Journal of Gastroenterology and Hepatology (Australia)

Liver cell death induced by stresses such as ischemia‐reperfusion, cholestasis and drug toxicity can trigger a sterile inflammatory response with activation of innate immune cells through release of damage‐associated molecular patterns (DAMPs). A similar inflammatory response can be induced by pathogen‐associated molecular patterns (PAMPs) such as endotoxin. Both DAMPs and PAMPs activate through toll‐like receptors the resident macrophages (Kupffer cells) and recruit activated neutrophils and monocytes into the liver. Central to this inflammatory response is promotion of reactive oxygen species (ROS) formation by these phagocytes. ROS are the principal toxic mediators by which inflammatory cells kill their targets, e.g. bacteria during host defense but also hepatocytes and other liver cells. The mechanism of ROS‐induced cell killing during inflammation involves the promotion of mitochondrial dysfunction through an intracellular oxidant stress in hepatocytes leading mainly to oncotic necrosis and less apoptosis. The additional release of cell contents amplifies the inflammatory injury. However, an inflammatory oxidant stress insufficient to directly cause cell damage can induce transcription of stress defence genes including antioxidant genes. This preconditioning effect of ROS enhances the resistance against future inflammatory oxidant stress and promotes the initiation of tissue repair processes. Despite the substantial progress in our understanding of mechanisms of inflammatory liver injury during the last decade, more research is necessary to better understand the role of ROS in acute liver inflammation and to develop clinically applicable therapeutic strategies that selectively target the detrimental effects of oxidant stress without compromising the vital function of ROS in host defense.

Hepatocellular carcinoma (HCC) is one of the major cancers in the world. There is a striking variation in HCC incidence rates between various countries, with a highest‐to‐lowest ratio of 112.5 for males and 54.7 for females. The high‐risk populations are clustered in sub‐Saharan Africa and eastern Asia. The male‐to‐female ratio for HCC ranges from < 1 to 6.4 and mostly from 2 to 4. There exist significant variations in the incidence of HCC among different ethnic groups living in the same area and among migrants of the same ethnic groups living in different areas. The age curves of HCC are significantly different in various countries, suggesting variability in exposure to risk factors. Chronic carriers of hepatitis B and C viruses (HBV and HCV, respectively) have an increased risk of HCC. The relative and attributable HCC risk of HBV and HCV carrier status varies in different countries. There exists a synergistic interaction on HCC between the two viruses. Aflatoxin exposure, cigarette smoking, heavy alcohol consumption, low vegetable intake, inorganic arsenic ingestion, radioactive thorium dioxide exposure, iron overload and the use of oral contraceptives and anabolic steroids have been documented as HCC risk factors. Recent molecular epidemiological studies have shown that low serum retinol levels as well as elevated serum levels of testosterone, neu oncoprotein and aflatoxin B₁‐albumin adduct are associated with an increased HCC risk. There is a synergistic interaction on HCC between chronic HBV infection and aflatoxin exposure. Familial aggregation of HCC exists and a major susceptibility gene of HCC has been hypothesized. Patients of some genetic diseases are at an increased risk of HCC. The genetic polymorphisms of cytochrome P450 2E1 and 2D6 and arylamine N‐acetyltransferase 2 are associated with the development of HCC. A doseresponse relationship between aflatoxin exposure and HCC has been observed among chronic HBV carriers who have null genotypes of glutathione S‐transferase M1 or T1, but not among those who have non‐null genotypes. Human hepatocarcinogenesis is a multistage process with the involvement of a multifactorial aetiology. Gene‐environment interactions are involved in the development of HCC in humans.

The incidence of inflammatory bowel diseases (IBD) in East has risen over the past decade to become a global disease. The increasing number of studies on the incidence and course of IBD in East has enabled us to explore East versus West differences in the epidemiology of IBD which could enhance our understanding of the heterogeneity of the disease and eventually assist in the discovery of novel therapeutic targets and design of preventive strategies.

Comparison of population‐based data in East and West reveals that the incidence of IBD has risen rapidly in East while plateauing in West. Furthermore, the clinical presentation and course of IBD differs between East and West with more patients in East presenting with complicated disease. Considering the scarcity of population‐based data from East and the lack of studies with long durations of follow‐up, it remains to be clarified whether these differences reflect true differences in disease presentation. The effects of genetic and environmental risk factors contributing to IBD also differ between Eastern and Western populations. Considering the differential effects of genetic and environmental risk factors in East and West, future studies should seek to discover novel genetic and environmental risk factors which might specifically apply to eastern populations.

In this narrative review, we compare the epidemiology of IBD between eastern and western countries by summarizing evidence from population‐based cohort studies in the last ten years. Furthermore, we look at differences in genetic susceptibility and environmental triggers of IBD between East and West.

Background and Aims:  Non‐alcoholic steatohepatitis (NASH) is commonly associated with type 2 diabetes mellitus (DM). Prevalence of NASH in type 2 DM has not been well studied and there is an epidemic rise in type 2 DM in Asian and Western populations. Its association with chronic liver disease in the form of NASH makes it an important health problem. Hence we have studied its prevalence and correlation of biochemical parameters with histological grades of non‐alcoholic fatty liver disease (NAFLD) in otherwise asymptomatic type 2 DM patients.

Methods:  One hundred and forty‐eight individuals were screened. Forty‐eight individuals were excluded due to history of alcohol intake or liver disease as a result of other causes. One hundred non‐alcoholic individuals with type 2 DM underwent abdominal ultrasonography (US abdomen). Forty‐nine patients had evidence of fatty liver on US abdomen, and 32 of these 49 patients underwent liver biopsy.

Results:  Four of 32 (12.5%) individuals had steatosis alone. Mild, moderate and severe NASH was present in 21/32 (65.5%), 4/32 (12.5%) and 3/32 (9.35%), respectively. Fibrosis was present in 7/32 (21.8%) patients (four grade 1 and three grade 3). There was no significant difference in body mass index (BMI), transaminase levels, serum cholesterol and triglyceride levels among patients with non‐alcoholic fatty liver disease.

Conclusion:  We conclude that the prevalence of NASH is high in type 2 DM patients and liver biopsy is the only investigation to differentiate between non‐alcoholic fatty liver and steatohepatitis.

Liver fibrosis is caused by many chronic diseases. Liver injury results in activation of collagen‐producing cells and excessive deposition of extracellular matrix proteins. This process is orchestrated by many cell types. Hepatocytes apoptosis and inflammatory cells trigger secretion of profibrogenic and proinflammatory cytokines, such as transforming growth factor‐β1, angiotensin II, leptin, which in turn activates hepatic stellate cells, the major source of collagen type I. This review is focused on recent progress in the study of the pathogenesis of liver fibrosis.

Background and Aim:  Multipotential mesenchymal stem cells (MSC), present in many organs and tissues, represent an attractive tool for the establishment of a successful stem cell‐based therapy in the field of regeneration medicine. Adipose tissue mesenchymal stem cells (AT‐MSC), known as adipose‐derived stem cells (ASC) are especially attractive in the context of future clinical applications because of their high accessibility and minimal invasiveness during the procedure to obtain them. The goal of the present study was to induce human ASC into functional hepatocytes in vitro within a very short period of time and to check their therapeutic potential in vivo.

Methods:  In vitro generated ASC‐derived hepatocytes were checked for hepatocyte‐specific markers and functions. Afterwards, they were transplanted into nude mice with liver injury. Twenty‐four hours after transplantation, biochemical parameters were evaluated in blood serum.

Results:  We have shown here that ASC can be differentiated into hepatocytes within 13 days and can reach the functional properties of primary human hepatocytes. After transplantation into mice with acute liver failure, ASC‐derived hepatocytes can restore such liver functions as ammonia and purine metabolism. Markers of liver injury, alanine aminotransferase, aspartate aminotransferase, as well as ammonia, were decreased after ASC‐derived hepatocyte transplantation.

Conclusions:  Our data highlight the properties of ASC as having a special affinity for hepatocyte differentiation in vitro and liver regeneration in vivo. Thus, ASC may be a superior choice for the establishment of a therapy for injured liver.

Chronic liver injury of many etiologies produces liver fibrosis and may eventually lead to the formation of cirrhosis. Fibrosis is part of a dynamic process associated with the continuous deposition and resorption of extracellular matrix, mainly fibrillar collagen. Studies of fibrogenesis conducted in many organs including the liver demonstrate that the primary source of the extracellular matrix in fibrosis is the myofibroblast. Hepatic myofibroblasts are not present in the normal liver but transdifferentiate from heterogeneous cell populations in response to a variety of fibrogenic stimuli. Debate still exists regarding the origin of hepatic myofibroblasts. It is considered that hepatic stellate cells and portal fibroblasts have fibrogenic potential and are the major origin of hepatic myofibroblasts. Depending on the primary site of injury the fibrosis may be present in the hepatic parenchyma as seen in chronic hepatitis or may be restricted to the portal areas as in most biliary diseases. It is suggested that hepatic injury of different etiology triggers the transdifferentiation to myofibroblasts from distinct cell populations. Here we discuss the origin and fate of myofibroblast in liver fibrosis.