14 research outputs found

    Evaluation of MEN1 risk in individuals bearing the R171Q polymorphism

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    Menin ist ein 65 kDa großes Tumorsuppressor- Protein, das ubiquitär exprimiert wird und hauptsächlich im Zellkern lokalisiert ist. Mutationen und andere Veränderungen dieses Gens sind mit dem familiären multiplen endokrinen Neoplasie Syndrom Typ 1 (MEN1) assoziiert. Personen mit diesem Syndrom entwickeln hauptsächlich Tumore der Nebenschilddrüse, Hypophyse und in enteropankreatischen endokrinen Geweben. Zurzeit sind bereits etwa 500 verschiedene Mutationen bekannt die alle zum Verlust der Tumorsuppressorfunktion von Menin führen. Nach Verlust des gesunden Allels entwickeln sich Tumore in mehreren Organen des Patienten. Aber nicht nur Mutationen, sondern auch viele Polymorphismen konnten bis jetzt entdeckt werden. Eine dieser Veränderungen ist ein Nukleotidaustausch von G zu A im Codon 171 im Exon 3 des MEN1- Gens. Dieser Austausch führt zum Einbau der Aminosäure Glutamin anstelle von Arginin. Basierend auf ihrer klinischen Diagnose wurden 98 MEN1- und 128 MEN2- Patienten auf den R171Q- Polymorphismus untersucht. Als Kontrollgruppe wurden 141 CAH- und 33 IDDM- Patienten herangezogen. Zusätzlich zu den genomischen Proben wurde auch Material von 100 endokrinen Tumoren analysiert. Insgesamt wurden 400 Personen untersucht. 171Q wurde 11-mal in heterozygoter Form detektiert (R171Q). „Loss of heterozygosity“ wurde in 2 von 100 Tumorproben identifiziert. In einem neuroendokrinen Pankreastumor wurde das 171Q- Allel verloren, wohingegen in einem Phäochromozytom das 171R- Allel fast nicht mehr detektierbar war. Der R171Q Polymorphismus wurde in ca. 3% der getesteten Personen detektiert und zwar sowohl in der MEN- als auch in der Kontrollpopulation. Dieser Prozentsatz ist in Tumorproben nicht erhöht. Bisherige Publikationen lassen einen Zusammenhang zwischen dem R171Q Polymorphismus und der Entwicklung eines MEN1- Syndroms vermuten. Die Ergebnisse der vorliegenden Diplomarbeit indizieren allerdings, dass R171Q eher einen Polymorphismus mit sehr niedriger Relevanz, als eine MEN1-auslösende Mutation darstellt. Da aber einige der untersuchten Patienten, die diese genetische Veränderung tragen, vielleicht noch zu jung sind um MEN1- assoziierte Symptome aufzuweisen, kann noch keine endgültige Aussage über die Tragweite dieses Polymorphismus getroffen werden.Menin, a 610-amino-acid tumor suppressor protein, is ubiquitously expressed and predominantly found in the cell nucleus. It has been identified in connection with the familial multiple endocrine neoplasia syndrome type I (MEN1). Mutations and alterations of this gene located at chromosome 11 have been the focus of investigations in individuals developing tumors in the parathyroid, the pituitary gland and enteropancreatic endocrine tissues. Approximately 500 different germline mutations that cause loss of the tumor suppressor function have been identified. Tumor formation occurs after loss of the remaining wild- type allele. Not only mutations but also several nucleotide polymorphisms have been found. One of them represents the non-synonymous nucleotide exchange of G to A in codon 171 in exon 3. This exchange leads to integration of the amino acid glutamine instead of arginine. Based on their suspected diagnosis 98 MEN1- and 128 MEN2-patients were analysed in comparison to a control population (141 CAH and 33 IDDM patients) with respect to the R171Q variation in the MEN1 gene. In addition, 100 different endocrine tumors derived from potential MEN1 or MEN2 target organ sites were studied. 400 individuals were tested at the germline level. 171Q was found in 11 individuals in heterozygous form and was not linked to a specific disease. Loss of heterozygosity was identified in 2 tumors and - most important - both alleles were alternatively undergoing LOH. The R171Q polymorphism is found in about 3% of the tested individuals in patients with suspected MEN1 or MEN2 as well as in individuals of our control population. This percentage is not increased in tumors. Previous literature indicates a possible role of the R171Q polymorphism in the development of a MEN1 syndrome. The results present in this diploma thesis underline that the R171Q alteration rather represents a polymorphism with lower relevance than a MEN1-causing mutation. But since some of the subjects carrying the R171Q polymorphism might be currently too young to develop a MEN1 related tumor, a final conclusion cannot be drawn yet. Clinical follow up of those carriers could reveal further knowledge in this respect and is suggested

    Total area of spontaneous portosystemic shunts independently predicts hepatic encephalopathy and mortality in liver cirrhosis

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    Background & Aims: Spontaneous portosystemic shunts (SPSS) frequently develop in liver cirrhosis. Recent data suggested that the presence of a single large SPSS is associated with complications, especially overt hepatic encephalopathy (oHE). However, the presence of >1 SPSS is common. This study evaluates the impact of total cross-sectional SPSS area (TSA) on outcomes in patients with liver cirrhosis. Methods: In this retrospective international multicentric study, CT scans of 908 cirrhotic patients with SPSS were evaluated for TSA. Clinical and laboratory data were recorded. Each detected SPSS radius was measured and TSA calculated. One-year survival was the primary endpoint and acute decompensation (oHE, variceal bleeding, ascites) was the secondary endpoint. Results: A total of 301 patients (169 male) were included in the training cohort. Thirty percent of all patients presented with >1 SPSS. A TSA cut-off of 83 mm2 was used to classify patients with small or large TSA (S-/L-TSA). Patients with L-TSA presented with higher model for end-stage liver disease score (11 vs. 14) and more commonly had a history of oHE (12% vs. 21%, p <0.05). During follow-up, patients with L-TSA experienced more oHE episodes (33% vs. 47%, p <0.05) and had lower 1-year survival than those with S-TSA (84% vs. 69%, p <0.001). Multivariate analysis identified L-TSA (hazard ratio 1.66; 95% CI 1.02–2.70, p <0.05) as an independent predictor of mortality. An independent multicentric validation cohort of 607 patients confirmed that patients with L-TSA had lower 1-year survival (77% vs. 64%, p <0.001) and more oHE development (35% vs. 49%, p <0.001) than those with S-TSA. Conclusion: This study suggests that TSA >83 mm2 increases the risk for oHE and mortality in patients with cirrhosis. Our results support the clinical use of TSA/SPSS for risk stratification and decision-making in the management of patients with cirrhosis. Lay summary: The prevalence of spontaneous portosystemic shunts (SPSS) is higher in patients with more advanced chronic liver disease. The presence of more than 1 SPSS is common in advanced chronic liver disease and is associated with the development of hepatic encephalopathy. This study shows that total cross-sectional SPSS area (rather than diameter of the single largest SPSS) predicts survival in patients with advanced chronic liver disease. Our results support the clinical use of total cross-sectional SPSS area for risk stratification and decision-making in the management of SPSS.Jonel Trebicka is supported by grants from the Deutsche Forschungsgemeinschaft (SFB TRR57, CRC1382), Cellex Foundation and European Union’s Horizon 2020 research and innovation program GALAXY study (No. 668031), LIVERHOPE (No. 731875) and MICROB-PREDICT (No. 825694) and the Cellex Foundation. Joan Genescà is a recipient of a Research Intensification grant from Instituto de Salud Carlos III, Spain. The study was partially funded by grants PI15/00066, and PI18/00947 from Instituto de Salud Carlos III and co-funded by European Union (ERDF/ESF, “Investing in your future”). Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivasis supported by Instituto de Salud Carlos III. Macarena Simón-Talero is a recipient of the grant JR 17/00029 from Instituto de Salud Carlos II

    Der Radiologe / Rolle der bildgebenden Verfahren zur Abklärung von Pneumoniekomplikationen

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    Klinisches Problem Pneumonien sind trotz antimikrobieller Therapien und multidisziplinärer Behandlungsstrategien unverändert mit einer hohen Morbiditäts- und Mortalitätsrate verbunden. Eine Infektion des Respirationstrakts kann zu Komplikationen wie Lungenempyem, -abszess und akutem Lungenversagen führen. Zusätzlich kommt es neben den intrapulmonalen Komplikationen häufig auch zur Beeinträchtigung anderer Organe. Kardiovaskuläre Grunderkrankungen wie Herzinsuffizienz, Arteriosklerose oder Rhythmusstörungen können sich im Rahmen einer Pneumonie entweder neu manifestieren oder infektbedingt verschlimmert werden. Eine frühzeitige Diagnose und Therapie dieser teils lebensbedrohlichen Komplikationen sind entscheidend und beeinflussen den Therapieerfolg maßgeblich. Radiologische Standardverfahren Zu den wichtigsten bildgebenden Verfahren zählen das Lungenröntgen und die Computertomographie des Thorax. Eine eindeutige Charakterisierung der Pathologie ist sowohl im Lungenröntgen als auch in der CT manchmal schwierig oder gar nicht möglich, trotzdem ergeben sich wichtige Hinweise auf intra- und extrapulmonale Komplikationen einer Pneumonie, die mithilfe der Radiologie frühzeitig erkannt werden können. Als zusätzliche portable Untersuchungsmodalität direkt am Patienten eignet sich der Pleuraultraschall zur weiteren Diagnosesicherung und Interventionshilfestellung. Empfehlung für die Praxis Das Lungenröntgen ist sowohl als unkomplizierte initiale Bildgebung als auch zur Kontrolle des Therapieverlaufs wichtig. Bei Verdacht auf Komplikationen, Fortschreiten der Erkrankung oder Diskrepanz zur klinischen Symptomatik sollte eine weiterführende CT des Thorax durchgeführt werden.Clinical issue Despite a considerable number of antimicrobial agents and interdisciplinary treatment options, lower respiratory tract infections are still associated with high morbidity and mortality rates. Infections of the respiratory tract can lead to severe complications, such as empyema, lung abscesses and acute respiratory distress syndrome (ARDS). Besides intrapulmonary complications pneumonia can also impair other organs due to a systemic inflammatory response. Underlying cardiovascular diseases, such as chronic heart failure, arteriosclerosis and dysrhythmia can either deteriorate due to infections or be newly manifested as a result of pneumonia. Early diagnosis and therapy of these sometimes life-threatening complications are crucial and can have a severe impact on disease outcome. Standard radiological methods The most important imaging techniques include chest Xray and computed tomography (CT) of the chest. Although a definite diagnosis is sometimes difficult or even impossible to establish using chest Xray or CT, there are several findings indicative of intrapulmonary or extrapulmonary complications of pneumonia. Another useful and portable tool is thoracic ultrasound directly on the patient, which can be used to further define the underlying disease or as guidance during procedures. Practical recommendations The chest Xray is useful in initial diagnosis and follow-up. If complications or disease progression are suspected or the clinical course differs from the Xray interpretation, a subsequent CT of the chest should be performed.(VLID)349743

    The role of tumor-initiating stem cells in pituitary adenoma formation and cell survival regulation

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    Hypophysenadenome sind vorwiegend gutartige Tumore der Sellaregion. Obwohl sie nur sehr selten infiltrativ und somit maligne werden, sind Hypophysenadenome mit signifikant erhöhter Morbidität und Mortalität assoziiert. Einerseits können diese Tumore durch eine vermehrte Expression von hypophysealen Hormonen die Hormonregulation des Körpers beeinflussen. Andererseits kann die Größenzunahme dieser eigentlich sehr kleinen Drüse benachbarte Strukturen komprimieren oder verdrängen. Da man nur sehr wenig über die Pathogenese von Hypophysentumoren weiß ist auch die Behandlungsbreite gering. Die meisten Adenome werden entweder transphenoidal entfernt, bestrahlt oder mit verschiedenen Medikamenten behandelt. Trotzallem liegt die Wiederauftretensrate bei ca. 50% innerhalb der ersten 10 Jahre. Vor wenigen Jahren hat man auch in der Hypophyse eine Population an adulten Stammzellen entdeckt. Dies bedeutete den Grundstein für die Erforschung von Tumor-initiierenden (Stamm-)zellen in Hypophysenadenomen. Die Theorie der Krebsstammzelle galt bisher nur für maligne Tumoren, könnte nun aber auch für die Hypophysenadenomforschung von großer Bedeutung sein. In der vorliegenden Arbeit wurde der Hedgehogsignalweg, welcher in der Regulierung von Stammzellen eine wichtige Rolle spielt, sowie mehrere Zellzyklusregulatoren und Stammzellmarker in humanen Hypophysenadenomen untersucht. Der Transkriptionsfaktor GLI1 steht an letzter Stelle des Hedgehogweges. Es konnte gezeigt werden, dass der Großteil der Hypophysenadenome GLI1 überexprimieren. Diese Expression war auch in Zusammenhang mit anderen untersuchten Regulationsfaktoren. Inhibierung von GLI1 in murinen Adenomzellen zeigte eine deutliche Reduktion der Zellviabilität als auch der Expression der beschriebenen Zielgene. Auf der anderen Seite zeigte eine Stimulierung des Hedgehogweges vermehrte Zellviabilität und Genexpression. Zusammenfassend weisen die vorliegenden Daten darauf hin, dass eine Aktivierung des Hedgehogweges auf dem Level von GLI1 Hypophysenadenomzellen einen deutlichen Vorteil des Überlebens einbringt und eventuell auch mit der Erhaltung von Tumor-initiierenden Zellen verbunden sein könnte.Pituitary adenomas are tumors originating from the anterior part of the hypophysis. They are slow growing, benign neoplasms that barely become infiltrative or aggressive. Nevertheless, due to either extensive expression of pituitary hormones or compression of adjacent structures they can cause significant morbidity and mortality in affected patients. Even with surgical removal, radiation therapy and specific medications, the relapse rate is about 50% within 10 years. Since the pathogenesis of pituitary adenomas is largely unknown, therapeutic options remain small. The identification of adult stem cells in the pituitary gland brought another aspect into the pituitary adenoma research field. Since stem-like cells seem to play an important role in the development and maintenance of cancer, the question now is whether some sort of stem cells are also involved in the pathogenesis of benign tumors like pituitary adenomas. First evidence of the existence of tumor-initiating stem cells in pituitary adenomas has been established and is now extensively studied. To provide another piece of evidence, this study focused on the stem cell pathway Hedgehog and several stem cell, proliferation and cell cycle markers including SOX2, TP53, SOD1, MKI67 and TLX. This study for the first time shows that transcription factor GLI1 is overexpressed in the majority of investigated human pituitary adenomas. Furthermore, GLI1 expression correlated with the expression of important cellular regulator genes. I could further show that inhibition of the Hedgehog pathway at the level of GLI1 could markedly reduce cell viability and target gene expression in mouse adenoma cells. Activation of the Hedgehog pathway caused the exact opposite effect. In conclusion, my findings indicate a so far unknown ligand-independent Hedgehog signalling pathway with GLI1 playing a major role in cell survival of pituitary adenomas possibly through the regulation of tumor-initiating cells.submitted by Katharina LampichlerAbweichender Titel laut Übersetzung der Verfasserin/des VerfassersMedizinische Universität Wien, Diss., 2018(VLID)296366

    A case report of pseudo-progression after pembrolizumab in metastatic gastric cancer and a review of immunotherapy in gastroesophageal tumors

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    In this report, we present the medical history of a 30-year-old male patient with HER2- and PD-L1-negative metastasized adenocarcinoma of the gastric cardia, who received three cycles of pembrolizumab (200mg every 2 weeks) after the failure of the first-line (1L) treatment with docetaxel, cisplatin, 5fluorouracil (DCF). A restaging computed tomography (CT) scan for the chest and abdomen revealed an apparent progressive disease; therefore, the treatment was terminated. Five months after the termination of the treatment, a new CT scan demonstrated a spontaneous treatment response although no treatment was given during this time period, indicating pseudo-progression of the tumor in the first restaging after three cycles of pembrolizumab. This finding is apparently due to the long-term sustainable immunological effects of pembrolizumab. The current report will present this rare case in more detail and summarize the closed and ongoing clinical trials of immunotherapy drugs in gastroesophageal cancer.(VLID)365613

    Circulating angiopoietin-2 and soluble Tie-2 in type 2 diabetes mellitus: a cross-sectional study

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    <p>Abstract</p> <p>Background</p> <p>Type 2 diabetes is associated with increased levels of Angiopoietin-2 (Ang-2) and soluble Tie-2 (sTie-2), but its impact on vascular disease is still unknown. This study aimed to further explore the associations of Ang-2 and sTie-2 with metabolic control and diabetic complications.</p> <p>Methods</p> <p>In a cross-sectional designed study, levels of Ang-2 and sTie-2 as well as their relationships to cardiometabolic parameters were determined in 80 type 2 diabetic subjects (age 65 ± 7 years, female 47.4%).</p> <p>Results</p> <p>After controlling for age and BMI, Ang-2 levels were associated with levels of sTie-2, diastolic blood pressure, plasma insulin, homeostasis model assessment of insulin resistance (HOMA-IR), creatinine, glomerular filtration rate (GFR), and gamma-glutamyl transferase (GGT) (all p < 0.02). Presence of diabetic macrovascular complications, polyneuropathy and insulin therapy were associated with higher Ang-2 levels (p < 0.05). Conversely, sTie-2 levels were associated with glycated hemoglobin (HbA<sub>1c</sub>), fasting plasma glucose and insulin, HOMA-IR, triglyceride, and liver function parameters (all p < 0.03). Multiple linear regression analysis showed that Ang-2 remained significantly associated only with levels of GGT (p < 0.04), whereas sTie-2 remained significantly associated with HbA<b><sub>1c</sub></b>, insulin levels, and HOMA-IR (p < 0.03). No differences in Ang-2 and sTie-2 levels were observed with regard to gender of participants.</p> <p>Conclusions</p> <p>Ang-2 is independently associated with levels of GGT while sTie-2 is independently associated with levels of HbA<b><sub>1c</sub></b>, plasma insulin and HOMA-IR in type 2 diabetic subjects. Therefore we suggest that the associations of Ang-2 and sTie-2 with type 2 diabetes are based on different patho-physiological mechanisms.</p

    Hepatology Research / Dysbalanced sex hormone status is an independent predictor of decompensation and mortality in patients with liver cirrhosis

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    Aims Endocrinological abnormalities, including low testosterone levels, are prevalent in cirrhosis. We assessed sexual hormone status in regard to hemodynamic abnormalities and its impact on hepatic decompensation and survival. Methods Males with cirrhosis were prospectively included in this study since 2010. Sexual hormones including bioavailable testosterone, total testosterone, luteinizing hormone, folliclestimulating hormone, prolactin, and sex hormonebinding globulin as well as ChildPugh score, Model for Endstage Liver Disease (MELD) score, and hepatic venous pressure gradient were recorded. Sarcopenia was also assessed in patients with available computed tomography scans. Clinical followup for hepatic decompensation, liver transplantation, and death was recorded until May 2017. Results One hundred fourteen male cirrhotic patients were included: age 55 9.4 years, MELD 13.5 (range, 720.7). Etiologies were alcoholic liver disease in 61(53.5%) patients, viral in 30 (26.3%) patients, and other in 23 (20.2%). ChildPugh scores were A in 32 (28.1%) patients, B in 48 (42.1%), and C in 34 (29.8%). Levels of bioavailable testosterone and total testosterone decreased with advanced ChildPugh score (P 12 mmHg). Median bioavailable testosterone (0.25 ng/mL [0.071.7] vs. 0.97 ng/mL [0.152.74)]; P = 0.017) and total testosterone levels (1.28 ng/mL [0.257.32] vs. 4.32 ng/mL [0.4313.47]; P = 0.031) were significantly lower in sarcopenic patients. Median followup was 13 months (0.275 months) and liverrelated events were recorded in 46 patients (40.4%; death, 31 [27.2%]). Low total testosterone was associated with an increased risk for hepatic decompensation and/or death, even after adjusting for ChildPugh score, MELD, and other relevant factors (ChildPugh score model: hazard ratio 2.503, 95% confidence interval, 1.2145.157, P = 0.013; MELD model: hazard ratio 3.065, 95% confidence interval, 1.5236.169, P = 0.002). Conclusion In parallel to increasing severity of cirrhosis, levels of testosterone decline whereas prolactin levels increase. However, low testosterone levels are independently associated with a higher risk for hepatic decompensation and mortality.(VLID)341392

    Wiener klinische Wochenschrift / Anticoagulation in non-malignant portal vein thrombosis is safe and improves hepatic function

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    Background Non-malignant portal vein thrombosis (PVT) is common in patients with advanced liver disease. Anticoagulation (AC) increases the chances of recanalization and may improve liver function in patients with cirrhosis. Aim We retrospectively assessed the course of non-malignant PVT in patients receiving AC. Methods Parameters related to hepatic injury (aspartate aminotransferase [AST]/alanine aminotransferase [ALT]), severity of disease (ascites) and synthesis function (albumin) as well as AC, rates of PVT regression/progression and AC-associated complications were documented. Results Among 122 patients with PVT, 51 patients with non-malignant PVT (27 incomplete, 24 complete) were included, 12 patients (25%) received long-term AC therapy (9 months) as compared to 36 patients without long-term AC. We observed a trend towards higher regression rates with long-term AC of 58% (vs. 28% without AC; p = 0.08) and lower progression rates of 25% (vs. 42% without AC; p = 0.15). In the subgroup of patients with decompensation prior to PVT diagnosis (n = 39), long-term AC (n = 10, 25.6%) resulted in a significantly higher rate of PVT regression/resolution (70% vs. 24%, p = 0.031). Interestingly, AST/ALT tended to decrease (19%/16%) and the proportion of patients with ascites became lower (33%) with long-term AC (without AC: 0%). Furthermore, there was a significant improvement in albumin levels (+9%/+3.6 g/dl) when compared to patients without long-term AC (2%/0.8 g/dl; p = 0.04). Additionally, 10 patients were treated with direct oral anticoagulants (DOACs) for splanchnic vein thrombosis. Importantly, there were no AC-associated bleeding events in patients with conventional AC and one bleeding event in patients with DOAC treatment (10%). Conclusion Our findings support anticoagulation in patients with non-malignant PVT, since AC seems safe and associated with superior PVT regression rates and might also decrease hepatic injury and improve liver synthesis.(VLID)359102

    Evolution of spontaneous portosystemic shunts over time and following aetiological intervention in patients with cirrhosis.

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    BACKGROUND & AIMS Spontaneous portosystemic shunts (SPSS) develop frequently in cirrhosis. Changes over time and the effect of aetiological interventions on SPSS are unknown, so we aimed to explore the effect of these variables on SPSS evolution. METHODS Patients with cirrhosis from the Baveno VI-SPSS cohort were selected provided a follow-up abdominal CT or MRI scan was available. Clinical and laboratory data were collected at baseline and follow-up. Imaging tests were reviewed to evaluate changes in the presence and size of SPSS (large (L)-SPSS was ≥8 mm) over time. Regarding alcohol- or HCV-related cirrhosis, two populations were defined: cured patients (abstinent from alcohol or successful HCV therapy), and non-cured patients. RESULTS A total of 617 patients were included. At baseline SPSS distribution was 22% L-SPSS, 30% small (S)-SPSS, and 48% without (W)-SPSS. During follow-up (median follow-up of 63 months), SPSS distribution worsened: L-SPSS 26%, S-SPSS 32%, and W-SPSS 42% (p <0.001). Patients with worse liver function during follow-up showed a simultaneous aggravation in SPSS distribution. Non-cured patients (n = 191) experienced a significant worsening in liver function, more episodes of liver decompensation and lower transplant-free survival compared to cured patients (n = 191). However, no differences were observed regarding SPSS distribution at inclusion and at follow-up, with both groups showing a trend to worsening. Total shunt diameter increased more in non-cured (52%) than in cured patients (28%). However, total shunt area (TSA) significantly increased only in non-cured patients (74 to 122 mm2, p <0.001). CONCLUSIONS The presence of SPSS in cirrhosis increases over time and parallels liver function deterioration. Aetiological intervention in these patients reduces liver-related complications, but SPSS persist although progression is decreased. IMPACT AND IMPLICATIONS There is no information regarding the evolution of spontaneous portosystemic shunts (SPSS) during the course of cirrhosis, and especially after disease regression with aetiological interventions, such as HCV treatment with direct-acting antivirals or alcohol abstinence. These results are relevant for clinicians dealing with patients with cirrhosis and portal hypertension because they have important implications for the management of cirrhosis with SPSS after disease regression. From a practical point of view, physicians should be aware that in advanced cirrhosis with portal hypertension, after aetiological intervention, SPSS mostly persist despite liver function improvement, and complications related to SPSS may still develop
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