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The status of cellular cytotoxic activity in Hepatocellular Carcinoma (HCC) patients was compared to that in normal individuals by testing the cytotoxicity against K562 and five established HCC cell line targets. Natural killer (NK) activity of fresh peripheral blood mononuclear (PBM) cells in HCC patients to K562 cell line target was lower than that in normal donors. NK activity of unstimulated PBM cells from either source was minute against all five HCC cell line targets. Three different activation systems were employed to examine the cellular cytotoxicity of activated PBM cells: (1) conventional mixed lymphocyte culture (MLC), (2) allogeneic mixed lymphocyte tumor culture (MLTC), and (3) lymphokine-activated killer (LAK) cell culture. The cytotoxic effects of PBM cells in all three activation conditions were significantly lower in HCC patients than in normal donors (P less than 0.05 to P less than 0.01). These results suggest that, in addition to naturally present NK cells, the degree of in vitro activation of PBM cells may also have decreased in HCC patients.

— The acute effects of Nifedipine on hepatic venous pressure gradient (HVPG) and estimated hepatic blood flow (EHBF) were investigated in six patients with HBsAg-positive cirrhosis and portal hypertension by simultaneous hepatic venous catheterization. The mean arterial pressure significantly decreased by 18% at 1 h after sublingual administration of 10 mg Nifedipine. Significant increases in heart rate (13%) and cardiac output (20%) were also demonstrated in our patients 1 h after administration of Nifedipine. However, there were no significant changes in HVPG and EHBF after Nifedipine. We conclude that in patients with HBsAg-positive cirrhosis who receive Nifedipine, EHBF is maintained despite a substantial change in systemic hemodynamics, and that Nifedipine is not effective in acutely reducing HVPG.

Background and Aim: To compare the efficacy and safety of endoscopic variceal ligation (EVL) with propranolol in prophylaxis on the rate of first esophageal variceal bleeding in patients with cirrhosis. Methods: A prospective, randomized trial was conducted in 100 cirrhotic patients with no history of previous upper gastrointestinal bleeding and with esophageal varices endoscopically judged to be at high risk of hemorrhage. The end-points of the study were bleeding and death. Results: Life-table curves showed that prophylactic EVL and propranolol were similarly effective for primary prophylaxis of variceal bleeding (11/50 [22%]vs 12/50 [24%]; P = 0.68) and overall mortality (14/50 [28%]vs 12/50 [24%]; P = 0.49). The 2-year cumulative bleeding rate was 18% (9/50) in the EVL group and 16% (8/50) in the propranolol group. The 2-year cumulative mortality rate was 28% (14/50) in the EVL group and 24% (12/50) in the propranolol group. Comparison of Kaplan-Meier estimates of the time to death of both groups showed no significant difference in mortality in both groups (P = 0.86). Patients undergoing EVL had few treatment failures and died mainly of hepatic failure. In the propranolol group, the mean daily dosage of the drug was 68.2 ± 32.8 mg, which was sufficient to reduce the pulse rate by 25%. 20% of patients withdrew from propranolol treatment due to adverse events. Conclusions: Prophylaxis EVL is as effective and as safe as treatment with propranolol in decreasing the incidence of first variceal bleeding and death in cirrhotic patients with high-risk esophageal varices.

Background: It has been suggested that increased blood haemoglobin attenuates splanchnic vasodilatation in portal-hypertensive rats by nitric oxide inactivation. However, the haemodynamic effect of anaemia in cirrhotic patients of varying severity has been rarely discussed. The aim of this study was to evaluate the influence of anaemia on systemic and splanchnic haemodynamics in cirrhotic patients of differing severity. Methods: Two hundred and twenty-five cirrhotic patients were included in this study. All biochemical and haemodynamic results were utilized for analysis. Anaemia was defined as a haemoglobin level below the cut-off value of 12g/dL, which might best predict low systemic vascular resistance. Results: Compared with non-anaemic patients, anaemic patients had decreased mean arterial pressure (90 ± 1 vs 95 ± 1 mmHg, P = 0.002), and decreased systemic vascular resistance (1022 ± 25 vs 1227 ± 30, P < 0.0001), and increased cardiac index (4.3 ± 0.1 vs 3.8 ± 0.1 L/min per m2, P < 0.0001) and increased hepatic venous pressure gradient (16.7 ± 0.5 vs 14.4 ± 0.6 mmHg, P = 0.006). Haemoglobin concentration exerted an influence on the degree of vasodilatation in cirrhotic patients, with Child–Pugh’s A class (but not in Child–Pugh’s B and C classes), and in patients without ascites (but not in patients with ascites). Conclusions: It was concluded that anaemia has a negative effect on hyperdynamic circulation in patients with early cirrhosis which is not observed in patients with advanced cirrhosis.

Gall-bladder wall thickening is commonly seen in patients with cirrhosis, but its exact causes have not been well established. We evaluated clinical, biochemical and haemodynamic data of patients with cirrhosis with respect to the presence of thickening of the gall-bladder wall. After excluding patients who presented with gallstones, acute or chronic cholecystitis, heart failure, a serum creatinine level greater than 2 mg/dL and/or a serum alanine aminotransferase level greater than 400 U/L, 77 patients with cirrhosis (75 male, two female; mean age 58 +/- 8 years) were enrolled in the study. Clinical, biochemical, ultrasound and haemodynamic data were obtained in every patient. Forty-one (53%) of 77 patients with cirrhosis had gall-bladder wall thickening (> 4 mm). Compared with patients with a normal gall-bladder wall, patients with gall-bladder wall thickening had significantly lower serum albumin levels (3.6 +/- 0.6 vs 2.9 +/- 0.7 gm/dL, respectively; P < 0.05), a longer prothrombin time (13 +/- 6 vs 16 +/- 6 s, respectively; P < 0.05), more patients with Child-Pugh class C (6 vs 37%, respectively; P < 0.05) and more patients with ascites (8 vs 50%, respectively; P < 0.05). In addition, compared with patients with a normal gall-bladder wall, those patients with gall-bladder wall thickening had a higher hepatic venous pressure gradient (13.9 +/- 4.5 vs 17.1 +/- 4.1 mmHg, respectively; P < 0.01) and a lower systemic vascular resistance (SVR; 1144 +/- 332 vs 1010 +/- 318 dyn.s/cm5, respectively; P < 0.05). Using a multivariate analysis, the presence of ascites and SVR lower than 900 dyn.s/cm5 were independently correlated with the presence of gall-bladder wall thickening, while a hepatic vein pressure gradient greater than 10 mmHg had only a marginally significant association. The presence of ascites, decreased SVR and portal hypertension are related to the occurrence of gall-bladder wall thickening in patients with cirrhosis, indicating that the development of gall-bladder wall thickening may be multifactorial.

Plasma glucagon concentrations were measured in 160 cirrhotic patients (Pugh's grade A in 52 patients, Pugh's grade B in 64 patients and Pugh's grade C in 44 patients). These values were compared with plasma glucagon concentrations in 57 age and sex-matched healthy subjects. Systemic and portal haemodynamic measurements, effective renal plasma flow and creatinine clearance were recorded for each patient. Plasma glucagon levels were significantly increased in cirrhotic patients compared with healthy subjects. In addition, plasma glucagon levels were higher in cirrhotic patients with ascites than in those without ascites and were increased in relation to the severity of cirrhosis as assessed by Pugh's score. Multiple linear regression found that only Child-Pugh's score was estimated to be an independent predictor of hyperglucagonaemia in cirrhotic patients. However, in patients with different degrees of oesophageal varices and in patients without oesophageal varices, plasma glucagon concentrations were no different among the different groups of patients, but were still higher than plasma glucagon concentrations in healthy subjects. In contrast, plasma glucagon levels were negatively correlated with mean arterial pressure and systemic vascular resistance. The results of the present study suggest that impairment of liver function plays, in part, a role in increased plasma glucagon levels observed in patients with cirrhosis. In addition, these data support the hypothesis that hyperglucagonaemia may contribute, at least in part, to the pathogenesis of peripheral arterial vasodilatation in cirrhosis with portal hypertension.

In order to investigate the effects of verapamil on renal haemodynamics in rats with portal hypertension, verapamil was given at either a low (0.2 mg/kg) or high (2 mg/kg) dose to rats after portal vein ligation. An approximate 12% decrease in mean arterial pressure followed administration of low dose verapamil, with a significant decrease in cardiac output and renal blood flow, as well as reduced portal pressure, observed; these signs were all indicative of a rise in renal vascular resistance. In contrast, the marked fall in both mean arterial pressure and cardiac output with high dose verapamil, accompanied by a significant decrease in portal pressure and no change in renal blood flow, suggests a reduction in renal vascular resistance. This study shows that the acute effects of verapamil on renal haemodynamics may vary with the dose used. Also, acute verapamil administration tends to decrease renal blood flow to alter the autoregulation of the kidney; thus, caution should be taken in the clinical use of verapamil in the treatment of cirrhosis with portal hypertension.

This study investigated the role of endotoxaemia in the development of hyperdynamic circulation observed in rats with extrahepatic (high collateralization) or intrahepatic (low collateralization) portal hypertension. Compared with sham-operated rats, decreased mean arterial pressure and systemic vascular resistance were detected on days 1, 4, and 14 following partial portal vein ligation. By day 1, the cardiac index of portal vein-ligated rats was similar to that of sham-operated rats and progressively increased, thereafter, reaching statistically higher values days 4 and 14. No differences in plasma endotoxin levels were found between portal vein-ligated and sham-operated rats throughout the observation period. Both carbon tetrachloride-induced cirrhotic rats with and without ascites had a higher cardiac index and lower systemic vascular resistance. Plasma endotoxin levels were higher in cirrhotic rats with ascites (8.6 +/- 2.0 pg/mL; P < 0.01) than those of control rats (2.2 +/- 0.3 pg/mL) and cirrhotic rats without ascites (2.4 +/- 0.6 pg/mL). These results suggest that factors other than endotoxaemia play a role in the development of hyperdynamic circulation observed in rats with extrahepatic portal hypertension and cirrhotic rats without ascites, but that endotoxaemia may contribute to the maintenance of hyperdynamic circulation found in cirrhotic rats with ascites. The severity of liver disease may be a more important factor than the presence of portosystemic shunting for the development of endotoxaemia in portal hypertensive states.

The haemodynamic effects of a combination of propranolol and clonidine were evaluated in 20 patients with post-hepatitic cirrhosis. Haemodynamic measurements were taken before and 30 min after an intravenous injection of 0.1 mg/kg of propranolol. Thereafter, each patient was given an oral dose of 150 micrograms of clonidine and re-measured 60 min later. In this series, eight patients were defined as 'non-responders' (a decrease in hepatic venous pressure gradient of < 10%) after propranolol treatment. Of both the responders and non-responders, propranolol caused expected decreases in the cardiac index and heart rate while mean arterial pressure remained unchanged. Of the propranolol responders, a significant decrease in hepatic venous pressure gradient was observed. After the addition of clonidine, in both the responders and non-responders there was a further decrease in hepatic venous pressure gradient with a concurrent drop in mean arterial pressure, but cardiac index and heart rate remained unaltered. In conclusion, the combination of propranolol and clonidine in post-hepatitic cirrhotic patients enhanced the reduction of portal pressure achieved by propranolol alone. The beneficial effects of the combination of the two in the reduction of portal pressure appeared to be similar in both the propranolol responders and non-responders. However, the drop in mean arterial pressure following the addition of clonidine may be hazardous to cirrhotic patients.

The pressure of oesophageal varices was determined by fine needle direct puncture in 19 patients with hepatitis B surface antigen (HBsAg)-positive cirrhosis after the first episode of variceal bleeding before endoscopic sclerotherapy. Both the stability and reliability of the measurement of intravariceal pressure by fine needle puncture were confirmed. Seven patients received intravenous 1 mL normal saline. Intravariceal pressure did not change before and after injection of normal saline (16.3 +/- 4.0 vs 16.0 +/- 4.0 mmHg, P > 0.05). Twelve patients received intravenous 1 units vasopressin and this caused a significant reduction in intravariceal pressure (15.6 +/- 2.6 vs 10.3 +/- 2.9 mmHg, P < 0.0001). The average basal intravariceal pressure in these patients was 15.8 +/- 3.1 mmHg. After intravariceal pressure was recorded, the needle was left in situ and endoscopic sclerotherapy commenced immediately. During the investigation, no adverse reaction or complication was encountered. It was concluded that the measurement of intravariceal pressure by fine needle direct puncture followed by immediate sclerotherapy is a safe and simple method to evaluate the short-term effect of drug prevention from oesophageal variceal bleeding and that vasopressin causes reduction of intravariceal pressure.

Somatostatin has been used to effectively control acute variceal haemorrhage, with conjectured mechanisms on portal hypertension. We, therefore, evaluated the effects of somatostatin on hepatic and systemic haemodynamics in 15 patients with hepatitis B-related cirrhosis and portal hypertension. All patients received an intravenous, continuous infusion of somatostatin 250 micrograms/h, following a bolus injection of 250 micrograms. In systemic haemodynamics, the mean arterial pressure (MAP) increased (P < 0.05), associated with a reflex bradycardia within 3 min following bolus injections, compared with basal values. The right atrial pressure, pulmonary capillary wedge pressure, inferior vena cava pressure, cardiac index, and systemic vascular resistance remained unaffected after drug infusion. In hepatic haemodynamics, the wedge hepatic vein pressure remained unchanged after drug administration. However, there was an increase in free hepatic vein pressure (FHVP; P < 0.05), and a trend toward a decrease in the hepatic vein pressure gradient (HVPG; P = 0.063), within 3 min after bolus injection. Furthermore, the hepatic blood flow decreased significantly at 10 and 30 min after somatostatin infusion (P < 0.05). The effective sinusoidal perfusion assessed by indocyanine green infusion also decreased progressively at 10 min (P = 0.057) and 30 min (P < 0.05). We concluded that somatostatin, at the dose used in this study, caused a transient and bolus-related vasoconstrictive effect, resulting in increases in MAP and FHVP, a decrease in heart rate, and a trend toward lower HVPG. In addition, somatostatin reduced the hepatic blood flow and effective sinusoidal perfusion which may be hazardous to cirrhotic patients during variceal haemorrhage.

A total of 461 patients at the Veterans General Hospital, Taipei who had received blood transfusions since March 1981 were followed prospectively with serum biochemistry tests and viral hepatitis markers before and after the blood transfusions, periodically for at least 6 months. Sixty-three (13.7%) patients developed post-transfusion hepatitis (PTH). Of the patients with PTH, 71.4% were found to have antibody to hepatitis C virus (anti-HCV) seroconversion during the 1 year follow-up period by the first-generation of the hepatitis C virus (HCV) enzyme immunoassay (EIA) antibody test, but the second-generation EIA detected an increase to 88.9%. All sera positive by the first-generation EIA were also positive by the second-generation EIA. Their mean incubation of serum alanine aminotransferase (ALT) elevation was 6.5 weeks. The mean interval between the day of blood transfusion and the onset of active anti-HCV seroconversion was 18.3 weeks if tested by the first-generation EIA, but shortened to 9.5 weeks if tested by the second-generation EIA. Of 49 acute PTH C patients who were followed up for more than 1 year, 32 (65.3%) still had abnormal serum ALT levels. The results of this study demonstrate that acute hepatitis C is a frequent and important complication in blood transfusions in Taiwan. The second-generation HCV antibody EIA derived from HCV genes encoding both capsid and non-structural proteins is more sensitive for detection of HCV infection than recombinant c100-3 assay derived from the non-structural region of the viral genome only.

In an attempt to interrupt perinatal and postnatal transmission of hepatitis B virus (HBV) infection, hepatitis B vaccine trials were initiated in October 1981 in Taiwan, starting in neonates of hepatitis B e antigen (HBeAg)-positive hepatitis B surface antigen (HBsAg) carrier mothers and extending to neonates of non-carrier mothers. All neonates had received a four-dose schedule of Pasteur plasma-derived hepatitis B vaccine. Among neonates of HBeAg-positive HBsAg carrier mothers, the protective efficacy rate of vaccination was 75% in those who received vaccine alone and 90% in those who received vaccine plus hepatitis B immunoglobulin (HBIG) at birth. Among neonates of HBeAg-negative HBsAg carrier mothers, the protective efficacy rate was 100% whether they had received vaccine alone or vaccine plus HBIG at birth. The protective efficacy rate was also 100% in neonates of non-carrier mothers. During 6–9 years of long-term follow-up, 12 (6%) responsive vaccinees of HBeAg-positive carrier mothers, one (2%) child of HBeAg-negative carrier mothers and one child (0.4%) of non-carrier mothers had seroconverted to antibody to hepatitis B core antigen (anti-HBc) positivity. ‘Natural booster’ phenomenon, defined as a spontaneous sharp rise in serum antibody to HBsAg (anti-HBs) titres in the absence of anti-HBc and HBsAg, was observed in 7% of vaccinees whose mothers were HBeAg-positive, 6% of vaccinees whose mothers were HBeAg-negative HBV carriers, and 8% in vaccinees of non-HBV carrier mothers. None of the responsive vaccinees had seroconverted to HBsAg. Thus, in the first decade of life, the protective efficacy in neonates who responded to plasma-derived hepatitis B vaccine was 100%.

A randomized controlled trial was designed to investigate whether a high dose of terlipressin could control acute variceal haemorrhage more effectively than a low dose of terlipressin. Forty cirrhotic patients with bleeding oesophageal varices were included, with low-dose terlipressin in 21 patients and high-dose terlipressin in 19 patients. The two groups of patients were similarly matched for all parameters on admission. High-dose terlipressin (84%) seemed to be more effective in the initial control of bleeding than low-dose terlipressin (67%); however this difference was not significant. Complete control of bleeding during 24 h of drug infusion was achieved in 53% of patients receiving high-dose terlipressin and in 48% of those treated with low-dose terlipressin (P greater than 0.05). There were no major complications in either group. Mortality in relation to variceal bleeding and transfusion requirements were similar in the two groups. This study shows that high dose terlipressin is not superior to low dose terlipressin in acute variceal bleeding.

To ascertain whether acid inhibition or Helicobacter pylori (HP) colonization is the decisive factor in the healing of duodenal ulcer, we treated 54 patients with famotidine and carried out long-term follow-up. Helicobacter pylori colonization was found in 70.4% of patients before treatment. There were no differences in the pre-treatment characteristics between patients with HP positive or HP negative ulcers. The 4-week and 8-week healing rates after famotidine treatment were 72.5% and 82.4% respectively. No difference in HP colonization was found between patients with ulcer healed and those with ulcer not healed (78.4% vs 64.3% at 4th week and 77.3% vs 71.4% at 8th week, P greater than 0.05). In patients with ulcer healed at 4th week, the intragastric pH was raised significantly and the antral acute inflammation was less severe than those with ulcer not healed. Ulcer recurrence was found in 76.9% of patients within 1 year, but there was no difference in ulcer recurrence between the patients with positive or negative HP colonization at the time of ulcer healing. Our results suggest that duodenal ulcer healing and recurrence are closely related to acid inhibition rather than to HP colonization.

Among 30 consecutive patients diagnosed with primary biliary cirrhosis (PBC) in Taiwan, 27 were females and the median age of symptom onset was 54.5 years. Most had similar clinical manifestations to those reported in the Western countries, but ascites and oesophageal varices as commonly found at the late stages of cirrhosis of liver were noted in nine patients (30%) and 13 patients (43%) respectively. Only one patient was asymptomatic. Hyperbilirubinaemia was noted in 21 patients (70%) and hypoalbuminaemia in 8 patients (27%). All patients had elevated serum alkaline phosphatase and alanine aminotransferase and 28 (93%) had antimitochondrial antibodies. Ten out of 21 patients (48%) were positive in antinuclear antibodies, of which most were of speckled type. Sixteen out of 18 patients (89%) had elevated serum IgM levels. Interestingly, only one of 26 patients (3.8%) was positive for hepatitis B surface antigen, in contrast to its high prevalence (15%) in the Taiwan population. Special associated diseases, including systemic lupus erythematosus, scleroderma, malignant lymphoma and hepatocellular carcinoma, were each noted in one patient respectively. Eight patients had a history of gallstones before the diagnosis of PBC. The mean follow-up period was 23.6 +/- 19.8 months, and nine patients died during that period. In conclusion, the clinical manifestations of PBC in Taiwan are similar to those in Western countries, but most of our cases were at later stages.

Focal hepatic fatty infiltration may be mistaken for hepatic neoplasm on ultrasonography. A sonographic feature mimicking "space occupying lesions" was identified in 41 cases with focal fatty liver, which led to the recognition of four sonographic patterns: (1) Ten patients in whom the livers were characterized by irregular configurations of hyperechoic and hypoechoic areas. Although confusing to inexperienced sonographers, all of them were properly interpreted by experienced sonographers. (2) One patient in whom the hepatic sonography revealed a hyperechoic nodule, but which was correctly diagnosed by computed tomography (CT) scan. (3) Six patients in whom the livers were characterized by multiple confluent hyperechoic lesions, which were all misinterpreted by sonographers and misinterpreted following CT scans in 4 cases and angiography in 3 cases. (4) Twenty-four patients in whom the livers revealed focal spared areas, which was misdiagnosed by sonographers in 14 cases, but correctly diagnosed by CT scan in all 24 cases.

To elucidate the effects of verapamil on splanchnic haemodynamics in rats with portal hypertension, verapamil was given at a low dose (0.2 mg/kg) and a high dose (2 mg/kg) to the rat model after portal vein ligation. Approximately 10% decrease in arterial pressure was caused by the low dose of verapamil, with significant decreases in cardiac output and portal venous inflow as well as reduced portal pressure; these were all indicative of a rise in portal vascular resistance. In contrast, the marked fall in both arterial pressure and cardiac output in the high dose, accompanied by a significant decrease in the portal pressure and the unchanged portal venous inflow, suggested a reduction in portal vascular resistance. This study shows that the acute effects of verapamil on portal hypertension may vary with the dosage used. These results also demonstrate that, since the therapeutic efficacy and safety of verapamil is only in a very limited range of dose, caution should be taken in its clinical use in the treatment of cirrhosis with portal hypertension.