Viral detection is an important part of clinical hepatology. For many years practical clinical tests have been serological but recently newer molecular techniques have become available for virus detection, although these have yet to become routine and some, such as PCR of viral nucleic acid in blood or tissue are not yet consistently reliable. Serology remains the mainstay at present for routine diagnosis. Hepatitis A testing in clinical practice is entirely serological, the IgM response representing acute infection and the IgG response immunity, although more sophisticated molecular techniques have been applied experimentally. A second agent of epidemic enteral hepatitis, the hepatitis E virus, has recently been cloned and sequenced and serological tests for this virus are available, although experience in their use is necessarily limited and a commercial IgM assay has yet to be produced. Serological tests for the hepatitis B virus are well developed. The IgM anticore response differentiates acute infection from chronic, the latter being characterized by the persistence of hepatitis B surface antigen for over six months. Chronic carriers are at risk of liver damage and this risk is best assessed by the amount of viral DNA circulating, which can be determined using a hybridization assay. More sensitive techniques such as the branched chain DNA assay or PCR can detect lower levels of viral DNA but their clinical relevance remains to be established. The hepatitis D virus is defective and relies on hepatitis B to replicate. Serology for antibody and antigen is well established although PCR for circulating viral genome may come to supplant hepatic viral antigen as a test for hepatitis D replication. For hepatitis C serology is feasible only for antibodies, not antigens; although early tests were prone both to false positives and false negatives, current versions are more reliable. PCR has been much used for detection of hepatitis C RNA in blood and tissues and a bDNA assay is now commercially available. Cytomegalovirus detection is confounded by the problem of distinguishing asymptomatic viral replication from disease. Serology is helpful, especially in primary infections, but viral culture is a widely used method. PCR (especially quantitative modifications) or the pp65 antigenaemia assay are experimental approaches which may prove specific enough for general use.

A wide array of biochemical findings can be seen in patients with liver disease. Depending upon the setting, these findings can either be used to confirm the presence of a liver disease, document its complications or suggest its presence. Thus, physicians need to be aware of them and recognize and use them as the specific case indicates.

For optimal timing of liver transplantation and for the evaluation of new pharmacotherapeutic options, objective modalities for estimating the liver's functional reserve and prognosis in an individual patient are highly desirable. In the past a number of tests and several scoring systems have been proposed and validated to varying degrees for this purpose. The issues still to be clarified include: (1) any observed prognostic value of individual quantitative function tests and of scoring systems must be validated in independent, large enough and well defined patient populations; (2) it must be prospectively defined which (serially performed) quantitative test(s) add(s) prognostic information for the individual patient to the survival estimates defined by the more universally available scores and in which disease state(s); and (3) existing scoring systems must be validated, or new ones developed, that allow follow-up data to be used in order to adapt the original prognosis estimate to the evolution of the disease, e.g. during therapy.

The clinical history and examination is essential in the evaluation of patients with liver disease. This chapter details important points in the clinical history and examination allowing the physician to identify likely causes of liver damage and their investigation. The evaluation should allow the physician to differentiate acute and chronic liver diseases, and in the latter case separate those with obstructive or chronic parenchymal liver disease. It should also allow identification of important complications such as encephalopathy, ascites and portal hypertension. Identification of these main features or complications of liver disease by the clinical evaluation leads to a logical plan of investigation and prompt diagnosis and management of the liver disease.

The genetic basis of cancer involves certain classes of genes, particularly oncogenes, tumor-suppressor genes, and DNA mismatch repair genes. Originally identified in bacteria and yeast, the human homologues of DNA mismatch repair genes have been implicated in the pathogenesis of the hereditary nonpolyposis colorectal cancer syndromes, as well as a variety of different sporadic cancers. An appreciation of their role in cancer is predicated on an understanding of their function in the processes of DNA repair. This article reviews the recent developments and advances in the biology of the human DNA mismatch repair genes and their involvement in the pathogenesis of cancer.

Ischemia is increasingly recognized as a cause of cholangiopathy. The aim of this study was to report a case of association of paroxysmal nocturnal hemoglobinuria with abrupt-onset cholangiopathy. Anomalies resembling sclerosing cholangitis were documented in a patient suffering from recurrent biliary pain. None of the conditions that have been associated with primary sclerosing cholangitis or other forms of cholangiopathy was present, but shortly thereafter, paroxysmal nocturnal hemoglobinuria occurred. Hepatic vein thrombosis later complicated the course of the disease. Because the fortuitous coincidence of these uncommon conditions is unlikely, this case indicates that paroxysmal nocturnal hemoglobinuria is a cause of ischemic cholangiopathy. Other thrombogenic conditions may also be implicated in some instances of apparently idiopathic cholangiopathy.

Although sclerotherapy is the current standard therapy for bleeding esophageal varices, the best method for initial control is unclear. The aim of this meta-analysis was to compare the efficacy and toxicity of somatostatin and vasopressin in short-term treatment of hemorrhage from esophageal varices.

Following the demonstration of Helicobacter pylori as a major gastroduodenal pathogen there was a need to develop animal models in order to investigate mechanisms of pathogenesis and to be able to test new treatment strategies. Helicobacter pylori will only colonize a limited number of hosts including non-human primates, germ-free or barrier raised piglets, germ-free dogs and recently laboratory raised cats. Although these models have proved useful there is a need for more convenient small animal models. The ferret infected with its natural gastric organism, Helicobacter mustelae, is the only other animal to show peptic ulceration and has been successfully used to investigate gastritis and antimicrobial agents. The other commonly used animal model is the laboratory mouse or rat infected with either Helicobacter felis or Helicobacter heilmannii, bacteria that normally colonize cat or dog gastric mucosae. Active/chronic gastritis, gastric atrophy, and lymphoma-like lesions have been shown to develop in H. felis infected mice. The most recent and exciting use of an animal model has been the use of the H. felis mouse model in the development of human vaccines against H. pylori. Mice can be protected against infection with large doses of viable H. felis by oral immunization using sonicates of H. felis or H. pylori or recombinant H. pylori urease together with cholera toxin or cholera toxin-B subunit as the mucosal adjuvant. More importantly it has been shown that immunization of already infected animals results in eradication of infection. This raises the intriguing possibility that therapeutic immunization might be a viable option in the management of Helicobacter-associated disease. If immunization as a therapy of peptic ulcers was combined with short-term acid suppression, the possibility of reinfection may also be eliminated. In those countries where H. pylori infection rates are very high and infection occurs at an early age, large scale oral immunization of sections of the community would not only protect the young from the deleterious consequences of long-term H. pylori infection but could also cure existing disease.

Although there are numerous publications reporting eradication results, the general picture is confused by the bewildering multiplicity of treatment schedules employed by the various workers. The over-riding need now is for large scale trials, and more especially for direct comparisons of different treatment regimens in the same populations of patients. Such data are entirely absent from the literature at present. Standardization of definitions and of methodology pertaining to diagnosis of eradication, recording of side effects, measurement of compliance and determination of recurrence or of reinfection, is badly needed. As the definition of eradication remains arbitrary, it is important to include genome fingerprinting techniques in the long-term follow-up for recurrence, so that the question of reinfection versus recrudescence can be examined (Bell et al, 1993b; Xia et al, 1994). Because of the wide differences in the agents used in H. pylori eradication therapies, proper double-blinding of treatment trials remains a difficult problem. This can be dealt with to some extent by ensuring that the interpretation of tests for H. pylori eradication is performed by personnel unaware of the clinical details. Review of the existing data on eradication of H. pylori indicates that clinically useful results can be achieved in some 70 to 95% of patients, on an intention to treat basis. Compliance, side effects and resistance to metronidazole remain the limiting factors. Efficacy, freedom from side effects, simplicity and low cost will determine the success of any regimen in the future. At present, it is not possible to make firm recommendations in favour of one regimen over another, but it seems reasonable to forecast that dual therapies consisting of a PPI and an antibiotic will receive much attention. Preparations consisting of an H2RA associated with a bismuth compound, which are used together with an antibiotic are an interesting approach. Compliance should be as good as with a normal dual therapy and the eradication results look promising (Wyeth et al, 1994; Webb et al, 1994). The advantages of dual therapies that include a PPI lie in their simplicity, in not relying on imidazole for their anti-H. pylori effect but on the profound inhibition of acid output produced by the PPI. Thus PPI based dual therapy can probably evoke better compliance than the more complicated regimens. The use of PPIs has other advantages in addition to decreasing the MIC90 of the antibiotic combined with it. This is because administration of a powerful inhibitor of gastric acid secretion, such as a PPI, will aid the rapid healing of an ulcer crater and will rapidly relieve the symptoms of peptic ulceration. Gastrin releasing peptide-stimulated acid secretion is raised in duodenal ulcer patients to approximately sixfold over control levels according to El-Omar et al (1993b), and although it returns to normal following the eradication of H. pylori, this process takes time to become effective (El-Omar et al, 1993a). Suppression of acid output provides an immediate therapeutic shield, while the decrease in inflammation and acid output secondary to H. pylori eradication can be established. The most widespread resistance to antibiotics exhibited by H. pylori is with respect to imidazoles. The prevalence of metronidazole resistance is widespread in the emergent countries (Glupczynski et al, 1990), but it is also appreciable in the West, especially in women, who may have been given metronidazole in the treatment of pelvic infections (Rautelin et al, 1992; Banatvala et al, 1994). Moreover, H. pylori becomes resistant to metronidazole very easily and often as a result of treatment which includes an imidazole compound (Malfertheiner, 1993; Banatavala et al, 1994). On the other hand, H. pylori resistance to macrolides is not widespread and does not develop easily during their administration. It is difficult to forecast which antibiotic will be the most widely used agent

In 1985, gastric cancer was the second most common cause of cancer death in the world. The rapid decline in gastric cancer rates over the last few decades has been attributed to a decline in the prevalence of environmental risk factors for gastric cancer and/or an increase in the prevalence of protective factors. One such risk factor could be the bacterium Helicobacter pylori. Epidemiological studies have shown that areas with high gastric cancer rates often have a correspondingly high prevalence of H. pylori and prospective studies have shown that subjects with serological evidence of H. pylori infection were significantly more likely to go on to develop gastric cancer than those who did not. Helicobacter pylori itself does not appear to be either genotoxic or mutagenic. Infection is, however, associated with increased cell turnover, a chronic immune response accompanied by increased levels of reactive oxygen metabolites and a reduction in gastric levels of ascorbic acid, all conditions that could favour the development of cancer. Nonetheless, the majority of those who are infected with H. pylori do not go on to develop gastric cancer and other factors, such as the strain of the infecting organism or consumption of dietary antioxidants including vitamin C, could also affect the risk of cancer. Finally, it has been estimated that more than one third, and possibly as many as 90% of gastric cancers might be attributable to infection with H. pylori. Prevention and treatment of infection are, therefore, possible approaches to reducing gastric cancer rates. It is, however, unclear what, if any, effect eradication of the infection would have on an individual's risk of gastric cancer and, to date, anti-Helicobacter therapy has only been shown to be of potential benefit in the treatment of low grade gastric MALT lymphomas.

To date, the precise role of Helicobacter pylori in the pathogenesis of NUD remains uncertain. There is some evidence to suggest that the organism is implicated in specific subgroups (mostly the ulcer-like form), but it is not enough for any firm conclusions to be drawn as to the importance of the bacterium as a cause of dyspeptic symptoms or as to the efficacy of anti-infective regimens in the treatment of NUD. Large, well-designed prospective studies with a long-term follow-up are needed to establish which subgroups of dyspeptic patients may benefit most from eradication of H. pylori.

The decision to treat a patient should in general always be based on potential risk and advantage. Widespread and uncontrolled use of all kinds of anti-H. pylori regimens may promote development of antimicrobial resistant strains. In particular, antimicrobial monotherapy is associated with failure to eradicate H. pylori and induction of resistant strains. Polychemotherapy is much more effective and has a lower risk for development of antimicrobial resistant H. pylori strains but carries the risk of significant drug-related side effects. If the prescribed anti-H. pylori regimen is not effective in at least 80%, or if the patient is not compliant, this type of therapy should not be considered. Also if reinfection is to be expected, the risk may outweigh potential benefits (Graham, 1993). Guidelines published in 1990 by an international working party during the World Congress of Gastroenterology recommended H. pylori eradication only in patients where duodenal ulcer was a serious management problem requiring lifelong maintenance therapy, and in whom complications (bleeding, perforation) had occurred or surgery was considered (Tytgat et al, 1990). Recently less stringent guidelines were recommended. A National Institutes of Health (NIH) Consensus Development Conference has recommended that all patients with gastric or duodenal ulcer who are H. pylori infected should be treated with antimicrobials including patients presenting with an ulcer for the first time. In addition, patients on maintenance antisecretory medication should also be contacted and treated for H. pylori infection (Anonymous, 1994). The ulcer relapse rate during prolonged follow-up after H. pylori eradication is very low. Despite this, it is advised that antisecretory medication is continued after successful H. pylori eradication in patients with previous ulcer complications. In all other patients maintenance antisecretory medication can be stopped after successful eradication. It is not known whether H. pylori eradication lowers the risk of NSAID-induced ulceration or whether the risk of ulcer complications is reduced.

Helicobacter pylori is the major cause of antral gastritis in children, however, it is not always associated with symptoms. The exception to this occurs in duodenal ulcer disease with which H. pylori is linked in children albeit less strongly than in adults. Duodenal ulcers do not recur in older children following eradication of H. pylori. The importance of asymptomatic carriage of H. pylori in children, particularly in relation to the duration of this infection and the subsequent development of gastric cancer, remain to be established. Helicobacter pylori is associated with both hypochlorhydria and persistent diarrhoea in children in developing countries, but the significance of this association is still unknown. Although there is no consensus on the optimal regimen for treating H. pylori infection in children, dual therapy with amoxycillin and bismuth subcitrate for 2 weeks followed by monotherapy with bismuth subcitrate for a further 6 weeks will eradicate H. pylori infection in the majority of children. Those who relapse may be treated with a repeat course plus metronidazole for 4 weeks. Compliance with such regimens is a problem and shorter treatment courses that are equally effective in children need to be defined. Similarly, studies are required on the influence of the intrafamilial reservoir of H. pylori infection on relapse after treatment and the need for whole family eradication therapy.

Several techniques have been proposed to diagnose H. pylori infection based either on the direct or indirect detection of the bacteria. [table: see text] The current direct methods are performed on biopsy specimens obtained at endoscopy. Histological examination must always be performed because in addition to H. pylori detection it allows observation of the lesions present. Culture, while more demanding in terms of transport conditions, is a sensitive technique which is worthwhile when the patient might be treated with antibiotics to which the bacteria may be resistant. PCR has been more recently introduced and exhibits a good sensitivity and specificity. Rapid tests, such as the rapid urease test and examination of a Gram stained biopsy smear, are convenient and cheap but of lower sensitivity. Indirect methods are based either on the serological IgG response or the labelled urea breath test. Both are sensitive. The breath test is especially adapted to post-treatment control while serology is of interest for screening patients and epidemiological studies. New techniques have recently been proposed but are not yet applicable to routine diagnosis: detection of H. pylori in faeces by culture or PCR; detection of IgG antibodies in saliva or urine.

Research is asking how H. pylori causes diseases, and also why the same bacteria produces different conditions in different persons. The process involves bacterial factors and the host's response. Some bacterial factors such as urease are produced by all strains of H. pylori. This enzyme may damage the gastric epithelium by practically releasing ammonia. Other bacterial factors such as vacuolating toxin are only produced by some strains, and these strains are more likely to cause ulcers or cancer. The host's response has been studied by physiologists, immunologists, and histologists, but the separation of systems is artificial. For example, physiologists find that H. pylori stops gastric D-cells from expressing somatostatin normally, which impairs reflex inhibition of acid secretion, but the D-cell malfunction is probably due to inflammatory factors. In H. pylori gastritis, the gastric epithelial cells behave like immunocytes and express class II molecules and cytokines such as interleukin-8. The patient's histological response to H. pylori is quite closely related to the disease outcome. Patients who respond by developing gastric atrophy are more likely to get gastric ulcers or stomach cancer, but patients whose gastric corpus remains healthy tend to secrete more acid and develop duodenal ulcers, particularly if they have gastric metaplasia in their duodenum. Studies of disease mechanisms provide a valuable insight into the development of these common diseases, and may enable us to identify at-risk groups who particularly merit eradication therapy.

It is interesting that the principal histological features of acute H. pylori gastritis, surface epithelial degeneration and neutrophil polymorph infiltration, remain as the most sensitive indicators of the 'activity' of infection in the chronic phase. It is not surprising therefore that these are the first features to resolve after successful H. pylori eradication therapy. In one of the earliest studies of histological response to eradication, McNulty et al (1986) endoscoped patients immediately after a three-week treatment regime and found a highly significant decline in polymorph scores. The response was even more striking four weeks after the end of treatment, as at that time biopsies from responders were virtually devoid of polymorphs (Valle et al, 1991). Indeed the disappearance of polymorphs from a post-treatment biopsy is a useful indicator of successful eradication. Less attention has been paid to the recovery of the surface epithelium yet this is an impressive feature when comparing pre- and post-treatment biopsies. Using subjective grading of surface epithelial lesions, Solcia et al (1994) found a dramatic and highly significant improvement in mean grade immediately after anti-H. pylori treatment. Recently a morphometric approach was used to demonstrate a significant increase in surface epithelial cell height corresponding to the recovery that accompanies successful H. pylori eradication (Hassan et al, 1993). Chronic inflammatory cell infiltrate resolution is much slower. There is only a gradual reduction in cell density so that even 6 months after eradication treatment the mean score had only fallen by 50% of pre-treatment values (Solcia et al, 1994). In the author's experience, a minor increase in such cells persists for many months and may never completely resolve, in that more lymphocytes and plasma cells are seen than in a truly normal (pre-infection) stomach. Valle et al (1991) found resolution of chronic inflammation in only 15% of subjects at 6 months and in 51% at one year after eradication. The long delay in disappearance of lymphocytes and plasma cells poses a question over continuing antigenic stimulation in the absence of infection. Possible answers could involve persistence of antigenic moieties in dendritic cells of the lamina propria, or sensitization to host antigens brought about by infection so that an element of autoimmunity persists after eradication. Unravelling these mechanisms will add important new elements to our understanding of the long-term consequences of this fascinating infection.

A gastroenterologist, treating a patient with H. pylori, must decide whether the unit of treatment is only the ill individual, or the family, perhaps including close contacts. If it is the family and close contacts, is it all family members and contacts, or are there some ages, relationships, or clinical characteristics that increase the risk of transmission to the patient after successful treatment of their infection? In preventing reinfection, the available data suggest: the natural infectious dose has not been determined infection may occur from oral or faecal shedding children are more infectious than adults socio-economic factors are important in any comparison of infection rates food and water seem unlikely vehicles in the developed world travel in the third world may increase risk of infection seropositivity in adults predominantly reflects exposure in childhood infection is frequently with more than one strain reinfections are not more frequent in families with other members infected reinfections are infrequent with strains different from the original strain reinfection might be more frequent in developing countries no need for all family members to be treated to reduce reinfection rates. In considering vaccine, the available data suggest: breast milk IgA can reduce infection rate antibodies induced by vaccine may reduce infection in animals late benefit of childhood vaccination in developed countries probable early benefit of childhood vaccination in developing countries vaccination of already infected adults would have cost-benefit.

The discovery and first isolation of H. pylori in pure culture from gastric biopsies in 1982 provided the basis for a completely new area of microbiology. Since then, H. pylori has been an intensively pursued topic world-wide, and extensive data have been acquired on all aspects of its basic microbiology, both at the conventional phenotypic level and at the molecular level. H. pylori is a remarkable microorganism because of its ability to readily colonize a major proportion of human population worldwide and to persist successfully for long periods (probably decades) in a hostile environment. At the same time it interacts with the host immune system in such a way as to permit long-term survival. Blaser (1993) proposed a model in which both host and parasite adapt to down regulate inflammatory phenomena to promote survival. Urease production by H. pylori (an important factor in that process) is one of its most distinct features with a key role in its success as an infective agent. Another less obvious yet highly significant feature of H. pylori is the ability to achieve a high degree of interstrain diversity in genomic DNA nucleotide sequences, while maintaining overall genetic homology and phenotypic homogeneity amongst strains. The selective advantage this diversity provides the bacterium is not understood. A key objective of future microbiological studies should be to understand the population genetic structure of H. pylori. Most species of bacteria are clonal in natural population structure, yet all genomic data suggest the contrary is true for H. pylori. Furthermore, it is not clear if all strains of H. pylori are equally pathogenic, and that some subsets may possess additional pathogenicity factors that are responsible for the development of different disease pathologies. A phylogenetic framework of the genetic relationships of the clones within H. pylori would enable an examination of the total genetic diversity, with respect to ethnic or geographical population and the nature of the disease caused. A second aim would be to understand the mode of transmission of H. pylori from individual to individual. Although there is some evidence for either an oral-oral or a faecal-oral route, no reliable microbiological protocols exist for the isolation of H. pylori from non-gastric sites. There is therefore, considerable scope for the development of microbiological media and test methods for isolation from faeces and dental plaque, and possibly even food and environmental sources. To conclude, the availability of new information on the above aspects would greatly facilitate the monitoring of therapy; would enable more accurate epidemiological studies on the age of acquisition and spread of H. pylori infection; and would provide a basis for future prevention of disease by identification of individuals at high risk of infection with a particular pathogenic strain type.