Aleksander Krag

Low cardiac output predicts development of hepatorenal syndrome and survival in patients with cirrhosis and ascites.

Objectives: Recent studies suggest that cardiac dysfunction precedes development of the hepatorenal syndrome. In this follow-up study, we aimed to investigate the relation between cardiac and renal function in patients with cirrhosis and ascites and the impact of cardiac systolic function on survival. Patients and design: Twenty-four patients with cirrhosis and ascites were included. Cardiac function was investigated by gated myocardial perfusion imaging (MPI) for assessment of cardiac index (CI) and cardiac volumes. The renal function was assessed by determination of glomerular filtration rate (GFR) and renal blood flow (RBF) and the patients were followed up for 12 months. Results: In patients with a CI below 1.5 l/min/m2 on MPI, GFR was lower (39 (SD 24) vs 63 (SD 23) ml/min, pu200a=u200a0.03), RBF was lower (352 (SD 232) vs 561 (SD 229) ml/min, pu200a=u200a0.06), and serum creatinine was higher (130 (SD 46) vs 78 (SD 29) μmol/l, p<0.01). The number of patients who developed hepatorenal syndrome type 1 within 3 months was higher in the group with low CI than in the high CI group (43% vs 5%, pu200a=u200a0.04). Patients with the lowest CI (Nu200a=u200a8) had significantly poorer survival at 3, 9, and 12 months compared to those with a higher CI (Nu200a=u200a16), p<0.05. In contrast, the Model for End-stage Liver Disease (MELD) score failed to predict mortality in these patients. Conclusions: The development of renal failure and poor outcome in patients with advanced cirrhosis and ascites seem to be related to a cardiac systolic dysfunction. Other parameters may be more important than MELD score to predict prognosis.

Novel serological neo-epitope markers of extracellular matrix proteins for the detection of portal hypertension

The hepatic venous pressure gradient (HVPG) is an invasive, but important diagnostic and prognostic marker in cirrhosis with portal hypertension (PHT). During cirrhosis, remodelling of fibrotic tissue by matrix metalloproteinases (MMPs) is a permanent process generating small fragments of degraded extracellular matrix (ECM) proteins known as neoepitopes, which are then released into the circulation.

Meta-analysis: the safety and efficacy of vaptans (tolvaptan, satavaptan and lixivaptan) in cirrhosis with ascites or hyponatraemia.

Vaptans may correct hyponatraemia and mobilise ascites through an increased excretion of water. The effect on clinical outcomes is debated.

Treatment of acute variceal bleeding

UNLABELLEDnThe management of variceal bleeding remains a clinical challenge with a high mortality. Standardisation in supportive and new therapeutic treatments seems to have improved survival within the last 25 years. Although overall survival has improved in recent years, mortality is still closely related to failure to control initial bleeding or early re-bleeding occurring in up to 30-40% of patients. Initial procedures are to secure and protect the airway, and administer volume replacement to stabilize the patient. Treatment with vasoactive drugs should be started as soon as possible, since a reduction in portal pressure is associated with a better control of bleeding and may facilitate later endoscopic procedures. Vasopressin and its analogues Terlipressin and somatostatin and analogues are the two types of medicine, which has been evaluated. In meta-analysis, only Terlipressin have demonstrated effects on control of bleeding and on mortality. Somatostatin and its analogues improve control of bleeding, but show in meta-analysis no effects on mortality. Approximately 20% of patients with variceal bleeding will suffer from an infection, when they are hospitalized. Invasive procedures will further increase the risk of bacterial infections. Meta-analysis of clinical trials comparing antibiotics with placebo demonstrates that antibiotic prophylaxis improves survival with 9% (p<0.004). Quinolones or intravenous cephalosporins should be preferred. Early endoscopy should be performed in patients with major bleeding. Endoscopic therapy increases control of bleeding and decreases the risks of rebleeding and mortality. Ligation is probably more effective than sclerotherapy with fewer complications and should therefore be preferred, if possible. In case of gastric variceal bleeding, tissue adhesives should be used.nnnIN CONCLUSIONnImprovements in resuscitation and prevention of complications have together with introduction of vasoactive drugs and refinement of endoscopic therapy majorily changed the prognosis of the patient presenting with variceal bleeding.

The cardiorenal link in advanced cirrhosis

A considerable number of patients with advanced cirrhosis develop a hepatorenal syndrome. The pathogenesis involves liver dysfunction, splanchnic vasodilatation, and activation of vasoconstrictive systems. There are now several observations that indicate a relation between the renal failure and impaired cardiac function in patients with advanced cirrhosis. Cirrhotic cardiomyopathy has been described as a condition with impaired contractile responsiveness to stress and altered diastolic relaxation. We propose a cardiorenal interaction in patients with advanced cirrhosis and renal dysfunction that refers to a condition where cardiac dysfunction in cirrhosis is a major determinant of kidney function and survival. Thus, the relation between cardiac dysfunction and renal insufficiency should be target for future studies and development of new treatments should focus on ameliorating the cardiac dysfunction.

Cardiac dysfunction in cirrhosis - does adrenal function play a role? A hypothesis

Cirrhotic cardiomyopathy (CCM), a condition of unknown pathogenesis, is characterized by suboptimal ventricular contractile response to stress, diastolic dysfunction and QT interval prolongation. It is most often found in patients with advanced cirrhosis. It is clinically relevant during stressful conditions, such as sepsis, bleeding and surgery. CCM reverses after liver transplantation and potentially has a role in the pathogenesis of hepatorenal syndrome. In adrenal insufficiency (AI), cardiac dysfunction is a feature with low ejection fraction, decreased left ventricular chamber size and electrocardiographic abnormalities, including QT interval prolongation. With optimal diagnostic tests, AI is present in approximately 10% of patients with cirrhosis, particularly in those with advanced disease. Down‐regulation and decreased number of beta‐adrenergic receptors, and high catecholamine levels are common to both cardiac conditions. Thus, AI may play a role in CCM. Steroid replacement therapy reverses cardiac changes in AI, and may do so for CCM, with important therapeutic implications; this needs formal evaluation.

Pulmonary dysfunction and hepatopulmonary syndrome in cirrhosis and portal hypertension

Background: Pulmonary dysfunction including the hepatopulmonary syndrome (HPS) is an important complication to cirrhosis and portal hypertension. However, the precise relation to liver dysfunction and the prevalence of HPS are unclear.

Efficacy and safety of terlipressin in cirrhotic patients with variceal bleeding or hepatorenal syndrome.

Terlipressin is an analog of the natural hormone arginine-vasopressin. It is used in the treatment of patients with cirrhosis and bleeding esophageal varices (BEV) and in patients with hepatorenal syndrome (HRS): two of the most dramatic and feared complications of cirrhosis. Terlipressin exerts its main pharmacological effect through stimulation of vasopressin-1 receptors. These receptors are located in vascular smooth muscle and mediate vasoconstriction. In patients with cirrhosis and portal hypertension, treatment with terlipressin increases mean arterial pressure and decreases portal flow and pressure within minutes of administration. Furthermore, in patients with ascites terlipressin improves glomerular filtration and excretion of sodium. Terlipressin decreases failure of initial hemostasis by 34%, decreases mortality by 34%, and is considered a first-line treatment for BEV, when available. Terlipressin in combination with albumin reverses type 1 HRS in 33%–60% of cases and is the only treatment with proven efficacy in randomized trials. The safety profile is favorable when considering the clinical efficacy and the high mortality of these clinical entities. Adverse events are mostly cardiovascular and related to vasoconstriction. Mortality and withdrawal of terlipressin due to adverse events occurs in less than 1% of cases. Mild adverse events related to terlipressin treatment occur in 10%–20% of patients. The benefit, however, of terlipressin on long-term survival in HRS remains to be determined. At present, treatment with terlipressin and albumin is considered the most efficient therapy and should therefore be recommended for the treatment of type 1 HRS-1.

The heart and the liver.

Cardiac failure affects the liver and liver dysfunction affects the heart. Chronic and acute heart failure can lead to cardiac cirrhosis and cardiogenic ischemic hepatitis. These conditions may impair liver function and treatment should be directed towards the primary heart disease and seek to secure perfusion of vital organs. In patients with advanced cirrhosis, physical and/or pharmacological stress may reveal a reduced cardiac performance with systolic and diastolic dysfunction and electrophysical abnormalities, termed cirrhotic cardiomyopathy. Pathophysiological mechanisms include reduced β-adrenergic receptor signal transduction and defective cardiac electromechanical coupling. However, the QT interval is prolonged in approximately half of patients with cirrhosis and it may be improved by β-blockers. No specific therapy can be recommended but it should be supportive and directed against the heart failure. Transjugular intrahepatic portosystemic shunt insertion and liver transplantation affect cardiac function in portal hypertensive patients and cause stress to the cirrhotic heart, with a risk of perioperative heart failure. The risk and prevalence of coronary artery disease are increasing in cirrhotic patients and since perioperative mortality is high, careful evaluation of such patients with dobutamine stress echocardiography, coronary angiography and myocardial perfusion imaging is required prior to liver transplantation. Future research should focus on beneficial effects of treatment on cardiac function and mortality.

The recent reduction in mortality from bleeding oesophageal varices is primarily observed from Days 1 to 5

Background: Several new treatments of bleeding oesophageal varices (BOV) have been introduced during the last 25 years; among these are vasoactive drugs, improved endoscopic techniques and prophylactic antibiotics.