TAFRO syndrome presenting as intrahepatic cholangitis on autopsy.
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ABSTRACT:
SUBMITTER: Nishioka H
PROVIDER: S-EPMC8077398 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Background & aimsPrimary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease characterized by progressive inflammatory and fibrotic injury to the biliary tree. We sought to further delineate the contribution of macrophage lineages in PSC pathobiology.MethodsHuman liver tissues and/or blood samples from patients with PSC, primary biliary cholangitis, other non-cholestatic/non-autoimmune diseases, including alcohol-related liver disease and non-alcoholic steatohepatitis, as well as normal liver, were sourced from our liver transplantation program. Liver fibrosis was studied using Van Gieson staining, while the frequencies of infiltrating monocyte and macrophage lineages, both in the circulation and the liver, were investigated by flow cytometry, including the expression of TGR-5, a G protein-coupled receptor (GPBAR1/TGR-5).ResultsSignificantly higher frequencies of CD68+CD206+ macrophages were detected in the livers of patients with PSC (median 19.17%; IQR 7.25-32.8%; n = 15) compared to those of patients with other liver diseases (median 12.05%; IQR 5.61-16.03%; n = 12; p = 0.0373). CD16+ monocytes, including both intermediate (CD14+CD16++) and non-classical (CD14dimCD16++) monocytes, were preferentially recruited into chronically diseased livers, with the highest recruitment ratios in PSC (median 15.83%; IQR 9.66-29.5%; n = 15), compared to other liver diseases (median 6.66%; IQR 2.88-11.64%, n = 14, p = 0.0152). The expression of TGR-5 on CD68+ intrahepatic macrophages was increased in chronic liver disease; TGR-5 expression on intrahepatic macrophages was highest in PSC (median 36.32%; IQR 17.71-63.61%; n = 6) and most TGR-5+ macrophages were CD68+CD206+ macrophages.ConclusionsUnderlying a potential role for macrophages in PSC pathobiology, we demonstrate, using patient-derived tissue, increased CD16+ monocyte recruitment and a higher frequency of CD68+CD206+ macrophages in the livers of patients with PSC; the CD68+CD206+ macrophage subset was associated with significantly higher TGR-5 expression in PSC.Lay summaryPrimary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease associated with progressive inflammation of the bile duct, leading to fibrosis and end-stage liver disease. In this study we explore the role of a type of immune cell, the macrophage, in contributing to PSC as a disease, hoping that our findings direct scientists towards new treatment targets. Our findings based on human liver and blood analyses demonstrate a greater frequency of a particular subset of immune cell, the CD68+CD206+ macrophage, with significantly higher TGR-5 expression on this subset in PSC.
| S-EPMC7005651 | biostudies-literature
Project description:Thrombocytopenia, anasarca, fever, reticulin fibrosis, organomegaly (TAFRO) syndrome is a unique clinicopathologic subtype of multicentric Castleman's disease that has recently been identified in Japan. However, little is known about its renal histological changes and the optimal treatment for TAFRO syndrome. An 80-year-old Japanese woman was admitted to our hospital for evaluation of severe anasarca and weight gain (10 kg in a month). She had polyneuropathy, monoclonal plasma cell proliferative disorder with positive kappa M-protein, a sclerotic bone lesion, elevation of vascular endothelial growth factor (VEGF), skin changes, and extravascular volume overload, which fulfilled the diagnostic criteria for POEMS (polyneuropathy, organomegaly, endocrinopathy, and monoclonal protein, skin changes) syndrome. However, kappa-type M-protein and thrombocytopenia with positivity of platelet-associated immunoglobulin G antibody were unusual, and fitted the diagnostic criteria for TAFRO syndrome. Renal biopsy showed diffuse endocapillary proliferative glomerulonephritis with endothelial swelling and the infiltration of monocytes and neutrophils without specific immunoglobulin deposits. Her systemic symptoms were refractory to initial treatment with high-dose melphalan and glucocorticoids. Alternative therapy with an anti-interleukin-6 (IL-6) receptor antibody (tocilizumab) effectively controlled the symptoms, while a thrombopoietin receptor agonist (romiplostim) was effective for her thrombocytopenia. Results suggest that IL-6-VEGF axis and an autoimmune mechanism may be responsible for TAFRO syndrome with clinical features of POEMS and refractory thrombocytopenia, which can be successfully treated with combination of tocilizumab and romiplostim.
| S-EPMC5886949 | biostudies-literature
Project description:ObjectivesTo identify prognostic factors for TAFRO syndrome, a rare inflammatory disorder of unknown etiology characterized by thrombocytopenia, anasarca, fever, reticulin myelofibrosis, renal dysfunction, and organomegaly.MethodsData of patients with TAFRO syndrome were extracted from a Japanese patient registry. Patients were divided into groups according to the clinical and laboratory parameters at initial presentation. Cut-off values for the laboratory parameters were determined using receiver operating characteristic curve analysis and by clinical relevance. Patient survival was analyzed by the Kaplan-Meier method. Univariable analysis was performed using log-rank tests. Multivariable analyses were performed with the logistic regression model and the Cox proportional hazards model.ResultsWe extracted the data of 83 patients with TAFRO syndrome from the registry. Univariable analysis identified several potential prognostic factors. Of these factors, age ≥60 years and D-dimer ≥18 μg/dL remained significant predictors of poor overall survival in the multivariable Cox proportional hazards model. Based on these results, we developed a simple prognostic scoring system for TAFRO syndrome (TS-PSS).ConclusionPatients in our cohort were stratified into low, intermediate, and high-risk groups by the TS-PSS. This system should be verified with independent patient cohorts in future studies.
| S-EPMC8085640 | biostudies-literature
Project description:BACKGROUND:TAFRO syndrome is a systemic inflammatory disorder that manifests as thrombocytopenia (T), anasarca (A), fever (F), reticulin fibrosis (R), and organomegaly (O). Renal dysfunction is frequently complicated with TAFRO syndrome, however, it is challenging to perform kidney biopsy in patients with TAFRO syndrome in the presence of thrombocytopenia. Renal histology in TAFRO syndrome mainly shows membranoproliferative glomerulonephritis (MPGN)-like lesions or thrombotic microangiopathy (TMA)-like glomerulopathy. We review our case and previous reports of TAFRO syndrome with kidney biopsy findings and discuss the renal pathophysiology of TAFRO syndrome. CASE PRESENTATION:We describe a previously healthy 48- year-old woman with TAFRO syndrome. Kidney biopsy performed before the treatment showed diffuse global endocapillary proliferative changes with endothelial cell swelling, double contours of partial capillary walls, and mesangiolysis, consistent with TMA-like glomerulopathy. Glucocorticoid therapy including steroid pulse was ineffective and she developed anasarca, renal dysfunction and oliguria. Hemodialysis was required. However, the anti-Interleukin (IL)-6 receptor antibody (tocilizumab) therapy was very effective. An increase in urinary volume was achieved about 2 weeks after the tocilizumab therapy and hemodialysis was discontinued. To investigate the renal pathophysiology of TAFRO syndrome, we performed immunohistological staining of vascular endothelial growth factor (VEGF)-A, CD34, and D2-40, in our case and a normal control kidney. Glomerular VEGF-A was especially positive in podocytes both, in the control and in the case, with no significant difference and there was a significant increase of VEGF-A staining area in the cortical peritubular capillaries in the case. Both glomerular and renal cortical CD34 expression were significantly decreased in our case. D2-40 expression in cortex was not significantly different. CONCLUSIONS:We reviewed our case and other 10 previous reports about renal biopsy findings in TAFRO syndrome and found that glomerular microangiopathy was a common finding. IL-6-VEGF-axis-induced glomerular microangiopathy may play a crucial role in developing acute kidney injury in TAFRO syndrome and the anti-IL-6 receptor antibody therapy may be useful for TAFRO syndrome refractory to glucocorticoids. About the pathophysiology of VEGF in TAFRO syndrome, VEGF balance in the glomerulus and perhaps in the peritubular capillary system as well may be critical. Further investigation is needed.
| S-EPMC6798393 | biostudies-literature
Project description:TAFRO syndrome, a clinical subtype of idiopathic multicentric Castleman disease (iMCD), consists of a constellation of symptoms/signs including thrombocytopenia, anasarca, fever, reticulin fibrosis/renal dysfunction, and organomegaly. The etiology of iMCD-TAFRO and the basis for cytokine hypersecretion commonly seen in iMCD-TAFRO patients has not been elucidated. Here, we identified a somatic MEK2P128L mutation and a germline RUNX1G60C mutation in two patients with iMCD-TAFRO, respectively. The MEK2P128L mutation, which has been identified previously in solid tumor and histiocytosis patients, caused hyperactivated MAP kinase signaling, conferred IL-3 hypersensitivity and sensitized the cells to various MEK inhibitors. The RUNX1G60C mutation abolished the transcriptional activity of wild-type RUNX1 and functioned as a dominant negative form of RUNX1, resulting in enhanced self-renewal activity in hematopoietic stem/progenitor cells. Interestingly, ERK was heavily activated in both patients, highlighting a potential role for activation of MAPK signaling in iMCD-TAFRO pathogenesis and a rationale for exploring inhibition of the MAPK pathway as a therapy for iMCD-TAFRO. Moreover, these data suggest that iMCD-TAFRO might share pathogenetic features with clonal inflammatory disorders bearing MEK and RUNX1 mutations such as histiocytoses and myeloid neoplasms.
| S-EPMC7148173 | biostudies-literature
Project description: Not available
| S-EPMC8490184 | biostudies-literature
Project description:ERα, one of the classical receptors of estrogen, has been found to be abnormally up-regulated in patients with primary biliary cholangitis (PBC), which is an important factor leading to ductopenia. ERα-mediated signaling pathways are involved in proliferation of human intrahepatic biliary epithelial cells (HiBECs) and portal inflammation. Our previous studies have shown that the expression levels of ERα in the liver tissues of PBC patients are positively correlated with the levels of serum pro-inflammatory cytokines. The present study was designed to assess the relationship between abnormal ERα expression in small bile ducts and the progression of PBC. We examined the levels of multiple cytokines and analyzed their relationship with clinical parameters of livers functions in a cohort of 43 PBC patients and 45 healthy controls (HC). The levels of ERα expression and the relation with the levels of cytokines were further assessed. The localization of cytokines and ERα-mediated signaling pathways in liver were examined using immunohistochemistry. The possible underlying mechanisms of these alterations in PBC were explored in vitro. Our results demonstrated that the levels of IL-6, IL-8, and TNF-α were increased in PBC patients, and positively correlated with the serum AKP levels and ERα expression levels. Moreover, the expression of these cytokines were up-regulated in HiBECs that were stimulated with 17β-estradiol and PPT (an ERα agonist) and they also were positive in intrahepatic bile duct of PBC patients. The ERα-mediated expression of pro-inflammatory cytokines was induced by JNK, P38, and STAT3 phosphorylation in HiBECs. In addition, the CD54 expression was increased in HiBECs after ERα activation, which induced peripheral blood monouclear cells (PBMCs) recruitment. In conclusion, the present study highlighted a key role of abnormal ERα expression in inducing an inflammatory phenotype of HiBECs, which was critical in the development of inflammation and damage in small bile duct.
| S-EPMC6907097 | biostudies-literature
Project description:Magnetic resonance imaging with magnetic resonance cholangiopancreatography (MRI-MRCP) in primary sclerosing cholangitis (PSC) is currently based on qualitative assessment and has high interobserver variability. We investigated the utility and performance of quantitative metrics derived from a three-dimensional biliary analysis tool in adult patients with PSC. MRI-MRCP, blood-based biomarkers, and FibroScan were prospectively performed in 80 participants with large-duct PSC and 20 healthy participants. Quantitative analysis was performed using MRCP+ (Perspectum Ltd., United Kingdom), and qualitative reads were performed by radiologists. Inter-reader agreements were compared. Patients were classified into high risk or low risk for disease progression, using Mayo risk score (MRS), Amsterdam-Oxford model (AOM), upper limit of normal (ULN) alkaline phosphatase (ALP), disease distribution, and presence of dominant stricture. Performance of noninvasive tools was assessed using binomial logistic regressions and receiver operating characteristic curve analyses. Quantitative biliary metrics performed well to distinguish abnormal from normal bile ducts (P < 0.0001). Interobserver agreements for MRCP+ dilatation metrics (intraclass correlation coefficient, 0.90-0.96) were superior to modified Amsterdam intrahepatic stricture severity score (κ = 0.74) and Anali score (κ = 0.38). MRCP+ intrahepatic dilatation severity showed excellent performance to classify patients into high-risk and low-risk groups, using predictors of disease severity as the reference (MRS, P < 0.0001; AOM, P = 0.0017; 2.2 × ULN ALP, P = 0.0007; 1.5 × ULN ALP, P = 0.0225; extrahepatic disease, P = 0.0331; dominant stricture, P = 0.0019). MRCP+ intrahepatic dilatation severity was an independent predictor of MRS >0 (odds ratio, 31.3; P = 0.035) in the multivariate analysis. Conclusion: Intrahepatic biliary dilatation severity calculated using MRCP+ is elevated in patients with high-risk PSC and may be used as an adjunct for risk stratification in PSC. This exploratory study has provided the groundwork for examining the utility of novel quantitative biliary metrics in multicenter studies.
| S-EPMC8948671 | biostudies-literature
Project description:A 59-year-old woman who had been diagnosed with cirrhotic primary biliary cholangitis (PBC) 5 years earlier was admitted for severe jaundice (total bilirubin: 30.1 mg/dL). We suspected that her cirrhotic PBC had deteriorated acutely for some reason. Her general condition deteriorated quickly, and she passed away on day 18 of admission. Hepatitis E virus (HEV)-IgA antibodies were positive, and Genotype 3b HEV involvement was confirmed from a blood sample taken on admission. Histopathological findings revealed cirrhosis and submassive loss and necrosis of hepatocytes. Clinicians should consider the possibility of acute HEV infection as a trigger for acute PBC exacerbation.
| S-EPMC8263169 | biostudies-literature
Project description:To describe experience of long QT (LQT) molecular autopsy in sudden infant death syndrome (SIDS).Descriptive audit from two distinct periods: (1) A prospective, population-based series between 2006 and 2008 ('unselected'). (2) Before and after 2006-2008, with testing guided by a cardiac genetic service ('selected'). LQT genes 1, 2, 3, 5, 6 and 7 were sequenced. Next of kin were offered cardiac evaluation.New Zealand.102 SIDS cases.Nil. Main outcome measures Detection of genetic variants.Maori 49 (47%), and Pacific island 24 (23%), infants were over-represented. Risk factors were common; bed sharing was reported in 49%. Rare genetic variants were commoner within the selected than unselected populations (5 of 31 infants (16%) vs 3 of 71 infants (4%) p?<?0.05). In the selected population two infants had variants of definite or probable pathogenicity (KCNQ1, E146K; KCNH2, R1047L), two had novel variants of possible pathogenicity in SCN5A (I795F, F1522Y) and one had R1193Q in SCN5A, of doubtful pathogenicity. R1193Q was also the only variant in the three cases from the unselected population and occurred as a second variant with R1047L. Engaging families proved challenging. Only 3 of 8 (38%) variant-positive cases and 18 of 94 (19%) of variant-negative families participated in cardiac/genetic screening.LQT molecular autopsy has a very low diagnostic yield among unselected SIDS cases where risk factors are common. Diagnostic yield can be higher with case selection. Engagement of the family prior to genetic testing is essential to counsel for the possible uncertainty of the results and to permit family genotype-phenotype cosegregation studies.
| S-EPMC4078670 | biostudies-literature