrometry-based absolute quantification.

Amyloidosis is triggered by the truncation of amyloid precursor proteins, causing organ damages. While previous studies found the truncation of amyloid A (AA) and amyloid transthyretin (ATTR) occurs in C- and N-terminal, respectively, the detailed mechanism of the fibril formation remains unclear.Liquid chromatography mass spectrometry is usually applied for a qualitative purpose, and thus quantification of tryptic peptide residue is difficult. We therefore employed a mass spectrometry-based quantification by isotope-labeled cell-free (MS-QBIC) to analyze the truncation processes in amyloid fibrillogenesis of AA and ATTR using the formalin-fixed paraffin-embedded tissues of autopsy cases. In this study, the process of transthyretin from an 'early fibril state' consisting of full-length ATTR to a 'mature ATTR amyloid fibril' with a truncated low-amyloidogenic segment has been mathematically revealed. The amount of full-length ATTR was nine times higher than in mature fibers. Large cohort studies using MS-QBIC may shed light on the clinical significance of amyloid fibrils.

DP25 Widespread subcutaneous nodular kappa light chain amyloidosis

Abstract A 69-year-old woman was referred to the dermatology department for evaluation of multiple widespread subcutaneous lesions involving the neck, torso and limbs. These lesions, initially diagnosed in the community as lipomas, had been slowly progressing in size and number for 3 years. She had remained systemically well. Her only medical history was essential thrombocythaemia. She took no regular medication. On examination, there were multiple subcutaneous lesions appreciated on palpation with no overlying epidermal change. The patient was experiencing pain in a sciatic distribution. Magnetic resonance imaging of the femur showed a 12-cm enhancing area of subcutaneous nodularity encasing the sciatic nerve. Computed tomography of the chest, abdomen and pelvis showed multiple subcutaneous, ill-defined, soft tissue lesions of the anterior abdominal wall with no lymphadenopathy or organ abnormality. Deep incisional biopsies from two separate locations were completed. There was an unremarkable epidermis and dermis. In the subcutaneous fat, the septae appeared thickened alongside thickened elastic fibres and a prominent multifocal granulomatous reaction with a high degree of elastophagocytosis. There were multifocal aggregates of plasma cells that displayed no cytological atypia. In situ hybridization showed strong kappa light chain restriction. Plasma protein electrophoresis was completed and confirmed a paraprotein band in the gamma region of IgM kappa. Full blood count revealed a high platelet count (585 × 109 cells L–1) but was otherwise unremarkable alongside normal renal and liver function, bone profile, lactate dehydrogenase, B2 microglobulin, Bence–Jones proteins and infection screen. A Congo red stain was performed on the original histological samples. This showed apple green birefringence under polarized light-confirming amyloid. Haematology completed a bone marrow biopsy, which was normal. Referral to the National Amyloid Centre was made. Serum amyloid P scan showed no visceral involvement. A diagnosis of subcutaneous amyloid kappa light chain subtype (AL) was made. The patient has since commenced rituximab, bortezomib (Velcade®), cyclophosphamide and dexamethasone (R-VCD) chemotherapy at 4-weekly intervals over a 4-month period. Primary localized cutaneous amyloidosis is characterized by extracellular deposition of amyloid protein in the skin without evidence of systemic involvement and is often subtyped into macular, papular and nodular. Amyloidoma (tumoral amyloidosis) is rare and defined as a solitary localized deposit of amyloid. There are only four case reports in the literature of multiple subcutaneous amyloid deposits, and only one of these cases was of AL (light chain) vs. amyloid A (AA) subtype. This case showed nodules restricted to the neck (Nguyen TU, Oghalai JS, McGregor DK et al. Subcutaneous nodular amyloidosis: a case report and review of the literature. Hum Pathol 2001; 32:346–8). To our knowledge, this is the first case of widespread kappa light chain subcutaneous amyloidosis.