Efficacy of lamivudine on hepatitis B viral status and liver function in patients with hepatitis B virus‐related hepatocellular carcinoma

Background/Aims: Treatment of patients with hepatocellular carcinoma (HCC) depends on the tumour extent and underlying liver function. Antiviral therapy with nucleoside/nucleotide analogues has been shown to be effective in improving the liver function of chronic hepatitis B (CHB) patients. We assessed whether lamivudine could induce biochemical and virological improvements in patients with hepatitis B virus‐related HCC. Patients/Methods: Of 148 CHB patients treated with 100 mg/day lamivudine for at least 6 months, 80 had HCC (CHB/HCC group) and 68 did not (CHB group). Biochemical and virological parameters were serially monitored. Results: Compared with the CHB group, the CHB/HCC group was older, had higher male predominance, bilirubin levels and liver cirrhosis rate, and lower albumin and hepatitis B virus (HBV) DNA levels and hepatitis B e antigen (HBeAg) positivity (P<0.05 each). The two groups showed similar cumulative rates of alanine aminotransferase normalization, HBV DNA seroconversion, HBeAg loss and viral breakthrough during 12 months of lamivudine treatment. After 12 months, the CHB/HCC group showed, relative to baseline, increased albumin levels (3.51±0.5 vs. 3.72±0.5 mg/ml) and decreased ascites scores (1.63±0.7 vs. 1.45±0.6) and Child–Pugh scores (6.92±1.9 vs. 6.02±1.38) (P<0.05 each). Conclusion: Lamivudine had comparable antiviral effects both in patients with CHB and CHB/HCC, and improved underlying liver function in the latter group. Treatment of HBV may increase the chance of curative treatments in patients with HBV‐related HCC.     

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.     

Diagnostic value of the copper/zinc ratio in hepatocellular carcinoma: a case control study

Background: The aim of this study was to assess the accuracy of the copper/zinc ratio in the evaluation of a group of patients with hepatocellular carcinoma (HCC). Methods: A total of 105 patients were studied and separated into three groups: group I (n = 40), patients with HCC, group II (n = 25), patients with liver cirrhosis, and group III (n = 40), patients with benign digestive disease. Serum levels of copper and zinc were measured by atomic absorption spectrophotometry. Results: The serum levels of copper (μg/dl) in patients with HCC (97.4 ± 27.2; P < 0.05) were significantly higher than those in patients with liver cirrhosis (73.7 ± 17.5) or benign digestive disease (77.1 ± 20.8), and the serum levels of zinc (μg/dl) were significantly lower (71.6 ± 30.5; P < 0.05) than those in patients with benign digestive disease (81.7 ± 17.7 μg/dl) and were similar to those in cirrhotic patients (68.5 ± 17.1). The Cu/Zn ratio was also significantly higher in patients with HCC (1.52 ± 0.64; P < 0.05) than in patients with liver cirrhosis (1.06 ± 0.2) or patients with benign digestive disease (0.95 ± 0.39). Considering a cutoff value of 1.15, the sensitivity of the Cu/Zn ratio was 87.5%, with a specificity of 86.1%, a positive predictive value of 79.5%, and a negative predictive value of 91.8%. Conclusions: The Cu/Zn ratio was found to be significantly higher in patients with HCC compared with that in age and sex-matched controls, with a sensitivity of 87.5%; this ratio might be useful in the evaluation of suspected hepatocellular malignancy. Received: February 15, 2002 / Accepted: June 14, 2002 Acknowledgments. This work was partially supported by grant No. D-113-903903 from the Consejo Nacional de Ciencia y Tecnología, Mexico City, México. Reprint requests to: J.L. Poo, Centro de Investigación Farmacológica y Biotecnológica, Hospital Médica Sur, Puente de Piedra No 150, 14050, Mexico City, Mexico Editorial on page 104     

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.     

Serum trace metals in chronic viral hepatitis and hepatocellular carcinoma in Thailand

This study was conducted to determine and compare serum trace metal levels in viral hepatitis-associated chronic liver disease. Of 98 patients aged 43 (± 13) [mean (± SD)] years, 83 (85%) were seropositive for hepatitis B surface antigen (HBsAg) and 15 (15%) were seropositive for anti-hepatitis C virus (HCV). Twenty-five patients had chronic persistent hepatitis, 32 chronic active hepatitis, 21 post-necrotic cirrhosis, and 20 hepatocellular carcinoma. Determination of fasting serum trace metal levels (zinc, copper, calcium, magnesium, and phosphorus) was performed after the patients had been on a 2-day diet containing 10–12 mg zinc/day. Compared to healthy volunteers (n=30), serum zinc levels were significantly decreased in patients with chronic active hepatitis, cirrhosis, and hepatocellular carcinoma (P≤0.0001), and copper levels were significantly elevated only in patients with hepatocellular carcinoma (P<0.0001). The overall serum levels of calcium, magnesium, and phosphorus were within normal ranges, and levels of calcium and magnesium correlated with serum zinc (P=0.01–0.03). Serum zinc levels correlated with bilirubin, albumin, and cholesterol (P=0.0004≤0.0001), but not with daily urinary zinc excretion. Serum copper levels correlated with alkaline phosphatase and gamma-glutamyltransferase (P=0.008–0.0001). These results suggested that changes in liver cell pathology compounded by functional impairment may alter the metabolism of trace metals, in particular, zinc and copper. The possible relationship of these changes to the pathogenesis of chronic liver disease is discussed.     

Fibrosis evolution in chronic hepatitis B e antigen‐negative patients across a 10‐year interval

The degree of liver fibrosis in chronic hepatitis B (CHB) infection influences outcome and management. Existing data describing the long‐term dynamic changes of liver fibrosis are limited. This study aimed to evaluate the evolution of liver fibrosis in CHB across a 10‐year period. CHB patients with liver stiffness measurement (LSM) by transient elastography 10 years ago were recruited for follow‐up LSM. Fibrosis stages were classified according to EASL‐ALEH guidelines. Fibrosis progression/regression was arbitrarily defined as ≥1 fibrosis stage change from baseline. A total of 459 hepatitis B e antigen (HBeAg)‐negative patients (224 untreated, 235 treated with nucleos(t)ide analogues [NAs]) were recruited. The mean age at baseline LSM was 41.7 ± 9.0 years (56.2% male). Over 10 years, the proportion of patients with advanced fibrosis/cirrhosis significantly reduced from 16.3% to 5.7% (P < 0.001). Fibrosis progression and regression were observed in 8.7% and 37.5%, respectively. No treatment with NAs (OR 2.259, 95% confidence interval [CI]: 1.032‐4.945), metabolic syndrome (OR 4.379, 95% CI: 1.128‐16.999) and hepatic steatosis (OR 7.799, 95% CI: 2.271‐26.776) was associated with fibrosis progression. Liver stiffness decline demonstrated positive correlation with the time after HBsAg seroclearance (r = ?0.50, P < 0.001). Median liver stiffness was higher both at baseline (14.0 vs 6 kPa, P < 0.001) and 10 years (9.1 vs 4.9 kPa, P < 0.001) in patients with cirrhosis‐related complications/hepatocellular carcinoma compared with those without. In conclusion, CHB‐related liver fibrosis changed dynamically across 10 years. Metabolic syndrome and hepatic steatosis were associated with fibrosis progression, while antiviral therapy was associated with fibrosis regression. Patients with HBsAg seroclearance demonstrated time‐dependent decline in liver stiffness.     

Reduced hepatic glycogen stores in patients with liver cirrhosis

Abstract: Background: Patients with alcoholic liver cirrhosis have reduced hepatic glycogen stores but the mechanisms leading to this finding are not clear. Methods: We therefore determined the hepatic glycogen content in patients with alcoholic (n = 9) or biliary cirrhosis (n = 8), and in control patients undergoing liver surgery (n = 14). All patients were in the postabsorptive state. In addition, we performed a morphometric analysis of the livers, and measured activities and mRNA expression of several enzymes involved in glycogen metabolism. Cirrhotic and control patients were similar regarding age and body weight. Results: Cirrhotic patients had a reduced glycogen content per gram liver wet weight (17 ± 11 versus 45 ± 17 mg/g, P < 0.05), per milliliter hepatocytes (28 ± 16 versus 52 ± 21 mg/ml, P < 0.05) and per liver (28 ± 17 versus 64 ± 22 g, P < 0.05), the reduction being observed in both patients with alcoholic or biliary cirrhosis. Liver histology confirmed these findings and revealed that the decrease in liver glycogen in cirrhotic patients was not homogenous across cirrhotic lobules. Activities of glycogen synthase and phosphorylase (total activity and active form) were not different between cirrhotic and control patients, whereas hepatic mRNA expression was decreased in cirrhotics by approximately 50%. The activity of glucokinase was decreased in cirrhotic as compared in control patients (0.06 ± 0.30 versus 0.42 ± 0.21 U/ml hepatocytes, P < 0.05), the reduction being observed in both patients with alcoholic or biliary cirrhosis. Conclusions: We conclude that patients with alcoholic or biliary cirrhosis have decreased hepatic glycogen stores per volume of hepatocytes and per liver. Decreased activity of glucokinase may represent an important mechanism leading to this finding.     

Long‐term outcomes of direct acting antivirals in post‐transplant advanced hepatitis C virus recurrence and fibrosing cholestatic hepatitis

Long‐term functional outcomes of sofosbuvir‐based antiviral treatment were evaluated in a cohort study involving 16 Italian centres within the international compassionate use programme for post‐transplant hepatitis C virus (HCV) recurrence. Seventy‐three patients with cirrhosis (n=52) or fibrosing cholestatic hepatitis (FCH, n=21) received 24‐week sofosbuvir with ribavirin±pegylated interferon or interferon‐free sofosbuvir‐based regimen with daclatasvir/simeprevir+ribavirin. The patients were observed for a median time of 103 (82‐112) weeks. Twelve of 73 (16.4%) died (10 non‐FCH, 2 FCH) and two underwent re‐LT. Sustained virological response was achieved in 46 of 66 (69.7%): 31 of 47 (66%) non‐FCH and 15 of 19 (79%) FCH patients. All relapsers were successfully retreated. Comparing the data of baseline with last follow‐up, MELD and Child‐Turcotte‐Pugh scores improved both in non‐FCH (15.3±6.5 vs 10.5±3.8, P<.0001 and 8.4±2.1 vs 5.7±1.3, P<.0001, respectively) and FCH (17.3±5.9 vs 10.1±2.8, P=.001 and 8.2±1.6 vs 5.5±1, P=.001, respectively). Short‐treatment mortality was higher in patients with baseline MELD≥25 than in those with MELD<25 (42.9% vs 4.8%, P=.011). Long‐term mortality was 53.3% among patients with baseline MELD≥20 and 7.5% among those with MELD<20 (P<.0001). Among deceased patients 75% were Child‐Turcotte‐Pugh class C at baseline, while among survivors 83.9% were class A or B (P<.0001). Direct acting antivirals‐based treatments for severe post‐transplant hepatitis C recurrence, comprising fibrosing cholestatic hepatitis, significantly improve liver function, even without viral clearance and permit an excellent long‐term survival. The setting of severe HCV recurrence may require the identification of “too‐sick‐to‐treat patients” to avoid futile treatments.     

Cardiovascular risk factor management is poorer in diabetic patients with undiagnosed peripheral arterial disease than in those with known coronary heart disease or cerebrovascular disease. Results of a nationwide study in tertiary diabetes centres

Aims To assess whether patients with Type 2 diabetes mellitus and unrecognized peripheral arterial disease (PAD), detected by the ankle–brachial index (ABI), have poorer cardiovascular risk factor management (CVRFs) and receive fewer medications than patients previously diagnosed with coronary heart disease (CHD) or cerebrovascular disease (CVD). Methods In 31 diabetes centres throughout Spain, 1303 patients with Type 2 diabetes mellitus were screened for PAD using the ABI. Patient history of CHD and CVD and treatment and control of CVRFs were recorded. Results Forty-one patients had an ABI > 1.30 and were excluded, leaving 1262 patients (age 65.3 ± 7.7 years) for the study. Of those screened, 790 patients had a normal ABI (ABI > 0.9) and no known history of CHD or CVD (no CHD/CVD/PAD group), 194 had unrecognized PAD (ABI ≤ 0.9) with no known history of CHD or CVD (undiagnosed PAD group) and 278 had a known history of CHD and/or CVD (CHD/CVD group). The undiagnosed PAD group had higher low-density lipoprotein (LDL) cholesterol (2.9 ± 0.83 vs. 2.4 ± 0.84 mmol/l; P < 0.001) and systolic blood pressure (150 ± 20 vs. 145 ± 21 mmHg; P < 0.001) compared with the CHD/CVD group. They were less likely to take statins (56.9 vs. 71.6%; P < 0.001), anti-hypertensive agents (75.9 vs. 90.1%, P = 0.001), and anti-platelet agents (aspirin, 28.7 vs. 57.2%; P < 0.001; clopidogrel, 5.6 vs. 20.9%; P < 0.001) and more likely to smoke (21.0 vs. 9.2%; P < 0.001). Higher LDL in the undiagnosed PAD group was associated with the underutilization of statins. Conclusions Measurement of ABI detected a significant number of patients with PAD, who did not have CHD or CVD, but whose CVRFs were under treated and poorly controlled compared with subjects with CHD and/or CVD.     

Intrahepatic angiogenesis increases portal hypertension in hepatitis B patients with cirrhosis

Aim

It remains unclear whether intrahepatic angiogenesis increases portal hypertension (PH) in hepatitis B with cirrhosis. We aim to investigate the relationship between intrahepatic angiogenesis and PH in hepatitis B patients with cirrhosis.

Methods

Sixty hepatitis B patients with cirrhosis and 40 healthy subjects were included in this study. Angiogenesis markers vascular endothelial growth factor receptor‐2 (VEGFR2), von Willebrand factor (vWF), and fibrosis marker α‐smooth muscle actin (α‐SMA) were observed by immunohistochemistry. Sirius Red staining was also used to determine liver fibrosis. Correlations between levels of intrahepatic angiogenesis and Child–Pugh classes, liver fibrosis degree, and portal vein pressure were examined. We also analyzed the relationship between levels of intrahepatic angiogenesis and complications of PH, including esophageal varices (EV), ascites, and hypersplenism.

Results

Correlation was observed between the levels of VEGFR2 (r = 0.590, P < 0.01), vWF (r = 0.524, P < 0.01) in tissue, and Child–Pugh classes. Significant correlations were observed between levels of VEGFR2 and α‐SMA (r = 0.710, P < 0.01), VEGFR2 and Sirius Red (r = 0.841, P < 0.01), vWF and α‐SMA (r = 0.768, P < 0.01), and vWF and Sirius Red (r = 0.825, P < 0.01). Patients with hepatic venous pressure gradient (HVPG) ≥12 mmHg showed higher levels of VEGFR2 and vWF expression compared to those with (HVPG) <12 mmHg (2.60 ± 1.28% vs. 1.09 ± 0.73%; 5.85 ± 2.45% vs. 2.31 ± 1.34%, P < 0.01), respectively. Moreover, complications of PH, including size of esophageal varices (P < 0.01), presence of ascites (P < 0.01), and spleen volume (P < 0.01) were significantly affected by the levels of intrahepatic angiogenesis.

Conclusion

Intrahepatic angiogenesis increases PH in hepatitis B patients with cirrhosis. The study provides the potential ways to intervene in the progresses for therapeutic benefits in cirrhosis and PH.

     

Antipyrine clearance in chronic and neoplastic liver diseases: A study of 518 patients

Antipyrine metabolism is widely used as an index of the drug-metabolizing reserve of the liver. It is well known that metabolism of this drug is impaired in subjects with acute hepatitis or cirrhosis, but conflicting data have been reported regarding patients with chronic postinfectious hepatitis or liver cancer. We studied conventional liver-function parameters and antipyrine metabolism (antipyrine per o.s. 18mg/kg) in 518 subjects. One hundred and one patients had liver metastases (various primaries). Based on the number and size of lesions, the hepatic involvement was considered minimal in 47 and massive in 54 (groups B1 and B2, respectively). One hundred and two had chronic active hepatitis (CAH); 51 patients with histological evidence of fibrosis/early cirrhosis and 51 patients were without histological evidence of fibrosis/early cirrhosis. Ninety-two had histologically confirmed cirrhosis (group D), and the remaining 120 had cirrhosis and hepatocellular carcinoma (group E). The control group was composed of 103 subjects with healthy livers (group A). Antipyrine clearance (AP Cl) in CAH patients with fibrosis (0.246 ± 0.98 mL/min per kg) was similar to that observed in patients with cirrhosis (0.223 ± 0.148 mL/min per kg), and both values were significantly lower than that found in CAH patients without fibrosis (0.406 ± 0.159 mL/min per kg, P < 0.01). Antipyrine clearance in patients with liver metastases (0.426 ± 0.174 mL/min per kg) was similar to that of the healthy group (0.489 ± 0.210 mL/min per kg). Cirrhotics and cirrhotics with hepatocellular carcinoma (HCC) presented similar degrees of impairment. Antipyrine clearance was positively correlated with serum albumin (r²= 0.10, P= 0.01) and prothrombin time (r²= 0.129, P < 0.01) in all groups, except those with liver metastases. In patients with CAH, the presence of fibrosis/cirrhosis is associated with impaired antipyrine metabolism. The lack of impairment in groups with liver metastases suggests that the functional hepatic reserve is maintained even in the presence of massive neoplastic invasion.     

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.     

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.     

Regional variations in the concentrations of ketone bodies in cirrhosis and hepatic encephalopathy: a study in patients with TIPSS

Background: Little is known about the metabolism of acetoacetate and β‐hydroxybutyrate in patients with cirrhosis and encephalopathy. Aims: We investigated the fate of ketone bodies in these conditions. Materials and methods: We studied 18 cirrhotic patients with encephalopathy and 17 cirrhotics without. At the time of insertion of a transjugular intrahepatic portosystemic stent shunt (TIPSS) or at the time of portographical assessment of the shunt's patency, we collected blood from the internal jugular, the right atrium, the inferior vena cava, the hepatic, the portal, the splenic veins and the radial artery. We used nuclear magnetic resonance spectroscopy to measure the concentrations of acetoacetate and β‐hydroxybutyrate. Results: There was no difference in the total ketone body concentrations between the two groups. The mitochondrial redox potential was significantly higher in the encephalopathics (142/54=2.63 vs 52/83=0.62) (P<0.01). β‐hydroxybutyrate was significantly lower in the portal vein of encephalopathics (52 ± 4 vs 28 ± 3) (P<0.02) and in the splenic vein (48 ± 6 vs 32 ± 5) (P<0.04). Acetoacetate was significantly higher in encephalopathics in the internal jugular vein (134 ± 12 vs 92 ± 16) (P<0.03), the right atrium (112 ± 18 vs 68 ± 11) (P<0.03), the hepatic vein (162 ± 25 vs 115 ± 19) (P<0.05), the portal vein (133 ± 20 vs 81 ± 14) (P<0.02) and the splenic vein (167 ± 24 vs 122 ± 21) (P<0.04). All measurements are expressed in μmols/L. Conclusions: There are significant variations in the regional concentrations of the ketone bodies in encephalopathy.     

Cardiac catheterization in patients with end‐stage liver disease: Safety and outcomes

Introduction : Patients with end‐stage liver disease (ESLD) awaiting transplant are at increased risk of bleeding. Nevertheless, these patients routinely undergo cardiac catheterization for various indications. Safety and outcomes of cardiac catheterization in these patients are not well reported. Methods : In a case–control study 43 patients with ESLD who underwent angiography for liver transplant work‐up were compared to 43 age and gender‐matched controls with no liver dysfunction. In‐hospital outcomes and procedural variables were compared. Results : Patients with ESLD had a lower baseline hemoglobin (12.1 ± 2.1 vs. 13.7 ± 1.8, P < 0.0005), lower platelet counts (86.8 ± 66 vs. 247 ± 80, P < 0.0001) and higher international normalized ratio (INR) (1.4 ± 0.2 vs. 1.1 ± 0.2, P < 0.0001) than controls. Among ESLD group, five (11.6%) patients received platelet transfusions, one received blood transfusion, and three patients (7%) with INR > 1.6 received fresh frozen plasma (FFP) compared with none in the control group. Smaller size (four French) vascular sheaths were used more frequently in the group with ESLD (16% vs. 4%, P = 0.04). There were no significant vascular or bleeding complications in either group. Conclusions : Elective cardiac catheterization can be safely performed in patients with ESLD with outcomes (vascular and bleeding complications, length of hospital stay and in‐hospital mortality) similar to patients without liver disease despite significant thrombocytopenia and elevated INR in patients with ESLD. Practices such as platelet transfusion for platelets <60,000 μL, prophylactic FFP transfusion for INR ≥≥ 1.6, less frequent use of antiplatelet therapy and more frequent use of smaller vascular sheaths may have contributed to the safety of cardiac catheterization in ESLD patients. © 2010 Wiley‐Liss, Inc.     

Relationship between HBxAg and Fas/FasL in patients with hepatocellularcarcinoma

AIM To assess the relationship between HBV X-gene, X-gene product and Fas/ FasL which mediatehepatocellular apoptosis in patients with hepatocellular carcinoma.METHODS Tissue from 34 patients with hepatocellular carcinoma was tested for the expression of HBxAg.Quantitative ELISA assay was used to detect sFas; and sFasL and PCR were used to detect the HBV X-genein sera from 30 patients with hepatocellular carcinoma, 32 patients with liver cirrhosis and 20 normalcontrols.RESULTS The positive expression of HBxAg, Fas and FasL in carcinoma tissue was 97.06%, 85.29% and100%, respectively. The positive signal was mainly presented in the plasma, and all of these three positivestaining may appear in the same area. Redit analysis showed that there was no significant difference amongthese three positive staining (P >0.05). The mean levels of sFas in sera from hepatocellular carcinoma, livercirrhosis and normal controls were 722.97±321.12, 801.90±419.94 and 224.07±148.23, respectively,showing that sFas levels in patients with hepatocellular carcinoma and liver cirrhosis were significantlyelevated than that in normal controls (P < 0.0l). The mean levels of sFasL in sera from hepatocellularcarcinoma, liver cirrhosis and normal controls were 152.27±7.99, 162.97±12.40 and 154.99 ± 6.96,showing that sFasL level in patients with liver cirrhosis was significantly higher than that in patients withhepatocellular carcinoma and normal controls (P< 0.01). HBV X-gene was found to be positive in sera of30% patients with hepatocellular carcinoma; HBV X-gene was found to be positive in sera of 43.75% ofpatients with liver cirrhosis. There was no significant difference in sFas/sFasL level between HBV X-genepositive patients and HBV X-gene negative patients (P >0.05).CONCLUSION The expression of HBxAg and Fas/FasL in the tissue of hepatocellular carcinoma seemed tobe almost the same, but relation between cause and effect is unclear. The detection of sFas and sFasL inpatient sera may reflect the state of apoptosis mediated by Fas/FasL system. Our data showed that HBV X-gene expression in sera seemed to have no relation to sFas/sFasL level; however, these data also suggestedthat some patients with negative HBsAg in sera might have integrated HBV X-gene in liver tissues, andtherefore X-gene is detectable in those patient sera.     

Diabetes mellitus as an independent prognostic predictor and its association with renal dysfunction in patients with hepatocellular carcinoma

Background: Patients with hepatocellular carcinoma (HCC) often have coexisting cirrhosis, which may predispose to the development of diabetes mellitus (DM). Diabetic HCC patients may have renal insufficiency and a subsequent worse outcome. This study investigated the interaction between DM, cirrhosis and renal dysfunction and the impact of these factors on HCC. Methods: A prospective database of 1713 HCC patients was analysed. Results: A total of 392 (22.9%) patients were diabetic. Diabetic patients had a significantly higher Child–Turcotte–Pugh (CTP) score, model for end‐stage liver disease score and serum creatinine level, but had significantly lower serum albumin, sodium, alanine aminotransferase, aspartate aminotransferase and bilirubin levels. The serum creatinine level progressively increased and correlated well with increasing CTP class in both diabetic and non‐diabetic patients. After a mean follow‐up of 18 ± 16 months, DM was shown to be an independent predictor of mortality in the Cox proportional hazard model after adjusting for other predictors [hazard ratio (HR): 1.2, 95% confidence interval (CI): 1.02–1.42]. Diabetic patients more often had renal insufficiency, defined as serum creatinine >1.5 mg/dl (17.3 vs 8.3%, P<0.0001). Renal insufficiency was an independent prognostic predictor in diabetic patients (HR: 2.26, 95% CI: 1.57–3.24) but not in non‐diabetic patients, because it was significantly associated with the severity of cirrhosis in the non‐diabetic group (P<0.001) but not in the diabetic group (P=0.143). Conclusions: DM is associated with inadequate liver reserve and independently predicts decreased survival in HCC patients. Both advanced cirrhosis and DM are associated with renal insufficiency, which is a poor prognostic predictor for HCC.     

Prolongation of QTc interval: relationship with etiology and severity of liver disease,mortality and liver transplantation

Background: A prolonged QTc interval has been reported in patients with liver disease. The objectives of our study were to determine whether a prolonged QTc interval was an independent predictor of mortality in patients with cirrhosis and to examine the effect of liver transplantation (LT) on QTc interval. Patients and methods: We retrospectively studied two cohorts of patients – QTc interval was measured in 409 patients (pre‐transplant group), and in 162 patients (transplant group) before and 6 months after LT. QT interval (mean) corrected (QTc) for ventricular rate was read from a 12‐lead EKG. Patients with known cardiovascular disease or other risk factors that are known to cause a prolonged QTc interval were excluded. Results: Pre‐transplant group. One hundred and sixty‐two patients (40%) had a prolonged QTc interval (>440 ms). By binary logistic regression, age (P=0.005), alcoholic cirrhosis (P=0.007) and Child–Pugh scores (P=0.007) were independent predictors of prolonged QTc interval. Sixty‐six patients died during a mean follow‐up of 8.9 years. Although the Kaplan–Meier survival curve showed a lower survival in patients with a prolonged QTc interval (P=0.03 by log rank test), when survival was adjusted for the Child–Pugh score by Cox regression survival analysis, there were no survival differences in patients with and without prolonged QTc interval. Cox regression analysis showed that the Child–Pugh score (hazard ratio 1.5, CI 1.3–1.6, s<0.001) was the only independent predictor of survival. Transplant group. In this cohort, 91 patients (56%) had prolonged QTc (>440 ms) before LT. Mean QTc improved significantly after LT (429 ± 29 ms vs. 450 ± 39 ms P<0.002). Of the 91 patients with prolonged QTc, 50 (55%) normalized, three (3.3%) remained unchanged, 12 (13.3%) showed further prolongation, and 26 (28%) showed improvement but remained above normal limits. An additional nine patients who had normal QTc before LT developed prolonged QTc (>440 ms) after LT. Conclusion: A prolonged QTc interval was common in patients with cirrhosis, but its presence had no independent effect on mortality. Prolonged QTc returns to normal values in about half of the patients after LT, suggesting that liver disease plays a role, but may not be the only factor in the pathogenesis of prolonged QTc.     

Hemodynamic Studies in Acute-on-Chronic Liver Failure

Background Patients with decompensated cirrhosis and acute liver failure have circulatory dysfunctions leading to high portal pressure and cardiac output (CO) and low systemic vascular resistance (SVR). Circulatory changes in acute-on-chronic liver failure (ACLF) patients have not been studied. We studied the portal, systemic, and pulmonary hemodynamics in patients with ACLF and compared them with compensated and decompensated cirrhotics. Patients and Methods Clinical features and hemodynamic profile were studied in patients with ACLF and compared with age- and sex-matched compensated and decompensated cirrhotics with portal hypertension. Results The study cohort comprised 144 patients categorized into one of three groups (ACLF, compensated cirrhosis, and decompensated cirrhosis), with 48 (33%) patients in each group. All values are given as the mean ± standard deviation, except for frequencies (%). The mean arterial pressure (MAP) and SVR were lower in the ACLF than the compensated group and were similar to those of the decompensated group (MAP 90 ± 16 vs. 99 ± 15 vs. 96 ± 16 mmHg; SVR 912 ± 435 vs. 1350 ± 449 vs. 891 ± 333 dyn s/cm⁵). The mean CO of the ACLF patients was higher than that of the compensated group and similar to that of the decompensated group (CO 8.9 ± 3.5 vs. 6.1 ± 1.7 vs. 9.0 ± 3.0 l/min). The pulmonary vascular resistance (PVR) and pulmonary capillary wedge pressures (PCWP) were similar in all the three groups (PVR 78 ± 48 vs. 109 ± 70 vs. 61 ± 47 dyn s/cm⁵; PCWP 8 ± 4 vs. 8 ± 4 vs. 10 ± 5 mmHg). The mean hepatic venous pressure gradient (HVPG) in the ACLF group was 15.1 ± 6.3 mmHg, which was significantly higher than that of the compensated group (11.7 ± 6.3 mmHg), but lower than that of the decompensated cirrhosis group (20.2 ± 6.0 mmHg). When patients of ACLF were categorized on the basis of their variceal size, the mean HVPG in ACLF patients with small varices was similar to that of compensated cirrhotics (13.7 ± 5.7 vs. 11.7 ± 6.3 mmHg; P = 0.146), while in the ACLF patients with large varices, the HVPG was comparable to that of the decompensated cirrhotics (18.7 ± 6.6 vs. 20.2 ± 6.0 mmHg; P = 0.442). Conclusions The systemic hemodynamics in patients with ACLF is similar to that in decompensated cirrhotics. The portal pressure in these patients is higher than that in the compensated cirrhotics, and in the subgroup with large varices, it becomes similar to that of decompensated cirrhotics.     

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.