Quantitative defect of glycoprotein ib in severe cirrhotic patients

A decrease of platelet agglutination induced by ristocetin has been described in Cirrhotic patients. In order to investigate the relationship of such phenomenon with a putative defect on piatelet membrane glycoprotein Ib, we have studied the quantitative and functional status of Gp Ib in eleven severe alcoholic cirrhotic patients, and the ability of their formalin-fixed platelets to agglutinate in the presence of normal plasma plus ristocetin. Interestingly, we found a significant decrease of immunoreactive GP Ib molecules (9,978 ± 1,534 vs. 17,064 ± 404 molecules per platelet) and ristocetin-dependent binding of vWF (9,113 ± 1,338 vs. 13,992 ± 1,968 molecules per platelet) (P < 0.01) in comparison to the levels found in a control group of healthy subjects. Immunoblotting analysis of platelet lysates confirmed the reduction of GP Ib level in cirrhotic patients, but showed no modification on the precipitation pattern of this glycoprotein. The ristocetin-induced platelet agglutination (light transmission %) was also significantly lower in patients with Cirrhosis (48 ± 7.6 vs. 92 ± 3.6, P < 0.01), and correlated with the binding of normal vWF (r = 0.863, P = 0.0013). Patients with bleeding times longer than 7 min and/or clinical history of bleeding episodes showed the lowest values of platelet agglutination and GP Ib level. In conclusion, our present results indicate that llver cirrhosis is associated with a relevant decrease of functional GP Ib molecules on the platelet surface. This reduction might be related to the prolongation of bleeding time and to the bleeding diathesis observed in cirrhotic patients. © 1994 Wiley-Liss, Inc.     

Plasma interleukin-8 levels in patients with post-hepatitic cirrhosis: Relationship to severity of liver disease, portal hypertension and hyperdynamic circulation

The present study investigated plasma levels of interleukin-8 (IL-8) in patients with post-hepatitic cirrhosis and correlated it with the severity of liver diseases and haemodynamic parameters. Plasma IL-8 levels were significantly higher in 57 post-hepatitic cirrhotic patients (7.5 ± 1.8 pg/mL; P< 0.005) than those in 41 healthy subjects (2.0 ± 0.2 pg/mL). Elevated (> 5 pg/mL) plasma IL-8 levels were found in up to 30% of cirrhotic patients. In cirrhotic patients, plasma IL-8 levels progressively increased in relation to the severity of liver dysfunction (4.5 ± 1.0, 4.9 ± 1.4 and 20.5 ± 8.3 pg/mL for Pugh's class A, B and C, respectively; P<0.005). A significant correlation was observed between plasma IL-8 levels and serum bilirubin levels (r = 0.72; P<0.001). There were no differences in the hepatic venous pressure gradient (15.4 ± 1.1 vs 15.1 ± 0.9 mmHg; P>0.05) and systemic vascular resistance (1119 ± 118 vs 1199 ± 54 dyn.s/cm⁵; P>0.05) between cirrhotic patients with and without elevated plasma IL-8 levels. In addition, plasma IL-8 levels did not correlate with hepatic venous pressure gradient (r = 0.26; P>0.05) and systemic vascular resistance (r=-0.24; P>0.05). These results demonstrate that plasma IL-8 levels are increased in patients with post-hepatitic cirrhosis. The severity of liver cirrhosis is an important factor for the occurrence of enhanced IL-8 levels. IL-8 does not play a role in the hyperdynamic circulation observed in patients with post-hepatitic cirrhosis.     

Prolonged bleeding time in cirrhotic patients: Relationship to peripheral vasodilation and severity of cirrhosis

Abstract A prolonged bleeding time (>540 s), measured with a Simplate single template device, was found in 0% of 50 patients with chronic hepatitis and 38% of 154 cirrhotic patients. Cirrhotic patients with a prolonged bleeding time (n= 59) had lower platelet counts (P < 0.001) and a longer prothrombin time (P < 0.001) and activated partial thromboplastin time (P < 0.001) compared with cirrhotic patients with a normal bleeding time (n= 95). A weak but significant negative correlation existed between the bleeding time and platelet count in cirrhotic patients (n= 154, r= -0.3668, P < 0.001). Patients with decompensated cirrhosis had a longer bleeding time in comparison to patients with compensated cirrhosis (621±39 vs 478 ± 27 s, respectively, P < 0.01). The prolonged bleeding time was also discovered in 25% of 83 cirrhotic patients with a platelet count >80 × 10⁹/L and a prothrombin time < 17 s (usually taken as safe limits for invasive procedures). Twenty-seven of the 83 cirrhotic patients received a haemodynamic study by Swan-Ganz catheterization. A lower systemic vascular resistance was found in cirrhotic patients with an abnormal bleeding time than in cirrhotic patients with a normal bleeding time (844 ± 57 vs 1171 ± 60 dyne·s·cm^?5, respectively, P < 0.001), whereas both groups had similar hepatic venous pressure gradient (16.2 ± 1.2 vs 18.1 ± 1.4 mmHg, respectively, P > 0.05). There was a significant negative correlation observed between systemic vascular resistance and bleeding time in cirrhotic patients with a platelet count >80 × 10⁹/L and a prothrombin time < 17 s (n= 27, r= -0.63, P < 0.001). These results demonstrate that prolonged bleeding time is common in patients with cirrhosis. Peripheral vasodilation is probably an important factor in addition to platelet counts and the severity of liver disease in determining the bleeding time in cirrhosis.     

Quantification of gluconeogenesis in cirrhosis: Response to glucagon

Background & Aims: Accelerated starvation and early recruitment of alternate fuels in cirrhosis have been attributed to reduced availability of hepatic glycogen. The aim of this study was to measure gluconeogenesis (as a marker of protein oxidation) in relation to total glucose production and glucagon-stimulated glycogenolysis. Methods: Glucose and urea production, gluconeogenesis, and glycogenolysis were calculated using stable isotope methods before and during glucagon infusion (3 ng · kg⁻¹ · min⁻¹) in 5 cirrhotic patients and 5 matched controls before and after glycogen repletion. Results: In the basal state, cirrhotic patients had a normal rate of glucose production, but the contribution of gluconeogenesis was increased (74.3% ± 4.1% vs. 55.6% ± 12.1%; P < 0.005). Glycogen repletion normalized the rate of gluconeogenesis. The glycemic response to glucagon (3 ng · kg⁻¹ · min⁻¹) was blunted in cirrhotic patients because of a lower rate of glycogenolysis (0.63 ± 0.23 vs. 1.22 ± 0.23 mg · kg⁻¹ · min⁻¹; P < 0.01) and was not affected by glycogen repletion. Despite increased gluconeogenesis, the simultaneously measured rate of urea synthesis was lower in cirrhotic patients (3.11 ± 1.02 vs. 5.0 ± 1.0 mg/kg; P < 0.05). Conclusions: These data show that in cirrhosis, glucose production is sustained by an increased rate of gluconeogenesis. The hepatic resistance to glucagon action is not caused by reduced glycogen stores.GASTROENTEROLOGY 1998;115:1530-1540     

Different hemodynamic patterns of alcoholic and viral endstage cirrhosis: Analysis of explanted liver weight,degree of fibrosis and splanchnic Doppler parameters

Objective. In cirrhosis, portal hemodynamics is usually considered independently of the disease etiology. The objective of this study was to investigate the role of the etiology of liver disease on the relationship between liver blood flow and liver pathology in endstage cirrhosis. Material and methods. Portal blood velocity and volume, congestion index of the portal vein, and hepatic and splenic pulsatility indices were evaluated with echo-Doppler in cirrhotic patients immediately before liver transplantation. When a patent paraumbilical vein was present, its blood flow was measured and effective portal liver perfusion was calculated as portal blood flow minus paraumbilical blood flow. The hemodynamic parameters were correlated with liver weight and the pattern of the liver fibrosis morphometrically assessed in explanted livers. A total of 131 patients with alcoholic or viral cirrhosis were included in the study. Results. In alcoholic cirrhosis, liver weight was higher than that in viral disease (1246±295 g versus 1070±254 g, p=0.001), portal liver perfusion per gram of liver tissue was lower (0.49±0.36 ml g^?1 min^?1 versus 0.85±0.56 ml g^?1 min^?1, p=0.004) and hepatic pulsatility indices were higher (1.45±0.31 versus 1.26±0.30, p=0.018). The degree of liver fibrosis was similar in alcoholic and viral cirrhosis (11.7±5.5% versus 11.0±4.4%, p=NS). An inverse relationship between liver weight and Child-Pugh score was disclosed in viral (p<0.001) but not in alcoholic disease. Conclusions. A different hemodynamic pattern characterizes the advanced stage of cirrhosis of alcoholic and viral origin. A more severe alteration of intrahepatic portal perfusion, probably coexisting with a more severe hepatocyte dysfunction, and a higher liver weight can be detected in alcoholic cirrhosis.     

Resting myocardial dysfunction in cirrhosis quantified by tissue Doppler imaging

Background: Cirrhotic cardiomyopathy is described as latent cardiac failure. However, it remains to be investigated whether the myocardial dysfunction is present even at rest. Aims: The aim of the present study was to quantify left ventricular function at rest by means of tissue Doppler imaging in patients with cirrhosis and relate the findings to liver status and cirrhosis aetiology. Methods: Forty‐four consecutive patients and 23 age‐matched healthy controls were included. Conventional echocardiographic‐ and tissue Doppler‐derived indices of systolic and diastolic function were obtained. Liver function was quantified by the galactose elimination capacity and clinical stage by the Child–Pugh and MELD scores. Results: Both systolic and diastolic myocardial functions were compromised in the patients at rest. Left ventricular ejection fraction (56.4 ± 6.1 vs. 59.9 ± 3.9%, P<0.02), mean peak systolic tissue velocity (4.6 ± 0.9 vs. 5.6 ± 0.7 cm/s, P<0.001) and mean systolic strain rate (?1.23 ± 0.19 vs. ?1.5 ± 0.14/s, P<0.001) were all reduced in cirrhosis patients. Thirty‐four patients (54%) had diastolic dysfunction, 11 had impaired diastolic relaxation pattern (25%), 12 had the more severe pseudonormal filling pattern (27%) and one had restrictive filling or severe diastolic dysfunction (2%). None of the echocardiographic findings were related to the cirrhosis aetiology. Conclusion: Tissue Doppler imaging during rest detected substantial systolic and diastolic myocardial dysfunction in cirrhotic patients. This supports the existence of a distinct cirrhotic cardiomyopathy.     

Comparison of transient elastography,serum markers and clinical signs for the diagnosis of compensated cirrhosis

Background and Aims: Non‐invasive diagnosis of compensated cirrhosis is important. We therefore compared liver stiffness by transient elastography, APRI score, AST/ALT ratio, hyaluronic acid and clinical signs to determine which modality performed best at identifying compensated cirrhosis. Methods: Patients undergoing evaluation at a single center were recruited and had clinical, serological, endoscopy, radiological imaging, liver stiffness measurement and liver biopsy. Patients were stratified into cirrhotic and non‐cirrhotic. Results: In 404 patients (124 cirrhosis), transient elastography was diagnostically superior to the other modalities yielding an AUC 0.9 ± 0.04 compared with hyaluronic acid (AUC 0.81 ± 0.04: P < 0.05), clinical signs (AUC 0.74 ± 0.04: P < 0.05), APRI score (AUC 0.71 ± 0.03: P < 0.05) and AST/ALT ratio (AUC 0.66 ± 0.03: P < 0.05). The optimum cut‐off for transient elastography was 12 kPa giving a sensitivity of 89% and specificity of 87% for cirrhosis. In 238 hepatitis C patients (87 cirrhosis), transient elastography yielded an AUC 0.899 ± 0.02 for cirrhosis and in 166 non‐HCV patients (37 cirrhosis) the results were similar with an AUC 0.928 ± 0.03; with transient elastography being superior to HA, APRI, AST/ALT and clinical signs for all etiologies of cirrhosis (P < 0.05 for all). Importantly, transient elastography was statistically superior at identifying cirrhosis in 38 biopsy proven Childs Pugh A cirrhotics with no clinical, biochemical or radiological features of cirrhosis or portal hypertension (AUC 0.87 ± 0.04). Conclusion: Transient elastography accurately identified compensated cirrhosis; a liver stiffness of >12 kPa represents an important clinical measurement for the diagnosis of cirrhosis.     

Hepatic Stellate Cells and Liver Retinoid Content in Alcoholic Liver Disease in Humans

Body retinoids are stored in the lipid droplets of hepatic stellate (Ito) cells. In chronic liver disease, the stellate cells differentiate into myo-fibroblast-like cells, a process whereby they lose their retinoid-con-taining lipid droplets. We studied the relation between liver retinoid content, the number of lipid droplets per stellate cell, and the number of stellate cells per mm² in human alcoholic liver disease. Semithin sections of liver biopsies from normal subjects and patients with early (steatosis, inflammation, and mild fibrosis) and late (cirrhosis and cirrhosis with acute alcoholic hepatitis) alcoholic liver disease were morphometrically evaluated. Liver retinoid content was determined by HPLC. In normal patients, liver retinoid content was 901 ± 213 lU/g of liver (mean ± SEM). There was a decrease in liver retinoid content in early alcoholic liver disease (409 ± 50 IU/g) and a further reduction in cirrhosis (153 ± 50 IU/g). In patients with acute alcoholic hepatitis, retinoid content was strikingly low (5.2 ± 1.8 IU/g). There was a progressive decrease in the number of stellate cells per mm² associated with progressive liver damage. We found a fair correlation between the number of stellate cells per mm² and liver retinoid content in all patient groups (overall correlation: 0.71). In normal subjects, the mean number of lipid droplets per stellate cell was 7.4 ± 0.7. In patients with early alcoholic liver disease and in patients with alcoholic cirrhosis, this value was increased to 13.6 ± 0.8 and 10.4 ± 2.0, respectively. In patients with acute alcoholic hepatitis, only a few lipid droplets were present (4.2 ± 0.5). There was a good correlation between liver retinoid content and mean number of lipid droplets in normal patients (r= 0.58). In alcoholic cirrhosis, however, correlation was poor (r= 0.34). In early alcoholic liver disease, the correlation was absent (r= 0.004). In conclusion, the major finding of our study is that the correlation between the mean number of lipid droplets per stellate cell and liver retinoid content varies according to the hepatic pathology considered. Marked lipid droplet accumulation occurs in stellate cells in early alcoholic liver disease and, to a lesser extent, in alcoholic cirrhosis, but there is no correlation between the mean number of lipid droplets per stellate cell and liver retinoid content. Therefore, not retinoids but probably lipids are responsible for the accumulation of lipid droplets. We also find that there is a fair correlation between the number of stellate cells per mm² and liver retinoid content in all patient groups. Finally, we confirm the decrease in hepatic retinoid content that occurs in alcoholic liver disease in humans, even at the early stages of the disease.     

Hepatocytes of cirrhotic rat liver accumulate glycogen more slowly than normal ones

Purpose

To investigate the accumulation of glycogen in cirrhotic rat liver at several time intervals after per os administration of glucose to fasted animals.

Methods

Liver cirrhosis was produced by inhalation of the hepatotropic poison CCl₄. Glycogen concentration in the liver was determined biochemically. Glycogen content in hepatocytes was measured cytofluorimetrically in the smears stained with a fluorescent PAS reaction. Glycogen content in the hepatocytes of the portal and the central zone of the liver lobule was determined by absorption cytophotometry.

Results

Rats poisoned with CCl₄ for 6 months developed typical liver cirrhosis characterized by a fourfold (p < 0.001) increase in the proportion of the connective tissue. In the cirrhotic rats fasted for 48 h, glycogen concentration in the liver and glycogen content in hepatocytes were lower as compared with the control by 36 and 27 % (p < 0.01), respectively. According to data obtained by different methods, the control animals accumulated glycogen at a high rate. In particular, the glycogen content in hepatocytes increased by 34 % after 10 min (p < 0.01). In the cirrhotic rats, glycogen content remained at the same level for 20 min. In both groups of animals, hepatocytes of the portal zone accumulated more glycogen than those of the central zone.

Conclusions

Glycogen accumulation in cirrhotic rats starts after a delay and proceeds at a lower rate than in the norm.     

Relationship between hepatic blood flow,liver tests,haemodynamic values and clinical characteristics in patients with chronic liver disease*

Although hepatic blood flow (HBF) has been measured in patients with liver disease for many years, the results of these studies have not provided clear information concerning the usefulness of this measurement. Hepatic blood flow was measured in 392 patients with either cirrhosis (n= 356) or hepatic fibrosis (n= 36). The control group included 59 subjects with normal liver architecture. Hepatic clearance of indocyanine green (ICG) was markedly reduced in patients with cirrhosis and hepatic fibrosis compared with controls (182±5, 276±22 and 421±25 mL/min, respectively). In patients with cirrhosis, ICG clearance and extraction were significantly correlated, but were not correlated to HBF. Although HBF did not differ between patients with cirrhosis and controls (1.26±0.04 vs 1.35±0.07 L/min, respectively), patients with hepatic fibrosis had lower HBF (1.04±0.07 L/min; P< 0.05). In patients with cirrhosis, no correlation was observed between HBF and cardiac output, mean arterial pressure, azygos blood flow, the hepatic venous pressure gradient or Pugh's score. However, a significant difference in HBF was observed in patients with and without hepatic encephalopathy (1.00±0.09 vs 1.28±0.03 L/min, respectively; P<0.05). In conclusion, the present study shows that, in patients with cirrhosis, HBF is normal and is not related to other haemodynamic values or liver tests. These results discourage the measurement of HBF in the evaluation of patients with cirrhosis.     

Wedged Hepatic Venous Pressure Does Not Reflect Portal Pressure in Patients with Cirrhosis and Hepatic Veno–Venous Communications

Some cirrhotic patients have hepatic veno–venous communications (HVVC) and large porto-systemic collaterals. However, the relationship between wedged hepatic vein pressure (WHVP) and portal vein pressure (PVP) in such patients is not clear. The aim of this study was to determine the relationships between simultaneously measured WHVP and PVP, and occluded hepatic and splenic portal venography in 100 cirrhotic patients (40 alcoholic and 60 hepatitis C virus (HCV)-related cirrhosis). PVP and WHVP were closely related in both groups (alcoholic-cirrhosis: 27.8 ± 4.7 and 27.5 ± 4.8 mmHg, HCV-cirrhosis: 27.3 ± 3.7 and 26.2 ± 4.4 mmHg, respectively). Occluded hepatic venography revealed that 13 of the 100 patients had HVVC (alcoholic-cirrhosis: 4, HCV-cirrhosis: 9). In patients with HVVC, PVP (27.9 ± 3.0 mmHg) was significantly higher than WHVP (21.9 ± 3.3 mmHg, P < 0.001). Large porto-systemic collaterals did not affect the relationship. We conclude that HVVC affects the relationship between PVP and WHVP. When WHVP is measured, occluded hepatic venography should be examined to detect HVVC.     

Hepatic Venous Pressure Gradient in Cirrhosis: Correlation with the Size of Varices, Bleeding, Ascites, and Child's Status

The hepatic venous pressure gradient (HVPG) clearly reflects portal pressure in cirrhotic portal hypertension. Its relation with variceal bleeding has been well studied. We undertook to study the relation of HVPG to variceal size, Child's status, and etiology of cirrhosis. Patients with cirrhotic portal hypertension with esophageal varices underwent HVPG measurement as part of a prospective evaluation. One hundred seventy-six cirrhotics with varices (M:F, 140:36; mean age, 42.6 ± 13.4 years), 104 with CLD related to viral etiology, 40 with alcoholic liver disease, 26 cryptogenic with cirrhosis, and 6 with miscellaneous causes of CLD underwent HVPG measurement. The mean HVPG was lower in patients with small varices (n = 77; 14.6 ± 5.9 mm Hg) than in patients with large varices (n = 99; 19.2 ± 6.6 mm Hg; P < 0.01). In patients with large varices, the mean HVPG in bleeders (n = 37) was higher than in nonbleeders (n = 62) (21.7 ± 7.2 vs 17.9 ± 6.2 mm Hg; P < 0.01). The mean HVPG was significantly higher in Child's B (n = 97; 17.4 ± 6.9 mm Hg) and C (n = 56; 19.0 ± 5.7 mm Hg) compared to Child's A cirrhotics (n = 23; 12.2 ± 5.9 mm Hg; P < 0.01), and Child's C compared to Child's B cirrhotics (P = 0.05). HVPG was higher in alcoholic compared to nonalcoholic cirrhotics (20.8 ± 7.3 vs 16.4 ± 6.3 mm Hg; P < 0.05), but this was not significant in multivariate analysis. The HVPG was comparable between hepatitis B- and hepatitis C virus-related cirrhotics (P = 0.8). Cirrhotics with ascites had a higher HVPG than those without ascites (18.5 ± 5.6 vs 16.6 ± 7.6 mm Hg; P = 0.02). In multivariate analysis, only Child's status, size of varices, and variceal bleed predicted higher HVPG. HVPG is higher in cirrhotics with large varices and a history of bleed. There is a good correlation between HVPG and large varices, bleeder status, and ascites. A higher HVPG reflects more severe liver disease. The etiology of liver disease did not influence the portal pressure.     

A non-invasive method for evaluating cirrhotic portal hypertension by administration of 99mTc-MIBI per rectum

Abstract A study was performed to evaluate radio-isotopic imaging using technetium-99m hexakis 2-meth-oxyisobutyl isonitrile administered per rectum to assess portal collateral circulation. The heart-liver ratios (H/L; mean ± standard deviation) in 15 controls, 13 cases of histologically confirmed viral hepatitis and 57 cirrhosis patients were 0.27 ± 0.11, 0.43 ± 0.14 and 1.00 ± 0.28, respectively (P < 0.001). Among the cirrhosis patients those with the Child-Pugh classification A, B and C had H/L of 0.56 ± 0.14, 1.00 ± 0.20 and 1.19 ± 0.26, respectively (P < 0.001). A high value of H/L was associated with a high risk of hepatic encephalopathy (1.25 ± 0.17, P < 0.01) and oesophageal varices (1.02 ± 0.20, P < 0.01). There were associations between H/L and serum bilirubin (P < 0.01), albumin (P < 0.05) and prothrombin time (P < 0.05). The results also showed a good correlation between H/L and portal vein pressure measured during operation in 13 patients (P < 0.001, r= 0.87). The regression equation: y= 6.77 + 32.5 H/L, allowed portal vein pressure to be estimated. The prognostic value of the test was supported by the fact that good correlations were observed between the H/L ratio and widely accepted prognostic classification (Child-Pugh). It is suggested that this new method could be a reliable non-invasive way to give an indication of the degree of portasystemic shunting to evaluate the prognosis and to follow up the effects of medications for reducing portal hypertension in patients with cirrhotic portal hypertension.     

Prevalence of Intrapulmonary Vascular Dilatations in Normoxaemic Patients with Early Liver Cirrhosis

Background: The aim of this study was to determine the prevalence of intrapulmonary vascular dilatations (IPVD) in normoxaemic patients with early liver cirrhosis and to compare their occurrence in progressive alcoholic versus postviral hepatic insufficiency. Methods: Pulmonary function tests and arterial blood gas measurements were performed in 75 consecutive patients with cirrhosis of alcoholic and postviral aetiology. Contrast-enhanced echocardiography was used to identify IPVD. Results: All patients were grade A or B in accordance with the Child-Pugh modified classification. Arterial blood gas analyses showed normoxaemia in all patients. Eight of 75 patients (10.7%) had a positive contrast echocardiogram, all with a decreased diffusion capacity (Dl_CO &lt; 75% of the expected value). The abnormality was more prominent with advancing stage of liver failure (4.5% in grade A versus 19.4% in grade B; P &lt; 0.05) and more common in patients with alcoholic cirrhosis (17.5% in alcoholic versus 2.9% in postviral cirrhosis; P &lt; 0.05). Conclusion: In normoxaemic patients with early liver cirrhosis subclinical pulmonary vasodilatation, as assessed with contrast echocardiography, can occur. The finding is more prominent in alcoholic cirrhosis and possibly reflects an advancing degree of liver insufficiency.     

Prevalence of subclinical hepatic encephalopathy in patients with cirrhosis determined by psychometric tests

OBJECTIVE: To investigate the prevalence of subclinical hepatic encephalopathy (SHE) in patients with stable hepatic cirrhosis. METHODS: One hundred and seventy‐five consecutive cirrhotic patients (mean age 53 years, range 27?72 years) without overt clinical encephalopathy were screened for SHE using the number connection test (NCT) part A and symbol digit test (SDT). Subclinical hepatic encephalopathy was defined as the presence of at least one abnormal psychometric test. The age‐corrected normal value was defined as the mean ± 2SD obtained from 356 subjects without liver disease and in normal mental condition. Illiterate patients and patients with concurrent use of alcohol or psychotropic drugs, and those with previous portosystemic shunt and were excluded. RESULTS: In different age subgroups, the NCT scores and SDT quotients for cirrhotic patients were significantly different compared with those for controls (P < 0.05?0.001). Fifty patients (28.6%) were found to be abnormal in both the NCT and SDT, 16 (9.1%) patients were abnormal only in the SDT and 34 patients (19.4%) only in the NCT. Taken together, SHE was diagnosed in 100 patients (57.1%) by using the two tests. The prevalence of SHE increased from 46.8% and 53.0% in Child?Pugh grades A and B, to 76.6% in Child?Pugh grade C (P < 0.05). No significant correlation was found between the development of SHE and the etiology of cirrhosis, patient age and smoking habit. CONCLUSION: By using a combination of NCT and SDT, SHE was diagnosed in 57.1% of cirrhotic patients without overt clinical encephalopathy. The prevalence of SHE was significantly correlated with the severity of liver cirrhosis.     

Acute administration of sildenafil enhances hepatic cyclic guanosine monophosphate production and reduces hepatic sinusoid resistance in cirrhotic patients

Aim: In liver cirrhosis, the increased production of nitric oxide (NO) contributes to increased systemic and splanchnic vasodilatation. The inhibition of phosphodiesterase-5 (PDE-5), an enzyme responsible for the degradation of cyclic guanosine monophosphate (cGMP), is widely used in the treatment of erectile dysfunction. The aim of our study is to evaluate the overall effects of PDE-5 inhibitor administration on splanchnic, pulmonary and systemic hemodynamics in cirrhotic patients. Methods: Sildenafil, a specific PDE-5 inhibitor, was administrated orally to cirrhotic patients (n = 7) to see the hemodynamic changes. A control group receiving a placebo was used as a point of comparison (n = 6). Results: Compared to the control group, the hepatic vein NO and cGMP levels were significantly increased after sildenafil administration in the sildenafil group (NO from 112.3 ± 43.5 to 325.3 ± 117.5 nM, P = 0.018; cGMP from 7.3 ± 0.4 to 19.2 ± 4.2 pmol, P = 0.018). The hepatic venous pressure gradient in the sildenafil group did not differ from that of the control group. However, a significantly decreased hepatic sinusoidal resistance in the sildenafil group (1999 ± 1243 vs. 1563 ± 1014 dyne/s/cm⁻⁵, P < 0.05) was noted. The study also found that the right arterial pressure, mean pulmonary arterial pressure and pulmonary capillary wedge pressure were reduced at 60 min after administration, compared with the basal parameters in cirrhotic patients receiving sildenafil (RAP1.3 ± 2.0 vs −0.6 ± 1.3 mmHg, MPAP 14.1 ± 11.3 vs 11.7 ± 9.5 mmHg, PCWP 4.6 ± 1.7 vs 2.9 ± 1.6 mmHg, P < 0.05 respectively). Conclusions: An oral administration of 50 mg of sildenafil significantly decreased the mean pulmonary arterial pressure and hepatic sinusoid resistance with a significant increase in hepatic NO and cGMP production, and did not worsen portal hypertension in cirrhotic patients.     

The Beneficial Effect of Aspirin and Enoxaparin on Fibrosis Progression and Regenerative Activity in a Rat Model of Cirrhosis

The aim of this study was to examine the effect of the antithrombotic drugs aspirin and enoxaparin on fibrosis progression and regenerative activity in a rat model of liver cirrhosis and to determine if these two drugs are beneficial in animals with advanced fibrosis or with established cirrhosis undergoing partial hepatectomy. Thioacetamide-induced cirrhotic rats received saline (N=10), aspirin (N=7), or enoxaparin (N=11) for a 5-week treatment period. Hepatic fibrosis was assessed according to METAVIR score. Liver regeneration was monitored using PCNA immunostaining. Compared to untreated cirrhotic controls, a significant improvement in fibrosis grade was observed in the aspirin (43%; χ²=54, P < 0.001) and enoxaparin (36%; χ²=43, P < 0.001) treated groups. Postoperatively, total serum bilirubin levels were lower in the aspirin (1.4±0.18 mg/dl; P < 0.01) and enoxaparin (1.8±0.35 mg/dl; P < 0.05)-treated groups compared to untreated cirrhotic controls (3.2±0.6 mg/dl). Hepatic regenerative activity was significantly improved in the aspirin group (57.3%±6.8%, versus 34.2%±7.2% in untreated cirrhotic controls; P < 0.01) but unchanged in the enoxaparin group. We conclude that aspirin and enoxaparin hold promise as a useful therapy for patients with extensive fibrosis.     

Night‐time sleep disturbance does not correlate with neuropsychiatric impairment in patients with cirrhosis

Background: Sleep–wake disturbances are common in patients with cirrhosis and are generally attributed to the presence of hepatic encephalopathy. Aim: To determine the relationship between sleep and neuropsychiatric disturbances in patients with cirrhosis. Methods: The study population comprised 87 patients, classified as neuropsychiatrically unimpaired or as having minimal/overt hepatic encephalopathy. Nineteen healthy volunteers served as controls. Validated questionnaires were used to assess sleep quality [Pittsburgh sleep quality index (PSQI)], day‐time sleepiness [Epworth sleepiness scale (ESS)] and diurnal preference. Health‐related quality of life (H‐RQoL) was assessed using the 36‐item short form health profile (SF‐36v1) and the chronic liver disease questionnaire. Results: Patients slept significantly less well than the healthy volunteers (PSQI score: 8.4 ± 4.9 vs. 4.6 ± 2.5, P<0.01) and had more pronounced day‐time sleepiness (abnormal ESS: 21 vs. 0%; χ²=3.8, P=0.05). No significant relationships were observed between sleep indices and the presence/degree of hepatic encephalopathy. H‐RQoL was significantly impaired in the patients (SF‐36v1 physical score: 36 ± 15 vs. 50 ± 10, P<0.001; SF‐36v1 mental score: 46 ± 11 vs. 50 ± 10, P<0.01); night‐time sleep disturbance was an independent predictor of poor H‐RQoL (P<0.01). Conclusions: Sleep–wake abnormalities are common in patients with cirrhosis; they significantly affect H‐RQoL but are not related to the presence of hepatic encephalopathy.     

Serum 1,5-anhydro-d-glucitol levels in liver cirrhosis

We studied the serum 1,5-anhydro-d-glucitol (AG) levels, a marker of glycemic control, in liver cirrhotic patients who had no evidence of glycosuria in 24-h urine samples in order to clarify the effects of impaired liver function on serum AG metabolism. We showed first that serum AG concentrations were significantly lower in cirrhotic patients than in age- and sex-matched healthy controls (17.6±1.6 vs 26.3±1.7 μg/ml, P<0.05). Moreover, serum AG levels were found to be positively correlated with both serum cholinesterase and albumin levels. The observations indicate that serum AG levels were decreased in liver cirrhosis, especially in cases of severely reduced hepatic functions, suggesting the possibility of altered AG synthesis in liver cirrhosis. Received: 6 August 1997 / Accepted in revised form: 14 November 1997     

An endothelin receptor antagonist TAK-044 ameliorates carbon tetrachloride-induced acute liver injury and portal hypertension in rats

ABSTRACT— Hepatic levels of a powerful vasoconstrictor endothelin-1 (ET-1) and its receptors increase in human and carbon tetrachloride (CCl₄)-induced liver cirrhosis. The aim of this study was to determine whether antagonism of hepatic ET-1 receptors ameliorates CCl₄-induced hepatic injury and portal hypertension in rats. Acute liver injury was induced by a single intraperitoneal injection of CCl₄ (0.3 ml/kg), whereas cirrhosis and portal hypertension were induced by CCl₄ treatment (0.15 ml/kg twice a week) for 8 weeks. Hepatic morphology, ET-1 and its receptors, and portal venous pressures were determined. Increases in ET-1 and its receptors occurred within 24 h of CCl₄ administration, and progressively thereafter during the development of cirrhosis. The acute CCl₄-induced hepatic injury was characterized by significant increases in portal pressure (from 8.7 ± 1.8 to 17.6 ± 3.3 mmHg; p<0.01) and serum levels of liver enzymes, as well as massive hepatocellular necrosis (62±8%). Intravenous administration of an ET-1 receptor antagonist TAK-044 reduced portal pressure to 13.6±2.8 mmHg (p<0.05), and ameliorated hepatocellular necrosis by about 35% (p<0.001). TAK-044 treatment also produced significant reduction in serum levels of liver enzymes. In cirrhotic rats, portal venous infusion of TAK-044 reduced portal hypertension by about 40% (p<0.05). In conclusion, these results indicate involvement of ET-1 in acute liver injury as well as portal hypertension associated with hepatic cirrhosis, and a potential for ET-1 receptor antagonists in the treatment of these pathologic conditions.