Autoantibodies associated with primary biliary cholangitis are common among patients with systemic lupus erythematosus even in the absence of elevated liver enzymes.

Knowledge of concomitant autoimmune liver diseases (AILD) is more detailed in primary Sjögren's syndrome (pSS) compared to systemic lupus erythematosus (SLE). Herein, the prevalence of autoantibodies associated with autoimmune hepatitis (AIH) and primary biliary cholangitis (PBC) was investigated in stored sera from patients with SLE (n = 280) and pSS (n = 114). Antibodies against mitochondria (AMA), liver-kidney microsomal (LKM) antigen, smooth muscle (SMA) and anti-nuclear antibodies (ANA) were analysed with immunofluorescence microscopy. In addition, AILD-associated autoantibodies were tested with immunoblot. Prior to sampling, eight SLE (2·9%) and three pSS (2·6%) cases were diagnosed with AILD. Among SLE-cases without known AILD (n = 272), 26 (9·6%) had PBC-associated autoantibodies, 15 (5·5%) AIH-associated autoantibodies (excluding ANA) and one serological overlap. Most subjects with PBC-associated autoantibodies had liver enzymes within reference limits (22 of 27, 81%) or mild laboratory cholestasis (two of 27, 7·4%), while one fulfilled the diagnostic PBC-criteria. AMA-M2 detected by immunoblot was the most common PBC-associated autoantibody in SLE (20 of 272, 7·4%). The prevalence of SMA (4·4%) was comparable with a healthy reference population, but associated with elevated liver enzymes in four of 12 (25%), none meeting AIH-criteria. The patient with combined AIH/PBC-serology had liver enzymes within reference limits. Among pSS cases without known AILD (n = 111), nine (8·1%) had PBC-associated, 12 (10·8%) AIH-associated autoantibodies and two overlapped. PBC-associated autoantibodies were found as frequently in SLE as in pSS but were, with few exceptions, not associated with laboratory signs of liver disease. Overall, AILD-associated autoantibodies were predominantly detected by immunoblot and no significant difference in liver enzymes was found between AILD autoantibody-negative and -positive patients.

Resistin is associated with breach of tolerance and anti-nuclear antibodies in patients with hepatobiliary inflammation.

Resistin is a cysteine-rich protein, which is abundantly expressed at the site of inflammation, and acts as a regulator of the NF-kB-dependent cytokine cascade. The aim of this study was to evaluate resistin levels in relation to inflammatory mediators, disease phenotype and autoantibody status in a spectrum of pathological conditions of the gastrointestinal tract. Resistin levels were measured with an ELISA in sera originated from 227 patients and 40 healthy controls (HC). Fifty patients diagnosed with non-alcoholic fatty liver disease (NAFLD), 53 ulcerative colitis (UC), 51 Crohn's disease (CD), 46 autoimmune hepatitis (AIH) and 27 primary sclerosing cholangitis (PSC) were included. The sera were analysed with respect to biochemical parameters of systemic inflammation and liver function and to the presence of antibodies to nuclear antigens (ANA), mitochondria (AMA) and smooth muscle (SMA). Compared with HC, resistin levels were raised in AIH (P = 0.017) and PSC (P = 0.03); compared with NAFLD, levels were elevated in CD (P = 0.041), AIH (P < 0.001) and PSC (P < 0.001). Patients with elevated levels of resistin were more often treated with corticosteroids, but no difference was found between active disease and clinical remission. Resistin levels were significantly higher in ANA-positive individuals compared with ANA-negative (P = 0.025). Resistin levels were directly correlated with IL-6 (r = 0.30, P = 0.02) and IL-8 (r = 0.51, P < 0.001). Elevated levels of resistin were prominent in patients with hepatobiliary inflammation and were associated with breach of self-tolerance, i.e. ANA positivity. Thus, we propose that resistin may be an important marker of disease severity in autoantibody-mediated gastrointestinal inflammatory diseases.

The effects of capsaicin on gastrin secretion in isolated human antral glands: before and after ingestion of red chilli.

BACKGROUND: Capsaicin is known to have regulatory effects on gastrointestinal functions via the vanilloid receptor (VR1). We reported previously that endocrine-like cells in the human antrum express VR1. AIM: To identify VR1-expressing endocrine-like cells in human antral glands and to examine whether stimulation with capsaicin causes release of gastrin, somatostatin, and serotonin. Further, to investigate the effects of a chilli-rich diet. METHODS: Gastroscopic biopsies were received from 11 volunteers. Seven of the 11 subjects agreed to donor gastric biopsies a second time after a 3-week chilli-rich diet containing 1.4-4.2 mg capsaicin/day. VR1-immunoreactive cells were identified by double-staining immunohistochemistry against gastrin, somatostatin, and serotonin. For the stimulation studies, we used an in vitro method where antral glands in suspension were stimulated with 0.01 mM capsaicin and physiological buffer was added to the control vials. The concentrations of secreted hormones were detected and calculated with radioimmunoassay (RIA). Results The light microscopic examination revealed that VR1 was localized in gastrin cells. The secretory studies showed an increase in release of gastrin and somatostatin compared to the control vials (P = 0.003; P = 0.013). Capsaicin-stimulation caused a consistent raise of the gastrin concentrations in the gland preparations from all subjects. A chilli-rich diet had an inhibitory effect on gastrin release upon stimulation compared to the results that were obtained before the start of the diet. CONCLUSION: This study shows that capsaicin stimulates gastrin secretion from isolated human antral glands, and that a chilli-rich diet decreases this secretion.

Fast-food-based hyper-alimentation can induce rapid and profound elevation of serum alanine aminotransferase in healthy subjects.

OBJECTIVE: To study the effect of fast-food-based hyper-alimentation on liver enzymes and hepatic triglyceride content (HTGC). DESIGN: Prospective interventional study with parallel control group. SETTING: University Hospital of Linköping, Sweden. PARTICIPANTS: 12 healthy men and six healthy women with a mean (SD) age of 26 (6.6) years and a matched control group. INTERVENTION: Subjects in the intervention group aimed for a body weight increase of 5-15% by eating at least two fast-food-based meals a day with the goal to double the regular caloric intake in combination with adoption of a sedentary lifestyle for 4 weeks. MAIN OUTCOME MEASURES: Weekly changes of serum aminotransferases and HTGC measured by proton nuclear magnetic resonance spectroscopy at baseline and after the intervention. RESULTS: Subjects in the intervention group increased from 67.6 (9.1) kg to 74.0 (11) kg in weight (p<0.001). Serum ALT increased from 22.1 (11.4) U/l at study start to an individual mean maximum level of 97 (103) U/l (range 19.4-447 U/l). Eleven of the 18 subjects persistently showed ALT above reference limits (women >19 U/l, men >30 U/l) during the intervention. Sugar (mono- and disaccharides) intake during week 3 correlated with the maximal ALT/baseline ALT ratio (r = 0.62, p = 0.006). HTGC increased from 1.1 (1.9)% to 2.8 (4.8)%, although this was not related to the increase in ALT levels. ALT levels were unchanged in controls. CONCLUSION: Hyper-alimentation per se can induce profound ALT elevations in less than 4 weeks. Our study clearly shows that in the evaluation of subjects with elevated ALT the medical history should include not only questions about alcohol intake but also explore whether recent excessive food intake has occurred.

Histological progression of non-alcoholic fatty liver disease: a critical reassessment based on liver sampling variability.

BACKGROUND: In non-alcoholic fatty liver disease, histological lesions display a significant sampling variability that is ignored when interpreting histological progression during natural history or therapeutic interventions. AIM: To provide a method taking into account sampling variability when interpreting crude histological data, and to investigate how this alters the conclusions of available studies. METHODS: Natural history studies detailing histological progression and therapeutic trials were compared with the results of a previously published sampling variability study. RESULTS: Natural history studies showed an improvement in steatosis, which was significantly higher than expected from sampling variability (47% vs. 8%, P < 0.0001). In contrast, no study showed a change in activity grade or ballooning higher than that of sampling variability. There was only a marginal effect on fibrosis with no convincing demonstration of a worsening of fibrosis, a conclusion contrary to what individual studies have claimed. Some insulin sensitizing drugs and anti-obesity surgery significantly improved steatosis, while most did not significantly impact on fibrosis or activity. CONCLUSIONS: Sampling variability of liver biopsy is an overlooked confounding factor that should be considered systematically when interpreting histological progression in patients with non-alcoholic fatty liver disease.

Treatment of anaemia in inflammatory bowel disease with iron sucrose.

BACKGROUND: Inflammatory bowel disease (IBD)-associated anaemia usually responds to intravenous iron. If not, additive treatment with erythropoietin has been proposed. The objective of the present retrospective study was to evaluate the effectiveness of treatment with iron sucrose alone. METHODS: Sixty-one patients with IBD and anaemia (average haemoglobin 97 g/L) were treated with iron sucrose (iron dose 1.4 +/- 0.5 g). The indications for iron sucrose were poor response and/or intolerance to oral iron. Treatment response was defined as an increase in haemoglobin of > or = 20 g/L or to normal haemoglobin levels (> or = 120 g/L). Two independent investigators retrospectively assessed laboratory variables, clinical findings, and concomitant medication. RESULTS: Two patients were transferred to other hospitals after treatment and therefore could not be evaluated. Fifty-four of the remaining 59 patients (91%) responded within 12 weeks. Sixty percent of the patients had responded within 8 weeks. Five patients had no or only a partial response to iron sucrose of which three had prolonged gastrointestinal blood losses. Eight patients with normal or elevated levels of ferritin could be considered to have anaemia of chronic disease, and all of them responded to iron sucrose. During a follow-up period of 117 +/- 85 (4-291) (mean +/- s (standard deviation) (range)) weeks 19 patients (32%) needed at least one second course of iron sucrose because of recurrent disease. CONCLUSIONS: Anaemia associated with IBD can be successfully treated with intravenously administered iron sucrose, provided that bowel inflammation is treated adequately and enough iron is given. Treatment with iron sucrose is safe. Follow-up of haemoglobin and iron parameters to avoid further iron deficiency anaemia is recommended.

Morphological support for paracrine inhibition of gastric acid secretion by nitric oxide in humans.

BACKGROUND: Functional studies have shown that nitric oxide (NO) inhibits gastric acid secretion in a variety of species, including man. We have performed a morphological study with the intention of localizing the endothelial NO synthase (eNOS) in the human gastric mucosa. METHODS: Fifteen healthy subjects voluntarily participated in the study, and mucosal biopsies were obtained from the cardia, corpus and antrum. The presence and localization of eNOS were studied using immunohistochemical techniques. RESULTS: eNOS-immunoreactivity (eNOS-IR) is found in surface mucous cells of cardia, corpus and antrum. Unique to the oxyntic mucosa is the presence of eNOS-IR in 'endocrine-like' cells, found in close contact with parietal cells. CONCLUSIONS: eNOS-IR cells in close apposition to parietal cells provide morphological support for paracrine inhibition of gastric acid secretion by NO.

Influence of age, sex, and Helicobacter pylori infection before and after eradication on gastric alcohol dehydrogenase activity.

BACKGROUND: Gastric alcohol dehydrogenase may contribute to the metabolism of orally ingested ethanol and decrease the bioavailability of the drug. The aims of this study were to assess the impact of Helicobacter pylori infection and its eradication on gastric alcohol dehydrogenase activity and to relate the findings to gastric histology. Furthermore, the role of age- and sex-related differences in gastric alcohol dehydrogenase activity were studied. METHODS: A total of 76 subjects (39 women and 37 men) underwent upper gastrointestinal endoscopy, and biopsies were obtained from the corpus and antrum. The specimens were used for determining gastric alcohol dehydrogenase activity, histological examination, and urease testing. Subjects with H. pylori infection (n = 36) received medication to eradicate the infection, and repeat biopsies were taken 2 and 12 months later. RESULTS: No significant difference in gastric alcohol dehydrogenase activity was found between men and women (p > 0.05). Gastric alcohol dehydrogenase activity did not differ significantly between the subjects older than 50 years (n = 39) and those 50 years or younger (n = 37). In subjects with H. pylori infection, gastric alcohol dehydrogenase activity was significantly reduced in the antrum (p < 0.05). After eradication of H. pylori, alcohol dehydrogenase activity in the antrum increased significantly within 2 months (p < 0.01). Antral biopsies with the most pronounced inflammation and histological changes had significantly decreased alcohol dehydrogenase activity (p < 0.05). In contrast, no significant differences were found in corpus. CONCLUSIONS: H. pylori infection is associated with decreased antral alcohol dehydrogenase activity, which seems to be related to the severity of the inflammatory changes in the mucosa. Eradication of H. pylori normalizes antral alcohol dehydrogenase activity within 2 months.

Impact of gastric emptying on the pharmacokinetics of ethanol as influenced by cisapride.

AIMS: To examine the influence of cisapride on the pharmacokinetics of ethanol and the impact of gastric emptying monitored by the paracetamol absorption test. METHODS: Ten healthy male volunteers took part in a cross-over design experiment. They drank a moderate dose of ethanol 0.30 g kg-1 body weight exactly 1 h after eating breakfast either without any prior drug treatment or after taking cisapride (10 mg three times daily) for 4 consecutive days. In a separate study, the same dose of ethanol was ingested on an empty stomach (overnight fast). Paracetamol (1.5 g) was administered before consumption of ethanol to monitor gastric emptying. Venous blood was obtained at 5-10 min intervals for determination of ethanol by headspace gas chromatography and paracetamol was analysed in serum by high performance liquid chromatography (h.p.l.c.). Results The maximum blood-ethanol concentration (Cmax ) increased from 3.8+/-1.7 to 5.6+/-2.3 mmol l-1 (+/-s.d.) after treatment with cisapride (95% confidence interval CI on mean difference 0.28-3.28 mmol l-1 ). The area under the blood-ethanol curve (AUC) increased from 6.3+/-3.5 to 7.9+/-2.6 mmol l-1 h after cisapride (95% CI -0. 74-3.9 mmol l-1 h). The mean blood ethanol curves in the cisapride and no-drug sessions converged at approximately 2 h after the start of drinking. Both Cmax and AUC were highest when the ethanol was ingested on an empty stomach (Cmax 9.5+/-1.7 mmol l-1 and AUC 14. 6+/-1.9 mmol l-1 h), compared with drinking 1 h after a meal and regardless of pretreatment with cisapride. CONCLUSIONS: A small but statistically significant increase in Cmax occurred after treatment with cisapride owing to faster gastric emptying rate as shown by the paracetamol absorption test. However, the rate of absorption of ethanol, as reflected in Cmax and AUC, was greatest after drinking the alcohol on an empty stomach. The cisapride-ethanol interaction probably lacks any clinical or forensic significance.

Reliability of breath-alcohol analysis in individuals with gastroesophageal reflux disease.

Gastroesophageal reflux disease (GERD) is widespread in the population among all age groups and in both sexes. The reliability of breath alcohol analysis in subjects suffering from GERD is unknown. We investigated the relationship between breath-alcohol concentration (BrAC) and blood-alcohol concentration (BAC) in 5 male and 5 female subjects all suffering from severe gastroesophageal reflux disease and scheduled for antireflux surgery. Each subject served in two experiments in random order about 1-2 weeks apart. Both times they drank the same dose of ethanol (approximately 0.3 g/kg) as either beer, white wine, or vodka mixed with orange juice before venous blood and end-expired breath samples were obtained at 5-10 min intervals for 4 h. An attempt was made to provoke gastroesophageal reflux in one of the drinking experiments by applying an abdominal compression belt. Blood-ethanol concentration was determined by headspace gas chromatography and breath-ethanol was measured with an electrochemical instrument (Alcolmeter SD-400) or a quantitative infrared analyzer (Data-Master). During the absorption of alcohol, which occurred during the first 90 min after the start of drinking, BrAC (mg/210 L) tended to be the same or higher than venous BAC (mg/dL). In the post-peak phase, the BAC always exceeded BrAC. Four of the 10 subjects definitely experienced gastric reflux during the study although this did not result in widely deviant BrAC readings compared with BAC when sampling occurred at 5-min intervals. We conclude that the risk of alcohol erupting from the stomach into the mouth owing to gastric reflux and falsely increasing the result of an evidential breath-alcohol test is highly improbable.

Low-dose aspirin decreases blood alcohol concentrations by delaying gastric emptying.

OBJECTIVE: To determine if treatment with low-dose aspirin (ASA) influences the bioavailability of orally administered alcohol and to assess whether this is caused by altered gastric emptying as measured by the paracetamol absorption test. METHODS: In a single-center controlled crossover trial, ten healthy male medical students, aged 20-27 years, participated in two experiments in random order. Both times they took paracetamol (1.5 g together with a standardized breakfast) and drank ethanol (0.3 g/kg) 1 h after eating breakfast. On one drinking occasion, no previous medication was given. The other alcohol session was performed after the subjects had taken 75 mg ASA once daily for 7 days. On both occasions, venous blood samples were obtained at exactly timed intervals for a period of 3.5 h. RESULTS: The blood-ethanol profiles showed large interindividual variations for both experiments. After treatment with ASA, the maximum blood-ethanol concentration was distinctly lower in seven subjects, almost unchanged in two subjects and increased in one subject. Overall, a statistically significant decrease in the peak blood-ethanol concentration was observed. The time required to reach peak blood-ethanol levels was somewhat longer after treatment with ASA. Although the areas under the concentration-time profiles were smaller after ASA treatment, these differences were not statistically significant. The concentrations of paracetamol in plasma were lower when ethanol was ingested after treatment with ASA and the areas under the concentration-time curves (0-170 min) were smaller. CONCLUSIONS: Intake of low-dose ASA (75 mg daily) tends to delay the absorption of a moderate dose of ethanol, which results in lower peak blood-ethanol concentrations and smaller areas under the concentration-time curves. The underlying mechanism seems to be delayed gastric emptying as indicated by the paracetamol absorption test.

Effect of high-fat, high-protein, and high-carbohydrate meals on the pharmacokinetics of a small dose of ethanol.

AIMS: To investigate whether the relative amounts of fat, carbohydrate (CHO), or protein in a meal influence the pharmacokinetics of a small dose of ethanol. METHODS: Nine healthy men received ethanol (0.30 g kg-1 body weight) on five occasions in a randomized cross-over fashion. On three occasions the dose of ethanol was consumed within 15 min of eating a standardized breakfast of similar volume and calorific value but containing different amounts of fat, CHO, and protein. On two other occasions the same dose of ethanol was ingested on an empty stomach (overnight fast) or administered by intravenous (i.v.) infusion over 30 min. RESULTS: The blood-ethanol profiles showed large inter and intraindividual variations, especially when ethanol was ingested after eating food. The peak blood-alcohol concentrations (BAC) were 16.6 +/- 4.0, 17.7 +/- 7.1, and 13.3 +/- 4.0 mg dl-1 (mean +/- s.d.) after fat, CHO, and protein-rich meals and 30.8 +/- 4.3 and 54.3 +/- 6.4 mg dl-1 after fasting and i.v. infusion, respectively. The corresponding areas under the concentration-time profiles (AUC) were 1767 +/ -549, 1619 +/- 760 1270 +/- 406 mg dl-1 min after fat, CHO, and protein-rich meals compared with 3210 +/- 527 and 4786 +/- 446 mg dl-1 min after fasting and i.v. infusion, respectively. The time required to eliminate ethanol from the blood was shortened by 1-2 h in the fed-state. CONCLUSIONS: Drinking ethanol after eating a meal, regardless of the nutritional composition, decreases the systemic availability of ethanol. Because gastric emptying is slow and more prolonged with food in the stomach, the delivery of ethanol to the duodenum and the liver will be highly variable as will the hepatic clearance of ethanol. Provided that portal venous BAC remains fairly low and ethanol metabolizing enzymes are not fully saturated then part of the dose of ethanol can be cleared by hepatic first-pass metabolism (FPM), as one consequence of Michaelis-Menten elimination kinetics.

Immunocytochemical evidence for vesicular storage of glutamate in cat spinocervical and cervicothalamic tract terminals.

The densities of synaptic vesicles and gold particles, signaling fixed glutamate, were examined in spinocervical and cervicothalamic tract terminals. Statistically significant positive correlations between these parameters were detected in both terminal populations, whereas presumed inhibitory profiles displayed insignificant or negative correlations. These findings indicate a vesicular storage of glutamate in spinocervical and cervicothalamic tract terminals, and thus provide further evidence for glutamate as a neurotransmitter in the spinocervicothalamic pathway.

Compartmentation of glutamate and glutamine in the lateral cervical nucleus: further evidence for glutamate as a spinocervical tract neurotransmitter.

Previous observations indicate that spinocervical tract terminals contain relatively high levels of glutamate. To examine whether these high glutamate levels are likely to represent a neurotransmitter pool or an elevated metabolic pool, the distributions of glutamate- and glutamine-like immunoreactivities were examined in adjacent immunogold-labeled sections of the lateral cervical nucleus. Spinocervical tract terminals were identified by anterograde transport of horseradish peroxidase and wheat germ agglutinin-horseradish peroxidase conjugate from the spinal cord. Spinocervical tract terminals were found to contain significantly higher levels of glutamate-like immunoreactivity than other examined tissue compartments (large neuronal cell bodies, terminals with pleomorphic vesicles, astrocytes, and average tissue level). In contrast, the highest levels of glutamine-like immunoreactivity were detected in astrocytes. The different analyzed tissue elements formed three groups with respect to glutamate:glutamine ratios: one high ratio group including spinocervical tract terminals, a second group with intermediate ratios consisting of neuronal cell bodies and terminals containing pleomorphic synaptic vesicles, and a third low ratio group including astrocytes. Our findings indicate the presence of a compartmentation of glutamate and glutamine in the lateral cervical nucleus, similar to that postulated in biochemical studies of the central nervous system. The results also show that spinocervical tract terminals have high glutamate: glutamine ratios, similar to those previously observed in putative glutamatergic terminals in the cerebellar cortex. Thus, spinocervical tract terminals display biochemical characteristics that would be expected of glutamatergic terminals and the present findings therefore provide further evidence for glutamate as a spinocervical tract neurotransmitter.

Technical and clinical aspects of capnography in neonates.

This article reviews the current literature on the uses of capnometry and capnography as applied to neonates. The first part addresses the technical aspects and principles of the measurements, including definitions. The features of available carbon dioxide analysers are discussed and factors known to influence their accuracy are highlighted. In the second part of this paper, in vivo studies in neonates are reviewed, with particular emphasis on understanding why the accuracy of end-tidal CO2 measurements differs among studies. This is attributable to various factors: aspiration flow rate, the sampling site (whether distal or proximal) and the type of capnometer. The critical limitation of their overall accuracy in the presence of lung disease is discussed. Potential applications are considered, as are the current limitations of transcutaneous monitoring. We conclude that capnometry with capnography is a potentially useful tool to arterial CO2 tension (PaCO2) monitor infants with normal lungs.