F. Bendtsen

Long term prognosis of fatty liver: risk of chronic liver disease and death

Background and aims: Fatty liver is a common histological finding in human liver biopsy specimens. It affects 10–24% of the general population and is believed to be a marker of risk of later chronic liver disease. The present study examined the risk of development of cirrhotic liver disease and the risk of death in a cohort diagnosed with pure fatty liver without inflammation. Methods: A total of 215 patients who had a liver biopsy performed during the period 1976–1987 were included in the study. The population consisted of 109 non-alcoholic and 106 alcoholic fatty liver patients. Median follow up time was 16.7 (0.2–21.9) years in the non-alcoholic and 9.2 (0.6–23.1) years in the alcoholic group. Systematic data collection was carried out by review of all medical records. All members of the study cohort were linked through their unique personal identification number to the National Registry of Patients and the nationwide Registry of Causes of Death, and all admissions, discharge diagnoses, and causes of death were obtained. Results: In the non-alcoholic fatty liver group, one patient developed cirrhosis during the follow up period compared with 22 patients in the alcoholic group. Survival estimates were significantly (p<0.01) different between the two groups, for men as well as for women, with a higher death rate in the alcoholic fatty liver group. Survival estimates in the non-alcoholic fatty liver group were not different from the Danish population. Conclusions: This study revealed that patients with type 1 non-alcoholic fatty liver disease have a benign clinical course without excess mortality.

Increased circulating pro-brain natriuretic peptide (proBNP) and brain natriuretic peptide (BNP) in patients with cirrhosis: relation to cardiovascular dysfunction and severity of disease

Background and aims: Cardiac dysfunction may be present in patients with cirrhosis. This study was undertaken to relate plasma concentrations of cardiac peptides reflecting early ventricular dysfunction (pro-brain natriuretic peptide (proBNP) and brain natriuretic peptide (BNP)) to markers of severity of liver disease, cardiac dysfunction, and hyperdynamic circulation in patients with cirrhosis. Patients and methods: Circulating levels of proBNP and BNP were determined in 51 cirrhotic patients during a haemodynamic investigation. Results: Plasma proBNP and BNP were significantly increased in cirrhotic patients (19 and 12 pmol/l, respectively) compared with age matched controls (14 and 6 pmol/l; p<0.02) and healthy subjects (<15 and <5.3 pmol/l; p<0.002). Circulating proBNP and BNP were closely correlated (r = 0.89, p<0.001), and the concentration ratio proBNP/BNP was similar to that of control subjects (1.8 v 2.3; NS). Circulating proBNP and BNP were related to severity of liver disease (Child score, serum albumin, coagulation factors 2, 7, and 10, and hepatic venous pressure gradient) and to markers of cardiac dysfunction (QT interval, heart rate, plasma volume) but not to indicators of the hyperdynamic circulation. Moreover, in multiple regression analysis, proBNP and BNP were also related to arterial carbon dioxide and oxygen tensions. The rate of hepatic disposal of proBNP and BNP was not significantly different in cirrhotic patients and controls. Conclusion: Elevated circulating levels of proBNP and BNP in patients with cirrhosis most likely reflects increased cardiac ventricular generation of these peptides and thus indicates the presence of cardiac dysfunction, rather than being caused by the hyperdynamic circulatory changes found in these patients.

Terlipressin improves renal function in patients with cirrhosis and ascites without hepatorenal syndrome

Patients with advanced cirrhosis and ascites are characterized by circulatory dysfunction with splanchnic vasodilatation and renal vasoconstriction, which often lead to ascites. The vasoconstrictor terlipressin improves renal function in hepatorenal syndrome (HRS). The aim of this study was to evaluate if terlipressin also improves renal function in patients with ascites without HRS. Twenty‐three patients with cirrhosis participated; 15 with nonrefractory ascites were randomized to either terlipressin (N group, n = 11) or a placebo (P group, n = 4), and 8 had refractory ascites and received terlipressin (R group). The glomerular filtration rate (GFR), sodium clearance (CNa), lithium clearance (CLi), osmolal clearance (COsm), and urine sodium concentration (UNa) were assessed before and after the injection of 2 mg of terlipressin or the placebo. GFR increased in the N group (69 ± 19 versus 92 ± 25 mL/min, P < 0.005) and in the R group (31 ± 19 versus 41 ± 31 mL/min, P < 0.05) after terlipressin. In the N group, terlipressin induced an increase in CNa (0.89 ± 0.21 versus 1.52 ± 1.45 mL/min, P < 0.05), CLi (17.3 ± 8.9 versus 21.5 ± 11.6 mL/min, P < 0.05), and COsm (2.10 ± 0.81 versus 3.06 ± 2.0 mL/min, P < 0.05). In the R group, terlipressin induced an increase in CNa (0.11 ± 0.18 versus 0.35 ± 0.40 mL/min, P < 0.05) and CLi (5.5 ± 4.2 versus 9.5 ± 8.55 mL/min, P < 0.05). UNa increased in both groups after terlipressin (P < 0.005). Plasma norepinephrine (P < 0.05) and renin (P < 0.05) decreased after terlipressin. All parameters remained unchanged after the placebo. Conclusion: The vasopressin 1 receptor agonist terlipressin improves renal function and induces natriuresis in patients with cirrhosis and ascites without HRS. Vasoconstrictors may represent a novel future treatment modality for these patients. (HEPATOLOGY 2007.)

Dyssynchronous electrical and mechanical systole in patients with cirrhosis

BACKGROUND/AIMS Previous investigations have shown a prolonged QT interval in some patients with cirrhosis. The aim of this study was to investigate the relation between electrical and mechanical systole in patients with different degrees of severity of cirrhosis. METHODS Forty-eight patients with cirrhosis and portal hypertension, studied during a haemodynamic investigation, were compared to 17 controls. RESULTS A prolonged QTc (above 0.440 s(1/2)) was found in 37% of the cirrhotic patients vs. 5.9% in the controls (P=0.03), and there was a correlation to liver dysfunction (P<0.02). A direct relation between QT and time of mechanical systole (tS) was observed in controls (r=0.58, P<0.01), and cirrhotic patients (r=0.44, P<0.002). In patients with a prolonged QTc interval, the difference between electrical and mechanical systole time was substantially longer than in patients with a normal QTc interval (0.078 vs. 0.031 s, P<0.005). The QT values were related to markers of hyperdynamic circulation (r=-0.48 to 0.56, P<0.05-0.001). CONCLUSIONS; Prolonged repolarization, as evidenced by prolonged QTc, is related to both impaired liver function and systemic circulatory dysfunction. In addition these patients have alterations in the cardiac excitation-contraction relation with compromised association between electrical and mechanical function.

Prognostic variables in patients with cirrhosis and oesophageal varices without prior bleeding.

As identification of patients at risk of bleeding or death is essential for prophylaxis, we determined the prognostic influence of various patient characteristics on the risk of bleeding and death. Fifty-five patients with cirrhosis and oesophageal varices without previous bleeding were included in the study and followed up after an average observation period of 446 days (range: 5-1211 days). A total of 55 clinical, biochemical, haemodynamic, and endoscopic variables were classified as systemic haemodynamic, portal haemodynamic, or metabolic. Using univariate analysis, the following variables showed a significant relation with an increased risk of bleeding or death: high plasma volume (p < 0.02), high azygos blood flow (p < 0.004), elevated hepatic venous pressure gradient (p < 0.02), marked prominence of varices (p < 0.05), poor nutritional status (p < 0.0001), decreased clotting factor 2,7,10 (p < 0.002), poor incapacitation index (p < 0.004), low serum albumin (p < 0.005), increased serum bilirubin (p = 0.05), elevated alkaline phosphatases (p < 0.02), low arterial oxygen saturation (p = 0.02), and encephalopathy (p < 0.007). In a Cox regression model, poor nutritional status (p < 0.00005), increased serum bilirubin (p < 0.001), short central circulation time (p < 0.03), low serum albumin (p < 0.02), and decreased clotting factor 2, 7, 10 (p < 0.05) were independently associated with a higher risk. In conclusion, the results support the prognostic value of metabolic variables as described earlier. The prognostic significance of central circulation time stresses the importance of the hyperdynamic systemic circulation in assessing the increased risk of bleeding or death.(ABSTRACT TRUNCATED AT 250 WORDS)

Systematic review with meta-analysis: the effects of rifaximin in hepatic encephalopathy

Rifaximin is recommended for prevention of hepatic encephalopathy (HE). The effects of rifaximin on overt and minimal HE are debated.

Determinants of the hyperdynamic circulation and central hypovolaemia in cirrhosis

Background Patients with advanced cirrhosis often develop a hyperdynamic circulation with central hypovolaemia. The events that initiate the systemic haemodynamic abnormalities and the coupling of these factors to splanchnic haemodynamics are still unclear. Objective On the basis of a large population of patients with cirrhosis to identify splanchnic and clinical characteristics associated with the development of the hyperdynamic circulation and survival. Methods We included 410 patients with cirrhosis. In all patients, a full haemodynamic investigation was performed. The data were analysed using regression analyses, principal components analyses, and Cox proportional hazards analyses. Results Multivariate regression analyses showed that higher cardiac output was independently associated with higher hepatic venous pressure gradient (HVPG) and higher hepatic blood flow (HBF) (p<0.00001). Higher heart rate was independently associated with presence of ascites and higher HVPG (p<0.0001). Central blood volume and circulation time were independently associated with higher HBF and lower postsinusoidal resistance, respectively (p<0.0001). Systemic vascular resistance was independently associated with lower HVPG (p<0.0001). The final Cox proportional hazards model showed that decreased survival was independently associated with higher age (p=0.003), lower blood haemoglobin concentration (p=0.0006), higher plasma creatinine (p=0.01), higher plasma alkaline phosphatase (p=0.007), lower right atrial pressure (p=0.004), and higher heart rate (p=0.002). Conclusion The development of the hyperdynamic circulation and central hypovolaemia are mainly explained by changes in portal pressure and HBF. Together with indicators of liver dysfunction, central hypovolaemia is associated with poorer prognosis.

eHealth: individualisation of infliximab treatment and disease course via a self‐managed web‐based solution in Crohn's disease

Infliximab (IFX) maintenance therapy for Crohns disease (CD) is administered every 8 weeks, but inter‐patient variation in optimal treatment intervals may exist.

Plasma cystatin C as a marker of renal function in patients with liver cirrhosis

Cystatin C is a low molecular weight protein and the plasma level of cystatin C is mainly determined by glomerular filtration, making cystatin C an endogenous marker of glomerular filtration rate. The aim of the study was to elucidate the applicability of plasma cystatin C as a marker of renal function in patients with liver cirrhosis. Serum cystatin C and creatinine concentrations were compared with creatinine clearance. Thirty-six patients (14 females and 22 males aged between 33 and 81 years) with liver cirrhosis with normal to severely impaired kidney function were included. Plasma cystatin C was measured by an automated particle-enhanced nephelometric immunoassay (Dade Behring Diagnostics) and plasma creatinine by an enzymatic method. Plasma levels of cystatin C and creatinine were found to increase with decreasing values of creatinine clearance. The reciprocal values of cystatin C and creatinine were compared with those for creatinine clearance revealing an r 2 of 0.37 and 0.18, respectively. Comparison of the areas under the curves (AUC ) of the non-parametric receiver-operating characteristic plots for plasma cystatin C (AUC = 0.7364; SE = 0.0929) and plasma creatinine (AUC = 0.6309; SE = 0.1028) revealed a significant difference between plasma cystatin C and plasma levels of creatinine (p-value = 0.03). The results demonstrate that the diagnostic accuracy of plasma cystatin C was better than plasma creatinine in identifying liver cirrhotic patients with reduced glomerular filtration rate.

Vasoactive substances in the circulatory dysfunction of cirrhosis

Patients with cirrhosis and portal hypertension exhibit characteristic haemodynamic changes with a hyperkinetic systemic circulation, abnormal distribution of the blood volume, and neurohumoral dysregulation. Moreover, the circulating levels of several vasoactive substances may be elevated. Splanchnic vasodilatation is of pathogenic significance for the low systemic vascular resistance and abnormal volume distribution, which are important elements in the development of the concomitant cardiac dysfunction, recently termed cirrhotic cardiomyopathy. The systolic and diastolic functions are impaired with direct relation to the degree of liver dysfunction. Significant pathophysiological mechanisms seem to include a reduced beta-adrenergic receptor signal transduction, defective cardiac excitationcontraction coupling, and conductance abnormalities. Various vasodilators, such as nitric oxide and calcitonin gene-related peptide, are among candidates in the vasodilatation and the increased arterial compliance recently described in advanced cirrhosis. Reflex-induced enhanced sympatho-adrenal activity, activation of the renin-angiotensin-aldosterone system, and elevated circulating vasopressin and endothelin-1 are implicated in the haemodynamic counter-regulation in cirrhosis. Recent research has focused on the assertion that the haemodynamic and neurohumoral abnormalities in cirrhosis are part of a general cardiovascular dysfunction influencing the course of the disease, with reduction of organ function and sodium-water retention as the outcome. These aspects are relevant to therapy.