Volume 63 - 2000 - Fasc.4 - Symposium
Lamivudine for the treatment of chronic hepatitis B
Lamivudine (ZeffixTm) is the first of a new class of antiviral agents to become available for the treatment of chronic hepatitis B. The results of controlled clinical trials indicate that in most patients, lamivudine improves necro-inflammatory liver disease, reduces the progression of hepatic fibrosis, normalises serum alanine aminotransferase, and enhances hepatitis B e antigen (HBeAg) seroconversion. For patients with HBeAg-positive chronic hepatitis B, one year of lamivudine therapy results in HBeAg seroconversion rates similar to those obtained with a standard course of inierferon-alpha. Moreover, results from two and three years of lamivudine therapy show that the cumulative HBeAg seroconversion rate continues to increase with extended lamivudine therapy. Even in the absence of HBeAg seroconversion, lamivudine therapy leads to improvements in liver disease in many patients. HBV strains (YMDD variants) with reduced in vitro sensitivity to lamivudine were detected in some patients after at least 9 months therapy. Although the clinical benefits to lamivudine were greatest for those patients who remained free of YMDD variants, one year of lamivudine therapy led to improvements in most response parameters compared with placebO. regardless of whether YMDD variants were detected. Controlled and open-label studies show that lamivudine may provide similar benefits to other important groups of patients with chronic hepatitis B, including those with pre-core mutant disease and those with hepatic decompensation. Lamivudine was well tolerated in all patient groups studied. The incidence of adverse events was consistently similar in patients who received lamivudine compared with those given placebo. In conclusion, extensive clinical data provide evidence that lamivudine is a well-tolerated, effective, and convenient medicine for patients with chronic hepatitis B.
Chronic hepatitis B therapy with lamivudine in clinical practice. Summary of the discussion
Hepatitis A and hepatitis B vaccination of patients with chronic liver disease
Hepatitis vaccination in chronic liver disaeses
Fibrosis of liver, pancreas and intestine: common mechanisms and clear targets ?
Chronic diseases of the liver, pancreas, intestine, kidneys, skin and lungs are usually accompanied by scarring. Loss of organ function is often progressive despite the use of immunosuppressive, antiviral or antiinflammatory agents. Therefore, well tolerated antifibrotic therapies are urgently needed. The targets for such therapies are activated mesenchymal cells that synthesize an excess of matrix proteins and resemble the myofibroblasts of healing wounds. These cells derive from normally quiescent fibroblasts or smooth muscle cells and from stellate cells of liver and pancreas. Their activation is triggered and maintained by mechanical stress and several fibrogenic modulators and cytokines. Some agents inhibit myoribroblast proliferation and collagen synthesis in vitrO. but only few of them are effective in vivo. Potential antifibrotic drugs have been tested mainly in models of liver fibrosis. In the suitable rat model of biliary fibrosis, an antiflbrotic effect was demonstrated for silymarin, a defined mixture of flavonoids, and to a lesser degree for pentoxifylline. A spin-off of the large multicenter trials for hepatitis C is the finding that interferon-" given for 6-12 months may halt or reverse fibrosis, even in virological non-responders. This has to be proven in prospective randomized trials. Specific inhibitors of the endothelin-A-receptor which are orally available can suppress liver collagen accumulation by 4060%. Other strategies aim at inhibition of the profibrogenic cytokines TGF-0 or connective tissue growth factor. Effective drug targeting to the fibrogenic liver cells is now possible by use of cyclic peptides that bind to receptors which are specifically upregulated on activated stellate cells. Blockade of such activation receptors can induce stress-relaxation which reverts the fibrogenic cells to a ribrolytic, collagen degrading phenotype. Fibrosis has been discovered as a novel target for the pharmaceutical industry. This implies the use of combinatorial chemistry and an automatized screening machinery, greatly speeding up the design and selection of specific antifibrotic agents. Combined with the rapidly evolving validation of serological markers of fibrogenesis and fibrolysis unforeseen progress in the treatment of organ fibrosis can be expected.
Contribution of morphology for the comprehension of mechanisms of fibrosis in inflammatory enterocolitis
Strictures are a common complication of Crohn's disease and an indication for surgery in approximately 50% of patients. Morphologic studies have shown that fibrosis of the submucosa and muscularis propria are common in Crohn's disease, especially in strictures. Immunohistochemical and in situ hybridization studies have demonstrated a marked increase of various subtypes of collagens in Crohn's disease. Collagens type I and III are present in ulcerated areas where they appear around capillaries and in a linear deposition at the junction between the granulation tissue and the necrotic debris. Coliagens type IV and V show a prominent perivascular expression, increased deposition in the muscularis propria and increased expression around ganglia. Initiation and maintenance of the connective tissue changes are related with the inflammatory infiltrate. Inflammatory cells can further alter smooth muscle proliferation and migration and promote the formation of myofibroblasts. These alterations together with increased coltagen deposition are involved in the complex process of strictures and bowel wall alterations in Crohn's disease.
Genetics of Crohn's disease behaviour
Crohn's disease is probably an heterogeneous entity. This heterogeneity may be linked to either genetics or environment. In particular the behaviour of the disease, i.e. the tendency to develop stricturing and/or penetrating lesions, may be linked to the genetic background. While epidemiological and clinical data suggest the relevance of these behavioural classifications, the progresses in the characterization of the immuno-inflammatory reaction in the bowel wall shed a new light on possible candidate genes for these genetic predispositions to various Crohn's disease behaviours. Association studies an linkage analysis focusing on growth factors, metalloproteinases and their tissue inhibitors as well as cytokines may bring new interesting data in this field.
Helicobacters of possible zoonotic origin : a review
Since the isolation of Helicobacter pylori, many new Helicobacter species have been identified from the gastrointestinal tract in humans and animals. In humans, a spiral organism different from H. pylon and provisionally named "Helicobacter heilmannii", has been associated with gastritis, gastric ulceration and to a lesser degree, gastric cancer. In addition Helicobacter cinaedi, Helicobacterfennelliae, Helicobacterpullorum and "Flexispira rappini" have been isolated from cases of enteric disease, bacteremia and pneumonic illness. In the biliary tract, the presence of Helicobacter bills, Helicobacter pullorum and "Flexispira rappinill has been demonstrated. Morphological, epidemiological and genotypic data suggest the involvement of animal helicobacters in these infections. In this paper, a review of the literature addressing the current knowledge about epidemiology, diagnosis, pathogenesis and therapy of these infections is given.
Evidence based medicine and extradigestive manifestations of Helicobacter pylori
A putative pathogenetic role has been ascribed to Helicobacter pylori in several extradigestive diseases, including vascular (atherosclerosis and ischaemic heart disease, primary Raynaud phenomenon, primary headache), autoimmune (Sj6gren's syndrome, Henoch-Schiinlein purpura, autoimmune thyroiditis, idiopathic arrythmias, Parkinson's disease, nonarterial anterior optic ischemic neuropathy), and skin diseases (chronic idiopathic urticaria, rosacea, alopecia areata), sideropenic anemia, growth retardation, late menarche, extragastric MALT lymphoma, diabetes mellitus, hepatic encephalopathy, sudden infant death syndrome, and anorexia of aging. We examine critically the strength of the evidence linking these diseases to Helicobacter pylori, using ischaemic heart disease as an example of epidemiological techniques, and skin diseases as an example of treatment studies. By the standards of evidence-based medicine, studies have been often of low quality. The best evidence usually is not indicative of a role for Helicobacter pylori in these diseases.
Helicobacter in extragastric intestinal and liver disease
The long term consequences of endoscopic sphincterotomy