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Background and aims The cardiovascular hormones renin/angiotensin/aldosterone (RAA), brain-type natriuretic peptide (BNP)and arginine-vasopressin (AVP) are key regulators of systemic circulatory homeostasis in portal hypertension (PH). We assessed (i) the activation of renin, BNP and AVP across distinct stages of PH and (ii) whether activation of these hormones correlates with clinical outcomes. Methods Plasma levels of renin, proBNP and copeptin (AVP biomarker) were determined in 663 patients with advanced chronic liver disease (ACLD) undergoing hepatic venous pressure gradient (HVPG) measurement at the Vienna General Hospital between 11/2011 and 02/2019. We stratified for Child stage (A–C), HVPG (6–9 mmHg, 10–15 mmHg, ≥ 16 mmHg) and compensated vs. decompensated ACLD. Results With increasing PH, hyperdynamic state was indicated by higher heart rates (6–9 mmHg: median 71.0 [IQR 18.0] bpm, 10–15 mmHg: 76.0 [19.0] bpm, ≥ 16 mmHg: 80.0 [22.0] bpm; p p = 0.032) and lower serum sodium (6–9 mmHg: 139.0 [3.0] mmol/L, 10–15 mmHg: 138.0 [4.0] mmol/L, ≥ 16 mmHg: 138.0 [5.0] mmol/L; p p p = 0.002) and copeptin (7.8 [7.7] vs. 5.6 [8.0] vs. 10.7 [18.6] pmol/L; p = 0.024) increased with severity of PH. Elevated renin levels independently predicted first hepatic decompensation (adjusted hazard ratio [aHR]: 1.69; 95% confidence interval [95% CI] 1.07–2.68; p = 0.025) and mortality in compensated patients (aHR: 3.15; 95% CI 1.70–5.84; p p = 0.046). Elevated copeptin levels predicted mortality in decompensated patients (aHR: 5.77; 95% CI 1.27–26.33; p = 0.024) and in the overall cohort (aHR: 3.29; 95% CI 1.36–7.95; p = 0.008). ProBNP levels did not predict clinical outcomes. Conclusions The cardiovascular hormones renin, proBNP and AVP are activated with progression of ACLD and PH. Renin activation is a risk factor for hepatic decompensation and mortality, especially in compensated patients. Increased plasma copeptin is a risk factor for mortality, in particular in decompensated patients.

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.

Portal hypertension (PH) is responsible for the most severe complications of cirrhosis and leading cause of death and liver transplantation. The standard pharmacological treatment available for PH currently consists of the use of a non-selective beta-blocker. However, a significant proportion of patients do not respond to pharmacological treatment. This has led to the development of identifiable targets for the discovery of new horizons in PH treatment. Recently, there has been significant progress in understanding the mechanism behind PH, which is a product of increased hepatic vascular resistance including structural changes and functional change due to endothelial dysfunction. Moreover, increased portal inflow is the outcome of dilation of splanchnic vessels and hyperdynamic circulation. Here, challenges in formulating potential pharmacological treatment as well as current potential targets for PH will be reviewed. During the past decades, there have been many efforts to explore new techniques to stimulate liver regeneration in addition to pharmacological treatment. The bone marrow (BM) stem cells which differentiate into mature hepatocytes are thought to contribute to liver regeneration and have been found to demonstrate great potential as regenerative medicine in different therapeutic applications. Based on these insights, we explore the current and potential novel therapeutic uses of BM stem cell therapy in PH.

Infections and sepsis are more common in cirrhotic than in the general population and constitute the commonest cause of sudden worsening and death. The diagnosis of systemic inflammatory syndrome and sepsis are challenging in cirrhotics due to an underlying a state of hyperdynamic circulation. Further, poor nutritional and bone marrow reserves lead to modest host immune response, the so called immunoparalysis state and the outcome of antibiotic therapy is suboptimal. In this review, a comprehensive description of current and emerging concepts in the pathogenesis and diagnosis of sepsis with importance to current and novel biomarkers for diagnosis of sepsis in cirrhosis is presented. Furthermore, novel treatment options and preventive strategies are discussed to improve the overall survival.

Acute kidney injury (AKI) is one of the most severe complications of cirrhosis and is associated with significant morbidity and mortality. Liver fibrosis and liver insufficiency, portal hypertension, systemic vasodilation, and a subsequent hyperdynamic circulation undermine the renal and cardiac function, making cirrhotic patients more susceptible to hemodynamic incidents. In addition, the immune system is impaired in cirrhosis, leading to an exaggerated production of vasoactive mediators, and the adrenal cortisol response is insufficient, which causes further impairment of the vascular tonus, cardiac output, and renal perfusion. Consequently, the cardiovascular and renal dysfunction is aggravated, resulting in a hepatorenal syndrome (HRS). HRS is seen exclusively in patients with liver disease and has been considered an entirely functional prerenal dysfunction, rather than a structural dysfunction, but is not responsive to volume expansion. Recent research indicates that development of hepatic nephropathy represents a continuous spectrum of functional and structural dysfunction and may be precipitated by the inherent immunologic, adrenal, and hemodynamic incompetence in cirrhosis. New research explores several new markers of renal dysfunction that may replace serum creatinine in the future and give new insight on the hepatic nephropathy. Our understanding of the pathophysiological mechanisms causing the immunologic, adrenal, and hemodynamic incompetence, and the impact on renal dysfunction, has improved in recent years, and in this review we aim to highlight recent achievements in this field.

For many years, it has been known that impaired liver function and portal hypertension are associated with a pronounced splanchnic vasodilatation. This leads to important circulatory changes with displacement of the circulating blood volume resulting in central hypovolemia [1]. The combination of effective hypovolemia, arterial hypotension, and baroreceptor-activation of potent vasoconstricting systems such as the sympathetic nervous system leads to a hyperdynamic circulation and a multi-organ failure including impaired function of the heart [2]. In a patient with a full-blown decompensated state of cirrhosis, the heart rate and cardiac output are typically increased [1]. Both experimental and clinical studies have shown that the dimensions of the cirrhotic heart are augmented and the contractility and electromechanical function are impaired [3, 4]. This condition has been termed cirrhotic cardiomyopathy, which designates a cardiac dysfunction that includes impaired cardiac contractility with systolic and diastolic dysfunction and electromechanical abnormalities in the absence of other known causes of cardiac disease [4]. Cirrhotic cardiomyopathy can be demasked by physical or pharmacological stress, which may reveal in particular a systolic dysfunction, which seems to contribute to several cirrhotic complications such as the formation of ascites [5, 6] and the development of hepatic nephropathy [7, 8]. Additionally, cirrhotic cardiomyopathy seems associated with the development of heart failure in relation to invasive procedures such as shunt insertion and liver transplantation [9, 10]. Abnormal left ventricular diastolic function, caused by decreased left ventricular compliance and relaxation, implies an abnormal filling pattern of the ventricles. The transmitral blood flow is changed, with an increased atrial contribution to the late ventricular filling [4]. The pathophysiological background of the diastolic dysfunction in cirrhosis is an increased stiffness of the myocardial wall, most likely because of a combination of mild myocardial hypertrophy, fibrosis, and subendothelial edema [2, 3]. The increase in myocardial stiffness is also reflected by other parameters of diastolic dysfunction, such as a prolonged time for the ventricles to relax after diastolic filling at a specific end-diastolic volume, which reflects an increased resistance to the ventricular inflow [4]. Natriuretic peptides are regarded as markers of volume overload and impaired contractility, and are released by stretch of the atrial fibers such as in patients with ascites where the right atrium has been reported increased partly because of volume overload with expanded blood volume [1, 4]. However, the interpretation of increased natriuretic peptides in patients who from a functional point of view suffer from effective hypovolemia is complex. Activation of the renin–angiotensin–aldosterone system (RAAS) is associated with cardiac disease such as hypertrophy and heart failure, and seems to be related to diastolic dysfunction in both cirrhotic and non-cirrhotic patients with portal hypertension [11]. Furthermore, RAAS may induce fibrosis, and there is evidence of relationships between plasma aldosterone and E/A ratio; thus, RAAS may be both directly and indirectly involved in diastolic dysfunction [4]. Echocardiography is the method more frequently utilised for the detection of left ventricular diastolic dysfunction. Diastolic dysfunction is expressed as a decreased S. Moller (&) Department of Clinical Physiology and Nuclear Medicine 239, Faculty of Health Sciences, Hvidovre Hospital, Centre of Functional Imaging and Research, University of Copenhagen, 2650 Hvidovre, Denmark e-mail: soeren.moeller@regionh.dk