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Gall stone disease is a common cause of morbidity and cholecystectomy represents the most common elective abdominal operation in Western society. In the United Kingdom alone about 20% of the population may expect to develop cholelithiasis.' Initially most research had been focused on the biochemical changes that occur in bile during gall stone formation. Recent years have seen significant advances in our knowledge and it is now recognised that the gall bladder is not a passive reservoir but has several absorptive, secretory, and motor functions, which are integrated to produce concentrated bile. The interactions between gall bladder bile and mucosa are of paramount importance to maintain the fine balance between concentration and precipitation of the biliary constituents. The gall bladder mucosa has one of the highest rates of water absorption in the body and an 80-90% decrease in the initial volume of bile occurs within the gall bladder. This is achieved by the coupling of active sodium transport and passive water absorption resulting in isotonic fluid absorption.2 Fluid transport is subject to a variety of influences such as chronic inflammation or the presence of pharmacological agents (prostaglandins, prostacyclin, and various gastrointestinal peptides); fluid absorption is higher in daytime and is reversed to net secretion with feeding.3 Electrolyte transport has been extensively investigated; chloride is actively absorbed in exchange for bicarbonate, and potassium moves from the mucosa to the serosa according to electrochemical gradients.4 5 Calcium is also absorbed and its distribution across the gall bladder epithelium is of importance in the formation of gall stones.6

Subtle impairments of cognitive function may be an important cause of occupational and psychosocial morbidity in patients with chronic liver disease. Correlation of structural brain abnormalities with cognitive deficits has yielded inconsistent results. 10 patients with cirrhotic liver disease were compared with 10 age, education, and intelligence matched control subjects. Neuropsychological assessment revealed significant overall cognitive impairments in cirrhotic patients compared with controls (p = 0.02). Regional cerebral blood flow was measured by single photon emission computed tomography (SPET or SPECT) and showed increased uptake of radiotracer in the right and left posterior parts of the basal ganglia and right occipital lobe, together with reduced uptake in the right anterior cingulate region. The degree of cognitive impairment was directly correlated with functional abnormalities in the basal ganglia and limbic cortex (p less than 0.05). Our results suggest that impaired cognitive status may be associated with abnormalities of regional brain function in patients with chronic liver disease. Since these deficits are clinically inapparent, our findings have important implications for identification and management of patients with chronic liver disease.

1. We investigated arteriovenous exchanges of tyrosine and 3-methylhistidine across leg tissue in the postabsorptive state as specific indices of net protein balance and myofibrillar protein breakdown, respectively, in eight patients with cirrhosis and in 11 healthy control subjects. Whole-body protein turnover was also measured using l-[1-13C]leucine. 2. Leg efflux of tyrosine was 45% greater in cirrhotic patients than in normal control subjects [−6.5(1.4 to −19.1) vs −4.2 (−2.2 to −7.7) μmol min−1 100 mg−1 of leg, median (range), P 3. In cirrhosis, whole-body leucine flux was normal but whole-body leucine oxidation was elevated so that whole-body protein synthesis was depressed by 17%. 4. The results indicate the predominant mechanism of muscle wasting in cirrhosis to be a fall in muscle protein synthesis, which is accompanied by an overall fall in whole-body protein turnover.

Oesophageal biopsies were studied with the electron microscope. Three layers were identified, as in the light microscopy of the oesophageal epithelium: basal, prickle and funtional cell layers. A continuous basement membrane separated the lamina propria from the basal cells. The basal cell membrane carried hemidesmosomes, desmosomes and microvillous processes. Their cytoplasm contained the usual organelles plus free ribosomes and tonofirbrils. Prickle cells contained glycogen rosettes and many tonofilaments, and their cell membrane many microvillous and demosomal processes, in places elaborated into desmosome fields. In both these layers there was a wide intercellular space containing some particulate and membranous debris. The flattened cells of the functional layer had fewer desmosomes and microvilli but abundant glycogen and tonofilaments, and a narrow intercellular space. Membrane coating granules first reaching a maximum in the functional cell layer appeared in the upper prickle cell layer and few persisted into the surface cells. The apical cell membrane of the most superficial cells was thickened and had few small microvillous processes, which were covered with a filamentous "fuzzy" coat. No keratohyaline granules were present. Papillae of lamina propria contained capillaries, some with a fenestrated endothelium.

Gastroenterology is recognized as a speciality in most countries, especially in Europe and North America. The requirements for being acknowledged as a specialist vary from 1 1/2 to 4 years of training and education in gastroenterology in addition to 1-6 years of training and education in internal medicine/surgery. The requirement of theoretical education varying from 40 to 300 h is practiced in some countries only. In some countries training in endoscopy is separated from gastroenterology. A formal examination and post-specialization training program is required in only some of the countries answering the questionnaire. The number of centres per million inhabitants recognized for training and education also varied greatly. The number of specialists per million inhabitants was 3.6 to 15. In the Middle and Far East the organisation of gastroenterology was much inferior to that in Europe and North America because of insufficient education and organization programs and lack of economic support to perform them. The answers from the gastroenterological associations and personal reporters agreed on the following: A speciality in medical and surgical gastroenterology should be established in all countries around the world. Programs for training and education should be agreed upon in recognized teaching and training institutions of gastroenterology, probably of 3 years' duration in combination with a speciality in internal medicine. A gastroenterologist will in most cases be dealing with other diseases as well. The number of specialists per million inhabitants may be estimated to 10, the exact number not being possible to determine at present. In most countries the post-specialization programs were not required but were offered, a problem that has to be clarified.(ABSTRACT TRUNCATED AT 250 WORDS)

Passive permeability of small intestine to lactulose and mannitol was studied in children suspected of having intestinal disease, using a hypertonic differential sugar absorption test. Children with coeliac disease and cows' milk intolerance were shown to have an elevated urinary lactulose/mannitol recovery ratio when compared with controls, children with normal jejunal biopsy, or children in whom alternative explanations for failure to thrive had been demonstrated. The abnormality in permeability ratio principally reflects a reduced urinary recovery of mannitol following oral administration. This study demonstrates that a hypertonic sugar absorption test is well tolerated even by young children, is practicable in routine clinical pediatric practice, and is capable of demonstrating abnormal intestinal function in children with small intestinal disease.

The characteristics of cholesterol uptake by 83 human gall bladders (obtained at cholecystectomy) were studied with a modified Ussing technique. Real and artificial biles labelled with 14C-cholesterol and 3H-dextran (the latter to correct for adherent mucosal bile) were used; all gall bladders absorbed cholesterol (average 3.5 nmol/cm2/minute). Recovery of the absorbed cholesterol from the tissue showed that about 4% was esterified over 60 minutes. In artificial bile the rate of absorption of cholesterol increased as the bile saturation index rose, but became constant once supersaturation was achieved. In contrast, supersaturated real bile permitted greater absorption of cholesterol, possibly due to enhanced cholesterol solubilisation. Preincubation of gall bladder tissue in sodium cyanide (5 mM) caused a 30% reduction in cholesterol uptake indicating that, although absorption is predominantly a "passive" process, there is a partial "active" component. There were no pronounced differences in the rate of cholesterol absorption as gall bladders became more diseased, but there was a reduction in the amount of cholesterol ester formed.

198-Au-gold colloid liver scans and 75-Se-selenomethionine pancreas scans in 72 patients with extrahepatic obstructive jaundice were assessed by blind marking. They were compared with liver and pancreas scans from 20 control patients and liver scans from 33 patients with diffuse liver disease. 56 per cent of the liver scans in extrahepatic obstructive jaundice showed a filling defect in the hilar region of the liver. This was most frequently seen in the most deeply jaundiced patients, and was reported in 80 per cent of patients with a serum bilirubin greater than 15 mg/100 ml. The liver scan alone cannot distinguish between different forms of extrahepatic obstructive jaundice although severe loss of left lobe uptake appeared to favour a diagnosis of carcinoma of the bile or hepatic ducts. A normal pancreas scan virtually excludes a pancreatic carcinoma as the cause of obstructive jaundice. A pancreas scan showing severely reduced uptake suggests a carcinoma of the pancreas or of the lower end of the common bile duct.

Esterases active at neutral and acid pH have been demonstrated in human gallbladder epithelium. Reaction to a wide variety of inhibitors and activators suggests that they probably represent the same enzyme with two active sites while a close correlation with acid phosphatase, a known lysosomal enzyme, suggests a lysosomal localization. Esterase activity in the gallbladder mucosa in significantly decreased in chronic cholecystitis. Polyacrylamide gel electrophoresis suggests that cholesterol stones may be associated with a specific type of isoenzyme pattern. Esterase positive cells are present in the inflammatory infiltrate in the lamina propria of the gallbladder in most cases of chronic cholecystitis. Naphthol AS-D chloracetate esterase staining indicates that mast cells form a large part of the infiltrate. Bile acids modulate the enzyme activity in vitro. Although the exact substrate specificity is not known, several possibilities are discussed, implicating esterases in the pathogenesis of chronic cholecystitis.

It is suggested that duodenal polyps are more frequent in Gardner's syndrome than previously recognized. The polyps have a particular tendency to undergo malignant change. Two patients with Gardner's syndrome are reported in whom duodenal polyps were associated in one patient with periampullary cancer and in the other with a possible adenocarcinoma of the duodenum.

The oral ingestion of naturally occurring purified trypsin inhibitors from soybean, ovomucoid, and bovine pancreas has been demonstrated to be a potent stimulus to pancreatic digestive enzyme synthesis. This effect may be so marked as to lead to impairment of growth in the rat and chicken through the faecal loss of essential amino acids. This is thought to be due to the markedly potentiated secretion of pancreatic digestive enzyme protein overwhelming the normal digestive capacity of the gastrointestinal tract and resulting in a pancreatogenous protein-losing enteropathy. Experimental evidence is presented to suggest that this response to the trypsin inhibitors requires the mediation of the gastrointestinal tract and is independent of vagal innervation to the pancreas. The most satisfactory hypothesis would favour the release of a trophic stimulus from the intestinal mucosa (possibly pancreozymin-cholecystokinin) to the acinar cell of the pancreas in response to the presence of the trypsin inhibitor in the bowel lumen. It is suggested that a primary function of the endogenously secreted pancreatic trypsin inhibitor may be to potentiate enzyme synthesis by the acinar cell, providing an important stimulus for the repletion of the digestive enzymes. Some of the potential physiological and clinical implications of such a mechanism are discussed.

The Lundh test meal was administered to 32 normal subjects and 53 patients with suspected pancreatic disease. Tryptic activity was measured in the recovered duodenal juice. The level of activity distinguished the normal subjects from those with independently confirmed pancreatic disease, particularly chronic pancreatitis and carcinoma of the pancreas. The advantages and disadvantages of the test are discussed.

A new test of pancreatic exocrine function is described in which radioselenium is measured in duodenal aspirate after an intravenous injection of (75)Se-selenomethionine and administration of a Lundh test meal. Duodenal (75)Se activity gave good separation between normals and subjects with disease of the exocrine pancreas and correlated well with trypsin levels in the aspirate.

A technique has been developed which allows the position of the upper gastrointestinal tract, as determined radiographically, to be superimposed on the pancreatic photoscan, performed after an injection of (75)Se-selenomethionine. Results of the technique applied to 27 ;abnormal' and 23 ;normal' subjects are described. The importance of the additional information gained by the combined technique is discussed in terms of normal variation and increased diagnostic yield, and the situations in which it was found most useful are described. The addition of correlated duodenography rendered scan reporting more objective in 50% of cases.

An attempt has been made to determine why gallstones give rise to symptoms in some patients and not in others. The clinical features of patients undergoing gallbladder surgery for gallstones (symptomatic stones) have been compared with patients in whom gallstones were found incidentally at postmortem (‘silent’ stones). The gallstones found in these two groups of patients have been compared for number, size, and content of mucous substances. Patients with gallstone disease did not produce organ specific antibodies to the gallbladder tissues. No conclusions could be derived as to what determines whether or not a stone becomes symptomatic.

Operative biliary dilatation and prolonged percutaneous transhepatic biliary stenting have been useful in the management of primary sclerosing cholangitis, both intrahepatic and extrahepatic biliary strictures regressing after 12-16 months of treatment. We report the results of less prolonged treatment in a further four patients, in whom removal of a percutaneous transhepatic biliary stent 3-11 months after treatment led to an improvement in radiological appearances of the extrahepatic bile ducts, with no discernible effect on intrahepatic disease. Extrahepatic stricture recurred rapidly in one patient stented for only 3 months. Operative biliary dilatation and stenting for 5-11 months may lead to regression of extrahepatic biliary strictures in patients with primary sclerosing cholangitis, whereas intrahepatic disease requires stenting for 12-16 months. Further study is required to determine the applicability of this approach to primary sclerosing cholangitis.

In a study of 195 patients derived from five centres in northern Britain and with histologically confirmed alcoholic liver disease we have found an increased prevalence of serological markers of hepatitis B. This increased prevalence was found in each of the five centres; the overall frequency ranged from 11% sero-positivity in fatty liver, 12% in alcoholic hepatitis and 27% in cirrhosis.

We have examined normal and inflamed oesophageal biopsies for the distribution of alpha-D-mannosyl and alpha-D-glucosyl residues using the concanavalin A--horse radish peroxidase--Diamino-benzidine (DAB) technique at the light and electron microscope level. Receptors were found on the epithelial surface and in the nuclear membrane and endoplasmic reticulum. A similar distribution was found with the intrusive lymphocytes and polymorphonuclear leucocytes in the inflamed state. Some of the increased intercellular debris from inflamed biopsies contained concanavalin A receptors.

There has been a recent increase of interest in the effect of cardiovascular drugs on liver blood flow and portal pressure [1]. Much of the stimulus for this was the demonstration of the ability of propranolol to lower portal pressure [2] and its subsequent use in patients with alcoholic cirrhosis to decrease oesophageal variceal bleeding [3]. Propranolol, however, has numerous side-effects and may complicate resuscitation in patients who do not bleed from the gastrointestinal tract [4]. It is also metabolized in the liver, making it less than ideal for use in patients with cirrhosis. For these reasons other drugs without these disadvantages have been investigated. Glyceryl trinitrate (GTN) has been shown to be a portal hypotensive agent [5], but has a short duration of action. Oral isosorbide dinitrate has been shown to reduce portal pressure in one study [6] but not in another [7]. Isosorbide mononitrate (IS-5-MN), which does not undergo first-pass hepatic biotransformation, unlike the dinitrate [8], seems to be a more suitable agent in patients with liver disease.

The pharmacokinetics of piretanide, a new loop diuretic, were studied in seven patients with severe liver disease before and after resolution of ascites. The time to maximum concentration was significantly prolonged by the presence of ascites. Tmax after relief of ascites was similar to that seen for normal volunteers. Area under the curves, bioavailability, volumes of distribution and elimination half-lives did not change after resolution of the ascites: two patients in whom diuretic resistant ascites occurred showed similar pharmacokinetics to that of the diuretic responders. Reduced responsiveness to piretanide therapy in patients with gross ascites does not appear to be the result of decreased bioavailability.

A study of 510 patients in Scotland and northeastern England with hlstological evidence of alcohol-induced liver disease showed no difference in the age of presentation between males and females. Single men and widowed females were particularly susceptible to alcoholic liver disease. The social class distribution was similar to the population in general. Women were more reluctant to volunteer a history of alcoholism than men, they had a higher incidence of previous psychiatric illness (usually due to alcohol abuse) and they developed liver disease at lower consumption thresholds of alcohol than men. Patients under 40 years of age were more likely to have alcoholic fatty liver and less likely to have active cirrhosis than those over 40. Most often, the presenting symptoms were non-specific and tended to be related to the gastrointestinal system, particularly in women. Five per cent of patients were asymptomatic and 14% came to hospital for conditions other than alcoholic liver disease. Important clues to asymptomatic alcoholic liver disease included hepatomegaly, clubbing of the fingers and abnormal liver function tests. Gastro-oesophageal varices accounted for 40% of instances of haemorrhage and the mortality from upper gastrointestinal bleeding was 17%. Anaemia was the most common haematological abnormality. Alcoholic hepatitis was observed more frequently in the Glasgow area then elsewhere.

The epithelial cells from 40 gallbladders showing chronic cholecystitis and five with cholesterolosis were examined by electron microscopy. A number of features of non-specific cytological injury were noted some of which may have been related to the disease and others to anoxia. The basement membrane showed reduplication. Intraepithelial cells were identified as lymphocytes, polymorphonuclear leukocytes, macrophages and mast cells. Lipid droplets in the epithelial cells were found in 60 per cent. of the specimens.

This paper outlines an introductory course in teaching communication skills to medical students in a preclinical context. The aims of the course, its content and teaching methods are described. Novel features include the active participation of selected patients in teaching and assessment, and the use of a form of role-play named 'listening triads'. The main focus of the paper is assessment, and results are recorded, relating to a class of 114 second-year students during the academic session 1983-84. Assessment of the students' learning was measured by Modified Essay Question (MEQ); students' problems face-to-face with patients were identified by patients, students, and by staff members observing interactions. Problems of fitting these educational assessments into a traditional academic 'certifying' type of assessment remain unresolved at present. This course was found to be acceptable by the preclinical students, and their lack of clinical knowledge did not appear to interfere with their learning. They were enthusiastic about the supervised contact with patients, which appeared to contribute significantly to the way the course was received.

CD treatment inhibits hepatic cholesterol and bile acid formation. Preliminary reports suggest a plasma TG-lowering effect. This study was aimed at characterizing the alterations in TG concentration and turnover during CD treatment.

The results of pancreatic scanning with (75)Se-selenomethionine in 393 carefully documented patients over a two-year period are presented. On follow up 50 patients had operatively proven malignant tumours in the gland and a further 22 had similar tumours in adjacent organs, clinically mimicking carcinoma of the pancreas and in many cases causing scan abnormalities. Five patients had pancreatic adenomata. Remote tumours rarely affected the scan. Examination of the role of scanning in patients with neoplastic disease revealed that the test was effective in screening and in detection; false negative diagnoses were rare. By contrast, survival following diagnosis was extremely poor with only 8% of pancreatic tumours resectable and 50% metastasized at the time of surgery. Causes of pancreatic dysfunction, other than pancreatitis or carcinoma, which were associated with abnormalities on the scan are described and general aspects of reporting on the scan are discussed. The patterns seen in abnormal scans, while non-specific with regard to aetiology, were anatomically meaningful and useful adjuncts to the diagnosis of pancreatic disease. A normal scan excluded pancreatic cancer with a probability greater than 95%.

A patient with nodular lymphoid hyperplasia, who manifested defects in cellular immunity, is presented. The clinical course is discussed and a review included of the 23 patients thus far reported with nodular lymphoid hyperplasia and hypogammaglobulinaemia.

A case of primary carcinoma of the liver is reported in which the tumour was accurately localised using tran-splenic portal venography, hepatic venography and pneumoperitonography. The site of the growth, in the anterosuperior segment of the right hepatic lobe, was confirmed at operation. The radiological methods which may be used to delineate both primary and secondary tumours of the liver are discussed.

Four tests of pancreatic function—the conventional and subtraction pancreas scans, the Lundh test, and the radioselenium test—were performed in 80 patients in an attempt to clarify the indications for performing one or more of these tests in the diagnosis of pancreatic disease. All four tests were performed simultaneously in a single two-hour session. The scans were marked blindly by three independent observers. The radioselenium and Lundh tests were equally accurate in distinguishing between the normal and the abnormal pancreas. Thus only one of these two tests need be performed in a patient referred for pancreatic investigation. Routine performance of both a conventional and a subtraction scan is, however, indicated because the subtraction scan gave fewer false positive results in normal patients whereas the conventional scan yielded better resolution of filling defects. A normal pancreatic scan indicated a 94 per cent probability that the pancreas was normal. If the scan was normal the intubation test was always normal. An abnormal intubation test indicated a 100 per cent probability that the pancreas was abnormal. If the intubation test was abnormal the scan was always abnormal. However, abnormal (false positive) scans were seen in 25 per cent of the normal subjects and normal (false negative) intubation tests were seen in 35 per cent of patients with pancreatic carcinoma. Abnormal scans were seen in 95 per cent of patients with pancreatic carcinoma and in some instances the scans were very suggestive of carcinoma as a localized filling defect was seen. Thus the pancreatic scan is more reliable than an intubation test in establishing a diagnosis of pancreatic carcinoma. Diagnostic ability can, in general, be best improved by performing either one of the duodenal intubation tests together with both the conventional and the subtraction scan. But for some patients, either the scans on their own (if normal) or an intubation test alone (if abnormal) will suffice.

Twenty five patients with primary biliary cirrhosis were studied for vitamin A state. In nine patients found to have low circulating vitamin A concentrations no abnormality was found on electro-oculography or in dark adaptation. A positive correlation was found between retinol binding protein and vitamin A values (r = +0.88; p less than 0.001) and between serum albumin and vitamin A values (r = +0.75; p less than 0.001). A weaker and negative correlation was found between serum bilirubin (r = -0.47; p less than 0.05) and vitamin A values. Patients with primary biliary cirrhosis should not receive regular parenteral or even oral vitamin A supplementation unless dark adaptometry or electrooculography yields an abnormal result.

Breast milk was studied for the presence of bile salts. Cholate and chenodeoxycholate were found in all samples examined. In both colostrum and milk there was a predominance of cholate. Their biological activity remains to be determined.