Showing papers in "Journal of Gastroenterology and Hepatology in 1997"
TL;DR: 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, and there is a synergistic interaction on HCC between chronic HBV infection and a flatoxin exposure.
Abstract: 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 dose-response 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.
464 citations
TL;DR: The promotion of gradual weight loss in obese patients is the most widely recommended therapy but, unfortunately, this is very difficult to achieve and avoidance of precipitous weight loss and careful control of diabetes mellitus are important and undisputed parts of patient management.
Abstract: Nonalcoholic steatohepatitis (NASH) is a reasonably well-defined clinicopathological entity; it has been reported more commonly in women than in men or children of both sexes and it appears to be most closely associated with obesity, diabetes mellitus and related abnormalities, such as hyperlipidaemia and hyperglycaemia. However, the association with female gender, obesity and diabetes may not be as close as suggested by the literature and an underlying condition cannot be discerned in all cases. The natural history of the disease is poorly understood; the associated biopsy features span a wide spectrum, reaching from uncomplicated, clinically non-progressive fatty liver (not NASH in a strict sense) to a slowly progressive fatty liver with inflammation and fibrosis, to steatohepatitis with submassive hepatic necrosis, which has a subfulminant course and is often fatal. Non-progressive fatty liver appears to be very common but is of little clinical importance. The slowly progressive form of the disease represents NASH as encountered by most clinicians and pathologists. It is a common liver disease in current practice; patients may present with cirrhosis and even HCC arising from steatohepatitic cirrhosis. Subfulminant NASH has become exceedingly rare because many clinicians are now aware of the hazards of sudden weight loss, particularly in morbidly obese patients. Treatment options for NASH are still limited. The promotion of gradual weight loss in obese patients is the most widely recommended therapy but, unfortunately, this is very difficult to achieve. Avoidance of precipitous weight loss and careful control of diabetes mellitus are important and undisputed parts of patient management. Administration of UDCA as a treatment of NASH is still under study; it may be effective in some patients. The treatment of established steatohepatitic cirrhosis does not differ substantially from that of other types of cirrhosis and includes orthotopic liver transplantation.
260 citations
TL;DR: Recent progress in non‐surgical treatment of HCC has resulted in a breakthrough of regional therapy looking quite promising, and a combination of different types of regional therapies may yield better outcomes in selected individuals.
Abstract: A decade ago, surgery was the only satisfactory treatment modality for hepatocellular carcinoma (HCC), but it was limited only to selected cases. For the majority of cases of HCC, systemic chemotherapy was one of the few treatment alternatives, but provided only marginal benefit. In the past 20 years, diagnostic methods have improved to an extent that small HCC less than 1 cm can be detected. Moreover, non-surgical treatment is available, of which regional therapy has been shown to prolong patients' survival, and may even replace surgical resection in some cases. Regional therapy is indicated for the treatment of HCC when there is no extrahepatic metastasis and the patient has adequate liver function reserve, thus permitting repeated therapy. Transcatheter hepatic arterial embolization (TAE) using various embolizers has been well documented to include controlled studies. However, it is not indicated for patients with thrombosed main portal veins. Its therapeutic effect is also doubtful when the tumour is infiltrative in nature or is hypovascular, too large or too small. Additional chemotherapeutic agents mixed into the embolizer with lipiodol and degraded starch microspheres or styrene-maleic acid-neocarzinostatin in which chemotherapeutic agents are embedded, are used with a better response, but the survival rate has not shown significant improvement. Ultrasound-guided local injection therapy is another new method of treatment of HCC. Of these techniques, percutaneous ethanol injection therapy (PEIT) is widely used with excellent results for small, encapsulated tumours in livers with less than three HCC. Percutaneous ethanol injection therapy can also be used in cases with portal vein thrombosis, but it is not suitable for patients having coagulopathy or ascites. Using acetic acid, OK-432, interferon or anti-cancer drugs in the injection therapy shows no further benefit over ethanol alone. Transcatheter echoguided thermotherapy or cryotherapy has been reported in small series of patients, as has target therapy with immune or radiotherapy and conformal radiotherapy. Preliminary studies show encouraging results. Systemic therapy with either single drug or multidrugs is ineffective, with a response rate of less than 20%. Immunotherapy, such as with interferon or other cytokines, is not beneficial. Hormone therapy has not been promising, except for treatment with tamoxifen, which has been reported to show some beneficial effect. Gene therapy is still in its infancy. In summary, recent progress in non-surgical treatment of HCC has resulted in a breakthrough of regional therapy looking quite promising. Moreover, a combination of different types of regional therapies may yield better outcomes in selected individuals.
191 citations
TL;DR: Ursodeoxycholic acid (UDCA) administration provides a significant improvement in maternal pruritus and in the biochemical abnormalities, with no adverse effects in the mother or child.
Abstract: Intrahepatic cholestasis of pregnancy is characterized by skin pruritus and a biochemical cholestasis of mild to moderate severity appearing during pregnancy (mainly in the third trimester) and disappearing after delivery. It recurs in 40-60% of future pregnancies. The intensity of pruritus and the laboratory alterations (increased serum bile salts and transaminases in almost all patients, hyperbilirubinaemia in 20% of patients) fluctuate during one pregnancy and also vary in subsequent affected pregnancies. This disease has no meaningful consequences for the mother; in contrast, it is associated with an increased risk of foetal distress, causing premature deliveries and stillbirths. Cholestasis of pregnancy has been recognized in most countries and ethnic groups but its prevalence is higher in Chile (14% of deliveries in 1975 and approximately 4% in 1995) and in Sweden than in other countries. The cause in unknown. Sex hormones, mainly oestrogens and progesterone, appear to be involved in its pathogenesis. An interplay between a genetic metabolic predisposition and some environmental factor(s) is apparently relevant. Clinical and experimental studies suggest that a marginal selenium deficiency could be a dietary pathogenic factor. Some drugs attenuate pruritus and improve maternal cholestasis, but not the foetal prognosis. Ursodeoxycholic acid (UDCA) administration provides a significant improvement in maternal pruritus and in the biochemical abnormalities, with no adverse effects in the mother or child. Recent clinical and experimental studies show that UDCA administration improves maternal disease and foetal prognosis without any detectable adverse effects.
150 citations
TL;DR: The putative role of ethanol‐induced disturbances in iron metabolism in relation to iron as a pro‐oxidant factor is shown and investigations further implicate the endogenous glutathione—glutathione peroxidase system and catalase as important antioxidants and cytoprotective machinery in the hepatocytes exposed to ethanol.
Abstract: Oxidative stress is well recognized to be a key step in the pathogenesis of ethanol-associated liver injury. Ethanol administration induces an increase in lipid peroxidation either by enhancing the production of oxygen reactive species and/or by decreasing the level of endogenous antioxidants. Numerous experimental studies have emphasized the role of the ethanol-inducible cytochrome P450 in the microsomes and the molybdo-flavoenzyme xanthine oxidase in the cytosol. This review shows the putative role of ethanol-induced disturbances in iron metabolism in relation to iron as a pro-oxidant factor. Ethanol administration also affects the mitochondrial free radical generation. Many previous studies suggest a role for active oxygens in ethanol-induced mitochondrial dysfunction in hepatocytes. Recent studies in our laboratory in the Department of Internal Medicine, Keio University, using a confocal laser scanning microscopic system strongly suggest that active oxidants generated during ethanol metabolism produce mitochondrial membrane permeability transition in isolated and cultured hepatocytes. In addition, acetaldehyde, ethanol consumption-associated endotoxaemia and subsequent release of inflammatory mediators may cause hepatocyte injury via both oxyradical-dependent and -independent mechanisms. These cytotoxic processes may lead to lethal hepatocyte injury. Investigations further implicate the endogenous glutathione-glutathione peroxidase system and catalase as important antioxidants and cytoprotective machinery in the hepatocytes exposed to ethanol.
125 citations
TL;DR: The results suggest that an inflammatory reaction induced by H. pylori may be initially triggered by an array of pro‐inflammatery cytokines expressed by infected gastric epithelial cells.
Abstract: Despite the fact that Helicobacter pylori is known to be non-invasive, mucosal infiltration of inflammatory cells have been observed in the gastric mucosa. The exact pathogenesis of such an inflammatory reaction has not been well defined. We explored the repertoire of cytokine genes expressed in human gastric epithelial cells in response to coculture with H. pylori. After gastric epithelial cells, SNU-5 and KATO III, were infected with H. pylori, expression of several cytokine genes was assessed using quantitative reverse transcription polymerase chain reaction. Interleukin (IL)-8, -1 alpha and -1 beta mRNA were expressed in both gastric epithelial cells throughout the entire infection period. In SNU-5, IL-1 alpha and IL-8 mRNA were expressed at 1 h, reached a peak level at 4 h and then decreased. Interleukin-1 beta mRNA was expressed less frequently than IL-1 alpha, or IL-8 mRNA. In SNU-5 cells, granulocyte-macrophage colony-stimulating factor (GM-CSF), monocyte chemoattractant protein-1 (MCP-1), and tumour necrosis factor-alpha (TNF-alpha) mRNA were expressed at 9 h, but was not expressed in KATO III. Gene expression paralleled the amount of IL-8 protein measured by enzyme-linked immunoabsorbent assay (ELISA). Interleukin-8 mRNA expression was not observed in KATO III cells infected with Campylobacter fetus ssp. fetus, Campylobacter jejuni or Escherichia coli. IL-8 mRNA expression was increased not only in gastric epithelial cells but also in non-gastric cells infected with H. pylori. These results suggest that an inflammatory reaction induced by H. pylori may be initially triggered by an array of pro-inflammatory cytokines expressed by infected gastric epithelial cells.
125 citations
TL;DR: The correlation between liver cell damage and the Fas system in the liver of patients with chronic hepatitis C was examined and it was demonstrated that perforin‐ and Fas‐based mechanisms account for all T cell‐mediated cytotoxicity.
Abstract: Hepatitis C virus (HCV) and hepatitis B virus (HBV) are the major causative agents of chronic liver disease. However, the mechanisms responsible for liver cell injury remain to be clarified. Playing crucial roles in the clearance of viral infection are cytotoxic T lymphocytes. Recently, it has been demonstrated that perforin- and Fas-based mechanisms account for all T cell-mediated cytotoxicity. Therefore, we examined the correlation between liver cell damage and the Fas system in the liver of patients with chronic hepatitis C. Fas is a cell surface protein that mediates apoptosis with treatment of the Fas ligand or the anti-Fas antibody. To investigate the role of Fas in type C hepatitis, we examined the correlation between liver cell damage and Fas expression. Fas expression was found mainly in the cytoplasm of hepatocytes and these positive cells were found particularly among infiltrating lymphocytes. A high prevalence of Fas expression was shown in liver tissue with more severe inflammation. The Fas system-mediated death signal requires the interaction of Fas ligand with Fas on target cells. We isolated a 1.9 kb cDNA clone for the human Fas ligand and examined the expression of the Fas ligand in liver-infiltrating mononuclear cells obtained from patients with chronic hepatitis C. The open reading frame encodes 281 amino acids. Next, we examined the expression of the Fas ligand in liver-infiltrating mononuclear cells obtained from patients with chronic hepatitis C. The amplified products (231 bp) derived from Fas ligand transcripts were detected in liver-infiltrating mononuclear cells, whereas no signal was observed in liver tissues. In HCV infection, Fas expression in hepatocytes is up-regulated in accordance with the severity of liver inflammation. When HCV-specific T cells migrate into hepatocytes and recognize the viral antigen via the T cell receptor, they become activated and express Fas ligand that can transduce the apoptotic death signal to Fas-bearing hepatocytes. Thus, the Fas system plays an important role in liver cell injury by HCV infection.
101 citations
TL;DR: The results suggest that excessive hypochlorous acid, hydrogen peroxide, superoxide anion and hydroxyl radical are generated by the inflamed colonic mucosa, and that hypoch chlorous acid might be one of the causes of tissue injury induced by neutrophils.
Abstract: Administration of dextran sulphate sodium to animals induces acute colitis characterized by infiltration of large numbers of neutrophils into the colonic mucosa, which histologically resembles human active ulcerative colitis. It has been reported that neutrophils and the reactive oxygen metabolites produced by them are involved in the progress of ulcerative colitis. This study was intended to clarify their roles by using this animal model. First, possible sources and species of reactive oxygen metabolites were determined using luminol-dependent chemiluminescence with addition of enzyme inhibitors and reactive oxygen metabolite scavengers. Next, to examine whether neutrophils and hypochlorous acid derived from them contribute to tissue injury, we administered RP-3, a monoclonal antibody capable of selectively depleting neutrophils, and taurine, a hypochlorous acid scavenger, to rats treated with dextran sulphate sodium. Addition of azide, taurine, catalase, superoxide dismutase and dimethyl sulphoxide into colonic mucosal scrapings significantly inhibited chemiluminescence production, but allopurinol and indomethacin had no effects. These results suggest that excessive hypochlorous acid, hydrogen peroxide, superoxide anion and hydroxyl radical are generated by the inflamed colonic mucosa. Intraperitoneal injections of RP-3 significantly suppressed bleeding, tissue myeloperoxidase activity, chemiluminescence production and erosion formation. On the other hand, administration of taurine tended to inhibit bleeding and erosion formation to some extent, although it could not significantly suppress them. These data suggest that neutrophils play an important role in the development of this colitis and that hypochlorous acid might be one of the causes of tissue injury induced by neutrophils.
98 citations
TL;DR: The increased risk of H. pylori infection in Chinese and Indians points to either an inherent ethnic genetic predisposition or to socio‐cultural practices peculiar to the particular race which may be responsible for transmission of the infection.
Abstract: The aim of the present study was to determine the risk factors for Helicobacter pylori in a dyspeptic Malaysian population. A cross-sectional survey of 1060 consecutive patients presenting with dyspepsia at the Endoscopic Unit, University Hospital, Kuala Lumpur, Malaysia from January 1994 to July 1995 was undertaken. All patients answered a detailed questionnaire and underwent endoscopy, with two antral biopsies taken for diagnosis of H. pylori using a rapid urease test. An overall H. pylori prevalence of 49.0% was recorded. Helicobacter pylori prevalence in relation to the major endoscopic diagnoses were as follows: non-ulcer dyspepsia (NUD) 31.2%; duodenal ulcer (DU) 91.4%; and gastric ulcer (GU) 74.1%. The prevalence among the races were as follows: Malay 16.4%; Chinese 48.5%; and Indians 61.8%. Multiple logistic regression analysis identified the following as independent risk factors: >45 years old 1.5 (1.1,2.0); male gender 1.6 (1.2,2.1); ethnic group: Chinese 2.5 (1.7,3.7); Indians 4.9 (3.2,7.5); level of education: low 2.3 (1.5,3.5); middle 1.7 (1.1,2.6); and smoking 1.6 (1.2,2.3). Analysis was also performed on DU, GU and non-UD patients separately; in both DU and GU patients, H. pylori prevalence was high regardless of age, sex, race or level of education. However, in DU patients, Indian race had an independent risk factor (Odds ratio = 7.8 (1.2,48.4)). The findings in the NUD group reflected the findings in the 'all patients' group; > 45 years old, male gender, Indian and Chinese race, and low level of education were also significant, independent risk factors. The overall differences in H. pylori prevalence between the different subgroups were mainly due to differences in the NUD group. The increased risk of H. pylori infection in Chinese and Indians points to either an inherent ethnic genetic predisposition or to socio-cultural practices peculiar to the particular race which may be responsible for transmission of the infection.
89 citations
TL;DR: It is found that a distinct pathological type called ‘extrahepatic growth’ or ‘pedunculated HCC’ develops as a result of fusion of right‐sided adrenal metastasis of HCC and the liver, perhaps through the ‘adreno‐ hepatic fusion’ which is rather common in cirrhotic livers.
Abstract: The histopathology and clinical picture of hepatocellular carcinoma (HCC) varies between individual patients and regions. These variations are perhaps due to differences in the genetic alterations that precede hepatocarcinogenesis. In this study, the clinicopathological features of HCC were compared between southern African blacks and Japanese, indicating large differences in the frequency of underlying cirrhosis, grade of cancer cell differentiation and clinical course. Intra-abdominal bleeding and febrile, rapidly progressive HCC are more common among blacks. Such a difference is accounted for, in part, by frequent encapsulation of the tumour which is well differentiated, and grows slowly in an expanding fashion in Japan. Encapsulated HCC was not seen among the black patients studied. Other distinct clinicopathological types discussed in this paper include diffuse-type HCC which is usually caused by multiple portal spread occurring almost simultaneously; the clinical course is fulminant. Sclerosing carcinoma is frequently associated with hypercalcaemia in the United States, but not in Japan. Fibrolamellar carcinoma is nearly non-existent in Asia, whereas it is common among young adults in the West. Its prognosis is generally better than ordinary HCC. Hepatocellular carcinoma has a strong propensity to invade vessel and duct systems. Portal invasion does not produce distinct clinical signs although it may aggravate portal hypertension. Patients with tumour occlusion in the major portal vein may give rise to ischaemic hepatitis when blood pressure drops suddenly in the preterminal stage. Liver parenchyma develops submassive necrosis and clinically there is an acute rise in alanine aminotransferase (ALT). Invasion into a major hepatic vein and the inferior vena cava also occurs, but less frequently compared with portal invasion. The patient can live even with a tumour thrombus in the atrium crossing the tricuspid valves. Intraductal invasion causes acute jaundice as well as an occasional haemobilia with pain. We recently found that a distinct pathological type called 'extrahepatic growth' or 'pedunculated HCC' develops as a result of fusion of right-sided adrenal metastasis of HCC and the liver, perhaps through the 'adreno-hepatic fusion' which is rather common in cirrhotic livers.
89 citations
TL;DR: Genotype 3 is the most common isolate in HCV‐associated chronic liver disease in Pakistan; a significant proportion of HBsAg‐negative cirrhotics are non‐B, non‐C in aetiology; and half of the patients with HCC have serological evidence of HCV infection.
Abstract: UNLABELLED Hepatitis C virus (HCV) is classified into different types depending on nucleotide sequence variability. Detailed information on the distribution of various HCV genotypes in some geographical areas is available but little is known about Pakistan. In this study, a 5' non-coding region (NCR)-based restriction fragment length polymorphism (RFLP) genotyping assay was used to investigate the genotype distribution in a large series of HCV-infected patients in Karachi, Pakistan. Serum samples from 74 hepatitis B surface antigen (HBsAg)-negative patients with a clinical diagnosis of chronic liver disease (60 patients) and hepatocellular carcinoma (HCC) (14 patients) were assayed for anti-HCV antibody by second generation enzyme immunoassay and 48 were confirmed anti-HCV-positive (33 males, 15 females). Other causes of chronic liver disease (e.g. haemochromatosis, Wilson's disease and immune-mediated injury) were ruled out. Liver biopsy was done in 27/48 anti-HCV-positive patients and in all HCC patients. Genotypes were determined for 45/48 anti-HCV-positive study patients; 39/45 (87%) were type 3; four (9%) were type 1; one was type 2; and one was type 5. Past blood transfusion was the main identifiable risk factor found in 10 patients, all type 3. Seven of the 14 HCC patients were anti-HCV positive, (six were type 3). Most patients with hepatitis C presented with established cirrhosis and complications of portal hypertension and liver failure. IN CONCLUSION (i) genotype 3 is the most common isolate in HCV-associated chronic liver disease in Pakistan; (ii) a significant proportion of HBsAg-negative cirrhotics are non-B, non-C in aetiology; and (iii) half of the patients with HCC have serological evidence of HCV infection.
TL;DR: Sensitive assays for HDV‐RNA by polymerase chain reaction and sequencing techniques have clarified the patterns of HDV transmission and have confirmed the existence of unusual clinical forms of the virus and their relationship to replicative levels and genotypes ofHDV.
Abstract: The causative agent of hepatitis delta virus (HDV) is the most unusual of all causative agents for all hepatitis viruses. Current knowledge of the molecular biology of HDV strengthens its proposed classification within the satellites, a family of subviral agents, some of which are pathogens of higher plants. Hepatitis delta virus is the only virus in the satellite family known to infect animal species, with hepatitis D having affected more than 10 million people worldwide who are also infected with its helper virus, HBV. Recently, the world map for hepatitis D appears somewhat modified, with decreasing HDV prevalence in certain areas and some new foci of HDV endemicity. Despite changing HDV prevalence, hepatitis. D, particularly the chronic form, is still an important health problem worldwide in terms of morbidity and mortality (mainly due to chronic liver disease, including hepatocellular carcinoma). Molecular studies have greatly advanced our understanding of the life cycle of HDV and of the function of its proteins. The new molecular information is of clinical relevance, with implications for the pathogenesis of liver damage, the diagnosis of HDV infection, for the natural course of the disease and, potentially, for therapy. Sensitive assays for HDV-RNA by polymerase chain reaction and sequencing techniques have clarified the patterns of HDV transmission and have confirmed the existence of unusual clinical forms of the virus and their relationship to replicative levels and genotypes of HDV. Prevention and treatment of hepatitis D are still in their infancy. However, liver transplantation for delta cirrhosis has proven far more successful than in any other viral form of cirrhosis, with few reinfections of the grafted liver, and has given important information on HDV biology and the pathogenesis of liver damage.
TL;DR: Three clinicopathological phases of chronic hepatitis B virus (HBV) infection are identified and membrane staining of HBsAg on hepatocytes has been shown to correlate well with the presence of viraemia, and latent infection with residual integrated HBV.
Abstract: Three clinicopathological phases of chronic hepatitis B virus (HBV) infection are identified. First, is immune tolerance of HBV. High levels of viraemia are associated with normal alanine aminotransferase (ALT) levels and minimal histological lesions. More than 30-40% of hepatocytes have the hepatitis B core antigen (HBcAg), predominantly in their nuclei. Maternally derived hepatitis B e antigen (HBeAg) crossing the placenta may result in the elimination of T helper cells responsive to HBeAg/HBcAg. This phase can last for periods ranging from a few weeks to 10 or more years until the immune tolerance is lost. Second, is the immune clearance of HBV. Intermediate levels of viraemia are associated with fluctuating ALT levels and active and ongoing hepatitis. Approximately 20-30% of hepatocytes have HBcAg, predominantly in their cytoplasm. Expression of pre-core defective HBV mutants during chronic HBV infection may lead to a reduction in the secretion of HBeAg and may trigger the beginning of the immuno-elimination phase. The mechanism of intrahepatic shift of HBcAg from the nucleus to the cytoplasm and the decreased levels of viraemia in this phase may be, at least in part, secondary to liver damage and regeneration. Third, is latent infection with residual integrated HBV. Undetectable viraemia is associated with normal ALT levels and no virus-induced liver damage. With regard to hepatocyte expression of HBsAg in chronic HBV infection, membrane staining of HBsAg on hepatocytes has been shown to correlate well with the presence of viraemia. The degree of cytoplasmic hepatitis B surface antigen (HBsAg) expression inversely correlates with the level of viraemia. Therefore, HBsAg carriers with high levels of viraemia have low levels of cytoplasmic hepatitis B surface antigen (HBsAg) expression, while those with low levels of viraemia have high levels of cytoplasmic HBsAg expression. However, several exceptions have been identified. High levels of viraemia associated with high levels of cytoplasmic HBsAg expression were recognized in patients with fibrosing cholestatic hepatitis. In contrast, low levels of viraemia associated with low levels of cytoplasmic HBsAg expression were recognized in patients with hepatitis C virus but not hepatitis D virus superinfection.
TL;DR: It was concluded that active preventive measures directed against promiscuity and sexually transmitted disease and the promotion of disposable needles may have contributed to the decrease in HDV endemicity.
Abstract: Superinfection of hepatitis D virus (HDV) among hepatitis B virus (HBV) carriers is mainly through heterosexual contact in Taiwan. This study investigated the change of HDV endemicity and its associated contributory factors. Seventy-seven patients with acute HDV superinfection among 527 consecutive exacerbating hepatitis B surface antigen (HBsAg) carriers were identified over the past 12 years. The prevalence decreased significantly by each 3-year period from June 1983 to May 1995 (23.7, 15.5, 13.1 and 4.2%, respectively, P < 0.001). This trend was more significant in the hepatitis B e antigen (HBeAg)-negative group (P < 0.001) than in the HBeAg-positive group (P = 0.073). Subjects with a history of paid sex and prostitutes were also recruited for analysis both in 1989 and 1996. Although not statistically significant, there was a trend showing a decrease in the prevalence of serum antibody against HDV (anti-HDV) in each risk group: it was lower in 1996 among HBsAg-positive brothel-goers (10.3 vs 6.9%), licensed prostitutes (54.5 vs 50%) and unlicensed prostitutes (36.1 vs 30.8%). Accumulation of anti-HDV-positive subjects in risk groups may mask the actual decrease of new HDV-infected cases. The prevalence of the HBsAg carrier rate among all prostitutes has significantly decreased (18.3 vs 12.2%, P = 0.015). The efficacy of each preventive strategy was examined and mapped with the trend. It was concluded that active preventive measures directed against promiscuity and sexually transmitted disease and the promotion of disposable needles may have contributed to the decrease in HDV endemicity.
TL;DR: In conclusion, the incidence of antitubercuious drug‐induced liver injury was significantly higher in patients > 35 years of age than in patients < 35 years' age, but was not different between HBsAg carriers and non‐carriers.
Abstract: In order to evaluate the incidence, predisposing factors and clinical course of antituberculous drug-induced liver injury in hepatitis B surface antigen (HBsAg)-positive carriers and non-carriers, in an area endemic for hepatitis B, we prospectively followed 240 patients (154 male, 86 female; mean age 40 years) who had received daily isoniazid, rifampicin, ethambutol and pyrazinamide for the treatment of pulmonary tuberculosis. Patients with heavy alcohol consumption, with pretreatment serum alanine aminotransferase (ALT) elevation and who had less than 3 months post-treatment follow-up were excluded from the study. Thirty-one (13%) patients were positive for serum HBsAg before treatment. Sixty-three (26%; 95% CI: 21–32%) patients developed antituberculous drug-induced liver injury. The incidence of drug-induced liver injury was significantly more frequent in patients > 35 years of age than in patients > 35 years of age (33 vs 17%; P 0.05). Using step-wise logistic regression analysis, patient age > 35 years was the only independent variable for predicting antituberculous drug-induced liver injury, while sex, acetylator phenotype, HBsAg carrier status and severity of tuberculosis were not. The peak serum ALT levels in antituberculous drug-induced liver injury were not significantly different between HBsAg carriers and non-carriers. Only one 61-year-old HBsAg carrier developed severe jaundice after 6 months antituberculous therapy; he subsequently died of hepatic failure. In conclusion, the incidence of antitubercuious drug-induced liver injury was significantly higher in patients > 35 years of age than in patients > 35 years of age, but was not different between HBsAg carriers and non-carriers. Mortality occurred in an aged HBsAg carrier superimposed with antituberculous drug-induced liver injury.
TL;DR: The evidence that Chinese herbal medicines can be hepatotoxic will be reviewed and factors that predispose to dose‐dependent hepatic injury will be considered in relation to acetaminophen, an example of acute hepatotoxicity, and methotrexate, an agent that can produce hepatic fibrosis.
Abstract: Drugs and other chemical toxins account for less than 5% of cases of jaundice or acute hepatitis and fewer cases of chronic liver disease, but they are an important cause of more severe types of hepatic injury. Drug reactions produce an array of hepatic lesions that mimic all known hepatobiliary diseases; this poses a diagnostic challenge for physicians and pathologists. Diagnosis of drug-induced hepatic injury is circumstantial, with positive rechallenge being the only factor that unequivocally implicates a particular agent. Nonetheless, other aspects of the temporal relationship between drug ingestion and adverse reaction, exclusion of other diseases, the presence of extrahepatic features of drug hypersensitivity and some findings on liver biopsy can lend support to the diagnosis. Some of these issues will be explored in this review by considering contemporary paradigms of drug-induced hepatic injury. Factors that predispose to dose-dependent hepatic injury will be considered in relation to acetaminophen, an example of acute hepatotoxicity, and methotrexate, an agent that can produce hepatic fibrosis. Flucloxacillin will be discussed as an example of drug-induced cholestatic hepatitis often associated with prolonged cholestasis and the vanishing bile duct syndrome. Minocycline and diclofenac will be mentioned as two drugs for which drug hepatitis is an exceedingly rare complication. Finally, the evidence that Chinese herbal medicines can be hepatotoxic will be reviewed.
Abstract: Molecular techniques have been used to investigate the epidemiology of hepatitis C virus (HCV) at several different levels. At a global level, the time of divergence of the diverse HCV genotypes isolated from different geographical regions has been estimated from the rate of divergence observed among a cohort of individuals infected from a common source. Estimates of more than 300 years for virus subtypes and more than 500-2000 years for virus types are consistent with their current geographical distributions. Analysis of virus sequences has also provided evidence for a common source of infection in several large-scale outbreaks of HCV infection, although where there is evidence that the implicated source contains more than one variant it may be difficult to distinguish individuals infected by different sources. Finally, sequence analysis has been used to investigate the vertical or horizontal transmission of HCV between pairs of individuals. The hypervariable region of the E2 gene is the most informative region to study if samples are available soon after the transmission event, but evidence for more distant events can still be obtained from analysis of genes such as NS5b and E1. Interpretation of some studies is complicated by the conservation of the gene region studied, or by the failure to make comparisons with sequences from epidemiologically unrelated viruses.
TL;DR: The function of Peyer's patches as antigenic sampling sites involves the complex interplay of a variety of mechanisms that aim to recognize luminal antigens, induce an immunological response and decrease the incidence of antigen translocation across the mucosal epithelium.
Abstract: The function of Peyer's patches as antigenic sampling sites involves the complex interplay of a variety of mechanisms that aim to recognize luminal antigens, induce an immunological response and decrease the incidence of antigen translocation across the mucosal epithelium. This is achieved by M cells, which facilitate the uptake of luminal antigens, a vascular architecture that promotes the retention of absorbed antigens within the patch interstitium (allowing for maximal antigenic activation of lymphocytes) and the presence of lymphoid follicles that contain antigen-presenting cells and lymphocytes. Lymphocytes encountering antigen in the Peyer's patches proliferate, differentiate into fully mature antigen-specific effector cells and migrate to the mesenteric lymph nodes where they undergo final maturation. The mature lymphocytes then enter the systemic circulation and migrate throughout the other mucosa-associated lymphoid tissues of the body and "home' into the gut via high endothelial venules and gut-associated lymphoid tissue-specific adhesion molecules, providing antigen-specific lymphocytes at sites likely to re-encounter the antigen.
TL;DR: Depletion of the circulating antioxidants, vitamin A and cysteine, in active ulcerative colitis is likely to be important in the pathophysiology of the disease.
Abstract: Oxygen free radicals produced by neutrophils are important in the pathogenesis of mucosal damage in ulcerative colitis. Vitamin A, vitamin E and cysteine in the plasma can scavenge free radicals. In the present study, plasma levels of vitamin A, vitamin E, cysteine, cystine and protein-bound cysteine were measured in active ulcerative colitis before and immediately after treatment of the active disease, and correlated with disease severity, extent and activity. Plasma vitamin A and cysteine were significantly reduced in active ulcerative colitis compared with controls. Levels of vitamin E, cystine and protein-bound cysteine were not significantly altered in active ulcerative colitis. Vitamin A and cysteine concentrations returned to normal levels (P < 0.05) within 2 weeks of treating active colitis. There were significant negative correlations between clinical severity and the plasma concentrations of vitamin A and cysteine. Plasma cysteine levels also correlated inversely to disease extent. Depletion of the circulating antioxidants, vitamin A and cysteine, in active ulcerative colitis is likely to be important in the pathophysiology of the disease.
TL;DR: In this paper, the authors reviewed the molecular biology of HBeAg and examined its possible functions in the life cycle of hepatitis B virus (HBV) e antigen (HBeAg was discovered in 1972 as one of the serological markers of HBV infection.
Abstract: Hepatitis B virus (HBV) e antigen (HBeAg) was discovered in 1972 as one of the serological markers of HBV infection. Although 25 years have passed since its initial discovery, the function of this antigen in the life cycle of HBV has remained elusive. Mutations in the HBV genome that prevent the expression of HBeAg do not abolish the replication of HBV, indicating that this antigen is not essential for HBV replication. In contrast, the conservation of the HBeAg gene in the genomes of related animal viruses, including the distantly related duck HBV, argues for an important function of this antigen. The purpose of the present article is to review the molecular biology of HBeAg and to examine its possible functions in the life cycle of HBV.
TL;DR: Assessment of the effects of glycyrrhizin on immune‐mediated cytotoxicity using an antigen‐specific murine CD4+ T hybridoma line and a murine TNF‐α‐sensitive fibroblast line suggest that the decrease of elevated transaminase levels by glycy rhoizin in patients with chronic viral hepatitis is mediated in part by inhibition of immune‐ mediated cytot toxicity against hepatocytes.
Abstract: Intravenous administration of glycyrrhizin is known to decrease elevated plasma transaminase levels in patients with chronic viral hepatitis, in which immune-mediated cytotoxicity by cytotoxic T lymphocytes and tumour necrosis factor (TNF)-alpha is considered to play an important pathogenic role. However, the immunological interpretation of the transaminase-lowering action of glycyrrhizin is not known. Studies were performed to elucidate this action immunologically by assessing the effects of glycyrrhizin on immune-mediated cytotoxicity using an antigen-specific murine CD4+ T hybridoma line, which exhibits cytotoxicity against antigen-presenting cells after stimulation with specific antigen, and a murine TNF-alpha-sensitive fibroblast line. Glycyrrhizin inhibited the cytotoxic activity of the T cells against antigen-presenting cells and also suppressed TNF-alpha-induced cytotoxicity in the TNF-alpha-sensitive cell line in vitro. These results suggest that the decrease of elevated transaminase levels by glycyrrhizin in patients with chronic viral hepatitis is mediated in part by inhibition of immune-mediated cytotoxicity against hepatocytes.
TL;DR: Hepatitis B and hepatitis C are two common pathogens causing chronic hepatitis in patients with end‐stage renal disease (ESRD) and Combination therapy with interferodlamivudine for hepatitis B andInterferodribavirin for hepatitis C may offer a promise of effective control of viral replication in the future.
Abstract: Hepatitis B and hepatitis C are two common pathogens causing chronic hepatitis in patients with end-stage renal disease (ESRD). With the acceptance of hepatitis B s antigen (HBsAg) screening, infected patients have been identified and isolated over the past 20 years. Consequently, hepatitis B is now being seen less frequently in dialysis units. Even though hepatitis B has become less of a problem, non-A, non-B hepatitis has been recognized as a significant problem since 1979. With the availability of serological testing for hepatitis C virus (HCV), more specific information is now available in regard to HCV infection in dialysis patients. The prevalence of anti-HCV in haemodialysis (HD) patients is quite variable, ranging from 5 to over 50%. Anti-HCV positivity is associated with previous blood transfusions, mode of therapy and duration of haemodialysis. In Spain and Italy, the annual seroconversion rates of HCV antibodies in dialysis patients are 2-9%; this rate was much higher in Taiwan (15%). Whether patients with HCV infection should be identified and isolated during HD treatment is an issue of controversy. Transplantation is associated with increases in hepatitis B virus (HBV) replicative markers. The survival disadvantage in HBsAg-positive recipients usually did not become apparent until 8 years after transplantation. Hepatitis C virus-infected renal transplant recipients are presumably in a similar situation to patients with hepatitis B, although confirmatory data are currently lacking. Coinfection of HBV and HCV may lead to aggressive liver disease and cirrhosis. A hepatitis B vaccine is recommended for all susceptible dialysis patients. Dialysis patients have lower response rates to hepatitis B vaccines than do other people. Currently, no vaccine is available for hepatitis C. To date, there are no effective treatments available for hepatitis B and hepatitis C. Combination therapy with interferon/lamivudine for hepatitis B and interferon/ribavirin for hepatitis C may offer a promise of effective control of viral replication in the future.
Journal Article•
TL;DR: The prevalence of anti-HCV positivity is associated with previous blood transfusions, mode of therapy and duration of haemodialysis in patients with chronic hepatitis.
Abstract: Hepatitis B and hepatitis C are two common pathogens causing chronic hepatitis in patients with end-stage renal disease (ESRD). With the acceptance of hepatitis B s antigen (HBsAg) screening, infected patients have been identified and isolated over the past 20 years. Consequently, hepatitis B is now being seen less frequently in dialysis units. Even though hepatitis B has become less of a problem, non-A, non-B hepatitis has been recognized as a significant problem since 1979. With the availability of serological testing for hepatitis C virus (HCV), more specific information is now available in regard to HCV infection in dialysis patients. The prevalence of anti-HCV in haemodialysis (HD) patients is quite variable, ranging from 5 to over 50%. Anti-HCV positivity is associated with previous blood transfusions, mode of therapy and duration of haemodialysis. In Spain and Italy, the annual seroconversion rates of HCV antibodies in dialysis patients are 2-9%; this rate was much higher in Taiwan (15%). Whether patients with HCV infection should be identified and isolated during HD treatment is an issue of controversy. Transplantation is associated with increases in hepatitis B virus (HBV) replicative markers. The survival disadvantage in HBsAg-positive recipients usually did not become apparent until 8 years after transplantation. Hepatitis C virus-infected renal transplant recipients are presumably in a similar situation to patients with hepatitis B, although confirmatory data are currently lacking. Coinfection of HBV and HCV may lead to aggressive liver disease and cirrhosis. A hepatitis B vaccine is recommended for all susceptible dialysis patients. Dialysis patients have lower response rates to hepatitis B vaccines than do other people. Currently, no vaccine is available for hepatitis C. To date, there are no effective treatments available for hepatitis B and hepatitis C. Combination therapy with interferon/lamivudine for hepatitis B and interferon/ribavirin for hepatitis C may offer a promise of effective control of viral replication in the future.
Journal Article•
TL;DR: The molecular biology of HBeAg is reviewed and its possible functions in the life cycle of HBV are examined to suggest that this antigen is not essential for HBV replication.
Abstract: Hepatitis B virus (HBV) e antigen (HBeAg) was discovered in 1972 as one of the serological markers of HBV infection. Although 25 years have passed since its initial discovery, the function of this antigen in the life cycle of HBV has remained elusive. Mutations in the HBV genome that prevent the expression of HBeAg do not abolish the replication of HBV, indicating that this antigen is not essential for HBV replication. In contrast, the conservation of the HBeAg gene in the genomes of related animal viruses, including the distantly related duck HBV, argues for an important function of this antigen. The purpose of the present article is to review the molecular biology of HBeAg and to examine its possible functions in the life cycle of HBV.
TL;DR: Hepatitis B transmission is associated with low socioeconomic status, Chinese ethnic group and large family size, while hepatitis C isassociated with an older age and a history of transfusions, a high risk in population for both diseases.
Abstract: This study identifies the risk factors for hepatitis B virus (HBV) and hepatitis C virus (HCV) and measures the prevalence of hepatitis B surface antigen (HBsAg) and antibody to hepatitis C (anti-HCV) in the general population of Jakarta. A population-based sample of 985 people aged 15 and above was surveyed. Risk factors were identified through questionnaires and home visits. Serum was analysed for HBsAg, antibody to hepatitis B surface antigen (anti-HBs), anti-HCV, aspartate aminotransferase (AST) and alanine aminotransferase (ALT). The seroprevalence was: 4.0% (39/985) for HBsAg, 17.2% (170/985) for anti-HBs, and 3.9% (38/985) for anti-HCV. The risk factors for hepatitis B and hepatitis C infection had little in common. Low socioeconomic status was a strong risk factor for HBsAg (adjusted odds ratio (OR) 18.09; 95% confidence interval (CI) 2.35-139.50). In addition, the Chinese group has 2.97 higher risk of having HBV infection compared with the Malayan ethnic group (adjusted OR 2.97; 95% CI 1.22-7.83). There was moderate positive trend between family size and risk of HBsAg positivity (P = 0.130). Age over 50 (adjusted OR 14.72; 95% CI 4.35-49.89) and history of transfusion were significant risk factors for hepatitis C (adjusted OR 3.03; 95% CI 1.25-7.33). Hepatitis B and hepatitis C infections have different risk factors in Jakarta, a high risk in population for both diseases. Hepatitis B transmission is associated with low socioeconomic status, Chinese ethnic group and large family size, while hepatitis C is associated with an older age and a history of transfusions.
TL;DR: The endemic duration of HCV in Tzukuan seemed long enough to induce HCC, but the HCV appeared to be a newly introduced infection in Paisha.
Abstract: In Taiwan, we found two hepatitis B virus (HBV)- and hepatitis C virus (HCV)-endemic townships, Paisha and Tzukuan, with an anti-HCV prevalence of 19 and 37% in men, and 26 and 38% in women, respectively The hepatitis B surface antigen (HBsAg)-positive rates were 25 and 18%, for men and women in Paisha, and 25 and 22% in Tzukuan, respectively According to the national death certification database (1982 to 1991), the annual age-adjusted mortality rates per 100 000 population for liver cancer among men and women were 830 and 138, respectively, in Paisha, and 559 and 170 in Tzukuan compared with 309 and 91 in Taiwan as a whole The male-to-female ratios were 60 in Paisha and 33 in Tzukuan Aetiology of 11 cases of hepatocellular carcinoma (HCC) from Paisha and 14 cases from Tzukuan were analysed All HCC cases from Paisha were HBsAg positive, while 13/14 HCC cases from Tzukuan were anti-HCV positive The endemic duration of HCV in Tzukuan seemed long enough to induce HCC, but the HCV appeared to be a newly introduced infection in Paisha
TL;DR: Evidence to suggest that IFN therapy, when associated with response, tends to reduce the risk of cirrhosis or HCC and prolongs survival, and there is no doubt that satisfactory treatment of chronic viral infection will require more effective agents and demand optimal treatment strategies, many of which are yet to be found.
Abstract: Hepatitis B virus (HBV), hepatitis C virus (HCV) and hepatitis delta virus (HDV) are associated with clinically significant chronic infection that may lead to the development of cirrhosis or even hepatocellular carcinoma (HCC). Intervention at the earliest possible stage is needed to prevent such untoward sequelae. Currently, interferon (IFN) is the only approved and widely used agent for the treatment of these infections, including in HBV patients with precore mutant hepatitis or decompensated cirrhosis, but its efficacy is far from satisfactory. Corticosteroid priming has been shown to increase the efficacy of IFN therapy in HBV patients with low abnormal serum transaminase levels, but only a few responders will clear serum hepatitis Bs antigen (HBsAg). Ongoing randomized controlled trials of thymosin alpha 1, lamivudine and famcyclovir have demonstrated encouraging preliminary results. Therapeutic vaccines, such as polypeptides with human leucocyte antigen (HLA)-specific hepatitis B core antigen (HBcAg) epitopes, are under phase II/III clinical trial. For HDV infection, the use of IFN in the early phase of acute superinfection tends to prevent chronic progression. For HCV infection, IFN used at higher doses for a longer period of time is associated with a higher sustained response, but overall it is still not satisfactory. The combined use of ribavirin or corticosteroid priming may improve the effect of IFN therapy by enhancing the durability of the response. Interferon in the acute phase of HCV infection may also prevent chronic progression. There is evidence to suggest that IFN therapy, when associated with response, tends to reduce the risk of cirrhosis or HCC and prolongs survival. There is no doubt that satisfactory treatment of chronic viral infection will require more effective agents and demand optimal treatment strategies, many of which are yet to be found.
TL;DR: Congenital absence of the terminal portion of the portal vein with visceral venous return to the suprahepatic inferior vena cava, a rare malformation, was demonstrated in an 18‐year‐old Japanese woman who had nodular hyperplasia in the liver and a non‐functioning pancreatic endocrine tumour.
Abstract: Congenital absence of the terminal portion of the portal vein with visceral venous return to the suprahepatic inferior vena cava, a rare malformation, was demonstrated in an 18-year-old Japanese woman She had nodular hyperplasia in the liver and a non-functioning pancreatic endocrine tumour It is generally believed that reduction of portal venous flow causes atrophic changes and, subsequently, nodular hyperplasia occurs in a well-perfused area in the liver However, the liver was not perfused by the portal vein in this case It is suggested that nodular hyperplasia can occur without portal blood flow
TL;DR: The regulation of blood coagulation is dependent on a complex interplay between procoagULant, anticoagulant and fibrinolytic proteins and it is not surprising that the critically balanced coagulated system is dysregulated in patients with liver disease.
Abstract: The regulation of blood coagulation is dependent on a complex interplay between procoagulant, anticoagulant and fibrinolytic proteins. Most of these proteins are synthesised in the liver and their levels are altered in patients with liver disease. The liver also plays an important role in the regulation of haemostasis throughout the clearance of activated clotting factors. It is therefore not surprising that the critically balanced coagulation system is dysregulated in patients with liver disease. In moderate liver failure bleeding disorders predominate, whereas in more advanced liver disease intravascular coagulation is commonly observed and contributes to the overall dysregulation of blood coagulation. In some patients, liver disease can be primarily caused by an abnormality of the coagulation system. These patients usually have a hypercoagulable state caused by a deficiency of a component of the natural anticoagulant system. These include protein C, protein S and antithrombin III. More recently, activated protein C resistance caused by a point mutation in the Factor V gene has been identified as an important risk factor for thrombosis. In these patients the abnormal Factor V is resistant to cleavage by activated protein C resulting in ongoing uncontrolled procoagulant drive. Both hepatic and portal vein thrombosis have been reported in these patients. Appropriate management of these patients should include a thorough assessment of their natural anticoagulant proteins and exclusion of activated protein C resistance as the cause of their thrombotic disorder.
TL;DR: The low incidence of H CC in patients treated with IFN suggests that IFN may prevent the development of HCC, and the effectiveness of interferon (IFN) therapy is investigated.
Abstract: The aims of the present study were to clarify the risk factors for the development of hepatocellular carcinoma (HCC) in chronic hepatitis C virus (HCV) infection and to investigate the effectiveness of interferon (IFN) therapy. We retrospectively studied 343 patients who had been admitted to our hospital; 161 with chronic hepatitis, 49 with liver cirrhosis, 42 with chronic hepatitis bearing HCC and 91 with liver cirrhosis bearing HCC. The mean (+/- SD) observation period was 41.6 +/- 31.1 months. The mean age of HCC and non-HCC patients was 63.5 +/- 7.6 and 56.9 +/- 12.5 years, respectively (P < 0.001). The HCV genotype II (1b) was the most prevalent genotype (92.5%) in HCC patients and the mean age was higher among patients with this genotype (63.6 +/- 7.7 years). Multivariate analysis identified age (P < 0.001), the male gender (P < 0.01), HCV genotype II (1b) (P < 0.05) and excessive alcohol intake (P < 0.05) as independent factors associated with the development of HCC. There was no relationship between the development of HCC and serum HCV levels as quantified by branched DNA assay or competitive reverse transcription polymerase chain reaction. The incidence of HCC in patients who had not received IFN therapy was 10.4/100 person-year, while that of patients who had received IFN therapy was 1.2/100 person-year (P < 0.01) by the person-year method. The low incidence of HCC in patients treated with IFN suggests that IFN may prevent the development of HCC.