Interstitial Amyloid Deposits Research Articles

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.

Amyloid myopathy: expanding the clinical spectrum of transthyretin amyloidosis—case report and literature review

We identified two patients with transthyretin (ATTR) amyloid myopathy (one ATTR variant amyloidosis, ATTRv; one wild-type ATTR amyloidosis, ATTRwt). Myopathy was the initial manifestation in ATTRwt, whereas it followed neuropathy and cardiomyopathy in ATTRv. The ATTRwt patient showed muscular tracer uptake on 99mTc-DPD planar scintigraphy at the time of initial diagnosis, consistent with ATTR amyloid myopathy. The ATTRv patient underwent heart transplantation because of progressive heart failure. Within the next two years, progressive myopathic symptoms and extracardiac tracer uptake on 99mTc-DPD planar scintigraphy were documented, attributable to ATTR amyloid myopathy. Interstitial amyloid deposits were confirmed by muscle biopsy in both patients, with a particularly high amyloid burden in the adipose tissue. This case report highlights the frequent concomitant presence of cardiac ATTR amyloidosis and ATTR amyloid myopathy. ATTR amyloid myopathy may precede cardiac manifestation in ATTRwt or occur after heart transplantation in ATTRv. Due to the high diagnostic accuracy of 99mTc-DPD scintigraphy for detecting ATTR amyloid myopathy and the emergence of novel therapeutics, it is important to increase the awareness of its presence.

Clinical Correlation of Histopathological Classification, Scoring, and Grading in Amyloid Nephropathies: Single-Center Experience

Objective: Amyloidosis is disorder of various etiologies in which abnormally folded fibrillary protein deposits with more than thirty forms infiltrate into extracellular spaces of affected organs. Renal involvement is clinically characterized by decreased estimated glomerular filtration rate (eGFR) and proteinuria. The aim of present study was to classify and grade renal amyloidosis cases using renal amyloid prognostic score (RAPS) systems, correlate clinical data and chronic kidney disease (CKD) stages. Methods: We retrospectively analyzed kidney biopsies of 45 patients diagnosed with renal amyloidosis applied between 2017-2022 to our department and scored each of patients according to RAPS. Results: 8.9% of patients had RAPS score 1, 53.3% had 2 and 37.8% had 3. Urea, serum creatinine and proteinuria levels of RAPS3 patients were significantly higher and eGFR levels were lower compared to RAPS1 patients (p<0.01). According to CKD stages, no significant difference was observed in glomerular amyloid deposition class and score, vascular and interstitial amyloid deposition scores, and glomerular sclerosis (p>0.05). The interstitial fibrosis, inflammation values and RAPS scores were found to be significantly higher in advanced CKD stages (p<0.05). Majority of patients at CKD stage 1-2 had RAPS score 2 (73.68%), while 57.1% of at stage 3 and 66.7% at stage 4-5 had RAPS score of 3 (p=0.0015). Conclusion: As a result, the intestinal fibrosis, inflammation values, RAPS scores were significantly higher in advanced CKD stages. Distribution pattern of amyloid in the renal parenchyma compartment, grade of RAPS and eGFR were associated with urea/creatinine, proteinuria levels and thus with CKD stage.

Evaluation of contemporary echocardiographic and histomorphology parameters in predicting mortality in patients with endomyocardial biopsy-proven cardiac AL amyloidosis.

This study examined the role of echocardiographic and cardiac histomorphology parameters in predicting mortality in patients with cardiac AL amyloidosis. Patients with endomyocardial biopsy-proven cardiac AL amyloidosis treated at MD Anderson Cancer Center between 6/2011 and 6/2020 were identified. Stored echocardiographic images and endomyocardial biopsy samples were processed for myocardial strain analysis and a detailed histomorphology characterization. Of 43 patients; 44% were women and 63% white. Median age was 65 years; 51% underwent stem cell transplantation (SCT). Thirty patients (70%) died during follow up (median follow up: 4.1 years). Lower LA strain (<13.5%) and absence of SCT as a time-varying covariate were significantly associated with increased risk of death in the multivariate cox regression analysis. Higher LV mass and lower RV tricuspid annular plane systolic excursion were associated with increased odds of having ≥5% interstitial amyloid deposition on biopsy in the multivariate logistic regression analysis. Lower LA strain independently predicted mortality in our cohort, and its performance in the routine assessment of AL amyloidosis may be beneficial. Furthermore, SCT for cardiac AL amyloidosis was associated with improved OS. These findings need to be confirmed by larger studies in the era of contemporary systemic therapies.

Abstract 12022: Predictors of Mortality in Patients With Biopsy-Proven Cardiac AL Amyloidosis

Introduction: Cardiac involvement occurs in ~50% of patients with light-chain (AL) amyloidosis and conveys a poor prognosis. This study examined the role of histopathologic and echocardiographic parameters in predicting mortality. Methods: Patients with endomyocardial biopsy-proven cardiac AL amyloidosis treated at MD Anderson Cancer Center between 6/2011 and 6/2020 were identified. Stored echocardiographic images were processed for longitudinal strain (global [GLS], apical, mid, basal) as well as radial and circumferential strain of the left ventricle (LV), right ventricle (RV) free wall, left atrium (LA), and right atrium, using the Epsilon EchoInsight Software. A detailed histomorphologic characterization of stored endomyocardial biopsy samples was performed by a cardiac pathologist and scored as &lt; or &gt; 5% AL deposits. Results: We identified 43 patients; 44% were women and 63% white. Median age was 65 years (IQR 59-70). Twenty-two (51%) underwent stem cell transplantation (SCT). A total of 29 patients (67%) died during follow up period (median follow up: 4.2 years (95% CI, 2.8-8.6)). Median overall survival (OS) was 18 months (95% CI, 8.1-37). Lower LA GLS and absence of SCT as a time-varying covariate were significantly and independently associated with increased risk of death in the multivariable cox regression analysis (HR 3.8, 95% CI 1.4-10.2 for LA GLS &lt; 13.5 vs &gt;13.5, p=0.008 and 0.20, 0.06-0.65 for SCT vs no SCT, p&lt;0.001, respectively). Higher LV mass and lower RV TAPSE were associated with increased odds of having &gt;5% of interstitial amyloid deposition on biopsy in the multivariable logistic regression analysis (OR 5.5, 95% CI 1.1-26.8 for &gt;195.6g vs ≤195.6g, p=0.036 and 8.1, 1.2-54.3 for RV TAPSE&lt;1.6cm vs ≥1.6cm, p=0.032, respectively). Conclusions: LA GLS &lt; 13.5 was an independent predictor of mortality in our cohort, and its performance in the routine assessment of AL amyloidosis may be justified. Furthermore, SCT for cardiac AL amyloidosis was associated with improved OS. This finding needs to be confirmed by larger studies in the era of contemporary systemic therapies. Although LV mass and RV TAPSE were associated with higher interstitial amyloid deposition, histopathologic parameters did not predict mortality in this cohort.

Anoctamin 5 (ANO5) Muscle Disorders: A Narrative Review.

Anoctaminopathy-5 refers to a group of hereditary skeletal muscle or bone disorders due to mutations in the anoctamin 5 (ANO5)-encoding gene, ANO5. ANO5 is a 913-amino acid protein of the anoctamin family that functions predominantly in phospholipid scrambling and plays a key role in the sarcolemmal repairing process. Monoallelic mutations in ANO5 give rise to an autosomal dominant skeletal dysplastic syndrome (gnathodiaphyseal dysplasia or GDD), while its biallelic mutations underlie a continuum of four autosomal recessive muscle phenotypes: (1). limb–girdle muscular dystrophy type R12 (LGMDR12); (2). Miyoshi distal myopathy type 3 (MMD3); (3). metabolic myopathy-like (pseudometabolic) phenotype; (4). asymptomatic hyperCKemia. ANO5 muscle disorders are rare, but their prevalence is relatively high in northern European populations because of the founder mutation c.191dupA. Weakness is generally asymmetric and begins in proximal muscles in LGMDR12 and in distal muscles in MMD3. Patients with the pseudometabolic or asymptomatic hyperCKemia phenotype have no weakness, but conversion to the LGMDR12 or MMD3 phenotype may occur as the disease progresses. There is no clear genotype–phenotype correlation. Muscle biopsy displays a broad spectrum of pathology, ranging from normal to severe dystrophic changes. Intramuscular interstitial amyloid deposits are observed in approximately half of the patients. Symptomatic and supportive strategies remain the mainstay of treatment. The recent development of animal models of ANO5 muscle diseases could help achieve a better understanding of their underlying pathomechanisms and provide an invaluable resource for therapeutic discovery.

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.

Correlation between amyloid deposits affecting renal compartments and glomerular filtration rate during renal biopsy in a renal amyloidosis case series.

Amyloidosis comprises a group of disorders that accumulate modified autologous proteins in organs, mainly the kidneys. Few studies have addressed the amyloid compartmental distribution and associated clinical outcomes. The aim of this study was to present a case series of renal amyloidosis correlating histopathological data with glomerular filtration rate (GFR) during kidney biopsy. We studied 53 cases reviewed by nephropathologists from 2000 to 2018 in a single kidney biopsy center in Brazil. GFR was estimated using the CKD-EPI formula. Cases were divided into Group A ≥60 and Group B <60 mL·min−1·(1.73 m2)−1 using the estimated GFR during kidney biopsy. Semiquantitative histopathological study was performed, including extension and distribution of amyloid deposits by compartments (glomeruli, tubulointerstitial tissue, and vessels). Statistical analyses were made to understand associations with lower GFR. No difference was seen for age, gender, proteinuria, hematuria, subtype of amyloid protein, arteriosclerosis, interstitial fibrosis/infiltrate, or glomerular and interstitial amyloid deposits. After a previous P value <0.1 in the descriptive analysis, the following variables were selected: globally sclerotic glomeruli, high blood pressure, and the extension of vascular amyloid deposition. A binary logistic regression model with GFR as the dependent variable showed history of hypertension and vascular amyloid to be robust and independent predictors of Group B <60 mL·min−1·(1.73 m2)−1. Beyond the histopathologic diagnosis of amyloidosis, a semiquantitative approach on renal biopsy could provide new insights. Vascular amyloid is an independent predictor of renal dysfunction in cases of renal amyloidosis.

Transthyretin amyloidosis: Putting myopathy on the map.

Although peripheral neuropathy and cardiomyopathy are well-recognized manifestations of transthyretin (ATTR) amyloidosis, myopathy has been rarely reported. In this study we reviewed our muscle biopsy database (January 1998 to June 2018) to identify patients with ATTR amyloid myopathy confirmed by molecular or proteomic analysis. Clinical and laboratory findings were reviewed. We identified eight ATTR amyloid myopathy patients (5 hereditary ATTR [ATTRv] and 3 wild-type ATTR [ATTRwt]). Myopathy was the initial manifestation in all ATTRwt patients and followed peripheral neuropathy (4 patients) or cardiomyopathy (1 patient) in ATTRv patients. One ATTRv patient developed myopathy after liver transplant. Peripheral neuropathy and cardiac amyloidosis occurred in seven and six patients, respectively. Muscle biopsy showed interstitial amyloid deposition in all patients, rare necrotic/regenerating fibers in six, and vacuoles in four. Myopathy can be the initial manifestation of ATTRwt amyloidosis and can precede the peripheral neuropathy or occur after liver transplant in ATTRv amyloidosis.

SUN-009 ISOLATED BOWMAN CAPSULAR AMYLOID DEPOSITION

We have observed amyloid deposits along Bowman capsules (BC). We conducted this study to determine the frequency and significance of such a peculiar location for amyloid deposits and speculate about the potential mechanism for this deposition. We searched our pathology archives for kidney biopsies with a diagnosis of amyloidosis between January 2016 to August 2018. We reviewed a total of 20 cases of renal amyloidosis with an emphasis on the Congo red histochemical study. In particular, we were interested in isolated BC amyloid deposits, which were not contiguous with other glomerular, interstitial, or peritubular capillary amyloid deposits. We correlated the clinical data with the pathologic findings. 9 of 20 cases (45%) had isolated deposits involving BC. Glomerular involvement by amyloid was present in all 9 cases with Bowman capsular amyloid deposits (Figure), but in only 6 (54%) of the group without BC deposits. Nephrotic-range proteinuria was more common in cases with BC deposits, but this was not a statistically significant difference. The average number of glomeruli was also similar, so a sampling issue did not appear to account for the difference between the group with or without BC deposits. Isolated Bowman capsular amyloid deposits were frequently observed in AL and AA amyloidosis, but were not present in ALECT2 amyloidosis, which further supports a distinct mechanism of deposition. The reabsorption of glomerular filtrate which contains the amyloidogenic proteins by parietal epithelial cells or parietal podocytes may contribute to the deposition of amyloid involving Bowman capsules.

Specific Clinical and Morphological Characteristics of Amyloidosis of the Stomach and Duodenum

The aimof the study was to investigate specific clinical and morphological characteristics in biopsy specimens of the stomach and duodenum using immunohistochemical typing.Material and methods.Biopsy specimens – 19 from the stomach and 22 from the duodenum were examined. The specimens were obtained from 27 patients with later pathomorphologically verified amyloidosis. The specimens were fixed in 10% formalin solution, processed with the standard technique of histological tissue making and embedded into paraffin blocks. The tissue sections were stained with H&amp;E and congo red. A broad panel of antibodies to different types of amyloidosis was used for immunohistochemical typing of amyloid deposits.Results.In total, 41 biopsy specimen of the gastric and duodenal amyloidosis was examined. Histological findings included interstitial and vascular amyloid deposits in stomach and duodenum. Based on the results of immunohistochemical typing of 19 gastric biopsy specimens, ALλ amyloidosis was found in 7 cases, AAamyloidosis – in 6, ALλ amyloidosis and transthyretin amyloidosis – in 2 cases each, and mixed type – in 2 biopsy specimens. Among biopsy specimens of the duodenum, ALκ – amyloidosis was diagnosed in 10 cases, AAamyloidosis – in 5, ALλ amyloidosis – in 4, transthyretin amyloidosis – in 2, and mixed type – in one biopsy specimen.Conclusion.Based on the study results, ALκ- and AA-amyloidosis were the most frequent amyloidosis types in the gastric and duodenal biopsy specimens. Immunohistochemical typing was successful in all cases, thus proving that the selected method was adequate for amyloidosis diagnostics.

Intramuscular interstitial amyloid deposition does not impact anoctaminopathy-5 phenotype.

Recessive mutations in the anoctamin-5-encoding gene (ANO5) cause muscular dystrophy of various phenotypes. Intramuscular interstitial amyloid deposits were detected in a few patients with anoctaminopathy-5, some with cardiac involvement. The frequency of amyloid deposition in anoctaminopathy-5 and its impact on phenotype are unknown. We retrospectively identified patients with genetically proven anoctaminopathy-5 who had undergone muscle biopsy and reviewed their clinical and laboratory data. Eight of 15 patients with anoctaminopathy-5 had intramuscular interstitial amyloid deposits. The median age at onset of weakness was 40 and 45 years in the amyloidosis and nonamyloidosis groups, respectively. Mutations occurred throughout the entire gene in the amyloidosis group. Atrial arrhythmia was noted in 4 patients with amyloidosis and in 4 patients without amyloidosis. The latter group also had premature ventricular contractions. One nonamyloidosis patient had septal hypokinesia. Intramuscular amyloidosis occurred in 53% of patients with anoctaminopathy-5 who underwent muscle biopsy and had no impact on the phenotype. Muscle Nerve 59:133-137, 2019.

Unveiling Brain Aβ Heterogeneity Through Targeted Proteomic Analysis.

Amyloid β (Aβ) is the major constituent of the brain deposits found in parenchymal plaques and cerebral blood vessels of patients with Alzheimer's disease (AD). Besides classic full-length peptides, biochemical analyses of brain deposits have revealed high degree of Aβ heterogeneity likely resulting from the action of multiple proteolytic enzymes. This chapter describes a sequential extraction protocol allowing the differential fractionation of soluble and deposited Aβ species taking advantage of their differential solubility properties. Soluble Aβ is extracted by water-based buffers like phosphate-buffered saline-PBS-whereas pre-fibrillar and fibrillar deposits, usually poorly soluble in PBS, are extractable in detergent containing solutions or more stringent conditions as formic acid. The extraction procedure is followed by the biochemical identification of the extracted Aβ species using Western blot and a targeted proteomic analysis which combines immunoprecipitation with MALDI-ToF mass spectrometry. This approach revealed the presence of numerous C- and N-terminal truncated Aβ species in addition to Aβ1-40/42. Notably, the more soluble C-terminal cleaved fragments constitute a main part of PBS homogenates. On the contrary, N-terminal truncated species typically require more stringent conditions for the extraction in agreement with their lower solubility and enhanced aggregability. Detailed assessment of the molecular diversity of Aβ species composing interstitial fluid and amyloid deposits at different disease stages, as well as the evaluation of the truncation profile during various pharmacologic approaches will provide a comprehensive understanding of the still undefined contribution of Aβ truncations to AD pathogenesis and their potential as novel therapeutic targets.

Pathology and diagnosis of renal non-AL amyloidosis.

Renal amyloidosis is characterized by acellular Congo red positive deposits in the glomeruli, interstitium and/or arteries. Light chain restriction on immunofluorescence studies is present in AL-amyloidosis, the most common type of amyloidosis involving the kidney. The detection of Congo red positive deposits coupled with negative immunofluorescence studies is highly suggestive of non-AL amyloidosis. Some of the non-AL amyloidosis are common while others are relatively rare. The clinical features, laboratory and renal pathology findings are helpful in the diagnosis and typing of non-AL amyloidosis. Thus, ALECT2 amyloidosis is characterized by diffuse cortical interstitial amyloid deposits, AA amyloidosis shows vascular deposits in addition to the glomerular deposits, AFib amyloidosis is characterized by massive amyloid accumulation limited to the glomeruli resulting in the obliteration of glomerular architecture, AApoA1 and AApoAIV are characterized by large amyloid deposits restricted to the medulla, and AGel shows swirling patterns of amyloid fibrils on electron microscopy. While light microscopy is very helpful, accurate typing of non-AL amyloidosis then requires immunohistochemical or laser microdissection/mass spectrometry studies of the Congo red positive deposits. Immunohistochemical studies are available for some of the non-AL amyloidosis. On the other hand, mass spectrometry analysis is a one stop methodology for confirmation and typing of amyloidosis. The diagnosis and typing of amyloidosis by mass spectrometry is based on finding the signature amyloid peptides, apolipoprotein E and serum amyloid-P component, followed by detection of precursor amyloidogenic protein such as LECT2, fibrinogen-α, gelsolin, etc. To, summarize, non-AL amyloidosis is a group of amyloidosis with distinctive clinical, laboratory and renal pathology findings. Typing of the amyloidosis is best performed using mass spectrometry methodology. Accurate typing of non-AL amyloidosis is imperative for correct management, prognosis, and genetic counseling.

Aβ truncated species: Implications for brain clearance mechanisms and amyloid plaque deposition

Extensive parenchymal and vascular Aβ deposits are pathological hallmarks of Alzheimer's disease (AD). Besides classic full-length peptides, biochemical analyses of brain deposits have revealed high degree of Aβ heterogeneity likely resulting from the action of multiple proteolytic enzymes. In spite of the numerous studies focusing in Aβ, the relevance of N- and C-terminal truncated species for AD pathogenesis remains largely understudied. In the present work, using novel antibodies specifically recognizing Aβ species N-terminally truncated at position 4 or C-terminally truncated at position 34, we provide a clear assessment of the differential topographic localization of these species in AD brains and transgenic models. Based on their distinct solubility, brain N- and C-terminal truncated species were extracted by differential fractionation and identified via immunoprecipitation coupled to mass spectrometry analysis. Biochemical/biophysical studies with synthetic homologues further confirmed the different solubility properties and contrasting fibrillogenic characteristics of the truncated species composing the brain Aβ peptidome. Aβ C-terminal degradation leads to the production of more soluble fragments likely to be more easily eliminated from the brain. On the contrary, N-terminal truncation at position 4 favors the formation of poorly soluble, aggregation prone peptides with high amyloidogenic propensity and the potential to exacerbate the fibrillar deposits, self-perpetuating the amyloidogenic loop. Detailed assessment of the molecular diversity of Aβ species composing interstitial fluid and amyloid deposits at different disease stages, as well as the evaluation of the truncation profile during various pharmacologic approaches will provide a comprehensive understanding of the still undefined contribution of Aβ truncations to the disease pathogenesis and their potential as novel therapeutic targets.

Effect of chronic inflammation on coronary arteries in renal amyloidosis: More than renal dysfunction

Effect of chronic inflammation on coronary arteries in renal amyloidosis: More than renal dysfunction

Amyloid in biopsies of the gastrointestinal tract-a retrospective observational study on 542 patients.

In this retrospective observational study, we investigated the histopathological and demographic characteristics of amyloid in gastrointestinal biopsies. From the Amyloid Registry Kiel, we retrieved all cases with amyloid in biopsies of the stomach, duodenum, small intestine, large intestine, and rectum submitted for tertiary referral between January 2003 and April 2013. Amyloid was identified by Congo red staining in combination with polarization microscopy and classified by immunohistochemistry. The TTR-genotype was assessed in 56 patients. Amyloid type was correlated with demographic patient characteristics. Six hundred sixty-three biopsies from 542 patients were retrieved. Amyloid was found in each biopsy as vascular and/or interstitial amyloid deposits. Biopsies were obtained from the colon [254 biopsies (38.3 %)], stomach, [153 (23.1 %)], rectum [112 (16.9 %)], duodenum [105 (15.8 %)], and jejunum/ileum [39 (5.9 %)]. ALλ amyloid was found in 286 (52.8 %), ATTR in 88 (16.2 %), ALκ in 74 (13.7 %), AA in 58 (10.7 %), and ApoAI amyloid in 4 (0.7 %) patients. The remaining 21 cases were ALys amyloid in 4 (0.7 %), AL n.o.s. in 14 (2.6 %), and mixed type amyloidosis in 3 (0.6 %). The amyloid of 11 (2.0 %) cases remained unclassified. The median age of the patients was 68 years. Men [332 (61.7 %)] were significantly more prevalent than women [206 (38.3 %); p < 0.001]. TTR mutations were found in 24 % of the patients with ATTR amyloidosis. The median age, the histoanatomical distribution (proximal to distal; mucosal to submucosal), and the deposition pattern (vascular/interstitial) varied between different amyloid types. Amyloid in gastrointestinal biopsies mainly affects male elderly patients and shows amyloid-type-specific demographic patient characteristics.Electronic supplementary materialThe online version of this article (doi:10.1007/s00428-016-1916-y) contains supplementary material, which is available to authorized users.

Vertebral compression fractures as the initial presentation of AL amyloidosis: case series and review of literature

The clinical presentation of AL amyloidosis is highly variable. In this series, we describe five cases of AL amyloidosis with vertebral compression fractures as initial presentation. All five patients had evidence of bone marrow replacement on magnetic resonance imaging and bone marrow biopsies demonstrating diffuse interstitial amyloid deposition. Hepatomegaly and elevated liver enzymes, consistent with liver involvement with amyloidosis, were also seen in each case. All five patients responded well to anti-plasma cell chemotherapy, with normalization of serum free light chain levels, reduction in alkaline phosphatase and improvement in pain and functional status. Although rare, AL amyloidosis should be considered in the differential diagnosis of selected patients with spontaneous vertebral compression fractures. Moreover, there seems to be an association of vertebral compression fractures with liver involvement in AL amyloidosis.

Extensive Amyloid Deposit in Bone Marrow Aspirate

A 62-year-old female presented in the Hepatology OPD with progressive weakness, loss of appetite and dyspnoea. On examination she had icterus, anasarca and hepatomegaly. The liver was enlarged 8 cm below the right costal margin and hard on palpation with vague nodularity. There was no splenomegaly or lymphadenopathy. She was a known case of hypothyroidism. X-ray chest showed bilateral pleural and pericardial effusion. Echocardiography was suggestive of restrictive cardiomyopathy. MRI showed hyperintensity of liver on T2. Liver function tests were deranged. Kidney function tests were normal. Complete hemogram showed Hb of 11 gm/dl, total leukocyte count 7.8 × 109/L and platelets were 178 × 109/L. Liver biopsy performed for the workup revealed extensive amyloid deposit in the vessels and the sinusoids near completely replacing hepatic parenchymal cells. Endoscopic biopsies from duodenum and rectum showed amyloid deposition in blood vessels. Serum and urine electrophoresis and immunofixation did not showed monoclonal M band. Serum Ig-free light chain showed κ to λ ratio of 4.12 (normal 0.26–1.65) and β2 microglobulin was raised. Bone marrow aspirate and biopsy was performed to rule out multiple myeloma. Aspirate showed hypocellular marrow particles with extensive deposits of blue-pink acellular amorphous (Fig. 1A, B) extracellular congophilic material (Fig. 1C) displaying green bireferingence under polarised light. There was mild erythroid hyperplasia with adequate representation of myeloid and erythroid series of cells with normal maturation and no dysplastic changes. The plasma cells were approximately 6 % out of 500 cell count. A few isolated small aggregates of 4–6 plasma cells were also seen. Bone marrow biopsy also revealed homogenous pale eosinophilic acellular deposits of amyloid in the interstium and vessel walls (Fig. 1D). Plasma cell group or nodules were not seen. Immunohistochemistry for kappa and lambda was performed on the bone marrow biopsy which showed plasma cells showing positivity predominantly for kappa and focally for lambda. A final clinico-pathological diagnosis of plasma cell dyscrasia with AL (kappa) systemic amyloidosis was made. Fig. 1 Bone marrow aspirate showing extensive deposits of blue-pink acellular amorphous extracellular material (A, B) congophilic with congo red stain (C). Bone marrow biopsy also revealed homogenous pale eosinophilic acellular deposits of amyloid in the interstium ... Primary or AL amyloidosis is the commonest cause of systemic amyloidosis worldwide [1,2]. Bone marrow examination in these cases is performed in order to evaluate plasma cell infiltration. Plasma cells may be increased to the level of overt multiple myeloma or the number could be <10 % in which case it is classified as plasma cell dyscrasia or monoclonal gammopathy of unknown significance (MGUS). Amyloid is usually is not seen or is very sparse if present in aspirate, however biopsy usually shows amyloid deposition on vessel wall and rarely in interstitium [3]. In a study by Swan et al. the bone marrow core biopsy demonstrate amyloid deposition in 60 % cases out of 100 biopsies of patients with AL (primary) amyloidosis studied [2]. In their series plasma cell dyscrasia was observed in 83 cases with majority of lambda (65 cases) light chain disease. They also observed that interstitial amyloid deposition was significantly more commonly associated with patients with a monoclonal kappa light chain gammopathy, like in our case. Few studies have shown mean plasma cell percentages ranging from 7 to 14 % by analyzing the bone marrow core biopsy specimen in AL amyloidosis using immunohistochemical stains for light chain immunoglobulins [2, 4]. However, the finding of extensive bone marrow amyloid deposition in the aspirate smears is very unusual and rarely reported to the best of our knowledge.

Islet amyloid polypeptide in pancreatic islets from type 2 diabetic subjects

Aims/hypothesis: Islet amyloid polypeptide (IAPP) is a chief constituent of amyloid deposits in pancreatic islets, characteristic histopathology for type 2 diabetes. The goal of this study was to analyze islet cell composition in diabetic islets for the process of transforming water-soluble IAPP in β-cells to water-insoluble amyloid deposits by Immunocytochemical staining using different dilutions of anti-IAPP antibody. IAPP in β-cell granules may initiate β-cell necrosis through apoptosis to form interstitial amyloid deposits in type 2 diabetic islets. Results: Control islets revealed twice as much β-cells as α-cells whereas 15 of 18 type 2 diabetic cases (83%) revealed α- cells as major cells in larger islets. Diabetic islets consisted of more larger islets with more σ-cells than β-cells, which contribute to hyperglucagonemia. In control islets, percentage of IAPP-positive cells against β-cells was 40–50% whereas percentage for type 2 diabetic islets was about 25%. Amyloid deposits in diabetic islets were not readily immunostained for IAPP using 1: 800 diluted antibody, however, 1: 400 and 1: 200 diluted solutions provided stronger immunostaining in early stages of islet amyloidogenesis after treating the deparaffinized sections with formic acid. Methods: Using commercially available rabbit antihuman IAPP antibody, immunocytochemical staining was performed on 18 cases of pancreatic tissues from type 2 diabetic subjects by systematically immunostaining for insulin, glucagon, somatostatin (SRIF) and IAPP compared with controls. Sizes of islets were measured by 1 cm scale, mounted in 10X eye piece. Conclusions/Interpretation: α cells were major islet cells in majority of diabetic pancreas (83%) and all diabetic islets contained less IAPP-positive cells than controls, indicating that IAPP deficiency in pancreatic islets is responsible for decreased IAPP in blood. In diabetic islets, water-soluble IAPP disappeared in β-cell granules, which transformed to water-insoluble amyloid deposits. Amyloid deposits were not readily immunostained using IAPP 1: 800 diluted antibody but were stronger immunostained for IAPP in early stages of amyloid deposited islets using less diluted solutions after formic acid treatment. In early islet amyloidogenesis, dying β-cell cytoplasm was adjacently located to fine amyloid fibrils, supporting that IAPP in secretary granules from dying β cells served as nidus for islet β-sheet formation.