Portal hypertension: not a common Niemann.
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ABSTRACT:
SUBMITTER: Gopalaswamy V
PROVIDER: S-EPMC6904207 | biostudies-literature | 2019 Dec
REPOSITORIES: biostudies-literature
Publications
Portal hypertension: not a common Niemann.
Gopalaswamy Vinaya V Madhyastha Sharath P SP Acharya Raviraja R Manohar Chethan C
BMJ case reports 20191205 12
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Project description:Patients with common variable immunodeficiency (CVID) frequently develop liver disease and associated complications, which represent an increasingly prevalent unmet medical need. The main hepatic manifestation of CVID is nodular regenerative hyperplasia (NRH), resulting in non-cirrhotic portal hypertension (NCPH). Liver disease is often underdiagnosed, leading to poor outcomes and decreased survival. The increasing numbers of patients with CVID who are diagnosed late with progressive liver disease underscores the importance of appropriate clinical management and treatment of liver complications. At the same time, specific guidelines for the clinical management of CVID-related liver disease are still lacking. Here, we review the epidemiology of CVID-related liver disease, reveal new insights into NRH and NCPH biology and highlight recently uncovered opportunities for NCPH diagnostics in CVID. Finally, we focus on current management of liver disease, portal hypertension and its complications - the key challenge in patients with CVID. Specifically, we review recent data regarding the role of transjugular intrahepatic portosystemic shunt and liver transplantation in clinical management. The role for anticoagulants and immunosuppressants targeting the pathogenesis of NRH will also be discussed. We propose an updated algorithm for the diagnostic work-up and treatment of NCPH in CVID. Finally, we consider future needs and therapeutic opportunities for CVID-related liver disease.
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Project description:Portal hypertension (PH) is an important cause of pulmonary arterial hypertension(PAH), but its mechanism is still unclear. We used genetic data analysis to explore the shared genes and molecular mechanisms of PH and PAH. We downloaded the PH and PAH data from the GEO database, and used the weighted gene coexpression network analysis method (WGCNA) to analyze the coexpression modules of idiopathic noncirrhotic portal hypertension (INCPH) and cirrhotic portal hypertension (CPH) and pulmonary hypertension, respectively. Enrichment analysis was performed on the common genes, and differential gene expressions (DEGs) were used for verification. The target genes of INCPH and PAH were obtained by string and cytoscape software, and the miRNAs of target genes were predicted by miRwalk, miRDB, and TargetScan and their biological functions were analyzed; finally, we used PanglaoDB to predict the expression of target genes in cells. In WGCNA, gene modules significantly related to PAH, CPH, and INCPH were identified, and enrichment function analysis showed that the common pathway of PAH and CPH were "P53 signaling pathway," "synthesis of neutral lipids"; PAH and INCPH are "terminal," "Maintenance Regulation of Granules," and "Toxin Transport." DEGs confirmed the results of WGCNA; the common miRNA functions of PAH and cirrhosis were enriched for "P53 signaling pathway," "TGF-β signaling pathway," "TNF signaling pathway," and "fatty acid metabolism," and the miRNAs-mRNAs network suggested that hsa-miR-22a-3p regulates MDM2 and hsa-miR-34a-5p regulates PRDX4; the target genes of PAH and INCPH are EIF5B, HSPA4, GNL3, RARS, UTP20, HNRNPA2B1, HSP90B1, METAP2, NARS, SACM1L, and their target miRNA function enrichment showed EIF5B, HNRNPA2B1, HSP90B1, METAP2, NARS, SACM1L, and HSPA4 are associated with telomeres and inflammation, panglaoDB showed that target genes are located in endothelial cells, smooth muscle cells, etc. In conclusion, the mechanism of pulmonary hypertension induced by portal hypertension may be related to telomere dysfunction and P53 overactivation, and lipid metabolism and intestinal inflammation are also involved in this process.
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Project description:Oxaliplatin has been used as the first choice for the adjuvant chemotherapy of colorectal cancer and it has significantly improved the outcomes in patients with colorectal cancer. However, hepatotoxicity is the potentially problematic adverse effect of oxaliplatin. The pathological evaluation of non-tumoral liver from patients with advanced colorectal cancer undergoing neoadjuvant oxaliplatin-based treatment has provided histological evidence of hepatic sinusoidal injury. Oxaliplatin-induced sinusoidal injury can persist for more than 1 year after the completion of chemotherapy, and the increase in splenic volume may be a predictor of irreversible sinusoidal damage. In this current study, we aim to evaluate the efficacy of individualized treatment in patients with oxaliplatin-induced gastroesophageal varices after colorectal cancer surgery.
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Project description:In India, an unexplained enteropathy is present in a majority of non-cirrhotic intrahepatic portal hypertension (NCIPH) patients. Small intestinal bacterial contamination and tropical enteropathy could trigger inflammatory stimuli and activate the endothelium in the portal venous system. Groundwater contaminated with arsenic is an environmental factor of epidemic proportions in large areas of India which has similar consequences. Von Willebrand factor (a sticky protein) expressed by activated endothelium may promote formation of platelet microthrombi and occlusion of intrahepatic portal vein branches leading to NCIPH. Environmental factors linked to suboptimal hygiene and sanitation, which enter through the gastrointestinal (GI) tract, predispose to platelet plugging onto activated endothelium in portal microcirculation. Thus, NCIPH, an example of poverty linked thrombophilia, is a disease mainly affecting the lower socio-economic strata of Indian population. Public health measures to improve sanitation, provide clean drinking water and eliminate arsenic contamination of drinking water are urgently needed. Till such time as these environmental factors are addressed, NCIPH is likely to remain 'an Indian disease'.
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Project description:Portal hypertension is the cause of the clinical complications associated with cirrhosis. The primary complications of portal hypertension are ascites, acute variceal bleed, and hepatic encephalopathy. Hepatic venous pressure gradient measurement remains the gold standard test for diagnosing cirrhosis-related portal hypertension. Hepatic venous pressure gradient more than 10 mmHg is associated with an increased risk of complications and is termed clinically significant portal hypertension (CSPH). Clinical, laboratory, and imaging methods can also aid in diagnosing CSPH non-invasively. Recently, deep learning methods have been demonstrated to diagnose CSPH effectively. The management of portal hypertension is always individualized and is dependent on the etiology, the availability of therapies, and the degree of portal hypertension complications. In this review, we discuss the diagnosis and management of cirrhosis-related portal hypertension in detail. Also, we highlight the history of portal hypertension and future research areas in portal hypertension.
| S-EPMC9257868 | biostudies-literature
Project description:Portal hypertension develops as a result of increased intrahepatic vascular resistance often caused by chronic liver disease that leads to structural distortion by fibrosis, microvascular thrombosis, dysfunction of liver sinusoidal endothelial cells (LSECs), and hepatic stellate cell (HSC) activation. While the basic mechanisms of LSEC and HSC dysregulation have been extensively studied, the role of microvascular thrombosis and platelet function in the pathogenesis of portal hypertension remains to be clearly characterized. As a secondary event, portal hypertension results in splanchnic and systemic arterial vasodilation, leading to the development of a hyperdynamic circulatory syndrome and subsequently to clinically devastating complications including gastroesophageal varices and variceal hemorrhage, hepatic encephalopathy from the formation of portosystemic shunts, ascites, and renal failure due to the hepatorenal syndrome. This review article discusses: (1) mechanisms of sinusoidal portal hypertension, focusing on HSC and LSEC biology, pathological angiogenesis, and the role of microvascular thrombosis and platelets, (2) the mesenteric vasculature in portal hypertension, and (3) future directions for vascular biology research in portal hypertension.
| S-EPMC7090883 | biostudies-literature
Project description:The interplay between mechanical stimuli and cellular mechanobiology orchestrates the physiology of tissues and organs in a dynamic balance characterized by constant remodelling and adaptative processes. Environmental mechanical properties can be interpreted as a complex set of information and instructions that cells read continuously, and to which they respond. In cirrhosis, chronic inflammation and injury drive liver cells dysfunction, leading to excessive extracellular matrix deposition, sinusoidal pseudocapillarization, vascular occlusion and parenchymal extinction. These pathological events result in marked remodelling of the liver microarchitecture, which is cause and result of abnormal environmental mechanical forces, triggering and sustaining the long-standing and progressive process of liver fibrosis. Multiple mechanical forces such as strain, shear stress, and hydrostatic pressure can converge at different stages of the disease until reaching a point of no return where the fibrosis is considered non-reversible. Thereafter, reciprocal communication between cells and their niches becomes the driving force for disease progression. Accumulating evidence supports the idea that, rather than being a passive consequence of fibrosis and portal hypertension (PH), mechanical force-mediated pathways could themselves represent strategic targets for novel therapeutic approaches. In this manuscript, we aim to provide a comprehensive review of the mechanobiology of PH, by furnishing an introduction on the most important mechanisms, integrating these concepts into a discussion on the pathogenesis of PH, and exploring potential therapeutic strategies.
| S-EPMC10568428 | biostudies-literature
Project description:BackgroundCommon variable immunodeficiency disorder (CVID) manifests with recurrent infections and inflammatory complications, including liver disease. We report the clinical features, natural history, and outcomes of patients with CVID-related liver disease (CVID-rLD) from a tertiary immunology and hepatology center.MethodsTwo hundred eighteen patients were identified; CVID-rLD was defined by persistently abnormal liver function tests or evidence of chronic liver disease (CLD) or portal hypertension (PHTN) by radiological or endoscopic investigation, after exclusion of other causes. Patients with CVID-rLD were investigated and managed following a joint pathway between immunology and hepatology services. Data, including clinical parameters, investigations, and outcomes, were retrospectively collected.ResultsA total of 91/218 (42%) patients had evidence of CVID-rLD, and 40/91 (44%) had PHTN. Patients with CVID-rLD were more likely to have other noninfectious complications of CVID (85/91, 93.4% vs. 75/127, 59.1%, p<0.001) including interstitial lung disease, gut disease, and autoimmune cytopenias. Nodular regenerative hyperplasia (NRH) was identified in 63.8% of liver biopsies, and fibrosis in 95.3%. Liver stiffness measurements (LSMs) were frequently elevated (median 9.95 kPa), and elevated LSM was associated with PHTN. All-cause mortality was higher in those with CVID-rLD (24/91, 26.4% vs. 14/127, 11%, p=0.003), which was the only organ complication associated with mortality (HR 2.24, 1.06-4.74, p=0.04). Factors predicting mortality in CVID-rLD included PHTN, increasing fibrosis, and LSM.ConclusionsLiver disease is a common complication of CVID as part of complex, multi-organ involvement and is associated with high rates of PHTN and an increased hazard of mortality.
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Project description:Idiopathic portal hypertension (IPH) is characterized by portal hypertension due to obstruction or stenosis of the intrahepatic peripheral portal branches. Researchers have suggested that IPH may be attributed to intrahepatic peripheral portal vein thrombosis, splenic factors, abnormal autoimmunity, and related factors, however, the etiology of IPH remains unclear. We used microarrays to identify the functions of genes expressed in blood samples from patients with IPH. In order to examine the specific expression of genes in patients with IPH, we analyzed blood samples from three patients with IPH and three healthy volunteers as control using DNA microarrays.
2015-06-06 | E-GEOD-69601 | biostudies-arrayexpress
Project description:Splenomegaly is caused by several pathological conditions, including portal hypertension, which is most frequently caused by chronic liver disease (e.g., liver cirrhosis). The detailed mechanisms through which portal pressure induces splenomegaly and the precise pathophysiological conditions in portal hypertension-induced splenomegaly remain to be fully elucidated. We used microarrays to identify the differential gene expression underlying the portal hypertension-induced splenomegaly.
2018-11-21 | GSE113613 | GEO