There is a growing body of evidence supporting the hypothesis that members of the trefoil peptide family are involved actively in maintaining the integrity of the gastrointestinal mucosa and facilitating its repair. To date, three trefoil peptides are known in man: pS2, ITF and SP. Each is a secretory peptide expressed in specific compartments throughout the gut, in patterns that appear generally to be conserved between mammalian species. Ulceration, whether due to common pathological processes or experimentally induced, results in altered local expression of trefoil peptides. In diverse chronic ulcerative conditions in man, glandular structures develop within the mucosa, derived from the UACL. These UACL glands express three trefoil peptides, EGF and lysozyme, all potentially able to contribute to the healing process. In fact local goblet and endocrine cell types may also be recruited to secrete pS2 into the local environment. In experimental ulcers, in rate stomach or intestinal resection margins, there is also accentuation of trefoil peptide expression at the margins and in the poorly differentiated mucous cells extending out presumably in attempts to restore epithelial integrity. Several trefoil peptides have been expressed as 'recombinant' proteins in bacterial, baculoviral or yeast systems, and these procedures have allowed some of the biological properties of these peptides to be determined. In vitro, rITF, hITF and hSP are motogens, able to promote migration of epithelial cells. In vivo, rITF and hSP are able to prevent much of the gastric damage effect by a single dose of indomethacin, when given systemically. There is synergy between EGF and rITF both in vitro and in vivo, which may allow the development of new peptide therapies for ulceration that will maximize repair and minimize cell proliferation.

This chapter is focused on the relatively recent investigations demonstrating a pharmacological and pathophysiological role for bFGF and PDGF in ulcerative and inflammatory lesions in the upper and lower GI tract. Our initial animal model experiment revealed a potent healing of chronic cysteamine-induced duodenal ulcer in rats treated by intragastric administration of bFGF-w, the acid-resistant bFGF-CS23 or PDGF-BB without decreasing gastric acid secretion or concentration. Subsequently we and others have demonstrated that these peptides accelerate the healing of chronic gastric ulcers, chronic erosive gastritis and ulcerative colitis. Contrary to the potent ulcer healing properties of bFGF and PDGF, these growth factors exert no or modest acute gastroprotection. Nevertheless, new biochemical, molecular biological and immunohistochemical studies indicate that both bFGF and PDGF play a pathophysiological role in the natural history of ulcer healing.

Hallmarks of IGF-I action include synergy with other hormones and growth factors and the ability to stimulate proliferation or differentiated cell function dependent on physiological or pathophysiologial context. A complete understanding of IGF action in IBD will require analyses of mechanisms of IGF interaction with other growth factors, hormones and cytokines. GH and IGF-I may be administered to children over prolonged periods to correct growth disorders. The definition of the benefits and problems of GH/IGF-I therapy in IBD needs to distinguish between long-term and short-term effects. Short-term administration of GH and IGF-I to animal models of IBD such as the PG-PS and TNBS models, which share features of Crohn's disease (Sartor, 1992), and a recently developed murine model of ulcerative colitis induced by ingestion of dextran sulphate (Okayasu et al, 1990; Sartor, 1992; Cooper et al, 1993) could address the beneficial or detrimental consequences of short-term GH/IGF-I therapy. Adaptation of the PG-PS, TNBS and dextran sulphate models of inflammation to available transgenic mouse lines that over-express GH and IGF-I (Behringer et al, 1990; Ulshen et al, 1993), especially if over-expression is inducible, could help to define the potential benefits and problems of long-term GH/IGF-I therapy or the effects of GH/IGF-I on immune cell function and cytokine production during intestinal inflammation. It will be useful to study intestinal inflammation and complication in animal models of GH or IGF-I deficiency. In this regard, mice with targeted ablation of the IGF-I gene could be useful (Liu et al, 1993) although neonatal mortality in these models currently poses problems for in vivo studies. Development of mesenchymal cell lines from such animals could, however, provide a useful in vitro system to study the role of IGF-I in altered cell function in response to pro-inflammatory cytokines.

The last decade has been marked by tremendous advances in the biochemical and functional characterization of TGF-betas and their receptors in normal and transformed cells. TGF-betas have been shown to modulate proliferation, differentiation and motility of different cell types in a number of in vitro model systems and in some cases with some intriguing results. It is obvious that there is no simple pattern that explains the TGF-betas biological activity in vitro and their effects on cell behaviour need to be assessed in the context of an appropriate physiological cellular environment. Cell-cell and cell-matrix interactions, the differentiating status of the cell together with the functional activity of other soluble growth factors can influence how TGF-betas modulate cell behaviour. However, the overwhelming interest in this field shown by clinicians and basic scientists is rapidly increasing our understanding of how growth factors such as TGF-betas regulate the homeostasis of the GI mucosa and their role in gastrointestinal carcinogenesis.

Major advances in understanding growth factor biology, especially in epithelial cells, have resulted from work with TGF-alpha over the past decade. It is clear that TGF-alpha is a potent epithelial oncoprotein, but equally important biological activities in normal epithelial homeostasis have been described. A number of major challenges lie ahead. Foremost is the formidable task of dissecting out the individual contributions of each EGF-related peptide in the biological response to stimulation of the EGFR. Appreciation of the complexity of heterodimerization of receptors within the EGFR family will be equally important in the final analysis. These considerations assure the continued vitality and productivity of investigation of the EGF-related peptide/EGFR axis.

Despite the wealth of information concerning EGF and its related peptides, its precise role in the control of gastrointestinal functions is still not fully resolved. However, there is no doubt that it can have some very potent effects on the gastrointestinal tract. These may be related to the control of growth and development and to the regular control of cell renewal. Nevertheless, in the adult, EGF may only be active in response to luminal damage and repair, and furthermore this may also only occur if the luminal EGF is protected from proteolytic degradation. Notwithstanding this, 'EGF'-like responses may be evoked in the gut by intestinal TGF-alpha. The possible therapeutic use of EGF and members of its family in ulcer therapy will be discussed in later Chapters of this volume, other potential uses are in the control of necrotising enteritis and in the alleviation of the mucositis associated with cancer treatment.

Cytokines mediate immune responses and are detectable in the normal gastrointestinal mucosa. It is unclear how cytokines are physiologically regulated but in inflammatory enteropathies their expression is often greatly increased and may account for the tissue damage observed. T-cells may be sub-divided according to the pattern of cytokines which they secrete. TH1 cytokine expression is increased in delayed type IV cell mediate immune responses whereas TH2 cytokines are raised in diseases in which humoral mechanisms are more important. Cytokines are secreted by macrophages in relatively greater amounts than from T-cells. They are non-specific products of inflammation and may account for the majority of tissue damage seen in mucosal disease. The pattern of cytokine secretion may determine the immunopathogenesis of an inflammatory disorder. The ultimate goal of cytokine research is the development of therapeutic measures based on a better understanding of their actions which may be achieved with a better understanding of the molecular immune-microenvironment in inflammatory enteropathies. Studies with transgenic mice and gene targeted mice have important implications to the understanding of the immune system and its role in intestinal diseases.

Cytokines are a family of protein mediators that are important in transducing information between various cell types. These messengers are synthesized by a broad spectrum of cells. Cellular sources of cytokines include those cell types considered to play pivotal roles in the immune system as well as in inflammatory responses, including lymphocytes, monocytes and mast cells. Emerging data indicate that non-immune cells, including epithelial cells and fibroblasts, may also be important sources of certain cytokines. Cytokines fulfill a number of roles during immune and inflammatory reactions, and may display overlapping or redundant functions. In part, this redundancy may arise from the fact that cytokine receptors are not all unique entities, but may be divided into families. Many cytokine receptors have a subunit structure, with common subunits shared between receptors, and serving as affinity modifiers/signal transducers. Cytokines exert their effects on target cells by activating intracellular signalling mechanisms. In addition to 'classical' signal transduction path-ways, new data indicate that cytokines may also exemplify molecules that utilize novel signalling mechanisms, including the Jak-STAT pathways of transcriptional regulation and pathways involving the novel lipid second messenger, ceramide. In conclusion, molecular techniques have enabled the identification of many new cytokines, and the elucidation of their binding sites and mechanisms of action. This information has provided new insights into this complex area. Moreover, an understanding of the molecular basis of cytokine action and the pathways that lead to their acute and chronic effects may, in turn, facilitate interventions to prevent or modify their actions in disease states.

Helicobacter pylori is highly adapted to its unusual ecological niche in the human stomach. Urease activity permits H. pylori survival at a pH of <4 in vitro and is required for the organism to colonize in animal models. However, urease does not play an important role in the survival of the organism in a pH range between 4 and 7. Other mechanisms of pH homeostasis remain poorly understood, but preliminary studies indicate that novel proteins are produced when H.pylori cells are shifted from pH 7 to 3, and the gene encoding a P-type adenosine triphosphatase that may catalyze NH4+/H+ exchange across the cytoplasmic membrane has been cloned. Mechanisms of pH homeostasis in other enteric bacteria are reviewed and provide insight into additional pathways that may be used by H. pylori. An important adaptation of H. pylori to the gastric environment may be its ability to alter gastric acid secretion. Acute infection is associated with transient hypochlorhydria, whereas chronic infection is associated with hypergastrinemia and decreased somatostatin levels. Thus, the survival of H. pylori in the gastric environment may be attributed to both the development of specialized intrinsic defenses and the organism's ability to induce physiological alterations in the host environment.

Gastrointestinal endoscopy and laparoscopic general surgery have been significantly affected by the emergence of new techniques. These two disciplines share many similarities, including the use of sophisticated and expensive technologies. Their proper assessment is essential because they are developed amidst ever-decreasing health care budgets. Gastroenterologists and general surgeons must both participate in such evaluations and feel confident in interpreting pertinent published data. The present review uses a clinician's point of view with relevant examples to discuss the methodologies adopted in technology assessment and to highlight common pitfalls encountered in study design, patient selection, timing and selection of the study, blinding, and outcome measurement. Cost and statistical considerations, as well as ethical issues, are also reviewed in the context of technology assessment.

Two years before the appearance of distal peripheral manifestations of thromboangiitis obliterans (Buerger's disease), a young man had acute peritonitis attributable to an ischemic perforation of the sigmoid colon. Only the histological examination of excised tissue was able to differentially diagnose this entity unambiguously.

An overview is given of the technical aspects and the diagnostic usefulness of liver biopsy. From the clinical side, the procedures for taking liver biopsies and the various types of biopsy are summarized. The histopathology section mentions precautions for tissue sampling and processing, and reviews the diagnostically useful techniques and special microscopy procedures. Consideration is given to the factors which determine the accuracy of histopathological diagnosis, both those relating to the tissue specimen and those relating to the interpreter. Published studies on quantitation and semi-quantitation of liver biopsy findings and their reproducibility are mentioned, with a final remark on the contribution of liver biopsy to diagnosis and therapy. Emphasis is placed throughout on the necessity for close collaboration between clinician and pathologist.

The choice of management for the patient with HCC hinges on precise localization and staging of the disease process. All the major imaging modalities are employed to achieve this end. US is frequently the initial means of detection of the lesion. Since percutaneous needling may lead to tumour dissemination, the temptation to proceed to imaging-guided biopsy should be resisted until a full evaluation has been completed and it is clear that neither curative surgery nor transplantation is a therapeutic option. CT scanning is considered to be superior to ultrasound both in detection and staging of the disease. A variety of modifications to the technique, including CT arterio-portography and lipiodol-CT, is used to obtain optimum results. The role of MRI has not yet been established but initial results suggest that this may be the optimum means of scanning the patient following percutaneous or intra-arterial therapy. Angiography is generally performed prior to resection and may be combined with the delivery of chemotherapeutic and embolic agents pre-operatively or as a definitive palliative procedure. Imaging-guided percutaneous alcohol is also a useful palliative measure where the lesion is small. In the majority of cases, resection is not feasible. In a selected few liver transplantation is an option. Imaging requirements of the potential liver transplant candidate depend on the nature of the underlying liver problem. A general assessment including a chest X-ray and US with Doppler imaging of the hepatic vascular structures is sufficient in the majority. In children with complex structural anomalies and in patients with bile duct disease or tumours, the full range of investigations is required. US, cholangiography CT and angiography may all be required in the diagnosis and management of post-transplant complications.

The degree of portal hypertension and its haemodynamic complications can be easily determined. However, the interpretation of these values is not entirely clear and further clinical and experimental studies are needed to explain why some patients with portal hypertension bleed from oesophageal varices while others do not.

Laparoscopy under sedation is a safe and a well tolerated procedure which can be readily performed in the endoscopy suite. In the investigation of patients with chronic liver disease it is more accurate than histology alone in staging the severity of disease and adds valuable prognostic information. In patients with focal liver disease it has a high degree of sensitivity and this is likely to increase with technological advances, such as sonolaparoscopy. We strongly believe that in many countries diagnostic laparoscopy is an under utilized diagnostic tool which deserves wider incorporation into clinical practice and training programmes.

The number of autoantibodies associated with chronic liver disease continues to burgeon and characterization of these immunoreactivities will undoubtedly enhance understanding of the autoantigens that are targeted by cytodestructive immunocytes. Assays for the majority of these immunoserological species are not generally available and in most instances, assessments are restricted to individual laboratories with vested interests in characterizing a particular species. For clinical diagnosis and management of autoimmune liver disease, assays for ANA, SMA, anti-LKM1 and AMA are essential. This conventional armamentarium, however, must be upgraded on a regular basis to ensure availability and application of the most useful assays. Unfortunately, there are no formal mechanisms for improving the diagnostic resources and standardizing testing strategies. An important first step must be taken by the basic laboratories that advocate individual assay systems. These facilities must share methodologies and exchange serum samples so that the most clinically pertinent and cost-effective immunoserological batteries can be defined and promulgated. Industry can then respond to need and facilitate the commercialization of assays for general use. Currently, the assays that warrant dissemination are those that detect antibodies to the E2 subunits of the pyruvate dehydrogenase complex and antibodies to asialoglycoprotein receptor. Both assays have high diagnostic specificity and each reflects reactivity to an important target autoantigen of probable pathogenic importance. Each autoantibody species can supplant conventional assays such as those for AMA and ANA and they each may impart useful clinical information. In the case of antibodies to the E2 subunits, titres may reflect histological progression of PBC. In the case of anti-ASGPR, disappearance of the autoantibodies in patients with autoimmune hepatitis may secure a confident treatment end-point. Great progress has been made in defining the immunoserological manifestations of chronic liver disease but little has been done to distribute the resources.