Analysis of baseline hepatitis B virus DNA levels in chronic hepatitis B patients with non-hematological malignancies prior to the initiation of cancer chemotherapy.

Reactivation of hepatitis B virus (HBV) infection is common (~20-50%) during cancer chemotherapy. Baseline HBV replication status is an important risk factor for HBV reactivation. To date, data on the baseline HBV DNA level for chronic hepatitis B (CHB) patients prior to chemotherapy, particularly for non-hematological malignancies, are limited. A total of 105 consecutive CHB patients with solid tumors who received prophylactic antiviral therapy prior to chemotherapy from November, 2011 to December, 2014, were enrolled in this study. The patients' tumors included: Breast cancer (37.1%), lung cancer (18.1%), colon cancer (17.1%), head and neck cancer (10.5%), other gastrointestinal tract malignancies (8.6%), gynecological cancer (4.8%) and others (3.8%). The mean age of the enrolled patients was 55.2±1.1 years, 48 of the patients were male, 3 were hepatitis B e antigen-positive, and 26.7% had abnormal alanine aminotransferase (ALT) levels at baseline. The median HBV DNA level measured by quantitative polymerase chain reaction assay prior to chemotherapy was 3.30 log10 IU/ml and 49.5% of the enrolled patients had a baseline HBV DNA level >2,000 IU/ml. A wide range of HBV distribution was found: <20 IU/ml (15.2%), 20≤DNA<2,000 IU/ml (35.3%), 2,000≤DNA<20,000 IU/ml (26.6%), 20,000≤DNA<106 IU/ml (17.2%) and <106 IU/ml (5.7%). Age and baseline ALT level were not strongly associated with virological activity. The mean HBV DNA and the percentage of patients with HBV DNA >2,000 IU/ml were comparable between different cancer groups. Quantitative HBsAg level was a major determinant of baseline HBV DNA, and a significant correlation was noted between log10 hepatitis B surface antigen and log10 HBV DNA levels (γ=0.641, P<0.001). Our study demonstrated a wide distribution of baseline HBV DNA level among CHB patients diagnosed with non-hematological malignancies. Of note, approximately half of the patients (i.e., those with HBV DNA >2,000 IU/ml) had a higher risk of HBV reactivation if no appropriate antiviral prophylaxis was undertaken.

Association of insulin resistance with hepatic steatosis and progression of fibrosis in Chinese patients with chronic hepatitis C.

BACKGROUND/AIMS: To investigate the relationships between insulin resistance, hepatic steatosis, and fibrosis in consecutive non-diabetic Chinese CHC patients with biopsy results. METHODOLOGY: A total of 192 patients were enrolled. Insulin resistance was evaluated by homeostasis model assessment (HOMA-IR). Steatosis was assessed as the percentage of hepatocytes containing macrovesicular fat droplets and degree of hepatic fibrosis was graded by the METAVIR scoring system. RESULTS: As compared with no steatosis group, patients with hepatic steatosis had significantly higher BMI (24.5+/-0.4 vs. 22.3+/-0.3 kg/m2, p<0.001) and HOMA-IR value (3.04+/-0.15 vs. 2.41+/-0.13, p=0.002). Patients with F3-F4 fibrosis had significantly lower ALT/AST ratio (1.38+/-0.06 vs. 1.76+/-0.05, p=0.022), lower platelet count (155+/-6 vs. 207+/-5 x 1000/cumm, p<0.001), and higher HOMA-IR value (3.29+/-0.17 vs. 2.50+/-0.12, p<0.001) as compared with F1-F2 fibrosis group. In addition, mean HOMA-IR progressively elevated along with the severity of hepatic fibrosis (F1: 2.04+/-0.15, F2: 2.77+/-0.17, F3: 3.11+/-0.25, F4: 3.46+/-0.23). Multivariate analyses showed platelet count <150,000/cumm (odds ratio: 3.88, 95% C.I.=2.87-12.05, p<0.001) and HOMA-IR >2.5 (odds ratio: 2.46, 95% C.I.=1.24-4.90, p=0.010) as independent factors associated with F3-F4 fibrosis. CONCLUSIONS: In Chinese CHC patients, insulin resistance can occur in earlier stage of infection and closely related with hepatic steatosis and fibrosis.

Kinetics of hepatitis C virus RNA load during pegylated interferon plus ribavirin therapy in Treatment-naive Chinese patients.

BACKGROUND/AIMS: To investigate the viral kinetics of Chinese CHC patients received pegylated interferon plus ribavirin and examine the impact of HCV genotypes and severity of liver disease. METHODOLOGY: 65 treatment-naove CHC patients who finished a 24-week therapy with peginterferon (alpha-2b (1.5 mcg/kg/week) plus ribavirin (1000-1200 mg /day) and 24 weeks of follow-up were enrolled. Hepatic fibrosis was graded by the METAVIR scoring system. Serum quantitative HCV RNA was determined by Versant HCV RNA 3.0 assay (Bayer Inc.). RESULTS: Genotype non-1 patients responded quickly and a higher percentage of them achieved undetectable HCV RNA (< 615 IU/mL) at week 4 compared with genotype 1 patients (93% vs. 69%, p = 0.018). Degree of hepatic fibrosis significantly affected end-of-treatment and sustained response (SVR). For patients who did not achieve early virological response (EVR), the negative predictive value for SVR was 100%. In genotype 1 patients, undetectable HCV RNA by week 4 was a good marker to predict treatment response, with a positive predictive value of 84% and a negative predictive value of 82%. CONCLUSIONS: EVR can be applied to Chinese patients as an early stopping rule. A 24-week duration of pegylated IFN/ribavirin might be adequate for genotype 1 patients who rapidly responded to therapy.

Role of hepatic nitric oxide synthases in rats with thioacetamide-induced acute liver failure and encephalopathy.

BACKGROUND: Hepatic encephalopathy is neuropsychiatric derangement secondary to hepatic decompensation or portal-systemic shunting. Nitric oxide (NO) synthase inhibition aggravates encephalopathy and increases mortality in rats with thioacetamide (TAA)-induced acute liver failure, suggesting a protective role of NO. This study investigated the roles of endothelium-derived constitutive NO synthase (eNOS) and inducible NOS (iNOS) in the liver of rats with fulminant hepatic failure and encephalopathy. METHODS: Male Sprague-Dawley rats (300-350 g) were randomized to receive TAA 350 mg/kg/day, by intraperitoneal injection or normal saline for 3 days. Severity of encephalopathy was assessed with the Opto-Varimex animal activity meter. Plasma levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, and bilirubin were measured. Hepatic iNOS and eNOS RNA and protein expressions were assessed by reverse transcription-polymerase chain reaction and Western blot analyses, respectively. RESULTS: The TAA group showed lower motor activity counts than the normal saline group. Hepatic eNOS, but not iNOS, mRNA and protein expressions were enhanced in the TAA group. In addition, hepatic eNOS mRNA expression was negatively correlated with total movement but positively correlated with ALT and AST. Protein expression of hepatic eNOS was positively correlated with ALT, AST and bilirubin. CONCLUSION: Upregulation of hepatic eNOS was observed in rats with TAA-induced fulminant hepatic failure and encephalopathy, which might play a regulatory role.

Chronic indomethacin treatment enhances the portal-systemic collateral vascular response to vasopressin in bile-duct ligated rats.

BACKGROUND: Liver cirrhosis is often accompanied by portal-systemic collateral formation with hemorrhage and encephalopathy. Prostacyclin participates in hyperdynamic circulation and vascular hyporeactiveness to vasoconstrictors in cirrhosis. It has been shown that arginine vasopressin (AVP) induces direct collateral vasoconstriction in portal hypertensive rats, which is potentiated by indomethacin preincubation. However, the influence of chronic indomethacin administration in cirrhosis remains unexplored. METHODS: This study was performed on male Sprague-Dawley rats with liver cirrhosis induced by common bile duct ligation. They received subcutaneous indomethacin (5 mg/kg/day) or distilled water (control) injection from the 36th to 42nd day after operation. On the 43rd day, systemic and portal hemodynamics were evaluated and the following experiments were performed with an in situ collateral perfusion model: in the first series, concentration-response curves to AVP (10(-10) to 10(-7) M) were obtained; in the second series, flow-pressure curves were plotted (Krebs solution, 6-18 mL/min), where the slope represents an index of collateral vascular resistance (the higher the resistance, the smaller the amount of shunting vessels, that is, the lower the degree of shunting). RESULTS: The mean arterial pressure and portal pressure were similar between indomethacin and control groups (p > 0.05). Indomethacin elevated the collateral perfusion pressure to AVP (3 x 10(-9), 10(-8) M, p < 0.05) but did not influence the slope of the flow-pressure curve (p > 0.05). CONCLUSION: In bile duct-ligated cirrhotic rats, indomethacin improves the portal-systemic collateral vascular responsiveness to AVP without alleviating the severity of shunting.

Plasma levels of interleukin-6 and interleukin-8 in Chinese patients with non-alcoholic fatty liver disease.

BACKGROUND/AIMS: NAFLD with pathological features resembles alcohol-induced liver injury but its pathogenesis remained unclear. IL-6 and IL-8 belonged to pro-inflammatory cytokines and previous studies in alcoholic liver disease showed plasma levels of IL-6 and IL-8 correlated with disease severity. There has been no report regarding plasma levels of IL-6 and Il-8 in Chinese patients with NAFLD. METHODOLOGY: A total of 94 NAFLD patients and 50 age and sex-matched control subjects were enrolled to compare the clinical characteristics and plasma levels of IL-6/IL-8. IL-6 and IL-8 were determined by commercially available enzyme-linked immunosorbent assay (R&D systems, USA). RESULTS: As compared with control group, NAFLD patients had significantly higher BMI (p<0.001), fasting sugar (p=0.002), cholesterol (p=0.017), and triglyceride (p<0.001) level. NAFLD patients with abnormal ALT had the highest plasma levels of IL-6 but it did not reach the statistical differences as compared with other groups. Plasma IL-8 measurement showed NAFLD patients with abnormal serum ALT had the highest level (42.87+/-16.58 pg/mL), followed by NAFLD with normal ALT (13.53+/-2.32 pg/mL) and control groups (9.19+/-1.75 pg/mL, p=0.028 as compared with NAFLD with abnormal ALT). CONCLUSIONS: Through the chemotactic and proinflammatory effects, IL-8 may play a role in the pathogenesis of NAFLD in Chinese patients.

Risk factors associated with non-alcoholic fatty liver disease in Chinese patients and the role of tumor necrosis factor-alpha.

BACKGROUND/AIMS: Tumor necrosis factor-alpha (TNFalpha) has been reported to be associated with insulin resistance and induce inflammatory cytokines formation. Previous studies in human and animals showed inhibition of TNF-alpha improved severity of non-alcoholic fatty liver disease (NAFLD). The aims of this study were to measure plasma levels of TNFalpha in NAFLD and healthy subjects and investigate potential risk factors. METHODOLOGY: A total of 144 patients (90 NAFLD, 50 controls) were enrolled. Clinical and laboratory data of each patient were collected. Plasma levels of TNF-alpha were measured with a commercially available solid phase sandwich enzyme-linked immunosorbent assay (R&D systems, USA). The lower detection limit of this assay was 0.12 pg/mL. RESULTS: Multivariate analyses showed elevated triglyceride (odds ratio: 7.30, p<0.001) and BMI >25 kg/m2 (odds ratio: 3.57, p<0.005) were the two factors associated with NAFLD. Mean plasma level of TNF-alpha was significantly higher in NAFLD patients with abnormal ALT than controls (2.63+/-0.44 pg/mL vs. 1.56+/-0.10 pg/mL, p=0.016). Modest correlations were noted between plasma levels of TNF-alpha with ALT (r=0.25, p<0.005) and triglyceride (r=0.40, p<0.001). CONCLUSIONS: TNF-alpha may participate in the pathogenesis of NAFLD. Inhibition of TNF-alpha activity by drugs or antibodies may be a potential approach to treat NAFLD patients.

Lack of detrimental or therapeutic effects of cyclooxygenase inhibition in bile duct-ligated rats with hepatic encephalopathy.

BACKGROUND: The pathogenetic mechanisms of hepatic encephalopathy (HE) are not fully understood. Cerebral blood flow regulated by cyclooxygenase (COX) may be involved in the development of HE. There are no comprehensive data concerning the effects of COX inhibition on HE in chronic liver disease. METHODS: Male Sprague-Dawley rats weighing 240-270 g at the time of surgery were selected for experiments. Secondary biliary cirrhosis was induced by bile duct ligation (BDL). Those rats were then divided into two groups to receive i.p. injection of indomethacin (5 mg/kg per day) or distilled water for 7 days from day 36 to day 42 after BDL. The control group consisted of rats receiving a sham operation. Severity of encephalopathy was assessed by counts of motor activity. Plasma levels of tumor necrosis factor (TNF)-alpha and 6-keto-prostaglandin F(1alpha) (6-keto-PGF(1alpha)), and liver biochemistry tests were determined after treatment. RESULTS: The motor activity in both groups of BDL rats were significantly lower than that of the control group (P < 0.001). As compared with the BDL rats treated with distilled water, BDL rats treated with indomethacin had significant lower levels of 6-keto-PGF(1alpha), but the motor activity, TNF-alpha levels and serum biochemistry tests were not significantly different between both BDL groups. CONCLUSIONS: Chronic indomethacin administration did not have significantly detrimental or therapeutic effects on the severity of encephalopathy in BDL rats.

Effects of gabexate mesilate on serum inflammatory cytokines in rats with acute necrotizing pancreatitis.

Gabexate mesilate is a synthetic protease inhibitor. The effectiveness of gabexate mesilate in patients with acute pancreatitis is controversial. Proinflammatory cytokines are associated with systemic inflammatory response syndrome (SIRS) in acute pancreatitis. A compensatory anti-inflammatory response occurs in parallel with SIRS. We investigated the effects of gabexate mesilate on acute necrotizing pancreatitis in rats, emphasizing the changes in serum levels of proinflammatory and anti-inflammatory cytokines. Acute necrotizing pancreatitis was induced by retrograde infusion of sodium taurodeoxycholate into the pancreatobiliary duct in rats. The rats were divided into three groups. Group I was given gabexate mesilate 2 mg/kg/h i.v. continuously 1 h before the induction of acute pancreatitis. Group II was given gabexate mesilate the same dose immediately after the induction of acute pancreatitis. Group III was given normal saline as the controls. Serum levels of amylase, lipase, tumor necrosis factor alpha, interleukin-6, and interleukin-10, pancreatic histopathology and hemodynamics were examined at 5h after the induction of acute pancreatitis. Gabexate mesilate significantly reduced serum levels of amylase, lipase, tumor necrosis factor alpha and interleukin-6 at 5 h. Serum levels of interleukin-10 significantly increased in Group I, as compared with Groups II and III. The severity of pancreatic histopathology, the reduction of mean arterial pressure, the volume of ascites and pancreatic wet weight/body weight ratios were also significantly improved by the administration of gabexate mesilate. The beneficial effects of gabexate mesilate on acute pancreatitis may be, in part, due to the modulation of inflammatory cytokine responses.

Evidence against a role for endotoxin in the hepatic encephalopathy of rats with thioacetamide-induced fulminant hepatic failure.

BACKGROUND AND AIMS: Endotoxin has been proposed to participate in the development of hepatic encephalopathy. However, there is no published data concerning the effects of endotoxin neutralization on the degree of hepatic encephalopathy. The present study investigated the effect of chronic intraperitoneal injection of polymyxin B, a neutralizing antagonist of endotoxin, on hepatic encephalopathy in rats with thioacetamide (TAA)-induced fulminant hepatic failure. METHODS: Male Sprague-Dawley rats weighing 300-350 g were used. Fulminant hepatic failure was induced by intraperitoneal injection of TAA (350 mg/kg/day) for 3 days. Two series of rats were designed to compare the effects of low dose (0.1 mg) or high dose (0.2 mg) intraperitoneal polymyxin B administration versus normal saline (NS) on hepatic encephalopathy. The injection was twice daily started from 2 days prior to TAA administration and lasted for 5 days. Severity of encephalopathy was assessed by the counts of motor activity in an Opto-Varimex animal activity meter. Plasma levels of endotoxin and tumor necrosis factor-alpha (an index of liver injury) were measured by Limulus assay and the ELISA method, respectively. RESULTS: Neutralization of endotoxin by either low dose or high dose polymyxin B administration did not significantly alleviate the degree of hepatic encephalopathy, as represented by the counts of motor activities (P > 0.05). Plasma levels of endotoxin and tumor necrosis factor-alpha were comparable between rats treated with polymyxin B or NS (P > 0.05). CONCLUSION: Our findings do not support the notion that endotoxin plays a major role in the pathogenesis of hepatic encephalopathy in rats with TAA-induced fulminant hepatic failure.

Response of blood endothelin-1 and nitric oxide activity in duodenal ulcer patients undergoing Helicobacter pylori eradication.

AIM: To investigate the effect of Helicobacter pylori eradication on endothelin-1 (ET-1) and nitric oxide (NO) in duodenal ulcer (DU) patients. METHODS: Sixty-six H pylori-infected active DU patients were consecutively enrolled to receive one-week triple therapy (rabeprazole, amoxicillin and metronidazole) and then one-month rabeprazole therapy. They were asked back to determine ulcer and H pylori status using endoscopy one month later. Thirty-seven healthy controls (H pylori +/-: 17/20) were enrolled for comparison. Blood samples were collected in each visit to measure plasma ET-1 and nitrate/nitrite levels using an enzyme immunoassay kit. RESULTS: Sixty DU patients finished trial per protocol. The ulcer healing and H pylori-eradication rates were 86.7% and 83.3%, respectively. Plasma ET-1 level in DU patients was higher than that of H pylori-negative and positive controls (3.59+/-0.96 vs 0.89+/-0.54 vs 0.3+/-0.2 pg/mL, P<0.01), while nitrate/nitrite levels among them were also significantly different (8.55+/-0.71 vs 5.27+/-0.68 vs 6.39+/-0.92 mumol/L, P<0.05). H pylori eradication diminished ET-1 levels (3.64+/-0.55 vs 2.64+/-0.55 pg/mL, P<0.01) but elevated nitrate/nitrite level (8.16+/-0.84 vs 11.41+/-1.42 mumol/L, P<0.05). CONCLUSION: Both plasma ET-1 and nitrate/nitrite levels increase in active DU patients. After an effective H pylori eradication, DU healing is associated with diminished blood ET-1 level and elevated nitrate/nitrite level.

Nitric oxide synthase expression in the splanchnic hyposensitivity to glypressin of a hemorrhage-transfused rat model with portal hypertension.

BACKGROUND: Nitric oxide (NO) has been proposed to participate in the vascular hyporesponsiveness to vasopressin and its long-acting analogue glypressin during hemorrhage in portal hypertensive states. This study surveyed the role of NO regarding splanchnic hyporeactivity to glypressin and NO synthases (NOS) expression in different vascular beds in bleeding portal-hypertensive rats. METHODS: Under general anesthesia with ketamine, partially portal vein-ligated male Sprague-Dawley rats without or with bleeding were used to investigate the hemodynamic effects of glypressin (0.07 mg/kg intravenously) and constitutive (cNOS) and inducible NOS (iNOS) mRNA expression over the abdominal aorta and superior mesenteric artery. RESULTS: Splanchnic hyposensitivity to glypressin was noted in the hemorrhage-transfused rats with enhanced cNOS expression of superior mesenteric artery. No significant differences of cNOS and iNOS expression in abdominal aorta and iNOS in superior mesenteric artery were found between the with-bleeding and without-bleeding groups. CONCLUSIONS: In rats with portal hypertension and acute hemorrhage, cNOS over-expression in superior mesenteric artery may take a part in the splanchnic hyposensitivity to glypressin.

Loss of sympathetic coordination appears to delay gastrointestinal transit in patients with spinal cord injury.

Patients with spinal cord injury (SCI) often suffer from many gastrointestinal (GI) complaints, while delayed GI transit exists in these patients. We are interested in whether the lost sympathetic activity is one of the mechanisms leading to disturbed GI transit in these subjects. Using a noninvasive hydrogen breath test representing orocecal transit time (OCTT) to study GI transit, 36 SCI patients and 12 age- and sex-matched healthy volunteers were enrolled in our study. Meanwhile, electrocardiogram was performed for all subjects. Finally, spectral analysis of heart rate variability (HRV) was then obtained to assess their sympathovagal balance. SCI patients had higher occurrences of GI symptoms, e.g., nausea/vomiting, belching/hiccup, and constipation, compared to controls (P < 0.05). OCTT was delayed in SCI patients compared to controls (180.8 +/- 10.7 vs 98.3 +/- 14.4 min; P < 0.001). The OCTTs of SCI patients were negatively correlated with their low frequencies of HRV (r = -0.384, P = 0.021). In addition, OCTT was further delayed in quadriplegic patients than paraplegic patients (195.8 +/- 14.5 vs 143.6 +/- 19.4 min; P = 0.031). However, neither the SCI etiology, the injury duration, nor the high frequency of HRV had any influence on the delayed OCTT in SCI patients. We conclude that the GI transit of SCI patients is delayed. This transit disturbance is probably due to loss of sympathetic activity, which is one of the essential components in the coordination of GI peristalsis.

Effects of nitric oxide synthase inhibitors on retrograde bile salt-induced pancreatitis rats.

BACKGROUND: The serum levels of proinflammatory cytokines have been reported to be significantly higher in severe acute pancreatitis compared with mild pancreatitis. Nitric oxide (NO) produced by cytokine-inducible NO synthase might be involved as the mechanisms for the progression of pancreatitis and the occurrence of systemic complications. The aim of the study was to evaluate the effects of a non-selective NO synthase inhibitor, nitro-L-arginine methyl ester (L-NAME), and an inducible NO synthase inhibitor, L-canavanine, on sodium taurodeoxycholate-induced acute necrotizing pancreatitis in rats. METHODS: Twenty-eight rats were randomized into 3 groups to receive L-NAME 5 mg/kg/h, L-canavanine 20 mg/kg/h, and equivalent volume of saline, respectively, i.v. infusion after the induction of pancreatitis for 5 hours. The serum levels of amylase and lipase and mean arterial pressure and heart rate at baseline and 5 hours, and cardiac output, systemic vascular resistance, the amount of ascites and pancreatic histopathology at 5 hours were examined. RESULTS: Five hours after induction of pancreatitis, all rats treated with L-canavanine and all but 1 treated with saline survived; however, all rats treated with L-NAME died. As compared with the control group, L-canavanine significantly reduced serum levels of amylase and lipase, the severity of pancreatic edema and necrosis, and the volume of ascites in 5 hours. In addition, L-canavanine significantly improved the reduction of mean arterial pressure and systemic vascular resistance at 5 hours. CONCLUSIONS: L-NAME results in the mortality of acute necrotizing pancreatitis. L-canavanine reduces serum pancreatic enzymes and improves the changes of pancreatic histopathology and systemic hemodynamics at the early stage of acute pancreatitis. Inducible NO synthase inhibitor is beneficial for severe acute pancreatitis.

Spider angiomas in patients with liver cirrhosis: role of vascular endothelial growth factor and basic fibroblast growth factor.

AIM: To investigate whether vascular endothelial growth factor (VEGF) and basic fibroblastic growth factor (bFGF) are associated with spider angiomas in patients with liver cirrhosis. METHODS: Eighty-six patients with liver cirrhosis were enrolled and the number and size of the spider angiomas were recorded. Fifty-three healthy subjects were selected as controls. Plasma levels of VEGF and bFGF were measured in both the cirrhotics and the controls. RESULTS: Plasma VEGF and bFGF were increased in cirrhotics compared with controls (122 +/- 13 vs. 71 +/- 11 pg/mL, P=0.003 for VEGF; 5.1 +/- 0.5 vs. 3.4 +/- 0.5 pg/mL, P=0.022 for bFGF). In cirrhotics, plasma VEGF and bFGF were also higher in patients with spider angiomas compared with patients without spider angiomas (185 +/- 28 vs. 90 +/- 10 pg/mL, P=0.003 for VEGF; 6.8 +/- 1.0 vs. 4.1 +/- 0.5 pg/mL, P=0.017 for bFGF). Multivariate logistic regression showed that young age and increased plasma levels of VEGF and bFGF were the most significant predictors for the presence of spider angiomas in cirrhotic patients (odds ratio [OR]=6.64, 95 % confidence interval [CI]=2.02-21.79, P=0.002; OR=4.35, 95% CI=1.35-14.01, P=0.014; OR=5.66, 95% CI=1.72-18.63, P=0.004, respectively). CONCLUSION: Plasma VEGF and bFGF are elevated in patients with liver cirrhosis. Age as well as plasma levels of VEGF and bFGF are significant predictors for spider angiomas in cirrhotic patients.

Early changes of serum proinflammatory and anti-inflammatory cytokines after endoscopic retrograde cholangiopancreatography.

INTRODUCTION: Endoscopic retrograde cholangiopancreatography (ERCP)-induced pancreatitis provides a model to study the time course of cytokine release during the initiation phase of pancreatitis. The early changes of inflammatory cytokines after ERCP have been unclear. AIMS: To evaluate the early changes in serum levels of proinflammatory and antiinflammatory cytokines after ERCP and to assess their value in the early recognition of post-ERCP pancreatitis. METHODOLOGY: Seventy-eight consecutive patients undergoing ERCP were prospectively studied. The serum concentrations of tumor necrosis factor alpha, interleukin-1beta, interleukin-6, interleukin-8, and interleukin-10 were determined immediately prior to and 1, 4, 8, and 24 hours after ERCP. RESULTS: Seven of 78 patients (9.0%) developed post-ERCP pancreatitis. Serum levels of tumor necrosis factor alpha, interleukin-1beta, interleukin-6, interleukin-8, and interleukin-10 significantly increased at 8 and 24 hours but not at 1 and 4 hours after ERCP in patients with post-ERCP pancreatitis, in comparison with patients without pancreatitis. Using a cutoff level of 36 pg/mL for interleukin-6 at 8 hours after ERCP, we found that the sensitivity and specificity for recognition of post-ERCP pancreatitis were 100% and 87%, respectively. Serum levels of interleukin-6 and interleukin-8 modestly increased from baseline values, 1 to 24 hours after uncomplicated ERCP. CONCLUSION: Proinflammatory and antiinflammatory cytokines significantly increased in the early stage after ERCP-induced pancreatitis. Among the inflammatory cytokines, interleukin-6 is the most useful for recognition of post-ERCP pancreatitis.

Delayed gastrointestinal transit in patients with hepatocellular carcinoma.

BACKGROUND AND AIM: Disturbed gastrointestinal (GI) motility exists in cirrhotic patients; however, less is known about the character of GI transit in hepatocellular carcinoma (HCC) patients. It is interesting to study the GI transit in HCC patients and to explore the patient factors modulating GI transit. METHODS: A non-invasive hydrogen breath test, which measured the orocecal transit time (OCTT), was used to study GI transit in 40 HCC patients, 20 cirrhotics and 40 age- and sex-matched healthy volunteers with normal bowel habits. Meanwhile, their clinical manifestations and various blood parameters, such as platelet count, prothrombin time, erythrocyte sedimentation rate etc. were collected. The plasma endothelin-1 and nitrate/nitrite levels were also measured. RESULTS: The OCTT were delayed in HCC and cirrhotic patients compared with controls (116.3 +/- 7.8 and 104.5 +/- 10.6 vs 75.3 +/- 5.1 min, P < 0.05). Neither the severity of liver damage, presence of ascites, tumor size, portal hypertension, nor various blood parameters, such as nitrate/nitrite, endothelin-1, platelet count etc., had any influence on GI transit. Only serum alpha-fetoprotein levels exhibited a trend toward positive correlation with the OCTT (r = 0.271, P = 0.091). CONCLUSIONS: Hepatocellular carcinoma patients have delayed GI transit. The confounding factor responsible for the disturbance of GI transit in HCC patients needs further exploration.

Clinical significance of the changes of platelet counts and serum thrombopoietin levels in chronic hepatitis C patients treated with different doses of consensus interferon.

Thrombocytopenia is commonly seen in patients with cirrhosis. Both splenomegaly and inadequate thrombopoietin (TPO) production by the cirrhotic liver are responsible for thrombocytopenia. In addition, thrombocytopenia is frequently observed in chronic hepatitis patients who received interferon therapy, and may even lead to the discontinuation of treatment. The aim of this study is to evaluate the clinical significance of the changes of platelet counts and serum TPO levels in chronic hepatitis C patients treated with different doses of consensus interferon (CIFN). Data from 75 chronic hepatitis C patients who received subcutaneous injection of either CIFN 9 (25 patients) or 3 &mgr;g (26 patients) or placebo (24 patients), three times a week for 24 weeks, were analyzed from a randomized controlled study. All patients received a 24-week observation period after the end of the treatment. The results showed a significantly higher degree of decrease in platelet counts and elevated serum TPO in patients receiving CIFN 9 or 3 &mgr;g as compared with placebo at week 12 and week 24 of treatment, respectively. These changes were more obvious in patients receiving CIFN 9 &mgr;g than in patients receiving CIFN 3 &mgr;g. However, both the decrease of platelet counts and elevated serum TPO levels returned to the baseline values after stopping CIFN therapy. Lower hepatic fibrosis score, lower pretreatment serum HCV RNA level, genotype non-1b infection and patients with sustained response to CIFN were manifested with higher degree of serum TPO elevation in response to the CIFN-induced thrombocytopenia. Multivariate logistic regression analysis showed that an age of less than 45 years and a serum TPO level elevation greater than 50% of baseline level at week 12 of CIFN treatment were significantly independent predictors associated with the sustained response to the CIFN treatment. In conclusion, the changes of platelet counts and serum TPO levels in chronic hepatitis C patients during CIFN therapy were reversible, and the degree of changes were more prominent in higher doses of CIFN treatment. The serum TPO response to CIFN-induced thrombocytopenia may serve as a marker for the degree of liver fibrosis, and also as a parameter for predicting therapeutic response.

Role of chronic Helicobacter pylori infection in hyperdynamic circulation of cirrhotic patients.

BACKGROUND/AIMS: Hyperdynamic circulation observed in portal hypertension is characterized by generalized vasodilatation, increased cardiac index, and increased systemic and regional blood flows, and mediated at least partly by increased nitric oxide activities. Recent studies have demonstrated that Helicobacter pylori (H. pylori) infection can stimulate nitric oxide synthase expression and activities. This study investigated if chronic H. pylori infection might be involved in the development of hyperdynamic circulation in cirrhotic patients. METHODOLOGY: Fifty-eight patients with cirrhosis and thirty-six healthy subjects entered this study. The serologic evidence of H. pylori infection was determined with ELISA in both groups. In addition, in cirrhotic patients hemodynamic studies were performed by Swan-Ganz catheterization and thermodilution technique. RESULTS: No significant differences in age (65.5 +/- 0.8 vs. 63.7 +/- 1.1 years), sex (male/female: 43/15 vs. 29/7) and seroprevalence of H. pylori (74.1% vs. 80.6%) were observed between cirrhotic patients and healthy subjects (P > 0.05). The seropositive rate of H. pylori in patients with cirrhosis was not associated with severity of cirrhosis and size of esophageal varices (P > 0.05). There were no significant differences in systemic vascular resistance and hepatic venous pressure gradient between cirrhotic patients with and those without chronic H. pylori infection (P > 0.05). CONCLUSIONS: The seroprevalence of H. pylori in cirrhotic patients is similar to that of healthy controls, and not related to the severity of cirrhosis and degree of portal hypertension. Chronic H. pylori infection does not play a major role in the hyperdynamic circulation observed in cirrhotic patients.