The 2008 Okuda lecture: Management of hepatocellular carcinoma: From surveillance to molecular targeted therapy.

Hepatocellular carcinoma (HCC) is responsible for approximately 600 000–700 000 deaths worldwide. It is highly prevalent in the Asia-Pacific region and Africa, and is increasing in Western countries. Alpha fetoprotein (AFP) alone is insufficient for HCC screening. A combination with other tumor markers, such as PIVKA-II and AFP-L3, and periodical ultrasound surveillance is necessary. Sensitivity of AFP in depicting HCC is highest, followed by PIVKA-II and AFP-L3, but the order of the specificity is inverse, AFP-L3, PIVKA-II, and AFP. Sonazoid-enhanced ultrasound (US) is extremely useful to characterize hepatic tumors equal to or more than multidetector row computed tomography (MDCT). Sonazoid-enhanced US with defect re-perfusion imaging is a breakthrough technique in the treatment of HCC. Defect re-perfusion imaging will markedly change the therapeutic strategy for liver cancer. Gd-EOB-DTPA-magnetic resonance imaging is a newly developed imaging technique in the detection and diagnosis of HCC. It is the most sensitive tool in the differentiation of early HCC from dysplastic nodules. Regarding the treatment strategy, there has been no established systemic chemotherapy for advanced HCC, except for Sorafenib. Empirically, intrahepatic arterial infusion chemotherapy using implanted reservoir port is known to be effective in response rate and overall survival for advanced HCC with vascular invasion. Sorafenib in combination with transcatheter arterial chemoembolization or adjuvant use after ablation or resection will significantly prolong the life expectancy if ongoing clinical trials provide positive results. In conclusion, it is expected that readers will gain deeper insight into the latest progress and updated diagnosis and treatment of HCC described in this review.

Source: Journal of Gastroenterology and Hepatology


Hepatitis C virus induces oxidative stress, DNA damage and modulates the DNA repair enzyme NEIL1

Hepatitis C virus (HCV)-induced chronic inflammation may induce oxidative stress which could compromise the repair of damaged DNA, rendering cells more susceptible to spontaneous or mutagen-induced alterations, the underlying cause of liver cirrhosis and hepatocellular carcinoma. In the current study we examined the induction of reactive oxygen species (ROS) resulting from HCV infection and evaluated its effect on the host DNA damage and repair machinery.

Methods:  HCV infected human hepatoma cells were analyzed to determine (i) ROS, (ii) 8-oxoG and (iii) DNA glycosylases NEIL1, NEIL2, OGG1. Liver biopsies were analyzed for NEIL1.

Results:  Human hepatoma cells infected with HCV JFH-1 showed 30–60-fold increases in ROS levels compared to uninfected cells. Levels of the oxidatively modified guanosine base 8-oxoguanine (8-oxoG) were significantly increased sixfold in the HCV-infected cells. Because DNA glycosylases are the enzymes that remove oxidized nucleotides, their expression in HCV-infected cells was analyzed. NEIL1 but not OGG1 or NEIL2 gene expression was impaired in HCV-infected cells. In accordance, we found reduced glycosylase (NEIL1-specific) activity in HCV-infected cells. The antioxidant N-acetyl cystein (NAC) efficiently reversed the NEIL1 repression by inhibiting ROS induction by HCV. NEIL1 expression was also partly restored when virus-infected cells were treated with interferon (IFN). HCV core and to a lesser extent NS3-4a and NS5A induced ROS, and downregulated NEIL1 expression. Liver biopsy specimens showed significant impairment of NEIL1 levels in HCV-infected patients with advanced liver disease compared to patients with no disease.

Conclusion:  Collectively, the data indicate that HCV induction of ROS and perturbation of NEIL1 expression may be mechanistically involved in progression of liver disease and suggest that antioxidant and antiviral therapies can reverse these deleterious effects of HCV in part by restoring function of the DNA repair enzyme/s.

Source: Journal of Gastroenterology and Hepatology


Preoperative staging of gastric cancer by endoscopic ultrasonography and multidetector-row computed tomography.

The aim of this study was to determine the accuracy of endoscopic ultrasonography (EUS) and multidetector-row computed tomography (MDCT) for the locoregional staging of gastric cancer. EUS and computed tomography (CT) are valuable tools for the preoperative evaluation of gastric cancer. With the introduction of new therapeutic options and the recent improvements in CT technology, further evaluation of the diagnostic accuracy of EUS and MDCT is needed.

Methods:  In total, 277 patients who underwent EUS and MDCT, followed by gastrectomy or endoscopic resection at Bundang Hospital, Seoul National University, from July 2006 to April 2008, were analyzed. The results from the preoperative EUS and MDCT were compared to the postoperative pathological findings.

Results:  Among the 277 patients, the overall accuracy of EUS and MDCT for T staging was 74.7% and 76.9%, respectively. Among the 141 patients with visualized primary lesions on MDCT, the overall accuracy of EUS and MDCT for T staging was 61.7% and 63.8%, respectively. The overall accuracy for N staging was 66% and 62.8%, respectively. The performance of EUS and MDCT for large lesions and lesions at the cardia and angle had significantly lower accuracy than that of other groups. For EUS, the early gastric cancer lesions with ulcerative changes had significantly lower accuracy than those without ulcerative changes.

Conclusions:  For the preoperative assessment of individual T and N staging in patients with gastric cancer, the accuracy of MDCT was close to that of EUS. Both EUS and MDCT are useful complementary modalities for the locoregional staging of gastric cancer.

Source: Journal of Gastroenterology and Hepatology


Terlipressin therapy for reversal of type 1 hepatorenal syndrome: A meta-analysis of randomized controlled trials

Hepatorenal syndrome (HRS) is a serious complication of advanced liver disease and carries a poor prognosis. Recent trials have indicated that terlipressin may be effective in reversing HRS. Our aim was to evaluate the efficacy of terlipressin therapy in reversing type 1 HRS defined as a serum creatinine <1.5 mg/dL during treatment.

Methods:  Randomized controlled trials in which patients with type 1 HRS received at least 3 days of terlipressin therapy and albumin in the intervention arm were included after a systematic search of the published English reports. Studies with other vasoconstrictor therapies in the control group were excluded.

Results:  A total of 223 patients with HRS type 1 in four different trials, were included in the final analysis. Alcohol-related cirrhosis was the most common underlying etiology. The risk ratio for reversal in type 1 HRS with terlipressin therapy was 3.66 (95% confidence interval 2.15–6.23). Recurrence of HRS was low (8%). Serious side-effects requiring discontinuation of therapy were seen only in 6.8% of patients on terlipressin therapy. There was a trend towards improved transplant-free survival at 90 days in the terlipressin group (relative risk 1.86 95% confidence interval 1.0–3.4, P = 0.05).

Conclusions:  Terlipressin is effective in reversing HRS type 1. Recurrence of HRS is rare with at least 14 days of therapy. Serious side-effects requiring discontinuation of therapy are less common. There appears to be a survival benefit in patients with HRS treated with terlipressin.

Source: Journal of Gastroenterology and Hepatology



Irritable bowel syndrome: Epidemiology, diagnosis and treatment: An update for health-care practitioners.

Irritable bowel syndrome (IBS), a chronic gastrointestinal disorder, affects from 3–20% of the US population, depending on sociocultural and comorbid factors. IBS is characterized by a symptom complex of abdominal pain and abnormal bowel habits that present as diarrhea or constipation, and general physical weakness in the absence of abnormal morphological, histological or inflammatory markers. The main diagnostic Rome III criteria as established by international professional organizations are based on exclusion criteria and the occurrence and rate of symptoms. Because the pathophysiology and causes of IBS are poorly understood, treatment approaches are mainly focused on symptom management to maintain everyday functioning and improve quality of life for persons with IBS. The mainstay of intervention is pharmacological treatment with antispasmodics and antidiarrheals for diarrhea, prokinetics and high-fiber diets for constipation, and supportive therapy with low-dose antidepressants to normalize gastrointestinal motility. Other interventions include lifestyle and dietary changes, psychotherapy, herbal therapies and acupuncture. The purpose of this review is to critically assess benefits and risks of current treatment approaches as well as promising complementary and alternative therapies.

Source: Journal of Gastroenterology and Hepatology



A fresh look at NASH pathogenesis.

The strong relationship between over-nutrition, central obesity, insulin resistance/metabolic syndrome and non-alcoholic fatty liver disease (NAFLD) suggest pathogenic interactions, but key questions remain. NAFLD starts with over-nutrition, imbalance between energy input and output for which the roles of genetic predisposition and environmental factors (diet, physical activity) are being redefined. Regulation of energy balance operates at both central nervous system and peripheral sites, including adipose and liver. For example, the endocannabinoid system could potentially be modulated to provide effective pharmacotherapy of NAFLD. The more profound the metabolic abnormalities complicating over-nutrition (glucose intolerance, hypoadiponectinemia, metabolic syndrome), the more likely is NAFLD to take on its progressive guise of non-alcoholic steatohepatitis (NASH). Interactions between steatosis and insulin resistance, visceral adipose expansion and subcutaneous adipose failure (with insulin resistance, inflammation and hypoadiponectinemia) trigger amplifying mechanisms for liver disease. Thus, transition from simple steatosis to NASH could be explained by unmitigated hepatic lipid partitioning with failure of local adaptive mechanisms leading to lipotoxicity. In part one of this review, we discuss newer concepts of appetite and metabolic regulation, bodily lipid distribution, hepatic lipid turnover, insulin resistance and adipose failure affecting adiponectin secretion. We review evidence that NASH only occurs when over-nutrition is complicated by insulin resistance and a highly disordered metabolic milieu, the same ‘metabolic movers’ that promote type 2 diabetes and atheromatous cardiovascular disease. The net effect is accumulation of lipid molecules in the liver.

Source: Journal of Gastroenterology and Hepatology


Evidence-based dietary management of functional gastrointestinal symptoms: The FODMAP approach

Functional gastrointestinal symptoms are common and their management is often a difficult clinical problem. The link between food intake and symptom induction is recognized. This review aims to describe the evidence base for restricting rapidly fermentable, short-chain carbohydrates (FODMAPs) in controlling such symptoms.

Methods:  The nature of FODMAPs, their mode of action in symptom induction, results of clinical trials and the implementation of the diet are described.

Results:  FODMAPs are widespread in the diet and comprise a monosaccharide (fructose), a disaccharide (lactose), oligosaccharides (fructans and galactans), and polyols. Their ingestion increases delivery of readily fermentable substrate and water to the distal small intestine and proximal colon, which are likely to induce luminal distension and induction of functional gut symptoms. The restriction of their intake globally (as opposed to individually) reduces functional gut symptoms, an effect that is durable and can be reversed by their reintroduction into the diet (as shown by a randomized placebo-controlled trial). The diet has a high compliance rate. However it requires expert delivery by a dietitian trained in the diet. Breath hydrogen tests are useful to identify individuals who can completely absorb a load of fructose and lactose so that dietary restriction can be less stringent.

Conclusions:  The low FODMAP diet provides an effective approach to the management of patients with functional gut symptoms. The evidence base is now sufficiently strong to recommend its widespread application.

Source: Journal of Gastroenterology and Hepatology


Role of renin-angiotensin system in gastric oncogenesis.

The renin-angiotensin system (RAS) plays an important role not only in homeostasis but also in carcinogenesis. Recent epidemiological studies suggest that hypertensive patients with upregulated systemic RAS functions are at a significantly increased risk for the subsequent development of cancers with poor outcomes, and moreover that RAS inhibitors reduce tumor development, progression, and metastasis. Notably, Helicobacter pylori infection, one of the major predictors of gastric carcinogenesis, generally leads to RAS component overexpression, as exemplified by that of angiotensin I, angiotensin II, angiotensin I converting enzyme and angiotensin II receptor. Gastric mucosal RAS expression gradually increases with time after H. pylori infection with respect to the severity of inflammatory cell infiltration. Gastric carcinogenic potential is therefore considered to relate to RAS component expression levels and activities. This hypothesis is supported by findings that RAS genotypic variation can lead to high component expression levels (e.g. angiotensin I converting enzyme, chymase and angiotensinogen), and thereby increase the risk of development of gastric cancer. Thus, the RAS may be potently associated with the pathogenesis of H. pylori-related gastric carcinogenesis, and RAS inhibitors may provide tools for specifically preventing this disease.

Source: Journal of Gastroenterology and Hepatology

Immunopathogenesis and prognostic immune markers of chronic hepatitis B virus infection.

Host immune responses induced by hepatitis B virus (HBV) infection not only substantially drive disease progression, but also significantly influence efficacy of antiviral treatments in HBV-infected individuals. Therefore, it is important to fully understand the course of immune pathogenesis and to find efficient immunological markers that can predict the disease progression of chronic HBV infection. This review introduces the current progress in clinical immunology and analyzes the mechanisms of antiviral effects and liver injury, which are induced by both innate and adaptive immune responses. The recently identified immunological markers indicated to be closely correlated with disease progression and antiviral efficacy during HBV infection are also summarized. Careful monitoring of these immune markers may help physicians to make decisions on when to begin or withdraw antiviral drugs, or to formulate the prognosis of acute-on-chronic liver failure (ACLF) patients in the clinic. Finally, this review highlights some novel therapeutic strategies to modulate host immunity that have been proposed to sustain antiviral control of chronic HBV infection, as well as the challenges that we are presently facing in the field.

Source: Journal of Gastroenterology and Hepatology


Colorectal cancer mouse models: Integrating inflammation and the stroma.

Sequences of molecular events that initiate and advance the progression of human colorectal cancer (CRC) are becoming clearer. Accepting that these events, once they are in place, accumulate over time, rapid disease progression might be expected. Yet CRC usually develops slowly over decades. Emerging insights suggest that the tumor cell microenvironment encompassing fibroblasts and endothelial and immune cells dictate when, whether, and how malignancies progress. Signaling pathways that affect the microenvironment and the inflammatory response seem to play a central role in CRC. Indeed, some of these pathways directly regulate the stem/progenitor cell niche at the base of the crypt; it now appears that the survival and growth of neoplastic cells often relies upon their subverted engagement of these pathways. Spurned on by the use of gene manipulation technologies in the mouse, dissecting and recapitulating these complex molecular interactions between the tumor and its microenvironment in the gastrointestinal (GI) tract is a reality. In parallel, our ability to isolate and grow GI stem cells in vitro enables us, for the first time, to complement reductionist in vitro findings with complex in vivo observations. Surprisingly, data suggest that the large number of signaling pathways underpinning the reciprocal interaction between the neoplastic epithelium and its microenvironment converge on a small number of common transcription factors. Here, we review the separate and interactive roles of NFκB, Stat3, and Myb, transcription factors commonly overexpressed or excessively activated in CRC. They confer molecular links between inflammation, stroma, the stem cell niche, and neoplastic cell growth.

Source: Journal of Gastroenterology and Hepatology