Han Chieh Lin

Endotoxemia in patients with chronic liver diseases: relationship to severity of liver diseases, presence of esophaegeal varices, and hyperdynamic circulation.

Plasma endotoxin levels were investigated using a quantitative Limulus assay in patients with chronic liver diseases and correlated with the severity of liver diseases, the presence of esophageal varices, and hemodynamic parameters. The plasma endotoxin levels were significantly higher in chronic hepatitis patients with acute exacerbation (10.1 +/- 1.3 pg/ml, n = 13, p < 0.05) and patients with cirrhosis (7.0 +/- 0.7 pg/ml, n = 126, p < 0.05) than in healthy subjects (2.9 +/- 0.2 pg/ml, n = 45). Chronic hepatitis patients (n = 30) had plasma endotoxin levels which were similar to those in healthy subjects (4.6 +/- 0.5 vs. 2.9 +/- 0.2 pg/ml, p > 0.05) but lower than those in chronic hepatitis patients with acute exacerbation (4.6 +/- 0.5 vs. 10.1 +/- 1.3 pg/ml, p < 0.05). Endotoxemia (plasma endotoxin level > 5.7 pg/ml) was found in 27%, 85% and 41% of patients with chronic hepatitis, chronic hepatitis with acute exacerbation, and cirrhosis, respectively. In patients with cirrhosis, the plasma endotoxin levels progressively increased in relation to the severity of liver dysfunction (Pughs class A/B/C = 4.9 +/- 0.5/7.9 +/- 1.4/10.2 +/- 2.0 pg/ml, p < 0.05). In contrast, plasma endotoxin levels were comparable between patients with cirrhosis with and without esophageal varices (p > 0.05). Chronic hepatitis patients with acute exacerbation (no collaterization) had much higher plasma endotoxin levels than those in patients with cirrhosis and large varices (p < 0.05), whereas compensated patients with cirrhosis and large esophageal varices had plasma endotoxin levels similar to those seen in chronic hepatitis patients (no collaterization) (p > 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Survival Rates Are Comparable After Radiofrequency Ablation or Surgery in Patients With Small Hepatocellular Carcinomas

BACKGROUND & AIMS Differences in efficacy of radiofrequency ablation (RFA) and surgical resection (SR) are not clear for patients with hepatocellular carcinoma (HCC). METHODS From 2002 to 2007, 419 patients with HCCs ≤5 cm were enrolled consecutively in the study. Among these patients, 190 and 229 patients received RFA and SR, respectively, as their first treatment. Factors were analyzed in terms of overall survival and recurrence by multivariate analysis and propensity score matching analysis. RESULTS The SR group had younger age, a higher male-to-female ratio, higher prevalence of hepatitis B virus, lower prevalence of hepatitis C virus, better liver function reserve, and larger tumor size than the RFA group. The cumulative 5-year overall survival rates were 79.3% in the SR group and 67.4% in the RFA group. During the follow-up period, tumors recurred in 244 patients in a median time of 14.5 ± 15.7 months. Before propensity-score matching, the RFA group had shorter overall survival time (P = .009) and higher tumor recurrence rate (P < .001) than the SR group. After matching, RFA was comparable to SR in overall survival time (P = .519), but the RFA group still had a greater incidence of tumor recurrence (P < .001). In patients with Barcelona Clinic Liver Cancer (BCLC) stage 0 HCC, RFA was as effective as SR for overall survival time and recurrence. CONCLUSIONS Patients with small HCCs have a higher rate of tumor recurrence following RFA than surgery, but overall survival rates are comparable between therapies. RFA is as effective as surgery in patients with BCLC stage 0 HCC.

Relationships between the severity of cirrhosis and haemodynamic values in patients with cirrhosis

Abstract The relationship between the severity of cirrhosis and systemic and hepatic haemodynamic values was evaluated in 193 patients with cirrhosis, most of whom were diagnosed with post‐necrotic cirrhosis. It was found that the hepatic venous pressure gradient and cardiac output in Pughs A patients (13.6 ± 4.8 mmHg and 6.2 ± 1.6 L/min, mean ± s.d.) were significantly lower than in both Pughs B (16.8 ± 4.3 mmHg and 7.3 ± 2.1 L/min) and Pughs C (18.8 ± 5.5 mmHg and 7.4 ± 2.3 L/min) patients (P < 0.01), respectively. In contrast, the systemic vascular resistance in Pughs A patients (1232 ± 369 dyn/s per cm5) was significantly higher than in both Pughs B (1016 ± 345 dyn/s per cm5) and Pughs C (935 ± 234 dyn/s per cm5) patients (P < 0.01), respectively. Additionally, not only was there a positive correlation found between Pughs score and cardiac output and hepatic venous pressure gradient, but a negative correlation was found between Pughs score and systemic vascular resistance. It was also confirmed that the degree of portal hypertension and the hyperdynamic circulation were more severe in patients with ascites than in those without ascites. However, there were no statistically significant differences in hepatic venous pressure gradient among patients with F1, F2 and F3 esophageal varices (15.7 ± 4.0, 17.0 ± 4.8 and 18.0 ± 4.8 mmHg, respectively). It is concluded that in those patients with cirrhosis, the severity of cirrhosis is closely related to the degree of the hyperkinetic circulatory state and portal hypertension.

Updated thresholds for serum alanine aminotransferase level in a large-scale population study composed of 34 346 subjects

The sensitivity of current upper limit of normal (ULN) of serum alanine aminotransferase (ALT) levels for detecting chronic liver disease has been challenged recently.

Administration of a low dose of sildenafil for 1 week decreases intrahepatic resistance in rats with biliary cirrhosis: the role of NO bioavailability.

Increasing NO bioavailability improves hepatic endothelial dysfunction, which ameliorates intrahepatic resistance and portal hypertension. Acute administration of sildenafil increases hepatic production of NO with a reduction in hepatic sinusoid resistance in cirrhotic patients and enhances the vasorelaxation response to NO in cirrhotic rat livers. However, the mechanisms were still unclear. Therefore, our present study aims to evaluate the effects and mechanisms of administration of sildenafil for 1 week on the hepatic microcirculation of cirrhotic rats. Cirrhosis was induced by bile duct ligation with sham-operated rats serving as normal controls. Intrahepatic resistance was evaluated by in situ liver perfusion. Expression of phospho-eNOS (endothelial NO synthase), iNOS (inducible NO synthase), phospho-Akt, PDE-5 (phosphodiesterase-5) and sGC (soluble guanylate cyclase) were determined by Western blot analysis. Biosynthesis of BH4 (tetrahydrobiopterin) and GTPCH-I (GTP cyclohydrolase I) activity were examined by HPLC. Intravital microscopy was used to observe the direct change in hepatic microcirculation. In cirrhotic rat livers, sildenafil treatment increased hepatic sinusoid volumetric flow, NO bioavailability, BH4, GTPCH-I activity, and the protein expression of phospho-Akt, phospho-eNOS and sGC. These events were associated with reduced protein expression of PDE-5, portal perfusion pressure and portal vein pressure. In contrast, sham rats did not produce any significant change in these measurements. In conclusion, sildenafil treatment improves endothelial dysfunction by augmenting NO bioavailability in the hepatic microcirculation.

Prognosis of Early-Stage Hepatocellular Carcinoma: The Clinical Implications of Substages of Barcelona Clinic Liver Cancer System Based on a Cohort of 1265 Patients

AbstractThe prognostic implication of Barcelona Clinic Liver Cancer (BCLC) substages in Asian patients with hepatocellular carcinoma (HCC) is still obscure.The aim to this study is to compare the prognoses among HCC patients in different substages of the BCLC stage 0 and A.We enrolled 1265 treatment-naive HCC patients with BCLC stage 0 or A from 2007 to 2014. Factors in terms of prognoses were analyzed by multivariate analysis.There were 184, 446, 271, 92, and 272 patients in substage 0, A1, A2, A3, and A4, respectively. After a median follow-up period of 21.0 months, patients in stages 0 and A1 had comparable prognoses (P = 0.136). Both of them had significantly higher overall survival rates than those in stages A2–A4 (all P < 0.001). Multivariate analysis revealed that the factors associated with mortality were serum albumin ⩽3.5 g/dL (hazard ratio [HR] 1.459), alpha-fetoprotein >20 ng/mL (HR 1.863), tumor size >3 cm (HR 1.542), BCLC stage A2–A4 (HR 1.488), and treatment modality. Surgical resection had the highest overall survival rate followed by radiofrequency ablation (RFA) (HR 1.598), transarterial chemoembolization (HR 2.224), and other treatments (HR 3.707). Verus patients receiving RFA, those who underwent resection had a higher overall survival rate and lower recurrence rate especially in BCLC stages A2–A4.The BCLC-staging system provided good prognostic stratification for early-stage HCC. Patients with a single tumor >2 cm but without portal hypertension or jaundice had similar prognosis to those in BCLC stage 0. Curative therapies—especially hepatic resection—are suggested in early-stage HCC.

External Validation of Fatty Liver Index for Identifying Ultrasonographic Fatty Liver in a Large-Scale Cross-Sectional Study in Taiwan

Background and Aims The fatty liver index (FLI) is an algorithm involving the waist circumference, body mass index, and serum levels of triglyceride and gamma-glutamyl transferase to identify fatty liver. Although some studies have attempted to validate the FLI, few studies have been conducted for external validation among Asians. We attempted to validate FLI to predict ultrasonographic fatty liver in Taiwanese subjects. Methods We enrolled consecutive subjects who received health check-up services at the Taipei Veterans General Hospital from 2002 to 2009. Ultrasonography was applied to diagnose fatty liver. The ability of the FLI to detect ultrasonographic fatty liver was assessed by analyzing the area under the receiver operating characteristic (AUROC) curve. Results Among the 29,797 subjects enrolled in this study, fatty liver was diagnosed in 44.5% of the population. Subjects with ultrasonographic fatty liver had a significantly higher FLI than those without fatty liver by multivariate analysis (odds ratio 1.045; 95% confidence interval, CI 1.044–1.047, p< 0.001). Moreover, FLI had the best discriminative ability to identify patients with ultrasonographic fatty liver (AUROC: 0.827, 95% confidence interval, 0.822–0.831). An FLI < 25 (negative likelihood ratio (LR−) 0.32) for males and <10 (LR− 0.26) for females rule out ultrasonographic fatty liver. Moreover, an FLI ≥ 35 (positive likelihood ratio (LR+) 3.12) for males and ≥ 20 (LR+ 4.43) for females rule in ultrasonographic fatty liver. Conclusions FLI could accurately identify ultrasonographic fatty liver in a large-scale population in Taiwan but with lower cut-off value than the Western population. Meanwhile the cut-off value was lower in females than in males.

A prognostic model for patients with hepatocellular carcinoma within the Milan criteria undergoing non-transplant therapies, based on 1106 patients

The Milan criteria are used to select candidates with small hepatocellular carcinoma (HCC) for liver transplantation. Due to severe shortage of donors, majority of patients within the Milan criteria need to seek alternative treatments.

Decrypting Cryptogenic Hepatocellular Carcinoma: Clinical Manifestations, Prognostic Factors and Long-Term Survival by Propensity Score Model

Background and Aims The clinical aspects of cryptogenic hepatocellular carcinoma (HCC), defined as HCC in patients without hepatitis B, C or alcoholism, are not clear. We investigated its clinical presentations, long-term survival and prognostic predictors. Methods A total of 2645 HCC patients were studied. One-to-one matched pairs between viral/alcoholic and cryptogenic HCC patients were generated by using the propensity model. The survival analysis was performed with the Kaplan-Meier method and log-rank test, and hazard ratios were calculated with Cox proportional hazards model. Results Among 366 (14%) patients with cryptogenic HCC, 34% of patients were presented with abdominal discomfort, and 31% of patients were identified incidentally. Compared to patients with viral/alcoholic HCC, cryptogenic HCC patients were significantly older (p<0.0001), with poorer performance status (p = 0.0031) and less often underwent curative treatment (p = 0.0041). They also had larger tumor burden (p<0.0001), poorer renal function (p<0.0001), lower α-fetoprotein level (p<0.0001), and more advanced Barcelona Clinic Liver Cancer stages (p<0.0001). With propensity score model, 366 pairs of similar HCC patients were selected and similar long-term survival between the two groups of patients was found (p = 0.1038). For cryptogenic HCC patients, α-fetoprotein ≧49 ng/mL (hazard ratio [HR]: 1.955, p = 0.0002), Child-Turcotte-Pugh class B/C (HR: 2.798, p<0.0001), performance status ≧1 (HR: 2.463, p<0.0001) and vascular invasion (HR: 1.608, p = 0.0257) were independent predictors of poor prognosis. Conclusions Patients with cryptogenic HCC are usually diagnosed with poor general condition at late stages. However, cryptogenic HCC patients have similar prognostic predictors and long-term survival compared with viral/alcoholic HCC patients. Diagnosis at an early stage may improve their clinical outcomes.

Gastric secretion in Chinese patients with cirrhosis

The role of gastric secretion has been controversial in patients with cirrhosis. Except for studies of gastric secretion in cirrhotic patients who underwent a shunt operation, there is no report correlating gastric secretion with portal pressure in patients with cirrhosis. In this study, we evaluated gastric secretion in cirrhotic patients and correlated it with hemodynamic parameters. Within 12 months, 20 normal volunteers and 16 cirrhotic patients were enrolled. Gastric secretion was assessed in all patients, but portal pressure hemodynamic studies were performed only in cirrhotic patients. We found that the median basal acid output, maximal acid output, and basal pepsin output in the controls (1.41 mmol/h, 9.2 mmol/h, and 0.02 mg/h, respectively) and in the cirrhotic patients (0.6 mmol/h, 7.84 mmol/h, and 1.5 mg/h, respectively) were not statistically different. However, maximal pepsin output was lower in the cirrhotic patients (1.5 mg/h) than in the normal subjects (5.14 mg/h) (p < 0.05). Gastric secretion correlated poorly with hepatic venous pressure gradient (HVPG) and the presence of congestive gastropathy in cirrhotic patients. The severity of congestive gastropathy correlated poorly with HVPG. Helicobacter pylori has difficulty replicating in the stomach when HVPG is > 14 mm Hg. We conclude that patients with cirrhosis have a lower maximal pepsin output than that of the healthy subjects. Gastric secretion correlates poorly with HVPG and the presence of congestive gastropathy in patients with cirrhosis.