Randomised clinical study: gluten challenge induces symptom recurrence in only a minority of patients who meet clinical criteria for non-coeliac gluten sensitivity.

BACKGROUND: It is unknown whether symptoms in non-coeliac patients (non-CD) meeting clinical diagnostic criteria for noncoeliac gluten sensitivity (NCGS) are specifically triggered by gluten. AIM: To assess gluten sensitivity in patients diagnosed with NCGS. METHODS: We studied 35 non-CD subjects (31 females) that were on a gluten-free diet (GFD), in a double-blind challenge study. Participants were randomised to receive either gluten-containing flour or gluten-free flour for 10 days, followed by a 2-week washout period and were then crossed over. The main outcome measure was their ability to identify which flour contained gluten. Secondary outcome measures were based upon Gastrointestinal Symptoms Rating Scale (GSRS) scores. RESULTS: The gluten-containing flour was correctly identified by 12 participants (34%), who were classified as having NCGS. Their mean GSRS dimension scores were significantly higher following gluten challenge compared to baseline. The scores were: pain, 1.7 ± 0.8 vs. 2.6 ± 1.0; reflux, 1.6 ± 0.5 vs. 2.2 ± 0.9; indigestion, 1.9 ± 0.7 vs. 3.2 ± 1.1; diarrhoea, 1.6 ± 0.7 vs. 2.9 ± 1.5 and constipation, 1.9 ± 0.9 vs. 2.9 ± 1.3. Seventeen participants (49%) erroneously considered the gluten-free flour to contain gluten. Their mean GSRS dimension scores were significantly higher following gluten-free flour challenge compared to baseline. The scores were: pain, 1.6 ± 0.9 vs. 3.0 ± 0.9; reflux, 1.4 ± 0.5 vs. 2.3 ± 1.1; indigestion, 2.0 ± 1.1 vs. 3.7 ± 1.1; diarrhoea, 1.6 ± 0.7 vs. 3.0 ± 1.2 and constipation, 1.6 ± 0.9 vs. 2.6 ± 1.3. The other six participants (17%) were unable to distinguish between the flours. CONCLUSION: Double-blind gluten challenge induces symptom recurrence in just one-third of patients fulfilling the clinical diagnostic criteria for non-coeliac gluten sensitivity.

Slow gallbladder emptying reverts to normal but small intestinal transit of a physiological meal remains slow in celiac patients during gluten-free diet.

BACKGROUND: Alterations of small intestinal transit and gallbladder (GB) motility have been reported in celiac disease (CD) in studies involving, in most cases, non-physiological experimental conditions and artificial stimuli to motility. Our aims were to quantitate non-invasively small intestinal transit time and GB emptying during administration of a physiological and palatable solid meal, and to assess the effect of gluten-free diet (GFD). METHODS: We simultaneously measured mouth-to-cecum transit time (MCTT) using a validated H(2) breath test, and GB motility using ultrasonography. We studied CD patients before (n = 19) and during (n = 14) GFD, and healthy volunteers (n = 24) following administration of a physiological solid meal (Kcal 539). KEY RESULTS: Mouth-to-cecum transit time was more prolonged in CD (mean ± SEM: 235 ± 96 min) than in controls (169 ± 65 min, P = 0.0039). The GB fasting volume and postprandial residual volume were significantly higher in CD than in controls, and GB emptying constant was slower in CD than in controls. During GFD, GB emptying reverted to normal, but MCTT remained unchanged (229 ± 69 min) and more prolonged in CD than in controls (P = 0.0139). During GFD, duodenal infiltration with lymphocytes and mast cells persisted higher than that in controls, and the number of mast cells lying in proximity of nervous endings did not change. CONCLUSIONS & INFERENCES: Slow postprandial MCTT in response to a physiological meal does not revert to normal during GFD, an effect mirroring incomplete histopathologic recovery.

Helicobacter pylori and ischemic heart disease.

In the last years, a considerable number of studies have been performed on the relationship between infection from Helicobacter Pylori and atherosclerotic diseases, like stroke and ischemic heart disease. In particular, some infections could have a role on the genesis and development of damage to the vascular wall and of atheromatous plaque. It has been suggested that HP could influence the development of IHD through different pathways, such as endothelial cells colonization, changes in the lipid profiles, increased coagulation and platelet aggregation levels, induction of molecular mimicry mechanisms and the promotion of a low-grade systemic inflammation. Based on this hypothesis, it has been performed a considerable number of studies in order to investigate the role of HP in the development and pathogenesis of CAD. Most of this trials gave conflicting results, some denying the presence of a possible relationship between HP infection and increased risk of CAD. Despite of that, results from these studies have raised new interesting perspectives on coronary heart disease, especially regarding the possibility of modifying the clinical history of the disease through eradication of these microorganisms. The results are contradictory and require further investigation.

Exhaled nitric oxide as a marker of lung involvement in Crohn's disease.

Crohn's disease is an inflammatory bowel disease associated with a variety of systemic manifestations, including large and small airway involvement. The latter is most often a subclinical one, and requires expensive and invasive diagnostic approaches. Nitric oxide (NO) can be detected non-invasively in the exhaled air (eNO) and be considered as a surrogate marker of airway inflammation. eNO tested at multiple expiratory flows can be used to distinguish the alveolar concentration of NO (CalvNO) from the total amount of fractional eNO (FeNO). The aim of our study is to compare FeNO and concentration of alveolar nitric oxide (CalvNO) levels and to assess their relationship with pulmonary involvement in Crohn's patients differing in clinical stage and therapeutic regimens versus a group of healthy subjects. Thirty Crohn's patients not showing clinical evidence of pulmonary diseases and 21 non-smoking, non-atopic healthy controls were enrolled. FeNO (14.9±10.2 ppb vs 10.1±6.3 ppb, p=0.049) and CalvNO (4.4±2.2 ppb vs 2.6±1.9; p=0.006) values were found to be significantly higher in Crohn's patients than in healthy controls. Both FeNO and CalvNO correlated positively with the Crohn's Disease Activity Index. In conclusion, our results for FeNO and CalvNO confirm the presence of subclinical pulmonary involvement in Crohn's disease. eNO measurement may be of clinical value in the follow-up of Crohn's patients.

Complete recovery of intestinal mucosa occurs very rarely in adult coeliac patients despite adherence to gluten-free diet.

BACKGROUND: Expected benefits of gluten-free diet (GFD) in coeliac patients include healing of small intestinal mucosa, but it remains unclear to what extent this benefit is achieved in adults. AIM: To assess factors affecting histological outcome of GFD in a large cohort of adult coeliac patients. METHODS: We extracted information on 465 consecutive coeliac patients studied before and during GFD. RESULTS: Duodenal biopsies at diagnosis were classified as Marsh I in 11, II in 25 and III in 429 cases. After a median 16 months GFD, 38 (8%) patients had histological 'normalization', 300 (65%) had 'remission' with persistent intraepithelial lymphocytosis, 121(26%) had 'no change' and 6 (1%) had 'deterioration'. Coeliac disease related serology was negative in 83% of patients with Marsh III lesion during GFD. Male gender and adherence to GFD were independently associated with histological 'normalization' and 'remission'. Persistence of intraepithelial lymphocytosis was not associated with human lymphocyte antigen gene dose or with Helicobacter pylori infection. CONCLUSIONS: Complete normalization of duodenal lesions is exceptionally rare in adult coeliac patients despite adherence to GFD, symptoms disappearance and negative CD related serology. Control biopsies are mandatory to identify lack of response to gluten-free diet.

Elevation of serum gamma-glutamyltranspeptidase activity is frequent in chronic hepatitis C, and is associated with insulin resistance.

BACKGROUND AND AIMS: Serum gamma-glutamyltranspeptidase level is often increased in patients with chronic hepatitis C, and we aimed to identify factors associated with this phenomenon in patients completely abstinent from alcohol (teetotaller). PATIENTS AND METHODS: 71 teetotaller patients have been identified by personal history, questioning of relatives, CAGE questionnaire administration and unscheduled alcoholemia measurements. RESULTS: 39 patients (55%) had elevated (>50IU/L) gamma-glutamyltranspeptidase level. Body mass index, insulin and C-peptide level, insulin resistance, piecemeal necrosis score > or =3, fibrosis score > or =2 and steatosis score > or =1 were significantly higher in these patients than in those (n=32) with normal gamma-glutamyltranspeptidase. At multiple linear regression analysis gamma-glutamyltranspeptidase level was associated with C-peptide level, insulin resistance and histopathologic grading. At multiple logistic regression analysis, C-peptide level (OR=2.13) and piecemeal necrosis score > or =3 (OR=4.59) were the only factors independently associated with elevated gamma-glutamyltranspeptidase. Sustained virological response during pegylated interferon plus ribavirine treatment was achieved by 97% and 49% patients with normal and elevated gamma-glutamyltranspeptidase, respectively (p=0.0001). CONCLUSION: Serum gamma-glutamyltranspeptidase level is often elevated in chronic hepatitis C and is associated with metabolic and inflammatory factors; this phenomenon may contribute to explain and to predict resistance to treatment in this subgroup of patients.

The multidisciplinary team for management of inflammatory bowel diseases.

Crohn's disease (CD) and ulcerative colitis (UC) are inflammatory bowel diseases (IBD) characterized by a relapsing clinical pattern that typically affect people during their adult and economically productive lives. Affected patients require clinical follow-up because of periodic disease flare-up and of the risk of long-term complications. Extensive diagnostic procedures, medical and surgical treatments are often needed over a lifetime. The challenge posed by management of IBD is better faced by a multidisciplinary team that includes health care providers with complementary diagnostic or therapeutic skills. The team is expected to provide the best practice to manage IBD by defining a realistic "diagnostic and therapeutic pathway" for the patients to follow based on locally available professional, structural and technological resources. This approach appears to improve quality of care for IBD patients and to be cost-effective.

Coeliac disease: a histological follow-up study.

AIMS: To assess the histological response to a gluten-free diet (GFD) in a series of coeliac patients in clinical remission, of different ages and with varying degrees of mucosal damage at diagnosis. METHODS AND RESULTS: Biopsy samples from 249 coeliac patients (F 165, M 84) were analysed basally and after clinical and biochemical remission following a GFD. All patients showed an improvement in mucosal findings after starting a GFD, but complete histological normalization was observed in 74.1% of paediatric cases (diagnosed before 14 years of age) and in only 17.5% of adults. Statistical analysis showed that sex, the clinical picture at diagnosis and the length of time between biopsy at the time of diagnosis and on a GFD were not related to histological normalization. In contrast, the age at diagnosis was statistically significantly related to it (P < 0.0001). In addition, the presence/absence of Helicobacter pylori was independent of the normalization of the duodenal mucosa. CONCLUSIONS: In clinical practice the criteria for diagnosis of coeliac disease are sufficiently standardized, whereas for follow-up they are less well defined. We suggest that in order to compare the results from different studies, it should be stated whether remission after treatment is based on clinical or histological criteria or both.

Circulating ghrelin level is increased in coeliac disease as in functional dyspepsia and reverts to normal during gluten-free diet.

BACKGROUND: It is controversial whether serum ghrelin concentration is altered in coeliac disease and whether this alteration is related to nutritional impairment or to inflammatory changes of duodenal mucosa. AIM: To investigate clinical and histopathological variables affecting circulating ghrelin in coeliac patients by comparison with dyspeptic patients and with healthy controls. METHODS: We measured serum ghrelin and obtained gastric and duodenal biopsies in 44 coeliac patients before and after 1-year gluten-free diet, in 39 dyspeptic patients and 53 healthy controls. RESULTS: Serum ghrelin concentration was significantly higher in coeliac (531 +/- 29 pg/mL, P < 0.05) and in dyspeptic patients (526 +/- 14 pg/mL, P < 0.01) than in healthy controls (451 +/- 8 pg/mL), and body mass index was significantly lower in coeliac (20 +/- 1) and in dyspeptic patients (20 +/- 1) than in healthy controls (22 +/- 1, P < 0.05). In coeliac patients serum ghrelin concentration was not related to the severity of duodenal lesions. Serum ghrelin reverted to normal (399 +/- 30 pg/mL) and body mass index increased significantly (0.6 +/- 0.1 kg/m(2) increase, P < 0.05) during gluten-free diet despite persistent duodenal lymphocytic infiltration. CONCLUSIONS: Ghrelin concentration is increased and body mass index is decreased in coeliac and in dyspeptic patients irrespective of presence and severity of duodenal inflammation. Nutritional impairment is a key factor in elevating plasma ghrelin levels in coeliac disease.

Intraepithelial lymphocytes in the villous tip: do they indicate potential coeliac disease?

BACKGROUND: The counting of intraepithelial lymphocytes (IELs) in the villous tips of architecturally normal small bowel biopsy specimens was proposed as a method to measure mucosal infiltration in gluten sensitive patients. AIMS: To apply this straightforward method in duodenal biopsy specimens from patients affected by potential coeliac disease (PCD) to verify whether it can discriminate these patients from controls. METHODS: Paraffin wax embedded duodenal sections from 11 patients affected by PCD were stained with an antihuman CD3 antibody. Sections from 19 patients affected by treated coeliac disease (TCD) and 17 patients in whom coeliac disease was excluded were stained with the same antibody to serve as controls. The slides were examined blindly. IELs/20 enterocytes in five randomly chosen villous tips were counted. Patients affected by PCD were all on a gluten containing diet. They had an architecturally normal duodenal mucosa and were positive for endomysial antibody. Both TCD and non-coeliac controls were negative for endomysial antibody. RESULTS: The mean villous tip IEL scores were 4.6 (SD, 1.5; range, 1.4-7.8) in non-coeliac controls, 7.9 (SD, 4.0; range, 2.0-18.6) in TCD, and 9.2 (SD, 4.7; range, 5.8-21.8) in patients with PCD. The difference between PCD and non-coeliac controls was significant. CONCLUSIONS: This is a very simple and sufficiently reliable method to count IELs. In patients with an architecturally normal duodenal mucosa, the IEL count in villous tips helps to distinguish between patients with PCD and non-coeliac controls.

Is under diagnosis of celiac disease compounded by mismanagement in the primary care setting?. A survey in the Italian Province of Brescia.

AIM: Celiac disease is under diagnosed in the primary care setting, mainly because of lack of awareness on the heterogenic manifestation of the disease. Furthermore, patients diagnosed at open access endoscopy may be mismanaged with incomplete dietary information. The aim of this paper was to evaluate prevalence and incidence in 1996 and 1997 for celiac disease in the Italian Province of Brescia and to obtain information on the extent of underdiagnosis and mismanagement. METHODS: The authors assessed the under diagnosis of celiac disease by relating the number of patients on gluten-free diet at 31 December 1997 (prevalent cases) to the expected number of patients in a population of 1,055,499 assuming 1/200 disease prevalence. Post-diagnosis management was assessed by questionnaire for all incident cases in the hospital practice and in the primary care setting. RESULTS: Five hundred and ninety-four prevalent cases were identified compared with an estimated disease prevalence of 5,000 cases, a figure corresponding to 8/9 under diagnosis. One hundred and thirty-five incident cases during 1996-1997 have been identified. Overall 80% of incident cases were symptomatic, but 40% only with the classical symptoms of malabsorption. Forty-three of the 135 incident cases did not receive appropriate dietary education following diagnosis, a figure corresponding to 1:3 mismanagement, and all of them were diagnosed in the primary care setting at open access endoscopy. CONCLUSIONS: Our study indicates that under diagnosis of celiac disease in the primary care setting is compounded by disease mismanagement, a finding suggesting the need for increasing awareness not only on the heterogenicity of clinical manifestation but also on the appropriate dietary management of celiac disease.

Value of measuring gallbladder motility in clinical practice.

Measurement of gallbladder motility is a powerful research tool, but its value in clinical practice is uncertain. Three main conditions have been investigated for potential clinical application of this measurement. The first potential application is for identification of patients at risk of recurrence following gallstone dissolution with medical therapy. Results in this clinical setting are disappointing due to the low positive predictive value for gallstone recurrence in sluggish gallbladder emptying. The second potential application is for identification of obese patients at risk of gallstone formation during rapid weight loss. In this condition, a high negative predictive value has been reported for a normal gallbladder emptying pattern. The third potential application is for patients with recurrent biliary colic and acalcolous gallbladder disease. The diagnostic value of a provocative test involving intravenous cholecystokinin injection as a method of identifying patients likely to benefit from cholecystectomy is uncertain, partly as a consequence of non-standardized methodology. The balance of evidence reported in this review suggests a low inherent value of measurement of gallbladder motility in clinical practice. Acalcolous gallbladder disease is the clinical setting deserving further investigation on the value of the cholecystokinin provocative test, but this test needs to be standardized.

Intestinal absorption of the bile acid analogue 75Se-homocholic acid-taurine is increased in primary biliary cirrhosis, and reverts to normal during ursodeoxycholic acid administration.

BACKGROUND: Whether ileal absorption of bile acid is up or downregulated in chronic cholestasis is still debated, and most evidence has come from animal studies. AIMS: To compare ileal bile acid absorption in patients with primary biliary cirrhosis (PBC) and in healthy control subjects, and to assess the effect of ursodeoxycholic acid (UDCA). PATIENTS: We studied 14 PBC patients before and during (n=11) UDCA administration, 14 healthy control subjects, and 14 Crohn's disease patients (as disease controls). METHODS: We used cholescintigraphy to measure retention in the enterohepatic circulation over five successive days of the bile acid analogue (75)Se-homocholic acid-taurine ((75)SeHCAT) as an index of ileal bile acid absorption. Results were expressed as (75)SeHCAT fractional turnover rate (FTR) and t(1/2)12. RESULTS: (75)SeHCAT FTR was 0.19 (0.11)/day, 0.34 (0.11)/day (p<0.001), and 0.83 (0.32)/day in PBC patients, healthy controls (p<0.0001), and Crohn's patients (p<0.001), respectively, which increased to 0.36 (0.16)/day in PBC patients during UDCA treatment (p<0.005). (75)SeHCAT t(1/2)12 was 4.8 (2.1) days in PBC patients, 2.2 (0.5) days (p<0.001) in healthy controls, and 1.0 (0.5) days (p<0.001) in Crohn's disease patients. (75)SeHCAT t(1/2)12 decreased to 2.2 (0.93) days (p< 0.001) in PBC patients during UDCA treatment. CONCLUSIONS: Our results support the concept that ileal bile acid absorption is upregulated in PBC patients, and that this effect may contribute towards damaging the cholestatic liver. This upregulation of bile acid absorption is abolished by UDCA.

Effect of chronic administration of tauro-hyodeoxycholic acid on biliary bile acid composition and on biliary lipid secretion in humans.

BACKGROUND: Tauro-hyodeoxycholic acid is a hydrophilic bile acid of potential interest for treating cholestatic liver diseases. Bile acid pool is enriched with this bile acid during acute administration in patients with interrupted enterohepatic circulation. The aim of our study was to check the effect of chronic administration of tauro-hyodeoxycholic acid on biliary lipid composition and secretion in man with intact enterohepatic circulation. METHODS: We studied 7 dyspeptic patients before and during taurohyodeoxycholic acid 750 mg/day given for 6-8 weeks. We measured bile acid composition in duodenal aspirate, and biliary lipid secretion was also measured in 5 of these patients using a duodenal perfusion technique. RESULT: Tauro-hyodeoxycholic was undetectable in duodenal aspirate in all patients before treatment, and was 2%, 4%, 5%, 7%, 7%, 8% and 13% of biliary bile acid during treatment in individual patients. The proportion of cholic, deoxycholic, chenodeoxycholic ursodeoxycholic and lithocholic acid was similar before and during treatment. Bile acid duodenal output remained unchanged during taurohyodeoxycholic by comparison with pretreatment with median difference -0.3 mmol (95% confidence interval 1.6 mmol). The corresponding difference for duodenal cholesterol and phospholipid output was 0.1 mmol (0.2 mmol) and 0.2 mmol (0.6 mmol). CONCLUSIONS: By contrast with acute administration in patients with interrupted enterohepatic circulation, chronic administration of tauro-hyodeoxycholic to man with intact enterohepatic circulation has little effect on biliary lipid composition and secretion.

Ursodeoxycholic acid alone or with chenodeoxycholic acid for dissolution of cholesterol gallstones: a randomized multicentre trial. The British-Italian Gallstone Study group.

BACKGROUND: Combination therapy using ursodeoxycholic acid plus chenodeoxycholic acid has been advocated for dissolution of cholesterol gallstones because the two bile acids have complementary effects on biliary lipid metabolism and cholesterol solubilization. AIM: To compare the clinical efficacy of combination therapy with ursodeoxycholic acid monotherapy. PATIENTS AND METHODS: A total of 154 symptomatic patients with radiolucent stones (< or = 15 mm) in functioning gallbladders were enrolled from six centres in England and Italy. They were randomized to either a combination of chenodeoxycholic acid plus ursodeoxycholic acid (5 mg.day/kg each) or to ursodeoxycholic acid alone (10 mg.day/kg). Dissolution was assessed by 6-monthly oral cholecystography and ultrasonography for up to 24 months. RESULTS: Both regimens reduced the frequency of biliary pain and there was no significant difference between them in terms of side-effects or dropout rate. Complete gallstone dissolution on an intention-to-treat basis was similar at all time intervals. At 24 months this was 28% with ursodeoxycholic acid alone and 30% with combination therapy. The mean dissolution rates at 6 and 12 months were 47% and 59% with ursodeoxycholic acid, and 44% and 59% with combination therapy, respectively. CONCLUSION: There is no substantial difference in the efficacy of combined ursodeoxycholic acid and chenodeoxycholic acid and that of ursodeoxycholic acid alone in terms of gallstone dissolution rate, complete gallstone dissolution, or relief of biliary pain.

Review article: the 'mechanical pumps' and the enterohepatic circulation of bile acids--defects in coeliac disease.

Bile acid pool size is maintained relatively constant at about 3-5 g in healthy subjects by two mechanisms, enterohepatic circulation and de novo synthesis of bile acids. This latter mechanism compensates for the daily faecal loss (about 0.2-0.6 g) of bile acids, whereas the bulk of the pool is conserved by the former mechanism. The driving forces of the enterohepatic circulation are constituted by chemical pumps, including intestinal absorption and hepatic uptake, and by mechanical pumps, including gall-bladder and intestinal motility. The latter provide the main propulsive forces for bile acids to reach the site of intestinal absorption, and by contrast with the very rapid chemical pumps, mechanical pumps have storage capacity for the bile acid pool and therefore comprise the slow limb of the enterohepatic circulation. In coeliac disease, a disease classically described as a malabsorption syndrome associated with mucosal atrophy of the small intestine, both gall-bladder and small intestinal motor functions are impaired, and in this article we review the mechanisms involved in these defects, how they influence the enterohepatic circulation of bile acids, and the evidence supporting the concept that both the gall-bladder and the small intestinal motor functions represent the main factors affecting the kinetics of the enterohepatic circulation.

Risk factors for the development of gallstone recurrence following medical dissolution. The British-Italian Gallstone Study Group.

OBJECTIVE: To assess risk factors for gallstone recurrence following non-surgical treatment. DESIGN: A prospective follow-up of a multicentre cohort of post-dissolution gallstone patients. SETTING: Six gastroenterology units in the UK and Italy. PARTICIPANTS: One hundred and sixty-three patients with confirmed gallstone dissolution following non-surgical therapy (bile acids or lithotripsy plus bile acids), followed up by ultrasound scan and clinical assessment at 6-monthly intervals for up to 6 years (median, 25 months; range, 6-70 months). OUTCOME MEASURES: Subject-related variables (sex, age, height, weight, body mass index), gallstone-related variables (number, diameter, presence of symptoms, months to complete stone clearance), treatment modalities (bile acid therapy, extracorporeal shock wave lithotripsy) and follow-up related variables (weight change, use of non-steroidal anti-inflammatory agents, statins, pregnancies and/or use of oestrogens) were assessed by univariate and multivariate analysis as putative risk factors for gallstone recurrence. RESULTS: Forty-five gallstone recurrences were observed during the follow-up period. Multiple primary gallstones and length of time to achieve gallstone dissolution were the only variables associated with a significant increase in the recurrence rate. Appearance of biliary sludge during follow-up was also significantly related to development of gallstone recurrence. Use of statins or non-steroidal anti-inflammatory agents did not confer protection against recurrence. CONCLUSIONS: Patients with primary single stones are the best candidates for non-surgical treatment of gallstones, because of a low risk of gallstone recurrence. The positive association of recurrence with biliary sludge formation and time to dissolution of primary stones may provide indirect confirmation for the role of impaired gallbladder motility in the pathogenesis of this condition.

Effect of long term simvastatin administration as an adjunct to ursodeoxycholic acid: evidence for a synergistic effect on biliary bile acid composition but not on serum lipids in humans.

BACKGROUND: Stimulated bile acid synthesis preferentially utilises newly synthesised cholesterol, raising the possibility that combination of simvastatin (an inhibitor of cholesterol synthesis) with ursodeoxycholic acid (UDCA; a stimulator of bile acid synthesis) may result in reduced bile acid synthesis and greater enrichment of the pool with UDCA than that achieved with UDCA treatment alone. AIMS: To investigate the effect of simvastatin and UDCA given alone and in combination on serum and biliary lipid and biliary bile acid composition. METHODS: Eighteen patients with primary non-familial hypercholesterolaemia were studied during treatment with simvastatin 20 mg/day, UDCA 10 mg/kg/day, and a combination of the two drugs. Each regimen was given in random order for three months following a three month lead in period. RESULTS: Simvastatin significantly reduced serum low density lipoprotein (LDL) cholesterol but biliary cholesterol concentration remained unchanged. Combination of the two drugs had no synergistic effect on serum cholesterol concentration, but significantly increased the proportion of UDCA in the bile acid pool from 35% during UDCA to 48% during combination treatment (p<0.04). CONCLUSIONS: Results showed that: (1) simvastatin reduces serum LDL cholesterol but has no effect on biliary cholesterol concentration, supporting the concept that newly synthesised cholesterol is not the preferential source for biliary cholesterol; and (2) combination of simvastatin with UDCA has the predicted effect of enhancing the proportion of UDCA in the pool. This effect may be of benefit in the treatment of cholestatic liver diseases.