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Gallbladder stones form the majority of biliary disease, and are conveniently detected by ultrasonography (US).

The importance of the rectal examination cannot be over-stressed: it should ideally form part of every complete bowel examination. A measure of the importance of the rectal examination is gauged by the fact that about 15% of all large bowel cancers can be felt digitally. It is usually possible to reach further with a finger than can be seen with an anoscope.

The anatomy of the liver and spleen and the physiology of the portal circulation can be investigated in numerous ways. Some of the techniques are too specialized for general use, but many have found a place in routine diagnosis.

Objective: An acute increase in portal pressure is associated with an immediate reduction in renal blood flow. It has been suggested that this supports the presence of an hepatorenal reflex. In this study, we used TIPSS placement as a model to investigate the effect of an acute reduction in portal pressure on renal blood flow and cardiopulmonary hemodynamic parameters. Methods: Eleven cirrhotic patients were studied during elective TIPSS placement for variceal hemorrhage (n = 9) or refractory ascites (n = 2). Unilateral renal blood flow (RBF) was measured before and at 5, 15, 30, 45, and 60 min after shunt insertion. Heart rate (HR), mean arterial pressure (MAP), right atrial pressure (RAP), mean pulmonary artery pressure (PAP), pulmonary capillary wedge pressure (PCWP), cardiac output (CO), and systemic vascular resistance (SVR) were also measured before and 30 min after TIPSS placement. Results: Despite significant increases in CO (p = 0.001), RAP (p < 0.001), PAP (p < 0.001), and PCWP (p = 0.001), and a fall in SVR (p = 0.003), no change was observed in RBF, HR, or MAP after TIPSS placement. The fall in the portoatrial pressure gradient correlated only with the rise in CO (p < 0.05) and the drop in SVR (p < 0.05). Conclusion: Despite the fall in portal pressure and the systemic hemodynamic changes caused by TIPSS placement, there is no immediate effect on RBF. Any improvement in renal function after TIPSS procedure does not appear to be due to an acute increase in RBF.

The sodium and water retention and renal vasoconstriction exhibited by patients with cirrhotic ascites are similar to the changes observed by stimulation of renal adenosine 1 receptors. The aim of this study was to investigate the effects of FK352 (an adenosine 1 antagonist) on renal and systemic hemodynamics and renal function in cirrhotic patients with ascites.p-Aminohippuric acid and inulin clearance, urine flow rate, sodium and potassium excretion, and free water clearance were measured for 2 hours before and after FK352 administration. Cardiac output, systemic vascular resistance, plasma angiotensin II level, plasma renin activity, and noradrenaline, adrenaline, and adenosine 3', 5'-cyclic monophosphate (cAMP) levels were also measured before and after FK352.Urine sodium excretion and urine flow rate increased after FK352 by a mean of 199.9% +/- 43.0% (P0.001) and 51.2% +/- 17.5% (P0.02), respectively. Plasma cAMP and angiotensin II levels and plasma renin activity also increased by 10. 8% +/- 3.2% (P0.01), 36.9% +/- 11.3% (P0.01), and 247.9% +/- 82.6% (P0.02), respectively. No change was detected in any other parameter.The isokaliuretic improvement in natriuresis and diuresis suggests a role for adenosine 1 antagonism in the treatment of the renal abnormalities found in advanced cirrhosis.

Transjugular intrahepatic portosystemic stent-shunts (TIPSS) are becoming widely used in the management of oesophageal variceal haemorrhage (OVH). Their place in the treatment of gastric variceal haemorrhage (GVH), a condition with a traditionally poor prognosis, remains unclear. The aims of our study were to compare portal haemodynamics and patient outcome in patients undergoing TIPSS for either GVH or OVH.106 consecutive patients undergoing TIPSS at our institution for either GVH (32 patients) or OVH (74 patients) were studied. The groups were similar with regard to patient age, aetiology and severity of liver disease and number of procedures carried out as an emergency (34.4% vs. 36.5%). Episodes of shunt insufficiency, rebleeding, encephalopathy and other clinical sequela were recorded. Mean follow-up was similar in both patient groups (14.2 vs. 12.1 months).Baseline portocaval pressure gradient was lower in patients with GVH compared with those with OVH (13.0+/-0.9 mmHg vs. 19.0+/-0.6 mmHg) (P0.001). Rates of variceal rebleeding, encephalopathy and shunt insufficiency during follow-up were similar in both groups and there was no difference in survival.Patients with GVH had markedly lower portocaval pressure gradients than those with OVH, but shunt and clinical complications and survival were similar during follow-up. TIPSS appears to be an effective treatment for GVH and should be compared with endoscopic or surgical techniques in controlled trials.

Background/Aims: Vagal dysfunction is reported in about 70% of patients with cirrhosis, irrespective of aetiology, as detected by cardiovascular reflex tests. We have previously shown that RR-variability on 24-h ECG is a more sensitive marker of vagal dysfunction in cirrhosis. Angiotensin II inhibits vagal function in animals, and it is elevated in cirrhosis and may be the cause of the vagal dysfunction. Our aim was to observe the effect of captopril on vagal dysfunction in cirrhosis. Methods: Eight patients with cirrhosis (biopsy proven, male two, female six, mean age 54.25) had 24-h ECG RR-variability performed. They then received captopril 25 mg t.d.s. for 48 h. The 24-h ECG was repeated on therapy. Results: Mean blood pressure remained unchanged: baseline 89.8±4.8 mmHg (mean±sem) versus 91.8±5.9 mmHg, p =not significant. Median baseline RR-variability was 791 (range 18–5344) counts/24 h and increased in all but one patient, with captopril, to 1548 (56–4824) p =0.008. Three increased into the normal range. Conclusion: The vagal dysfunction of cirrhosis is caused by neuromodulation by angiotensin II and is not due to a neuropathy.

BACKGROUND: Adenosine is a potent vasoactive substance that may be responsible for mediating the altered haemodynamics found in patients with cirrhosis. AIM: The administration of oral theophylline was used to investigate the effect of adenosine receptor antagonism upon the circulation of patients with cirrhosis. METHODS: Twenty eight patients were given oral theophylline and intravascular haemodynamic measurements obtained over approximately one hour. RESULTS: After 240 mg of oral theophylline elixir the hepatic venous pressure gradient mean fell from 21.8 (2.1) to 19.9 (2.4) mm Hg (p < 0.01), and azygos blood flow fell from 481 (94) to 375 (83) ml/min (p < 0.05). There were no changes in cardiac output or systemic vascular resistance despite a fall in mean arterial pressure (92.2 (2.0) to 89.2 (1.8) mm Hg; p < 0.05) and a rise in heart rate (78.3 (3.0) to 82.4 (3.2); p < 0.001). Left renal vein flow measured by a reverse thermodilution catheter rose from 387 (91) to 601 (119) ml/ min (p < 0.05). The proportion of cardiac output perfusing the left kidney rose from 5.0 (1.3) to 9.7 (2.8)%. CONCLUSIONS: These changes indicate a significant role for adenosine in the renal vasoconstriction and a more minor role in the maintenance of portal hypertension.

Brain dysfunction is common in patients with advanced liver disease; it is often manifested as hepatic encephalopathy, but its cause is not clearly understood.Intracranial blood flow velocity parameters, including peak systolic velocity, end diastolic velocity and mean velocity of both middle cerebral arteries were measured by transcranial Doppler ultrasonography in 37 patients with cirrhosis without encephalopathy (16 Child's A, 10 Child's B and 11 Child's C) and 12 normal controls. The cause was alcohol-related in 24 and non-alcohol-related in 13.No significant differences in any of the Doppler parameters were detected in Child's group A when compared with controls. However, a statistically significant decrease in middle cerebral artery blood flow velocity was evident when Child's B and C patients without clinically apparent encephalopathy were compared with controls irrespective of the cause. Our results demonstrate that intracranial blood flow is abnormal in patients with advanced liver disease without clinically apparent encephalopathy.

Objective: Various immunocytochemical characteristics of the human gall bladder innervation and epithelial secretor status were studied in an attempt to identify whether consistent changes might be found in gallstone formation and cholecystitis. Material and methods: A total of 44 gall bladders were studied; 32 had been removed because of symptomatic disease and 12 gallstone-free gall bladders were obtained from donors of hepatic transplants. The gall bladders were assessed by routine haematoxylin and eosin staining and by immunocytochemical staining for neuronal and axonal structures, nerve sheaths, neuroendocrine cells and markers of epithelial secretion and differentiation. Results: No difference between normal and inflamed gall bladders were found in neuroendocrine, epithelial secretory and differentiation markers

Previous studies have shown that changes in the peripheral circulation occur in patients with liver disease. We have investigated the temperature of the hands of 26 patients and 13 controls using a liquid crystal contact thermography system. Significant differences in resting hand temperature and appearance were observed when the patients were categorised according to Child's score. The appearance depended upon the severity of liver disease; Child's A patients have warm hands of normal thermographic appearance; Child's B patients have cold hands with an abnormal thermographic appearance; whilst Child's C patients have warm hands with an abnormal thermographic appearance. After right-hand ice-cold water immersion, right-hand recovery was abnormally slow in Child's B & C groups compared with Child's A patients and controls. In addition, there was left-hand reflex vasoconstriction during the right-hand warm-up period in those with severe liver disease. With regard to autonomic function, no significant difference in right-hand temperature, thermographic appearance or warm-up rate was detected between those with and those without autonomic neuropathy. These results indicate that autonomic nervous system dysfunction is not the predominant cause of these changes.

The effects of acute and chronic administration of isosorbide-5-mononitrate on portal and systemic circulation was studied in patients with cirrhosis and portal hypertension. Acute administration reduced the mean arterial pressure and hepatic venous pressure gradient (18.4 +/- 0.9 to 16.5 +/- 0.9 mmHg), whilst having a variable effect on azygos blood flow. The hepatic venous pressure gradient fell consistently only in patients in whom the azygos blood flow increased acutely. With chronic administration no reduction in mean arterial and hepatic venous pressure gradient was identified before rechallenge, despite a marked and consistent reduction in azygos flow (540 +/- 89 to 306 +/- 60 ml/min). Rechallenge with isosorbide-5-mononitrate in patients on chronic nitrate therapy reproduced the haemodynamic effects identified with acute administration, lowering mean arterial and hepatic venous pressure gradient (19 +/- 1.5 to 16.0 +/- 1.8 mmHg) with a variable effect on azygos flow. The wedged hepatic venous pressure was significantly lower than pretreatment values (19.9 +/- 1.6 compared with 23.4 +/- 2.1 mmHg). We conclude that acute nitrate administration lowers the hepatic venous pressure gradient, either by reducing portal venous inflow or by reducing portal-collateral resistance. Chronic administration reduces portal-collateral flow without consistently lowering the hepatic venous pressure gradient. No evidence of nitrate tolerance or tachyphylaxis was observed.

Objective: To study the capacity of the human gall bladder with and without gallstones to secrete H + ions. Design: Human gall bladders were studied in vitro which permitted the measurement of the electrical potential difference and secretion of H + ions. Results: Thirty-three gall bladders were studied (five normal, 20 with cholesterol and eight with pigment gallstones). The normal gall bladder group secreted 14.53 ± 1.04 nmol (mean ± SEM), the mildly inflamed group 8.27 ± 1.71 nmol and the moderately inflamed group 4.03 ± 0.94 H + over 60 min in the mucosal bathing fluid. H + secretion was significantly different when the mildly and moderately inflamed groups were compared with the normal group (P < 0.002 and P < 0.009, respectively)

Gall bladder epithelial cells serve numerous biological functions and abnormalities in their function are important in the pathogenesis of several gall bladder diseases. Direct studies on cell function are rare due to lack of reliable methods to culture this epithelium. This study reports a reliable and reproducible method of harvesting and culturing gall bladder epithelial cells. Normal bovine gall bladder epithelium, obtained within 20 minutes of slaughter, was rinsed with modified Hanks's balanced salt solution, the mucosa separated and incubated in trypsin--EDTA solution at 37 degrees C. The cells were isolated and resuspended in Dulbeco's modification of Eagles' medium containing 10% fetal calf serum and, after filtration and centrifugation, were plated under aseptic conditions. The growth rate was established by flow cytometry and the morphological characteristics of the growing cells by electron microscopy. Gall bladder epithelial cells grew successfully and visible clusters of cells were present by day two, confluency being reached at 8 to 10 days in collagen coated plates and 12 to 14 days in uncoated plates. Electron microscopy showed typical gall bladder epithelia with microvilli, tight junctions, and mucus droplets. This method proved reliable and reproducible for the culture of gall bladder epithelial cells and should allow direct studies of the biological properties of these cells in human tissue.

The insertion of a transjugular intrahepatic portasystemic stent shunt (TIPSS) was evaluated in 22 patients with recurrent upper gastrointestinal haemorrhage related to portal hypertension (bleeding from oesophageal varices 10, gastric varices six, portal hypertensive gastropathy six). TIPSS was successfully performed electively in 15 patients and as an emergency in three patients. Twelve patients have had no further admissions with bleeding after TIPSS. Single episodes of bleeding were noted in six patients after TIPSS associated with shunt thrombosis (two), intimal hyperplasia within the shunt (two), and shunt migration (one). Another patient presented with reaccumulated ascites suggesting poor shunt function but died from massive variceal haemorrhage before further assessment could be performed. There was one death related to the procedure. Two patients developed encephalopathy after TIPSS, in one patient this was controlled by the insertion of a smaller diameter stent within the existing TIPSS. Several complications arose in earlier patients that have not recurred after modification of the initial technique. TIPSS can be life saving and is effective in controlling variceal haemorrhage and rebleeding from oesophageal or gastric varices and portal hypertensive gastropathy. Larger and longer term studies are required, however, to define the role of TIPSS in the overall management of such patients.

SynopsisIn this paper we deal with those methods which are used, or which may be used, to ensure that research in the biomedical and health services field is of a satisfactory standard. We discuss not only what is undertaken to ensure that the quality of the applications which are funded is of the best, but also those activities which may be pursued in an endeavour to stimulate a healthy quantity of high-quality applications for research. This latter point is an issue relating primarily to health services research. We cover the topic of quality assurance of biomedical and health services research from an experience which is derived mainly, but not solely, from involvement with Scottish funding agencies. Consideration is given to the allocation of budgets for research in medicine and the impact that this has on the quality of biomedical and health services research.

We report the 10-year survival of 510 patients with a histological diagnosis of alcoholic liver disease. Eight centres in Scotland and North England contributed to this study. Information was available on 92% of the initial cohort. Age was important, with each decade increasing mortality by 55%. A highly significant interaction between sex and histology was observed with a marked survival benefit for males with non-cirrhotic alcoholic liver disease, while in cirrhotic subjects the pattern was reversed. Patients with decompensated liver disease had a relative increase in mortality in excess of 86% while the increase in mortality for alcoholic hepatitis, 'active' cirrhosis and 'inactive' cirrhosis were 52%, 57% and 91% relative to fatty liver. Alcohol intake at the time of diagnosis did not influence outcome. This study emphasises yet again the increased mortality rate of individuals abusing alcohol compared with the general population.

A computer assisted apparatus for the continuous measurement of azygos blood flow is described. The system was validated in vitro and changes in flow which occur with respiration and Valsalva manoeuvre are illustrated. This apparatus allows real time inspection of flow values which enables changes in flow over short periods to be readily studied.

OBJECTIVE Portal haemodynamics vary in response to eating and other stimuli, but any increase in portal venous pressure (PVP) in cirrhotic patients may be a risk factor for variceal bleeding. We directly assessed post-prandial splanchnic haemodynamics in cirrhotic patients with a transjugular intrahepatic portosystemic stent-shunt (TIPSS) in situ. METHODS A thermodilution catheter was inserted via the patent TIPSS into the portal vein in 12 cirrhotic patients. PVP,portal venous flow (PVF) (thermodilution method), portal vascular resistance (PVR), porto-atrial pressure gradient (PPG), heart rate, mean arterial pressure (MAP) and right atrial pressure (RAP) were measured. A 505 kcal meal was given and all haemodynamic measurements were repeated at 15 min intervals for 60 min. RESULTS Following the meal, there was a significant rise in PVP from 11.2 +/- 1.5 to 14.0 +/- 1.9 mmHg at 15 min, and 14.0 +/- 1.8 mmHg at 30 min (P < 0.001); in PPG from 9.5 +/- 1.4 to 12.7 +/- 2.2 mmHg at 15 min and 12.7 +/- 2.1 mmHg at 30 min (P < 0.005); and in PVF from 1110.2 +/- 141.1 to 1543.2 +/- 227.6 ml/min at 30 min (P < 0.01). PVR feil from 0.08 +/- 0.01 to 0.05 +/- 0.01 RU at 30 min (P < 0.05). Heart rate increased from 77 +/- 4.1 to 80.5 +/- 5.4 bpm at 15 min (p < 0.05), but MAP and RAP remained unchanged. CONCLUSION In cirrhotic patients with TIPSS, significant changes in portal haemodynamics occur at 15-30 min following a meal, with minimal effect on systemic haemodynamics. This model offers a new technique to directly assess the causes for and possible treatments of post-prandial splanchnic hyperaemia in cirrhosis.

Background—Propranolol and isosorbide-5-mononitrate (ISMN) are increasingly used in the prophylaxis of variceal haemorrhage in cirrhosis. However, recent studies have suggested that these drugs may compromise renal function, possibly by reducing renal blood flow.Aims—To assess the acute effects of propranolol and ISMN on renal blood flow and other haemodynamic parameters in cirrhosis.Patients and methods—Twenty six cirrhotic patients were given either 80 mg propranolol, 20 mg ISMN, or a combination of the two drugs. Unilateral renal blood flow (RBF), azygos blood flow (AZBF), hepatic venous pressure gradient (HVPG), mean arterial pressure (MAP), and heart rate (HR) were recorded prior to and one hour after drug administration.Results—Propranolol caused a reduction in HR (pConclusions—Despite the anticipated changes in other haemodynamic parameters, acute propranolol and/or ISMN administration did not reduce RBF. These drugs do not seem to compromise RBF in cirrhosis.

Acute cellular rejection is common after orthotopic liver transplantation and an important cause of graft dysfunction. Eosinophils, potent mediators of tissue damage, have been implicated in the pathogenesis of acute rejection. We studied 55 patients, all of whom had a protocol biopsy 7 days after transplantation and whose peripheral eosinophil count was monitored daily for 11 days after transplantation. Patients were divided clinicopathologically into two groups: group A, without rejection, group B, with rejection. Group B (36% of patients) developed rejection within the 11-day study period. The pretransplant eosinophil count was significantly higher in group B, compared with group A (0.31 +/- 0.08 v 0.10 +/- 0.01 (x10(9)/L), p.001). After transplantation, the eosinophil count fell to low levels in both groups. By day 3 there was a statistically significant rise in the eosinophil count in group B compared with group A, with a maximum at day 7 [0.51 +/- 0.06 v 0.26 +/- 0.03 (x10(9)/L) p.001]. After treatment with steroids, the eosinophil count dropped to values similar to those in group A and remained low thereafter in 16 of 20 patients. Four patients had a second episode of rejection; in each of these, eosinophils were raised again and decreased with resolution of the rejection. An eosinophil count threshold of 0.13 (x10(9)/L) before transplantation and 0.33 (x10(9)/L) on day 7 after transplantation predicted the development of rejection (sensitivity 72/70%, specificity 66/63%, negative predictive value 82/79%). We conclude that a raised eosinophil count is associated with acute rejection. The raised eosinophil count before transplantation in group B suggests that these patients are predisposed to acute rejection, and earlier intervention may be indicated.

The aetiology of ascites may be obvious from the history and physical examination. However, it is generally necessary to examine the fluid microscopically, chemically and bacteriologically. Even when the cause is clinically apparent, for example hepatic cirrhosis and portal hypertension, it may not be possible to exclude either superimposed infection or hepatocellular cancer.

The exact diagnosis of patients with haematemesis, dyspepsia and other upper abdominal symptoms cannot be made on the history alone. Diseases may simulate each other and different disorders can affect the same patient. Fibreoptic endoscopy with photography, biopsy and cytology has played a major role in evaluation and management. The technique is safe with a few contraindications, but requires training and experience to yield good results. It is usual for operators and assistants to wear disposable waterproof gloves. Special precautions are needed for patients known to carry hepatitis B virus, and those known or suspected of carrying HIV, including gowns and masks with visors. Endoscopy staff should be immunized against hepatitis B.

Combinations of beta-blockers and vasodilators have been assessed for their ability to lower portal pressure and so prevent variceal haemorrhage. However, reservations have been raised particularly with respect to renal function and perfusion after the use of these medicines in patients with chronic liver disease. We studied the acute effects of carvedilol, a new vasodilating beta-blocker which combines non-selective beta-blockade with alpha-1 receptor antagonism, upon the haemodynamics of patients with cirrhosis.Sixteen patients completed the study which measured the changes approximately 1 h after the administration of 25 mg oral carvedilol.The hepatic venous pressure gradient fell from 16.7 +/- 0.9 to 13.6 +/- 1.0 mmHg (p0.00001), accounted for largely by reductions in the wedged hepatic venous pressure. Despite this, the azygos blood flow did not change. There was a significant fall in mean arterial pressure (94.8 +/- 4.4 cf. 84.6 +/- 4.3 mmHg; p = 0.0001), which was particularly apparent in the diastolic blood pressure of those patients with ascites. The heart rate only fell significantly in the ascitic subjects. No significant changes occurred in the cardiac output or systemic vascular resistance. Unilateral renal vein flow as measured by the reverse thermodilution technique remained constant.Carvedilol is therefore a potent acute portal hypotensive agent which does not appear to compromise renal perfusion. However, patients with ascites are at greater risk of its systemic hypotensive action.

OBJECTIVE To assess the relationship between neutrophil activation and indices of disease severity in patients with chronic liver disease. METHODS Plasma neutrophil elastase was measured by radioimmunoassay as a marker of neutrophil activation, and disease severity assessed by standard clinical, biochemical, haematological and histological techniques. PATIENTS Eighty-eight patients with chronic liver disease were studied, Thirty-nine had alcohol-induced liver disease (ALD), 18 autoimmune chronic hepatitis, 13 cryptogenic cirrhosis, seven primary biliary cirrhosis, six primary sclerosing cholangitis, three haemochromatosis and two secondary biliary cirrhosis. Seventy-three patients were cirrhotic and 15 were non-cirrhotic, confirmed by biopsy. RESULTS Levels of neutrophil elastase were raised in Childs C cirrhotic patients with ALD compared with Childs A or B patients with ALD (P < 0.01), Childs A or B patients with non-ALD (P < 0.01), and Childs C patients with non-ALD (P = 0.02). In patients with ALD, neutrophil elastase correlated with prothrombin time (r = 0.679, P = 0.001), bilirubin (r = 0.587, P < 0.001), Child-Pugh score (r = 0.546, P < 0.001) and inversely with serum albumin (r = -0.511, P < 0.001). In patients with non-ALD, there were no correlations with the measurements of with transaminase levels. CONCLUSION Neutrophil activation, as measured by plasma neutrophil elastase, is a marker of disease severity in patients with alcohol-induced chronic liver damage, but not in those with other causes of liver disease.

Background/Aims: Autonomic and cardiac dysfunction have been reported in patients with cirrhosis. We studied left ventricular and autonomic function in 20 patients with both alcoholic and non-alcoholic cirrhosis. Methods: Autonomic function was assessed by a standard battery of cardiovascular reflex tests. Supine exercise radionuclide ventriculography was used to assess the cardiac response to exercise. Results: Exercise capacity was reduced in all patients in association with marked chronotropic incompetence (peak heart rates 120.5±6 bpm). Unlike normal subjects thee was no increase in left ventricular ejection fraction on exercise. Stroke volume increased by 23±6%, mediated by an increase in end-diastolic volume of >20%. Cardiac output was subnormal at maximal exercise, increasing by only 96±14% and 97±11% in alcoholic and non-alcoholic groups respectively. The majority (83%) of our patients had autonomic reflex abnormalities. Conclusions: Patients with cirrhosis of alcohol and non-alcohol related aetiologies have significantly impaired cardiovascular responses to exercise, which are similar to those of a denervated heart. This may have important clinical implications for the ability of these patients to withstand cardiovascular stress.

SUMMARY Background: Propranolol has been shown to be effective in both primary and secondary treatment of variceal haemorrhage; most primary prevention trials have only included patients with large oesophageal varices. Aim of the study: The aim of this study was to look at the effect of propranolol in the primary prevention of variceal bleeding and its long-term effects on mortality in unselected patients with chronic liver disease. Methodology: Three hundred and nineteen patients were included in a double-blind parallel group study in three centres to receive propranolol 160 mg long-acting (LA) or placebo. Patients were followed up for a minimum of one year. Results: There were eleven episodes of variceal bleeding and 38 deaths with no statistically significant difference in bleeding rates between the two treatment groups. Child's group and history of ascites were the most important prognostic factors determining the likelihood of early death and variceal bleeding respectively. Conclusions: In this study we failed to demonstrate a significant effect of propranolol on first variceal bleeding or in prolonging survival in unselected patients with chronic liver disease. Our results, however, might have been influenced by the low event rate observed in these unselected group of patients and suggest that careful selection of patients who are most likely to benefit from propranolol is important.

Gall bladder bile is more acid that hepatic bile and this has been attributed to bicarbonate absorption by the gall bladder epithelium. The aim of this study was to investigate in vitro the acid base changes that occur across the human gall bladder mucosa. Fresh gall bladder tissue was obtained at cholecystectomy and placed in an Ussing Chamber and perfused with Ringer-Krebs glucose bicarbonate solution. The viability of the gall bladder was assessed by measuring the potential differences across the epithelium and by the morphology of the epithelial cells at the end of the experiments. Aliquots from the solutions were taken at two, 45 and 70 minutes and pCO2, hydrogen ion and bicarbonate concentrations were measured. In the mucosal side of the chamber a consistent and significant decrease was observed from two minutes to 70 minutes in bicarbonate concentration while pCO2 and hydrogen ion concentrations significantly increased. The degree of inflammation correlated well with the ability for acidification, the more inflamed the tissue the less its ability to acidify. When the gall bladder was exposed to amiloride or sodium free solution acidification was abolished in the mucosal side. When tissue metabolism was irreversibly inhibited by exposure to formaldehyde, hydrogen ion concentration and pCO2 were significantly decreased in the mucosal side of the chamber compared with the viable gall bladder. The human gall bladder is capable of secreting acid and this may be an important mechanism for preventing calcium precipitation and gall stone formation.

Most biological processes are catalysed by means of enzymes and study of these in health and disease is important for our understanding of both biology and disturbed function. The glutathione S-transferases (GST:E.C.2.5.1.18) are a complex multigene family of enzymes that are widely distributed in the animal kingdom. ' These enzymes possess many biological functions, the most important of which is detoxification, conjugating reduced glutathione with a large number of electrophiles.2 Such conjugation reactions result in the synthesis of mercapturic acids and represent an important excretory route for xenobiotics including carcinogens, toxins, and drugs.' As well as being concerned in the metabolism of xenobiotics, GST are involved in the metabolism of endogenous substances such as leukotriene A4 and prostaglandin A1.3 GST are also involved in non-substrate binding to such substances as bilirubin and bile acids and have an important role in hepatic anion transport. Several GST isoenzymes possess selenium-independent glutathione peroxidase activity with certain organic hydroperoxides such as linoleic and arachidonic hydroperoxide but not with hydrogen peroxide.5 In humans the cytosolic GST isoenzymes are dimeric and can be subdivided on the basis of their physicochemical and immunological properties into three major groups, namely pi, alpha, and mu class GST (Table6). In humans

Background~Aims: Combinations of beta-blockers and vasodilators have been assessed for their ability to lower portal pressure and so prevent variceal haemorrhage. However, reservations have been raised particularly with respect to renal function and perfusion after the use of these medicines in patients with chronic liver disease. We studied the acute effects of carvedilol, a new vasodilating betablocker which combines non-selective beta-blockade with alpha-1 receptor antagonism, upon the haemodynamics of patients with cirrhosis. Methods: Sixteen patients completed the study which measured the changes approximately 1 h after the administration of 25 mg oral carvediloi. Results: The hepatic venous pressure gradient fell from 16.7_+0.9 to 13.6+1.0 mmHg (p

Chronic liver disease is frequently associated with a hyperdynamic circulation, with warm hands and capillary pulsations. In our experience, however, a significant number of patients with alcoholic liver disease complain of cold hands. In this study, we have investigated the presence of the subjective feeling of hand temperature in 114 patients with alcoholic liver disease compared with 96 healthy controls, and studied possible correlations of this subjective feeling with the severity of liver disease. Significantly more patients with alcoholic liver disease complained of cold hands than did normals, and these differences were more prominent in the male group. The awareness of cold hands appears to be commoner in an intermediate group of patients, between those with noncirrhotic liver disease without varices and those with cirrhosis with varices. A similar pattern of awareness of hand temperature was found when patients were staged according to the severity of their liver disease. We conclude that a staging can be made; at an early stage of liver disease, patients tend to have warm hands, subsequently develop cold hands, and at a later stage, their hands become warm again.

Bile acid derivatives have been prepared by reaction of their mixed anhydrides with diaminoethane. The new compounds have side chains modified by amide bond formation which extends the side chain by two carbon atoms and terminates in a primary amino group. Important properties of the new compounds are their solubility in acid, and their ability to act as nucleophiles in the carbodiimide reaction or mixed anhydride reaction. The derivatives have been used to prepare high molar ratio immunogens with bovine serum albumin and to prepare I labelled ligands for radioimmunoassay

Tissue culture of gall-bladder was attempted in the following media: Dulbecco, Eagle's minimum essential medium, NCTC 135, medium 199 and Ham's F12. Growth occurred in all of them for up to 2 weeks assessed by light microscopy. No enhancement of growth was induced by collagenase trypsin insulin or hydrocortisone. Scanning electron microscopy confirmed that new cells colonised the free surface of the explant. Transmission electron microscopy showed good preservation of the original tall epithelial cells for the period of study. The new migrating cells were flatter, but retained the morphological features of the columnar cells. Secretory granules were absent after 1 day in culture but increased amounts of glycogen and lipid began to appear in the epithelium.

Total and individual serum bile acid concentrations were studied in 18 patients with viral hepatitis. The initial high values returned to the normal range at approximately the same time as the conventional liver function tests. Chenodeoxycholic acid was the predominant bile acid initially, but cholic acid predominated as the disease resolved. All patients had proportionately less doexycholic acid than controls. It is concluded that the measurement of serum bile acid does not provide added information of value in the management of patients with viral hepatitis.

Two patients diagnosed as having small intestinal hyperplastic villous atrophy and being treated with a gluten free diet were investigated because of persistent watery diarrhoea. Both were found to have collagenous colitis. Previous reports of this condition have emphasised the presence of normal small intestinal mucosal architecture and the association of collagenous colitis with intestinal villous atrophy has not previously been reported. Both cases responded to oral steroid therapy, but not to other previously recommended treatment regimens.

The value of serum bile acids (SBA) in the diagnosis of hepatobiliary disease has been investigated. A modified GLC method was used, with an overall coefficient of variation of +/- 11% in the control range. Serum was obtained after a 12 hour fast, and two hours after a fatty meal from 73 patients and 14 control subjects. In controls the total fasting SBA of 2.17 +/- 0.86 mumol/l increased significantly (p less than 0.001) to 3.81 +/- 1.14 mumol/l after a meal. All icteric patients had raised SBA, but in 23 anicteric patients there was no significant difference in the detection of chronic liver disease by fasting SBA, postprandial SBA, AST, or gamma GTP. Compared with controls, serum in patients contained proportionately less deoxycholic acid (p less than 0.001), there was proportionately more cholic acid in extrahepatic obstruction (p less than 0.001), and proportionately more chenodeoxycholic acid in patients with cirrhosis, viral hepatitis, and neoplasia (p less than 0.001). In control subjects, the fasting cholic:chenodeoxycholic acid ratio ranged from 0.5-1.0, and differed significantly (p less than 0.001) from patients with extrahepatic obstruction 0.96-3.6, and cirrhosis 0.1-0.5. It is concluded that serum bile acids measured by sensitive methods can provide useful diagnostic information.

Histochemically, alkaline phosphatase was localised in epithelial brush-border and capillary endothelium of the lamina propria in 41 gallbladders studied. Three distinct patterns of the brush-border enzyme distribution were observed, namely, complete delineation, patchy localisation and a brush-border totally devoid of enzyme activity. Where no histochemical activity was found, biliary chenodeoxycholate was 50 per cent. higher than in cases of patchy distribution and twice as high as in cases with complete staining of the brush-border. Conversely, biliary cholate levels were significantly higher in completely stained cases. Biliary cholesterol was higher in the cases with no histochemical activity and this was reflected in a significantly higher lithogenic index. Significant quantities of cholesterol esters were found in bile from the focal activity group only. Total alkaline phosphatase activity assayed in gallbladders from 112 patients with cholecystitis and/or lithiasis showed that activity was significantly lower in patients with pigment stones than patients with cholecystitis and/or cholesterol stones. This activity was not related to biliary lipid composition in the 77 bile samples analysed. This evidence indicates that biliary lipid composition is associated with the histochemical distribution of alkaline phosphatase in gallbladder mucosa.

Glutathione S-transferase (GST; EC 2.5.1.18), a sensitive marker of hepatocellular damage, was measured in patients on therapy for histologically proven, autoimmune chronic active hepatitis at various stages of the disease. GST levels were elevated in 65% of serum samples despite immuno-suppressive treatment compared with aspartate transaminase (AST) which was increased in only 23% of samples. In 55% of samples with normal AST concentrations, GST was elevated. No samples demonstrated abnormal transaminase with normal GST levels. It is concluded that continuing hepatocellular damage occurs in patients with autoimmune chronic active hepatitis on immuno-suppressive treatment.

The effects of four different doses of ursodeoxycholic acid (250, 500, 750, and 1000 mg daily) on biliary lipids were studied in 24 patients with radiolucent gallbladder stones. There was a significant increase in the proportion of ursodeoxycholic acid in bile after all doses, being greatest with 750 and 1000 mg daily. Unsulphated lithocholic acid was also increased in the bile after therapy, while the other major bile acids were reduced. The cholesterol content of bile was reduced by all doses, and this change was most marked after 1000 mg (from 10.9 +/- 1.4 to 5.6 +/- 0.5 mol%, P < 0.01). Biliary cholesterol saturation improved significantly only after 750 and 1000 mg daily.

Glutathione S-transferases are a group of drug metabolising and detoxification enzymes. We have studied the distribution of four isoenzymes, acidic, basic, neutral, and microsomal GST in human liver, gall bladder, and small and large intestinal epithelium by immunohistochemistry. Antibodies were raised in rabbits to purified GST subunits and several formalin fixed paraffin sections of each human tissue studied using the peroxidase-antiperoxidase method. Staining density was graded from very strong (+++) to negative (-). All four enzymes were identified within the liver, the acidic GST being found almost exclusively within the biliary epithelium. The gall bladder epithelium stained strongly for acidic and basic GST. In the small intestinal epithelium the acidic and neutral GST were readily identified in villi and crypts, whilst basic GST was found only in the villi and microsomal only in the crypts. In the colonic mucosa only acidic GST could consistently be identified. This histological heterogeneity may have functional implications for these enzymes in human hepatobiliary and intestinal tissue.