Occlusive and non-occlusive gastrointestinal ischaemia: a clinical review with special emphasis on the diagnostic value of tonometry.
Kolkman JJ. Groeneveld AB.
Dept. of Gastroenterology, Medical Spectrum Twente, Enschede, The Netherlands.
BACKGROUND: To review clinical features of the occlusive splanchnic ischaemia syndromes with special emphasis on the diagnostic value of tonometry. METHODS: The English literature was reviewed with an emphasis on papers concerning anatomy and physiology of splanchnic perfusion, the clinical presentation and diagnostic procedures in occlusive splanchnic ischaemia syndromes. RESULTS: Splanchnic ischaemia can result from hypovolaemic states, resulting in splanchnic vasoconstriction and ischaemia with normal splanchnic vessels (non-occlusive ischaemia) or from vascular stenoses (occlusive ischaemia). The former is frequently encountered in critically ill patients, whereas the latter is considered rare, despite a relatively high incidence of splanchnic atherosclerosis. The main problem hindering assessment of the incidence of symptomatic chronic splanchnic ischaemia is the lack of a diagnostic procedure separating symptom-free from symptomatic splanchnic atherosclerosis. Although angiography provides precise anatomical information, the correlation with symptoms is poor. From various studies it emerges that tonometry of luminal PCO2 enables assessment of ischaemia. CONCLUSIONS: Splanchnic ischaemia may be more common than currently assumed, but a gold standard diagnostic tool is lacking. Tonometry of the gastric PCO2 may be the most promising technique for detecting and grading splanchnic ischaemia.
13C breath test in gastroenterological practice.
Swart GR. van den Berg JW.
Dept. of Gastroenterology and Hepatology, University Hospital Dijkzigt, Rotterdam, The Netherlands.
Breath tests (BTs) are used in gastroenterological practice to study (patho)physiological and metabolic processes in an indirect way. In these tests the appearance in breath of a metabolite of a specific test substance is studied. The assumption underlying each BT is that one step-the process of interest-in the absorption and metabolism of the tracer is rate-limiting. Both hydrogen gas excretion and carbon dioxide appearance in breath can be studied. When a carbon-labelled test substance is used. the stable isotope 13C is preferred to the radioactive isotope 14C. Measurements of 13C in expired air are performed by mass spectrometry. Because of the indirect nature of BTs, involving a sequence of reactions and metabolic pools, they usually supply semiquantitative data. The tests are nevertheless useful because they often replace invasive techniques with a simple procedure that is safe because there is no radioactivity involved. BTs have been used to measure gastric emptying, the presence of Helicobacter pylori in the stomach, small-bowel bacterial overgrowth, exocrine pancreatic function as well as liver metabolic capacity; other potential applications of BTs are being studied.
Gastric asthma: a pathophysiological entity?
Peters FT. Kleibeuker JH. Postma DS.
Dept. of Gastroenterology, University Hospital Groningen, The Netherlands.
BACKGROUND: Gastro-oesophageal reflux disease (GORD) is manifested by typical reflux symptoms and atypical extra-oesophageal symptoms. Important in this respect are respiratory conditions. Gastric asthma is a prominent example of these extra-oesophageal manifestations of GORD. There is, however, much debate about its prevalence, pathophysiology and clinical importance. METHODS: Narrative review of the literature. RESULTS: In asthmatics, the prevalence of GORD is generally reported to be higher than in normals, but with a wide range, probably due to patient selection. In a minority of asthmatics GORD aggravates or triggers asthma. The pathogenetic mechanisms can be a vagally transmitted reflex as well as micro-aspiration of refluxed material. The association with inflammatory mediator release has been insufficiently investigated. Selecting those who are likely to respond to anti-reflux measures is important: those with difficult to treat asthma, non-allergic asthma, adult-onset asthma with GORD. Oesophageal pH-metry to prove GORD and gastroscopy to diagnose Barrett's metaplasia are advisable.
Otolaryngologic manifestations of gastro-oesophageal reflux disease.
Dept of Gastroenterology, Free University Hospital, Amsterdam, The Netherlands.
At present, gastro-oesophageal reflux disease (GORD) is believed to be an important contributing etiologic factor in many laryngopharyngeal disorders. Endoscopic oesophagitis, however, is found in less than 25% of these patients. Prolonged oesophageal pH monitoring with a dual pH probe is the most sensitive test for diagnosing GORD-related ear, nose and throat (ENT) problems. Based on the therapy studies one may recommend the use of, preferably, proton-pump inhibitors in higher doses than in typical GORD patients. Therapy may be necessary for prolonged intervals or for a lifetime.
Is there a place for laparoscopic antireflux surgery in The Netherlands?
Dept. of Surgery, University Hospital Utrecht, The Netherlands.
BACKGROUND: Antireflux surgery has not gained wide acceptance in The Netherlands in the past two decades. The introduction of laparoscopic fundoplication seems to have had no impact on the number of antireflux operations performed per year. METHODS: The SIG data were consulted in order to compile an inventory on the number of antireflux operations performed in The Netherlands between 1977 and 1995. The data were compared with those kindly supplied by the Laparoscopic Societies of the Scandinavian countries. RESULTS: The number of antireflux operations per year in The Netherlands, 1.7/100,000 per year, is far less than reported in the four Scandinavian countries, 15/100,000 per year, and also far below the 10/100,000 per year needed for antireflux surgery on a yearly basis. CONCLUSIONS: In The Netherlands, 1.7/100,000 inhabitants per year undergo antireflux surgery. This figure has remained virtually stable in the past two decades, i.e. it has not changed even since the introduction of H2-receptor antagonists, proton-pump inhibitors and laparoscopic antireflux surgery. The success of medical treatment and personal, anecdotal, experience of gastroenterologists with patients they have referred for surgery explain the low number of antireflux operations performed. Currently, a randomized trial is being conducted in The Netherlands comparing the effectivity, costs and quality of life after conventional Nissen fundoplication with the laparoscopic approach. All operations are performed or supervised by a limited number of experienced surgeons who have gone through the learning curve of both the open and conventional technique.
The constipated stomach. An underdiagnosed problem in patients with abdominal pain?
den Hartog G. Mulder CJ. Thies JE. Wiersma TG.
Dept of Hepatogastroenterology, Rijnstate Hospital Arnhem, The Netherlands.
The number of dyspeptic patients with upper abdominal pain that are referred for investigation is increasing and will undoubtedly continue to increase, because these days peptic ulcer disease is increasingly becoming a primary care management issue, the specialist being left to deal with the patients who cannot be helped by antibiotics and antisecretory drugs prescribed by their general practitioner. Many of these patients are referred for an upper endoscopy to rule out organic disease. Carefully taken history, however, shows that a great number of those dyspeptics, on the basis of their clinical manifestations, do have a functional gastrointestinal disorder, representing the 'irritable gut'. A probable better term reflecting the direct relation is the syndrome of 'the constipated stomach'. In our opinion these patients are an important and increasing clinical problem for general practitioners, gastroenterologists, surgeons and physicians. The aim of this article is to make the practitioner aware of advancements in understanding pathophysiologic and psychosocial processes, as well as to give an overview of the great overlap between many functional gastrointestinal disorders, the important role of history-taking and some insights into the functional rectal outlet syndrome.
Endoscopic dilatation of the biliary sphincter for removal of bile duct stones: an overview of current indications and limitations.
Bergman JJ. Tytgat GN. Huibregtse K.
Dept. of Gastroenterology, Academic Medical Center, University of Amsterdam, The Netherlands.
Endoscopic balloon dilatation (EBD) of the biliary sphincter may be an alternative to endoscopic sphincterotomy (EST) for removal of bile duct stones. After EBD of the biliary sphincter to a diameter of 8 mm, stones are removed according to standard guidelines. In the event that stone removal fails after EBD, an additional EST is performed. The overall success rate of stone removal after EBD (90%) is comparable to that of EST. After EBD, an additional EST and mechanical lithotripsy are required in 10% and 30% of patients, respectively. In patients with bile duct stones < 10 mm and a stone number < or = 3, EBD is nearly always successful without the need for additional EST or mechanical lithotripsy. Pancreatitis post-EBD occurs at a rate of 5-7%, which is not significantly different from that after EST. Significant bleeding post-EBD has not been observed in over 400 patients undergoing EBD. EBD is a valuable alternative to EST, especially in patients with smaller bile duct stones and in patients with haemostatic disorders.
Autoimmune hepatitis: pathogenesis, diagnosis and treatment.
van den Berg AP.
Dept. of Gastroenterology and Hepatology, University Hospital Groningen, The Netherlands.
BACKGROUND: Autoimmune hepatitis (AIH) is a chronic necro-inflammatory disease of the liver. Early recognition is important in order to prevent the development of cirrhosis. This review discusses recent developments in the fields of diagnosis, pathophysiology and management of AIH. METHODS: Relevant manuscripts were identified using an electronic database, and by hand search of a personal library. RESULTS AND CONCLUSIONS: Description of new auto-antibodies, and formulation of diagnostic criteria and a scoring system by an international panel constitute important advances that may help diagnosis of the disease at an early stage. While a satisfying animal model of the disease is lacking, clinical observations have led to the formulation of a pathophysiological model. Current treatment has a failure rate of about 13%, and is unable to induce a permanent remission in most patients. New immunosuppressive agents (cyclosporine, tacrolimus and mycophenolate mofetil) appear promising, and should be evaluated in controlled trials.
Alcohol consumption and alcohol-related liver disease in The Netherlands.
Adang RP. Wensing JW. Stockbrugger RW.
Dept. of Gastroenterology and Hepatology, University Hospital Maastricht, The Netherlands.
BACKGROUND: No data have so far been published concerning the extent of the problem of alcohol-related liver diseases in The Netherlands. METHODS: Figures on alcohol consumption and admission and mortality rates due to alcohol-related liver disorders in The Netherlands in 1994 were obtained from various sources and the data were considered in a historical perspective. Special attention was paid to regional differences. RESULTS: The per capita alcohol consumption in 1994 in The Netherlands was 86 litres of beer, 16 litres of wine and 1.8 litres of pure alcohol as spirits. The total alcohol per capita consumption of individuals upwards of 15 years of age showed a decrease from 11.7 litres in 1975 to 9.7 litres in 1994. In the same period the estimated number consuming more than 10 cl pure alcohol (8 units) per day remained at about 180,000. The number of general hospital admissions as a result of alcohol-related liver disease as well as the number of deaths because of cirrhosis has hardly changed since 1985. In 1994, 657 men and 407 women were admitted due to alcohol-related liver disease, and 269 men and 125 women died from an alcohol-related liver disorder. The admission and mortality rates from alcohol-related liver disease differed markedly among the various provinces of The Netherlands.
Palliation of malignant dysphagia from oesophageal cancer. Rotterdam Oesophageal Tumor Study Group.
Siersema PD. Dees J. van Blankenstein M.
Dept. of Gastroenterology and Hepatology (Internal Medicine II), University Hospital Rotterdam-Dijkzigt, The Netherlands.
Palliative therapies for advanced oesophageal cancer include surgery, radiation therapy, chemotherapy, endoscopic procedures and combinations of these. Of the non-endoscopic modalities is external beam radiation therapy (EBRT) effective and non-invasive. A disadvantage is that relief of dysphagia only occurs over a period of 4-6 weeks. Brachytherapy is more rapid in locally controlling tumour growth and in relieving dysphagia. One of the more commonly used endoscopic procedures is laser therapy, which provides symptomatic relief with low complication rates. Recurrent dysphagia is a problem necessitating repeated treatment sessions. Self-expanding metal stents offer a high degree of palliation and are associated with fewer complications compared with prosthetic tubes. Longer palliation and perhaps even longer survival might be achieved by the combination of different therapies. Most promising are the combination of EBRT plus brachytherapy or chemoradiation. Now is the time to determine which treatment (combination) is best for individual patients.
Extracolonic manifestations of familial adenomatous polyposis: desmoid tumours, and upper gastrointestinal adenomas and carcinomas.
Griffioen G. Bus PJ. Vasen HF. Verspaget HW. Lamers CB.
Dept. of Gastroenterology-Hepatology, Leiden University Medical Center, University Hospital Leiden, The Netherlands.
It is well known that patients with familial adenomatous polyposis (FAP) are at considerable risk of developing extracolonic manifestations of the disease. Particularly, desmoid tumours of the abdominal cavity, and duodenal adenomas and carcinomas are the most serious ones. It is estimated that some 10% of the FAP patients will develop desmoids, whereas 50-90% of the FAP patients will get duodenal adenomas predominantly concentrated on or around the major papilla. Desmoid tumours and duodenal carcinomas are major causes of death in those patients in whom a prophylactic (procto)colectomy has been performed. Desmoids are histologically benign tumours, composed of mature fibroblasts. They usually grow slowly but they can become quite large and may compress or infiltrate surrounding viscera, which might cause significant morbidity as well as mortality. Successful treatment of these tumours is extremely difficult as surgical therapy often requires the removal of considerable lengths of small bowel. Moreover, surgical therapy may lead to uncontrollable bleeding and is seldom radical. Chemotherapy with cytoxic agents seems promising but so far the data are too few for firm conclusions to be drawn. The same holds true for drug regimens which interfere with the metabolic and hormonal metabolism of the tumour. Although various lines of evidence suggest that the adenoma-carcinoma sequence, which is generally accepted for colorectal adenomas, also applies for the duodenal adenomas in FAP patients, it is not clear whether we should screen these patients for upper gastrointestinal adenomas or not. As these polyps are usually small, sessile, multiple and difficult to remove, the benefit of endoscopic surveillance would be the early detection of cancer rather than eradication of the polyps. In addition, evidence that screening and early treatment leads to improvement of the prognosis is not available. Although the role of (procto)colectomy in the treatment of large-bowel polyps is well established in FAP patients, the treatment of their duodenal counterparts is still open for debate. The risk of the development of periampullary cancer is not high enough to warrant an aggressive prophylactic surgical approach, i.e. a Whipple's procedure, immediately after the discovery of duodenal adenomas. The considerable morbidity and mortality rates of this procedure must be weighted against a putative benefit of screening.
Azathioprine: state of the art in inflammatory bowel disease.
Mayo Clinic, Rochester, MN, USA.
INTRODUCTION: The use of 6-mercaptopurine (6MP) and its prodrug azathioprine (AZA) for inflammatory bowel disease (IBD) has increased in recent years. The pharmacology, patient response in controlled trials, new formulations and routes of administration and safety for these agents are reviewed. PHARMACOLOGY: AZA is rapidly converted to 6MP, which is then further metabolized to the active metabolites, the 6-thioguanine nucleotides (6TGN). The half-life of 6TGN in erythrocytes is prolonged and weeks to months may be required to reach steady state. This prolonged time to 6TGN steady state may help explain the clinical observation that prolonged treatment (3-4 months) with 6MP/AZA for IBD is required before a therapeutic response occurs. CLINICAL RESPONSE: Controlled trials of 6MP (1.5 mg/kg/d) or AZA (1.0-3.0 mg/kg/d) support the following treatment indications for 6MP/AZA: inflammatory Crohn's disease; fistulizing Crohn's disease; steroid-sparing; and remission maintenance. Controlled trials of AZA (1.5-2.5 mg/kg/d) in UC have suggested efficacy for the indications of steroid sparing and remission maintenance, as well as a possible effect in chronically active disease. A therapeutic response appears to require > or = 17 weeks for most patients, and it has been suggested that a greater cumulative dose of AZA may result in increased likelihood of response to AZA. A recent pilot study suggested that administration of an i.v. loading dose of AZA (20-44 mg/kg over 36 h) may decrease the time to response in Crohn's disease patients treated with AZA, perhaps by administering a portion of the necessary cumulative dose more rapidly. Two recent pharmacokinetic studies demonstrated that use of a delayed release oral AZA formulation which delivers AZA directly to the ileocolon markedly reduces systemic absorption of AZA. This 'topical' or 'local' approach to AZA treatment of IBD holds the promise of equal or improved efficacy with a significant reduction in toxicity, and dose-ranging clinical trials with delayed release oral AZA are planned in the near future. SAFETY: Side effects of AZA/6MP include pancreatitis, fever, nausea, leukopenia, infection, and hepatitis. It appears that the risk of malignancy during or following monotherapy with AZA/6MP for IBD is not increased relative to the general population. CONCLUSIONS: AZA/6MP therapy is efficacious and reasonably safe for selected patients with IBD. Indications for treatment with AZA/6MP include refractory Crohn's disease, fistulizing Crohn's disease, steroid-dependent Crohn's disease, Crohn's disease remission maintenance, and possibly refractory UC, steroid dependent UC, and UC remission maintenance. The use of these immune modifier drugs in patients with IBD represents a significant therapeutic advance.
Crohns disease of the upper gastrointestinal tract: the value of endoscopic examination.
Witte AM. Veenendaal RA. Van Hogezand RA. Verspaget HW. Lamers CB.
Dept. of Gastroenterology and Hepatology, Leiden University Medical Center, The Netherlands.
The involvement of the upper gastrointestinal (GI) tract has been considered to be a rare manifestation of Crohn's disease (CD). Retrospective studies have reported prevalence figures of 0.5-13%. The diagnosis of CD of the upper GI tract is based on clinical, radiological, endoscopic and histologic features. In contrast to the retrospective studies, prospective studies, in which patients with CD underwent routine endoscopic evaluation with biopsies, revealed a much higher frequency of endoscopic and histologic abnormalities. Since Helicobacter pylori is the most frequent cause of gastritis and the most important etiologic factor in peptic ulcer disease, it is important to assess the contribution of H. pylori in the interpretation of the abnormalities observed in the upper GI tract in patients with CD. Therapy for CD of the upper GI tract consists of drug therapy and endoscopic or surgical interventions and is in fact similar to that for distal CD. Corticosteroids are still the most important drugs in the treatment of CD of the upper GI tract. Sometimes adjunctive therapy, e.g. gastric antisecretory drugs and mucosa protective agents, is beneficial. Endoscopic evaluation of the upper GI tract with biopsies should be part of the work-up of CD patients.
Development of analogues: successes and failures.
Bosch J. Lebrec D. Jenkins SA.
Liver Unit, Hospital Clinic i Provincial, University of Barcelona, Spain.
The search for new pharmaceutical treatments has led to the isolation of products from a range of natural sources. Analogues synthesized from these products may possess an improved therapeutic effect over their natural counterparts. Two natural peptides, vasopressin and somatostatin, possess pronounced in vivo effects, so do their analogues terlipressin and octreotide. Vasopressin is a powerful vasopressor, reducing portal pressure, and has been used to treat gastrointestinal haemorrhages. However, a number of adverse cardiovascular effects resulting from an increase in peripheral vascular resistance have been associated with this drug. Terlipressin, however, is more effective, has an improved safety profile and is associated with fewer side effects than vasopressin. Somatostatin, a growth regulatory hormone, achieves haemostasis by decreasing splanchnic blood flow, and is effective in preventing early rebleeding. Somatostatin is effective in treating bleeding oesophageal varices (BOV) and is associated with fewer and more transient side effects than terlipressin. Octreotide, however, has greater stability and a longer half-life than somatostatin, but has a less favourable safety profile. Octreotide displays a number of therapeutic advantages over somatostatin, but not in the treatment of gastrointestinal indications. The development of terlipressin from vasopressin has demonstrated a number of clinical advantages, while the development of octreotide from somatostatin has not shown any significant advantage in the treatment of BOV.
Optimizing emergency care of upper gastrointestinal bleeding in cirrhotic patients.
Burroughs AK. Planas R. Svoboda P.
Dept. of Liver Transplantation and Hepatobiliary Medicine, Royal Free Hospital, London, UK.
The type of emergency treatment administered to patients with suspected variceal bleeding is important, as the episode is associated with a high mortality rate. Moreover, rebleeding is common during the first few days after the initial haemorrhage. Several techniques are available to control variceal haemorrhage including pharmacotherapy (vasopressin, terlipressin, somatostatin and octreotide), balloon tamponade, endoscopic techniques, transjugular intrahepatic portosystemic shunt and shunt surgery. The majority of these require specialized equipment and/or experienced personnel, which are not always available in every hospital. In such situations, pharmacotherapy represents the most practical method of establishing haemodynamic control prior to the administration of definitive treatment. Pharmacotherapy can be initiated immediately upon admission to stabilize the patient prior to diagnostic endoscopy, which subsequently improves the efficacy and ease of administration of further endoscopic intervention. The optimal pharmacological agent should be both effective and safe. A drug with no side effects will not complicate the management of critical patients and can be administered over an extended period to reduce the incidence of rebleeding and improve prognosis. Meta-analysis of clinical studies has revealed that of the vasoactive drugs available somatostatin is effective with significantly fewer side effects and currently appears to represent the best choice for treatment. The available evidence suggests that the early administration of pharmacotherapy, as part of a specific treatment regimen, offers significant benefit to patients with variceal bleeding and its administration optimizes emergency care.
Emergency endoscopy strategies for improved outcomes.
De Franchis R. Banares R. Silvain C.
Gastroenterology and Gastrointestinal Endoscopy Service, University of Milan, IRCCS Ospedale Maggiore Policlinico, Italy.
Variceal haemorrhage is the most serious complication of portal hypertension and is associated with a high mortality rate. The first stage of treatment is to stabilize the patient, followed by emergency diagnostic endoscopy to identify the source of the bleeding. If active variceal bleeding is found, endoscopic intervention is performed to induce haemostasis. The endoscopic techniques commonly used to treat bleeding gastro-oesophageal varices include injection sclerotherapy and band ligation. Sclerotherapy achieves haemostasis through the induction of thrombosis or by external compression of the vessel and should be performed during diagnostic endoscopy. Band ligation achieves haemostasis by physical constriction of the varix. Band ligation may be less effective than sclerotherapy in the treatment of actively bleeding oesophageal varices and is therefore recommended for subsequent elective treatment of non-bleeding varices. However, such techniques are difficult to perform during active bleeding. This has prompted the search for improved treatment protocols. Vasoactive drugs which lower portal hypertension have been administered before, during and after endoscopy and may offer an improvement in treatment. Data from several trials have suggested that pharmacotherapy in combination with endoscopic intervention is more effective than endoscopic treatment alone. Furthermore, pharmacotherapy continued for 5 days following endoscopy significantly reduces the incidence of variceal rebleeding. A strict regimen for emergency endoscopy should be used with sclerotherapy forming the basis of treatment--administered in combination with pharmacotherapy, to optimize clinical outcome. However, there is still debate concerning what is the most effective drug for treating variceal haemorrhage.
Advances in the immunogenetics of coeliac disease. Clues for understanding the pathogenesis and disease heterogeneity.
Pena AS. Garrote JA. Crusius JB.
Dept. of Gastroenterology and Hepatology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.
Recent studies using the technique of the human genome screening in families with multiple siblings suffering from coeliac disease have suggested the presence of at least four different chromosomes in the predisposition to suffer from coeliac disease. Two loci in chromosome 6 appear to be important in disease susceptibility. Other studies based on cytokine gene polymorphisms have found a strong association with a particular haplotype in the TNF locus. This haplotype carries a gene for a high secretor phenotype of TNFalpha. The finding may be important in understanding the heterogeneity of inflammatory response. Evidence has been presented in favour of a predominantly Th1 pattern of cytokine production by the coeliac disease associated HLA-DQ restricted T cell clones. HLA-DQ2 and -DQ8 restricted gliadin-specific T cells have been shown to produce IFN-gamma, which appears to be an indispensable cytokine in the damage to enterocytes encountered in the small intestine, since the histological changes can be blocked by anti-IFN-gamma antibodies in vitro. TNF-alpha, also produced by several T cell clones, may in conjunction with IFN-gamma have a toxic effect or enhance the IFN-gamma-induced increase of HLA-class II expression on surface enterocytes. In the lamina propria this leads to an increased expression of adhesion molecules such as ICAM-1 on T lymphocytes and macrophages. Th1 cells also activate cytotoxic CD8+ T cells that migrate in the epithelial layer, and stimulate further LPL macrophages to produce IFN-gamma and TNF-alpha enhancing the inflammatory response. During this process autoreactive T cells proliferate, creating a situation which is very similar to the process that takes place in autoimmune diseases. Occasionally, this inflammatory destruction of the small intestinal integrity initiated by gluten peptides goes further and develops into a proper autoimmune disease which requires the use of immunosuppressive drugs in addition to a gluten-free diet.