Gin-Ho Lo

Heavy alcohol consumption increases the incidence of hepatocellular carcinoma in hepatitis B virus-related cirrhosis

BACKGROUND & AIMS Taiwan has a high prevalence of hepatitis B viral (HBV) infection and hepatocellular carcinoma (HCC) with increasing consumption of alcohol. We investigated the impact of heavy alcohol consumption and HBV infection on HCC in cirrhotic patients. METHODS 966 cirrhotic patients (132 with HBV infection and alcoholism, 632 with HBV infection, and 202 patients with alcoholism) were enrolled between 2000 and 2009 and followed until 2011. The primary end point was newly developed HCC. RESULTS Within the three patient groups (cirrhotic patients with HBV infection and alcoholism, HBV infection alone, and alcoholism alone) 38 (28.8%), 100 (15.8%), and 21 (10.4%) showed newly developed HCC, respectively. The 10-year cumulative (52.8% vs. 39.8% vs. 25.6%, p <0.001) and annual incidences (9.9%, 4.1%, and 2.1%) of HCC were significantly higher in cirrhotic patients with HBV infection and alcoholism than those in patients with HBV infection or alcoholism alone. For patients with HBV infection and alcoholism, baseline serum HBV DNA (OR=16.8, p=0.025), antiviral nucleos(t)ides analogues (NUCs) therapy (OR=0.01, p=0.035), and serum α-fetoprotein (OR=1.18, p=0.045) were risk predictors of HCC by multivariate logistic regression models. The cumulative incidence of HCC was higher in patients with higher baseline serum HBV DNA. Antiviral NUCs therapy reduced the incidence of HCC. CONCLUSIONS Heavy alcohol consumption significantly increased the risk of HCC in HBV-related cirrhotic patients. Elevated baseline serum HBV DNA was a strong risk predictor of HCC and antiviral NUCs therapy reduced the incidence of HCC in cirrhotic patients with HBV infection and alcoholism.

Controlled trial of ligation plus nadolol versus nadolol alone for the prevention of first variceal bleeding

Both nadolol and ligation have proved to be effective in the prophylaxis of first variceal bleeding. This study was conducted to evaluate the effects and safety of combining nadolol with ligation. Cirrhotic patients with high‐risk esophageal varices but without a bleeding history were considered for enrolment. Eligible patients were randomized to receive band ligation plus nadolol (Combined group, 70 patients) or nadolol alone (Nadolol group, 70 patients). In the Combined group multiligators were applied. Patients received regular ligation treatment at an interval of 4 weeks until variceal obliteration. Nadolol was administered at a dose to reduce 25% of the pulse rate in both the Combined group and the Nadolol group. Both groups were comparable in baseline data. In the Combined group 50 patients (71%) achieved variceal obliteration. The mean dose of nadolol was 52 ± 16 mg in the Combined group and 56 ± 19 mg in the Nadolol group. During a median follow‐up of 26 months, 18 patients (26%) in the Combined group and 13 patients (18%) in the Nadolol group experienced upper gastrointestinal bleeding (P = NS). Esophageal variceal bleeding occurred in 10 patients (14%) in the Combined group and nine patients (13%) in the Nadolol group (P = NS). Adverse events were noted in 48 patients (68%) in the Combined group and 28 patients (40%) in the Nadolol group (P = 0.06). Sixteen patients in each group died. Conclusion: The addition of ligation to nadolol may increase adverse events and did not enhance effectiveness in the prophylaxis of first variceal bleeding. (HEPATOLOGY 2010)

Controlled trial of ligation plus vasoconstrictor versus proton pump inhibitor in the control of acute esophageal variceal bleeding.

Endoscopic therapy combined with vasoconstrictor was generally recommended to treat acute variceal bleeding. However, up to 30% of patients may still encounter treatment failure.

The role of endoscopy in secondary prophylaxis of esophageal varices.

The rate of rebleeding from esophageal varices remains appreciably high after cessation of acute esophageal variceal hemorrhage. Many measures have been developed to prevent the occurrence of rebleeding. Endoscopic therapy plays a central role in the prevention of variceal bleeding. In the 1980s sclerotherapy played a pivotal role in the prevention of variceal rebleeding, but now yields to endoscopic variceal ligation. Compared with sclerotherapy, a lower incidence of complications and rebleeding is associated with banding ligation. On the other hand, beta-blockers are also noted to be able to reduce portal pressure, leading to the reduction of variceal rebleeding. The reduction of variceal rebleeding with beta-blockers plus nitrates is as effective as banding ligation. The combination of beta-blockers and endoscopic variceal ligation has proven to be more efficacious than banding ligation alone in the reduction of variceal rebleeding and is the treatment of choice for patients with failure in either medical or endoscopic therapy. Patients with repeated rebleeding despite endoscopic therapies may require transjugular intrahepatic portosystemic stent shunt or shunt operation as a rescue therapy.

Determinants of hepatocellular carcinoma in cirrhotic patients treated with nucleos(t)ide analogues for chronic hepatitis B

OBJECTIVES We aimed to identify determinants of hepatocellular carcinoma (HCC) in cirrhotic patients who received nucleos(t)ide analogues for chronic hepatitis B (CHB). PATIENTS AND METHODS This retrospective-prospective study screened all patients (n = 1630) who received antiviral therapy for CHB between 1 September 2007 and 31 March 2013 at the E-Da Hospital and enrolled 210 consecutive cirrhotic patients with pretreatment viral DNA >2000 IU/mL. Those who developed HCC within 3 months of treatment were excluded. All participants were observed until occurrence of HCC, death or 1 January 2014. The incidence and determinants of HCC were estimated using competing risk analyses adjusted for mortality. RESULTS Thirty-five (16.7%) patients developed HCC during a median follow-up of 25.2 months (IQR, 16.3-37.3 months), with a cumulative incidence of 24.1% (95% CI, 16.3%-32.0%) at 5 years. Multivariate-adjusted analyses identified age >55 years [adjusted hazard ratio (HR), 2.19; 95% CI, 1.03-4.66], male gender (adjusted HR, 3.07; 95% CI, 1.05-9.02), model for end-stage liver disease (MELD) score >12 points (adjusted HR, 2.16; 95% CI, 1.10-4.23) and diabetes mellitus (DM; adjusted HR, 3.49; 95% CI, 1.54-7.91) as independent risk factors after adjusting for multiple covariates, including antidiabetes medication. A scoring formula that used information on age, gender, MELD score, DM and antidiabetes regimen significantly discriminated patients at high or low risk of HCC, with sensitivity and specificity of 82.9% and 62.3%, respectively. CONCLUSIONS Age, gender, hepatic dysfunction, DM and medication for DM are baseline factors that stratify the risk of HCC in cirrhotic patients who receive nucleos(t)ide analogues for CHB.

Management of Acute Esophageal Variceal Hemorrhage

Acute esophageal variceal hemorrhage (AEVH) is a severe complication of portal hypertension. Its management has rapidly evolved in recent years. Traditional methods included vasoconstrictor and balloon tamponade. Vasoconstrictors were shown to control approximately 80% of the bleeding episodes and are generally used as a first‐line therapy. Following the use of vasoconstrictors, endoscopic therapy is often used to arrest the bleeding varices and prevent early rebleeding. A meta‐analysis showed that the combination of vasoconstrictor and endoscopic therapy is superior to endoscopic therapy alone for controlling AEVH. Balloon tamponade may be used to achieve temporary control of the hemorrhage in case of severe bleeding. A transjugular intrahepatic portosystemic stent shunt may be needed in patients with refractory acute variceal hemorrhage. Surgical intervention is now widely contraindicated during acute variceal hemorrhage, except for patients with good liver reserve. Conversely, apart from the control of acute variceal hemorrhage, prophylactic antibiotics were shown to be helpful in the prevention of bacterial infection and to prevent early variceal rebleeding. With the introduction of new treatment modalities and the measures taken to manage patients with AEVH, the mortality due to AEVH has significantly decreased in recent years.

A controlled trial of early versus delayed feeding following ligation in the control of acute esophageal variceal bleeding

Background The impact of feeding after endoscopic treatment of gastroesophageal varices has rarely been thoroughly investigated. We conducted a controlled study to evaluate whether delayed feeding causes a reduced incidence of rebleeding on patients receiving emergency endoscopic therapy for bleeding gastroesophageal varices. Methods Cirrhotic patients presenting with acute esophageal variceal bleeding were provided critical treatment through emergency endoscopic variceal ligation. After bleeding from the varices had been arrested, the eligible participants were randomized to two groups. The early‐feeding group and the delayed‐feeding group were asked to fast for 4 hours and 48 hours, respectively, after endoscopic therapy. The primary end points were initial hemostasis, very early rebleeding, and ulcer‐bleeding rates. Results There were 36 patients enrolled in the early‐feeding group and 34 patients in the delayed‐feeding group. Both groups were comparable in baseline data. Initial hemostasis was achieved in 100% in both groups, and very early rebleeding was not encountered in either group. The incidence of adverse events was similar between both groups. The mean hospitalization days were 6.0 ± 2.4 days (range: 2–17 days) in the early‐feeding group, and 7.5 ± 3.1 days (range: 3–22 days) in the delayed‐feeding group (p < 0.05). Conclusion Early feeding with liquid diet after a successful endoscopic therapy of bleeding varices did not have any impact on hemostasis.

Peptic ulcer bleeding in patients with cirrhosis: Is it as bad as variceal bleeding?

Peptic ulcer bleeding (PUB) is among the most common causes of hospitalization worldwide, however, advances in endoscopic and pharmacological therapies have reduced the case fatality rate to 2.1% (1). In contrast, 6-week mortality of acute variceal bleeding (AVB) remained as high as 20% (2-3). Despite the considerable incidence of peptic ulcers with 6-33% and high recurrence rate of PUB in patients with cirrhosis (4), the specific mechanisms responsible for peptic ulcers remain largely unknown in the setting of cirrhosis (4). This article is protected by copyright. All rights reserved.

Autophagy-related gene LC3 expression in tumor and liver microenvironments significantly predicts recurrence of hepatocellular carcinoma after surgical resection

Background: The role of autophagy‐related markers as the prognostic factor of post‐operative hepatocellular carcinoma (HCC) recurrence remained controversial. Methods: Overall, 535 consecutive HCC patients undergoing curative resection from 2010 to 2014 were followed and classified with early (ER, <2 years) or late recurrence (LR). Autophagy‐related markers, LC3, Beclin‐1, and p62 expression was immunohistochemically assessed in HCC and adjacent non‐tumor (ANT) tissues. Results: HCC recurred in 245 patients: 116 with ER and 129 with LR. The cumulative incidence of recurrence at 1, 3, 5, and 7 years was 9.7%, 33.9%, 53.3%, and 66.3%, respectively. In multivariate analysis, HCC recurrence was significantly associated with low LC3 expression in tumor and ANT tissues, HCC tissues only and ANT tissues only (hazard ratio/95% confidence interval: 6.12/2.473–17.53, 4.18/1.285–13.61, and 1.89/1.299–2.757) and macrovascular invasion (1.63/1.043–2.492) and cirrhosis (1.59/1.088–2.326). ER was significantly associated with low LC3 expression in tumor and ANT tissues, HCC tissues only and ANT tissues only (6.54/2.934–15.81, 3.26/1.034–10.27, and 2.09/1.313–3.321) and macrovascular and microvascular invasion (2.65/1.306–5.343 and 2.55/1.177–5.504). LR was significantly associated with low LC3 expression in tumor and ANT tissues, HCC tissues only and ANT tissues only (5.02/1.372–18.83, 3.19/1.13–12.09, and 1.66/1.051–2.620) and cirrhosis (1.66/1.049–2.631). Patients with low and high LC3 expression in tumor and ANT tissues showed a 5‐year cumulative recurrence of 94.3% and 41.7%, respectively (p < 0.001). Conclusions: The high LC3 expression in the tumor and liver microenvironments is significantly associated with lower HCC recurrence. Furthermore, tumor characteristics and liver microenvironment were also significantly associated with ER and LR, respectively. Translational impact: The analysis for LC3 expression in both the HCC and ANT tissues could identify patients at risk of HCC recurrence.

The autophagy marker LC3 strongly predicts immediate mortality after surgical resection for hepatocellular carcinoma

The remnant livers ability to regenerate may affect post-hepatectomy immediate mortality. The promotion of autophagy post-hepatectomy could enhance liver regeneration and reduce mortality. This study aimed to identify predictive factors of immediate mortality after surgical resection for hepatocellular carcinoma (HCC). A total of 535 consecutive HCC patients who had undergone their first surgical resection in Taiwan were enrolled between 2010 and 2014. Clinicopathological data and immediate mortality, defined as all cause-mortality within three months after surgery, were analyzed. The expression of autophagy proteins (LC3, Beclin-1, and p62) in adjacent non-tumor tissues was scored by immunohistochemical staining. Approximately 5% of patients had immediate mortality after surgery. The absence of LC3, hypoalbuminemia (<3.5 g/dl), high alanine aminotransferase, and major liver surgery were significantly associated with immediate mortality in univariate analyses. Multivariate logistic regression demonstrated that absence of LC3 (hazard ratio/95% confidence interval: 40.8/5.14-325) and hypoalbuminemia (2.88/1.11-7.52) were significantly associated with immediate mortality. The 3-month cumulative incidence of mortality was 12.1%, 13.0%, 21.4% and 0.4%, respectively, among patients with absence of LC3 expression, hypoalbuminemia, both, or neither of the two. In conclusion, the absence of LC3 expression in adjacent non-tumor tissues and hypoalbuminemia were strongly predictive of immediate mortality after resection for HCC.