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Esteatosi hepàtica; Hipertensió portal Liver steatosis; Portal hypertension Esteatosis hepática; Hipertensión portal No financial support was received for data analysis or writing assistance. JRE is a PhD student at Universitat Autònoma de Barcelona, Spain. JMP reports having received consulting fees from Boehringer Ingelheim, MSD and Novo Nordisk. He has received speaking fees from Gilead, Intercept, and Novo Nordisk, and travel expenses from Gilead, Rubió, Pfizer, Astellas, MSD, CUBICIN, and Novo Nordisk. He has received educational and research support from Madrigal, Gilead, Pfizer, Astellas, Accelerate, Novartis, Abbvie, ViiV, and MSD. Funds from European Commission/EFPIA IMI2 853966-2, IMI2 777377, H2020 847989, and ISCIII PI19/01898 (PI22/01770). JG has received consulting fees from Boehringer Ingelheim, speaking fees from Echosens and travel expenses from Gilead and Abbie. Funds from ISCIII PI18/00947 and PI21/00691. All other authors: nothing to disclose.

Low plasma sex hormone-binding globulin (SHBG) levels are present in fatty liver disease, which represents a spectrum of diseases ranging from hepatocellular steatosis through steatohepatitis to fibrosis and irreversible cirrhosis. We have previously determined that fat accumulation reduces SHBG production in different nonalcoholic fatty liver disease mouse models. In the present work, we are interested in elucidating the molecular mechanisms reducing SHBG plasma levels in liver fibrosis. For this purpose, in vivo studies were performed using the human SHBG transgenic mice developing liver fibrosis induced by carbon tetrachloride (CCl

582 Background: Ampullary carcinoma (AC) is a rare heterogeneous group of diseases with an abysmal prognosis. Treatment options are limited, and the molecular landscape of this disease and its therapeutic implications have been incompletely explored. Here, we aim to provide a clinical and genomic characterization of AC and explore opportunities for precision oncology. Methods: Patients diagnosed with AC and treated at a single tertiary institution between 2010 and 2022 were reviewed. Molecular profiles were analyzed by applying an in-house exome-targeted panel or the FoundationOne CDx panel. Gene mutations were categorized into molecular pathways and potentially targetable alterations were classified according to the ESCAT scale. Overall survival (OS) and disease-free survival (DFS) were estimated by using the Kaplan-Meier method. Results: We included 64 patients with a median age of 66 years, 51.6% were women, most were classified as pancreatobiliary tumours (PB, 58.3%), followed by intestinal (INT, 33.3%) and mixed histologies (8.3%). 18.8%, 23.4%, 32.8% and 25.0% of the patients were diagnosed at stage I, II, III and IV, respectively. 81.2% of the patients were treated with surgery. The INT subtype was enriched in WNT pathway alterations (28.6 vs 6.2%, p=0.02) and showed a non-significant enrichment in the apoptotic pathway (57.1 vs 34.4%, p=0.08). Conversely, BP showed a non-significant enrichment in HRR pathway alterations (16.7 vs 54.5%, p=0.3). The frequency of KRAS mutations were similar in both subtypes (38.1 vs 37.5%). Potentially actionable molecular alterations were found in 46.7% of the patients (9 ERBB2, 8 HRD, 8 PI3KCA, 2 MSI, 2 BRAF, 2 PTEN and 1 KRAS G12C). Importantly, KRASwt tumours were enriched in potentially targetable alterations (ESCAT I-IIIA), including 20% ERBB2 amplification/mutations, 6% MSI and 3% BRCA1. 6 patients received matched targeted therapies during their disease course, 66% of which responded and 100% stable disease, with a median TTD of 7 months. Conclusions: More than 45% of AC harbor potentially targetable genomic alterations that may provide novel therapeutic opportunities and enhance personalized medicine in this rare disease entity.

Hepatoencephalopathy due to combined oxidative phosphorylation deficiency type 1 (COXPD1) is a recessive mitochondrial translation disorder caused by mutations in GFM1, a nuclear gene encoding mitochondrial elongation factor G1 (EFG1). Patients with COXPD1 typically present hepatoencephalopathy early after birth with rapid disease progression, and usually die within the first few weeks or years of life. We have generated two different mouse models: a Gfm1 knock-in (KI) harboring the p.R671C missense mutation, found in at least 10 patients who survived more than 1 year, and a Gfm1 knock-out (KO) model. Homozygous KO mice (Gfm1

Carcinoma hepatocelular; Elastografía transitoria Carcinoma hepatocel·lular; Elastografia transitòria Hepatocellular carcinoma; Transient elastography Background: The potential role of non-invasive tests (NITs) for liver fibrosis for hepatocellular carcinoma (HCC) prediction remains poorly known. Methods: Retrospective analysis of a NAFLD cohort from a single university hospital in Barcelona, Spain. Incidence rates and cumulative incidence for the overall cohort, as well as cirrhotic and non-cirrhotic patients were calculated. Logistic regression analyses were carried out to investigate risk factors of HCC. Results: From the entire cohort of 1040 patients, 996 patients (95.8%) were analyzed, in whom 35 cases of HCC were detected, of which 26 (72.4%) HCC incident cases were newly diagnosed during a median follow-up of 2.5 (1.9–3.6) years. Two-hundred and thirty-one (23.2%) were cirrhotic at baseline. With the exception of 2 (7.7%) cases of HCC, the rest were diagnosed in cirrhotic patients. Overall HCC cumulative incidence was 9.49 (95% CI 6.4–13.9) per 1000 person-years. The incidence rate for cirrhotic patients was 41.2 (95% CI 27.6–61.6) per 1000 person-years and 0.93 (95% CI 0.23–3.7) per 1000 person-years for patients without cirrhosis. Overall mortality was significantly higher amongst patients with HCC (4.4% vs. 30.8%, p < 0.001). In patients with available liver biopsy (n = 249, 25%), advanced fibrosis (F3–F4) was significantly associated with higher HCC incidence, but not steatosis, lobular inflammation, nor ballooning. In the overall cohort, FIB-4 ≥1.3 (HR 8.46, 95% CI 1.06–67.4, p = 0.044) and older age (HR 1.06, 95% CI 1.01–1.11, p = 0.025) were associated with increasing risk of HCC over time, whereas in cirrhotic patients predictors of HCC included decreasing values of albumin (HR 0.34, 95% CI 0.13–0.87, p = 0.024), platelets (HR 0.98, 95% CI 0.98–0.99, p = 0.001), and increasing values of liver stiffness (HR 1.03, 95% CI 1.00–1.06, p = 0.016). Conclusions: In a Spanish cohort of NAFLD patients, HCC was rare in non-cirrhotic patients. NITs might play a relevant role at predicting HCC. The study was conducted in accordance with the Declaration of Helsinki and approved by the Vall d’Hebron University Hospital Campus Institutional Review Board (study protocol code PR(AG)626/2021).

Context There is emerging evidence that SHBG is substantially reduced in chronic metabolic diseases, including obesity and nonalcoholic fatty liver disease (NAFLD). We have recently reported, through use of in vitro (HepG2 cells) and in vivo (SHBG-C57BL/ksJ-db/db mice) models, that SHBG could play a role in arresting the progression of NAFLD by downregulating lipogenesis. Objective The main aim of this study was to investigate the mechanisms by which SHBG prevents hepatic lipogenesis by examining the relationship between SHBG and a key lipogenic enzyme, such as acetyl-coenzyme A carboxylase (ACC) in the liver of obese persons. Participants and methods SHBG and ACC mRNA levels, as well as triglyceride content, were analyzed in 41 liver samples from nondiabetic obese patients with NAFLD who had undergone bariatric surgery. We also studied the effect of SHBG overexpression in HepG2 cells cultured under high-glucose conditions. Results SHBG mRNA and protein levels were lower in patients with metabolic syndrome than in those without metabolic syndrome; however, these differences were significant only for mRNA level. SHBG mRNA levels correlated positively with SHBG protein levels and hepatic triglyceride content. In addition, SHBG mRNA and protein levels correlated negatively with ACC mRNA levels and triglyceride content. Furthermore, SHBG overexpression abrogated the increase in ACC expression induced by high-glucose treatment in HepG2 cells. Conclusions Our findings suggest that SHBG plays a role in regulating hepatic lipogenesis by reducing ACC levels. These results suggest a strategy for the treatment of NAFLD.

Restoration of kidney tubular epithelium following sublethal injury sequentially involves partial epithelial–mesenchymal transition (pEMT), proliferation, and further redifferentiation into specialized tubule epithelial cells (TECs). Because the immunosuppressant cyclosporine-A produces pEMT in TECs and inhibits the peptidyl-prolyl isomerase (PPIase) activity of cyclophilin (Cyp) proteins, we hypothesized that cyclophilins could regulate TEC phenotype. Here we demonstrate that in cultured TECs, CypA silencing triggers loss of epithelial features and enhances transforming growth factor β (TGFβ)-induced EMT in association with upregulation of epithelial repressors Slug and Snail. This pro-epithelial action of CypA relies on its PPIase activity. By contrast, CypB emerges as an epithelial repressor, because CypB silencing promotes epithelial differentiation, prevents TGFβ-induced EMT, and induces tubular structures in 3D cultures. In addition, in the kidneys of CypB knockout mice subjected to unilateral ureteral obstruction, inflammatory and pro-fibrotic events were attenuated. CypB silencing/knockout leads to Slug, but not Snail, downregulation. CypB support of Slug expression depends on its endoplasmic reticulum location, where it interacts with calreticulin, a calcium-buffering chaperone related to Slug expression. As CypB silencing reduces ionomycin-induced calcium release and Slug upregulation, we suggest that Slug expression may rely on CypB modulation of calreticulin-dependent calcium signaling. In conclusion, this work uncovers new roles for CypA and CypB in modulating TEC plasticity and identifies CypB as a druggable target potentially relevant in promoting kidney repair., Graphical abstract

Cyclophilins (Cyp) are peptidil-prolyl-isomerases and the intracellular receptors for the immunosuppressant Cyclosporine-A (CsA), which produces epithelial-mesenchymal-transition (EMT) and renal tubule-interstitial fibrosis. Since CsA inhibits Cyp enzymatic activity, we hypothesized that Cyp could be involved in EMT and fibrosis. Here, we demonstrate that CypB is a critical regulator of tubule epithelial cell plasticity on the basis that: i) CypB silencing caused epithelial differentiation in proximal tubule-derived HK-2 cells, ii) CypB silencing prevented TGFβ-induced EMT in HK-2, and iii) CypB knockdown mice exhibited reduced UUO-induced inflammation and kidney fibrosis. By contrast, silencing of CypA induces a more undifferentiated phenotype and favors TGFβ effects. EMT mediators Slug and Snail were up-regulated in CypA-silenced cells, while in CypB silencing, Slug, but not Snail, was down-regulated; thus, reinforcing the role of Slug in kidney fibrosis. CypA regulates Slug through its PPIase activity whereas CypB depends on its ER location, where interacts with calreticulin, a calcium modulator which is involved in TGFβ signaling. In conclusion, this work uncovers new roles for CypA and CypB in modulating proximal tubular cell plasticity.

Non-alcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease and is found in 70% of obese people. The evidence available to date suggests that bariatric surgery could be an effective treatment by reducing weight and also by improving metabolic complications in the long term. This work aimed to compare, in a diet-induced NAFLD animal model, the effect of both sleeve gastrectomy (SG) and very-low calorie diet (VLCD). Thirty-five Wistar rats were divided into control rats (n = 7) and obese rats fed a high-fat diet (HFD). After 10 weeks, the obese rats were subdivided into four groups: HFD (n = 7), VLCD (n = 7), and rats submitted to either a sham operation (n = 7) or SG (n = 7). Both liver tissue and blood samples were processed to evaluate steatosis and NASH changes in histology (Oil Red, Sirius Red and HE presence of endothelial damage (CD31, Moesin/p-Moesin, Akt/p-Akt, eNOS/p-eNOS), oxidative stress (iNOS) and fibrosis (αSMA, Col1, PDGF, VEGF) proteins in liver tissue; and inflammatory (IL6, IL10, MCP-1, IL17α, TNFα), liver biochemical function, and hormonal (leptin, ghrelin, visfatin and insulin) alterations in plasma. Both VLCD and SG improved histology, but only SG induced a significant weight loss, improved endothelial damage, and a decreased cardiovascular risk by reducing insulin resistance (IR), leptin, total cholesterol, and triglyceride levels. There were no relevant variations in the inflammatory and fibrosis markers. Our study suggests a slight superiority of SG over VLCD by improving not only the histology but also the IR and cardiovascular risk markers related to NAFLD.

Context: The dynamics of anti-phospholipase A2 antibody titers during treatment could predict clinical responses in patients with membranous nephropathy.Objectives: We analyzed the predictive value of the dynamics of these antibodies on clinical responses.Materials and methods: The serum antibody levels were measured before and during treatment in 79 patients with anti-phospholipase A2 receptor antibody membranous nephropathy treated with two different immunosuppression regimensResults: In both groups of patients, the relative reduction in antibody titers at 3 and 6 months preceded and predicted the clinical responses.Conclusions: Antibody titer dynamics was useful for predicting clinical responses.

4119 Background: AVC is a rare type of cancer with dismal prognosis and limited therapeutic options due to the lack of specific clinical trials. Two histologic subtypes predominate, namely pancreatobiliary and intestinal. A variety of molecular alterations have been described in AVC, but their clinical and therapeutic implications have not been studied in detail. Methods: Retrospective cohort study of patients (pts) diagnosed with AVC treated in our institution from 2010 to 2018. We routinely performed Next Generation Sequencing in all AVC tumors. Our main objectives were to describe the molecular profile of AVC and correlate with clinical outcomes. Results: Out of 26 pts with AVC, 13 pts were male (50%), median age 65 (range 43-83), 7 pts (27%) had stage IV disease at diagnosis. Histologic type was pancreatobiliary in 18 pts (69%), intestinal in 7 pts (27%) and mixed in one case (4%). We identified KRAS mutations (mut) in 10 pts (7 pancreatobiliary, 2 intestinal, 1 mixed), TP53 mut in 6 pts (4/1/1), PIK3CA mut in 3 pts (3/0/0), ERBB2 mut in 3 pts (2/1/0), CTNNB1 mut in 3 pts (2/1/0). In pancreatobiliary we found single cases with RNF43, BRCA1 and CHEK2 mut; while in intestinal we found single cases with NRAS and BRAF mut. One tumor of intestinal subtype had microsatellite instability (MSI). Three pts were included in phase I clinical trials, 2 of them with trials based on tumor profile (ERBB2 mut with pan-HER inhibitor and MSI with immunotherapy). Median overall survival (OS) was 21 months for pts with stage I, II and III disease (95% CI 12.37-not reached) and 13.2 months for stage IV disease at diagnosis (95% CI 5.73-not reached). In cox models, median OS was not dependent on KRAS or TP53 mutation status, or histological subtypes. Conclusions: AVC is a rare type of cancer with two differentiated histological subtypes harboring unique molecular alterations that can be matched to investigational therapies. A broader knowledge of the biology of these tumors is needed to improve patient outcomes.

Aims Restrictive Allograft Syndrome (RAS) and idiopathic pleuroparenchymal fibroelastosis (IPPFE) are two different diseases reported to share the same histology. RAS relates to chronic allograft dysfunction in lung transplantation with IPPFE being a rare condition in native lungs. Our aim is to compare their histologies, alongside biopsies of usual interstitial pneumonia (UIP), to determine if there are differences that might help to elucidate the pathogenesis. Methods and Results We selected 4 post-mortem allograft lungs from patients who developed clear clinical RAS pattern, 5 biopsies diagnosed as IPPFE, 5 UIP biopsies and 5 sections of normal lung. Histopathologic features were described without knowledge of clinical and radiological features. Both RAS allografts and IPPFE biopsies showed intra-alveolar fibrosis and elastosis (IAFE), but RAS allografts also showed concomitant obliterative bronchiolitis, vascular lymphoplasmacytic inflammation within fibro-intimal thickening, less fibroblastic foci at the advancing edge of the fibrosis (1 against 14.4 FF in 2mm2) and a slight reduction of the capillary network compared to UIP (p=0.07) and controls (p=0.06). The main differences seen in UIP were the lack of IAFE and the presence of honeycomb change. Conclusions RAS and PPFE histopathology both show IAFE, but display various differences, particularly in their vascular morphology that may allow further understanding of pathogenesis. This article is protected by copyright. All rights reserved.

Myc, a pleiotropic transcription factor that is deregulated and/or overexpressed in most human cancers, instructs multiple extracellular programs that are required to sustain the complex microenvironment needed for tumor maintenance, including remodeling of tumor stroma, angiogenesis, and inflammation. We previously showed in a model of pancreatic β-cell tumorigenesis that acute Myc activation in vivo triggers rapid recruitment of mast cells to the tumor site and that this is absolutely required for angiogenesis and macroscopic tumor expansion. More-over, systemic inhibition of mast cell degranulation with sodium cromoglycate induced death of tumor and endothelial cells in established tumors. Hence, mast cells are required both to establish and to maintain the tumors. Whereas this intimates that selective inhibition of mast cell function could be therapeutically efficacious, cromoglycate is not a practical drug for systemic delivery in humans, and no other systemic inhibitor of mast cell degranulation has hitherto been available. PCI-32765 is a novel inhibitor of Bruton tyrosine kinase (Btk) that blocks mast cell degranulation and is currently in clinical trial as a therapy for B-cell non–Hodgkin lymphoma. Here, we show that systemic treatment of insulinoma-bearing mice with PCI-32765 efficiently inhibits Btk, blocks mast cell degranulation, and triggers collapse of tumor vasculature and tumor regression. These data reinforce the notion that mast cell function is required for maintenance of certain tumor types and indicate that the Btk inhibitor PCI-32765 may be useful in treating such diseases.

INTRODUCTION AND OBJECTIVES: The number of discarded kidneys for transplantation approaches 25% in the Spanish transplant registry. The main cause(w50%) is the presence of advanced histological lesions in kidney pre-implantation biopsies. Transplants results with expanded criteria donors are poorer than results with standard donors and kidneys with advanced histological lesions are not used in many transplant centers. AIM: To analyze transplant results from deceased donors using pre-implantation biopsies to evaluate expanded donors in our renal transplant unit. METHODS: Since 2009 all kidneys offered to our transplant unit were accepted for clinical examination. A pre-implantation kidney biopsy is obtained in patients with expanded criteria. Pre-implantation biopsies are processed in paraffin and pathologists cathegorizes the biopsies according to the Banff criteria (from 0 to 3). Individual scores are added and a pre-implantation score ranging from 0 to 15 is obtained. In general, kidneys with a pre-implantation donor score > 7 are discarded. An old-for-old policy is applied for kidney allocation with a donor/recipient age difference lower than 15 years. Kidneys with a donor biopsy score >5 were only transplanted in recipients older than 60 years RESULTS: Between 2009 and 2013 we evaluated 404 kidneys and 41 (10%) were discarded. Only 20 kidneys (5%) were discarded due to a pre-implantation biopsy score >7. Thus, 362 transplants were performed and according to our protocol in 254 cases (70%) a pre-implantation biopsy was obtained. Donors with a pre-implantation biopsy were older (61 10 vs. 39 10 years, p 5, n1⁄479) have a similar renal function at 1 year (45 14 vs. 46 15 mL/min) and a similar 5-year graft survival (81.4% vs. 83.5%) than transplants from kidneys with lower scores (1 to 5). CONCLUSIONS: Careful evaluation and selection of deceased donors and renal transplant recipients allows to reduce the number of discarded kidneys (10% in our unit) and to maintain standard transplant results.

A 40-year-old man of Pakistani origin presented with a 2-week history of fever (39.5 8C), malaise and arthralgias. He had been living in Spain for 16 years, and he had not travelled to a foreign country in the prior 4 years. Three days before, conjunctival erythema and multiple painful and violaceous-erythematous nodules (red arrows in Panel B) appeared in both pretibial regions, preventing him from walking because of pain. Physical examination showed bilateral metacarpophalangeal, wrist, knee and ankle arthritis. Ophthalmologic examination showed bilateral anterior scleritis, with preserved visual acuity and without signs of uveitis (Panel A). A chest X-ray study demonstrated bilateral hilar and mediastinal adenopathies (blue arrows in Panel C). He was admitted to the internal medicine ward. Serum angiotensin conversor enzyme levels were normal. Human immunodeficiency virus serologies, Mantoux test, three sputum cultures with Ziehl–Neelsen staining and a bronchoalveolar lavage (BAL) ruled out infectious disease. The CD4/CD8 ratio in the BAL was 2:1. A transbronchial biopsy of an adenopathy showed nonnecrotizing granulomas, without microbiological findings. The patient was diagnosed as a case of sarcoidosis, with the clinical presentation of a Lofgren’s syndrome. Lung alterations corresponded to a stage II pulmonary sarcoidosis. The patient was treated with dexamethasone eye drops and oral dexketoprofen. Scleritis, temperature, joint swelling and arthralgias disappeared, and he was discharged home. Two weeks later, he again developed fever and mild dyspnoea. Lung functional tests were normal, with the exception of a slightly lowered carbon monoxide lung diffusion (71 %), which was normalized after volume correction. After ruling out etiologies different from sarcoidosis, oral prednisone 20 mg/day was administered for a 4-week course as indicated in refractory disease, with total disappearance of symptomology. Adenopathies and parenchymal lung alterations remained stable. Currently, he has completed the treatment, and remains asymptomatic. We have presented a case of sarcoidosis with a typical Lofgren’s syndrome, consisting of hilar adenopathies, erythema nodosum and polyarthralgia or polyarthritis. This syndrome is found more frequently in women, and the course is usually benign often with [1] spontaneous remission. Anterior scleritis is an unusual ophthalmologic finding in sarcoidosis, and it has been related with Lofgren’s syndrome in a few cases [2]. Sporadic case reports [3] describe a good response to corticosteroids, but in this case, the scleritis responded well to non-steroidal antiinflamatory medication. The treatment of sarcoidosis with corticosteroids is not recommended [4] for stage II pulmonary sarcoidosis because 50 % of the untreated patients heal spontaneously. Nevertheless, symptomatic Electronic supplementary material The online version of this article (doi:10.1007/s11739-014-1067-6) contains supplementary material, which is available to authorized users.

Background and objectivesSeveral studies have suggested that activation of the complement system is a contributing pathogenic mechanism in IgA nephropathy (IgAN). C4d staining is an inexpensive and easy-to-perform method for the analysis of renal biopsies. This study aimed to assess the clinical and prognostic implications of C4d staining in IgAN.Design, setting, participants, & measurementsThis retrospective cohort study included 283 patients with IgAN in 11 hospitals in Spain who underwent a renal biopsy between 1979 and 2010. The primary predictor was mesangial C4d staining. Secondary predictors included demographic, clinical, and laboratory characteristics, and Oxford pathologic classification criteria. The primary end point was the cumulative percentage of patients who developed ESRD, defined as onset of chronic dialysis or renal transplantation. C4d was analyzed by immunohistochemical staining using a polyclonal antibody. Kaplan-Meier and Cox proportional hazards analyses were performed to evaluate the effect of C4d staining on renal survival.ResultsThere were 109 patients (38.5%) and 174 patients (61.5%) who were classified as C4d positive and C4d negative, respectively. Renal survival at 20 years was 28% in C4d-positive patients versus 85% in C4d-negative patients (P50%; HR, 4.42; 95% CI, 1.40 to 13.88; P=0.01), and C4d-positive staining (HR, 2.45; 95% CI, 1.30 to 4.64; P=0.01).ConclusionsC4d-positive staining is an independent risk factor for the development of ESRD in IgAN. This finding is consistent with the possibility that complement activation is involved in the pathogenesis of this disease.