The first histamine H2-receptor antagonists were developed in the early 1970s, and they have a dominant role in today's management of peptic ulceration. The original regimens using either cimetidine or ranitidine attempted to control acidity across the 24 hours, but more 'modern' regimens use a large single dose of the H2-blocker in the evening, which produces a pulse of decreased intragastric acidity during the night with a normal acidity in the daytime. High-dose regimens using a new generation of extremely potent histamine H2-receptor antagonists may improve ulcer healing rates at 4 weeks, and may be particularly useful for the management of either severe oesophagitis or intractable duodenal ulceration.

Penetration of the pericardium and heart by benign peptic ulcers is rare. Before 1965 it was almost invariably fatal, but about 20% of recently reported cases have survived. We report 4 representative cases and review 91 additional cases from the literature. The ulcers arose in esophagus, hiatus hernias, abdominal stomach, and near anastomoses, and the predominant predisposing factor was previous surgery to the esophagogastric region. Whereas penetrating esophageal ulcers had a slightly better prognosis than gastric lesions, the principal determinant of clinical presentation, findings, and prognosis was the site of cardiac involvement. The clinicopathological features of pericardial, atrial, and ventricular involvement are distinct. We evaluate the different implications of these features for diagnosis, management, and prognosis and make some tentative recommendations regarding diagnostic procedures and treatment. Early diagnosis and prompt surgical intervention are critical to successful treatment of this entity, which may present with predominantly cardiac or gastrointestinal symptomatology.

Drugs can induce various vascular and sinusoidal lesions of the liver, in particular hepatic vein thrombosis, veno-occlusive disease, sinusoidal dilatation, peliosis hepatis, hepatoportal sclerosis and angiosarcoma. None of these lesions is specific of drug-induced injury and all of them can be determined by causes other than drugs. However, for one of these lesions, veno-occlusive disease, chemotherapy (and/or irradiation) represents the main aetiology.

The ability to induce granulomatous hepatitis has been attributed to numerous drugs; some sixty causative drugs have been culled from the literature for this review. Additionally, granulomas or granulomatoid lesions have resulted from occupational exposure to toxic substances (e.g. silica, copper sulphate, beryllium compounds), and particulate material from various therapeutic or diagnostic procedures (e.g. reactions to starch, talc, suture material, polyvinyl pyrrolidone, silicone, barium sulphate, thorium dioxide) or from intravenous drug abuse (e.g. talc). Clinically, patients with drug-induced or toxic granulomatous hepatitis may be asymptomatic. More frequently, the presentation is that of an acute febrile illness, with or without a rash and eosinophilia, followed by jaundice and biochemical evidence of hepatic dysfunction. The diagnosis of drug-induced granulomatous hepatitis is based largely on ruling out other aetiologies. Liver biopsy plays a key role in diagnosis. Recovery is the rule following withdrawal of the drug. Morphologically, drug-induced granulomas may be impossible to distinguish from those due to other causes. Associated lesions suggesting a drug aetiology include significant tissue eosinophilia, unicellular hepatocytic degeneration and necrosis, cholestasis and acute cholangitis or vasculitis. Special stains, polarizing and phase contrast microscopy, transmission and scanning electron microscopy and energy dispersive X-ray microanalysis all play a role in the aetiologic diagnosis of some types of granulomas.

Acute, drug-induced hepatocellular cholestasis (either pure or cholestatic hepatitis) is a common manifestation of drug-induced hepatic injury. The drugs most frequently responsible are hormonal steroids and psychopharmacological agents (in particular phenothiazines and some antidepressants). Cholestasis usually subsides without sequelae in less than six months. Acute, drug-induced ductular cholestasis is uncommon and can resemble biliary tract obstruction. Complete recovery occurs promptly after the withdrawal of the causative drug in most cases. The pathogenetic mechanism may be immunoallergic. Prolonged ductular or ductal cholestasis can follow drug-induced acute hepatitis despite prompt withdrawal of the offending drug. This syndrome, observed mainly with chlorpromazine and uncommonly with twenty other drugs, is characterized by the progressive disappearance of small bile ducts and by manifestations mimicking primary biliary cirrhosis. However, its prognosis appears to be better than that of primary biliary cirrhosis, the condition being reversible in the majority of cases or even subsiding completely. The mechanism is still unknown, but several features suggest some form of autoimmunity. Extrahepatic cholestasis related to sclerosing cholangitis is a frequent and long-term complication of intra-arterial infusion of floxuridine in patients treated for hepatic metastases from colorectal carcinoma. Although it may be reversible, floxuridine-induced sclerosing cholangitis has a poor prognosis and can lead to death in a few patients. The mechanism is probably related to the vascular supply of the common hepatic duct and its relationship to the perfusion territory of floxuridine.

Adverse drug reactions may mimic almost any kind of liver disease. Acute hepatitis is often due to the formation of reactive metabolites in the liver. Despite several protective mechanisms (epoxide hydrolases, conjugation with glutathione), this formation may lead to predictable toxic hepatitis after hugh overdoses (e.g. paracetamol), or to idiosyncratic toxic hepatitis after therapeutic doses (e.g. isoniazid). Both genetic factors (e.g. constitutive levels of cytochrome P-450 isoenzymes, or defects in protective mechanisms) and acquired factors (e.g. malnutrition, or chronic intake of alcohol or other microsomal enzyme inducers) may explain the unique susceptibility of some patients. Formation of chemically reactive metabolites may also lead to allergic hepatitis, probably through immunization against plasma membrane protein epitopes modified by the covalent binding of the reactive metabolites. This may be the mechanism for acute hepatitis produced by many drugs (e.g. amineptine, erythromycin derivatives, halothane, imipramine, isaxonine, alpha-methyldopa, tienilic acid, etc.). Genetic defects in several protective mechanisms (e.g. epoxide hydrolase, acetylation) may explain the unique susceptibility of some patients, possibly by increasing exposure to allergenic, metabolite-altered plasma membrane protein epitopes. Like toxic idiosyncratic hepatitis, allergic hepatitis occurs in a few patients only. Unlike toxic hepatitis, allergic hepatitis is frequently associated with fever, rash or other hypersensitivity manifestations; it may be hepatocellular, mixed or cholestatic; it promptly recurs after inadvertent drug rechallenge. Lysosomal phospholipidosis occurs frequently with three antianginal drugs (diethylaminoethoxyhexestrol, amiodarone and perhexiline). These cationic, amphiphilic drugs may form phospholipid-drug complexes within lysosomes. Such complexes resist phospholipases and accumulate within enlarged lysosomes, forming myeloid figures. This phospholipidosis has little clinical importance. In a few patients, however, it is associated with alcoholic-like liver lesions leading to overt liver disease and, at times, cirrhosis. Subjects with a deficiency in a particular isoenzyme of cytochrome P-450 poorly metabolize perhexiline and are at higher risk of developing liver lesions. Prolonged, drug-induced liver-cell necrosis may also lead to subacute hepatitis, chronic hepatitis or even cirrhosis. This usually occurs when the drug administration is continued, either because the liver disease remains undetected or because its drug aetiology is overlooked. Several autoantibodies may be present.(ABSTRACT TRUNCATED AT 400 WORDS)

Drug-induced constipation is mostly caused by changes in gut motility, whilst diarrhoea is more frequently caused by an increase in intestinal fluid secretion. In both instances the drug has to reach the enteric nervous system or the enterocyte, either via the blood or from the lumen, in sufficient concentrations to affect the mediators that regulate motility and fluid transport. Diarrhoea and constipation are frequently mentioned as side-effects of drugs, and therapeutic agents for almost all organ systems have been implicated. However, both these side-effects are usually mild or moderate, and rarely necessitate interruption of drug treatment. An exception to this rule is the antibiotic-associated colitis seen in patients treated with antibiotics such as lincomycin or clindamycin; in principle almost all antibiotics may cause this severe and potentially life-threatening complication. Other rare forms of severe, drug-induced colitis and diarrhoea result from toxic or anaphylactic reactions against gold preparations, cytostatic agents and sulphonamides. Ischaemic colitis due to vascular complications has been described in some women taking oral contraceptives, and in patients treated with vasopressin or digitalis.

Aspirin and other NSAIDs are drugs for which the causal association with major gastrointestinal bleeding has not been adequately or conclusively demonstrated, although a certain degree of correlation is very likely. For aspirin ingestion in particular the increased risk is confined to patients taking the drug at heavy and regular dosages (less than 1% of users), and can be reduced further by the use of enteric-coated formulations. For non-aspirin NSAIDs, the relative risk of GI bleeding after repeated and prolonged exposure (in comparison to controls) has been quantified between 1.5 and 2.7, which is a small but significant figure, and it is increased by the age of the patients, by the duration of treatment and by the dose of drug. No consistent causal relationship can be found between major GI bleeding (or other major peptic ulcer complications) and steroids or other 'ulcerogenic' drugs. The therapy of drug-induced (or drug-associated) GI bleeding is probably not different from the usual treatment of upper GI haemorrhage. As far as the treatment of drug-associated gastroduodenal mucosal damage is concerned, it appears that with mucoprotective agents or H2 antagonists the healing rates of peptic ulcers is slower than observed in non-drug-associated disease. Prophylactic treatment with prostaglandins has only been proposed; and prophylactic treatment with H2 antagonists has been disappointing.

We reviewed the English-language literature pertaining to drug-induced pancreatitis and attempted to determine whether the reported association between each drug and pancreatitis was valid. The following drugs seem to cause pancreatitis: azathioprine, chlorothiazide and hydrochlorothiazide, oestrogens, frusemide, 6-mercaptopurine, methyldopa, sulphonamides, sulindac, tetracycline and valproic acid. Less convincing but suggestive evidence exists for colaspase, chlorthalidone, combination cancer chemotherapy, cimetidine, cisplatin, corticosteroids, cytosine arabinoside, diphenoxylate, ethacrynic acid, iatrogenic hypercalcaemia, methandienone, metronidazole, nitrofurantoin, pentamidine, phenformin, piroxicam and procainamide. In general, pancreatitis is a very rare complication of treatment with these drugs. The pathogenesis of the pancreatitis is usually obscure, but is probably mediated by an immune response. Certain drugs such as oestrogens cause hypertriglyceridaemia, which in turn may lead to pancreatitis.

Non-specific abdominal complaints are a very frequent cause of discomfort. Even if only comparatively few are brought to the attention of the physician, they account for a considerable portion of the reasons for seeking medical care, both in acute and chronic conditions. On the other hand, few drugs are free of the suspicion of causing abdominal complaints, which make up between one-tenth and one-third of reported adverse reactions. A wide variety of possible alternative or concomitant causes makes a clear causative attribution to suspected drugs very difficult. This holds especially true for the ill-defined conditions of indigestion and anorexia. For nausea and vomiting, specific scales have been developed which facilitate differentiation between drugs causing these effects most frequently and most intensively. They have been applied in cytostatic therapy, where this is one of the most frequently encountered problems, but nausea and vomiting can seriously affect compliance in many other treatments. Somatic abdominal pain results in most instances from the irritation of the parietal peritoneum and is usually the effect of a lesion. This may or may not be caused by a drug, but this cause should be the first consideration. Visceral pain may result from functional disturbance of secretory glands or of the muscular coat, from drug action on bowel content or from irritation of the mucosa, all of which are frequently interrelated. Most frequently suspected pharmacological causes are drugs with anticholinergic action, antibiotics, potassium supplements and non-steroidal, anti-inflammatory agents. Drug-induced hyperinsulinism and porphyria are rare cases. Abuse of laxatives should always be considered because of its prevalence. A great number of other untoward drug effects have been described in the literature, but rarely merit first consideration. With the exception of promptly occurring or persistent emesis, gastrointestinal symptoms usually are not pathognomonic for drug effects and are the result of several factors. The usual approach to identifying an adverse drug effect is to delineate the functional or structural disorder, and to associate this diagnosis with possible pharmacodynamic aetiologies.

Persisting retrosternal pain of sudden onset is suggestive of a drug-induced oesophageal lesion, particularly if it starts at night. After exclusion of a myocardial infarction, a carefully taken history and oesophagoscopy will rapidly clarify the cause and severity of the injury. Since almost any pill may produce oesophageal lesions, care has to be taken that tablets, capsules and other pills are always taken in an upright position together with a fluid chaser of at least 120 ml. If possible, less harmful liquid preparations of the drugs should be preferred. Lesions in the oesophageal wall and perioesophageal tissue are almost unavoidable side-effects of sclerotherapy of oesophageal varices. The patient and the doctor should be particularly aware of bleeding from oesophageal ulcers during the first week after sclerotherapy. Numerous drugs may weaken or strengthen contractions of the oesophagus and lower oesophageal sphincter. These potentially unwanted motor effects of the drugs have to be kept in mind, especially in patients with pre-existing gastro-oesophageal reflux disease and hypermotility states.

Humans are remarkably resistant to many carcinogens that readily produce liver tumours in rodents, particularly the rat. The neoplastic process has been extensively studied in animal experiments, but little is known so far of how it evolves in humans. Few drugs have been shown to cause liver tumours in humans, and the risk appears to be low. The best-known examples are C17-alkylated or ethinylated gonadal sex steroids. Oral contraceptives have now been in use by millions for thirty years, but only a few hundred cases at most of liver cell adenoma have been observed. The role of these substances in liver cell carcinoma remains controversial, and the evidence is weaker still in relation to focal nodular hyperplasia and other tumour-like conditions. Anabolic-androgenic steroids stand out as the major cause of peliosis, but liver cell tumours induced by them seem to be adenomas and not carcinomas as originally suggested. The effect that both oral contraceptives and anabolic-androgenic steroids have on liver vasculature is of great clinical importance as the most important complication of liver tumours is rupture, leading to life-threatening haemorrhage. For this reason, liver tumours arising in users of these drugs should be removed whenever feasible. Thorium dioxide will remain a risk factor for the development of angiosarcoma, liver cell carcinoma and bile duct carcinoma for some time yet, and the number of patients who have been exposed is high--tens of thousands at least. The evidence of a carcinogenic role for many other drugs is anecdotal or weak. Neoplasia in the liver seems to be the least important side-effect of drugs in clinical use.

Patients who have lost such a large portion of their small bowel that they permanently require total parenteral nutrition for survival would greatly benefit by receiving a small-intestinal transplant. Over the past two decades, many experimental studies have delineated the specific problems surrounding small-bowel transplantation and provided strategies for their control. Control of rejection, the most difficult problem, may be achieved with a combination of cyclosporine, azathioprine, prednisone, antithymocyte globulin, and monoclonal antibodies. The threat of graft-versus-host disease originating from the allogeneic lymphatic tissues in the allograft is abolished by in vitro x-irradiation of the cold, nonperfused graft with 1000 rads. Monitoring of the intestinal allograft is possible with the combination of a function test (maltose absorption, glucose absorption, or any other function test) and repeated graft biopsy. Effective short-term preservation of small-bowel segments for up to 18 h is possible by intravascular flushing with a balanced electrolyte solution containing 3% fructose and by subsequent hypothermic storage. Clinical small-bowel transplantation is certainly not an imminent therapeutic tool. However, clinical trials in highly selected patients could be envisioned on the basis of our present understanding of small-bowel transplantation and of transplantation biology in general, and in view of the clinical successes achieved with duodenal grafts transplanted in conjunction with pancreatic grafts.

Chronic intestinal pseudo-obstruction (CIP) is a clinical syndrome characterized by symptoms and signs of intestinal occlusion, in absence of any mechanical obstruction of the gut lumen. It causes impaired transit of intestinal contents and is determined by abnormalities of motor activity. The term CIP is used to indicate a heterogeneous group of disorders with many different pathogenic mechanisms. The defect in the regulation of intestinal transit can be at any level of motility control. Two main types of CIP are recognized, termed respectively myogenic (when smooth muscle cells are affected) and neurogenic (caused by abnormalities of extrinsic and/or intrinsic nervous supplies). Both types may be secondary to a variety of recognizable diseases or idiopathic. In myogenic CIP, intestinal transit is impaired because of lack of propulsive strength; in the neurogenic form, contractions are powerful but not sufficiently co-ordinated to propel intestinal contents aborally in an organized fashion. CIP belongs to the large and loosely defined group of digestive functional disorders. These disorders probably share common pathogenic mechanisms but with different expressiveness. The reasons why only some patients present recurrent symptomatological bouts resembling mechanical occlusion has not been clarified. This aspect is of great clinical relevance and deserves attention, as CIP patients, unlike other patients with severe functional disorders, may undergo repeated, useless and potentially dangerous operations. The diagnosis of CIP may be suggested by clinical features and is based on radiological, endoscopic, manometric, and histological findings. Recent technological improvements facilitate the recognition of this intriguing syndrome. In particular, manometric recording of the small bowel motility, which has long been considered an important research technique, can now also be regarded as a useful diagnostic tool.