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Journal of Gastrointestinal and Liver... Dec 2023Amyloidosis is a group of systemic disorders caused by extracellular deposition of misfolded serum proteins. Gastrointestinal (GI) involvement is associated with a...
BACKGROUND AND AIMS
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.
METHODS
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.
RESULTS
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%.
CONCLUSIONS
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.
Topics: Humans; Male; Adult; Middle Aged; Aged; Aged, 80 and over; Female; Retrospective Studies; Gastrointestinal Diseases; Amyloidosis; Gastrointestinal Hemorrhage
PubMed: 38147621
DOI: 10.15403/jgld-5107 -
Journal of Gastrointestinal and Liver... Dec 2020
Topics: Amyloidosis; Biopsy; Endoscopy, Digestive System; Gastric Mucosa; Humans; Immunoglobulin kappa-Chains; Immunohistochemistry; Male; Middle Aged; Stomach Diseases
PubMed: 33331333
DOI: 10.15403/jgld-3088 -
Molecular Neurodegeneration Jul 2023Previous studies show that antibiotic-mediated (abx) alteration of the gut microbiome (GMB) results in a reduction of amyloid beta (Aβ) plaques and proinflammatory...
BACKGROUND
Previous studies show that antibiotic-mediated (abx) alteration of the gut microbiome (GMB) results in a reduction of amyloid beta (Aβ) plaques and proinflammatory microglial phenotype in male APPPS1-21 mice. However, the effect of GMB perturbation on astrocyte phenotypes and microglial-astrocyte communication in the context of amyloidosis has not been examined.
METHODS
To study whether the GMB modulates astrocyte phenotype in the context of amyloidosis, APPPS1-21 male and female mice were treated with broad-spectrum abx leading to GMB perturbation. GFAP + astrocytes, plaque-associated astrocytes (PAA), PAA morphological parameters, and astrocyte complement component C3 levels were quantified using a combination of immunohistochemistry, immunoblotting, widefield microscopy, and confocal microscopy. Furthermore, these same astrocyte phenotypes were assessed in abx-treated APPPS1-21 male mice that received either fecal matter transplant (FMT) from untreated APPPS1-21 male donors to restore their microbiome or vehicle control. To assess complete absence of the GMB on astrocyte phenotypes, the same astrocyte phenotypes were quantified in APPPS1-21 male mice raised in germ-free (GF) or specific-pathogen free conditions (SPF). Lastly, we assessed whether microglia are necessary for abx-induced astrocyte phenotypes by depleting microglia in APPPS1-21 male mice via treatment with a colony-stimulating factor 1 receptor (CSF1R) inhibitor (PLX5622) and vehicle control or PLX5622 and abx.
RESULTS
Herein, we demonstrate that postnatal treatment of male APPPS1-21 mice with broad-spectrum abx leading to GMB perturbation reduces GFAP + reactive astrocytes and PAAs, suggesting that the GMB plays a role in regulating reactive astrocyte induction and recruitment to Aβ plaques. Additionally, we show that compared to controls, PAAs in abx-treated male APPPS1-21 mice exhibit an altered morphology with increased number and length of processes and reduced astrocytic complement C3, consistent with a homeostatic phenotype. GFAP + astrocyte reduction, PAA reduction, astrocyte morphological changes, and C3 levels are restored when abx-treated mice are subject to FMT from untreated APPPS1-21 male donor mice. Next, we found that APPPS1-21 male mice raised in GF conditions have similar astrocyte phenotypes as abx-treated male APPPS1-21 male mice. Correlational analysis revealed that pathogenic bacteria depleted by abx correlate with GFAP + astrocytosis, PAAs, and astrocyte morphological changes. Finally, we determined that abx-mediated reduction in GFAP + astrocytosis, PAAs, and astrocytic C3 expression is independent of microglia. However, abx-induced astrocyte morphological alterations are dependent on the presence of microglia, suggesting that there is both microglial independent and dependent GMB control of reactive astrocyte phenotypes.
CONCLUSIONS
We show for the first time, in the context of amyloidosis, that the GMB plays an important role in controlling reactive astrocyte induction, morphology, and astrocyte recruitment to Aβ plaques. GMB regulation of these astrocytic phenotypes is both independent and dependent on microglia.
Topics: Mice; Male; Female; Animals; Amyloid beta-Peptides; Alzheimer Disease; Microglia; Astrocytes; Amyloid beta-Protein Precursor; Gastrointestinal Microbiome; Mice, Transgenic; Gliosis; Amyloidosis; Plaque, Amyloid
PubMed: 37415149
DOI: 10.1186/s13024-023-00635-2 -
Respiratory Medicine Apr 2022Amyloid transthyretin amyloidosis (ATTR) is characterized by deposition of a misfolded conformation of the transport protein TTR, most commonly in cardiac and nerve... (Review)
Review
INTRODUCTION
Amyloid transthyretin amyloidosis (ATTR) is characterized by deposition of a misfolded conformation of the transport protein TTR, most commonly in cardiac and nerve tissue, causing clinical disease. Pulmonary amyloidosis, or deposition of ATTR in lung tissue, is a poorly characterized manifestation of this disease. We present the clinical course, imaging characteristics, pathology results, and outcomes of a patient cohort diagnosed with pulmonary ATTR.
METHODS
We retrospectively reviewed records of 28 patients with pulmonary ATTR seen at Mayo Clinic from September 30, 2005, through December 31, 2020. Data collected included information on demographics, subjective symptoms, tissue biopsy results, pulmonary function testing, imaging findings, and treatment.
RESULTS
Of the patients, 89% were men; the median age was 74.5 years (range, 50-99 years). Patients were typically diagnosed after persistent dyspnea and abnormal chest imaging resulted in lung biopsy, which yielded the ATTR diagnosis. Most patients had a preexisting diagnosis of cardiac ATTR. The disease was wild-type in 62% and hereditary in 38%. Normal pulmonary function tests followed by a restrictive pattern were the most common presentation. Of the patients, 93% had chest computed tomography, with common findings of diffuse nodularity, calcified granulomas, interlobular septal thickening, and pleural effusions. Almost all patients had pulmonary vascular involvement, and half had interstitial involvement on tissue biopsy. One-third received either anti-amyloid pharmacotherapy or a heart transplant. Half of patients had died before the time of study inclusion.
CONCLUSION
Pulmonary disease is a less common but clinically important manifestation of ATTR.
Topics: Aged; Amyloid Neuropathies, Familial; Humans; Lung; Lung Diseases; Male; Retrospective Studies
PubMed: 35217402
DOI: 10.1016/j.rmed.2022.106761 -
Clinical Journal of the American... Apr 2022Patients with monoclonal gammopathy and concomitant kidney diseases are frequently found in clinical practice. Some of them are diagnosed with monoclonal gammopathy of...
BACKGROUND AND OBJECTIVES
Patients with monoclonal gammopathy and concomitant kidney diseases are frequently found in clinical practice. Some of them are diagnosed with monoclonal gammopathy of renal significance (MGRS) due to the presence of monoclonal Ig-related kidney injuries. This study aimed to investigate the histopathologic spectrum and clinical characteristics associated with MGRS in a large cohort of patients with monoclonal gammopathy and biopsy-proven kidney diseases from a single Chinese nephrology referral center.
DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS
Patients who presented with monoclonal gammopathy (monoclonal spike on serum and/or urine immunofixation tests) and underwent kidney biopsy in the Peking University First Hospital from January 1, 1999 to December 31, 2020 were enrolled in this retrospective study. Patients with malignant hematologic diseases were excluded. Clinical and laboratory data were collected from the electronic medical record system. Comparisons of patients with and without MGRS and with and without amyloidosis were performed. The clinical characteristics associated with MGRS were identified using multivariable logistic regression.
RESULTS
A total of 700 patients with monoclonal gammopathy and kidney biopsy were identified. Thirteen patients with repeat kidney biopsies were analyzed separately. For the remaining 687 patients with one kidney biopsy, 261 patients (38%) had MGRS lesions, and the rest (426 patients, 62%) had non-MGRS kidney diseases. Ig-related amyloidosis accounted for the most MGRS cases (=164, 63%), followed by monoclonal Ig deposition disease (=23, 9%) and thrombotic microangiopathy (=22, 8%). In the non-MGRS group, membranous nephropathy was the most common diagnosis (=171, 40%). In the multivariable logistic regression model, the presence of abnormal serum free light chain ratio, older age, and greater proteinuria were independently associated with MGRS.
CONCLUSIONS
Monoclonal Ig amyloidosis is the leading cause of MGRS in Chinese patients with monoclonal gammopathy. The presence of abnormal free light chain ratio, older age, and greater proteinuria were associated with MGRS.
Topics: Amyloidosis; Humans; Immunoglobulin Light Chains; Kidney; Kidney Diseases; Monoclonal Gammopathy of Undetermined Significance; Paraproteinemias; Proteinuria; Retrospective Studies
PubMed: 35210280
DOI: 10.2215/CJN.12890921 -
JACC. Cardiovascular Imaging Apr 2023Bone scintigraphy is extremely valuable when assessing patients with suspected cardiac amyloidosis (CA), but the clinical significance and associated phenotype of...
BACKGROUND
Bone scintigraphy is extremely valuable when assessing patients with suspected cardiac amyloidosis (CA), but the clinical significance and associated phenotype of different degrees of cardiac uptake across different types is yet to be defined.
OBJECTIVES
This study sought to define the phenotypes of patients with varying degrees of cardiac uptake on bone scintigraphy, across multiple types of systemic amyloidosis, using extensive characterization comprising biomarkers as well as echocardiographic and cardiac magnetic resonance (CMR) imaging.
METHODS
A total of 296 patients (117 with immunoglobulin light-chain amyloidosis [AL], 165 with transthyretin amyloidosis [ATTR], 7 with apolipoprotein AI amyloidosis [AApoAI], and 7 with apolipoprotein AIV amyloidosis [AApoAIV]) underwent deep characterization of their cardiac phenotype.
RESULTS
AL patients with grade 0 myocardial radiotracer uptake spanned the spectrum of CMR findings from no CA to characteristic CA, whereas AL patients with grades 1 to 3 always produced characteristic CMR features. In ATTR, the CA burden strongly correlated with myocardial tracer uptake, except in Ser77Tyr. AApoAI presented with grade 0 or 1 and disproportionate right-sided involvement. AApoAIV always presented with grade 0 and characteristic CA. AL grade 1 patients (n = 48; 100%) had characteristic CA, whereas only ATTR grade 1 patients with Ser77Tyr had characteristic CA on CMR (n = 5; 11.4%). After exclusion of Ser77Tyr, AApoAI, and AApoAIV, CMR showing characteristic CA or an extracellular volume of >0.40 in patients with grade 0 to 1 cardiac uptake had a sensitivity and specificity of 100% for AL.
CONCLUSIONS
There is a wide variation in cardiac phenotype between different amyloidosis types across different degrees of cardiac uptake. The combination of CMR and bone scintigraphy can help to define the diagnostic differentials and the clinical phenotype in each individual patient.
Topics: Humans; Predictive Value of Tests; Tomography, X-Ray Computed; Amyloid Neuropathies, Familial; Heart; Immunoglobulin Light-chain Amyloidosis; Phenotype; Cardiomyopathies
PubMed: 36648052
DOI: 10.1016/j.jcmg.2022.07.008 -
Molecular Neurodegeneration Dec 2023Microglia, the brain-resident macrophages perform immune surveillance and engage with pathological processes resulting in phenotype changes necessary for maintaining...
Translational profiling identifies sex-specific metabolic and epigenetic reprogramming of cortical microglia/macrophages in APPPS1-21 mice with an antibiotic-perturbed-microbiome.
BACKGROUND
Microglia, the brain-resident macrophages perform immune surveillance and engage with pathological processes resulting in phenotype changes necessary for maintaining homeostasis. In preceding studies, we showed that antibiotic-induced perturbations of the gut microbiome of APPPS1-21 mice resulted in significant attenuation in Aβ amyloidosis and altered microglial phenotypes that are specific to male mice. The molecular events underlying microglial phenotypic transitions remain unclear. Here, by generating 'APPPS1-21-CD11br' reporter mice, we investigated the translational state of microglial/macrophage ribosomes during their phenotypic transition and in a sex-specific manner.
METHODS
Six groups of mice that included WT-CD11br, antibiotic (ABX) or vehicle-treated APPPS1-21-CD11br males and females were sacrificed at 7-weeks of age (n = 15/group) and used for immunoprecipitation of microglial/macrophage polysomes from cortical homogenates using anti-FLAG antibody. Liquid chromatography coupled to tandem mass spectrometry and label-free quantification was used to identify newly synthesized peptides isolated from polysomes.
RESULTS
We show that ABX-treatment leads to decreased Aβ levels in male APPPS1-21-CD11br mice with no significant changes in females. We identified microglial/macrophage polypeptides involved in mitochondrial dysfunction and altered calcium signaling that are associated with Aβ-induced oxidative stress. Notably, female mice also showed downregulation of newly-synthesized ribosomal proteins. Furthermore, male mice showed an increase in newly-synthesized polypeptides involved in FcγR-mediated phagocytosis, while females showed an increase in newly-synthesized polypeptides responsible for actin organization associated with microglial activation. Next, we show that ABX-treatment resulted in substantial remodeling of the epigenetic landscape, leading to a metabolic shift that accommodates the increased bioenergetic and biosynthetic demands associated with microglial polarization in a sex-specific manner. While microglia in ABX-treated male mice exhibited a metabolic shift towards a neuroprotective phenotype that promotes Aβ clearance, microglia in ABX-treated female mice exhibited loss of energy homeostasis due to persistent mitochondrial dysfunction and impaired lysosomal clearance that was associated with inflammatory phenotypes.
CONCLUSIONS
Our studies provide the first snapshot of the translational state of microglial/macrophage cells in a mouse model of Aβ amyloidosis that was subject to ABX treatment. ABX-mediated changes resulted in metabolic reprogramming of microglial phenotypes to modulate immune responses and amyloid clearance in a sex-specific manner. This microglial plasticity to support neuro-energetic homeostasis for its function based on sex paves the path for therapeutic modulation of immunometabolism for neurodegeneration.
Topics: Mice; Animals; Male; Female; Alzheimer Disease; Microglia; Mice, Transgenic; Anti-Bacterial Agents; Amyloidosis; Microbiota; Macrophages; Peptides; Mitochondrial Diseases; Epigenesis, Genetic; Amyloid beta-Peptides; Disease Models, Animal
PubMed: 38104136
DOI: 10.1186/s13024-023-00668-7 -
The Journal of International Medical... Dec 2022Amyloidosis is a disease caused by amyloid deposition in tissues or organs. According to the extent of the lesion, it can be divided into systemic amyloidosis and...
Amyloidosis is a disease caused by amyloid deposition in tissues or organs. According to the extent of the lesion, it can be divided into systemic amyloidosis and localized amyloidosis. Amyloidosis originating in the larynx accounts for approximately 0.5% to 1.0% of benign lesions of the larynx; such lesions are relatively rare and mostly localized. Nasopharyngeal amyloidosis combined with laryngeal amyloidosis is even rarer. We herein present a case involving a patient with amyloidosis in the nasopharynx and larynx who presented with a foreign body sensation and hoarseness in the pharynx. Electronic fiber laryngoscopy revealed a smooth neoplasm in the left nasopharynx and left vocal cord. The patient underwent surgical treatment, and the postoperative pathologic examination results suggested amyloidosis. Special staining performed using Congo red and crystal violet was positive, confirming amyloidosis. The patient recovered after surgery, and no recurrence was present at the 3- and 6-month follow-ups.
Topics: Humans; Larynx; Amyloidosis; Laryngeal Diseases; Immunoglobulin Light-chain Amyloidosis; Nasopharynx
PubMed: 36539964
DOI: 10.1177/03000605221144151 -
European Journal of Cell Biology Apr 2022Breast cancer (BC) and Alzheimer's disease (AD) have pronounced female-to-male disparities and both are the major causes of death in elderly women. Intriguingly, there...
Breast cancer (BC) and Alzheimer's disease (AD) have pronounced female-to-male disparities and both are the major causes of death in elderly women. Intriguingly, there is an inverse incidence between BC and AD. In our previous study, we found that the expression of ARSD, a female-biased gene on chromosome Xp22.3 that encodes arylsulfatase D, is significantly downregulated in triple-negative breast cancer (TNBC) cells and tissue samples, and that ectopic ARSD overexpression could inhibit proliferation and migration of BC cells. However, the exact mechanism remains unclear. In this study, ARSD-overexpressing MDA-MB-231 cell strains were established. RNA-Seq and qRT-PCR validation were performed followed by GO and KEGG analyses. Transcriptome sequencing unveiled that Alzheimer's/Parkinson's/prion diseases were enriched in ARSD overexpressing BC cells. Besides, the top enriched pathways included lipoprotein/cholesterol metabolism, molecular chaperone and misfolding protein binding, mitochondrial respiration, dysfunction of lysosomes, etc. In which, a battery of genes, e.g., SERF1A, APOE, CD36 etc., were upregulated, while a series of genes, e.g., NDUFA11, NDUFS3, NDUFV1, etc. were downregulated, which were closely related to amyloidosis. The amyloidosis of BC cells and nerval cells caused by ARSD overexpression was verified with western blotting, immunohistochemical and Congo red staining. Collectively, downregulated ARSD may be closely associated with BC, and upregulated ARSD may cause amyloidosis of BC cells. Our findings suggest that ARSD deserves to be considered a new promising target for treating TNBC or for AD.
Topics: Aged; Amyloidosis; Breast Neoplasms; Carcinoma; Cell Line, Tumor; Cell Proliferation; Epithelial Cells; Female; Humans; Male; Nerve Tissue Proteins; Transcription Factors; Triple Negative Breast Neoplasms
PubMed: 35066432
DOI: 10.1016/j.ejcb.2022.151199 -
ESC Heart Failure Jun 2022Wild-type transthyretin amyloid cardiomyopathy (ATTRwt CM) is a more common disease than previously thought. Awareness of ATTRwt CM and its diagnosis has been challenged... (Review)
Review
Wild-type transthyretin amyloid cardiomyopathy (ATTRwt CM) is a more common disease than previously thought. Awareness of ATTRwt CM and its diagnosis has been challenged by its unspecific and widely distributed clinical manifestations and traditionally invasive diagnostic tools. Recent advances in echocardiography and cardiac magnetic resonance (CMR), non-invasive diagnosis by bone scintigraphy, and the development of disease-modifying treatments have resulted in an increased interest, reflected in multiple publications especially during the last decade. To get an overview of the scientific knowledge and gaps related to patient entry, suspicion, diagnosis, and systematic screening of ATTRwt CM, we developed a framework to systematically map the available evidence of (i) when to suspect ATTRwt CM in a patient, (ii) how to diagnose the disease, and (iii) which at-risk populations to screen for ATTRwt CM. Articles published between 2010 and August 2021 containing part of or a full diagnostic pathway for ATTRwt CM were included. From these articles, data for patient entry, suspicion, diagnosis, and screening were extracted, as were key study design and results from the original studies referred to. A total of 50 articles met the inclusion criteria. Of these, five were position statements from academic societies, while one was a clinical guideline. Three articles discussed the importance of primary care providers in terms of patient entry, while the remaining articles had the cardiovascular setting as point of departure. The most frequently mentioned suspicion criteria were ventricular wall thickening (44/50), carpal tunnel syndrome (42/50), and late gadolinium enhancement on CMR (43/50). Diagnostic pathways varied slightly, but most included bone scintigraphy, exclusion of light-chain amyloidosis, and the possibility of doing a biopsy. Systematic screening was mentioned in 16 articles, 10 of which suggested specific at-risk populations for screening. The European Society of Cardiology recommends to screen patients with a wall thickness ≥12 mm and heart failure, aortic stenosis, or red flag symptoms, especially if they are >65 years. The underlying evidence was generally good for diagnosis, while significant gaps were identified for the relevance and mutual ranking of the different suspicion criteria and for systematic screening. Conclusively, patient entry was neglected in the reviewed literature. While multiple red flags were described, high-quality prospective studies designed to evaluate their suitability as suspicion criteria were lacking. An upcoming task lies in defining and evaluating at-risk populations for screening. All are steps needed to promote early detection and diagnosis of ATTRwt CM, a prerequisite for timely treatment.
Topics: Amyloid Neuropathies, Familial; Cardiomyopathies; Contrast Media; Gadolinium; Humans; Prealbumin; Prospective Studies
PubMed: 35343098
DOI: 10.1002/ehf2.13884