Pathophysiology of decompensated cirrhosis: Portal hypertension, circulatory dysfunction, inflammation, metabolism and mitochondrial dysfunction.
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ABSTRACT:
SUBMITTER: Engelmann C
PROVIDER: S-EPMC9272511 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundAlthough several risk factors for erectile dysfunction may be present in patients with cirrhosis, data on the actual prevalence and cause of erectile dysfunction is limited. The International Index of Erectile Function-5 (IIEF-5) is a well-validated survey to determine the presence and severity of erectile dysfunction in men. We assessed (i) the prevalence and severity of erectile dysfunction, and (ii) risk factors for erectile dysfunction in patients with cirrhosis.MethodsIn this prospective study, erectile dysfunction was defined as: absent (>21 IIEF-5-points), mild (12-21) and severe (5-11). Patients with overt hepatic encephalopathy, active alcohol abuse, extrahepatic malignancy, previous urologic surgery, previous liver transplantation and severe cardiac conditions were excluded.ResultsAmong n = 151 screened patients, n = 41 met exclusion criteria and n = 30 were sexually inactive. Thus, a final number of n = 80 male patients with cirrhosis were included. Patient characteristics: age: 53 ± 9 years; model for end-stage liver disease score (MELD): 12.7 ± 3.9; Child-Pugh score (CPS) A: 30 (37.5%), B: 35 (43.8%), C: 15 (18.7%); alcohol: 38 (47.5%), viral: 25 (31.3%), alcohol/viral: 7 (8.8%) and others: 10 (12.5%). The presence of erectile dysfunction was found in 51 (63.8%) patients with 44 (55%) and 7 (8.8%) suffering from mild-to-moderate and moderate-to-severe erectile dysfunction. Mean MELD and hepatic venous pressure gradient (HVPG) were significantly higher in patients with erectile dysfunction (P = .021; P = .028). Child-Pugh score C, MELD, creatinine, age, arterial hypertension, diabetes, low libido, low testosterone and high HVPG were associated with the presence of erectile dysfunction. Interestingly, beta-blocker therapy was not associated with an increased risk. In multivariate models, arterial hypertension (OR: 6.36 [1.16-34.85]; P = .033), diabetes (OR: 7.40 [1.31-41.75]; P = .023), MELD (OR: 1.19 [1.03-1.36]; P = .015) and increasing HVPG (n = 48; OR: 1.11 [1.002-1.23]; P = .045) were independent risk factors for the presence of erectile dysfunction.ConclusionAbout two-thirds of male patients with cirrhosis show erectile dysfunction. Severity of liver dysfunction, portal hypertension, arterial hypertension and diabetes were identified as risk factors for erectile dysfunction.
| S-EPMC6766949 | biostudies-literature
Project description:BackgroundIt is unclear whether hepatocyte function and/or portal hypertension improves if a sustained virologic response (SVR) is achieved with direct-acting antivirals in patients with decompensated hepatitis C-related cirrhosis.MethodsWe examined the safety and efficacy of a 12-week course of sofosbuvir/velpatasvir (SOF/VEL) in 20 patients with decompensated hepatitis C-related cirrhosis. We also investigated changes in the hepatocyte receptor index (LHL15) and blood clearance index (HH15) by Tc-99 m-galactosyl human serum albumin scintigraphy, liver stiffness measurement (LSM) by transient elastography, and hepatic venous pressure gradient (HVPG) in patients who achieved an SVR at 24 weeks after treatment (SVR24).ResultsOne patient discontinued treatment because of rectal variceal hemorrhage, and 19 patients completed treatment. SVR24 was achieved in 17 patients (89%). Median LHL15 increased from 0.72 pre-treatment to 0.82 after SVR24 (p = 0.012), and median HH15 decreased from 0.82 pre-treatment to 0.76 after SVR24 (p = 0.010). The percentage of patients with LSM ≥ 20 kPa was 90% before treatment and remained at 90% after SVR24. However, the percentage with severe portal hypertension (defined as HVPG ≥ 12 mmHg) decreased from 92% pre-treatment to 58% after SVR24 (p = 0.046). Patients with a decreased HVPG from pre-treatment to after SVR24 had a smaller pre-treatment spleen volume than those with an increased HVPG (median, 252 vs. 537 mL, p = 0.028).ConclusionAchieving SVR24 with SOF/VEL treatment in patients with decompensated hepatitis C-related cirrhosis can be expected to improve hepatocyte function and portal hypertension on short-term follow-up.
| S-EPMC10049944 | biostudies-literature
Project description:Portal hypertension, defined as increased pressure in the portal vein, develops as a consequence of increased intrahepatic vascular resistance due to the dysregulation of liver sinusoidal endothelial cells (LSECs) and hepatic stellate cells (HSCs), frequently arising from chronic liver diseases. Extrahepatic haemodynamic changes contribute to the aggravation of portal hypertension. The pathogenic complexity of portal hypertension and the unsuccessful translation of preclinical studies have impeded the development of effective therapeutics for patients with cirrhosis, while counteracting hepatic and extrahepatic mechanisms also pose a major obstacle to effective treatment. In this review article, we will discuss the following topics: i) cellular and molecular mechanisms of portal hypertension, focusing on dysregulation of LSECs, HSCs and hepatic microvascular thrombosis, as well as changes in the extrahepatic vasculature, since these are the major contributors to portal hypertension; ii) translational/clinical advances in our knowledge of portal hypertension; and iii) future directions.
| S-EPMC8318926 | biostudies-literature
Project description:Background and aimsCurrent prognostic scores of patients with acutely decompensated cirrhosis (AD), particularly those with acute-on-chronic liver failure (ACLF), underestimate the risk of mortality. This is probably because systemic inflammation (SI), the major driver of AD/ACLF, is not reflected in the scores. SI induces metabolic changes, which impair delivery of the necessary energy for the immune reaction. This investigation aimed to identify metabolites associated with short-term (28-day) death and to design metabolomic prognostic models.MethodsTwo prospective multicentre large cohorts from Europe for investigating ACLF and development of ACLF, CANONIC (discovery, n=831) and PREDICT (validation, n=851), were explored by untargeted serum metabolomics to identify and validate metabolites which could allow improved prognostic modelling.ResultsThree prognostic metabolites strongly associated with death were selected to build the models. 4-Hydroxy-3-methoxyphenylglycol sulfate is a norepinephrine derivative, which may be derived from the brainstem response to SI. Additionally, galacturonic acid and hexanoylcarnitine are associated with mitochondrial dysfunction. Model 1 included only these three prognostic metabolites and age. Model 2 was built around 4-hydroxy-3-methoxyphenylglycol sulfate, hexanoylcarnitine, bilirubin, international normalised ratio (INR) and age. In the discovery cohort, both models were more accurate in predicting death within 7, 14 and 28 days after admission compared with MELDNa score (C-index: 0.9267, 0.9002 and 0.8424, and 0.9369, 0.9206 and 0.8529, with model 1 and model 2, respectively). Similar results were found in the validation cohort (C-index: 0.940, 0.834 and 0.791, and 0.947, 0.857 and 0.810, with model 1 and model 2, respectively). Also, in ACLF, model 1 and model 2 outperformed MELDNa 7, 14 and 28 days after admission for prediction of mortality.ConclusionsModels including metabolites (CLIF-C MET) reflecting SI, mitochondrial dysfunction and sympathetic system activation are better predictors of short-term mortality than scores based only on organ dysfunction (eg, MELDNa), especially in patients with ACLF.
| S-EPMC10359524 | biostudies-literature
Project description:This study is aimed at examining the impact of repeated intraportal autologous bone marrow transfusion (ABMT) in patients with decompensated liver cirrhosis after splenectomy. A total of 25 patients with decompensated liver cirrhosis undergoing splenectomy were divided into ABMT and control groups. The portal vein was cannulated intraoperatively using Celsite Implantofix through the right gastroomental vein. Both groups were given a routine medical treatment. Then, 18?mL of autologous bone marrow was transfused through the port in the patients of the ABMT group 1 week, 1 month, and 3 months after laminectomy, while nothing was given to the control group. All patients were monitored for adverse events. Liver function tests, including serum albumin (ALB), alanine aminotransferase (ALT), total bilirubin (TB), prothrombin activity (PTA), cholinesterase (CHE), ?-fetoprotein (AFP), and liver stiffness measurement (LSM), were conducted before surgery and 1, 3, and 6 months after surgery. Significant improvements in ALB, ALT, and CHE levels and decreased LSM were observed in the ABMT group compared with those in the control group (P < 0.05). TB and PTA improved in both groups but with no significant differences between the groups. No significant changes were observed in AFP in the control group, but it decreased in the ABMT group. No major adverse effects were noted during the follow-up period in the patients of either group. Repeated intraportal ABMT was clinically safe, and liver function of patients significantly improved. Therefore, this therapy has the potential to treat patients with decompensated liver cirrhosis after splenectomy. This trial was registered with the identification number of ChiCTR-ONC-17012592.
| S-EPMC6231388 | biostudies-other
Project description:Caspases play a central role in apoptosis, inflammation, and fibrosis. They produce hemodynamically active, proinflammatory microparticles that cause intrahepatic inflammation, vasoconstriction, and extrahepatic splanchnic vasodilation. Emricasan is a pan-caspase inhibitor that lowers portal hypertension (PH) and improves survival in murine models of cirrhosis. This exploratory study assessed whether emricasan lowers PH in patients with compensated cirrhosis. This multicenter, open-label study enrolled 23 subjects with compensated cirrhosis and PH (hepatic vein pressure gradient [HVPG] >5 mm Hg). Emricasan 25 mg twice daily was given for 28 days. HVPG measurements were standardized and performed before and after emricasan. A single expert read all HVPG tracings. Median age was 59 (range 49-80); 70% were male. Cirrhosis etiologies were nonalcoholic steatohepatitis and hepatitis C virus. Subjects were Child class A (87%) with a median Model for End-Stage Liver Disease score of 8 (range 6-15). Twelve had severe PH (HVPG ≥12 mm Hg). Overall, there was no significant change in HVPG after emricasan (mean [standard deviation, SD] -1.1 [4.57] mm Hg). HVPG decreased significantly (mean [SD] -3.7[4.05] mm Hg; P = 0.003) in those with severe PH: 4/12 had a ≥20% decrease, 8/12 had a ≥10% decrease, and 2/12 HVPG decreased below 12 mm Hg. There were no significant changes in blood pressure or heart rate. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) decreased significantly in the entire group and in those with severe PH. Serum cleaved cytokeratin 18 and caspase-3/7 decreased significantly. Emricasan was well tolerated. One subject discontinued for nonserious adverse events. Conclusion: Emricasan administered for 28 days decreased HVPG in patients with compensated cirrhosis and severe PH; an effect upon portal venous inflow is likely, and concomitant decreases in AST/ALT suggest an intrahepatic anti-inflammatory effect.
| S-EPMC6587783 | biostudies-literature
Project description:Background and aimsHemodynamic response to pharmacotherapy improves survival in patients with cirrhosis post variceal bleeding, but long-term outcomes remain unexplored especially in this part of the world. We aimed to study the long-term impact of portal pressure reduction on liver-related outcomes after index variceal bleed.MethodsPatients with hepatic venous pressure gradient (HVPG) more than 12 mm Hg after index variceal bleed were given non-selective beta-blockers in combination with variceal band ligation. HVPG response was assessed after 4 weeks. Patients were followed up for rebleed events, survival, additional decompensation events and safety outcomes. Rebleed and other decompensations were compared using competing risks analysis, taking death as competing event, and survival was compared using Kaplan-Meier analysis.ResultsForty-eight patients (29 responders and 19 non-responders) were followed up for a median duration of 45 (24-56) months. Rebleeding rates at 1, 3 and 5 years were 10.3%, 20.7% and 20.7% in responders and 15.8%, 44.7% and 51.1% in non-responders, respectively (Gray's test, P = 0.044). Survival rates at 1, 3 and 5 years were 89.7%, 72.1% and 51.9% in responders and 89.5%, 44% and 37.7% in non-responders, respectively (log-rank test, P = 0.1). Both severity of liver disease (MELD score, multivariate sub-distributional hazards ratio: 1.166 [1.014-1.341], P = 0.030) and HVPG non-response (multivariate sub-distributional hazards ratio: 2.476 [1.87-7.030], P = 0.045) predicted rebleeding risk while survival was dependent only on severity of liver disease (MELD > 12, multivariate hazards ratio: 2.36 [1.04-5.38], P = 0.041).ConclusionBaseline severity of liver disease predicted survival and rebleed in these patients. Hemodynamic response, although associated with lower rebleeding rate, had limited impact on survival.
| S-EPMC8267357 | biostudies-literature
Project description:OBJECTIVE:To assess the clinical and haemodynamic effects of carvedilol for patients with cirrhosis and portal hypertension. DESIGN:A systematic review and meta-analysis. DATA SOURCES:We searched PubMed, Cochrane library databases, EMBASE and the Science Citation Index Expanded through December 2015. Only randomised controlled trials (RCTs) were included. OUTCOME MEASURE:We calculated clinical outcomes (all-cause mortality, bleeding-related mortality, upper gastrointestinal bleeding) as well as haemodynamic outcomes (hepatic venous pressure (HVPG) reduction, haemodynamic response rate, post-treatment arterial blood pressure (mean arterial pressure; MAP) and adverse events). RESULTS:12 RCTs were included. In 7 trials that looked at haemodynamic outcomes compared carvedilol versus propranolol, showing that carvedilol was associated with a greater reduction (%) of HVPG within 6?months (mean difference -8.49, 95% CI -12.36 to -4.63) without a greater reduction in MAP than propranolol. In 3 trials investigating differences in clinical outcomes between carvedilol versus endoscopic variceal band ligation (EVL), no significant differences in mortality or variceal bleeding were demonstrated. 1 trial compared clinical outcomes between carvedilol versus nadolol plus isosorbide-5-mononitrate (ISMN), and showed that no significant difference in mortality or bleeding had been found. 1 trial comparing carvedilol versus nebivolol showed a greater reduction in HVPG after 14?days follow-up in the carvedilol group. CONCLUSIONS:Carvedilol may be more effective in decreasing HVPG than propranolol or nebivolol and it may be as effective as EVL or nadolol plus ISMN in preventing variceal bleeding. However, the overall quality of evidence is low. Further large-scale randomised studies are required before we can make firm conclusions. TRIAL REGISTRATION NUMBER:CRD42015020542.
| S-EPMC4861122 | biostudies-other
Project description:Decompensated cirrhosis is a common reason for admission to the acute medical unit, and such patients typically have complex medical needs and are at high risk of in-hospital death. It is therefore vital that these patients receive appropriate investigations and management as early as possible in their patient journey. Typical presenting clinical features include jaundice, ascites, hepatic encephalopathy, hepato-renal syndrome or variceal haemorrhage. A careful history, examination and investigations can help identify the precipitating cause (infections, gastrointestinal bleeding, high alcohol intake / alcohol-related hepatitis or drug-induced liver injury), so appropriate treatment can be given. A 'care bundle' that has been endorsed by the British Society of Gastroenterology is available to help guide the management of patients with decompensated cirrhosis for the first 24 hours and ensure all aspects are addressed. Specific management of complications, such as infections, gastrointestinal bleeding, hepatic encephalopathy and hepatorenal syndrome, are discussed.
| S-EPMC6334027 | biostudies-literature
Project description:Background & aimsInfection is a major problem in advanced liver disease secondary to monocyte dysfunction. Elevated prostaglandin (PG)E2 is a mediator of monocyte dysfunction in cirrhosis; thus, we examined PGE2 signalling in outpatients with ascites and in patients hospitalised with acute decompensation to identify potential therapeutic targets aimed at improving monocyte dysfunction.MethodsUsing samples from 11 outpatients with ascites and 28 patients hospitalised with decompensated cirrhosis, we assayed plasma levels of PGE2 and lipopolysaccharide (LPS); performed quantitative real-time PCR on monocytes; and examined peripheral blood monocyte function. We performed western blotting and immunohistochemistry for PG biosynthetic machinery expression in liver tissue. Finally, we investigated the effect of PGE2 antagonists in whole blood using polychromatic flow cytometry and cytokine production.ResultsWe show that hepatic production of PGE2 via the cyclo-oxygenase 1-microsomal PGE synthase 1 pathway, and circulating monocytes contributes to increased plasma PGE2 in decompensated cirrhosis. Transjugular intrahepatic sampling did not reveal whether hepatic or monocytic production was larger. Blood monocyte numbers increased, whereas individual monocyte function decreased as patients progressed from outpatients with ascites to patients hospitalised with acute decompensation, as assessed by Human Leukocyte Antigen (HLA)-DR isotype expression and tumour necrosis factor alpha and IL6 production. PGE2 mediated this dysfunction via its EP4 receptor.ConclusionsPGE2 mediates monocyte dysfunction in decompensated cirrhosis via its EP4 receptor and dysfunction was worse in hospitalised patients compared with outpatients with ascites. Our study identifies a potential drug target and therapeutic opportunity in these outpatients with ascites to reverse this process to prevent infection and hospital admission.Lay summaryPatients with decompensated cirrhosis (jaundice, fluid build-up, confusion, and vomiting blood) have high infection rates that lead to high mortality rates. A white blood cell subset, monocytes, function poorly in these patients, which is a key factor underlying their sensitivity to infection. We show that monocyte dysfunction in decompensated cirrhosis is mediated by a lipid hormone in the blood, prostaglandin E2, which is present at elevated levels, via its EP4 pathway. This dysfunction worsens when patients are hospitalised with complications of cirrhosis compared with those in the outpatients setting, which supports the EP4 pathway as a potential therapeutic target for patients to prevent infection and hospitalisation.
| S-EPMC8603213 | biostudies-literature