The effects of propranolol on hepatic encephalopathy in patients with cirrhosis and portal hypertension.

Beta adrenoreceptor blocking drugs have been used for the prevention of haemorrhage from oesophageal varices. However, it is possible that these agents, by virtue of their effects on hepatic blood flow, may impair liver function and precipitate hepatic encephalopathy. We have therefore studied the effect of the beta blocking drug propranolol on hepatic encephalopathy in patients with cirrhosis and portal hypertension. Twenty patients were randomly assigned to receive 4 weeks treatment with propranolol or an identical-looking placebo, the former given in a dose sufficient to reduce resting pulse rate by greater than or equal to 25%. Before and after treatment patients were assessed for the severity of liver disease and the presence of encephalopathy. EEG mean cycle frequency and fasting arterial ammonia concentrations were also measured, and in order to detect latent hepatic encephalopathy, each patient underwent a battery of psychometric tests. Patients were blinded as to their treatment, as were those assessing their responses. Neither propranolol nor placebo had any significant effect on the parameters measured. On propranolol median EEG mean cycle frequency fell from 9.08 ct s-1 (range 8.63-11.0 ct s-1) to 8.73 ct s-1 (range 8.27-11.44 ct s-1), and median fasting arterial ammonia concentration fell from 66 mumol litre-1 (range 40-329 mumol litre-1) to 49 mumol litre-1 (range 37-188 mumol litre-1). Psychometric test values, while initially abnormal and suggestive of latent hepatic encephalopathy in the majority of patients, did not change significantly during the study.

Deficiency of serum "pregnancy-associated" alpha 2-glycoprotein alpha 2-PAG): association with disease.

The serum concentrations of "pregnancy-associated" alpha 2-glycoprotein (alpha 2-PAG) were measured in 129 healthy women and 141 healthy men to establish a normal range, using a sensitive enzyme linked immunosorbent assay. In the normal population 2.8% of men and 5.4% of women had low serum alpha 2-PAG concentrations. Low concentrations occur, however, much more commonly in patients, particularly male patients, with certain diseases, including dermatitis herpetiformis (three of 12 or 25%) and urticaria (two of five or 40%). One female patient with absolute deficiency was also identified. In view of the recently confirmed association of alpha 2-PAG with IgA and the fact that alpha 2-PAG seems to have immunosuppressive properties, it seems likely that deficiency of alpha 2-PAG could result in the subject becoming sensitised to various dietary antigens. Interestingly, none of the 24 patients with IgA deficiency showed concomitant deficiency of alpha 2-PAG.

Laparoscopic excision of a triple gallbladder.

Triplication of the gallbladder is a rare congenital anomaly of the biliary tract; there are only nine reported cases to date. We report a case in which laparoscopic cholecystectomy was performed in a patient with biliary colic and choledocholithiasis. Preoperative assessment with ultrasound and endoscopic retrograde cholangiopancreatography (ERCP) failed to reveal the eventual findings of a triple gallbladder. Successful excision of the triple gallbladder was carried out laparoscopically, and the final diagnosis was confirmed by the pathologist. The patient made an uneventful postoperative recovery and was free of gastrointestinal symptoms at follow-up. This case report describes the first laparoscopic excision of a triple gallbladder and highlights the importance of pre-/perioperative imaging to allow for the safe dissection of rare anomalies of the biliary tract via the laparoscopic approach.

Fertility and pregnancy in inflammatory bowel disease.

OBJECTIVE: A retrospective study of women with inflammatory bowel disease, aged 16-45 years during the 20-year period 1967-1986, was carried out in North East Scotland. METHOD: Five-hundred and three women were identified: 15 patients had died from unrelated causes and 22 had emigrated, but 409 of the remaining 466 patients (88%) replied to the study questionnaire. RESULTS: Women with ulcerative colitis and Crohn's disease had normal fertility when compared with the general population of north east Scotland. However, unresolved infertility problems were more frequent in women who had undergone surgery for inflammatory bowel disease compared with those who had not (12% vs. 5% for Crohn's disease; 25% vs. 7% for ulcerative colitis). Disease relapse rates did not increase in pregnancy. CONCLUSIONS: Overall, at conception women with active disease were as likely to have a normal full-term pregnancy as those in remission. However, spontaneous abortion occurred in five (36%) pregnancies of women who had undergone previous surgery for Crohn's disease and had evidence of recurrent disease. Three of these pregnancies were associated with active disease.

Nonspecific proctocolitis in northeastern Scotland: a community study.

An extensive retrospective survey of patients with onset of symptoms of nonspecific protocolitis arising in the decade 1967-1976 was carried out in northeastern Scotland, including the Grampian region, Orkney, and Shetland. Five hundred and thirty-seven cases were identified, and a 97% follow-up was achieved. One hundred and twenty nonhospitalized cases were included. The average annual incidence was 11.3 per 10(5) population, the highest recorded in Europe to date. Moreover, a striking rise in the incidence was noted. A bimodal age distribution and urban predominance was found. The frequency of both nonspecific proctocolitis and Crohn's disease in first-degree relatives was high. The disease was found to be less severe and extensive at onset than suggested by other surveys, 70% having only distal involvement and 68% having a mild first attack. The overall mortality and surgical resection rates in the first attack were both 3%. Severe first attacks carried a striking 23% mortality. The observed long-term mortality differed little from the expected, except in patients with extensive disease or severe first attacks, or both. The risk of relapse correlated with decreasing age at onset but not with the initial extent or severity of disease. The surgical resection rate after 5 yr was 8%. Twelve percent of patients extended their disease by 5 yr. Using the patient-year concept, 68% of patient years were remission years. The youngest age group had the highest percentage of attack years. The percentage of attack years for all patients correlated more closely with extent of disease in each patient year rather than extent of disease at diagnosis.

The microvillus in adult jejunal mucosa--an electron microscopic study.

The increase in surface area contributed by microvilli per square unit mucosal surface area in the jejunal villus, i.e. amplification factor, has been studied in four normal adults and three adults with treated coeliac disease. Villi were split into three regions, photomicrographs of microvilli were taken from each region and the microvillus amplification factor calculated. The mid-villus region contributed a significantly greater microvillus amplification factor than either the low or upper regions in all patients studied. In addition surface cell heights were greatest in the low- and mid-villus regions. This suggests that the enterocytes in the mid-villus region are best adapted for absorption, and that the enterocytes in the upper-villus regions are undergoing an ageing process.

A phase II study of mitomycin C, cisplatin and protracted infusional 5-fluorouracil in advanced pancreatic carcinoma: efficacy and low toxicity.

BACKGROUND: The effective treatment of unresectable pancreatic carcinoma represents a formidable challenge. There is a need to develop systemic therapies which combine efficacy with acceptable toxicity. The current 'gold standard' gemcitabine gives an objective response rate of the order of 20% and median survival up to 6 months. Here we have evaluated the efficacy and toxicity of mitomycin C, cisplatin and protracted infusional 5-fluorouracil (MCF). PATIENTS AND METHODS: Forty-five patients with locally advanced (13 patients) or metastatic (32 patients) pancreatic carcinoma were treated with mitomycin C 7 mg/m(2) 6 weekly, cisplatin 60 mg/m(2) 3 weekly and protracted venous infusion 5-FU 300 mg/m(2)/day. Patients were evaluated for response after three cycles and received six cycles in total in the absence of progressive disease or poor tolerance. Median age was 62 (45-75) years; 41 patients were World Health Organization performance status 0-1. RESULTS: Treatment was well tolerated with 36 (84%) patients completing three or more cycles. Grade 3 or 4 toxicities were uncommon: anaemia in three patients (7%), mucositis in two (5%), nausea and vomiting in three (7%) and diarrhoea in one (1%). An objective response was seen in 21 (46%) patients. There was one complete response. The median survival overall was 7.1 months and 10.5 months in responders. The median duration of response was 4.3 months. One-year survival was 29%, 2-year survival was 18%. CONCLUSIONS: MCF combines efficacy with low toxicity in the treatment of advanced pancreatic carcinoma. The efficacy is at least comparable and may be superior to single-agent gemcitabine and MCF may therefore provide a cost-effective alternative.

Protease inhibitors in liver disease.

Measurements of the principal protease inhibitors were carried out in patients with two types of chronic liver disease: alcoholic cirrhosis and primary biliary cirrhosis. Measurement of the two major protease inhibitors operative in the haemostatic mechanism--that is, antithrombin III and alpha 2-antiplasmin--showed significantly reduced levels in the alcoholic cirrhosis group, who satisfied clinical and biochemical criteria of impaired hepatocellular function, but not in the primary biliary cirrhosis group, who had relatively good preservation of hepatocellular function. Significant correlation of levels of both these major protease inhibitors with the serum albumin concentration was also found. No evidence of disseminated intravascular coagulation was detected, and therefore failure of synthesis by the liver is the likely explanation of the low levels noted.

Improving the selection of patients for upper gastrointestinal endoscopy.

A retrospective study was undertaken to investigate how endoscopies yielding positive findings differ a priori from those yielding negative findings: and how those judged 'helpful' (in the sense of influencing management) differ a priori from those judged 'unhelpful'. A total of 483 patients undergoing endoscopy was sampled and a wide range of data abstracted, including 48 patient characteristics available to the gastroenterologist at the time of the decision to perform endoscopy. Sixty nine per cent of endoscopies were positive. Multivariate statistical analysis identified four variables which taken together were strongly predictive of a positive endoscopy. The resulting mathematical formula correctly predicted the outcome of 76% of endoscopies. Eighty two per cent of the endoscopies were retrospectively classified by the gastroenterologists as helpful. Six variables were strongly predictive of a helpful endoscopy. The corresponding formula correctly predicted the finding of 84% of endoscopies. Comparison of the two analyses shows that the two sets of predictions differ substantially. Thus it is important that decision tools should be based not on the crude distinction between positive and negative, but on the more useful distinction between helpful and unhelpful in influencing management.

Distal proctocolitis and n-3 polyunsaturated fatty acids (n-3 PUFAs): the mucosal effect in situ.

It has been postulated that patients with ulcerative colitis (UC) have altered reactivity of gut-associated lymphoid tissue. In such cases there is intense infiltration of the mucosa with immune competent cells and associated tissue damage. We have shown previously that the dietary supplementation with the n-3 polyunsaturated fatty acids (n-3 PUFAs), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) results in significant systemic immune suppression. The aim of this study, therefore, was to evaluate the in situ effect of n-3 PUFAs on distal proctocolitis. Each patient received either fish oil extract (EPA 3.2 g, DHA 2.4 g) (n = 9) or sunflower oil (n = 9) daily in a double blind manner for six months. Monthly assessment included: (1) disease activity using clinical, sigmoidoscopic, and histological scores and (2) immunohistochemical analysis (immunoglobulins, CD profiles) of rectal biopsy specimens (before and after six months supplementation) using monoclonal antibodies and quantitative computer-assisted video image analysis. Prior to receiving supplementation, patients with proctocolitis (n = 18) showed significantly higher numbers of cells expressing CD3 (pan T cells) and HLA-DR and IgM containing cells compared with non-colitic controls (n = 8). Six months supplementation with n-3 PUFAs resulted in significant reduction in the number of cells expressing CD3 and HLA and the percentage of cells containing IgM. There was no significant change in the CD20 nor the percentage of IgG or IgA containing cells in either group of patients with procto-colitis. In patients receiving n-3 PUFA supplementation, there was improvement in the disease activity and histological scores, compared with pretreatment evaluation. This study has demonstrated both evidence of suppression of in situ immune reactivity and concurrent reduction in disease activity in patients with proctocolitis receiving n-3 PUFA supplementation. This may have important implication for therapy in patients with ulcerative colitis.

Distal procto-colitis, natural cytotoxicity, and essential fatty acids.

OBJECTIVES: Recently, it has been postulated that patients with ulcerative colitis have altered natural cytotoxicity, in particular natural killer (NK) and lymphokine-activated killer (LAK) cell activities. These cellular mechanisms have been postulated to play an etiological role in the pathogenesis of the disease process. We have shown previously that the essential fatty acids (EFA) eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) specifically inhibit natural cytotoxicity. Our aim was to evaluate the role of omega-3 EFA in the modulation of natural cytotoxicity and disease activity in patients with distal procto-colitis. METHODS: In this pilot study patients were randomized into two groups. Each patient received either fish oil extract (EPA, 3.2 g, and DHA, 2.4 g) (n = 9) or sunflower oil (placebo) (n = 9) daily in a double-blind manner for 6 months. Monthly assessments of disease activity (clinical and sigmoidoscopic scores) and histological evaluation of mucosal biopsies were carried out. Also, the circulating levels and activities of NK and LAK cells, using flow cytometric analysis (CD16+ CD56+) and in vitro 51 chromium release assays (K562), respectively, were monitored. RESULTS: After 6 months' supplementation with EFA, there was improvement in the clinical activity compared with pretreatment evaluation. There was significant reduction in the sigmoidoscopic and histological scores in the EFA group compared with the placebo group. Essential fatty acid supplementation for 6 months also induced significant reduction in the circulating numbers of CD16+ and CD56+ cells and the cytotoxic activity of NK cells, compared with the placebo group. CONCLUSIONS: This pilot study has demonstrated that omega-3 fatty acids can suppress natural cytotoxicity and reduce disease activity in patients with distal procto-colitis. These findings suggest a therapeutic strategy for managing patients with inflammatory bowel disease.

The role of an open-access bleeding unit in the management of colonic haemorrhage. A 2-year prospective study.

BACKGROUND: Major colonic haemorrhage poses difficult diagnostic and therapeutic problems and, in contrast to upper gastrointestinal bleeding, has no generally accepted plan of management. METHODS: We report community-based prospective data accumulated over 2 years (1991-93) on 1602 patients referred to an open-access bleeding unit with suspected gastrointestinal haemorrhage. RESULTS: Of 278 (17%) admissions with suspected lower GI haemorrhage, 252 were confirmed. Forty-eight per cent were defined as "significant' bleeds, with a decrease in haemoglobin and cardiovascular compromise. Of 102 significant bleeds in subjects more than 60 years old, 29% rebled, and 12.6% required emergency surgery. Diverticular disease (24%) was the commonest diagnosis, with tumours, infective colitis, and inflammatory colitis each at 10%. The overall 30-day mortality for colonic bleeding was 5.1% (13 of 252), with only 1 death occurring in the group less than 60 years old. CONCLUSIONS: This study provides a unique database for the natural history of colonic bleeding and its management within the setting of a specialized bleeding unit.

Upper gastrointestinal bleeding in an open-access dedicated unit.

The open-access high dependency bleeding unit in Aberdeen admits all patients with suspected gastrointestinal bleeding from a stable adult population of 468,000. The aim is to reduce mortality, morbidity and hospital stay, and create a prospective whole community database. An agreed management protocol is based on prompt resuscitation and early diagnosis. From October 1991 to September 1993 there were 1,602 consecutive admissions with suspected upper or lower gastrointestinal haemorrhage. Bleeding was confirmed in 1,098 of 1,324 patients with presumed upper gastrointestinal haemorrhage, (117 bleeding episodes per 100,000 per year). The overall 30-day mortality was 3.9%, with all deaths attributable to significant concurrent illness. Mortality from peptic ulcer bleeding was 5.3%, with an operation rate of 17% and surgical mortality of 8%. Rapid diagnosis allowed 48% of 523 patients with trivial bleeds to be discharged after a median stay of 24 hours. Centralised expertise and equipment is the essence of the unit's success. The interests of patient care are better served, nursing skills are better developed and teaching opportunities better structured. The major improvement in clinical care, welcomed by hospital colleagues, management and general practitioners, makes the unit an indispensable part of acute medical provision.

Neuropsychological deficits and morphological MRI brain scan abnormalities in apparently healthy non-encephalopathic patients with cirrhosis. A controlled study.

By means of psychometric testing, we have determined the frequency of latent hepatic encephalopathy in a group of 19 cirrhotics with no clinical evidence of encephalopathy. Magnetic resonance imaging (MRI) of the brain was performed in order to determine whether morphological cerebral abnormalities were associated with latent encephalopathy. Nineteen age and educationally matched patients with normal liver function acted as controls. Significant differences (P less than 0.05) between cirrhotics and controls were found in tests of short-term visual memory and speed of reaction to light (cirrhotics 316 +/- 132 ms vs. controls 225 +/- 36 ms), sound (cirrhotics 361 +/- 152 ms vs. controls 236 +/- 52 ms) and choice (cirrhotics 651 +/- 190 ms vs. controls 406 +/- 101 ms) stimuli (all values mean +/- S.D.). Reitan trail test performance, however, was similar in both groups. (Trail A: cirrhotics 43 +/- 19 s vs. controls 35 +/- 13 s; Trail B: cirrhotics 105 +/- 66 s vs. controls 93 +/- 36 s.) In patients with cirrhosis, MRI revealed statistically significant increases in the maximum fissure width of right frontal sulci, right and left parietal sulci, inter-hemispheric fissure width and in bicaudate index. These changes, indicating cerebral atrophy, were largely confined to alcoholics. There was poor correlation between measurements of cerebral morphology and neuropsychological performance, only 10% of associations achieving statistical significance.