Explore the vast range of titles available.

Since the Asian Pacific Association for the Study of the Liver (APASL) published guidelines on non-cirrhotic portal fibrosis/idiopathic portal hypertension in 2007, there has been a surge in new information, especially with the introduction of the term porto-sinusoidal vascular disorder (PSVD). Non-cirrhotic intra-hepatic causes of portal hypertension include disorders with a clearly identifiable etiology, such as schistosomiasis, as well as disorders with an unclear etiology such as non-cirrhotic portal fibrosis (NCPF), also termed idiopathic portal hypertension (IPH). This entity is being increasingly recognized as being associated with systemic disease and drug therapy, especially cancer therapy. An international working group with extensive expertise in portal hypertension was assigned with formulating consensus guidelines to clarify the definition, diagnosis, histological features, natural history, and management of NCPF/IPH, especially in the context of PSVD. The guidelines were prepared based on evidence from existing published literature. Whenever there was paucity of evidence, expert opinion was included after detailed deliberation. The goal of this manuscript, therefore, is to enhance the current understanding and help create global consensus on the issues surrounding NCPF/IPH.

Liver microcirculatory dysfunction is one of the key mechanisms that promotes the progression of chronic liver disease. In this Review, the authors explore the role of liver microcirculatory dysfunction in cirrhotic portal hypertension, the preclinical models used to study liver circulation and potential therapeutics.

Portal hypertension is a major complication of cirrhosis, and its consequences, including ascites, esophageal varices, hepatic encephalopathy, and hepatorenal syndrome, lead to substantial morbidity and mortality. The past several decades have seen major improvements in the clinical management of complications of portal hypertension, resulting in substantial gains in patient outcomes. However, important challenges remain. This review focuses on the pathophysiology and diagnosis of portal hypertension and discusses general approaches in the management of patients with ascites as a result of portal hypertension.

Clinical decompensation of cirrhosis is associated with poor prognosis. Clinically significant portal hypertension (CSPH), defined by a hepatic venous pressure gradient (HVPG) ≥10 mm Hg, is the strongest predictor of decompensation. This study aimed at assessing whether lowering HVPG with β blockers could decrease the risk of decompensation or death in compensated cirrhosis with CSPH. This study on β blockers to prevent decompensation of cirrhosis with portal hypertension (PREDESCI) was an investigator-initiated, double-blind, randomised controlled trial done in eight hospitals in Spain. We enrolled patients with compensated cirrhosis and CSPH without high-risk varices. All participants had HVPG measurements with assessment of acute HVPG-response to intravenous propranolol. Responders (HVPG-decrease ≥10%) were randomly assigned to propranolol (up to 160 mg twice a day) versus placebo and non-responders to carvedilol (≤25 mg/day) versus placebo. Doses were individually determined during an open-label titration period after which randomisation was done with 1:1 allocation by a centralised web-based system. The primary endpoint was incidence of cirrhosis decompensation (defined as development of ascites, bleeding, or overt encephalopathy) or death. Since death in compensated cirrhosis is usually unrelated to the liver, an intention-to-treat analysis considering deaths unrelated to the liver as competing events was done. This study is registered with ClinicalTrials.gov, number NCT01059396. The trial is now completed. Between Jan 18, 2010, and July 31, 2013, 631 patients were evaluated and 201 were randomly assigned. 101 patients received placebo and 100 received active treatment (67 propranolol and 33 carvedilol). The primary endpoint occurred in 16 (16%) of 100 patients in the β blockers group versus 27 (27%) of 101 in the placebo group (hazard ratio [HR] 0·51, 95% CI 0·26–0·97, p=0·041). The difference was due to a reduced incidence of ascites (HR 0·42, 95% CI 0·19–0·92, p=0·03). The overall incidence of adverse events was similar in both groups. Six patients (four in the β blockers group) had severe adverse events. Long-term treatment with β blockers could increase decompensation-free survival in patients with compensated cirrhosis and CSPH, mainly by reducing the incidence of ascites. Spanish Ministries of Health and Economy.

The clinical course of cirrhosis has been typically described by a compensated and a decompensated state based on the absence or, respectively, the presence of any of bleeding, ascites, encephalopathy or jaundice. More recently, it has been recognized that increasing portal hypertension and several major clinical events are followed by a marked worsening in prognosis, and disease states have been proposed accordingly in a multistate model. The development of multistate models implies the assessment of the probabilities of more than one possible outcome from each disease state. This requires the use of competing risks analysis which investigates the risk of several competing outcomes. In such a situation, the Kaplan–Meier risk estimates and the Cox regression may be not appropriate. Clinical states of cirrhosis presently considered as suitable for a comprehensive multistate model include: in compensated cirrhosis, early (mild) portal hypertension with hepatic venous pressure gradient (HVPG) >5 and <10 mmHg, clinically significant portal hypertension (HVPG ≥ 10 mmHg) without gastro-esophageal varices (GEV), and GEV; in decompensated cirrhosis, a first variceal bleeding without other decompensating events, any first non-bleeding decompensation and any second decompensating event; and in a late decompensation state, refractory ascites, sepsis, renal failure, recurrent encephalopathy, profound jaundice, acute on chronic liver failure, all predicting a very short survival. In this review, we illustrate how competing risks analysis and multistate models may be applied to cirrhosis.

The term gut–liver axis is used to highlight the close anatomical and functional relationship between the intestine and the liver. The intestine has a highly specialized epithelial membrane which regulates transport across the mucosa. Due to dysbiosis, impairment of the intestinal barrier and altered immunity status, bacterial products can reach the liver through the portal vein, where they are recognized by specific receptors, activate the immune system and lead to a proinflammatory response. Gut microbiota and bacterial translocation play an important role in the pathogenesis of chronic liver diseases, including alcoholic and non-alcoholic fatty liver disease, cirrhosis, and its complications, such as portal hypertension, spontaneous bacterial peritonitis and hepatic encephalopaty. The gut microbiota also plays a critical role as a modulator of bile acid metabolism which can also influence intestinal permeability and portal hypertension through the farnesoid-X receptor. On the other hand, cirrhosis and portal hypertension affect the microbiota and increase translocation, leading to a “chicken and egg” situation, where translocation increases portal pressure, and vice versa. A myriad of therapies targeting gut microbiota have been evaluated specifically in patients with chronic liver disease. Further studies targeting intestinal microbiota and its possible hemodynamic and metabolic effects are needed. This review summarizes the current knowledge about the role of gut microbiota in the pathogenesis of chronic liver diseases and portal hypertension.

BMP9 (bone morphogenetic protein 9) is a circulating endothelial quiescence factor with protective effects in pulmonary arterial hypertension (PAH). Loss-of-function mutations in BMP9, its receptors, and downstream effectors have been reported in heritable PAH. To determine how an acquired deficiency of BMP9 signaling might contribute to PAH. Plasma levels of BMP9 and antagonist soluble endoglin were measured in group 1 PAH, group 2 and 3 pulmonary hypertension (PH), and in patients with severe liver disease without PAH. BMP9 levels were markedly lower in portopulmonary hypertension (PoPH) versus healthy control subjects, or other etiologies of PAH or PH; distinguished PoPH from patients with liver disease without PAH; and were an independent predictor of transplant-free survival. BMP9 levels were decreased in mice with PH associated with CCl -induced portal hypertension and liver cirrhosis, but were normal in other rodent models of PH. Administration of ALK1-Fc, a BMP9 ligand trap consisting of the activin receptor-like kinase-1 extracellular domain, exacerbated PH and pulmonary vascular remodeling in mice treated with hypoxia versus hypoxia alone. BMP9 is a sensitive and specific biomarker of PoPH, predicting transplant-free survival and the presence of PAH in liver disease. In rodent models, acquired deficiency of BMP9 signaling can predispose to or exacerbate PH, providing a possible mechanistic link between PoPH and heritable PAH. These findings describe a novel experimental model of severe PH that provides insight into the synergy between pulmonary vascular injury and diminished BMP9 signaling in the pathogenesis of PAH.

Portal pulmonary hypertension (PoPH), a severe complication of portal hypertension (PHTN), is marked by elevated pulmonary arterial pressure, but its pathophysiological mechanisms are unclear. This study used proteomics to identify differentially expressed proteins (DEPs) and genes in Patients with PoPH compared to those with PHTN and healthy controls (HC), aiming to uncover potential biomarkers for diagnosis and treatment. Patients with liver cirrhosis and PHTN, admitted between January 2023 and May 2024, were classified into PoPH and non-PoPH (PHTN) groups based on echocardiography. Serum from 12 PoPH, 12 PHTN, and 6 HC was analyzed using data-independent acquisition (DIA) proteomics to identify DEPs. Protein-protein interaction (PPI) networks identified key DEPs, and ELISA was performed for biomarker validation. Compared to HC, 374 proteins were upregulated and 115 downregulated in PoPH, while 18 were upregulated and 38 downregulated in PHTN. KEGG and GO analyses linked DEPs to immune response, metabolism, and cell signaling. Thirty-five proteins distinguish PoPH from HC and PHTN. Vitronectin (VTN, P04004) was correlated with RDW ( R = -0.56, P  < 0.01) and PLT ( R  = 0.52, P  < 0.01). ELISA confirmed lower VTN levels in PoPH ( P  < 0.05). This study identified 35 serum proteins involved in PoPH, with VTN as a potential biomarker for distinguishing PoPH from PHTN and HC. Further research is needed to explore these findings.

Idiopathic non-cirrhotic portal hypertension (INCPH) is a rare disease characterized of intrahepatic portal hypertension in the absence of cirrhosis or other causes of liver disease and splanchnic venous thrombosis. The etiology of INCPH can be classified in five categories: 1) immunological disorders (i.e. association with common variable immunodeficiency syndrome, connective tissue diseases, Crohn’s disease, etc.), 2) chronic infections, 3) exposure to medications or toxins (e.g. azathioprine, 6- thioguanine, arsenic), 4) genetic predisposition (i.e. familial aggregation and association with Adams-Oliver syndrome and Turner disease) and 5) prothrombotic conditions (e.g. inherited thrombophilias myeloproliferative neoplasm antiphospholipid syndrome). Roughly, INCPH diagnosis is based on clinical criteria and the formal exclusion of any other causes of portal hypertension. A formal diagnosis is based on the following criteria: 1) presence of unequivocal signs of portal hypertension, 2) absence of cirrhosis, advanced fibrosis or other causes of chronic liver diseases, and 3) absence of thrombosis of the hepatic veins or of the portal vein at imaging. Patients with INCPH usually present with signs or symptoms of portal hypertension such as gastro-esophageal varices, variceal bleeding or splenomegaly. Ascites and/or liver failure can occur in the context of precipitating factors. The development of portal vein thrombosis is common. Survival is manly limited by concomitant disorders. Currently, treatment of INCPH relies on the prevention of complications related to portal hypertension, following current guidelines of cirrhotic portal hypertension. No treatment has been studied aimed to modify the natural history of the disease. Anticoagulation therapy can be considered in patients who develop portal vein thrombosis.

Advanced fibrosis and portal hypertension influence short-term mortality. Lipocalin 2 (LCN2) regulates infection response and increases in liver injury. We explored the role of intrahepatic LCN2 in human alcoholic hepatitis (AH) with advanced fibrosis and portal hypertension and in experimental mouse fibrosis. We found hepatic LCN2 expression and serum LCN2 level markedly increased and correlated with disease severity and portal hypertension in patients with AH. In control human livers, LCN2 expressed exclusively in mononuclear cells, while its expression was markedly induced in AH livers, not only in mononuclear cells but also notably in hepatocytes. Lcn2 −/− mice were protected from liver fibrosis caused by either ethanol or CCl 4 exposure. Microarray analysis revealed downregulation of matrisome, cell cycle and immune related gene sets in Lcn2 −/− mice exposed to CCl 4 , along with decrease in Timp1 and Edn1 expression. Hepatic expression of COL1A1 , TIMP1 and key EDN1 system components were elevated in AH patients and correlated with hepatic LCN2 expressio n. In vitro , recombinant LCN2 induced COL1A1 expression. Overexpression of LCN2 increased HIF1A that in turn mediated EDN1 upregulation. LCN2 contributes to liver fibrosis and portal hypertension in AH and could represent a new therapeutic target.