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Aims: Identification and characterisation of monoclonal gammopathies of renal significance (MGRS) is critical for therapeutic purposes. Amyloidosis represents one of the most common forms of MGRS, and renal biopsy remains the gold standard for their classification, although mass spectrometry has shown greater sensitivity in this area., Methods: In the present study, a new in situ proteomic technique, matrix-assisted laser desorption/ionisation mass spectrometry imaging (MALDI-MSI), is investigated as an alternative to conventional laser capture microdissection MS for the characterisation of amyloids. MALDI-MSI was performed on 16 cases (3 lambda light chain amyloidosis (AL), 3 AL kappa, 3 serum amyloid A amyloidosis (SAA), 2 lambda light chain deposition disease (LCDD), 2 challenging amyloid cases and 3 controls). Analysis began with regions of interest labelled by the pathologist, and then automatic segmentation was performed., Results: MALDI-MSI correctly identified and typed cases with known amyloid type (AL kappa, AL lambda and SAA). A 'restricted fingerprint' for amyloid detection composed of apolipoprotein E, serum amyloid protein and apolipoprotein A1 showed the best automatic segmentation performance (area under the curve >0.7)., Conclusions: MALDI-MSI correctly assigned minimal/challenging cases of amyloidosis to the correct type (AL lambda) and identified lambda light chains in LCDD cases, highlighting the promising role of MALDI-MSI for amyloid typing., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

POEMS syndrome is a rare monoclonal plasma cell disorder, with unique symptoms distinct from those of other plasma cell neoplasms, including high serum VEGF levels. Because the prospective isolation of POEMS clones has not yet been successful, their real nature remains unclear. Herein, we performed single-cell RNA-Seq of BM plasma cells from patients with POEMS syndrome and identified POEMS clones that had Ig λ light chain (IGL) sequences (IGLV1-36, -40, -44, and -47) with amino acid changes specific to POEMS syndrome. The proportions of POEMS clones in plasma cells were markedly smaller than in patients with multiple myeloma (MM) and patients with monoclonal gammopathy of undetermined significance (MGUS). Single-cell transcriptomes revealed that POEMS clones were CD19+, CD138+, and MHC class IIlo, which allowed for their prospective isolation. POEMS clones expressed significantly lower levels of c-MYC and CCND1 than MM clones, accounting for their small size. VEGF mRNA was not upregulated in POEMS clones, directly indicating that VEGF is not produced by POEMS clones. These results reveal unique features of POEMS clones and enhance our understanding of the pathogenesis of POEMS syndrome.

IgD myeloma is an extremely rare haemopathy with severe clinical presentation. It can be confused with non-secretory or free light chain myeloma. We here report the case of a 72-year old female patient presenting with bone pain and diffuse ecchymosis and deterioration of her general condition. Laboratory tests showed monoclonal gammopathy associated with severe acute renal failure and low total protein (TP) (48%) with factor X deficiency. Etiological assessment confirmed the diagnosis of IgD lambda myeloma stage IIIb, according to Durie and Salmon, International Staging System (ISS) score III unfavorable cytogenetics. Patient's outcome was favorable after treatment with proteasome inhibitor, anti-CD 38 and corticosteroid therapy. Adequate treatment of IgD myeloma, using new therapeutic approaches and hematopoietic stem cell autotransplantation, can improve the prognosis., Competing Interests: Les auteurs ne déclarent aucun conflit d´intérêts., (Copyright: Najat Lasri et al.)

AL amyloidosis is a life-threatening disease characterized by the deposition of amyloidogenic immunoglobulin light chain secreted from clonal plasma cells. Here we established an in-vitro screening system of amyloid inhibition of a variable domain in λ6 light chain mutant (Vλ6), Wil, and screened a food-additive compound library to identify compounds inhibiting the fibril formation. We found gossypetin and isoquercitrin as novel inhibitors. NMR analysis showed that both compounds directly interacted with natively-folded Wil, and proteolysis experiments demonstrated that these compounds conferred proteolytic resistance, suggesting that the compounds enhance the kinetic stability of Wil. Since gossypetin and isoquercitrin specifically interacted with the protein at micromolar concentrations, these compounds could be used as lead to further develop inhibitors against AL amyloidosis., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest associated with the contents of this article., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Light chain amyloidosis is one of the most common forms of systemic amyloidosis. The disease is caused by the misfolding and aggregation of immunoglobulin light chains to insoluble fibrils. These fibrils can deposit in different tissues and organs such as heart and kidney and cause organ impairments that define the clinical presentation. In this study, we present an overview of IGLV-IGLJ and IGLC germline utilization in 85 patients classified in three clinically important subgroups with dominant cardiac, renal as well as cardiac and renal involvement. We found that IGLV3 was the most frequently detected IGLV-family in patients with dominant cardiac involvement, whereas in renal patients IGLV1 were most frequently identified. For patients with dominant heart and kidney involvement IGLV6 was the most frequently detected IGLV-family. In more detailed analysis IGLV3-21 was observed as the most dominant IGLV-subfamily for patients with dominant heart involvement and IGLV1-44 as the most frequent IGLV-subfamily in the group of patients with dominant kidney involvement. For patients with dominant heart and kidney involvement IGLV6-57 was the most frequently detected IGLV-subfamily. Additionally, we were able to show an exclusive linkage between IGLJ1 and IGLC1 as well as between IGLJ2 and IGLC2 in the fully assembled IGL mRNA., Competing Interests: The authors have declared that no competing interests exist.

In general, purification of bispecific antibody (bsAb) is more challenging than that of monospecific antibody due to the increased complexity in byproduct profile. Like in the case of monospecific antibody purification, immunoglobulin-binding protein-based affinity chromatography is an indispensable tool for bsAb purification. For example, Protein A affinity chromatography has been widely used to capture Fc-containing bsAbs whereas other affinity media such as Protein L and KappaSelect, which bind kappa light chain, are used to capture bsAbs that do not contain a Protein A-binding site. In fact, affinity chromatography also possesses the capability of removing certain product-related impurities in bsAb purification when it is conducted with suitable medium and under appropriate conditions. Fully exploring the potential of affinity chromatography in bsAb purification to achieve both product capture and byproduct removal is highly desirable, as this can greatly alleviate the purification burden on subsequent polishing steps and hence improves the overall robustness of the downstream process. This article briefly reviews the byproduct clearance potential of several commonly used affinity media under relevant bsAb purification scenarios., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Primary cutaneous follicle center lymphoma (PCFCL) is the most common cutaneous B-cell lymphoma. The typical immunophenotype includes expression of both CD20 and BCL6, with the majority of cases lacking expression of CD10, BCL2, and the characteristic t(14;18)/IGH-BCL2 rearrangement seen in systemic follicular lymphoma (FL). Plasmacytic differentiation (PD) is an uncommon finding in both systemic and cutaneous FLs and presents a diagnostic challenge when present, leading to the potential for misdiagnosis as marginal zone lymphoma (MZL). Limited reports have described light chain restriction in the plasma cell component of FLs with PD, and rare cases of PCFCL with PD have been described. While the IGH-BCL2 translocation has been identified in a subset of FLs with PD, the presence of the BCL2 translocation in monotypic plasma cells of PCFCL has not been previously described to our knowledge. Here, we report a case of PCFCL with extensive PD in a 77-year-old woman that was favored to represent primary cutaneous MZL on an initial punch biopsy. Excisional biopsy, however, revealed that the atypical lymphocytes expressed CD10, BCL6, and BCL2, while the plasma cell component demonstrated light-chain lambda restriction. FISH studies showed the presence of an IGH-BCL2 translocation in both the lymphocytic and plasmacytic components., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Follicle center lymphomas, including primary cutaneous follicle center lymphoma (PCFCL), may rarely show plasmacytic differentiation. Such cases can pose a diagnostic challenge and can be mistaken for other lymphomas that more commonly include plasma cells. Here, we report four cases of PCFCL and one case of systemic follicular lymphoma involving the skin with associated monotypic plasma cells, including the clinical, morphologic and immunophenotypic features., (© 2020 John Wiley & Sons A/S . Published by John Wiley & Sons Ltd.)

Extensive studies have characterized the development and differentiation of murine B cells in secondary lymphoid organs. Antibodies secreted by B cells have been isolated and developed into well-established therapeutics. Validation of murine B cell development, in the context of autoimmune prone mice, or in mice with modified immune systems, is a crucial component of developing or testing therapeutic agents in mice and is an appropriate use of flow cytometry. Well established B cell flow cytometric parameters can be used to evaluate B cell development in the murine peritoneum, bone marrow, and spleen, but a number of best practices must be adhered to. In addition, flow cytometric analysis of B cell compartments should also complement additional readouts of B cell development. Data generated using this technique can further our understanding of wild type, autoimmune prone mouse models as well as humanized mice that can be used to generate antibody or antibody-like molecules as therapeutics.

Glycosylation is one of the major post-translational modifications in eukaryotic cells and has been reported to affect the amyloid fibril formation in several amyloidogenic proteins and peptides. In this study, we expressed a Vλ6 light chain mutant, Wil, which is an amyloidogenic mutant in AL amyloidosis, by the yeast Pichia pastoris. After separation by cation exchange chromatography, we obtained the O-glycosylated and non-glycosylated Wil mutants in high yield. The structures of these Wil mutants were identical except with respect to glycosylation, and the stabilities were also identical. On the other hand, the O-glycosylation retarded the amyloid fibril formation in a sugar size-dependent manner. From these results, we discussed the role of covalently attached glycan in the retardation of amyloid fibril formation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background and Objectives: Immunohistopathology is an essential technique in the diagnostic workflow of a kidney biopsy. Deep learning is an effective tool in the elaboration of medical imaging. We wanted to evaluate the role of a convolutional neural network as a support tool for kidney immunofluorescence reporting., Design, Setting, Participants, & Measurements: High-magnification (×400) immunofluorescence images of kidney biopsies performed from the year 2001 to 2018 were collected. The report, adopted at the Division of Nephrology of the AOU Policlinico di Modena, describes the specimen in terms of "appearance," "distribution," "location," and "intensity" of the glomerular deposits identified with fluorescent antibodies against IgG, IgA, IgM, C1q and C3 complement fractions, fibrinogen, and κ - and λ -light chains. The report was used as ground truth for the training of the convolutional neural networks., Results: In total, 12,259 immunofluorescence images of 2542 subjects undergoing kidney biopsy were collected. The test set analysis showed accuracy values between 0.79 ("irregular capillary wall" feature) and 0.94 ("fine granular" feature). The agreement test of the results obtained by the convolutional neural networks with respect to the ground truth showed similar values to three pathologists of our center. Convolutional neural networks were 117 times faster than human evaluators in analyzing 180 test images. A web platform, where it is possible to upload digitized images of immunofluorescence specimens, is available to evaluate the potential of our approach., Conclusions: The data showed that the accuracy of convolutional neural networks is comparable with that of pathologists experienced in the field., (Copyright © 2020 by the American Society of Nephrology.)

Amyloidosis is classified according to the amyloid precursor protein, and accurate diagnosis of the amyloidosis type may guide appropriate treatment. Immunohistochemistry and Congo red staining are the most frequently used methods used to distinguish types of amyloidosis, but problems with specificity and sensitivity indicate the need for an alternative diagnostic method. In this study, we evaluated laser microdissection-liquid chromatography-tandem mass spectrometry (LMD-LC-MS/MS) for the diagnosis of amyloid light-chain (AL) amyloidosis in animals. Plasmacytomas with amyloid deposits from 15 dogs and 2 cats were subjected to Congo red staining with or without potassium permanganate pretreatment, immunohistochemistry for kappa and lambda light chains, and LMD-LC-MS/MS. Congo red staining was diagnostic in 12 of 17 cases based on resistance to potassium permanganate pretreatment, but in 5 of 17 cases the pretreatment unexpectedly reduced Congo red staining or abrogated the birefringence and a definitive diagnosis could not be reached. Immunohistochemistry detected kappa or lambda light chains in 6 of 17 cases. With LMD-LC-MS/MS, immunoglobulin lambda light chain was detected in all 17 cases. The amyloid signature proteins ApoA-I, ApoA-IV, and ApoE were detected in 9, 1, and 3 of the 15 canine cases by LMD-LC-MS/MS, but not in the feline cases. In conclusion, LMD-LC-MS/MS consistently determined the amyloid type in all examined specimens, while Congo red staining after potassium permanganate treatment and immunohistochemistry were less sensitive tests.

Background: IgG4-related disease (IgG4-RD) is a newly classified but poorly understood immune-medicated systemic disease. It causes potential fibroinflammation in one or more organs, characterized by tumescent organs and marked IgG4-positive plasma cells infiltration in the affected tissues. There have been a few cases revealing close relationship between IgG4-RD and formation of B cell lymphoma. Diffuse large B cell lymphoma (DLBCL) and extranodal marginal zone lymphoma (EMZL) of mucosa-associated lymphoid tissue are the most common sub-types ever described, whereas the exact mechanism remain unclear., Case Presentation: We report a 64-year old Chinese male who presented chronic kidney disease and was initially diagnosed typical IgG4-RD. Pathological findings revealed there was restricted expression of lambda light chain in the kidney. There was also elevated uptake abnormality observed in 18 F-FDG-PET/CT. Prednisone combined with oral cyclophosphamide helped the patient to get a partial remission of renal function and an obvious decrease of IgG4 level. However, he developed DLBCL 16 months after IgG4-RD diagnosis. The DLBCL is speculated to transform from a pre-existing but possible missed diagnosed EMZL., Conclusions: Concurrent IgG4-RD with kidney-origin EMZL developing DLBCL has never been reported in the literature. Clinicians should keep in mind that lymphoma may occur in IgG4-RD. The mechanism of lymphomagenesis potential in IgG4-RD needs further study.

An 84-year-old woman with a history of haemodialysis for renal failure from approximately 1 year before death. Autopsy revealed numerous spheroid-type amyloid deposits in the kidney that were observed mainly in the interstitium but not the glomeruli and vessels. In addition, intracytoplasmic small globular amyloid deposits in the proximal tubules in addition to amyloid casts were identified. Immunohistochemistry and proteomic analyses indicated these deposits were composed of λ light chains. Amyloid deposition was also found in the lung and heart. λ-type monoclonal protein was detected in her serum and increased numbers of CD138-positive cells with λ-restriction was observed in the bone marrow. The case was diagnosed as amyloid tubulopathy (AT) associated with systemic ALλ amyloidosis related to plasma cell neoplasm. This case indicates that AT is associated with ALλ amyloidosis, which developed systemically with characteristic amyloid deposition forms. These pathological features may be associated with her rapid progressive renal failure.

Objective: To validate kappa free light chain (KFLC) and lambda free light chain (LFLC) indices as a diagnostic biomarker in multiple sclerosis (MS)., Methods: We performed a multicenter study including 745 patients from 18 centers (219 controls and 526 clinically isolated syndrome (CIS)/MS patients) with a known oligoclonal IgG band (OCB) status. KFLC and LFLC were measured in paired cerebrospinal fluid (CSF) and serum samples. Gaussian mixture modeling was used to define a cut-off for KFLC and LFLC indexes., Results: The cut-off for the KFLC index was 6.6 (95% confidence interval (CI) = 5.2-138.1). The cut-off for the LFLC index was 6.9 (95% CI = 4.5-22.2). For CIS/MS patients, sensitivity of the KFLC index (0.88; 95% CI = 0.85-0.90) was higher than OCB (0.82; 95%CI = 0.79-0.85; p  < 0.001), but specificity (0.83; 95% CI = 0.78-0.88) was lower (OCB = 0.92; 95% CI = 0.89-0.96; p  < 0.001). Both sensitivity and specificity for the LFLC index were lower than OCB., Conclusion: Compared with OCB, the KFLC index is more sensitive but less specific for diagnosing CIS/MS. Lacking an elevated KFLC index is more powerful for excluding MS compared with OCB but the latter is more important for ruling in a diagnosis of CIS/MS.

We report a 58-year-old Japanese woman who presented with nephrotic syndrome. Steroid therapy and cyclosporine A administration were initiated, but hematological remission and renal response were not achieved. Renal biopsy revealed amyloid deposits in the mesangial region and the small arteries. Proteomic analysis based on laser microdissection and mass spectrometry showed that the amyloid deposits were composed of the constant region of the lambda light chain. She received vincristine, adriamycin, and dexamethasone therapy followed by high-dose melphalan and autologous stem cell transplantation, resulting in hematological complete remission and renal response with negative urinary Bence-Jones protein and proteinuria. Renal biopsy was performed four times during follow-up, demonstrating that amyloid deposits decreased gradually, while glomeruli showing global sclerosis increased from 3 to 62%. This case suggests that glomerular amyloid deposits can be cleared via tissue remodeling, if stem cells producing amyloid precursors are completely replaced by unrelated cells after stem cell transplantation.

Objective: To determine the types of paraproteins in patients with multiple myeloma in a tertiary care setting., Methods: The cross-sectional study was conducted at the Liaquat National Hospital, Karachi, from November 2015 to May 2016, and comprised patients with multiple myeloma selected using consecutive, non-probability sampling technique. Detailed history was taken and immunofixation assay was conducted to assess the type of paraproteins in the patients. Data was recorded on a proforma and analysed using SPSS 22., Results: Of the 87 patients, 62(71.3%) were males and 25(28.7%) were females. The overall mean age was 57.41±10.53 years. Of the total, 52(71.3%), patients had Immunoglobulin G kappa and 61(70%) had Immunoglobulin A kappa paraprotein., Conclusions: The most common types of paraprotein was found to be Immunoglobulin G kappa followed by Immunoglobulin A kappa.

Background: Accumulation of middle-weight uraemic toxins in haemodialysis (HD) patients results in increased morbidity and mortality. Whether medium cut-off HD (MCO-HD) improves removal of middle-weight uraemic toxins remains to be demonstrated., Methods: This cross-over prospective study included 40 patients randomly assigned to receive either 3 months of MCO-HD followed by 3 months of high-flux HD (HF-HD), or vice versa. The primary endpoint was myoglobin reduction ratio (RR) after 3 months of MCO-HD. Secondary endpoints were the effect of MCO-HD on other middle-weight toxins and protein-bound toxins, and on parameters of nutrition, inflammation, anaemia and oxidative stress., Results: Compared with HF-HD, MCO-HD provided higher mean RR of myoglobin (36 ± 8 versus 57 ± 13%, P < 0.0001), beta2-microglobulin (68 ± 6 versus 73 ± 15%, P = 0.04), prolactin (32 ± 13 versus 59 ± 11%, P < 0.0001), fibroblast growth factor 23 (20 ± 21 versus 41 ± 22%, P = 0.0002), homocysteine (43 ± 7 versus 46 ± 9%, P = 0.03) and higher median RR of kappa [54 (48-58) versus 70 (63-74)%, P < 0.0001] and lambda free light chain (FLC) [15 (9-22) versus 44 (38-49)%, P < 0.0001]. Mean ± SD pre-dialysis levels of beta2-microglobulin (28.4 ± 5.6 versus 26.9 ± 5.1 mg/L, P = 0.01) and oxidized low-density lipoprote (6.9 ± 4.4 versus 5.5 ± 2.5 pg/mL, P = 0.04), and median (interquartile range) kappa FLC [145 (104-203) versus 129 (109-190) mg/L, P < 0.03] and lambda FLC [106 (77-132) versus 89 (62-125) mg/L, P = 0.002] were significantly lower. Mean albumin levels decreased significantly (38.2 ± 4.1 versus 36.9 ± 4.3 g/L, P = 0.004), without an effect on nutritional status as suggested by unchanged normalized protein catabolic rate and transthyretin level., Conclusions: Compared with HF-HD, MCO-HD provides higher myoglobin and other middle molecules RR and is associated with moderate hypoalbuminemia. The potential benefits of this strategy on long-term clinical outcomes deserve further evaluation., (© The Author(s) 2019. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.)

Purpose: The integration of expertise between oncologist and clinical biochemist for the monitoring and diagnosis of plasma cell dyscrasia is crucial. In some cases, medical laboratory scientists can provide an original contribution using the appropriate techniques to arrive at a diagnosis., Methods: We report a case of 67-year-old woman who was admitted to our hospital for bone pain. Imaging studies showed multiple diffuse bone lytic lesions, and a laboratory screen revealed anemia and altered creatinemia; serum capillary zone electrophoresis confirmed a monoclonal peak in the γ-zone that had been known since 2011, typed as immunoglobulin G kappa by immunosubtraction electrophoresis. The patient had undergone surgery for breast cancer in 2013, and based on her clinical history, the oncologist suspected the presence of bone metastases from the breast cancer and opted for relative therapy. Immunosubtraction, however, showed a very small reduction in lambda free light chains in the beta zone, but it was difficult to establish if was a monoclonal component, and consequently additional tests were performed., Discussion: A monoclonal component composed of only lambda free light chains was evidenced. This result in association with multiple diffuse bone lytic lesions observed led us to suspect multiple myeloma and not bone metastases from the breast cancer. Based on these observations, we encouraged the oncologist to conduct an osteomedullary biopsy, allowing us to make a diagnosis of low-grade stage II lambda light chain multiple myeloma., Conclusion: In this report, we show how the expertise of the clinical biochemist was instrumental in solving this case.

Lichen myxedematosus is a chronic cutaneous mucinosis that can present on a spectrum from localized cutaneous lesions to systemic disease of scleromyxedema. The clinical presentation of localized cutaneous lichen myxedematosus is waxy lichenoid papules, nodules, and/or plaques that have histopathologic findings of mucin deposition and a variable degree of fibroblast proliferation. There is an absence of serum paraproteins, and there are no other systemic causes of cutaneous mucinosis such as thyroid disease. The pathogenesis of lichen myxedematosus is unknown. We report 3 cases of localized cutaneous lichen myxedematosus with a light chain-restricted plasmacytic component by in situ hybridization. Our findings deliver an insight for disease pathogenesis and highlight for the first time, the significance of plasma cells in lesions of localized cutaneous lichen myxedematosus. We suggest that plasma cell light chain restriction could represent a clue to distinguish localized cutaneous disease from systemic disease.

Cardiac dysfunction is the most frequent cause of morbidity and mortality in amyloid light chain (AL) amyloidosis caused by a clonal immunoglobulin light chain (LC). Previously published transgenic animal models of AL amyloidosis have not recapitulated the key phenotype of cardiac dysfunction seen in AL amyloidosis, which has limited our understanding of the disease mechanisms in vivo, as well as the development of targeted AL therapeutics. We have developed a transgenic zebrafish model in which a λ LC derived from a patient with AL amyloidosis is conditionally expressed in the liver under the control of the Gal4 upstream activation sequence enhancer system. Circulating LC levels of 125 µg/ml in these transgenic zebrafish are comparable to median pathological serum LC levels. Functional analysis links abnormal contractile function with evidence of cellular and molecular proteotoxicity in the heart, including increased cell death and autophagy. However, despite pathological and functional phenotypes analogous to human AL, the lifespan of the transgenic fish is comparable to control fish without the expressed AL-LC transgene. Nuclear labeling experiments suggest increased cardiac proliferation in the transgenic fish, which can be counteracted by treatment with a small molecule proliferation inhibitor leading to increased zebrafish mortality because of cardiac apoptosis and functional deterioration. This transgenic zebrafish model provides a platform to study underlying AL disease mechanisms in vivo further. NEW & NOTEWORTHY Heart failure is a major cause of mortality in amyloid light (AL) amyloidosis, yet it has been difficult to model in animals. We report the generation of a transgenic zebrafish model for AL amyloidosis with pathological concentration of circulating human light chain protein that results in cardiac dysfunction. The light chain toxicity triggers regeneration in the zebrafish heart resulting in functional compensation early in life, but with age develops into cardiac dysfunction.

Gastro-oesophageal reflux disease (GORD) has long been associated with poor asthma control without an established cause-effect relationship. 610 asthmatics (421 severe/88 mild-moderate) and 101 healthy controls were assessed clinically and a subset of 154 severe asthmatics underwent proteomic analysis of induced sputum using untargeted mass spectrometry, LC-IMS-MS E . Univariate and multiple logistic regression analyses (MLR) were conducted to identify proteins associated with GORD in this cohort. When compared to mild/moderate asthmatics and healthy individuals, respectively, GORD was three- and ten-fold more prevalent in severe asthmatics and was associated with increased asthma symptoms and oral corticosteroid use, poorer quality of life, depression/anxiety, obesity and symptoms of sino-nasal disease. Comparison of sputum proteomes in severe asthmatics with and without active GORD showed five differentially abundant proteins with described roles in anti-microbial defences, systemic inflammation and epithelial integrity. Three of these were associated with active GORD by multiple linear regression analysis: Ig lambda variable 1-47 (p = 0·017) and plasma protease C1 inhibitor (p = 0·043), both in lower concentrations, and lipocalin-1 (p = 0·034) in higher concentrations in active GORD. This study provides evidence which suggests that reflux can cause subtle perturbation of proteins detectable in the airways lining fluid and that severe asthmatics with GORD may represent a distinct phenotype of asthma., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Impact Statement: A multistep proteomics fractionation strategy was developed and validated for the discovery of proteomic biomarkers which could be used as potential diagnostic biomarkers for monitoring the progression of disease in smokers and COPD patients towards lung cancer.

CD3 + /CD57 + T-cell large granular lymphocyte leukemia (T-LGLL) is an indolent neoplasm, exhibiting mostly CD8 + , less frequently CD4 + phenotypes, and T-LGLL consisting of 2 populations with CD8 + and CD4 + phenotypes is markedly rare. An 87-year-old female was admitted under a diagnosis of immune thrombocytopenia (ITP) with a platelet count of 5.0×10 9 /L and increased number of LGL with unknown etiology. Her neutrophil count also decreased to 0.27×10 9 /L and she was positive for antineutrophil antibody. The WBC count was 2.7×10 9 /L with 34.7% LGL and flow cytometry (FCM) analysis revealed 16% CD3 + /CD4 + /CD8 dim /CD57 + and 20.9% CD3 + /CD8 + /CD57 + populations. These populations also expressed granzyme B and perforin. Circulating mononuclear cells were found to be clonal by PCR analysis of T-cell receptor β-chain gene. Serum immunofixation and bone marrow FCM analyses demonstrated 2 clonal B-cells producing IgG-λ and IgA-λ. Deep amplicon sequencing of STAT3 and STAT5B genes revealed a STAT3 R302G mutation with an allele burden of 2.6%. The thrombocytopenia and neutropenia were successfully treated by prednisolone and romiplostim with negative conversion of antineutrophil antibody. This is the first reported case of T-LGLL with dual components of CD4 + /CD8 dim and CD4 - /CD8 + populations in terms of multiple comorbidities related to the respective CD8 + and CD4 + T-LGLLs.

Talks, Ben J., Susie B. Bradwell, John Delamere, Will Rayner, Alex Clarke, Chris T. Lewis, Owen D. Thomas, and Arthur R. Bradwell. Urinary alpha-1-acid glycoprotein is a sensitive marker of glomerular protein leakage at altitude. High Alt Med Biol. 19:295-298, 2018.-Proteinuria is an established feature of ascent to altitude and may be caused by a loss of negative charges on glomerular capillary walls (GCWs). To test this hypothesis, we measured two similar sized but oppositely charged proteins in urine: negatively charged alpha-1-acid glycoprotein (α1-AGP, 41-43 kDa) and positively charged dimeric lambda free light chains (λ-FLCs, 50 kDa). Twenty-four-hour urinary leakage was compared with albumin, a 66 kDa negatively charged protein. We studied 23 individuals (ages 23-78 years, male = 17) at baseline (140 m) and daily during an expedition to 5035 m. The results showed a significant increase in median urinary leakage of α1-AGP (p < 0.0001; 6.85-fold) and albumin (p = 0.0006; 1.65-fold) with ascent to altitude, but no significant increase in leakage of λ-FLCs (p = 0.39; 1.14-fold). α1-AGP correlated with the daily ascent profile (p = 0.0026) and partial pressure of oxygen (p = 0.01), whereas albumin showed no correlation (p = 0.19). Urinary α1-AGP was a more sensitive marker of altitude proteinuria than urinary albumin and λ-FLCs, and supported the possibility of loss of GCW negative charges at altitude.

Background: Light chain deposition disease (LCDD) is a monoclonal immunoglobulin deposition disease (MIDD) that is characterized by the deposition of monoclonal light chains in multiple organs, including the kidney. It is a rare disorder caused by an underlying monoclonal plasma cell dyscrasia. LCDD with renal involvement causes proteinuria, which sometimes can lead to nephrotic syndrome. The monoclonal light chains are mostly in the κ form. Treatment of LCDD is the same as that for multiple myeloma (MM); however, some conventional anticancer drugs show substantial toxicity and therefore cannot be administered to older patients or those with renal impairment., Case Presentation: An 80-year-old woman was referred to our department with severe nephrotic syndrome (13.6 g/gCr) and anemia. A renal biopsy showed mesangial proliferation and mesangial matrix expansion, and immunohistochemistry showed positive staining for λ chains along the glomerular basement membrane, but was negative for κ chains or amyloid deposition. A bone marrow biopsy revealed 64% plasma cells. Immunoglobulin G (IgG)-λ type M protein was detected, and the levels of free λ chain was significantly increased. We concluded that her nephrotic syndrome was caused by LCDD, which resulted from IgG-λ MM. The induction of a BCD (bortezomib, cyclophosphamide, and dexamethasone) treatment regimen did not lead to a hematological response or decrease in proteinuria. The administration of combination therapy of lenalidomide and prednisolone led to the successful reduction of proteinuria and hematuria., Conclusions: We presented a very rare case report describing the successful treatment of LCDD (λ chain)-induced nephrotic syndrome with lenalidomide.
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Amyloid formation and deposition of immunoglobulin light-chain proteins in systemic amyloidosis (AL) cause major organ failures. While the κ light-chain is dominant (λ/κ=1:2) in healthy individuals, λ is highly overrepresented (λ/κ=3:1) in AL patients. The structural basis of the amyloid formation and the sequence preference are unknown. We examined the correlation between sequence and structural stability of dimeric variable domains of immunoglobulin light chains using molecular dynamics simulations of 24 representative dimer interfaces, followed by energy evaluation of conformational ensembles for 20 AL patients' light chain sequences. We identified a stable interface with displaced N-terminal residues, provides the structural basis for AL protein fibrils formation. Proline isomerization may cause the N-terminus to adopt amyloid-prone conformations. We found that λ light-chains prefer misfolded dimer conformation, while κ chain structures are stabilized by a natively folded dimer. Our study may facilitate structure-based small molecule and antibody design to inhibit AL. This article is part of a Special Issue entitled: Accelerating Precision Medicine through Genetic and Genomic Big Data Analysis edited by Yudong Cai & Tao Huang., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: Multiple myeloma (MM) is a plasma cell dyscrasia characterized by the presence of a clonal proliferation of tumor cells. Cutaneous involvement of MM is very rare and remains poorly understood., Objective: The aim of this study was to examine the clinical and histopathologic characteristics of cutaneous involvement in MM and identify factors associated with overall survival of MM with cutaneous involvement., Methods: The medical records of 1228 patients with MM were retrieved and analyzed. Of those patients, 14 with cutaneous involvement of MM (1.14%) were further evaluated for their clinical and histopathologic findings., Results: Patients with cutaneous involvement showed significantly reduced overall survival compared with those without cutaneous involvement (median, 28 vs. 57 months; hazard ratio, 1.929; 95% confidence interval, 1.030-3.613). In subgroup analyses of patients with MM with cutaneous involvement, erythematous nodules (P = .004), multiple cutaneous lesions (P = .002), and absence of a grenz zone (P = .004) were clinicopathologic features associated with reduced overall survival after Bonferroni correction., Limitations: The retrospective design and the small sample size are the limitations., Conclusion: Cutaneous involvement accounted for about 1.14% of patients with MM and was associated with reduced overall survival., (Copyright © 2017 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

Proteomics is becoming the de facto gold standard for identifying amyloid proteins and is now used routinely in a number of centres. The technique is compound class independent and offers the added ability to identify variant and modified proteins. We re-examined proteomics results from a number of formalin-fixed paraffin-embedded amyloid samples, which were positive for transthyretin (TTR) by immunohistochemistry and proteomics, using the UniProt human protein database modified to include TTR variants. The amyloidogenic variant, V122I TTR, was incorrectly identified in 26/27 wild-type and non-V122I variant samples due to its close mass spectral similarity with the methyl lysine-modified WT peptide [126K Me ]105-127 (p.[146 K Me ]125-147) generated during formalin fixation. Similarly, the methyl lysine peptide, [50K Me ]43-59, from immunoglobulin lambda light chain constant region was also misidentified as arising from a rare myeloma-derived lambda variant V49I. These processing-derived modifications are not present in fresh cardiac tissue, non-fixed fat nor serum and do not materially affect the identification of amyloid proteins. They could result in the incorrect assignment of a variant, and this may have consequences for the immediate family who will require genetic counselling and potentially early clinical intervention. As proteomics becomes a routine clinical test for amyloidosis, it becomes important to be aware of potentially confounding issues such as formalin-mediated lysine methylation, and how these may influence diagnosis and possibly treatment.

The production of antibodies is accompanied by a slight excess of synthesis of κ and λ immunoglobulin light chains; small amounts of them are released in the peripheral blood and can also be found in various body fluids, such as synovial fluid, cerebrospinal fluid, urine and saliva. They are rapidly filtered by the glomerulus and >99% are reabsorbed from the cells of the proximal convoluted tubule, making them present in the urine in only trace amounts. The production of an excess of protein without a reason or a specific function in a biological system is rare. Free light chains, considered for years a waste product of Ig synthesis, are currently known to be very active molecules, able to bind antigens as well as whole immunoglobulin and helping to develop specific antibody affinity. The ability of free light chains to activate mast cells and then become an active part of the pathogenic mechanisms of chronic inflammatory diseases has increased interest in their clinical use, both as an attractive therapeutic target or as a biochemical marker of disease evolution or remission. This is an overview of relevant scientific interest that immunoglobulin light chains κ and λ have attracted over the years, a report on the progress in knowledge about their structure and function, with a special focus on their biological meaning and potential clinical utility in different diseases., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Multiple myeloma (MM) patients commonly present abnormal expression of cancer-testis antigens, which may serve as immunotherapeutic targets and prognostic factors. We previously reported that preferentially expressed antigen of melanoma (PRAME) overexpression in bone marrow mononuclear cells is related to progression in MM patients treated with non-bortezomib-containing regimens. The mechanism underlying variations in PRAME expression remains unknown. To investigate the impact of gene copy number variation (CNV) on PRAME expression, plasma cells were sorted from 50 newly diagnosed patients and 8 healthy volunteers to measure PRAME transcript levels and gene copy numbers by real-time quantitative polymerase chain reaction. A total of 14 (28.0%), 7 (14.0%), and 29 (58.0%) patients exhibited overexpression, expression within the normal range, and low expression, respectively. PRAME overexpression was significantly related to a lower 1-year progression-free survival rate compared with PRAME low expression (20.0% vs. 88.9%, p = 0.043). The mean PRAME gene copy number relative to albumin (ALB) in normal samples was ∼1.0, whereas 4.0%, 24.0%, 70.0%, and 2.0% of patients had PRAME gene relative copy numbers of approximately 0, 0.5, 1.0, and 2.0, respectively. Patients with PRAME gene deletion (relative copy number of 0 or 0.5) had significantly higher frequency of PRAME nonoverexpression and lambda light chain expression than those with no deletion (p = 0.011 and 0.003). Thus, PRAME gene CNV occurs in MM. Gene deletion may be one mechanism leading to PRAME nonoverexpression and related to immunoglobulin lambda light chain locus rearrangement. PRAME overexpression in plasma cells might be an adverse prognostic factor for progression in MM.

Immature B cells are the first B cell progenitors to express a fully formed B cell receptor and are therefore subject to extensive selection processes that act to mitigate the emergence of autoreactive clones. While it is well appreciated that most B cell generation in the bone marrow is highly dependent on access to molecules present in the local milieu, the existence of extrinsically provided factors that modulate immature B cell biology is ambiguous. Nonetheless, a population of CD49b+CD90lo cells has demonstrated in vitro potential to promote immature B cell survival. Using a mouse basophil reporter strain we confirmed the identity of these CD49b+CD90lo supportive cells as basophils. However, analysis of bone marrow B cell populations following lineage specific basophil depletion demonstrates that basophils do not have a significant role in vivo in modulating immature B cell biology during steady-state conditions.

Kappa (κ) or lambda (λ) free light chains (FLCs) are produced from B cells during immunoglobulin synthesis. FLCs have been shown to participate in several key processes of immune responses. They are necessary to adjust PMN functions and assist PMN pre-stimulation. Moreover, they cause mast cell degranulation which releases pro-inflammatory mediators and stimulates local inflammatory responses in some conditions such as inflammatory bowel disease (IBD). Having low molecular weights which may straightly be toxic to proximal tubule cells (PTCs), FLCs can also have an important role in renal diseases. In this review we have highlighted the involvement of light chains in the pathogenesis of some inflammatory diseases and discussed their potential to be the targets of therapeutic purposes., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

A 78-year-old man presented with subacute progressive proximal weakness and dysphagia. A biopsy specimen from the left biceps femoris revealed evidence of necrotic and regenerating muscle fibers, but lymphocyte infiltration was not noted. The patient was diagnosed with necrotizing myopathy with anti-signal recognition particle (SRP) antibodies. Concomitant therapy with prednisolone and azathioprine caused the serum CK level to return to normal and it caused clinical manifestations to abate. One year later, however, muscle weakness worsened. Immunoelectrophoresis of serum revealed IgG M protein, and muscle pathology revealed amyloid deposits in numerous blood vessels and at the periphery of a few muscle fibers, and deposits stained positive for anti-λ light chain antibody. The patient was diagnosed with amyloid myopathy, and therapy for systemic amyloid light chain amyloidosis caused muscle weakness to diminish. Amyloidosis is believed to be the primary pathology in this case based on the patient's response to treatment reaction, but the significance of a case involving both amyloid myopathy and necrotizing myopathy warranted examination.

Aim: To assess an impact of immunoglobulin free light chains (FLC) on short-term and long-term prognosis of clinical and radiological activity and progression of disability in multiple sclerosis (MS)., Material and Methods: A sample of 381 patients with definite MS was divided into 2 groups. In group 1, lumbar puncture was performed at the time of clinically isolated syndrome, and patients were prospectively followed up to 2 years (short-term prognosis group, n=97). In group 2, MS was diagnosed immediately after lumbar puncture, and retrospective analysis of the disease course with the duration not less than 5 years was performed (long-term prognosis group, n=284). The Expanded Disability Status Scale (EDSS) and the Multiple Sclerosis Severity Score (MSSS) were used to assess patient's status. Concentrations of kappa and lambda FLC in the CSF (K-FLC CSF , L-FLC CSF ) and serum (K-FLC SERUM , L-FLC SERUM ) as well as quotients of concentrations (Q-K and Q-L) were determined. Patients were stratified into subgroups with high and low concentrations of K-FLC and L-FLC using cut-offs from our previous studies: K-FLC CSF =0.595 mcg/l and L-FLC CSF =0.127 mcg/l., Results: In group 1, significant correlations were found only between EDSS score and concentrations of K-FLC CSF (r=0.377, p=0.00019) and Q-K (r=0.366, p=0.0012). FLC concentrations did not correlate with the number of relapses and new T2 lesions. The age and EDSS score at the disease onset didn't differ between patients with high and low K-FLC and L-FLC (K-FLC CSF : р=0.2658; L-FLC CSF : р=0.5502). A significant decrease of EDSS score after the disease onset was observed in all groups except for patients with high concentrations of K-FLC CSF (p=0.1844), so the EDSS score after 2 years was significantly higher in this subgroup of patients (p=0.0006). In group 2, significant correlations of K-FLC with EDSS score (r=0.181, p=0.002) and MSSS score (r=0.121, р=0.044) for long-term prognosis (median (IQR) = 8 (6-13) years) were found. No correlations of FLC concentrations with the number of relapses during the first 5 years were found. Survival analysis showed that high concentrations of K-FLC CSF were associated with the high risk of progression to EDSS 6 (HR=2.055, p=0.026) but not with EDSS 4 (HR=2.388, p=0.08)., Conclusion: Concentrations of kappa FLC can help to define the prognosis of MS early at the disease course. Although low concentrations of FLC do not exclude a severe disease phenotype, patients with high K-FLC CSF concentrations are at greater risk for faster MS progression, probably, due to impaired reparation of neural tissue. Measurement of FLC concentrations can be used to determine a therapeutic tactics in patients with MS.

TAK1 (MAP3K7) mediation of the IκB kinase (IKK) complex-nuclear factor-κB (NF-κB) pathway is crucial for the activation of immune response and to perpetuate inflammation. Although progress has been made to understand TAK1 function in the B-cell receptor (BCR) signaling, the physiological roles of TAK1 in B-cell development, particularly in the bone marrow (BM), remain elusive. Previous studies suggested that the IKK complex is required for the development of immunoglobulin light chain λ-positive B cells, but not for receptor editing. In contrast, NF-κB activity is suggested to be involved in the regulation of receptor editing. Thus, NF-κB signaling in early B-cell development is yet to be fully characterized. Therefore, we addressed the role of TAK1 in early B-cell development. TAK1-deficient mice showed significant reduction of BM Igλ-positive B-cell numbers without any alteration in the BCR editing. Furthermore, the expression of survival factor Bcl-2 was reduced in TAK1-deficient BM B cells as assessed by microarray and quantitative PCR analyses. Ex vivo over-expression of exogenous Bcl-2 enhanced the survival of TAK1-deficient Igλ-positive B cells. TAK1-IKK-NF-κB signaling contributes to the survival of λ-chain-positive B cells through NF-κB-dependent anti-apoptotic Bcl-2 expression., (© 2016 Molecular Biology Society of Japan and John Wiley & Sons Australia, Ltd.)

Mantle cell lymphoma (MCL) is a B cell neoplasm characterized by cyclin D1 overexpression; its prognosis is poor, especially when it exhibits a blastoid morphology. Cyclin D1-negative MCL is rare, and its pathogenesis and progression remain unclear. Herein, we describe a cyclin D1-negative, cyclin D2-positive MCL with a CCND2 and immunoglobulin lambda light chain (IGL) translocation. The patient was initially diagnosed with cyclin D1-negative MCL and achieved complete remission via combination chemotherapy and autologous stem cell transplantation. After relapsing, he was diagnosed with a blastoid variant of MCL that showed lymphoid cells with dispersed chromatin and more mitotic figures and higher p53 expression compared with the initial MCL. Despite salvage therapies, the disease became refractory, and the patient died 28 months after initiating chemotherapy. This case demonstrates that blastoid morphology in cyclin D1-negative MCL with IGL-CCND2 translocation indicates progression to a more aggressive neoplasm, similar to cyclin D1-positive MCL.

The mechanisms by which B cells undergo tolerance, such as receptor editing, clonal deletion, and anergy, have been established in mice. However, corroborating these mechanisms in humans remains challenging. To study how autoreactive human B cells undergo tolerance, we developed a novel humanized mouse model. Mice expressing an anti-human Igκ membrane protein to serve as a ubiquitous neo self-antigen (Ag) were transplanted with a human immune system. By following the fate of self-reactive human κ(+) B cells relative to nonautoreactive λ(+) cells, we show that tolerance of human B cells occurs at the first site of self-Ag encounter, the bone marrow, via a combination of receptor editing and clonal deletion. Moreover, the amount of available self-Ag and the genetics of the cord blood donor dictate the levels of central tolerance and autoreactive B cells in the periphery. Thus, this model can be useful for studying specific mechanisms of human B cell tolerance and to reveal differences in the extent of this process among human populations., (© 2016 Lang et al.)

Proliferative glomerulonephritis with monoclonal immunoglobulin deposits (PGNMID) has been described as a new entity resembling immune-complex glomerulonephritis (GN). The recurrence of proliferative GN with monoclonal IgG in the renal allograft has been reported. However, recurrence of proliferative GN with monoclonal IgA after renal allograft is undefined. We previously reported a case of a 35-year-old woman with proliferative glomerulonephritis with monoclonal lambda (λ) with mesangial and subendothelial paracrystalline deposits in the native kidney and initially undetectable circulating monoclonal protein or clone by bone marrow biopsy or flow cytometry. Despite immunosuppressive therapy, her renal disease progressed to end-stage of renal disease (ESRD) and the patient ultimately received a renal allograft. Transplantation was followed by recurrence of IgA-λ PGNMID 4 months after renal transplantation and was associated the diagnosis of multiple myeloma. To the best of our knowledge recurrence of IgA PGNMID with paracrystalline deposits has not been previously reported.

Introduction: Light chain amyloidosis is characterized by extracellular deposition of a fibrillar material derived from immunglobulin light chain fragments., Aim: The aim of the authors was to assess survival depending on cardiac involvement, therapy, and presence of myeloma., Method: The authors studied a retrospective cohort of 29 patients with light chain amyloidosis (13 kappa, 16 lambda) treated in their institution between 2005 and 2014., Results: Twenty-one patients had primary amyloidosis, while 8 had coexisting multiple myeloma. One, two and three or more organs were involved in 4, 8, and 17 patients, respectively. Cardiac involvement (22 cases) inversely correlated with survival. Fifteen (52%) patients received chemotherapy only, while 14 (48%) underwent autologous stem cell transplantation with a median survival of 87 and 11.4 months, respectively. Two patients had heart transplantation and survived 70 and 30 months. Median overall survival was 75.8 months., Conclusions: Cardiac transplantation followed by autologous stem cell transplantation is feasible in selected patients with light chain amyloidosis and heart failure.

B cell development past the pro-B cell stage in mice requires the Cul4-Roc1-DDB1 E3 ubiquitin ligase substrate recognition subunit VprBP. Enforced Bcl2 expression overcomes defects in distal VH-DJH and secondary Vκ-Jκ rearrangement associated with VprBP insufficiency in B cells and substantially rescues maturation of marginal zone and Igλ(+) B cells, but not Igκ(+) B cells. In this background, expression of a site-directed Igκ L chain transgene increases Igκ(+) B cell frequency, suggesting VprBP does not regulate L chain expression from a productively rearranged Igk allele. In site-directed anti-dsDNA H chain transgenic mice, loss of VprBP function in B cells impairs selection of Igκ editor L chains typically arising through secondary Igk rearrangement, but not selection of Igλ editor L chains. Both H and L chain site-directed transgenic mice show increased B cell anergy when VprBP is inactivated in B cells. Taken together, these data argue that VprBP is required for the efficient receptor editing and selection of Igκ(+) B cells, but is largely dispensable for Igλ(+) B cell development and selection, and that VprBP is necessary to rescue autoreactive B cells from anergy induction., (Copyright © 2015 by The American Association of Immunologists, Inc.)

Purpose: Conjunctival amyloidosis is a rare disorder. It is often clinically not suspected or diagnosed. This study intended to demonstrate the clinical and histopathologic features of this infrequent disease, including an immunohistochemical search for amyloidotic proteins., Methods: Retrospective case series of the clinical and histopathologic characteristics of six patients with conjunctival amyloidosis. Immunohistochemical analysis with respect to possible amyloidotic components of the conjunctival deposits was performed., Results: The diagnosis of amyloidosis was not suspected in all six cases presenting with an amelanotic conjunctival lesion. In three patients a conjunctival tumor of unknown origin, in one case each a papillomatous alteration of the conjunctiva, a conjunctival granulomatous inflammation, and a lymphoma were assumed respectively. The diagnosis of amyloidosis was made by histopathology. Immunohistochemical examination found lambda and kappa light chains as well as prealbumin within the amyloid deposits in one of the six specimens., Conclusions: The diagnosis of amyloidosis has to be kept in mind in cases with an unclear conjunctival mass or inflammatory process. Only a tissue biopsy is able to prove the diagnosis. A possible underlying systemic disease has to be ruled out.

Objective: to investigate the histopathology of amyloid in liver biopsy specimens. MATERIAL AND METHODS. A total of 46 liver biopsy specimens were investigated in patients with histologically verified amyloidosis in 2006 to 2009 from the Amyloid Registry of the Charité University Hospital (Berlin). The liver biopsy specimens were fixed in formalin and embedded in paraffin. The paraffin sections were stained with hematoxylin and eosin and with Congo red. Amyloid was immunohistochemically classified using antibodies against amyloid P component, AA amyloid, apolipoprotein Al, lysozyme, fibrinogen, transthyretin, and κ and λ light chains., Results: Amyloid deposits were diagnosed in the 46 liver biopsy specimens from 17 women and 29 men (mean age 60 years). Immunohistochemical subtyping was successful in 91% of the cases. AL amyloidosis was diagnosed in 87% of the biopsy specimens and further classified as AL lambda-light chain amyloidosis (57%) and AL kappa-light chain amyloidosis (30%). The 46 liver biopsy specimens showed one case of AA amyloidosis (2%) and one case of transthyretin amyloidosis (2%). The type of amyloid could not be classified in 9% of the biopsy specimens., Conclusion: The investigation revealed that the most common types of hepatic amyloidosis are AL lambda- and AL kappa-light chain amyloidosis associated with the signs of parenchymal atrophy and steatosis.