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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.

Reports that up to 26% of subjects with psoriasis develop cirrhosis have led to a recommendation of serial liver biopsies after each cumulative dose of 1500 mg of methotrexate.To evaluate the progression of liver injury in patients with psoriasis and the impact of monitoring by liver biopsy on their management.One hundred and twenty-one liver biopsies from 66 subjects (aged 11-79 years) with psoriasis, receiving a median cumulative dose of 3206 mg of methotrexate over a period of 280.5 weeks, were evaluated.The assessment of advanced fibrosis according to the Ishak system (or= 4) correlated perfectly with that of the Scheuer system (or= 3) and poorly with that of the Roenigk scale (or= 3b) (r2 = 1.0 and 0.31, respectively). Two of 24 pre-treatment biopsies showed advanced fibrosis and both subjects were heavy drinkers. The cumulative probabilities of advanced fibrosis (Ishakor= 4) were 0%, 2.6%, 2.6%, 8.2% and 8.2% at cumulative doses of 1500, 3000, 4500, 5000 and 6000 mg, respectively. None of the subjects developed cirrhosis during follow-up or discontinued therapy on the basis of liver biopsy findings.Advanced hepatic fibrosis with low-dose methotrexate therapy is much less frequent than previously reported. Pre-treatment or monitoring liver biopsies in accordance with the current guidelines have little impact on patient management.

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.

It has been suggested that gastric varices bleed at lower portosystemic pressure gradients (PSPG) than oesophageal varices and that transjugular intrahepatic portosystemic shunt (TIPS) is a particularly effective treatment in these patients.This study was undertaken to assess the difference in PSPG measured at the time of TIPS insertion between patients bleeding from gastric and those bleeding from oesophageal varices. Rebleeding and mortality rates between the two groups were also compared.In a five year period, 64 patients (36 males and 28 females) undergoing TIPS for acute variceal bleeding had PSPG measured at the time of TIPS insertion. 12 patients underwent TIPS for gastric variceal haemorrhage (GVH) and 52 for oesophageal variceal haemorrhage (OVH). The median age was 53 years and 40/64 patients (63%) had alcoholic liver disease. The median Child's Pugh score was 8 for GVH and 9 for OVH patients. Median follow up was 75 weeks.There was no significant difference in median PSPG between patients with GVH, 21 mmHg (range 15-30 mmHg) and OVH, 22 mmHg (range 12-45 mmHg). Following TIPS, PSPG was 8.5 mmHg (range 3-11 mmHg) and 9 mmHg (range 4-20 mmHg) in GVH and OVH patients respectively. Rebleeding occurred in 2/12 (16%) GVH patients and 12/52 (23%) OVH patients (p= 1.0). Mortality during follow up was 25% (4/12) in the GVH and 25% (13/52) in the OVH patients.In this study, there was no difference between the pressures at which gastric and oesophageal varices bled. Rebleeding and mortality rates were similar in the two groups. TIPS is equally effective in the treatment of both oesophageal and gastric variceal haemorrhage.

BACKGROUND: Rectal bleeding is common, but it is still unclear which patients require investigation to exclude serious pathology, although it is known that colectoral cancer is very rare under the age of 40 years. Few studies have examined all patients presenting to their primary health physician rather than screening whole populations. AIM: The aim of this study was to investigate the view that all patients over the age of 40 who present to their general practitioner with rectal bleeding should undergo investigation by colonoscopy to rule out serious pathology, regardless of symptomatology. METHOD: A prospective study was carried out of 99 consecutive patients over 40 years presenting with rectal bleeding to 17 general practices in Newcastle upon Tyne. RESULTS: Serious pathology was detected by colonoscopy in 44.4% of patients. The diagnoses were: colorectal carcinoma, eight cases (two Dukes' grade A, two Dukes' grade B, four Dukes' grade C); one or more polyps, 25 cases (in 17 cases at least one polyp was 5 mm or greater in diameter); inflammatory bowel disease, 11 cases. In the remaining 55 patients, bleeding was associated with diverticular disease (16 cases) and haemorrhoids (28 cases). No cause was found in 11 patients. This high rate of pathology may be partly caused by selection of cases for referral by the general practitioner, despite efforts to minimize this. Three symptoms as elicited by the colonoscopist were found to be significantly associated with serious disease: blood mixed with stool (P < 0.001); change in bowel habit (P < 0.005); and the presence of abdominal pain (P < 0.025). However, symptoms elicited on primary presentation were less helpful and symptoms changed significantly between consultation with the general practitioner and colonoscopy. CONCLUSION: All patients over the age of 40 years presenting with rectal bleeding should be referred for flexible sigmoidoscopy or colonoscopy. Symptoms are unhelpful in deciding who requires investigation.

Dysfunction of excitatory glutamatergic neurotransmission has been implicated in the cause of hepatic encephalopathy. Brain microdialysis studies in various animal models of portal systemic encephalopathy (PSE) and encephalopathy associated with acute liver failure, have established that an increase in extracellular glutamate occurs but the mechanisms of this are unclear. We have measured oxygen consumption, citrate synthase activity (as indices of energy state and mitochondrial content, respectively), calcium-dependent glutamate release, and high-affinity, sodium-dependent glutamate uptake by synaptosomes prepared from rats with thioacetamide-induced encephalopathy. (2 doses of thioacetamide 200 mg/kg with a 24-hour interval). Synaptosomes were prepared either by a modified P2 method (glutamate release study) or by discontinuous sucrose density gradient centrifugation (all other studies). There was no significant difference in synaptosomal oxygen consumption, citrate synthase activity, glutamate release, total synaptosomal glutamate content, or the Kd for glutamate uptake between the encephalopathy group and the controls. However, there was a marked decrease in the maximal velocity of transport (Vmax) for glutamate uptake in synaptosomes from encephalopathic rats, 2.64 versus 4.40 nmol/min/mg (P.05). The results of this study provide evidence of impaired glutamate uptake in the rat thioacetamide model of hepatic encephalopathy, which could account for the elevated extracellular glutamate seen in the condition.

Cirrhosis is characterized by paradoxical growth hormone secretion in response to glucose and insulin infusion. To ascertain whether this abnormality contributes to insulin resistance, euglycemic hyperinsulinemic glucose clamps were performed on six patients with cirrhosis and six normal control subjects. Each patient with cirrhosis underwent two clamps in random order, a clamp with somatostatin (250 micrograms/hr) together with insulin and glucagon replacement, and a control clamp without somatostatin. The normal subjects underwent the control clamp only. During the control clamp, growth hormone levels were considerably higher in the patients with cirrhosis (6.1 +/- 0.4 vs. 0.5 +/- 0.4 mU/L, p0.02), and glucose uptake was considerably lower (3.29 +/- 0.56 vs. 9.52 +/- 1.14 mg/kg/min, p0.001). Indirect calorimetry indicated that the defect was accounted for by lower nonoxidative glucose disposal (1.23 +/- 0.45 vs. 6.00 +/- 0.73, p0.001). Peripheral glucose uptake, exemplified by forearm glucose uptake (0.27 +/- 0.04 vs. 1.22 +/- 0.42 mg/100 ml/min, p0.02), and calculated insulin sensitivity (24 +/- 8 vs. 114 +/- 20 microliters/kg/min per mU/L) were particularly diminished. In the patients with cirrhosis somatostatin suppressed growth hormone levels (6.1 +/- 1.2 to 1.2 +/- 0.4 mU/L, p0.05). However, no significant changes occurred in whole-body glucose uptake (3.29 +/- 0.56 vs 3.01 +/- 0.54 mg/kg/min), forearm glucose uptake (0.27 +/- 0.04 vs 0.30 +/- 0.01 mg/100 ml/min) or insulin sensitivity (24 +/- 8 vs, 35 +/- 10 microliters/kg/min/mU/L, p = 0.42).(ABSTRACT TRUNCATED AT 250 WORDS)

The neurotransmitter serotonin has a profound effect on the control of sleep; thus excess serotonin activity in the brain could be responsible for impaired consciousness in hepatic encephalopathy. Furthermore, an increased brain level of 5-hydroxy-indoleacetic acid has been a consistent finding in various animal models of the condition. In this study, using high-performance liquid chromatography with fluorometric detection, we examined levels of brain serotonin (5-hydroxytryptamine) and its precursors and metabolites in 16 patients dying with hepatic encephalopathy complicating acute and chronic liver disease and 9 control subjects matched for age, sex, postmortem delay in brain retrieval and length of frozen tissue storage. In patients with chronic liver disease, serotonin level was significantly increased in thalamus (p0.02); levels of its metabolite 5-hydroxyindoleacetic acid were increased in frontal cortex (p0.05), globus pallidus (p0.05) and putamen (p0.01). Levels of the precursor amino acid tryptophan were increased in thalamus (p0.01) and globus pallidus (p0.01); in both patient groups levels of 5-hydroxytryptophan and the tryptamine metabolite indoleacetic acid were increased in all brain areas studied. 5-Hydroxytryptamine levels were also increased in thalamus, frontal cortex and globus pallidus in the three patients with fulminant liver failure. Our findings are consistent with disordered neurotransmission, especially in the thalamus, an area of particular importance in the regulation of consciousness, alertness and attention in human beings.

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.

The results of a 3-year, placebo-controlled trial of prednisolone treatment in primary biliary cirrhosis (PBC) are presented. The active (n = 19) and placebo (n = 17) arms were initially well matched for age, menopausal status and disease severity. At 3 years hepatic symptoms were relatively improved in the prednisolone group. Hepatic mortality was 3/19 (prednisolone), 5/17 (placebo) (p = n.s.). For all liver blood tests the trend favoured prednisolone treatment, though the differences were only significant for alkaline phosphatase and protein. All immunoglobulins fell significantly. Quantitative ELISA determination of antimitochondrial antibody showed a significant fall in the prednisolone group compared with placebo (p less than 0.001 at 1 year, p less than 0.05 at 3 years). Deterioration in histology (appearance of cirrhosis) was more common in the placebo group. Overall hepatic function (hepatic mortality, doubling in bilirubin, 6 milligrams fall in albumin, de novo appearance of cirrhosis or symptoms of portal hypertension) was significantly worse in the placebo group (p less than 0.01). After 3 years no significant differences could be detected in bone mineral content (single photon absorptiometry of radius and femur) between the two groups or in comparison with other PBC patients. Thus, after 3 years, prednisolone treatment was associated with a better overall hepatic outcome and little evidence of increased bone loss.

The number of verocytotoxin producing Escherichia coli (VTEC) present in the faeces during an infection may be very low, making their detection difficult. We report a method for enhancing toxin production by VTEC using mitomycin C as an inducing agent with the aim of improving the detection of VTEC. In pure culture, mitomycin C enhanced toxin production up to 100-fold. When applied to mixed faecal culture, toxin could be detected in mitomycin C treated samples when standard cultures were negative and when substantially fewer verocytotoxin-producing bacteria were present. Use of this method may aid in the detection of VTEC and is appropriate for use in the routine diagnostic laboratory.

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.

It has been suggested that polymer coating might retard jejunal absorption of 5-amino salicylic acid (5-ASA) and thus promote delivery to its colonic site of action. Twenty three patients with active (nine), or quiescent (14) ulcerative colitis were given either uncoated or coated 5-ASA (Asacol) 400 mg qds for one to three weeks, after which they ingested five 1.5 ml dialysis membrane sachets which were recovered from the stool in the next 72 hours. After one week of treatment the concentration of 5-ASA in the faecal dialysate, urine, and fasting plasma in those receiving the coated and uncoated preparations were respectively: 25.4 +/- 5.1 compared with 1.2 +/- 0.4 mmol/l (p less than 0.001); 0.34 +/- 0.21 compared with 0.70 +/- 0.29 mmol/24h (NS) and 11.1 +/- 4.2 compared with 0.07 +/- 0.03 mumol/l (p less than 0.02). Faecal excretion of the drug appeared to be greater in patients with active colitis than in those with quiescent disease. Thus coating with pH dependent methacrylic acid copolymer B is a very effective method of promoting delivery of 5-ASA to the colon, stool dialysate concentrations being 20 fold more than those in controls. Increased trough plasma concentrations in the polymer coating group probably reflect delayed intestinal absorption but no evidence of plasma accumulation after 21 days of therapy was found.

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 Four cases of ileo-caecal tuberculosis in Asian immigrants were seen in a 6-month period at The London Hospital. Although rare in Caucasians, this condition is an important cause of gastrointestinal symptoms in this ethnic group. Definitive diagnosis can frequently be made only by histological examination and culture of biopsy material obtained at laparotomy. However, in suitable cases, where there is a high index of clinical suspicion, a trial of chemotherapy may be preferable to operation. If laparotomy is performed, resection with subsequent chemotherapy is the treatment of choice.

Many patients with suspected colonic disease undergo rigid sigmoidoscopy, barium enema examination, and ultimately total colonoscopy, but the need for preliminary radiology has not been formally assessed. A total of 168 patients requiring large bowel investigation were therefore randomised to undergo either rigid sigmoidoscopy plus double contrast barium enema examination or total colonoscopy. Disease was found in 56 patients, including 14 with a carcinoma, 11 with polyps, and 16 with inflammatory bowel disease, the remainder having diverticular disease alone. Of the 89 patients allocated to double contrast barium enema examination, nine required a subsequent colonoscopy for suspected tumour or polyps, three because of incomplete radiological examination, and 12 for rectal bleeding for which no cause was found at the radiological examination. In 16 patients this yielded further information or altered treatment. Of the 79 patients undergoing total colonoscopy, only six required subsequent radiology. As both procedures were well tolerated with no major complications total colonoscopy may be the preferred initial investigation where facilities allow.

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.

During the 18 months following the introduction of a neodymium yttrium aluminium garnet laser in Newcastle upon Tyne 48 patients were treated, 23 for haemorrhage from peptic ulcers or vascular anomalies of the gut and 25 for palliation of inoperable tumours of the oesophagus, stomach and rectum. The treatment was tolerated well and was effective both for the arrest of haemorrhage and relief of dysphagia. Laser treatment has now entered the realms of routine clinical practice but its high cost and the operator expertise required suggest that its availability should be limited to designated centres.

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, aspartate 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.

One hundred and fifteen patients attending a gastroenterology clinic were investigated by flexible sigmoidoscopy as outpatients. There were asked to fast before the examination and give a high-volume enema and sedated before the examination. A standard long colonoscope was used rather than the 60-cm sigmoidoscope, which limits the distance that can be examined and forces the operator to work very close to the patient. Preparation was considered good in 95 patients and 49 were examined as far as the hepatic flexure or beyond. Sixty-one patients were found to have lesions of the colon, 25 of them ulcerative colitis, 16 a poly, and nine carcinoma. Despite the fact that these patients were selected (some of them had already had ulcerative colitis diagnosed), flexible sigmoidoscopy proved to be a valuable initial outpatient investigation. The proximal colon was well visualised in 46 patients and a subsequent barium enema was considered unnecessary. There were no complications and the procedure seemed to be well tolerated.

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.

SUMMARY The systemic and hepatic haemodynamic effects following terlipressin (Glypressin) administration were studied. Bolus intravenous injections of 1.25 and 2 mg significantly decreased wedged hepatic vein pressure gradient by 29% and 31%, respectively. With each dose there was a small increase in mean arterial blood pressure but after 1.25 mg of terlipressin, estimated hepatic blood flow fell by only 11% (not significant) compared to 24% after 2 mg, while the cardiac index fell by 12% compared to 29%. The adverse haemodynamic effects of terlipressin were diminished by a decrease in dosage, without any alteration in the beneficial effect of the drug upon portal pressure. Whether the smaller dose will be effective in arresting variceal haemorrhage remains to be determined.

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.

We have studied forty patients who were at risk of hepatic, renal, pancreatic or myocardial injury as a consequence of severe paracetamol overdosage and who were admitted to hospital within 10 h of ingestion. These were sequentially randomized into three treatment groups, comprising intravenous cysteamine therapy (3.6 g over 20 h, n = 14), oral methionine (10 g over 16 h, n = 13) or supportive therapy only (intravenous 10% dextrose with vitamins, n=13). All groups were matched for age, ingestion-treatment interval and severity of poisoning as estimated by stated amount ingested and a logarithmic paracetamol blood level index. One death occurred in the supportive therapy (S) group. Significant differences in peak serum aspartate aminotransferase levels were seen with geometric means in S of 1046 U/l, in cysteamine treatment of 96 U/l and in methionine treatment of 139 Ull (Wilcoxon sum of ranks p < 0.01 in favour of methionine, p < 0.002 in favour of cysteamine). Hepatic necrosis, as shown by ‘blind’ histological assessment, was significantly less frequent in actively treated patients (methionine p < 0.05, cysteamine p < 0.01). These differences in favour of cysteamine and methionine were also reflected in peak serum bilirubin and prothrombin ratio. No significant effects of active treatment were shown for serial plasma creatinine, serum amylase, myocardial enzymes or ECG changes. We conclude that in the context of a prospective controlled trial of active agents: A convincing hepatoprotective effect of early i.v. cysteamine and oral methionine has been demonstrated. No clear difference in efficacy of the two antidotes has been shown. Early methionine administration is associated with few, if any, undesirable side-effects.

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.

The effects of acute ethanol challenge on serum glycoprotein concentrations in man were studied. Serum levels of haptoglobin, alpha-2-macroglobulin and pre-albumin were measured fasting and 6 hr after oral ethanol 0.75 g/kg body weight in 8 healthy controls, 13 patients with alcoholic liver disease and 13 with non-alcoholic-related liver damage, both patient groups being further subdivided into those with and without cirrhosis. Basal levels of haptoglobin were significantly higher in non-cirrhotic alcoholics than controls and pre-albumin levels were lower in non-alcohol-related cirrhotic liver disease. In response to ethanol challenge, no consistent change was observed in any group, nor was there any significant difference between groups. There was, however, a significant correlation (r = 0.53, P less than 0.005) between the percentage changes in haptoglobin and alpha-2-macroglobulin. In 16 subjects (2 controls, 8 alcoholics and 6 non-alcoholics) blood levels of ethanol and acetaldehyde were measured serially: there was no relationship between the peak or mean concentration and the glycoprotein response. This study does not substantiate other reports which claimed to be able to predict the severity and reversibility of alcoholic liver disease on the basis of the serum glycoprotein response to ethanol: ethanol challenge with measurement of serum glycoproteins cannot substitute for proper histological assessment.

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.

The stools of 78% of 45 infants in a Special Care Baby Unit yielded Clostridium difficile on culture, and in 67% of these it was possible to detect C. difficile toxin by means of a tissue culture technique. The stools of six of the seven infants with necrotizing enterocolitis were positive for C. difficile, but neither of the two most severely affected contained C. difficile toxin. The incidence of C. difficile isolation was similar in infants treated by exchange transfusion, those treated with antibiotics, those of low birth weight, and those with respiratory distress. The serum of only 2 of 28 infants and 1 of 20 mothers contained a neutralizing factor to C. difficile toxin. The present study does not support a role for C. difficile in neonatal disorders and in particular necrotizing enterocolitis. The reason for the apparent tolerance of the neonatal bowel to C. difficile toxin remains to be explained.

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.