Breast calcifications on mammography from systemic amyloidosis: A case report.

Calcifications on mammography from systemic disease at times meet diagnostic criteria for histologic sampling to exclude malignancy. We present a case of bilateral groups of new calcifications on mammography that yielded amyloidosis on core biopsy. Awareness of our patient's known diagnosis of systemic light chain amyloidosis (AL) prompted use of Congo red staining to confirm the histologic diagnosis. Knowledge of systemic diseases with possible manifestations on mammography can facilitate cogent and clinically relevant radiology-pathology correlation.

Case report: Waldenstrom macroglobulinemia with systemic amyloidosis as the main manifestation.

Systemic amyloidosis is a rare protein misfolding and deposition disorder leading to progressive organ failure. Waldenström macroglobulinemia (WM) with systemic amyloidosis as the main manifestation is even rarer. The patient in this study presented with recurrent diarrhea and had not been diagnosed in other hospitals on multiple occasions. Later, his diarrhea worsened and was accompanied by sunken edema of both lower limbs and dizziness. Renal biopsy showed deposits of PAS light-staining material in the glomeruli, interstitium, and small arteries, which stained positively with Congo red. Cardiac ultrasound showed interventricular septum thickening of 17 mm, right ventricular wall myocardial thickening of approximately 0.6 cm, and septal thickening of approximately 0.5 cm, considering myocardial amyloidosis. Electromyography showed abnormal peripheral nerve conduction. Lymphoplasmacytic cells were found in the bone marrow. Taken together, he was diagnosed with WM. He was treated with a BR (Bendamustine + Rituximab) regimen. After 6 courses, the patient's discomfort was relieved, his weight gained 5 kg, the level of serum IgM and dFLC decreased, and cardiac and renal assessments were more relieved. The patient has been followed up for more than 1 month.

Physicochemical mechanisms of aggregation and fibril formation of α-synuclein and apolipoprotein A-I.

Deposition and accumulation of amyloid fibrils is a hallmark of a group of diseases called amyloidosis and neurodegenerative disorders. Although polypeptides potentially have a fibril-forming propensity, native proteins have evolved into proper functional conformations to avoid aggregation and fibril formation. Understanding the mechanism for regulation of fibril formation of native proteins provides clues for the rational design of molecules for inhibiting fibril formation. Although fibril formation is a complex multistep reaction, experimentally obtained fibril formation curves can be fitted with the Finke-Watzky (F-W) two-step model for homogeneous nucleation followed by autocatalytic fibril growth. The resultant F-W rate constants for nucleation and fibril formation provide information on the chemical kinetics of fibril formation. Using the F-W two-step model analysis, we investigated the physicochemical mechanisms of fibril formation of a Parkinson's disease protein α-synuclein (αS) and a systemic amyloidosis protein apolipoprotein A-I (apoA-I). The results indicate that the C-terminal region of αS enthalpically and entropically suppresses nucleation through the intramolecular interaction with the N-terminal region and the intermolecular interaction with existing fibrils. In contrast, the nucleation of the N-terminal fragment of apoA-I is entropically driven likely due to dehydration of large hydrophobic segments in the molecule. Based on our recent findings, we discuss the similarity and difference of the fibril formation mechanisms of αS and the N-terminal fragment of apoA-I from the physicochemical viewpoints.

Neurofilament Light Chains in Systemic Amyloidosis: A Systematic Review.

Peripheral and autonomic neuropathy are common disease manifestations in systemic amyloidosis. The neurofilament light chain (NfL), a neuron-specific biomarker, is released into the blood and cerebrospinal fluid after neuronal damage. There is a need for an early and sensitive blood biomarker for polyneuropathy, and this systematic review provides an overview on the value of NfL in the early detection of neuropathy, central nervous system involvement, the monitoring of neuropathy progression, and treatment effects in systemic amyloidosis. A literature search in PubMed, Embase, and Web of Science was performed on 14 February 2024 for studies investigating NfL levels in patients with systemic amyloidosis and transthyretin gene-variant (TTRv) carriers. Only studies containing original data were included. Included were thirteen full-text articles and five abstracts describing 1604 participants: 298 controls and 1306 TTRv carriers or patients with or without polyneuropathy. Patients with polyneuropathy demonstrated higher NfL levels compared to healthy controls and asymptomatic carriers. Disease onset was marked by rising NfL levels. Following the initiation of transthyretin gene-silencer treatment, NfL levels decreased and remained stable over an extended period. NfL is not an outcome biomarker, but an early and sensitive disease-process biomarker for neuropathy in systemic amyloidosis. Therefore, NfL has the potential to be used for the early detection of neuropathy, monitoring treatment effects, and monitoring disease progression in patients with systemic amyloidosis.

Chronic underlying gastrointestinal amyloidosis was revealed by cardiac echography: a case report from Syria.

Introduction and importance: Amyloidosis is an infiltrative disease caused by the deposition of abnormal proteins. While cardiac amyloidosis is relatively common, gastrointestinal (GI) tract involvement is less frequent. In this case, the authors report a delayed diagnosis of systemic amyloidosis presenting mainly with digestive symptoms. Case presentation: An 81-year-old male presented with the complaint of persistent diarrhoea for over a year and the progressive development of edemas during the last 4 months. Echocardiogram findings revealed the presence of the characteristic sparkling sign. The diagnosis of amyloidosis was confirmed by histopathological biopsies taken from the duodenum. Serum electrophoresis findings strongly suggested the possibility of plasma cell dyscrasia. Clinical discussion: What distinguishes this case is that the suspicion of amyloidosis as the underlying cause of the diarrhoea did not arise until an incidental echocardiogram revealed cardiac hypertrophy and a sparkling appearance. Conclusion: This case reminds us to consider amyloidosis as a possible underlying cause for unexplained gastrointestinal symptoms such as diarrhoea, especially in bad economic situations where the diagnosis of rare diseases may be delayed.

Longitudinal analysis of serum neurofilament light chain levels as marker for neuronal damage in hereditary transthyretin amyloidosis.

OBJECTIVE: To evaluate serum neurofilament light chain (sNfL) as biomarker of disease onset, progression and treatment effect in hereditary transthyretin (ATTRv) amyloidosis patients and TTR variant (TTRv) carriers. METHODS: sNfL levels were assessed longitudinally in persistently asymptomatic TTRv carriers (N = 12), persistently asymptomatic ATTRv amyloidosis patients (defined as asymptomatic patients but with amyloid detectable in subcutaneous abdominal fat tissue) (N = 8), in TTRv carriers who developed polyneuropathy (N = 7) and in ATTRv amyloidosis patients with polyneuropathy on treatment (TTR-stabiliser (N = 20) or TTR-silencer (N = 18)). Polyneuropathy was confirmed by nerve conduction studies or quantitative sensory testing. sNfL was analysed using a single-molecule array assay. RESULTS: sNfL increased over 2 years in persistently asymptomatic ATTRv amyloidosis patients, but did not change in persistently asymptomatic TTRv carriers. In all TTRv carriers who developed polyneuropathy, sNfL increased from 8.4 to 49.8 pg/mL before the onset of symptoms and before polyneuropathy could be confirmed neurophysiologically. In symptomatic ATTRv amyloidosis patients on a TTR-stabiliser, sNfL remained stable over 2 years. In patients on a TTR-silencer, sNfL decreased after 1 year of treatment. CONCLUSION: sNfL is a biomarker of early neuronal damage in ATTRv amyloidosis already before the onset of polyneuropathy. Current data support the use of sNfL in screening asymptomatic TTRv carriers and in monitoring of disease progression and treatment effect.

Mimicking kidney flow shear efficiently induces aggregation of LECT2, a protein involved in renal amyloidosis.

Aggregation of leukocyte cell-derived chemotaxin 2 (LECT2) causes ALECT2, a systemic amyloidosis that affects the kidney and liver. Previous studies established that LECT2 fibrillogenesis is accelerated by the loss of its bound zinc ion and stirring/shaking. These forms of agitation create heterogeneous shear conditions, including air-liquid interfaces that denature proteins, that are not present in the body. Here, we determined the extent to which a more physiological form of mechanical stress-shear generated by fluid flow through a network of narrow channels-drives LECT2 fibrillogenesis. To mimic blood flow through the kidney, where LECT2 and other proteins form amyloid deposits, we developed a microfluidic device consisting of progressively branched channels narrowing from 5 mm to 20 µm in width. Shear was particularly pronounced at the branch points and in the smallest capillaries. Aggregation was induced within 24 h by shear levels that were in the physiological range and well below those required to unfold globular proteins such as LECT2. EM images suggested the resulting fibril ultrastructures were different when generated by laminar flow shear versus shaking/stirring. Importantly, results from the microfluidic device showed the first evidence that the I40V mutation accelerated fibril formation and increased both the size and the density of the aggregates. These findings suggest that kidney-like flow shear, in combination with zinc loss, acts in combination with the I40V mutation to trigger LECT2 amyloidogenesis. These microfluidic devices may be of general use for uncovering mechanisms by which blood flow induces misfolding and amyloidosis of circulating proteins.

A case of AA amyloidosis complicated by proliferating pilomatricoma and a review of the literature.

Although AA amyloidosis is primarily caused by inflammatory conditions, associations between AA amyloidosis and solid cancers have occasionally been described. Herein, we report the case of a 48-year-old man in whom resection of a proliferating pilomatricoma with deposition of AA amyloid resulted in remission of concomitant AA gastrointestinal amyloidosis. A rapidly growing, giant, reddish, ulcerated tumor measuring 16 × 13 cm in size was identified on the upper left arm on a visit to our hospital. Gastrointestinal AA amyloidosis was diagnosed from colorectal mucosal biopsy at the same time, and weight loss and profuse diarrhea were clinically evident. As treatment, the tumor was resected with a 10-mm surgical margin. Histologically, the tumor predominantly comprised a lobular proliferation of basophilic cells peripherally, filled with eosinophilic, cornified material and shadow cells with mitoses observed in basophilic cells. Specimens revealed eosinophilic, homogeneous deposits around tumor nests, which were confirmed as amyloid deposits by positive staining with Congo red stain. These deposits were immunohistochemically positive on staining with anti-serum amyloid A antibody. Collectively, proliferating pilomatricoma with AA amyloidosis was diagnosed. After tumor resection, chronic diarrhea resolved and no amyloid deposition was apparent in colorectal biopsy. It is important to remember that if amyloid deposition is present in a tumor, aggressive tumor excision may alleviate systemic amyloidosis.

Hospitalization-based epidemiology of systemic and cardiac amyloidosis in the Veneto Region, Italy.

AIM: Defining the epidemiology of systemic and cardiac amyloidosis (CA) is a contemporary challenge. The present study aimed to estimate incidence and time trends in amyloidosis-related hospitalizations (AH) in Veneto Region (5 million inhabitants, Northeastern Italy). METHODS: International Classification of Diseases (ICD-9) codes were used to identify AH in Veneto from 2010 to 2020. AH were defined as any hospitalization with a discharge summary reporting an ICD-9 code for systemic amyloidosis. Hospitalization for CA was defined as records with ICD-9 code for systemic amyloidosis and ICD-9 code for heart failure,cardiomyopathy or arrhythmia. Hospital/outpatient encounters for carpal tunnel syndrome (CTS) surgeries also were extracted. AH incidence was estimated using a buffer of 5 years. RESULTS: In the time range 2015-2020, the incidence rate of AH was 23.5 cases per 106 (95% confidence interval, CI, 21.8; 25.3), mainly affecting patients>65 years (76.2%) and males (63.5%), with a progressively increasing trend (percent annual increase 17%, 95% CI 12; 22%). The 10 year prevalence of AH in 2020 was 124.5 per 106 (95% CI 114.9; 134.8). In 2020, annual hospitalized prevalent cases of CA were about 70% of all cases (159/228), mainly patients >65 years and males. Among patients with multiple CTS surgeries, a subsequent code for cardiac disease was found in 913 after a median of 3.9 years, more frequently in men than in women (463/6.526 7.1% versus 450/11.406 3.9%). CONCLUSIONS: In Veneto, we recorded a significantly increasing trend in the incidence of AH, with concordant increasing prevalence estimates.

Epidemiological study of the subtype frequency of systemic amyloidosis listed in the Annual of the Pathological Autopsy Cases in Japan.

Clinical presentation of systemic amyloidosis differs among subtypes, and accurate subtype classification is important for choosing the treatment. Amyloid transthyretin (ATTR) amyloidosis was the predominant among the recently consulted amyloidosis cases in Japan. To reveal the latest subtype frequency of systemic amyloidosis among autopsy cases in Japan. We analyzed systemic amyloidosis cases autopsied from January 2017 to December 2018, that were listed in the Annuals of the Pathological Autopsy Cases in Japan, Volumes 60 and 61. When the subtype was unclear, we performed a questionnaire survey, immunohistochemistry with in-house rabbit polyclonal anti-κ116 - 133 , anti-λ118 -134 , and anti-transthyretin115 -124 antibodies, and proteomic analysis. Out of 481 systemic amyloidosis cases listed in the Annuals, 411 cases were available for analysis (85.4%). We classified 399 of these systemic amyloidosis cases. ATTR was the most common subtype (44.4%, n = 177), followed by amyloid immunoglobulin light chain (AL) (38.8%, n = 155). Amyloid A and amyloid ß2 -microglobulin were 9.3% (n = 37) and 6.0% (n = 24), respectively. Double deposition of amyloid was identified in 1.6% (n = 6). In 168 cases (42.1%), systemic amyloidosis was the main cause of death. Of these cases, AL was the most common subtype (47.6%, n = 80), followed by ATTR (41.1%, n = 69). ATTR is the most predominant subtype among the current autopsy cases in Japan.

Ankylosing spondylitis status and risk of secondary systemic amyloidosis: A two-sample mendelian randomization study.

OBJECTIVES: There is still controversy regarding the causal relationship between ankylosing spondylitis (AS) and secondary systemic amyloidosis (SSA). This study utilized aggregated data from genome-wide association studies (GWAS) on population cohorts to investigate whether a causal relationship exists between AS and SSA. METHODS: The genetic causal relationship between AS status and SSA was analyzed utilizing a two-sample Mendelian randomization (TSMR). The analyses were conducted using the weighted mode method (WM2), inverse variance weighted method (IVW), simple mode (SM), weighted median method (WM1), and Mendelian randomization Egger regression (MR-Egger). Among these methods, the primary results were based on the IVW approach. The association was evaluated using the odds ratio (OR) along with a 95% confidence interval (95% CI). RESULTS: The IVW analysis revealed a positive causal relationship between AS status and SSA (OR = 1.411, 95 % CI = 1.069, 1.862, P = 0.015). Meanwhile, the WM1 (OR = 1.394, 95 % CI = 1.115, 1.742, P = 0.004) and WM2 (OR = 1.393, 95 % CI = 1.112, 1.743, P = 0.045) methods also identified a positive causal relationship between AS status and SSA. The MR-Egger method did not identify a causal relationship between AS and SSA (OR = 1.175, 95 % CI = 0.888, 1.555, P = 0.342). The SM results demonstrated that the observed genotypes did not exhibit statistically significant differences between AS and SSA (OR = 1.184, 95 % CI = 0.416, 3.366, P = 0.767). The results of the MR-Egger regression suggested that the results were unaffected by bias caused by genetic pleiotropy (Intercept = 0.283, SE = 0.134, P = 0.126). Cochran's Q test did not reveal any significant heterogeneity (Q = 1.759, P = 0.624). The "leave-one-out" analysis further confirmed that the absence of any single SNP did not impact the robustness of our results. CONCLUSION: This study revealed a positive causal relationship between AS status and the occurrence of SSA, providing new insights into the genetic analysis of SSA.

Human wild-type and D76N ß2-microglobulin variants are significant proteotoxic and metabolic stressors for transgenic C. elegans.

ß2-microglobulin (ß2-m) is a plasma protein derived from physiological shedding of the class I major histocompatibility complex (MHCI), causing human systemic amyloidosis either due to persistently high concentrations of the wild-type (WT) protein in hemodialyzed patients, or in presence of mutations, such as D76N ß2-m, which favor protein deposition in the adulthood, despite normal plasma levels. Here we describe a new transgenic Caenorhabditis elegans (C. elegans) strain expressing human WT ß2-m at high concentrations, mimicking the condition that underlies dialysis-related amyloidosis (DRA) and we compare it to a previously established strain expressing the highly amyloidogenic D76N ß2-m at lower concentrations. Both strains exhibit behavioral defects, the severity of which correlates with ß2-m levels rather than with the presence of mutations, being more pronounced in WT ß2-m worms. ß2-m expression also has a deep impact on the nematodes' proteomic and metabolic profiles. Most significantly affected processes include protein degradation and stress response, amino acids metabolism, and bioenergetics. Molecular alterations are more pronounced in worms expressing WT ß2-m at high concentration compared to D76N ß2-m worms. Altogether, these data show that ß2-m is a proteotoxic protein in vivo also in its wild-type form, and that concentration plays a key role in modulating pathogenicity. Our transgenic nematodes recapitulate the distinctive features subtending DRA compared to hereditary ß2-m amyloidosis (high levels of non-mutated ß2-m vs. normal levels of variant ß2-m) and provide important clues on the molecular bases of these human diseases.

Cardiac Amyloid Detection by PET/CT Imaging of Iodine (124I) Evuzamitide (124I-p5+14): A Phase 1/2 Study.

BACKGROUND: The noninvasive detection of cardiac amyloid, as well as deposits in other vital organs, is critical for early diagnosis and quantitative disease monitoring. Positron emission tomography is an intrinsically quantitative imaging modality suitable for high-resolution amyloid detection. OBJECTIVES: This study sought to evaluate the safety and efficacy of a novel amyloid-reactive peptide, designated p5+14, labeled with iodine-124 (124I), in patients with diverse types of systemic amyloidosis. METHODS: In a single-site, open label phase 1/2 study (NCT03678259), the safety, biodistribution, and sensitivity of a single intravenous infusion of 124I-evuzamitide was assessed in patients with systemic amyloidosis (n = 50), asymptomatic transthyretin sequence variant carriers (n = 2), and healthy volunteers (n = 5). Subjects were administered 1.4 ± 0.2 mg of 124I-evuzamitide (71.5 ± 12.4 MBq) and positron emission tomography/x-ray computed tomography images acquired at 5.2 hours (Q25-Q75: 4.9-5.4 hours) postinfusion. Images were assessed visually and semi-quantitatively for positive uptake of radiotracer in the heart and other major organs. RESULTS: Uptake of 124I-evuzamitide in the heart and other abdominothoracic organs was consistent with the patient's clinical presentation and the type of amyloidosis. The patient- and cardiac-associated sensitivity for imaging and clinical observations was 93.6% (95% CI: 82.8%-97.8%) and 96.2% (95% CI: 81.8%-99.8%), respectively. Semi-quantitative uptake of the radiotracer correlated significantly with serum N-terminal pro-B-type natriuretic peptide measurements in patients with light chain-associated amyloidosis. Cardiac uptake was not observed in any healthy volunteers. The agent was well tolerated, with 1 drug-related adverse event and no deaths. CONCLUSIONS: 124I-evuzamitide is an amyloid-binding radiotracer capable of detecting cardiac amyloid in patients with high sensitivity.

First Report of Lysozyme Amyloidosis with p.F21L/T88N Amino Acid Substitutions in a Russian Family.

Lysozyme amyloidosis is caused by an amino acid substitution in the sequence of this protein. In our study, we described a clinical case of lysozyme amyloidosis in a Russian family. In our work, we described in detail the histological changes in tissues that appeared as a result of massive deposition of amyloid aggregates that affected almost all organ systems, with the exception of the central nervous system. We determined the type of amyloidosis and mutations using mass spectrometry. Using mass spectrometry, the protein composition of tissue samples of patient 1 (autopsy material) and patient 2 (biopsy material) with histologically confirmed amyloid deposits were analyzed. Amino acid substitutions p.F21L/T88N in the lysozyme sequence were identified in both sets of samples and confirmed by sequencing of the lysozyme gene of members of this family. We have shown the inheritance of these mutations in the lysozyme gene in members of the described family. For the first time, we discovered a mutation in the first exon p.F21L of the lysozyme gene, which, together with p.T88N amino acid substitution, led to amyloidosis in members of the studied family.

Development and characterization of a prototypic pan-amyloid clearing agent - a novel murine peptide-immunoglobulin fusion.

Introduction: Systemic amyloidosis is a progressive disorder characterized by the extracellular deposition of amyloid fibrils and accessory proteins in visceral organs and tissues. Amyloid accumulation causes organ dysfunction and is not generally cleared by the immune system. Current treatment focuses on reducing amyloid precursor protein synthesis and slowing amyloid deposition. However, curative interventions will likely also require removal of preexisting amyloid deposits to restore organ function. Here we describe a prototypic pan-amyloid binding peptide-antibody fusion molecule (mIgp5) that enhances macrophage uptake of amyloid. Methods: The murine IgG1-IgG2a hybrid immunoglobulin with a pan amyloid-reactive peptide, p5, fused genetically to the N-terminal of the immunoglobulin light chain was synthesized in HEK293T/17 cells. The binding of the p5 peptide moiety was assayed using synthetic amyloid-like fibrils, human amyloid extracts and amyloid-laden tissues as substrates. Binding of radioiodinated mIgp5 with amyloid deposits in vivo was evaluated in a murine model of AA amyloidosis using small animal imaging and microautoradiography. The bioactivity of mIgp5 was assessed in complement fixation and in vitro phagocytosis assays in the presence of patient-derived amyloid extracts and synthetic amyloid fibrils as substrates and in the presence or absence of human serum. Results: Murine Igp5 exhibited highly potent binding to AL and ATTR amyloid extracts and diverse types of amyloid in formalin-fixed tissue sections. In the murine model of systemic AA amyloidosis, 125I-mIgp5 bound rapidly and specifically to amyloid deposits in all organs, including the heart, with no evidence of non-specific uptake in healthy tissues. The bioactivity of the immunoglobulin Fc domain was uncompromised in the context of mIgp5 and served as an effective opsonin. Macrophage-mediated uptake of amyloid extract and purified amyloid fibrils was enhanced by the addition of mIgp5. This effect was exaggerated in the presence of human serum coincident with deposition of complement C5b9. Conclusion: Immunostimulatory, amyloid-clearing therapeutics can be developed by incorporating pan-amyloid-reactive peptides, such as p5, as a targeting moiety. The immunologic functionality of the IgG remains intact in the context of the fusion protein. These data highlight the potential use of peptide-antibody fusions as therapeutics for all types of systemic amyloidosis.

Cryo-EM structure of a human LECT2 amyloid fibril reveals a network of polar ladders at its core.

ALECT2 systemic amyloidosis is associated with deposition of the leukocyte cell-derived chemotaxin-2 (LECT2) protein in the form of fibrils. In ALECT2 amyloidosis, ALECT2 fibrils deposit in the glomerulus, resulting in renal failure. Patients lack effective treatment options outside of renal transplant or dialysis. The structure of globular LECT2 has been determined but structures of ALECT2 amyloid fibrils remain unknown. Using single-particle cryo-EM, we find that recombinant human LECT2 forms robust twisting fibrils with canonical amyloid features. ALECT2 fibrils contain two mating protofilaments spanning residues 55-75 of the LECT2 sequence. The geometry of the ALECT2 fibril displays features in line with other pathogenic amyloids. Its core is tightly packed and stabilized by both hydrophobic contacts and hydrogen-bonded uncharged polar residues. The robustness of ALECT2 fibril cores is illustrated by their resistance to denaturants and proteases. This ALECT2 fibril structure presents a potential new target for treatments against ALECT2 systemic amyloidosis.

Gastrointestinal (GI) Amyloidosis Presenting As Chronic Diarrhea: A Diagnostic Dilemma.

This case report describes a 63-year-old male patient with a four-year history of chronic diarrhea. Extensive diagnostic investigations failed to reveal a cause. Subsequent upper and lower gastrointestinal (GI) endoscopic procedures revealed the presence of amyloidosis in the GI tract. The patient was referred for further evaluation, but unfortunately, he presented with hypotension and shock, and ultimately succumbed to systemic amyloidosis involving multiple organs. GI amyloidosis, although rare, should be considered in patients presenting with chronic diarrhea, unexplained weight loss, or GI bleeding. Early recognition and appropriate management are crucial for optimizing patient outcomes. Healthcare providers should maintain a high index of suspicion for GI amyloidosis to ensure timely intervention and improve patient care.

Lipid clearance and amyloid formation by serum amyloid A: exploring the links between beneficial and pathologic actions of an enigmatic protein.

Serum amyloid A (SAA) is named after a life-threatening disease, yet this small evolutionarily conserved protein must have played a vital role in host defense. Most circulating SAA binds plasma lipoproteins and modulates their metabolism. However, this hardly justifies the rapid and dramatic SAA upregulation in inflammation, which is concomitant with upregulation of secretory phospholipase A2 (sPLA2). We proposed that these proteins synergistically clear cell membrane debris from the sites of injury. The present study uses biochemical and biophysical approaches to further explore the beneficial function of SAA and its potential links to amyloid formation. We show that murine and human SAA1 are powerful detergents that solubilize diverse lipids, including mammalian biomembranes, converting them into lipoprotein-size nanoparticles. These nanoparticles provide ligands for cell receptors, such as scavenger receptor CD36 or heparin/heparan sulfate, act as substrates of sPLA2, and sequester toxic products of sPLA2. Together, these functions enable SAA to rapidly clear unprotected lipids. SAA can also adsorb, without remodeling, to lipoprotein-size nanoparticles such as exosomal liposomes, which are proxies for lipoproteins. SAA in complexes with zwitterionic phospholipids stabilizes α-helices, while SAA in complexes containing anionic lipids or micelle-forming sPLA2 products forms metastable ß-sheet-rich species that readily aggregate to form amyloid. Consequently, the synergy between SAA and sPLA2 extends from the beneficial lipid clearance to the pathologic amyloid formation. Furthermore, we show that lipid composition alters SAA conformation and thereby can influence the metabolic fate of SAA-lipid complexes, including their proamyloidogenic and proatherogenic binding to heparan sulfate.

ABCB4 gene mutation-associated cirrhosis with systemic amyloidosis: A case report.

BACKGROUND: Gene mutations in ATP-binding cassette, subfamily B (ABCB4) lead to autosomal recessive disorders. Primary light amyloidosis is a rare and incurable disease. Here, we report a rare case of liver cirrhosis caused by ABCB4 gene mutation combined with primary light amyloidosis. CASE SUMMARY: We report a case of a 25-year-old female who was hospitalized due to recurrent abdominal pain caused by calculous cholecystitis and underwent cholecystectomy. Pathological examination of the liver tissue suggested liver cirrhosis with bile duct injury. Exon analyses of the whole genome from the patient's peripheral blood revealed the presence of a heterozygous mutation in the ABCB4 gene. Bone marrow biopsy tissues, renal puncture examination, and liver mass spectrometry confirmed the diagnosis of a rare progressive familial intrahepatic cholestasis type 3 with systemic light chain type κ amyloidosis, which resulted in cirrhosis. Ursodeoxycholic acid and the cluster of differentiation 38 monoclonal antibody daretozumab were administered for treatment. Following treatment, the patient demonstrated significant improvement. Urinary protein became negative, peripheral blood-free light chain and urine-free light chain levels returned to normal, and the electrocardiogram showed no abnormalities. Additionally, the patient's lower limb numbness resolved, and her condition remained stable. CONCLUSION: This report presents the diagnosis and treatment of liver cirrhosis, a rare disease that is easily misdiagnosed or missed.