Showing papers in "Best Practice & Research in Clinical Gastroenterology in 2000"

Replication of the hepatitis C virus

Abstract: Infection with the hepatitis C virus (HCV) is a major cause of chronic liver disease. HCV is an enveloped plus-strand RNA virus closely related to flavi- and pestiviruses. The first cloning of the HCV genome, about 10 years ago, initiated research efforts leading to the elucidation of the genomic organization and the definition of the functions of most viral proteins. Despite this progress the lack of convenient animal models and appropriate in vitro propagation systems have hampered a full understanding of the way the virus multiplies. This review summarizes our current knowledge about HCV replication and describes attempts pursued in the last few years to establish efficient and reliable cell culture systems.

The hepatopulmonary syndrome

Abstract: The hepatopulmonary syndrome is a triad of liver disease, increased alveolar-arterial oxygen gradient and intrapulmonary vascular dilatations. Manifestations include orthodeoxia, platypnoea and hyperdynamic circulation. Intrapulmonary vascular abnormalities, perhaps mediated by nitric oxide, cause hypoxaemia by shunting, a perfusion-diffusion defect, and ventilation-perfusion mismatching. Contrast-enhanced echocardiography is the method of choice for demonstrating pulmonary vascular abnormalities, although perfusion lung scanning is a more specific and sensitive test. Angiography is best reserved for patients with poor response to 100% oxygen and defines whether vascular dilatations are of the diffuse 'spongy' type or, less commonly, discrete arteriovenous communications amenable to embolization. About 80% of patients with the hepatopulmonary syndrome eventually have improved oxygenation after liver transplantation, thereby making worsening hypoxaemia the primary indication for transplantation in many instances. Nevertheless, severe hypoxaemia carries a peri-operative mortality of 30% and reliable predictors of successful outcome after transplantation remain to be determined.

Epidemiology and natural history of reflux disease.

Abstract: Gastro-oesophageal reflux disease (GORD) is a highly prevalent condition in Western countries; at least 20% of the population have weekly symptoms. The incidence appears to be rising in the West and in some developing countries. Heartburn, based on a carefully elicited history, is reasonably specific for identifying GORD if it is a predominant complaint. Symptoms, however, appear to correlate poorly with oesophagitis; hence, severe symptoms do not indicate there is greater oesophageal damage. Only one-third to one-half of patients with GORD undergoing endoscopy have oesophagitis. GORD is usually a chronic disease but one-third may lose their symptoms over time. An ill-defined subset of patients over time may progress to develop abnormal acid exposure or oesophagitis, or both, when none existed at baseline. GORD has a significant negative impact on quality of life to the same degree as other chronic medical conditions, but impairment in quality of life is independent of oesophagitis.

Diagnosis and treatment of hepatic encephalopathy.

Abstract: Hepatic encephalopathy arises from the combination of hepatocellular dysfunction and portal-systemic shunting. Encephalopathy is more prominent in advanced stages of liver cirrhosis and signals the presence of fulminant hepatic failure in patients with acute liver injury. As important as the extent of shunting is the presence of large spontaneous collaterals. Ammonia continues to be a leading toxin influencing brain function. Endogenous benzodiazepines and cytokines may contribute to one of ammonia's key effects in the brain: astrocyte swelling. The diagnosis of hepatic encephalopathy is a diagnosis of exclusion; the search for a precipitating factor should be started immediately in all cases of encephalopathy. The treatment of hepatic encephalopathy has three aims: decrease the nitrogenous load from the gut, improve the extra-intestinal elimination of ammonia and counteract central abnormalities of neurotransmission. The mainstay of treatment is directed at the colon. Newer approaches targeting the brain, such as flumazenil, have become available.

Animal models of gastroduodenal ulcer disease.

Abstract: Animal models have played a significant role in research that aims to understand peptic ulceration. Firstly, they have helped define basic mechanisms of gastric mucosal defence and repair. The basis for gastric injury following NSAID administration was facilitated by animal models that correlated well with disease in humans. In early studies, ulceration was induced by grossly damaging insults to the gastric mucosa that were unphysiological. With refinement these models provided a clearer appreciation of stress ulceration. The discovery of Helicobacter pylori (H. pylori), as the cause of most ulcers, resulted in a need to re-evaluate the early literature and to look for new models. To date, these have contributed little to our understanding of the pathogenesis of H. pylori-induced ulcer. A major aim of this chapter is to suggest that thorough understanding of the animal models of Helicobacter infection may provide important new insights, in particular the factors controlling gastritis, the essential precursor lesion of ulceration. Available models include primates, cats, guinea pigs, ferrets and pigs. The mouse models provide opportunity for identifying both essential bacterial and host factors. The most severe pathologies are seen in the H. pylori-infected Mongolian gerbil with ulcers being formed in most animals. This is likely to become the standard animal model for investigation of peptic ulcer disease.

Cure of Helicobacter pylori -associated ulcer disease through eradication

Abstract: The eradication of Helicobacter pylori (H. pylori) infection has led to a dramatic benefit for patients with gastroduodenal ulcer disease, as the majority of these patients receive a lifelong cure. Relapses after successful H. pylori cure may be caused by either recrudescence or reinfection, both rare events nowadays, or be attributed to non-steroidal anti-inflammatory drugs or aspirin intake. In certain geographical areas, H. pylori-negative relapses are proposed as a new, pathophysiological and not yet elucidated entity. The cure of H. pylori infection in uncomplicated duodenal ulcer diseases consists of 7 days of proton pump inhibitor (PPI) based triple therapy, containing two antibiotics from clarithromycin, amoxicillin and metronidazole. In gastric ulcer, it is recommended that the PPI is continued for a further 3 weeks as these ulcers have a prolonged healing time. Rescue therapies after failure need to take into consideration the resistance pattern of the micro-organism and are offered in the form of quadruple therapy or a high-dose PPI with amoxicillin.

The role of gastrin in ulcer pathogenesis.

Abstract: Duodenal ulcer patients are characterized by an antrum-predominant, body-sparing, non-atrophic Helicobacter pylori ( H. pylori ) gastritis, which results in increased gastrin release and increased acid secretion. The increased gastrin release is caused by the infection impairing the acid-mediated inhibitory control of gastrin release. The elevated levels of the gastrin stimulate the healthy uninflamed, non-atrophic acid-secreting region of the stomach to secrete excess amounts of acid. The increased gastrin also exerts trophic effects on the oxyntic mucosa, causing hyperplasia of both the enterochromaffin-like cells and the parietal cells. These trophic changes in the mucosa further enhance its ability to secrete acid. The increased acid secretion results in an increased duodenal acid load, causing gastric metaplasia of the duodenal bulb and eventually the development of ulceration. In H. pylori -infected subjects without duodenal ulceration, a different pattern of gastritis is seen. This includes atrophy of the antrum, which reduces the number of G-cells and thus the degree of hypergastrinaemia induced by the antral infection. There are usually also varying degrees of inflammation and atrophy of the acid-secreting mucosa, which impair its ability to secrete acid in response to gastrin stimulation. The combined effects of the atrophy of the antrum and the inflammation of the antrum of the body mucosa therefore prevent H. pylori -induced acid hypersecretion and may result in varying degrees of hypochlorhydria. The particular pattern of gastritis that a subject develops in response to H. pylori infection and their likelihood of developing a duodenal ulcer is likely to be determinded by host genetic factors plus dietary factors.

Diagnosing portal hypertension

Abstract: It is important to diagnose portal hypertension owing to its devastating complications. Clinicians need to be able to recognize physical signs and symptoms associated with portal hypertensive states. When in doubt, appropriate diagnostic measures need to be performed and a definite diagnosis made. Hepatic venous pressure gradient (HVPG) is often used as a surrogate measurement of portal pressure. HVPG can be obtained safely and conveniently on an outpatient basis. It can also be used to assess efficacy of various treatment modalities. Knowledge of pathophysiology of portal hypertension has provided the basis for further trials in both novel treatment modalities and diagnostic methods.

Autoimmune tests in primary biliary cirrhosis.

Abstract: Primary biliary cirrhosis (PBC) is characterized by an immune mediated, irreversible destruction of the small intrahepatic bile ducts leading to progressive liver cirrhosis and frequently to liver failure. The course of the disease is variable and an early diagnosis is desirable to identify individuals with rapidly progressing disease, to initiate adequate therapeutic measures and to evaluate the necessity of liver transplantation. Serological tests represent the single most important diagnostic feature of PBC because liver histology, biochemistry, or clinical syndrome alone are not reliable in this respect. The molecular definition of the autoantigen targets of antimitochondrial antibodies (AMA) has resulted in the development of reproducible and effective serological testing strategies. AMA directed against the ketoacid dehydrogenase complex are highly disease-specific but not directed against liver-specific target structures. Despite a high disease specificity, their usefulness for predicting the course of disease, the timing of liver transplantation, or disease recurrence after transplantation is limited. The realization that about 5% of patients with PBC do not display AMA has led to the identification of PBC-specific antinuclear autoantibodies directed against the nuclear pore complex and other targets. The overlap of PBC with autoimmune hepatitis and primary sclerosing cholangitis represents a diagnostic challenge in which autoantibody determinations play a central role and contribute to the administration of suitable treatment options.

Conceivable mechanisms by which Helicobacter pylori provokes duodenal ulcer disease

Abstract: A conceivable concept for the development of duodenal ulcers in Helicobacter pylori (H. pylori) infected subjects is presented in this chapter. The concept includes an explanation of the fact that only a minority of all H. pylori-infected subjects will develop a duodenal ulcer. Helicobacter pylori infection of the antrum induces a hypersecretion of gastric acid secretion, giving rise to gastric metaplasia in the duodenal bulb. This gastric metaplasia is a prerequisite for H. pylori colonization of the bulb. These events are common to all H. pylori-infected subjects. However, a much higher density of H. pylori bacteria and colonization with virulent organisms has been found in the bulb of duodenal ulcer patients, resulting in a much stronger inflammatory reaction with active duodenitis and an impaired bicarbonate secretion. These characteristics, together with acid hypersecretion, seem to be the important factors in evoking a duodenal ulcer.

Helicobacter pylori infection and gastro-oesophageal reflux disease: coincidence or association?

Abstract: Concerning the relationship between Helicobacter pylori infection and gastro-oesophageal reflux disease (GORD), the debate is ongoing whether the infection confers protection, is harmful or whether both entities are independent. Epidemiological evidence is given for an increased prevalence of GORD and a decreased prevalence of H. pylori infection in the western world. The assumpton derived from it is that H. pylori protects from GORD. Pathophysiological aspects need to consider the type and expression of gastritis which is associated with varying changes of gastric function. Depending on the type of gastritis, acid secretion may either increase or decrease and thereby impact on acid exposure of the oesophagus. Other changes related to the role of H. pylori in pathophysiology of GORD are still hypothetical. Clinical data are controversial whether or not GORD increases after H. pylori eradication. Prospective studies including characterization of strains and gastric physiology will clarify this issue. An accelerated induction of gastric mucosal atrophy in patients on long-term proton pump inhibitors is reported in most available studies. An increase of inflammatory activity in fundic and corpus mucosa is a consistent phenomenon. Therefore, in the authors' opinion, eradication appears advisable.

Surgical treatment of portal hypertension

Abstract: The surgical treatment of portal hypertension has laxed and waned over the past century. Decompressive shunts for variceal bleeding hit their peak in the 1970s, but dissatisfaction with encephalopathy and liver failure led to further developments with selective shunts and devascularization procedures in the 1970s and early 1980s. Liver transplant is the major operative intervention currently in use and of advantage to patients with portal hypertension. The role of the surgeon is as part of the team involved in the full evaluation of patients with cirrhosis and portal hypertension with its complications. The current repertoire of surgical options includes decompressive shunts, either total, partial or selective, devascularization procedures and liver transplantation. These options must be fitted into the overall management schema of pharmacologic and endoscopic therapy as the first-line approaches to managing these patients.

Diagnosis of reflux disease

Abstract: There are numerous tests for which a diagnostic value in the context of gastro-oesophageal reflux disease has been claimed. Some of these tests (e.g. the acid perfusion test) have become obsolete after the advent of 24-hour oesophageal pH monitoring. With the latter test not only can excessive reflux be identified, but also, and more importantly, a temporal relationship can be demonstrated between a patient's symptoms and reflux episodes. Radiographical examination of the oesophagus has largely been replaced by endoscopy, although the use of the former test is still indicated in certain circumstances (e.g. in the differentiation of sliding from para-oesophageal hiatus hernia). In clinical practice, the so-called proton pump inhibitor test has gained considerable popularity. Despite several studies on the specificity and sensitivity of this test, its value has not yet been established with sufficient accuracy. Conventional manometric evaluation of lower oesophageal sphincter pressure has been over-emphasized as a diagnostic test in gastro-oesophageal reflux disease.

Autoimmunity and primary biliary cirrhosis.

Abstract: The history of primary biliary cirrhosis (PBC) began in 1851, with autoimmunity introduced in 1958 and expanded from the 1960s on. In PBC, autoantibodies are present to mitochondria-located antigens (AMA) and to nuclear-located antigens (ANA). The AMA react with E2 subunits of three members of the 2-oxoacid dehydrogenase complex family, but most frequently with pyruvate dehydrogenase complex (PDC); the inner lipoyl domain of PDC-E2 contains a major B- and T-cell epitope. The ANA react with three nuclear components, centromeric proteins, nuclear dot proteins and nuclear pore complex. Autoimmune diseases including PBC reflect a failure in mechanisms of self-tolerance which is developed in central lymphoid tissues in embryonic life by deletion of self-reactive lymphocytes, and maintained in peripheral tissues in post-natal life by regulatory processes. Primary biliary cirrhosis has not yet been identified with failure in any one particular tolerance mechanism. Genetic influences are revealed by familial occurrences and by associations with HLA alleles, and environmental influences by epidemiological data. A lead to pathogenesis is the accumulation uniquely in PBC of PDC-E2-like material at the plasma membrance of biliary epithelial cells (BECs). Although the origin of this accumulation of PDC-E2 at the surface of BECs is uncertain, it provides a credible 'tissue-specific' target for an autoimmune attack by T and B lymphocytes at the site of the actual pathology.

Recurrent primary biliary cirrhosis.

Abstract: Transplantation has become the accepted form of therapy for patients with end-stage liver disease. The diagnosis of recurrent disease in the allograft has been a matter of controversy, partly because of the difficulties in making the diagnosis in the allograft situation. The conventional criteria for diagnosing PBC may be inappropriate and there are many causes of bile duct damage in the graft. That the PBC-specific autoantibodies [such as antimitochondrial antibody (AMA) and gp-210] persist after transplantation is universally found, and some have reported the aberrant distribution of E2 in the allograft that is typical of PBC in the native liver, whether or not there is histological evidence of PBC recurrence. Most studies now accept that histological features of PBC, such as granulomatous bile duct damage, ductopenia and biliary-type fibrosis, may be found in the allograft; the histological features of PBC are variable and do not mirror the liver tests. The rate of recurrence increases with time, so that by 10 years, recurrence may be found in 30-50% of biopsies. There are no clear factors which identify those at risk of recurrence, but the pattern and degree of immunosuppression may be implicated. Cirrhosis has only rarely been reported. In the medium term, recurrence of PBC has little clinical impact. Ursodeoxycholic acid is used in some centres but there is no clear evidence for benefit.

Duodenogastro-oesophageal reflux

Abstract: The role of duodenogastro-oesophageal reflux (DGOR), once erroneously termed 'bile reflux', in causing oesophageal mucosal damage has been an area of interest in both animal and human studies. However, due to the lack of appropriate techniques for accurately measuring DGOR, extrapolation of findings from animal studies to humans was difficult to make. The recent advent of the Bilitec system, an ambulatory bilirubin monitoring device, is increasing our knowledge of the specific role of DGOR in oesophageal diseases. Studies suggest that the DGOR without acid reflux may result in symptoms but unless acid reflux is present simultaneously, it does not cause oesophagitis. Therefore, our therapies should aim at reducing both DGOR and acid reflux. Studies show that this may be accomplished by anti-reflux surgery or the use of proton pump inhibitors, which, by reducing gastric volume, decrease the damaging potential of both acid and DGOR.

Management of osteoporosis in primary biliary cirrhosis.

Abstract: Osteoporosis is not a significant problem in the majority of patients with primary biliary cirrhosis (PBC). However, substantial bone-related morbidity may occur in patients with advanced disease, in particular after liver transplantation. The cause of osteoporosis in PBC is multifactorial, and pathophysiological mechanisms specifically related to PBC have not been defined. In general, the principles of management followed in post-menopausal osteoporosis also apply in chronic liver disease. Dual energy X-ray absorptiometry is currently the method of choice for monitoring bone mineral density. Avoidance of conditions with potential negative effects on bone mass, and maintaining adequate serum vitamin D levels and calcium intake form the cornerstone in preventing osteoporosis. Bisphosphonates are the most logical choice when specific medical treatment of PBC-associated osteoporosis is indicated, as well as for preventing bone loss during glucocorticoid treatment and after liver transplantation. Recent studies suggest that active vitamin D analogues are effective alternatives in the post-transplant setting.

The problem of Helicobacter pylori-negative idiopathic ulcer disease.

Abstract: Ulcer disease is an infectious disease, but for how much longer? Reports of a large number of non-infectious ulcers are becoming more frequent, paralleling the changing prevalence of Helicobacter pylori (H. pylori) in many parts of the world. This chapter will address factors involved in the increasing proportion of H. pylori-negative ulcers, the probable cause of such ulcers and the clinical implications related to their management. This discussion is currently most relevant to those regions of the world where the prevalence of H. pylori is already low or rapidly decreasing. However, it is possible that, even in other areas of the world, the prevalence of infection will also eventually change and H. pylori-negative ulcer disease will become more important.

Destruction of bile ducts in primary biliary cirrhosis

Abstract: Primary biliary cirrhosis is characterized by the immune-mediated, progressive destruction of interlobular bile ducts. Lymphoid cells migrate into the biliary epithelial layer through integrin alpha(4)/fibronectin interaction and are responsible for chronic destructive cholangitis. The bile ducts express intercellular adhesion molecule-1 (ICAM-1) and vascular cellular adhesion molecule-1 (VCAM-1), and infiltrating lymphocytes express LFA1 and VLA4, facilitating their interaction. Epithelioid granulomas contain foamy cells ingesting biliary lipids, and CD1d was detectable in epithelioid granulomas, suggesting that the biliary substance(s) which are leaked is a trigger for chronic destructive cholangitis. Apoptotic biliary destruction is brought about by antigen-specific and non-specific reactions. Shrunken biliary epithelial cells with pyknotic nuclei positive for terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labelling (TUNEL) may reflect apoptotic processes. Increased expression of caspase-3 and -8 with DNA fragmentation factor on the bile ducts may reflect molecular events during apoptosis, and down-regulation of Bcl-2 of biliary epithelial cells seems to facilitate apoptosis. Multiple factors, particularly the Fas system, are stimuli of apoptosis. Anoikis with decreased biliary expression of integrin 6, a ligand for laminin, may also be involved in biliary epithelial apoptosis.

The pyruvate dehydrogenase complex as a target autoantigen in primary biliary cirrhosis

Abstract: Mitochondrial autoantigens and their B and T cell autoepitopes have been well defined in primary biliary cirrhosis (PBC). However, the relationships of the antimitochondrial antibodies and the mechanisms of bile duct destruction in PBC remain an enigma. The serological hallmark of PBC remains the presence of antibodies to mitochondria, particularly to the E2 component of the pyruvate dehydrogenase complex (PDC-E2). However, several mechanisms may now be proposed which may explain the immune-mediated bile duct damage in PBC. These include the possible role of T cell-mediated cytotoxicity as well as the interaction between the IgA class of antimitochondrial antibodies and the mitochondrial autoantigens. A prominent feature in this discussion is the highly directed and specific immune response to the mitochondrial antigens, including PDC-E2 as well as other members of the 2-oxo-acid dehydrogenase complexes. Ultimately, the mechanisms that lead to this immune reaction should provide data on other questions in PBC, including the reasons for female predominance, the absence of PBC in children and the relative ineffectiveness of immunosuppressive agents.

Management of gastroduodenal ulcers caused by non-steroidal anti-inflammatory drugs.

Abstract: Non-steroidal anti-inflammatory drugs (NSAIDs) are a major cause of morbidity and mortality, probably resulting in the death of 1200 patients per annum in the UK. The main mechanism of toxicity involves an inhibition of prostaglandin synthesis that results in mucosal erosion as a result of the abrogation of defence mechanisms. However, acid peptic attack can deepen this initial injury. Thus, logical treatments include prostaglandin analogues as 'replacement therapy', acid suppression, enteric coating to avoid topical effects and the use of safer NSAIDs, including those that have little or no effect on gastric mucosal prostaglandin synthesis. There is less logic to the strategy of Helicobacter pylori (H. pylori) eradication, and the status of this approach is controversial. Overall, proton pump inhibitors have the best profile of efficacy and side-effects for the healing and prevention of NSAID-associated ulcers. Misoprostol is also effective and appears to be superior to proton pump inhibitors for superficial erosive injury. Early indications are that selective inhibitors of the inducible cyclooxygenase-2 enzyme have little or no effect in causing ulcers. Growing experience with these agents will probably revolutionize the management of patients with arthritic conditions. However, the increasing use of low-dose aspirin for cardiovascular prophylaxis means that gastroenterologists will have to continue to grapple with the problems of NSAID-associated ulcers for some time to come.

Consequences of Helicobacter pylori cure in ulcer patients

Abstract: In the complex pathogenesis of genuine ulcer disease Helicobacter pylori ( H. pylori ) is an essential, although not on its own sufficient, causal factor. Eradication of the infection heals the active ulcer and, in the long term, leads to a drastic reduction in ulcer recurrence and attendant complications. Some patients remain symptomatic even without ulcer recurrence, and in these, pre-existing, exacerbated or induced gastro-oesophageal reflux disease is probably of some significance. Possible causes of ulcer relapse are reinfection, the use of ulcerogenic drugs and persistent gastric hypersecretion. In adults, and probably also in children from the age of six years, H. pylori reinfection is rare, provided that a sensitive and specific test for H. pylori is carried out at the earliest 4 weeks after concluding anti-bacterial treatment. The most common cause of the reappearance of H. pylori is recrudescence—true reinfection hardly ever occurs. The healing of H. pylori -associated ulcer disease improves the patient's quality of life and possibly also life expectancy. Computer-aided calculations, together with a randomized controlled study, have shown not only that individual patients benefit, but that also the health system profits financially. The hypothetical negative effects of H. pylori eradication treatment are still being controversially discussed.

Injection therapy for endoscopic haemostasis

Abstract: Endoscopic injection is widely used for the arrest of active ulcer bleeding and for prevention of re-bleeding from ulcers with visible vessels. Although of proven value in clinical trials, mechanisms of action are unclear; tamponade, vasoconstriction, endarteritis and a direct effect upon the clotting process at the site of the arterial defect have been proposed. Clinical trials show that dilute adrenaline is an effective agent and that the addition of sclerosants or alcohol confirms no extra benefit, yet risks serious side-effects. The best results are associated with injection of fibrin glue or thrombin which stimulate formation of a stable blood clot. The efficacy of injection, thermal modalities such as the heater probe and electrocoagulation using BICAP are comparable. In general, there is an advantage in combining injection with a thermal modality, although this may have merit in patients with severe, active ulcer bleeding. Patients who re-bleed following successful primary haemostatic injection treatment can be considered for further endoscopic intervention, but the decision to undertake a surgical operation or repeat endoscopic therapy is a matter of clinical judgement.

The pathophysiology of cholestasis with special reference to primary biliary cirrhosis.

Abstract: Cholestasis in primary biliary cirrhosis results from impairment of bile flow either by reduced transport at the level of the canaliculi or by disturbed bile flow through damaged intrahepatic bile ductules. Whatever its cause, the expression of hepatic transport proteins will be affected. In cholestatic rats: the expression of the multispecific organic anion transporter mrp2 is decreased; the bile salt export pump bsep and the phospholipid transporter mdr2 are less affected; the carrier protein for hepatic uptake of bile salts ntcp is sharply down-regulated; Mrp3, a basolateral ATP-dependent transporter for glucuronides and bile salts, is upregulated. Thus, bile salts that cannot exit the hepatocyte because of the cholestasis are effectively removed across the basolateral membrane. These may be adaptive responses in defence against overloading of hepatocytes with cytotoxic bile salts. These responses show that the expression of hepatic transporter proteins is highly regulated. This occurs by transcriptional and post-transcriptional mechanisms. Primary biliary cirrhosis starts as a disease of the small intrahepatic bile ducts and therefore the experimental evidence for 'cross-talk' between hepatocytes and cholangiocytes is of great interest for this disease and needs to be further investigated. New insights in bile physiology may enable the development of new therapies for cholestatic liver diseases as primary biliary cirrhosis.

Surgery in the acute management of bleeding peptic ulcer.

Abstract: The management of bleeding peptic ulcers is an increasing challenge in an ageing population. Endoscopic therapy reduces the need for emergency surgery in bleeding peptic ulcers, and ulcers that fail endoscopic therapy are often 'difficult' ulcers, highly demanding for most gastric surgeons. Mortality in patients requiring eventual salvage surgery is high. Planned urgent surgery is preferable to emergency surgery in elderly patients. Initial endoscopic control offers an opportunity for selecting high-risk ulcers for early surgery. Such a logical approach has, however, not been supported by evidence in the literature. At surgery, an aggressive approach is recommended. Post-operative bleeding is more common after lesser surgery, and this complication is often fatal. When re-bleeding occurs, a selective approach is suggested as emergency surgery carries with it a substantial mortality. Large chronic ulcers with exigent bleeding are less likely to respond to endoscopic re-treatment. Expedient surgery is advised for these patients.

Reflux in children.

Abstract: Gastro-oesophageal reflux (GOR) is an extremely common paediatric problem that often runs a harmless and self-limited course. Physiological GOR however can lead to marked parental anxiety, many unnecessary investigations and often unwarranted and potentially harmful therapeutic interventions. Our ability to better define GOR and gastro-oesophageal reflux disease (GORD) has improved in the past 15 years with a better understanding of the pathophysiology in infants and children due to the development and wider use of flexible endoscopy, 24-hour oesophageal pH monitoring and, more recently, the use of micromanometric methods for studying oesophageal motility. This will be further enhanced in the future with the development of non-invasive breath testing to study gastrointestinal motility and the use of electrical impedance to study fluid movement. Our therapeutic interventions have also improved particularly in the areas of acid suppression, improved surgical techniques and most recently laparoscopic fundoplication. This chapter reviews these advances in the paediatric area especially with regard to pathophysiology, diagnostic testing and therapeutic intervention.

Medical treatment of portal hypertension.

Abstract: In this chapter we give a quick review of the rationale for treatment of portal hypertension. The different scenarios for treatment of variceal bleeding will be discussed—that is, primary and secondary prophylaxis of variceal bleeding as well as the treatment of the acute bleeding episode. The role of the pharmacological, endoscopic and derivative treatments in each one of these scenarios will be discussed. Particular attention will be devoted to the potential role of the combination therapy of beta-blockers with isosorbide-5-mononitrate for preventing re-bleeding and to the best approach to patients with intolerance or contraindications to beta-blockers. We also give a rational review of the data comparing sclerotherapy against ligation as well as the potential role of the latter on primary prophylaxis.

Therapeutic options for HCV--management of the infected individual.

Abstract: Patients with chronic hepatitis C infection should be assessed by liver biopsy prior to consideration of anti-viral therapy. Patients with histologically mild disease should be observed at regular intervals and assessed with a repeat liver biopsy after an interval of 3–4 years. Those with severe disease should receive early treatment with interferon-α and ribavirin. The duration of therapy is determined by the genotype of the infecting virus–viral genotypes 2 and 3 require only 6 months of treatment but other genotypes should be treated for 12 months. Approximately 35–40% of treated patients will respond to therapy with a permanent cessation of viral replication and improvement in liver histology. New therapies including polyethylene glycol, PEGylated, interferons and combination regimes involving amantadine are currently under evaluation and it is hoped that improved regimes will be developed in the near future.

Complex management issues: management of HCV in the atypical patient.

Abstract: Some patients with chronic hepatitis C virus (HCV) infection demonstrate atypical features of presentation and clinical course. These features may be due to direct or indirect effects of the underlying HCV infection or may be part of a separate clinical syndrome. Patients that can be categorized as ‘atypical’ include immunosuppressed individuals (hypogammaglobulinaemic, co-infected with human immunodeficiency virus, recipients of solid organ or haematopoietic cell transplants, those with associated disease requiring chronic immunosuppressive therapy and patients with chronic renal failure on haemodialysis) as well as patients with various extra-hepatic (HCV-associated mixed cryoglobulinaemia, membranoproliferative glomerulonephritis etc) or autoimmune manifestations. Since many of these patients have been excluded from the large trials evaluating the efficacy of interferon-α alone or in combination with ribavirin, data regarding management are limited. In this chapter, the available information regarding the treatment of these patients is reviewed and the frequently encountered therapeutic dilemmas discussed. Finally, some reasonable therapeutic approaches are suggested while the need for controlled studies for these groups of patients is emphasized.

Drug treatment for bleeding oesophageal varices

Abstract: At the time of diagnosis of cirrhosis, varices are present in about 60% of decompensated and 30% of compensated patients. The risk factors for the first episode of variceal bleeding in cirrhotic patients are the severity of liver dysfunction, a large size of the varices and the presence of endoscopic red colour signs, but only a third of patients who suffer variceal haemorrhage demonstrate the above risk factors. The only treatment that does not require sophisticated equipment or the skills of a specialist, and is immediately available, is vasoactive drug therapy. Hence, drug therapy should be considered to be the initial treatment of choice and can be administered while the patient is transferred to hospital, as has been done in one recent study. Moreover, drug therapy is no longer considered to be only a 'stop-gap' therapy until definitive endoscopic therapy is performed. Several recent trials have reported an efficacy similar to that of emergency sclerotherapy in the control of variceal bleeding. Furthermore, recent evidence suggests that those patients with high variceal or portal pressure are likely to continue to bleed or re-bleed early, implying that prolonged therapy lowering the portal pressure over several days may be the optimal treatment. Pharmacological treatment with beta-blockers is safe, effective and the standard long-term treatment for the prevention of recurrence of variceal bleeding. The combination of beta-blockers with isosorbide-5-mononitrate needs further testing in randomized controlled trials. The use of haemodynamic targets for the reduction of the HVPG response needs further study, and surrogate markers of the pressure response need evaluation. Ligation has recently been compared with beta-blockers for primary prophylaxis, but there is as yet no good evidence to recommend banding for primary prophylaxis if beta-blockers can be given.