Jens H. Henriksen

Serum YKL-40 is increased in patients with hepatic fibrosis

BACKGROUND/AIMS YKL-40, a mammalian member of the chitinase family, is a lectin that binds heparin and chitin. The function of YKL-40 is unknown, but it may function in tissue remodelling. The aims of this study were to assess the level of circulating YKL-40 in patients with various kinds and degree of chronic liver disease and its possible relation to liver fibrosis. METHODS Serum YKL-40 levels were determined by radioimmunoassay in 129 patients with suspected liver disease and related to histological findings and immunohistochemical staining of YKL-40 in a liver biopsy taken simultaneously with the blood sample. RESULTS The median serum YKL-40 was highest in patients with alcoholic cirrhosis (532 microg/l), in particular in patients with additional alcoholic hepatitis (740 microg/l). Patients with alcoholic cirrhosis, post-hepatitic cirrhosis (425 microg/l) and non-cirrhotic fibrosis (330 microg/l) had significantly higher serum YKL-40 than normal subjects (102 microg/l), patients with fatty liver (195 microg/l) or patients with viral hepatitis without fibrosis (174 microg/l). Serum YKL-40 was significantly (p<0.001) related to the degree of liver fibrosis with the highest levels in patients with moderate (466 microg/l) to severe (676 microg/l) fibrosis. Serum YKL-40 was also increased (p=0.018) in patients with slight fibrosis (270 microg/l) compared to patients without fibrosis. Immunohistochemical analysis demonstrated positive staining for YKL-40 antigen in areas with fibrosis, particularly areas with active fibrogenesis. YKL-40 staining was never found in hepatocytes. CONCLUSIONS Our study indicates that the increased serum YKL-40 in patients with liver disease of various degree and aetiology seems to reflect fibrosis and fibrogenesis.

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, p = 0.03), RBF was lower (352 (SD 232) vs 561 (SD 229) ml/min, p = 0.06), 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%, p = 0.04). Patients with the lowest CI (N = 8) had significantly poorer survival at 3, 9, and 12 months compared to those with a higher CI (N = 16), 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.

Reduced central blood volume in cirrhosis

The pathogenesis of ascites formation in cirrhosis is uncertain. It is still under debate whether the effective blood volume is reduced (underfilling theory) or whether the intravascular compartment is expanded (overflow theory). This problem has not yet been solved because of insufficient tools for measuring the central blood volume. We have developed a method that enables us to determine directly the central blood volume, i.e., the blood volume in the heart cavities, lungs, and central arterial tree. In 60 patients with cirrhosis and 16 control subjects the central blood volume was assessed according to the kinetic theory as the product of cardiac output and mean transit time of the central vascular bed. Central blood volume was significantly smaller in patients with cirrhosis than in controls (mean 21 vs. 27 ml/kg estimated ideal body weight, p less than 0.001; 25% vs. 33% of the total blood volume, p less than 0.0001). The lowest values (18 ml/kg) were found in patients with gross ascites and a reduced systemic vascular resistance. In patients with cirrhosis central blood volume was inversely correlated to the hepatic venous pressure gradient (r = -0.41, p less than 0.01), and the total blood volume was inversely correlated to the systemic vascular resistance (r = -0.49, p less than 0.001), the latter being significantly reduced in the patient group. Patients with cirrhosis apparently are unable to maintain a normal central blood volume. This may be due to arteriolar vasodilation, portosystemic collateral flow, or sequestration of fluid in the peritoneal cavity, or any combination thereof. The present results indicate that central circulatory underfilling is an integral part of the hemodynamic and homeostatic derangement observed in cirrhosis.

Splanchnic and renal elimination and release of catecholamines in cirrhosis. Evidence of enhanced sympathetic nervous activity in patients with decompensated cirrhosis.

Plasma noradrenaline (NA) and adrenaline (A) concentrations were determined in different vascular areas in 32 patients with cirrhosis and in nine controls during a right sided heart, liver, and renal vein catheterisation. The patients were divided into four groups: (I) Compensated (without ascites); (II) Recompensated on diuretic treatment because of former ascites; (III) Decompensated (with ascites) without treatment and (IV) Decompensated on diuretic treatment. Median arterial noradrenaline concentrations were 1.48, 1.07, 2.66, 4.14 and 2.50 nmol/l in controls, group I, II, III, and IV, respectively, the three last mentioned values being significantly raised (p less than 0.01). Median arterial adrenaline concentrations were not significantly increased. In patients arterial-hepatic venous extraction ratios of noradrenaline and adrenaline were on the average 25% (p less than 0.01) and 20% (p less than 0.02) less than those of the controls, indicating a slightly reduced splanchnic elimination of catecholamines in cirrhoses. In controls and group I significant renal venous-arterial noradrenaline differences were absent (0.00 and 0.03 nmol/l) while renal venous-arterial noradrenaline differences were significantly increased in groups II, III and IV (0.47, 0.53 and 0.68 nmol/l, p less than 0.01), indicating a significant net release of noradrenaline from the kidneys in recompensated and decompensated patients. Renal extraction of adrenaline was normal. In conclusion, increased arterial noradrenaline in decompensated and recompensated cirrhosis is only to a limited extent owing to reduced net splanchnic elimination. More likely the increase is caused by release of noradrenaline from the kidneys and possibly other organs indicating enhanced sympathetic nervous tone in these conditions.

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.

Effect of volume expansion on systemic hemodynamics and central and arterial blood volume in cirrhosis

BACKGROUND & AIMS Systemic vasodilatation in cirrhosis may lead to hemodynamic alterations with reduced effective blood volume and decreased arterial blood pressure. This study investigates the response of acute volume expansion on hemodynamics and regional blood volumes in patients with cirrhosis and in controls. METHODS Thirty-nine patients with cirrhosis (12 patients with Child-Turcotte class A, 14 with class B, and 13 with class C) and 6 controls were studied. During hepatic vein catheterization, cardiac output, systemic vascular resistance, central and arterial blood volume, noncentral blood volume, and arterial pressure were determined before and during a volume expansion induced by infusion of a hyperosmotic galactose solution. RESULTS During volume expansion, the central and arterial blood volume increased significantly in patients with class A and controls, whereas no significant change was found in patients with either class B or class C. Conversely, the noncentral blood volume increased in patients with class B and C. In both patients and controls, the cardiac output increased and the systemic vascular resistance decreased, whereas the mean arterial blood pressure did not change significantly. CONCLUSIONS Only in mild cirrhosis is the effective blood volume able to increase in response to volume expansion. Our results are consistent with the peripheral vasodilatation hypothesis and the circulatory hyporeactivity occurring in advanced cirrhosis.

Plasma YKL-40: A New Potential Marker of Fibrosis in Patients with Alcoholic Cirrhosis?

BACKGROUND YKL-40 (human cartilage glycoprotein-39, or 38-kDa heparin-binding glycoprotein) is a mammalian member of a protein family that includes bacterial chitinases. YKL-40 mRNA is expressed by human liver and may play a role in tissue remodelling. The aims were to assess whether circulating YKL-40 is released or extracted in the hepatosplanchnic system and to localize YKL-40 in liver tissue. METHODS Plasma YKL-40 was determined by radioimmunoassay in 25 patients with liver diseases (alcoholic cirrhosis (n = 20), chronic active hepatitis (n = 2), cirrhosis of unknown aetiology (n = 2), and fatty liver (n = 1) and in 18 subjects with normal liver function during a haemodynamic investigation with catheterization of liver vein and the femoral artery. Immunohistochemical studies of the localization of YKL-40 in cryostal liver biopsy specimens were obtained from eight other patients with alcoholic liver disease. RESULTS Plasma YKL-40 was significantly increased in patients with alcoholic cirrhosis (median, 523 micrograms/l; P < 0.001) compared with controls (106 micrograms/l), and plasma YKL-40 in the hepatic vein was higher (P < 0.01) than that of the artery in both the patients and controls, showing release of YKL-40 from the hepatosplanchnic area. The release rate of YKL-40 from the hepatosplanchnic area was higher in patients with liver disease than in controls (11.0 versus 2.1 micrograms/min, P < 0.05). Furthermore, the highest plasma YKL-40 levels were found in patients with a moderate or severe degree of liver fibrosis, and immunohistochemical studies showed positive staining for YKL-40 antigen in areas of the liver biopsy with fibrosis. CONCLUSIONS The increased plasma YKL-40 in patients with alcoholic cirrhosis may reflect the remodelling of liver fibrosis.

Endothelin-1 and endothelin-3 in cirrhosis: Relations to systemic and splanchnic haemodynamics

BACKGROUND/AIMS Endothelins are isopeptides with potent vasoactive properties, but their implications in the hyperkinetic syndrome in cirrhosis are obscure. Therefore, the aim of the present study was to relate hepatic venous and circulating endothelin-1 and endothelin-3 to systemic and splanchnic haemodynamics. METHODS Endothelin-1 and endothelin-3 were measured in samples from a hepatic vein and the femoral artery in 42 patients with cirrhosis, eight hypertensive controls and 10 normotensive controls. RESULTS Hepatic venous endothelin-1 was significantly higher in the patients with cirrhosis, mean 21.2 +/- 0.9 pg/ml (SEM) than in the hypertensive controls, 12.4 +/- 2.4 pg/ml, and normotensive controls, 9.6 +/- 1.6 pg/ml (p < 0.00001). Similarly arterial endothelin-1 was significantly higher in the patients with cirrhosis than in the controls (p < 0.00001). Hepatic venous endothelin-1 was significantly correlated with the hepatic venous pressure gradient (r = 0.61, p < 0.00004), serum creatinine (r = 0.35, p < 0.03), diastolic blood pressure (r = -0.31, p < 0.05), central and arterial blood volume (-0.36, p < 0.05), central circulation time (r = -0.41, p < 0.02), and serum sodium (r = -0.56, p < 0.00002) in the patients with cirrhosis. The hepatosplanchnic release of endothelin-1, assessed as the arteriohepatic-venous difference adjusted for hepatic plasma flow, was higher in the group with cirrhosis, 1.5 +/- 0.4 ng/min, than in the normotensive controls, -0.1 +/- 0.2 ng/min (p < 0.01), and was furthermore correlated to the cardiac output in the group with cirrhosis (r = 0.35, p < 0.04). Hepatic venous endothelin-3 was higher in the patients with cirrhosis, 19.0 +/- 1.4 pg/ml (n = 23), as compared with hypertensive controls, 14.2 +/- 1.3 pg/ml, and normotensive controls, 10.0 +/- 1.4 pg/ml (p < 0.002). The same pattern was found in arterial endothelin-3. Hepatic venous endothelin-3 correlated significantly with central and arterial blood volume (r = 0.56, p < 0.02). The hepatosplanchnic release of endothelin-3 was higher in the patients with cirrhosis, 1.0 +/- 0.7 ng/min, than in the normotensive controls, -0.7 +/- 0.4 ng/min (p = 0.05). CONCLUSIONS In the presence of cirrhosis, hepatic venous and circulating endothelin-1 and endothelin-3 are elevated with significant relations to systemic and splanchnic haemodynamics, and the hepatosplanchnic release of both peptides is increased. This suggests that the endothelin system is implicated in both systemic and portal haemodynamic abnormalities in cirrhosis, although this study does not allow conclusions on causal relationships.

Hepatic blood flow determination: A comparison of 99mTc-diethyl-IDA and indocyanine green as hepatic blood flow indicators in man*

99mTc-diethyl-acetanilide-iminodiacetic acid (IDA) was compared with indocyanine green (ICG) as an indicator of hepatic blood flow (HBF). Twelve subjects (8 with cirrhosis, 2 with fatty liver, one with pancreatitis, and one with intestinal angina) were studied during hepatic vein catheterization. In 9 subjects the HBF measurements (indirect Fick-principle) were within 0.8-1.9 l/min, and no significant difference was observed between the values obtained by ICG and 99mTc-diethyl-IDA (mean 1.24 vs 1.26 l/min, P greater than 0.4). In 2 subjects with cirrhosis very high but almost identical values were found with the two indicators. In one subject ICG could not be measured in plasma because of hyperlipidaemia, but HBF was easily determined by 99mTc-diethyl-IDA. The results indicate that 99mTc-diethyl-IDA can be used as an indicator of HBF. This indicator is not superior to ICG in patients with decreased liver function, but offers advantages in that it can be used with small plasma samples and permits the determination of HBF in the presence of hyperlipidaemia.

Increased circulating calcitonin gene-related peptide (CGRP) in cirrhosis

The etiology of the hyperkinetic circulatory state in cirrhosis is equivocal and reduced peripheral vascular resistance is a major unsolved problem in hepatic pathophysiology. It is therefore sensible to search for vasodilators. A recently discovered neuropeptide, calcitonin gene-related peptide (CGRP), is a highly potent vasodilator. We determined the circulating concentration of immunoreactive CGRP in different vascular beds in 35 patients with cirrhosis and in eight patients with minor disorders. Plasma CGRP was significantly increased in the cirrhotic patients compared with patients with minor disorders (59 vs. 46 pmol/l, p less than 0.01), as well as with 232 healthy persons (37 pmol/l, p less than 0.0001). Moreover, circulating CGRP increased significantly with the severity of cirrhosis (Child-Turcotte group A, 56; group B, 59; group C, 71 pmol/l; p less than 0.025). No significant arterio-venous net extraction or release of CGRP was found across the hepato-intestinal system, kidney, lung or limb. In conclusion, elevated circulating CGRP may play a role in the haemodynamic derangement of cirrhosis. The lack of organ arterio-venous differences suggests a widespread release and degradation of CGRP in many tissues and gives no evidence of decreased degradation as the cause of increased plasma CGRP in patients with cirrhosis.