Interferon alone is currently the treatment of choice for chronic hepatitis C. The optimal treatment regimen continues to be defined and refined by clinical studies. The variability of the response to interferon seems to be influenced by several factors, including liver histology, viral genotype, level of viraemia, number of predominant quasispecies, and perhaps the type of interferon and treatment regimen. It is therefore quite likely that, in the future, treatment regimens will be tailored to the individual patient in order to maximize the likelihood of a beneficial outcome. It is also likely that the increasing availability of sensitive, quantitative, and affordable assays of hepatitis C viral levels will allow physicians to assess treatment response quite differently from the way we do so today. This will change our philosophy such that we will begin to view and treat chronic hepatitis C as an infection, instead of simply as a liver disease.

The natural history of hepatitis C is complex and still poorly known. Hepatitis C virus (HCV) replication can be detected very soon after exposure and, at least in the transfusional setting, it persists indefinitely in up to 90% of the cases. While liver damage during the acute phase of hepatitis is almost invariably mild (fulminant cases are exceptions), chronic sequelae of HCV infection may be severe in the long run. Chronic hepatitis C, in fact, is a long-lasting indolent process which leads to cirrhosis in approximately 20% of all infected patients. Hepatocellular carcinoma is a well-recognized complication of old infections, as are a number of extrahepatic manifestations, including type II cryoglobulinaemia. The determinants of the severity of the liver disease are still unclear. However, the risk of cirrhosis seems to be greater for patients with old infections, those infected with the genotype 1b and those with associated conditions. The latter are a heterogeneous and increasing group of 'problem' patients, including patients who are co-infected with the human immunodeficiency virus (HIV1), or who are being treated with cytotoxic or immunomodulating drugs. Data suggest that the natural history of hepatitis C is altered in patients with associated conditions, and this might have an impact on strategies of patient management and treatment.

In 20% of patients exposed to hepatitis C virus, infection is transient but, after a few months, the patient remains susceptible to infection with the same strain. Protective immunity is short-lived. This suggests that recovery is related to the cellular immune response, which presumably lyses infected cells, and that the need during recovery for a virus-neutralizing anti-envelope response, is transient. In 80% of patients the infection is persistent, and it seems that antigenic variation of the envelope proteins allows the virus to escape neutralization by anti-envelope responses. The fact that this antigenic variation occurs at a much lower rate in agammaglobulinaemic subjects suggests that the major immune pressure producing this variation is humoral. How the virus-infected cells avoid lysis by cytotoxic T cells, which can be demonstrated in small numbers in the infected liver, remains unclear. The recent observation, that HCV infects CD8 lymphocytes, raises the possibility that virus infection of CD8 cells may impair their function and contribute to persistent infection. The mechanisms of production of cryoglobulin and of autoantibody formation are both unclear.

A great deal of information on the molecular heterogeneity of hepatitis C virus (HCV) has been achieved since its discovery in 1989. However, little is known about the clinical significance of these variations. Based on the degree of sequence variation, HCV has been classified into six major groups or types, differing by 31-34% at the nucleotide level over the entire virus genome. Each type is divided into several subtypes that differ by 20-23% in nucleotide sequence. Viruses within the same subtype are up to 10% divergent and, within infected individuals, vary by up to 1.5%. Genotype distributions are not homogeneous around the world and may reflect both historical and recent parenteral routes of transmission. The clinical implication of these genomic variations are not yet fully elucidated: genotype 1b has been associated with end-stage liver disease, including liver cirrhosis and hepatocellular carcinoma, but this finding might rather reflect its earlier introduction to the populations studied. Consistent evidence exists that types 2 and 3 have a higher response rate to interferon treatment than type 1, although the interplay between genotype and viral load in determining the response is still unclear. Immunohistochemical studies indicate a stronger activation of the endogenous interferon system in the liver of patients infected with type 1 compared to those infected with types 2 and 3, explaining, at least in part, its low responsiveness to exogenous interferon treatment. Biological, sequence-dependent variations of genotypes have been poorly investigated to date, but differential efficiency of translation activity of the 5' non-coding region has been reported. The availability of "in vitro" systems for evaluating pathogenetic aspects and neutralization mechanisms will improve the present knowledge on this world-wide infectious disease and on the clinical usefulness of distinguishing between genotypes.

Hepatitis E has a world-wide distribution and causes substantial morbidity and mortality in some developing countries, particularly among pregnant women. Hepatitis E virus (HEV) has recently been cloned and sequenced, and new diagnostic tests have been developed. These tests have been used to begin to characterize the natural history and epidemiological features of HEV infection. Experimental vaccines have also been developed that offer the potential to prevent hepatitis E. However, much remains to be learned about HEV, including the mechanisms of transmission, the reservoir(s) of the virus, and the natural history of protective immunity in order to develop effective strategies to prevent this disease.

Hepatitis B virus (HBV) is an enveloped hepatotropic DNA virus. Acute and chronic HBV infection causes significant liver diseases such as acute hepatis, fulminant hepatitis and chronic active hepatitis that may lead to liver cirrhosis and the development of hepatocellular carcinoma. The use of molecular biological techniques has substantially improved our understanding of the HBV life cycle. In this review, we discuss recent advances that have contributed to a better understanding of HBV biology. Recent studies in the understanding of the life cycle of HBV such as viral entry, replication, transcriptional regulation, viral regulatory proteins, viral assembly and secretion, and nucleic acid based approaches to antiviral therapy will be emphasized. These advances in molecular biology and relationship to clinical disease will be instrumental in developing effective therapeutic approaches for the estimated 300 million individuals worldwide chronically infected with HBV.

In endemic areas infection with hepatitis B virus is a common cause of chronic liver disease in childhood. High levels of viral replication and mild ALT abnormalities are the rule in children infected perinatally and many of them are likely to maintain viral replication through their youth. Conversely about 90% of children infected later in life clear HBeAg and achieve sustained remission of liver disease before reaching adulthood. The eventual outcome of infection and disease in these patients remains unpredictable as reactivation of liver damage and viral replication may occur after several years of sustained remission. Cirrhosis is a rare and early complication of chronic HBV infection in children, and a risk factor for hepatocellular carcinoma. IFN therapy can accelerate HBV DNA clearance, improving the spontaneous anti-HBe seroconversion rate in Caucasian children by two to three times. Hepatitis delta is the most severe form of chronic viral hepatitis in childhood. Cirrhosis can be diagnosed in up to 26% of patients at presentation, and few cases respond to IFN therapy. Hepatitis C is relatively rare in children. Before the discovery of HCV, blood transfusions were the most common source of infection. Hepatitis C is usually a mild, asymptomatic disease in otherwise healthy children, but has a poor propensity to spontaneous remission over the years. For this reason, and based on the experience in adults, IFN treatment is now being evaluated.

A patient with cryptogenic multifocal ulcerous stenosing enteritis characterized by repeated bouts of intestinal obstruction, ulcerative stenosis of the small bowel relapsing after surgical resection, and steroid sensitivity is described. Fourteen strictures of the jejunum were found at laparotomy. Despite resection, abdominal pain persisted. Steroid therapy was effective but led to dependence. In our patient, cryptogenic multifocal ulcerous stenosing enteritis was associated with fever, asthma, Raynaud's phenomenon, sicca syndrome, heterozygous type I C2 deficiency (28-base pair gene deletion), stenosis, and aneurysms in selective mesenteric angiography. It is hypothesized that cryptogenic multifocal ulcerous stenosing enteritis might be related to a particular form of polyarteritis nodosa with mainly intestinal expression or to a yet unclassified independent vasculitis.

The aim of this study was to determine whether the current literature supports the use of Helicobacter pylori cure as the primary efficacy end point in peptic ulcer clinical trials. This could potentially reduce the complexity of future trials.

We have reviewed in a conceptual manner with appropriate scientific detail the role apoptosis plays in diseases of the gastrointestinal tract. This information should help the clinician and clinician investigator to better understand and treat gastrointestinal diseases. Future investigations in apoptosis probably will provide further insight into the cell-signaling cascades regulating apoptosis, the mechanism(s) by which Bcl-2 inhibits apoptosis, and the precise role of apoptosis in cancer initiation, promotion, and progression. We anticipate that in the future, the practicing gastroenterologist will have therapeutic strategies available to inhibit apoptosis for various gastrointestinal diseases associated with cell death and to induce apoptosis for the treatment of gastrointestinal neoplasia.

At present we are on the threshold of an enormous change in clinical practice. The application of molecular medicine has already started and the area of growth factor biology is particularly relevant to this endeavor (Figure 6) (Jankowski and Polak 1996). Perhaps the major limitation to this process is the rate at which the clinician can comprehend and then undertake carefully designed molecular studies in gastroenterology. In time monographs that specifically address the issue of molecular medicine in clinical gene analysis and manipulation may perhaps replace standard text books (see Jankowski and Polak, 1996).

Cytokines play an important role in the pathology of inflammatory bowel disease by determining the nature of the mucosal immune response. One way of establishing whether CD and UC are causally related to a defect in the host immune response is to look for polymorphisms that are over-represented in these populations. This is being carried out at great pace both for the cytokine genes and for some other immune response genes. A number of gene expression studies have established that those cytokines produced by activated macrophages such as IL-1, IL-6 and TNF are significantly elevated in both diseases. Differences between the two diseases are less clear, and, where they have been found, they probably reflect the accuracy and sensitivity of quantification. The picture is less clear for the T-cell-derived cytokines, which are generally expressed at a lower copy number in intestinal tissue compared to the monokines. For Crohn's disease, the TH1 cytokines IL-2 and IFN may be abnormally elevated or decreased. In contrast, the TH1/TH2 profile in UC is not significantly different from normal controls. Further work is required to confirm these findings.

A huge variety of peptides and cytokines are involved in the maintenance of mucosal integrity and in the inflammatory response at sites of ulceration. Most studies have focused on the effects of an individual factor in this complex process. However, it is becoming increasingly apparent that, to fully understand their importance in vivo, we should consider their function as part of a highly integrated system. It is also becoming clear that a relatively small number of common pathways are brought into play by the host in response to a wide variety of intestinal insults.