Hepatic encephalopathy after transjugular intrahepatic portosystemic shunt insertion: a decade of experience.

BACKGROUND: Since its introduction, transjugular intrahepatic portosystemic shunt (TIPS) has been extensively used for treatment of portal hypertension. We report a decade of experience with particular emphasis on characterizing post-TIPS hepatic encephalopathy (HE). AIM: To determine the frequency of clinically evident or minimal HE post-TIPS, identify predisposing factors and determine the impact of minimal HE on quality of life. DESIGN: Prospective data collection and retrospective case notes analysis. METHODS: Of 197 patients referred for TIPS insertion, 136 patients who survived the procedure by more than 4 weeks were available for assessment. Data collected at TIPS insertion was supplemented by case note analysis. Psychometric testing was performed and health profile questionnaires administered on patients still attending. RESULTS: Most patients had alcoholic liver disease (62.4%) and bleeding varices unresponsive to endoscopic therapy (86%). Clinically evident post-TIPS HE developed in 34.5% of patients, was of similar frequency in the groups treated with polytetrafluoroethylene covered and uncovered stents, and the only significant predictor was pre-TIPS HE. Post-TIPS HE necessitating liver transplant or contributing to death occurred in only 14 (10.3%) patients. Minimal encephalopathy (abnormal psychometry) was present in 49% of patients at 26 (3-123) months after TIPS but this frequency was similar in a cohort of cirrhotics being assessed for liver transplant. However, patients with abnormal psychometry had significantly lower quality of life scores than those with normal psychometry. CONCLUSION: Although, HE is relatively common after TIPS insertion, with careful selection of patients it is usually short-lived and easily managed. Minimal HE is no more prevalent than expected in a cirrhotic population without TIPS.

Importance of Helicobacter pylori eradcation for maintenance of remission of drug associated peptic ulcer disease.

BACKGROUND: The role of Helicobacter pylori (H. pylori) eradication in non-steroidal anti inflammatory drug (NSAID) users with peptic ulcer disease is controversial especially in countries with a high prevalence of the infection. Furthermore the value of low dose omeprazole for maintenance of remission is not yet known. PATIENTS AND METHODS: 138 symptomatic out-patients receiving continuous COX 1 NSAID therapy, were treated with omeprazole 40 mg/day upon endoscopic confirmation of gastro-duodenal ulceration or erosions while those infected with H. pylori received in addition clarithromycin 500 mg and amoxycillin 1000 mg twice daily during the first week of treatment. After endoscopic confirmation of healing at the end of week 5, the patients were randomized to receive omeprazole 10 mg (n=50) or 20 mg once daily (n=66) and endoscopy repeated after 20 weeks. RESULTS: The overall healing rate (per protocol) at five weeks (116/128) was 90.6% while in 85.5% (65/76) eradication was successful. The healing rate for the H. pylori eradicated patients (58/65) was 89.2%. For those who failed eradication (8/11) it was 72.7% (NS), while for patients not infected with H. pylori at entry to the study (50/52) it was 96.2% (NS). An intention to treat analysis showed that after 20 weeks of omeprazole prophylaxis with the 10mg dose 86% (43/50) had maintained healing while for the 20mg dose a similar figure was observed (87.9; 58/66). Only three patients in the two groups (pp) had persistent H. pylori infection, all of whom relapsed. No patients discontinued treatment because of adverse effects of the drugs. CONCLUSION: H. pylori eradication was not associated with impaired ulcer healing in a Middle Eastern population with symptomatic NSAID induced gastro/duodenal lesions, when a high healing dose of omeprazole (40 mg) was used. After eradication, omeprazole 10 or 20 mg per day were highly and equally effective for maintenance of gastroduodenal mucosal integrity during continued NSAID use. H. pylori should be eradicated from symptomatic Middle Eastern NSAID users with peptic ulcer disease.

Detection assessment and monitoring of hepatic fibrosis: biochemistry or biopsy?

Hepatic fibrosis is an important consequence of inflammatory disorders affecting the liver, and ultimately progresses to cirrhosis. Here we explore methods for the detection and monitoring of hepatic fibrosis, particularly in hepatitis C, alcoholic liver disease, non-alcoholic fatty liver disease and during methotrexate therapy, in all of which progressive fibrosis can develop over a number of years in a minority of patients. Liver biopsy currently remains the gold standard to assess fibrosis. However, it has several limitations, including manpower issues, cost, risk of patient injury, including mortality and morbidity, observer variability and sampling variation. Several non-invasive diagnostic tests for fibrosis and cirrhosis have therefore been evaluated. The usefulness of a laboratory test for screening for a pathological abnormality such as fibrosis is critically dependent on the prevalence of the pathology in the population under investigation. When the prevalence is expected to be low, screening tests should have a high negative predictive value so that large numbers of patients can be spared the next diagnostic step, namely liver biopsy. For the moment, clinical chemistry laboratories should offer the aspartate aminotransferase alanine aminotransferase ratio, AST/platelet ratio and the Rosenberg fibrosis index as part of their routine service for monitoring the development of hepatic fibrosis.

Amino acid challenge in patients with cirrhosis: a model for the assessment of treatments for hepatic encephalopathy.

BACKGROUND/AIMS: To mimic episodic hepatic encephalopathy after gastrointestinal bleeding under controlled conditions, cirrhotic patients were challenged with an amino acid mixture of comparable composition to haemoglobin. METHODS: Basal EEG, psychometric score (HE test), reaction times and venous blood ammonia were recorded. Following a 54 or 108 gm oral amino acid challenge, blood ammonia levels and EEG were recorded at 30-min intervals, and psychometric testing was repeated at 180 min. Ten controls (57 +/- 2) and 31 cirrhotics (52 +/- 2) of which 21 were Child's grade A or B and 10 grade C underwent the challenge. Nine had a transjugular intrahepatic porta-systemic shunt in situ. RESULTS: Seventeen patients had abnormal baseline HE scores. Basal blood ammonia and reaction time A were significantly greater in patients (52 +/- 5 micromol/l and 478 +/- 20 ms, respectively) than controls (19 +/- 2 micromol/l and 372 +/- 14 ms) (P < 0.001). Following the challenge, in patients with advanced liver disease (Child's grade B and C) the slowing of reaction time A (+85 +/- 38 and +71 +/- 31 ms, respectively; P < 0.03) and EEG (ratio of slow to fast wave activity +0.31 +/- 0.12 and +0.58 +/- 0.19; P < 0.02) were significantly greater than in controls (-3.3 +/- 8 ms and 0.00 +/- 0.03, respectively). Patients with an abnormal basal HE score had the most pronounced changes (reaction time A +110 +/- 39 ms, P < 0.01, EEG +0.52 +/- 13, P < 0.01, respectively). The change in EEG ratio correlated with the dose of amino acid administered (r = 0.96; P < 0.008). CONCLUSION: The amino acid challenge constitutes a reproducible human model of episodic, Type C hepatic encephalopathy unaffected by the complications usually encountered in clinical practice.

Quantitative assessment of fibrosis and steatosis in liver biopsies from patients with chronic hepatitis C.

BACKGROUND: Hepatic fibrosis is one of the main consequences of liver disease. Both fibrosis and steatosis may be seen in some patients with chronic hepatitis C and alcoholic liver disease (ALD). AIMS: To quantitate fibrosis and steatosis by stereological and morphometric techniques in patients with chronic hepatitis C and compare the results with a control group of patients with ALD. In addition, to correlate the quantitative features of fibrosis with the Ishak modified histological score. MATERIALS AND METHODS: Needle liver biopsies from 86 patients with chronic hepatitis C and from 32 patients with alcoholic liver disease (disease controls) were analysed by stereological and morphometric analyses using the Prodit 5.2 system. Haematoxylin and eosin and Picro-Mallory stained sections were used. The area fractions (A(A)) of fibrosis, steatosis, parenchyma, and other structures (bile duct and central vein areas) were assessed by stereological method. The mean diameters of fat globules were determined by morphometric analysis. RESULTS: Significant differences were found in the A(A) of fibrosis, including fibrosis within portal tract areas, between chronic hepatitis C patients and those with ALD (mean (SD): 19.14 (10.59) v 15.97 (12.51)). Portal and periportal (zone 1) fibrosis was significantly higher (p = 0.00004) in patients with chronic hepatitis C compared with the control group (mean (SD): 9.04 (6.37) v 3.59 (3.16)). Pericentral fibrosis (zone 3) occurred in both groups but was significantly more pronounced in patients with ALD. These results correlate well with the modified Ishak scoring system. However, in patients with cirrhosis (stage 6) with chronic hepatitis C the A(A) of fibrosis varied between 20% and 74%. The diameter of fat globules was significantly lower in patients with hepatitis C (p = 0.00002) than the ALD group (mean (SD): 14.44 (3.45) v 18.4 (3.32)). Microglobules were more frequent in patients with chronic hepatitis C than in patients with ALD. In patients with chronic hepatitis C, the fat globules had a zonal distribution in comparison with pan steatosis in ALD. CONCLUSION: Quantitative, stereological techniques are simple and reliable for evaluating hepatic fibrosis and steatosis in chronic hepatitis C. They are most useful for assessing the origin, location, and the stage of fibrosis. Stereology and morphometry are recommended for the quantitation of fibrosis and steatosis, particularly for the evaluation of new treatment strategies in patients with chronic hepatitis C.

Effect of L-ornithine-L-aspartate on patients with and without TIPS undergoing glutamine challenge: a double blind, placebo controlled trial.

BACKGROUND AND AIM: An oral glutamine load in cirrhotic patients awaiting liver transplantation was shown to cause a rise in blood ammonia and psychometric abnormalities which were reversed by hepatic transplantation. L-Ornithine-L-aspartate (LOLA) has been shown to reduce ammonia and improve psychometric function in patients with hepatic encephalopathy. The aim of the present study was to assess the effect of LOLA in healthy patients with cirrhosis and no evidence of clinical encephalopathy after challenging the central nervous system by administration of oral glutamine. PATIENTS AND METHODS: Eight cirrhotics (Child's B or C) without transjugular intrahepatic portosystemic shunts (TIPS) and seven with TIPS underwent two oral glutamine (20 g) challenges, receiving LOLA (5 g intravenously) on one occasion and placebo on the other in random order. Psychometric tests, including choice reaction time (CRT) and number connection test, were performed before and after glutamine, together with electroencephalography and blood ammonia. RESULTS: Mean basal ammonia was 27 (SEM 5) micromol/l in non-TIPS and 76 (10) micromol/l in TIPS patients (p<0.05). Basal CRT 2 was 0.643 (0.033) s in non-TIPS and 0.825 (0.076) s in TIPS patients (p<0.02). In non-TIPS patients, ammonia increased to 36 (10) micromol/l when LOLA was administered and to 62 (13) micromol/l with placebo (p<0.02). There was no alteration in psychometric function in non-TIPS patients after glutamine when LOLA was given but when placebo was given, glutamine caused prolongation of CRT (p=0.02). Glutamine did not affect psychometric function in TIPS patients with or without LOLA. CONCLUSION: This study showed that LOLA ameliorated the deleterious psychometric effects of glutamine in Child's grade B and C patients with cirrhosis without TIPS and supports its use in clinical practice in hepatic encephalopathy.

Hepatitis C virus genotypes in a cohort of Middle Eastern patients.

BACKGROUND: The epidemiology of hepatitis C virus infection has been well characterized in Western Europe, North America and Japan. Less is known about it in other regions of the world. In order to fully understand the relationship between host and virus, it is important to study the effect of virus infection in all regions of the world. In this report, we have analyzed patients from the United Arab Emirates, Egypt and Jordan. DESIGN AND METHODS: Serum from 81 Middle Eastern HCV ELISA-2-positive patients was analyzed for the presence of HCV RNA by PCR. RNA-positive patients were genotyped by selective hybridization of amplicons to HCV genotype-specific oligonucleotides (InnoLipa2, Innogenetics, Belgium). Where possible, data was also obtained on racial origin, liver histology, serum ALT, prothrombin time, albumin, and risk factors for infection. RESULTS: Sixty-five of 81 patients were HCV RNA-positive. A higher proportion of Middle Eastern patients were genotype 4 compared to equivalent studies from Western Europe, USA and Japan. However, the most common genotype was 1a. No significant difference in genotype was found between patients with chronic hepatitis and patients with cirrhosis. CONCLUSIONS: Eight of 65 (12%) patients were genotype 4, but the most common genotype was 1a, a âWesternâ genotype (24/65, 37%). The mean age of cirrhotics was low compared to Western studies. This may be due to infection in early childhood or race-related host factors. Twelve of 65 patients (18%) were not classifiable for genotype using InnoLipa2. This may be due to multiple infecting genotypes in these patients, or unusual, non 13 HCV genotypes which cannot be classified by InnoLipa2.

Quantitative studies of testicular atrophy following portacaval shunt in rats.

To evaluate the differential effects of portacaval shunting (PCS) on the morphological changes that occur in humans with portal-systemic encephalopathy, male rats underwent either PCS (13) or sham operations (10). Normal adult rats (6) were used as controls. All animals were killed 5 to 7 weeks after the surgery. The wet weight of the testes was obtained. Hematoxylin-eosin (HE)-stained sections at 5-micrometers thickness were used for stereological analysis using an image analysis system. Apoptosis was assessed quantitatively in HE and in in situ end-labeling (ISEL)-stained slides, while mitotic activity and mast cell numbers were assessed in 20 high-power fields. There was a significant reduction in the testicular mass (664 mg) in PCS rats in comparison with sham (2,199 mg) and control (1,937 mg) rats (P <.00001). The thickness of germinal epithelium was significantly reduced in PCS rats (64 micrometers) compared with sham (126 micrometers) and control groups (108 micrometers). The number of tubules per square millimeter and the mean curvature were significantly increased in PCS rats (P <.00001). There was a 112-fold increase in apoptosis in PCS rats (112) in comparison with the control and sham-operation groups (1.2 and 0.7, respectively). Mitosis was significantly reduced in the PCS group (P =.0089), but mast cells were unchanged. The results suggest that PCS in the absence of liver dysfunction produces testicular atrophy by reduction in mitosis, maturation arrest, and increased apoptosis of the germinal epithelium. PCS may therefore be responsible for gonadal atrophy that occurs with advanced liver disease in humans.

Quantitative assessment of gastric atrophy using the syntactic structure analysis.

AIM: To assess the topographical relation between gastric glands, using the minimum spanning tree (MST), to derive both a model of neighbourhood and quantitative representation of the tissue's architecture, to assess the characteristic features of gastric atrophy, and to assess the grades of gastric atrophy. METHODS: Haematoxylin and eosin stained sections from corporal and antral biopsy specimens (n = 139) from normal patients and from patients with nonatrophic gastritis and atrophic gastritis of grades 1, 2, and 3 (Sydney system) were assessed by image analysis system (Prodit 5.2) and 11 syntactic structure features were derived. These included both line and connectivity features. RESULTS: Syntactic structure analysis was correlated with the semiquantitative grading system of gastric atrophy. The study showed significant reductions in the number of points and the length of MST in both body and antrum. The standard deviation of the length of MST was significantly increased in all grades of atrophy. The connectivity to two glands was the highest and most affected by the increased grade of atrophy. The reciprocal values of the Wiener, Randic, and Balaban indices showed significant changes in the volume of gland, abnormality in the shape of glands, and changes in irregularity and branching of the glands in both types of gastric mucosa. There was a complete separation in the MST, connectivity, and index values between low grade and high grade gastric atrophy. CONCLUSIONS: (1) Gastric atrophy was characterised by loss of the gland, variation in the volume, reduction in the neighbourhood, irregularity in spacing, and abnormality in the shape of the glands. (2) Syntactic structure analysis significantly differentiated minor changes in gastric gland (low grade atrophy) from high grade atrophy of clinical significance. (3) Syntactic structure analysis is a simple, fast, and highly reproducible technique and appears a promising method for quantitative assessment of atrophy.

Oral glutamine challenge in cirrhotics pre- and post-liver transplantation: a psychometric and analyzed EEG study.

Latent or sub-clinical hepatic encephalopathy is a recognized complication of cirrhosis and is thought to represent one end of the spectrum of neuropsychiatric impairment, which occurrs as a result of portal-systemic shunting. We studied the psychometric, analyzed electroencephalography (EEG), and venous blood ammonia responses to an oral glutamine challenge in 17 patients with cirrhosis and in 4 normal controls. The cirrhotics were attending for liver transplant assessment and had no clinical evidence of hepatic encephalopathy. The oral glutamine challenge was repeated following liver transplantation. Five of sixteen patients (31%) showed impaired performance on at least one of the baseline psychometric tests. There was a correlation between fasting venous ammonia and choice reaction time (r = .7, P < .01). Following glutamine challenge there was a significant increase in blood ammonia from a mean fasting value ranging between 58 micromol/L to 120 micromol/L (P < .01), between significant prolongation of reaction times of 387 ms to 428 ms (P < .01), and an increase in mean EEG amplitude between 68.5 microV to 78.6 microV (P < .001). Four normal controls who were challenged with glutamine and 6 cirrhotic patients who were challenged with water showed no change in any of these parameters. Following orthotopic liver transplantation (OLT) the eight patients studied had normal baseline psychomotor performance with significant improvements in digit symbol, digit span, information processing, number connection tests (P < .05), and reaction time (P < .005). Posttransplantation, there were no significant changes in blood ammonia, analyzed EEG, or choice reaction time in response to oral glutamine challenge (six patients). We conclude that short lived changes in blood ammonia (in cirrhotics) can cause significant impairment of sensitive tests of brain function and that psychometric performance is improved following OLT.

Synaptosomal glutamate transport in thioacetamide-induced hepatic encephalopathy in the rat.

Dysfunction of excitatory glutamatergic neurotransmission has been implicated in the cause of hepatic encephalopathy. Brain microdialysis studies in various animal models of portal systemic encephalopathy (PSE) and encephalopathy associated with acute liver failure, have established that an increase in extracellular glutamate occurs but the mechanisms of this are unclear. We have measured oxygen consumption, citrate synthase activity (as indices of energy state and mitochondrial content, respectively), calcium-dependent glutamate release, and high-affinity, sodium-dependent glutamate uptake by synaptosomes prepared from rats with thioacetamide-induced encephalopathy. (2 doses of thioacetamide 200 mg/kg with a 24-hour interval). Synaptosomes were prepared either by a modified P2 method (glutamate release study) or by discontinuous sucrose density gradient centrifugation (all other studies). There was no significant difference in synaptosomal oxygen consumption, citrate synthase activity, glutamate release, total synaptosomal glutamate content, or the Kd for glutamate uptake between the encephalopathy group and the controls. However, there was a marked decrease in the maximal velocity of transport (Vmax) for glutamate uptake in synaptosomes from encephalopathic rats, 2.64 versus 4.40 nmol/min/mg (P < .05). The results of this study provide evidence of impaired glutamate uptake in the rat thioacetamide model of hepatic encephalopathy, which could account for the elevated extracellular glutamate seen in the condition.

The relationship between plasma and brain quinolinic acid levels and the severity of hepatic encephalopathy.

BACKGROUND/AIMS: Quinolinic acid is an endogenous neuroexcitant derived from tryptophan. Brain quinolinic acid concentrations are reportedly elevated in chronic liver failure. The aim of this study was to determine if brain quinolinic acid levels correlate with the severity of hepatic encephalopathy. METHODS: Postmortem samples of selected brain regions and plasma samples taken at several stages of encephalopathy were obtained from patients with acute and chronic liver failure. Quinolinic acid levels were measured by mass spectroscopy using [18O]quinolinic acid. RESULTS: Plasma quinolinic acid levels were significantly increased by stage I encephalopathy in patients with acute liver failure and by stages II and III in patients with chronic liver failure. Brain quinolinic acid levels were elevated only in patients with acute liver failure and were uniformly distributed at concentrations below those observed in plasma. CONCLUSIONS: The uniform distribution of quinolinic acid at subplasma concentrations in the brains of patients with acute liver failure suggests that it is synthesized peripherally and enters the brain across a permeabilized blood-brain barrier. Whereas the elevation of brain quinolinic acid levels in patients who died of acute but not chronic liver failure suggests that the involvement of quinolinic acid in the pathogenesis of hepatic encephalopathy is minimal, it could predispose these patients to seizures.

An HPLC assay for sn-1,2-diacylglycerol.

A method for the analysis of 1,2-diacylglycerols in biological samples is presented. After tissue extraction and derivatisation with 3,5-dinitrobenzoyl chloride, samples are analysed by normal phase HPLC, using a 3.9 x 300 mm microPorasil column, and ultraviolet detection at 254 nm. The method gives quantitative recovery of 1,2-diacylglycerol, and is of sufficient sensitivity to allow quantitation of 1,2-diacylglycerol in human muscle needle biopsy specimens, from as little as 10 mg muscle. Human skeletal muscle from fasted control subjects was found to have a 1,2-diacylglycerol content of 455 +/- 78 nmol/g wet weight. The method is robust, giving intra- and inter-assay coefficients of variation of 2.9% and 5.9%, respectively, and should prove useful for the analysis of 1,2-diacylglycerol levels in human disease states, such as diabetes, in which no measurements of 1,2-diacylglycerol have yet been undertaken.

Brain indoles in human hepatic encephalopathy.

The neurotransmitter serotonin has a profound effect on the control of sleep; thus excess serotonin activity in the brain could be responsible for impaired consciousness in hepatic encephalopathy. Furthermore, an increased brain level of 5-hydroxy-indoleacetic acid has been a consistent finding in various animal models of the condition. In this study, using high-performance liquid chromatography with fluorometric detection, we examined levels of brain serotonin (5-hydroxytryptamine) and its precursors and metabolites in 16 patients dying with hepatic encephalopathy complicating acute and chronic liver disease and 9 control subjects matched for age, sex, postmortem delay in brain retrieval and length of frozen tissue storage. In patients with chronic liver disease, serotonin level was significantly increased in thalamus (p < 0.02); levels of its metabolite 5-hydroxyindoleacetic acid were increased in frontal cortex (p < 0.05), globus pallidus (p < 0.05) and putamen (p < 0.01). Levels of the precursor amino acid tryptophan were increased in thalamus (p < 0.01) and globus pallidus (p < 0.01); in both patient groups levels of 5-hydroxytryptophan and the tryptamine metabolite indoleacetic acid were increased in all brain areas studied. 5-Hydroxytryptamine levels were also increased in thalamus, frontal cortex and globus pallidus in the three patients with fulminant liver failure. Our findings are consistent with disordered neurotransmission, especially in the thalamus, an area of particular importance in the regulation of consciousness, alertness and attention in human beings.

Culture negative cytotoxin positive stools in community acquired diarrhoea.

In a significant proportion of cases of community acquired diarrhoea no recognised pathogen is detected. Verocytotoxin producing Escherichia coli (VTEC) are associated with haemorrhagic colitis and the haemolytic uraemic syndrome but their role in community acquired diarrhoea is not fully understood. Using a method of toxin enhancement in mixed faecal culture, 175 stools negative on culture for recognised pathogens were tested for the presence of cytotoxin and 28% were found to be positive. Nine were neutralised by anti-VT1, 29 by anti-VT2, and eight by neither. No control stool samples yielded any cytotoxin. VTEC should be considered as a causative agent in sporadic community acquired diarrhoea.

A method of enhancing verocytotoxin production by Escherichia coli.

The number of verocytotoxin producing Escherichia coli (VTEC) present in the faeces during an infection may be very low, making their detection difficult. We report a method for enhancing toxin production by VTEC using mitomycin C as an inducing agent with the aim of improving the detection of VTEC. In pure culture, mitomycin C enhanced toxin production up to 100-fold. When applied to mixed faecal culture, toxin could be detected in mitomycin C treated samples when standard cultures were negative and when substantially fewer verocytotoxin-producing bacteria were present. Use of this method may aid in the detection of VTEC and is appropriate for use in the routine diagnostic laboratory.

Is topical therapy necessary in acute distal colitis? Double-blind comparison of high-dose oral mesalazine versus steroid enemas in the treatment of active distal ulcerative colitis.

Thirty-seven patients suffering an attack of acute distal ulcerative colitis of mild or moderate severity were randomized in a double-blind, double-dummy fashion to receive either 800 mg oral mesalazine four times daily (18 patients) or steroid enemas twice daily (19 patients) for 4 weeks. Both treatments were well tolerated with no adverse effects. Three patients in each group were withdrawn because of clinical deterioration but both treatments produced significant clinical improvement with decreases in stool frequency and scores for urgency, bleeding and tenesmus. There were no significant differences between the treatments although there was a slight trend in favour of the enemas for reduction in rectal bleeding. Activity of the colitis as graded at sigmoidoscopy also decreased significantly with both treatments and there were corresponding improvements in histological parameters of inflammatory activity assessed with the aid of a computerized morphometric system. Little correlation was seen between clinical, sigmoidoscopic and histological changes.

Effect of protein and lactulose on the production of gamma-aminobutyric acid by faecal Escherichia coli.

The value of lactulose treatment in hepatic encephalopathy is widely recognised but its mode of action remains controversial. Much evidence supports a role for gamma-aminobutyric acid in hepatic encephalopathy, and lactulose could alter its bacterial production in the gut. Using the rat synaptic membrane assay and gas chromatography mass spectrometry, the production of gamma-aminobutyric acid by faecal Escherichia coli, with and without the addition of albumin, haemoglobin, whole blood, and lactulose under aerobic and anaerobic conditions was determined. Using an inorganic medium, maximal gamma-aminobutyric acid production occurred after a culture period of between 25 and 50 hours. The concentration after 30 hours of aerobic culture at 37 degrees C by a single strain was mean (SEM), 101 (5) mumol/l (99% confidence intervals 87-114 mumol/l; n = 8; interassay coefficient of variation 14.7%). gamma-aminobutyric acid production was significantly increased by the addition of albumin and haemoglobin. Under anerobic conditions, it was one fifth of that produced aerobically, but the addition of albumin and haemoglobin increased production by greater than 700%. Lactulose did not significantly attenuate gamma-aminobutyric acid production under aerobic or anaerobic conditions. gamma-aminobutyric acid determined by the rat synaptic membrane assay showed a highly significant correlation (r = 0.99) with that detected by gas chromatography mass spectrometry. These data confirm that gamma-aminobutyric acid is produced by faecal E coli and that protein enhances its production considerably, and suggest that lactulose does not exert its therapeutic effect by attenuating gamma-aminobutyric acid production.

A pilot study of fluticasone propionate in untreated coeliac disease.

Although gluten withdrawal is likely to remain the mainstay of treatment for adult coeliac disease, many patients find the diet inconvenient and unpalatable and compliance among asymptomatic patients is often poor. Oral corticosteroids have been used for patients who seem to be resistant to gluten withdrawal but preparations with low systemic bioavailability might be preferable. We have given a new glucocorticoid (fluticasone propionate) to 12 adults with untreated coeliac disease for six weeks while they were on a normal diet. One patient defaulted and one suffered a relapse in a pre-existing neoplasm. Excluding these, there was an improvement of symptoms, a mean weight gain of 2 kg, and a rise in albumin of 5.4 g/l. There was a significant improvement in the lactulose/mannitol excretion ratio (p less than 0.05) and in all histological variables examined in paired biopsy specimens (surface and crypt intraepithelial lymphocyte/enterocyte and goblet cell/enterocyte ratios and enterocyte height, p less than 0.01 or better). In six paired specimens sucrase and alkaline phosphatase activity increased in all (p less than 0.05) and lactase in five of six. No appreciable side effects were observed, but two patients had suppressed cortisol values and synacthen responses at six weeks. A further three, with normal pretrial results, had a blunted tetracosactrin response at six weeks. Fluticasone propionate seems worthy of further assessment in the treatment of coeliac disease as an adjunct to gluten withdrawal.