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Introduction: Safe colonoscopy requires an understanding of sedation techniques. In 1991 the British Society of Gastroenterology (BSG) Endoscopy Committee recommended that cannulation should become standard practice for all endoscopic procedures. As part of the IBNC audit, venous access was assessed with regard to the status of the patient defined by the American Society of Anaesthesiology (ASA) Classification of physical status. 8902 colonoscopies were assessed in 73 units (44 District General, 10 Teaching, 5 Paediatric, 14 Private). Results: 95% of colonoscopies were carried out with intravenous sedation. Midazolam alone - 10.4%, Midazolam with Pethidine - 58.6%, Diazemuls with Pethidine - 9.0%, Midazolam with "other" - 14.9%. 8285/8902 (93.1%) of procedures were carried out with continuous intravenous access in situ throughout the colonoscopy. In 86.8% a plastic cannula was used and in 11.1% a butterfly was utilised. Oxygen was administered in 71% of procedures and a pulsoximeter was used in 93% of cases. `At risk' patients are defined as class 3-5 in the ASA classification (Classes 1-5). There were no Class 5 patients. There were 309/8902 (3.5%) patients in Classes 3 and 4. A plastic cannula or butterfly was used in 257/302 (85.1%) and 35/302 (11.6%) respectively. 7/309 (2.3%) class 3 and 4 patients did not have continuous venous access throughout the procedure, the reasons sited were `patient not considered at risk', and `no sedation given'. No reason was given for 2 patients. Oxygen was administered to 85.4% of `at risk' patients and a pulsoximeter was used in 96.1%. Conclusion: 93% of patients undergoing colonoscopy have intravenous access throughout their procedure and are given intravenous sedation. There are some `at risk' patients undergoing colonoscopy without intravenous access.

(1988) Carcinogenesis 9,321-325 9. Gooderham, N. J., Murray, B. P., Murray, S., Boobis, A. R. & Davies, D. S. ( 1989) Proceedings of the 5th International Conference on Environmental Mutagens, Alan R. Liss Inc., New York, in the press 10. Srebernik, N., Morgan, J. P., Baker, A. J. & Gooderham, N. J. (1 990) Biochem. Soc. Trans. 18,6 10-6 1 1 11. Hurley, J. V., Ryan, V. & Friedman, A. (1966) J. I'athol. Bacteriol. 11, 575-587 12. Fuller, R. W., O'Malley, G., Baker, A. J. & MacDermot, J. (1988) Pulmonary I'harmacol. 1, 101-106 13. Maron, D. M. & Ames, B. N. ( 1 983) Mut. Rex 113, 173-2 15

In patients with primary biliary cirrhosis, the chronic cholestasis, salivary, and lacrimal hyposecretion suggest that the disease is a "dry gland" syndrome. To determine whether or not pancreatic damage occurs in primary biliary cirrhosis and other forms of chronic cholestasis, we have studied pancreatic structure and function in primary biliary cirrhosis, and primary sclerosing cholangitis. In a retrospective study, retrograde pancreatograms were abnormal in 43% of 35 patients with primary biliary cirrhosis and 15% of 20 patients with primary sclerosing cholangitis (p less than 0.02). In a prospective study, serum pancreatic isoamylase was abnormal in 56% of 41 patients with primary biliary cirrhosis and 36% of 22 patients with primary sclerosing cholangitis (NS), indicating pancreatic damage in both diseases. After secretin-pancreozymin stimulation, patients with primary biliary cirrhosis, but not patients with primary sclerosing cholangitis, showed a significant reduction in duodenal juice flow rate (p less than 0.01) and immunoreactive trypsin output (p less than 0.01). The reduced trypsin output in patients with primary biliary cirrhosis indicates pancreatic hyposecretion. In neither patients with primary biliary cirrhosis nor patients with primary sclerosing cholangitis was the immunoreactive trypsin concentration, or tryptic activity in duodenal juice, significantly different from controls. Pancreatic involvement in primary biliary cirrhosis is closely associated with Sjogrens syndrome, and it is likely that the pancreatic hyposecretion is a component of the sicca complex. This association was not obvious in primary sclerosing cholangitis.

Penicillamine has an effect on immune complexes and immunoglobulins both in vivo and in vitro. We therefore studied the effect of penicillamine on immune complexes and immunoglobulins in primary biliary cirrhosis. Twenty-eight patients were randomly allocated into a treatment group receiving 600 to 900 mg of penicillamine, or a control group, and followed for a maximum of 24 months. After 12 and 24 months, serum immune complexes had fallen significantly in treated patients as compared to controls (P less than 0.05, P less than 0.01). Treatment reduced IgA, IgG and IgM concentrations, with IgM being significantly different from controls at six, 12 and 24 months (P less than 0.01). Over 24 months, serum aspartate transaminase levels fell in treated patients but rose in controls (P less than 0.01). Bilirubin concentrations increased at a slower rate in treated patients. Penicillamine may favorably influence the course of primary biliary cirrhosis by its immunologic action in addition to its copper-chelating action.

The vitamin E status of 146 adults with chronic liver disease was assessed by estimating both their serum vitamin E concentration and the ratio of serum vitamin E to serum cholesterol concentration. Low levels of vitamin E occurred most frequently in patients with primary biliary cirrhosis and other forms of chronic cholestatic liver disease. When a serum vitamin E concentration of 12.3 mumol/l (mean-2 SD of a control population) was taken as the lower limit of normal, 44% of patients with primary biliary cirrhosis and 32% with other chronic cholestatic liver disease had a reduced concentration, indicating a biochemical deficiency of vitamin E. If a vitamin E/total cholesterol ratio of 2.35 mumol/mmol was taken as the lower limit of normal, then 64% and 43% of patients with primary biliary cirrhosis and other chronic cholestatic liver disease, respectively, had a biochemical deficiency of vitamin E. Of the patients with chronic cholestasis and a serum bilirubin concentration greater than 100 mumol/l, 91% had a reduced vitamin E/cholesterol ratio. Twelve patients with primary biliary cirrhosis and severe vitamin E deficiency (serum vitamin E less than 5.0 mumol/l and a vitamin E/cholesterol ratio less than 1.0 mumol/mmol) underwent extensive neurological investigation. Five had a mild mixed sensorimotor peripheral neuropathy, which was not, however, typical of the neurological syndrome associated with vitamin E deficiency. In patients with severe biochemical deficiency of vitamin E (less than 5 mumol/l and less than 1 mumol/mmol total cholesterol), administration of large oral doses of vitamin E only increased serum concentrations to within the normal range in one patient; in the others even weekly parenteral administration over a 3-month period did not correct deficiency. In patients with less severe biochemical deficiency, the serum vitamin E concentration and vitamin E/total cholesterol ratio were restored to normal by oral or intramuscular supplements of the vitamin.

Twenty patients with biopsy proved liver disease, and roentgenologic features of hypertrophic osteoarthropathy have been studied, and the literature has been reviewed. The syndrome is a rare association of many chronic liver diseases, including primary biliary cirrhosis, bile duct carcinoma, benign bile duct stricture, chronic active hepatitis, posthepatitic cirrhosis and alcoholic cirrhosis. Patients may be asymptomatic, although bone pain, arthralgia or arthritis may be presenting symptoms. Ninety per cent of the patients are clinically jaundiced at the time of diagnosis, and 95 per cent have digital clubbing. The distal tibia and fibula are the first bones to become involved, although wrist, foot bones, femurs, hand bones and humeri may be affected in order of frequency. There is no correlation between the presence of esophageal varices or surgical portacaval shunts and the extent of the syndrome, neither is there a correlation with the degree of liver function impairment. Serum calcium and phosphate levels are normal, as is urinary hydroxyproline and estrogen excretion. There was no evidence to implicate elevated levels of growth hormone or overdossage of vitamin A. Although the majority of patients tested had mild arterial hypoxemia, increased cardiac output and evidence of right to left shunting, these were also present in disease-matched control subjects without osteoarthropathy. For screening purposes, patients with chronic liver disease and clubbing should have roentgenologic studies of the lower tibias and fibulas, to select those patients suitable for a more extensive skeletal survey.

In the healthy human adult, body iron content is regulated by intestinal iron absorption. However in neonates who are iron replete, iron absorption is inappropriately increased. In this study we have compared the kinetics of iron absorption in the proximal small intestine of the newborn and adult guinea pig in order to gain insight into the cellular mechanisms underlying this difference. Iron uptake was studied in vivo over the concentration range 20–2,000 μM. Total iron uptake could be resolved into saturable and linear components. The kinetic constants for the saturable component in the adult were similar to the neonate. In contrast, the rate of uptake via the linear pathway was 4 times greater in the neonate compared to the adult. It is concluded that the increased absorption of iron by the neonatal guinea pig is due to an enhanced uptake via the linear pathway. In contrast to total iron uptake, we were unable to detect developmental changes in iron transfer into the carcass.

The copper-chelating, immunological, and antifibrotic effects of D-penicillamine indicated that it might be suitable for the treatment of primary biliary cirrhosis (PBC). In a randomised clinical trail, 55 PBC patients received penicillamine (600 mg daily), and 32 received a placebo. Drug reactions developed in 16 patients on penicillamine. All deaths occurred in patients with stage 3 or 4 (late stage) liver histology on entry to the study. 5 (14%) of 37 penicillamine-treated patients and 10 (43%) of 23 placebo patients have died (p less than 0.01). Improvement in survival only became evident after 18 months. Survivors in the penicillamine group demonstrated a significant fall in serum aspartate transaminase, serum immunoglobulins, and liver copper concentrations. On follow-up liver biopsy 12-72 months (median 33) after joining the study, 21% of penicillamine-treated patients had less pronounced inflammation and piecemeal necrosis, whereas there had been no improvement in patients on placebo (p less than 0.02). Penicillamine did not retard the histological evolution of the liver disease from the early prefibrotic stages to the late fibrotic or cirrhotic stages. Both the copper-chelating and immunological effects of penicillamine are probably important in improving survival. The excellent prognosis of patients with PBC in its early histological stages, and the failure of penicillamine to prevent histological progression from early to late stages, suggests that penicillamine treatment should not be given to patients with PBC in the early (stage 1 or 2) histological phase of the disease. Penicillamine treatment is recommended in patients once liver biopsy has demonstrated histological results typical of late stage 3 or 4 PBC.

Primary biliary cirrhosis (PBC) is part of a disease complex characterised by dry eyes, dry mouth, and both biliary and pancreatic hyposecretion: it is a "dry gland" syndrome resulting from damage to ductular epithelium. Additional extraglandular features include scleroderma-like skin lesions, pigmentation, Raynaud phenomenon and severe abnormalities of both humoral and cellular immunity. Identical ductular and extraductal features, including abnormalities of the immune system, are seen in chronic graft-versus-host disease after bone-marrow transplantation. It is suggested that in PBC the ductular lesions and severe disturbance of the immune system including macroglobulinaemia and immune complex formation occur as a result of an immune response to the histocompatibility (HC) complex antigens which are present in high density on ductular epithelial cells of the biliary tree. This response could be caused by altered antigenicity of epithelial cell HC antigens or by failure of the HLA-dependent T cell self-recognition system.

Wilson's disease is an inborn error o: copper metabolism, characterised by raised liver-copper concentrations and low serum levels of copper and caeruloplasmin. The autosomal recessive mode of in heritance strongly suggests that mutation of a single gent causes the impairment of both caeruloplasmin synthesis and biliary copper excretion. The normal infant is born with the biochemical features of Wilson's disease (very high livercopper levels and low serum copper and caeruloplasmin). In duction of normal copper metabolism after birth results in a fall in liver-copper concentrations and rise in serum caeruloplasmin. The repression of normal copper metabolism in the fetus and its induction after birth is probably regulated by a controller gene. It is suggested that mutation of a controller rather than a structural gene underlies the pathogenesis of Wilson's disease and that the disease results from failure tc switch from the positive copper balance of the fetus to the normal copper balance of the child.

Rats fedon a copper-enricheddietdevelop increasedlivercopper concentrations, which correlatewell with hair copper content.Ithas been suggested that in man, hair copper analysismay be a usefulnoninvasive method forpredictinglivercopper concentrations.We have testedthishypothesis in 11 patientswith primary bihiarycirrhosis, a disease complicated by the accumulation of copper in the liver. Ten patients had increased liver copper concentrations, but only one had increased hair copper. In primary biliary cirrhosis, hair copper does not reflect liver copper content and is of no value as a biopsy material for copper analysis. Am. J. Clin. NuIr. 33: 965-967, 1980.

The copper profiles of neonatal mammals differ from those of the adult; in man they are similar to those found in people with Wilson’s disease (WD). WD patients handle an intravenous bolus of radioactive copper in a characteristic manner which aids diagnosis. In view of the similarity between neonatal mammals and WD patients, we have studied the fate of an intravenous bolus of 64Cu injected into neonatal and adult pigs. In adult pigs, plasma 64Cu activity fell for 10 h and then slowly increased over the next 14 h as newly synthesised caeruloplasmin was secreted. In the neonate a secondary rise in 64Cu activity was not observed. Gel filtration of the soluble supernatant revealed significant differences in the association of 64Cu with hepatic copper proteins. In adults 64Cu associated predominantly with superoxide dismutase whilst in the neonate the 64Cu associated with metallothionein and a protein of high molecular weight. This study indicates that 64Cu export from the neonatal pig liver is in many ways similar to that found in WD. Additionally, there are similarities in the profile of hepatic 64Cu-binding proteins.

The copper profile in Wilson's disease resembles that of human and guinea pig neonates. Microvesicular steatosis is characteristic of early histological damage in Wilson's disease. The aim of this study was to relate the histological, histochemical and ultrastructural changes seen in developing guinea pig liver to the developmental pattern of liver copper in these animals. Copper-stressed and control guinea pigs were studied. Liver biopsies were stained with haematoxylin and eosin, rhodanine (for copper), orcein (for copper-associated protein) and oil Red 0 (for fat). Selected specimens were examined by electron microscopy. Liver and serum copper levels and copper oxidase activity were also determined. Fetal liver copper increased during the last trimester of pregnancy, reaching five times the adult level in the perinatal period and falling rapidly in the 4 days after birth. Marked steatosis developed in both control and copper-stressed guinea pig liver. The fat score correlated strongly with liver copper concentration (r: 0.60; p less than 0.001). Orcein and rhodanine staining correlated with liver copper concentration (r: 0.52 and r: 0.40 respectively, p less than 0.01). Marked prenatal hepatic steatosis and its postnatal clearance correlates with changes in liver copper concentration. This experimental model provides an opportunity to study the pathogenesis of hepatic steatosis and the relationship between copper retention and steatosis.

The normal human neonate has a copper profile indistinguishable from Wilson's disease, and we have previously postulated that this disease is caused by genetic failure to switch from the fetal to adult mode of copper metabolism. This study validates the developing guinea pig as a suitable animal in which to study copper ontogeny. At birth, liver copper concentrations are 7 times higher than in adults and serum copper and ceruloplasmin are 27 and 21% of adult values, respectively. A 53% fall in liver copper occurs in the 4 days after birth. This is associated with a marked increase in bile copper output, which does not parallel increasing bile flow. Liver copper falls, and serum copper and ceruloplasmin increase to near adult levels in the 30 days after birth. Until the sixtieth day of gestation, liver copper was significantly increased in copper-stressed littermates, although paradoxically at birth, concentrations were significantly lower. In copper-stressed fetal animals, bile copper output increased markedly before birth. Metallothionein was the dominant copper-binding protein in the fetal liver but a minor component in the adult. Superoxide dismutase activity only developed after birth. We conclude that the postnatal switch from the fetal to adult mode of copper metabolism involves activation of biliary excretion and ceruloplasmin export as well as changes in the association of copper with hepatic copper proteins. Similarities between the fetus and Wilson's disease suggest that this disease is caused by failure of this postnatal adaptation process.

Primary biliary cirrhosis is a disease with progressive granulomatous destruction of small intrahepatic bile ducts. It is of unknown aetiology. The disease is associated with a profound immunological disturbance and this has been related to bile duct destruction (Table 8.1). The final event seems to be an attack by cytotoxic lymphocytes on biliary epithelium. The antigen might be the individual’s own human leukocyte antigens (HLA-ABC glycoproteins) which are present in high concentration on biliary epithelium. It is unclear why the reaction should be to normal rather than foreign proteins. Perhaps the patient’s own lymphoid system is at fault so that self and self antigens are not recognized. This could be due to failure of schooling by cytotoxic T-cells in the thymus. These cells are regulated by suppressor cells which have been shown to be diminished both in number and function in primary biliary cirrhosis1. Alternatively, and perhaps more likely, the HLA proteins may have become foreign due to an extrinsic environmental factor. The identification of such a factor is an ongoing challenge to all those investigating primary biliary cirrhosis.

Triethylene tetramine dihydrochloride (trien) is a copper chelating agent used as the alternative drug of choice in the treatment of Wilson's disease. Because of its apparent safety, we have used the drug in 4 patients with primary biliary cirrhosis in whom penicillamine had to be withdrawn because of serious side effects. Trien is an effective cupruretic drug in primary biliary cirrhosis, but its use is limited by the occurrence of side effects that occurred in all 4 patients. Three patients developed gastrointestinal side effects, and one of these patients developed a skin rash. The 4th patient developed acute rhabdomyolysis within 48 hr of receiving the first dose of the drug. One patient tolerated therapy for 20 wk, and, although her liver copper concentration did not show a marked fall, aspartate transaminase levels fell, and her IgM concentration fell to normal. Trien is an unsuitable copper chelating drug in primary biliary cirrhosis, although it remains the alternative drug of choice in Wilson's disease.

There is a significant decrease in the ratio of inducer (helper) to suppressor T lymphocytes in the peripheral blood of patients with primary biliary cirrhosis (PBC). These changes are not seen in other forms of cholestatic liver disease, but are similar to those described in chronic graft-versus-host disease. Cyclosporin A treatment increased the proportion of suppressor T lymphocytes and improved liver function in 6 patients with PBC. This indicates that cyclosporin A is an immunoregulatory drug. Unfortunately nephrotoxicity precluded long-term use.

Control pregnant guinea-pigs drinking normal water and their litters were compared to a matched group drinking 0.185% solution of CuSO4.5H2O. Animals were studied between 45 days gestation and 30 days after birth. Dams fed CuSO4 had similar liver copper concentrations (LCC) and serum copper, to time matched controls. At 45, 54 and 60 days gestation LCC values were significantly higher in copper fed dam litters than those of controls. LCC peaked at 60 days in copper fed litters compared to a peak at birth in controls. Biliary copper excretion in copper fed litters was significantly higher than controls at birth, before birth and 4 days after birth. These results are discussed in relation to the hypothesis that Wilson's disease is caused by failure to switch from fetal to an adult mode of copper metabolism.

The copper profiles of the neonatal mammals including man are indistinguishable from Wilson’s disease ie. high liver copper, low plasma copper and caeruloplasmin. Soon after birth there is a switch to the adult mode of copper metabolism, liver copper falls and both plasma copper and caeruloplasmin concentrations increase. We have previously postulated that Wilson’s disease is caused by genetic failure to switch from the fetal to adult mode of copper metabolism1. Wilson’s disease patients handle radioactive copper in a characteristic manner which aids diagnosis2. To test the hypothesis that WD is caused by perpetuation of the fetal mode of copper metabolism into childhood, we have studied copper profiles and 64Cu handling in neonatal and adult pigs.

The pattern of cortical bone modelling in healthy and diseased populations can be derived from simple measurements taken from radiographs of tubular bones. To determine the pattern of bone modelling in women with chronic cholestatic and parenchymal liver diseases, these parameters have been measured in 83 women with primary biliary cirrhosis (PBC), 34 with steroid-treated chronic active hepatitis (CAH) and 27 with parenchymal liver disease (PLD) not treated with corticosteroids. Bone modelling profiles have been compared in these groups with the expected pattern in healthy females. Abnormal bone modelling occurs in all three groups. In PBC, cortical thinning is progressive from the fourth decade onwards. In steroid-treated CAH, an initial increase in cortical thickness is observed in the third and fourth decades, after which cortical thinning occurs. In the PLD group, progressive loss of bone cortex is present from the fourth decade onwards. In all forms of liver disease, cortical thinning results from widening of the medullary cavity rather than resorption of the cortical surface.

Women with primary biliary cirrhosis malabsorb calcium, phosphate and vitamin D, and develop accelerated cortical bone thinning. We have assessed the value of parenteral vitamin D, oral hydroxyapatite (HA), and calcium gluconate (CG) in the treatment of cortical bone thinning in primary biliary cirrhosis. Sixty-four postmenopausal women with primary biliary cirrhosis were assigned randomly into three groups: one group receiving no mineral supplements (control), one group receiving HA, and one group receiving CG. All patients received parenteral vitamin D2 (100,000 IU monthly). Eleven patients withdrew from the study and 10 withdrew due to poor compliance (six HA, four CG). Over a 14-month follow-up period, none of the groups showed a significant change in serum calcium or inorganic phosphate levels. Pre- and posttreatment hand radiographs were used to assess changes in metacarpal cortical thickness using the technique of caliper radiogrammetry. Cortical bone loss occurred in the control group (p less than 0.01). The HA group showed a significant gain in cortical bone thickness (p less than 0.01), while no significant change occurred in the CG group. This study indicated that vitamin D2 does not halt metacarpal cortical bone thinning in primary biliary cirrhosis. The addition of CG prevents bone thinning, and HA promotes positive cortical bone balance.

We are conducting a multicentre, mixed methods study to examine the attitudes of health professionals to e-health in order to identify strategies to support increased uptake and utilization of e-health services. The first part of the work is a systematic literature review. After searching five electronic databases, a total of 66 review papers were identified which concerned barriers and facilitators to the implementation of e-health. Examination of the main themes from these reviews identified three major types of barriers/facilitators: (1) technology design factors, (2) health professional interactions, and (3) organizational factors. The utilization of e-health technologies by health-care professionals is complex, as demonstrated by the preliminary findings of the literature review.

A propos de 3 observations. L'accident cerebrovasculaire doit toujours etre envisage chez un malade atteint de cirrhose ou d'autres affections hepatiques presentant differents troubles evoquant l'encephalopathie

In ninety families with at least one proven case of Wilson's disease, seen over 32 years, all close relatives were examined and “presymptomatic” disease was diagnosed in 30.11 had one or more abnormal physical signs when examined and 7 of these had Kayser Fleischer rings. In a further 10 patients the abnormalities of copper metabolism were so pronounced as to leave no doubt as to the diagnosis. 6 patients were not seen until they had been on treatment for 2 years or more; in some, much of the evidence on which the diagnosis was based is not available. In 3 patients there were only minor histological abnormalities in the liver and no increase in urinary copper but other indices of copper metabolism pointed to a diagnosis of Wilson's disease. 2 patients had transient neurological signs after starting treatment; otherwise, all but one (who died in an accident) have remained well for up to 26 years.

The syndrome of primary biliary cirrhosis and limited scleroderma (the CREST syndrome) is described in 22 patients. The syndrome is expanded to include a serologic marker—the anticentromere antibody—and keratoconjunctivitis sicca. The acronym “PACK” (primary biliary cirrhosis, anticentromere antibody, CREST syndrome, and keratoconjunctivitis sicca) with “syndrome” is suggested to facilitate recall of the various components of this entity.