260 Gut, 1991, 32, 260-265 A pilot study offluticasone propionate in untreated coeliac disease Gut: first published as 10.1136/gut.32.3.260 on 1 March 1991. Downloaded from H C Mitchison, H Al Mardini, S Gillespie, M Laker, A Zaitoun, C 0 Record Abstract sion of the pituitary-adrenal axis and the authors Although gluten withdrawal is likely to remain concluded that these agents offered no benefit the mainstay of treatment for adult coeliac over prednisolone.S disease, many patients find the diet incon- Fluticasone propionate is a new corticosteroid venient and unpalatable and compliance among with poor systemic absorption after an oral dose asymptomatic patients is often poor. Oral and a high first pass metabolism leading to low corticosteroids have been used for patients bioavailability. Repeated oral doses of up to who seem to be resistant to gluten withdrawal 20 mg/day in volunteers have not been associated but preparations with low systemic bioavail- with low cortisol values, neither have these been ability might be preferable. We have given a a problem in clinical trials in patients with new glucocorticoid (fluticasone propionate) to ulcerative colitis. We have therefore undertaken 12 adults with untreated coeliac disease for six an open trial of fluticasone propionate in un- weeks while they were on a normal diet. One treated coeliac disease, looking for objective patient defaulted and one suffered a relapse in functional and histological improvement in the a pre-existing neoplasm. Excluding these, small bowel and for evidence of adrenal sup- there was an improvement of symptoms, a pression. mean weight gain of 2 kg, and a rise in albumin of5 4 g/l. There was a significant improvement in the lactulose/mannitol excretion ratio Methods (p<005) and in all histological variables Patients with untreated coeliac disease, of either examined in paired biopsy specimens (surface sex and over 18 years of age, were considered. A and crypt intraepithelial lymphocyte/entero- firm diagnosis of coeliac disease including a cyte and goblet cell/enterocyte ratios and duodenal or jejunal biopsy was required. enterocyte height, p<001 or better). In six Patients with contraindications to cortico- http://gut.bmj.com/ paired specimens sucrase and alkaline phos- steroids, lactating mothers, or those with phatase activity increased in all (p<0.05) and evidence of other small bowel disease associated lactase in five of six. No appreciable side with coeliac disease (such as lymphoma) were effects were observed, but two patients had excluded and women of childbearing age were suppressed cortisol values and synacthen only included if using adequate contraception. responses at six weeks. A further three, with normal pretrial results, had a blunted tetra- on September 27, 2021 by guest. Protected copyright. cosactrin response at six weeks. Fluticasone PRELIMINARY INVESTIGATIONS propionate seems worthy of further assess- Baseline symptoms were assessed, particularly ment in the treatment of coeliac disease as an gastrointestinal symptoms of weight loss, adjunct to gluten withdrawal. anorexia, nausea, bowel frequency and consis- tency, and abdominal discomfort. Physical examination and routine urine analysis were per- Coeliac disease is a condition where exposure to formed. Full blood count, red cell and serum gluten produces abnormalities in the upper small folate and serum iron (except in those patients on bowel that lead to malabsorption. Removal of haematinic drugs), urea and electrolytes. gluten from the diet leads to improvement in glucose, liver function tests (bilirubin, alanine most cases but necessitates life long compliance transaminase and alkaline phosphatase), with a socially inconvenient and unpalatable albumin, protein, immunoglobulin, and gliadin diet. Many patients are non-compliant and thus antibodies were measured. A short tetracosactrin show poor histological healing though symptoms test was performed. may be tolerably well controlled. In a proportion A differential sugar absorption study was Gastroenterology Unit of patients the removal of not H C Mitchison gluten is sufficient undertaken using lactulose and mannitol as H Al Mardini to produce clinical resolution and in these, in probes: after an overnight fast the subjects drank A Zaitoun particular, corticosteroids have been used with a test solution of 5 g lactulose and 2 g mannitol in C O Record improvements both in clinical state' and in 100 ml of tapwater containing 10-3 g glycerol to and Department of jejunal morphology,4 though the benefits do not achieve a hypertonic solution, osmolarity 1500 Clinical Biochemistry, outlive the period of treatment. Adrenal sup- mol/l. They continued to fast until the end of the Royal Victoria Infirmary pression has been a major worry and might be first urine collection. Urine was in and collected two University, avoidable if a Newcastle upon Tyne topically active but non-absorbed consecutive five hour periods and stored in NEI 4LP corticosteroid could be shown to be effective. containers holding 0.2 ml sodium methiolate. S Gillespie Bramble et al used clobetasone butyrate or The total volume was recorded and 20 ml M Laker betamethasone valerate over four months and aliquots stored at -20°C. Analysis was by gas- Correspondence to: showed biochemical and Dr C O Record. histological improve- liquid chromatography as previously described67 Accepted for publication ments in 10 untreated coeliac patients on a except that for mannitol methoxime derivatives 24 April 1990 normal diet but eight of 10 developed suppres- were formed before trimethylsilylation. A pilotstudy offluticavone propionate in untreated coeliac disease 261 Endoscopic duodenal biopsy specimens were three weeks they were reviewed for adverse obtained using a large channel endoscope (3.7 events and the following checked for safety: mm channel). Some of the tissue was fixed in urine analysis and 9 am cortisol, urea, electro- formalin for histological assessment, processed lyte, and glucose concentrations. Gut: first published as 10.1136/gut.32.3.260 on 1 March 1991. Downloaded from in paraffin wax, sectioned at 5 ,um intervals, and stained with haematoxylin and eosin and with alcian blue/periodic acid Schiff. Intraepithelial POSTTREATMENT INVESTIGATIONS lymphocytes were counted in the villous At six weeks all the preliminary assessments epithelium or superficial flat epithelium and also were repeated, full dietary advice on a gluten free in the crypt epithelium. At least 500 enterocytes diet given, and continuing follow up arranged. were counted in each case in sections performed at multiple levels to provide intraepithelial lymphocyte/enterocyte ratios for surface and STATISTICAL METHODS crypt epithelium. Enterocyte height was All paired results have been compared using the measured according to Howdle et aP and de Ritis Wilcoxon signed rank test except for the dif- et aP. At least 50 epithelial cells with basal ferential sugar absorption data where, after log10 centrally located nuclei were measured using transformation, Student's t test was used. All p multiple sections at different levels. Cells were values are two tailed. chosen at random throughout the epithelium of This study was performed in accordance with the villi or superficial flat epithelium. A crossed the Declaration of Helsinki and had ethical micrometer eye piece graticule was used for this committee approval. We had thought that it purpose. Goblet cells in the crypt epithelium would be desirable to perform insulin stress tests were counted and the ratio of goblet cells to to assess adrenal reserve but permission was not enterocytes obtained by counting a minimum of given for this. 500 enterocytes. The biopsy specimens were assessed blind. Intestinal enzyme activities were measured by Results taking a freshduodenal specimenandhomogenis- Twelve patients were entered into the study, and ing this in 1 ml of normal saline in a loose fitting 10 completed it with good compliance. One Potter-Elvehjem glass homogeniser. The speci- patient had a relapse in a pre-existing Hodgkin's men was then frozen until used. Before analysis lymphoma, necessitating withdrawal, and of protein content,'` lactase," sucrase," and remained severely symptomatic throughout. alkaline phosphatase"l activities, specimens were Another, with longstanding, mildly sympto- defrosted and sonicated three times at 0°C for 10 matic coeliac disease and known to be entirely http://gut.bmj.com/ seconds. The results are expressed as IU/g non-compliant with dietary measures, defaulted. protein. Biopsy specimens were also obtained Except where stated, these patients have not from 12 patients having endoscopies for other been included in paired assessments ofinitial and reasons and in whom routine duodenal histology end of treatment data. The Table gives details of was normal. the patients. The patients were issued with a diary card to record compliance and stool frequency and con- on September 27, 2021 by guest. Protected copyright. sistency. They received fluticasone propionate 5 CLINICAL EVENTS mg four times a day for six weeks (probably Initial clinical assessments are shown in the equivalent to 40 mg prednisolone a day). After Table. At six weeks seven patients were assessed Patient details After treatment Cortisol+tetracosactrin Before treatment response at 6 weeks (nmol/l) Clinical Weight Albumin Case Age Duration Reasonfor ratingof change change 30 min after No (years) ofdisease* diagnosis severity (kg) (gil) Baseline tetracosactrin 1 24 2-5 yr Diarrhoea, anaemia Moderate + 1 +5 <30 99 weight loss 2 54 4 mth Diarrhoea, anaemia Severe - -t weight loss 3 42 2-5 yr Diarrhoea Mild +4-4 +9 275 733 weight loss 4 44 33 yr Steatorrhoea Moderate +2 +2 396 519 5 42 6 mth Anaemia Moderate 0 + 1 138 365 6 51 3 yr Dermatitis Mild +0.5 +3 261 699 herpetiformis 7 22 2 mth Diarrhoea Mild +15 +14 <30f <30 weight loss 8 56 55 yr Failure to thrivet Mild -0.3 +3 524 690 9 35 32 yr Diarrhoea Mild - - - - weight loss 10 66 >30 yr Anaemia Moderate -0-2 -1 338t 466 11 67 20yr Anaemia Moderate +0.5 +3 289 598 12 68 3 mth Diarrhoea, anaemia Moderate +2 + 15 261t 465 weight loss *Estimated from history; tdiagnosed in childhood.