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Distal ulcerative colitis can be treated with oral or rectal mesalazine, or both. A foam enema preparation has been developed and its efficacy investigated. The aim of this study was to evaluate the efficacy and safety of mesalazine foam enemas compared with prednisolone foam enemas in the treatment of patients with acute distal ulcerative colitis. Patients aged over 18 years presenting with a relapse of distal ulcerative colitis were randomly allocated treatment with mesalazine foam enema (n = 149 evaluable patients) and prednisolone foam enema (n = 146 evaluable patients) for four weeks. A randomised multicentre investigator blind parallel group trial was conducted. It was found that after four weeks of treatment, clinical remission was achieved by 52% of mesalazine treated patients and 31% of patients treated with prednisolone (p < 0.001). There was a trend in favour of more patients in the mesalazine group achieving sigmoidoscopic remission (40% v 31%, p = 0.10). Histological remission was achieved by 27% and 21% of patients receiving mesalazine and prednisolone respectively. Symptoms improved in both treatment groups. Significantly more mesalazine patients had no blood in their stools after four weeks of treatment (67% v 40%, p < 0.001). Prednisolone treated patients had significantly fewer days with liquid stools than mesalazine patients, with a median of 0 and 1 days respectively by week 4 (p = 0.001). In this study mesalazine foam enema was superior to prednisolone foam enema with regards to clinical remission, this was supported by favourable trends in sigmoidoscopic and histological remission rates. Both treatments were well tolerated.

Morphometric measurements have been performed on small intestinal biopsy specimens from patients with untreated coeliac disease before and after six weeks oral treatment with a steroid of low systemic bioavailability (fluticasone propionate). Measurements were obtained by point counting and also by a computer-aided measuring system with reference to a constant area of the muscularis mucosa. Fluticasone propionate led to a parallel reduction in the intraepithelial lymphocyte count within the surface (P less than 0.001) and crypt epithelium (P less than 0.01). The intra-epithelial lymphocyte count assessed by reference to constant areas of the muscularis mucosa and surface epithelium were decreased two-fold (P less than 0.01) and seven-fold (P less than 0.001) respectively. Fluticasone propionate treatment also led to significant increases in the absorptive surface epithelium as shown by an increase in the villus:crypt ratio (P less than 0.01), the epithelial cell height (P less than 0.01) and two- to three-fold increases in the area and length of the surface epithelium (P less than 0.001). Short-term fluticasone propionate treatment appears to exert a powerful beneficial effect upon duodenal morphology in patients with coeliac disease. Whether the alterations seen are comparable to a similar period of gluten withdrawal is not yet known.

Summary The aminosalicylate group of drugs, used in the treatment of inflammatory bowel disease, has a variety of adverse effects, which include: Common adverse reactions Nausea, vomiting, abdominal pain — Up to 40% with sulphasalazine; much less with mesalazine or olsalazine Headache — 1–15% with sulphasalazine; less with mesalazine or olsalazine Blood dyscrasias — 1–3% with sulphasalazine Rare with mesalazine or olsalazine. Male intertility — 80% with sulphasalazine, None with mesalazine or alsalazine. Watery diarrhoea — All 5-ASA preparations; obout 15% with olsalazine. Rash fever — 0.5–5% with sulphasalazine; rare with mesalazine or olsalazine. Rare adverse reactions Nephrotoxicity — All drugs. Possibly more common with mesalazine. Pancreatitis — Possibly more common with mesalazine. Exacerbation of coiltis, hepatotoxicity, pulmonary fibrosis, polyarteritis — Very rare with a ninosalicylates.

Forearm glucose uptake during a hyperglycaemic (10 mmol/l) glucose clamp was diminished to 33% of the normal value (p = 0.012) in six cirrhotic patients compared with matched control subjects. Fasting insulin concentrations were significantly elevated in the cirrhotic patients confirming insulin resistance which may have been induced by chronic hyperinsulinaemia. The cirrhotic patients received one week of treatment with 50 micrograms octreotide subcutaneously three times daily which reduced pre-dose fasting insulin levels from 26.2 +/- 7.9 to 18.1 +/- 6.2 mU/l p < 0.005, and post dose levels to 7.0 +/- 3.5 mU/l p < 0.005. However when the glucose clamp was repeated 20 hours after the last dose of octreotide no change was detected in clamp glucose requirements, forearm glucose uptake, or stimulated insulin secretion. It was concluded that one week of lowering insulin levels does not reverse the insulin resistance of cirrhosis.

Grading of Helicobacter pylori induced atrophic gastritis using the updated Sydney system is severely limited by high interobserver variability. The aim of this study was to set up a quantitative test of gastric corpus mucosal atrophy in tissue sections and test its reproducibility and correlation with the Sydney scores of atrophy.Mucosal atrophy was assessed in 124 haematoxylin and eosin stained corpus biopsy specimens by two experienced gastrointestinal pathologists (EB, JL) according to the updated Sydney system as none (n = 33), mild (n = 33), moderate (n = 33), or pronounced (n = 25). In each specimen, the proportions of glands, stroma, infiltrate, and intestinal metaplasia in the glandular zone were measured as volume percentages using a point counting method. The optimal point sample size, intra-observer and interobserver reproducibility, discriminative power for degrees of atrophy, and correlations with H pylori status were evaluated.Counting 400 points in 200 fields of vision provided the smallest sample size that still had excellent intra-observer and interobserver reproducibility (ror = 0.96). Overall, the volume percentage of glands (VPGL), infiltrate (VPI), and stroma (VPS) correlated well with the Sydney scores for atrophy (por = 0.003). However, no differences were found between non-atrophic mucosa and mild atrophy. No correlation was found between age and either the Sydney grade of atrophy or the VPGL or VPS. In non-atrophic mucosa and mild atrophy, H pylori positive cases showed a significantly higher VPI than did H pylori negative cases. A lower VPGL was seen in H pylori positive cases than in H pylori negative cases in the mild atrophy group. VPS did not correlate with H pylori status within each grade of atrophy.Point counting is a powerful and reproducible tool for the quantitative analysis of mucosal corpus atrophy in tissue sections. These data favour the combination of "none" and "mild" atrophy into one category, resulting in a three class grading system for corpus atrophy, when using the updated Sydney system.

Fluticasone propionate is a corticosteroid with the potential for topical treatment of ulcerative colitis because of low systemic bioavailability. The drug was compared with prednisolone in the management of active left sided or total ulcerative colitis. Two hundred and five patients were studied in the multicentre four week double blind study. Prednisolone was given in a dose of 40 mg daily orally, reducing over four weeks to 10 or 20 mg. Fluticasone propionate was given in an oral daily dose of 20 mg. The primary end point was the investigator's overall assessment of response. Patient's assessment, sigmoidoscopic appearance, and histology were also studied. Patients improved more rapidly with prednisolone. Differences between the two groups were significant at two weeks. At four weeks differences were not significant, but there was a trend in favour of prednisolone. Corticosteroid side effects were minimal in the fluticasone propionate group, and there was minimal suppression of the hypothalamic pituitary adrenal axis. Fluticasone propionate 20 mg daily is not as effective in the treatment of active ulcerative colitis as prednisolone tapering from 40 mg daily to 10 or 20 mg. The complete absence of suppression of the corticoadrenal axis by fluticasone propionate was encouraging, however, and a higher dosage schedule should be assessed.

A series of 9 patients with acute hepatic failure and Grade IV hepatic coma received daily plasmapheresis until they recovered or death ensued. Of the nine, seven (77%) showed an improvement in coma grade and five (55%) survived to leave hospital. Plasmapheresis significantly decreased serum bilirubin, asparate aminotransferase and plasma ammonia concentrations. Survival following plasmapheresis appeared substantially better than in a non randomized group of similar patients not plasmapheresed. The simplicity of the procedure, biochemical improvements observed and apparent efficacy, suggest that further evaluation of the technique as a means of providing temporary hepatic support is indicated.

The effect of intraluminal hydrocortisone (100 mg/l) on sodium and water transport in the small intestine was investigated by jejunal perfusion (flow rate 15 ml/min) of healthy subjects with normal saline and saline containing 56 mmol/l galactose or alanine. Minimal absorption of sodium and water occurred with normal saline and did not change significantly in the presence of hydrocortisone. Galactose and alanine enhanced sodium and water absorption and further significant increases occurred in the presence of hydrocortisone. Glucocorticoid induced increases in absorption were detected within 20-30 min, while plasma cortisol concentrations were in the normal range. 43% of the perfused dose of hydrocortisone was absorbed with normal saline (p less than 0.01). There was a significant positive correlation (p less than 0.0025) between hydrocortisone and water absorption. Thus, in the presence of actively absorbed organic solutes, hydrocortisone rapidly increased sodium absorption and the concurrent increase in water absorption appears to have facilitated passive absorption of hydrocortisone.

In 28 patients with fulminant hepatic failure alkalaemia was present in 49 of a total of 65 observations. Alkalaemia was due primarlily to a low Pa, C02 in 30 instances and to raised plasma bicarbonate in 16 instances. Blood lactate, pyruvate, and acetoacetate were significantly raised, and in individual cases, blood citrate, succinate, and fumarate were elevated. Blood citrate rose progressively as the clinical condition worsened. Metabolic acidosis was only present in four patients. In three of these patients, all of whom had taken an overdose of paracetamol, the acidosis was severe, present before the onset of clinical heparic failure, and associated with hypoglycaemiaand mild hypotension. In two of these patients the acidosis was shown to be due to accumulation of lactic acid. Plasma free fatty acid concentrations were elevated out of proportion to the degree of ketosis.

Forty patients with duodenal ulcer were randomly allocated either ranitidine 150 mg twice daily or cimetidine 1 g daily on a single blind basis for 4 weeks initially, with an additional month of treatment if endoscopy showed incomplete healing. The endoscopist was unaware of the patients' treatment. After 8 weeks treatment, the healing rate was 85% for ranitidine and 95% for cimetidine; the difference was not statistically significant. An additional 19 patients who did not fulfill the trial criteria, 11 of whom had not responded to cimetidine, were openly treated with ranitidine 150 mg twice daily. In 16 of the patients, the ulcer had healed at 8 weeks (84%), but in one patient, the ulcer perforated after 6 weeks of therapy. Thus, although overall healing rates with ranitidine and cimetidine are similar, ranitidine may be useful in patients where cimetidine has proved ineffective.

Summary We describe a patient with chronic hypernatraemia (plasma sodium 148-155 mmol/l) and partial nephrogenic diabetes insipidus who had received prolonged lithium treatment. Despite stopping the drug for one year the abnormalities remained. Infusion of hypertonic saline (NaCl 855 mmol/l) allowed the characterization of osmoregulation of thirst and vasopressin secretion. Linear regression analysis of plasma vasopressin and osmolality defined the function, pAVP = 0.27 (pOsm - 301), and analysis of thirst measured by a visual analogue scale and plasma osmolality, the function, thirst = 0.16 (pOsm - 302) where pAVP and pOsm represent plasma arginine vasopressin and osmolality respectively. The slopes of the regression lines which describe the sensitivity of the osmoreceptors were within the normal range, but both abscissal intercepts, which define the thresholds for vasopressin release and thirst, were markedly elevated in comparison to normal (upper limit less than 290 mOsm/kg). Other investigations of electrolytes, anterior pituitary function and high definition computed tomographic scanning of hypothalamo-pituitary region were all normal. We conclude that this patient’s chronic hypernatraemia was due to resetting of the osmostats for both vasopressin release and thirst, a rarely described mechanism to account for hypernatraemia. Although it is probable that the partial nephrogenic diabetes insipidus was related to prolonged lithium therapy, the cause of the reset osmostats remains unclear.

During perfusion of an isotonic solution containing 56 mmol/l glucose and 122 mmol/l sodium chloride, net movements of water and sodium and glucose absorption were measured in the absence and presence of intraluminal hydrocortisone along 20-cm segments of proximal jejunum in five normal subjects and five patients with active coeliac disease. In normal subjects, the mean net absorption of water and sodium was significantly increased in the presence of hydrocortisone decreased. In the coeliac patients, the mean net secretion of water and sodium was significantly decreased. In neither group was the effect of hydrocortisone associated with a significant increase in glucose absorption. Similar changes in net movements of water and sodium occurred in both groups, even though absorption of hydrocortisone in coeliac patients was 44% of the control value. These results suggest that hydrocortisone may have exerted a local effect on the mucosal transport of water and sodium.

1. The metabolic and hormonal responses to intravenous glucose (0·5 g/kg body wt.) were studied in ten normal subjects and thirteen patients with active chronic hepatitis. Untreated patients showed a decreased initial insulin response and glucose intolerance (KG, 0·89 ± 0·10%/min compared with 2·34 ± 0·24%/min), together with a paradoxical rise in growth hormone. 2. Fasting blood lactate and pyruvate were normal but both metabolites showed a diminished rise after glucose. The rate of rise of lactate was directly related to initial insulin secretion in both hepatitis subjects and controls. 3. Fasting blood ketone bodies, blood glycerol, plasma triglycerides and free fatty acids were all significantly elevated in the patient group. Results were similar to those found in mild diabetes mellitus. 4. In two patients with a more severe cirrhosis fasting values of serum insulin, growth hormone, blood lactate, pyruvate and glycerol were raised. 5. After corticosteroid therapy hyperinsulinism was found together with a return towards normal of glucose tolerance (KG, 1·49 + 0·10%/min), ketone bodies, free fatty acids and triglycerides; blood glycerol remained elevated and lactate response to glucose was excessive. 6. It is suggested that in active chronic hepatitis there might be pancreatic dysfunction on an autoimmune basis.

SUMMARY The haemodynamic effects and clinical uses of drugs used in the management of patients with oesophageal variceal bleeding are reviewed. Vasoconstrictor agents (vasopressin, teripressin) alone or in combination with nitrates continue to be used for acute bleeding episodes, while somatostatin is an alternative. Alpha- and beta-adrenergic blocking drugs and vasodilators which lead to a sustained decrease in portal pressure can be used for the prevention of bleeding episodes, but despite numerous studies the pharmacological treatment of variceal bleeding remains controversial.

Glucose turnover and recycling from glucose derived 3-carbon intermediates were examined in overnight fasted patients with compensated hepatic cirrhosis and in age- and weight-matched normal control subjects. Fasting blood concentrations of glucose, lactate and glycerol were similar in both groups but blood pyruvate (60 +/- 10 vs. 80 +/- mumol/l, P less than 0.05), blood alanine (0.23 +/- 0.02 vs 0.34 +/- 0.02 mmol/l, P less than 0.01) were decreased and serum insulin increased (19 [13-24]v 7 [4-11] mU/l, P less than 0.01) in cirrhotic subjects. Absolute glucose turnover, assessed by analysis of decay of [3H]-3-glucose specific activity was decreased in cirrhotic patients (8.1 +/- 0.6 v 12.1 +/- 0.7 mol/kg-1 min-1). Glucose "recycling", assessed by the difference between absolute glucose turnover and that given by [14C]-1-glucose data, was normal in cirrhotic patients suggesting that Cori cycle (glucose-lactate-glucose) activity was normal. These data support previous findings of decreased peripheral glucose utilisation and insulin resistance in cirrhotic patients.

1. Glucose tolerance and metabolic changes after intravenous glucose were studied in fifteen patients with acute viral hepatitis and in eight patients after recovery. In the acute stage glucose tolerance was significantly impaired compared with control subjects or with patients after recovery from hepatitis. 2. Serum insulin concentrations were significantly higher in fasting acute hepatitis patients than in control subjects and the time-integrated serum insulin concentration in the first 5 min after glucose was inappropriately high for the observed glucose disappearance rate, indicating insulin resistance. Serum growth hormone concentrations in male acute hepatitis patients were significantly higher than controls and suppressed poorly. 3. Fasting blood lactate concentrations were significantly elevated and after intravenous glucose there was a variable response. 2-Oxoglutarate, glutamate and glutamine concentrations from blood of fasting subjects, were significantly higher in acute hepatitis patients than controls. 4. There were no significant differences in blood ketones, glycerol and plasma free fatty acid concentrations from fasting subjects, but plasma triglycerides were significantly increased in the acute hepatitis patients. 5. The results indicate that viral hepatitis is associated with glucose intolerance and insulin resistance. After recovery the lactate response after glucose is diminished compared with controls.

The stools of 65 of 92 (71%) infants in a special care nursery yielded Clostridium difficile on culture. Ninety percent of stools collected after 6 to 35 days in the unit were positive, and 36% of these also contained toxin. When tested in vitro, 94% of the isolates produced toxin. Of 110 swabs collected from the environment of the unit, 9% were positive for C. difficile, but the stools of 12 nurses working on the unit were negative. Thirty-five vaginal swabs collected from mothers just before delivery were negative for C. difficile on culture, but 16 of their infants had C. difficile in their stools. It was concluded that there is a high carriage rate in the stools of neonates of C. difficile acquired progressively during the course of their stay in the special care unit. Infection is mainly from environmental sources rather than maternal transmission.

Clinicians administering potent therapeutic agents must be aware of their side-effects. The gut is an important site of adverse drug reactions and drug-induced disease must always be considered in the differential diagnosis of patients presenting with gastrointestinal symptoms. A careful drug history must therefore be taken in all such patients. Symptoms can often be related to drug ingestion, but late effects also occur. The presence of blood in vomitus or stool is patho-gnomonic of serious pathology which may be drug-induced and requires further investigation. Upper gastrointestinal haemorrhage and pseudomembranous colitis are potentially fatal manifestations of drug therapy. Gastrointestinal symptoms can often be avoided if therapy is taken with meals or in a smaller dose, but drug withdrawal is always the first line of management in patients whose symptoms may be drug-induced.

Summary A 44-year-old man developed severe pruritus with jaundice which subsequently proved fatal. Liver histology showed intense cholestasis, but at post-morten the bile ducts were patent and there was no cirrhosis, the findings being consistent with a cholestatic drug reaction. The most likely precipitant was the benzodiazepine triazolam, and surveillance is indicated for any further reactions to this recently marketed hypnotic.

1. Intravenous glucose tolerance tests were performed in fourteen patients with mild or moderate liver damage due to paracetamol overdose. 2. In patients managed conservatively there was glucose intolerance associated with a diminished early insulin response to glucose, suggesting inadequate nutrition in the period between the overdose and the glucose tolerance test. 3. Patients given intravenous glucose supplements to maintain nutrition were also glucose intolerant and, in these, insulin responses to glucose were normal. The decreased fractional disappearance rate was partly due to an increase in glucose distribution space and partly due to a decrease in absolute glucose disappearance rate. 4. Impaired gluconeogenesis was suggested by mild fasting hypoglycaemia in four patients and raised fasting blood lactate concentrations. Serum growth hormone concentrations showed a paradoxical increase after glucose. 5. All these variables had returned to normal in four patients re-tested after recovery.

In an attempt to find the extent to which Clostridium difficile could be implicated as the cause of antibiotic-associated diarrhoea, the stools of 53 patients who had diarrhoea after a course of antibiotics were investigated for the presence of C. difficile toxin. Ten of the patients (19%) were found to be positive, but the stools of four out of 53 patients without diarrhoea after a course of antibiotics were also found to contain C. difficile toxin (7.5%). The titre of toxin in patients both with and without diarrhoea fell within the same range (up to 10(-5)). Neither the organism nor its toxin was found in the stool of 26 patients with ulcerative colitis, eight with Crohn's disease, 49 with non-specific diarrhoea, and 27 normal controls. We conclude that, while C. difficile is responsible for a proportion of cases of antibiotic-associated diarrhoea, the concentration of toxin is not the sole factor affecting the severity of this disorder.

Five patients with hepatorenal syndrome were treated with the orally active angiotensin-converting enzyme inhibitor captopril (25 or 50 mg 6 hourly) for up to 48 hours. Only one patient showed a significant increase in urinary sodium concentration (from less than 10 to 70 mmol/liter), but without associated diuresis; renal function continued to deteriorate in all patients with persistent oliguria and rising serum creatinine. The outcome was uniformly fatal. These results suggest that in the hepatorenal syndrome, captopril in standard dosage is without benefit, and provide further evidence that the changes in the renin-angiotensin system are probably secondary to reduced renal perfusion from some other cause.

Summary The incidence and types of viral hepatitis in the city of Newcastle upon Tyne have been studied by serological analysis of (a) all blood samples sent to the virological laboratory for hepatitis testing and (b) all blood samples sent by general practitioners to the biochemical laboratory for liver function testing. The annual detection rate of acute viral hepatitis was found to be 31.5 cases/100,000 population, of which 9.1 were hepatitis B. Only three sporadic cases of non-A non-B hepatitis were identified. The incidence of hepatitis is at least four-fold greater than suggested by notification rates and may be substantially higher as general practitioners rarely requested laboratory confirmation of household contacts of index cases.

Marked pancreatic islet cell hyperplasia was found in a patient with laxative-induced diarrhoea. It is suggested that laxative abuse might be an important aetiological factor in patients with pancreatic islet cell hyperplasia and the watery diarrhoea syndrome but in whom no hormonal excess can be demonstrated.

The pharmacokinetic disposition of prednisolone was studied following oral administration (10 mg) to eight patients with untreated coeliac disease of mild or moderate severity, seven coeliac patients on a strict gluten-free diet and ten normal subjects. No significant differences were shown in the peak prednisolone level, the time of the peak level, the area under the concentration versus time plot, the plasma half-life and the 24 h urinary recovery of prednisolone in the three subject groups. There was however considerable variability within each group. It is concluded that the presence of coeliac disease does not significantly alter the absorption or elimination of prednisolone.

Lactate elimination was studied in twenty-six healthy volunteers during primed constant lactate infusion or multiple lactate injection tests, at blood lactate concentrations of 1-8 mmol-1. Although lactate elimination fitted a single exponential curve over a 30 min period, a significant correlation between the rate removal constant (KL) and the peak blood lactate concentration (Lphi) was demonstrated: loge KL = -2.43-0.132 Lphi (P = 0.003, r = 0.63, n = 20) This suggests that lactate removal does not follow first order kinetics over a wide concentration range but becomes saturated at relatively low blood lactate concentrations. Estimates of the lactate distribution volume did not differ significantly at different dosage levels, but remained in the range 270-300 ml kg-1. Skeletal muscle uptake accounted for about 26% of the infused lactate load. Seven patients with well-compensated hepatic cirrhosis were compared with a group of six control subjects during primed constant infusion tests. Fasting and steady state blood lactate concentrations achieved were similar in both groups. A significant prolongation in lactate half-life was demonstrated in the cirrhotics (18.8 +/- 1.4 min (mean +/- SEM) compared to 14.7 +/- 2.2 min; P less than 0.02). Since peripheral uptake of lactate in the forearm was similar in the two groups, this suggests that hepatic lactate uptake was impaired, due either to hepatocyte dysfunction or portal diversion.

Using a Quinton hydraulic biopsy tube, jejunal biopsies were obtained from 10 patients with adult coeliac disease in remission and four healthy volunteers before and after administration of gluten fraction III into the proximal duodenum. The biopsies taken at hourly intervals for four hours, were analysed for changes in brush border enzymes, light microscopic appearances, and villous and crypt population counts. The results indicate that mucosal damage occurs within three to four hours of gluten administration with significant falls in brush border enzyme concentrations and villous population counts. The absence of any change in control biopsies indicates that gluten sensitivity is specific to the mucosa of patients with coeliac disease, the timing of the changes being consistent with a type III immune response or direct toxicity. Some recovery of the brush border enzymes but not the villous population was evident 24 hours after gluten administration while the crypt population showed evidence of a compensatory hyperplastic reaction.

Glucose tolerance and blood metabolite changes have been measured in starved rats either 24 h after D (+)-galactosamine treatment or 9 days after bile duct ligation. In galactosamine-treated rats (0.5 g/kg) there was enhanced glucose removal after intravenous glucose (1 g/kg) and hyper-insulinism in the early part of the test. Fasting blood lactate and pyruvate concentrations were elevated in galactosamine-treated rats (1 g/kg) and there was a greatly accentuated rise in blood lactate concentration after intravenous glucose (2.20 ±0.16 compared to 0.90 ± 0.23 mM), suggesting decreased gluconeogeneaia. Nine days after bile duct ligation there was enhanced glucose removal after intravenous glucose when compared to controls. Lactate and pyruvate concentrations were transiently elevated after intravenous glucose in the ligated rats consistent with the increased rate of glucose removal. Fasting ketone bodies were decreased in the ligated rats (2.87 ± 0.40 compared to 6.50 ± 0.87 mM) due to diminished fat stores and this decreased ketosis probably results in glucose removal comparable to that seen in fed rats.