Effects of conventional and a novel colonic-release bile acid sequestrant, A3384, on fibroblast growth factor 19 and bile acid metabolism in healthy volunteers and patients with bile acid diarrhoea.

BACKGROUND: Primary bile acid diarrhoea (BAD) is associated with increased bile acid synthesis and low fibroblast growth factor 19 (FGF19). Bile acid sequestrants are used as therapy, but are poorly tolerated and may exacerbate FGF19 deficiency. AIM: The purpose of this study was to evaluate the pharmacological effects of conventional sequestrants and a colonic-release formulation preparation of colestyramine (A3384) on bile acid metabolism and bowel function in patients with BAD. METHODS: Patients with seven-day 75selenium-homocholic acid taurine (SeHCAT) scan retention <10% were randomised in a double-blind protocol to two weeks treatment with twice-daily A3384 250 mg (n = 6), 1 g (n = 7) or placebo (n = 6). Thirteen patients were taking conventional sequestrants at the start of the study. Symptoms were recorded and serum FGF19 and 7α-hydroxy-4-cholesten-3-one (C4) measured. RESULTS: Median serum FGF19 on conventional sequestrant treatment was 28% lower than baseline values in BAD (p < 0.05). C4 on conventional sequestrant treatment was 58% higher in BAD (p < 0.001). No changes were seen on starting or withdrawing A3384. A3384 improved diarrhoeal symptoms, with a median reduction of 2.2 points on a 0-10 Likert scale compared to placebo, p < 0.05. CONCLUSIONS: Serum FGF19 was suppressed and bile acid production up-regulated on conventional bile acid sequestrants, but not with A3384. This colonic-release formulation of colestyramine produced symptomatic benefit in patients with BAD.

Cultured blood T-cell responses predict anti-TNF therapy response in patients with ulcerative colitis.

BACKGROUND: Anti-tumour necrosis factor (TNF) therapy is used for treatment of ulcerative colitis (UC). As approximately 30% of patients with UC do not benefit from the treatment, it is of clinical interest to identify biomarkers of response before therapy is initiated. AIM: To identify prognostic biomarkers of anti-TNF therapy response in anti-TNF therapy-naïve patients with UC. METHODS: Peripheral blood cells were obtained from 56 patients with UC before therapy started. Thirty-four patients were included in an exploratory cohort and 22 patients in a validation cohort. Blood cells were stimulated in vitro with influenza vaccine with and without anti-TNF. T-cell surface receptor expression and cytokine release were determined (in total 17 variables). Treatment response was evaluated using the Mayo score 12-14 weeks after the first infusion. RESULTS: In the exploratory cohort, blood cells from the patients showed stronger anti-TNF-dependent suppression of T-cell surface receptor expression and cytokine secretion among therapy responders than nonresponders. In particular, anti-TNF suppressed the expression of CD25 on T cells and secretion of interleukin 5, to a higher degree in responders than in nonresponders. These variables were used to a create model to predict therapy outcome, which was confirmed in the validation cohort. Correct classification of future therapy response was achieved in 91% of the cases in the validation cohort. CONCLUSION: The effects of anti-TNF on cultured blood T cells, obtained before therapy started, predict treatment outcome in patients with UC.

Comparison study of portable bladder scanner versus cone-beam CT scan for measuring bladder volumes in post-prostatectomy patients undergoing radiotherapy.

INTRODUCTION: In post-prostatectomy radiotherapy to the prostatic bed, consistent bladder volume is essential to maintain the position of treatment target volume. We assessed the differences between bladder volume readings from a portable bladder scanner (BS-V) and those obtained from planning CT (CT-V) or cone-beam CT (CBCT-V). Interfraction bladder volume variation was also determined. METHODS: BS-V was recorded before and after planning CT or CBCT. The percentage differences between the readings using the two imaging modalities, standard deviations and 95% confidence intervals were determined. Data were analysed for the whole patient cohort and separately for the older BladderScan™ BVI3000 and newer BVI9400 model. Interfraction bladder volume variation was determined from the percentage difference between the CT-V and CBCT-V. Treatment duration, incorporating the time needed for BS and CBCT, was recorded. RESULTS: Fourteen patients were enrolled, producing 133 data sets for analysis. BS-V was taken using the BVI9400 in four patients (43 data sets). The mean BS-V was 253.2 mL, and the mean CT-V or CBCT-V was 199 cm(3). The mean percentage difference between the two modalities was 19.7% (SD 42.2; 95%CI 12.4 to 26.9). The BVI9400 model produced more consistent readings, with a mean percentage difference of -6.2% (SD 27.8; 95% CI -14.7 to -2.4%). The mean percentage difference between CT-V and CBCT-V was 31.3% (range -48% to 199.4%). Treatment duration from time of first BS reading to CBCT was, on average, 12 min (range 6-27). CONCLUSIONS: The BS produces bladder volume readings of an average 19.7% difference from CT-V or CBCT-V and can potentially be used to screen for large interfraction bladder volume variations in radiotherapy to prostatic bed. The observed interfraction bladder volume variation suggests the need to improve bladder volume consistency. Incorporating the BS into practice is feasible.

Indirect evidence for increased mechanosensitivity of jejunal secretomotor neurones in patients with idiopathic bile acid malabsorption.

AIM: The interdigestive motor rhythm, the migrating motor complex (MMC), is accompanied by active secretion of chloride during periods of distally propagating maximal motor activity (MMC phase III). We studied the behaviour of this system in bile acid malabsorption (BAM), a relative common cause of chronic diarrhoea. We measured motor activity and transmucosal potential difference (PD, reflecting active chloride secretion), in the proximal jejunum in healthy controls (n = 18) and in a group of patients with BAM (n = 11). The phase III-generated voltage was related to the degree of BAM quantified by the (75)SeHCAT test. METHODS: We used a multi-channel intestinal infusion system to simultaneously measure jejunal pressure and PD. Saline passing calomel half-cells was infused into the jejunum and subcutaneously. Pressure and PD were recorded in the fasting state and after a test meal. RESULTS: In the absence of motor activity, jejunal PD was not significantly different from zero in either group. During MMC phase III, PD reached significantly higher mean and peak levels in BAM patients. The product of MMC phase III length multiplied by voltage, over 3 h, was also significantly higher in BAM patients (controls: median 307 mV x cm, range 70-398; BAM: median 511, range 274-2271, P < 0.01). This value was also significantly correlated with the degree of BAM as reflected by the (75)SeHCAT test (P < 0.05). CONCLUSION: Phase III induced jejunal secretion may be upregulated in BAM patients, resulting in overload of colonic reabsorption capacity.

Budesonide treatment is associated with increased bile acid absorption in collagenous colitis.

BACKGROUND: Bile acid malabsorption is frequent in collagenous colitis and harmful bile acids may play a pathophysiological role. Glucocorticoids increase ileal bile acid transport. Budesonide have its main effect in the terminal ileum. AIMS: To evaluate whether the symptomatic effect of budesonide is linked to increased uptake of bile acids. METHODS: Patients with collagenous colitis were treated with budesonide 9 mg daily for 12 weeks. Prior to and after 8 weeks of treatment, the (75)SeHCAT test, an indirect test for the active uptake of bile acid-s, measurements of serum 7alpha-hydroxy-4-cholesten-3-one, an indicator of hepatic bile acid synthesis, and registration of symptoms were performed. RESULTS: The median (75)SeHCAT retention increased from 18% to 35% (P < 0.001, n = 25) approaching the values of healthy controls (38%). The 7alpha-hydroxy-4-cholesten-3-one values decreased significantly among those with initially high synthesis (from 36 to 23 ng/mL, P = 0.04, n = 9); however, for the whole group the values were not altered (19 ng/mL vs. 13 ng/mL, P = 0.23, N.S., n = 19). CONCLUSION: The normalization of the (75)SeHCAT test and the reduction of bile acid synthesis in patients with initially high synthetic rate, suggests that the effect of budesonide in collagenous colitis may be in part due to decreased bile acid load on the colon.

Effect of budesonide enema on remission and relapse rate in distal ulcerative colitis and proctitis.

BACKGROUND: Glucocorticosteroid enemas are equally effective as 5-ASA enemas in the treatment of active distal ulcerative colitis (UC). With the introduction of budesonide, the risk of systemic side effects may be reduced. We investigated whether budesonide enema, 2 mg/100 ml, administered twice daily (b.i.d.) could increase the remission rate in comparison with the once daily (o.d.) standard regimen. Furthermore, we evaluated whether 2 mg budesonide enema, given twice weekly, could have a relapse preventing effect. METHODS: 149 patients with active distal UC were treated in a controlled, double-blind multicentre study with two parallel groups: placebo enema in the morning and budesonide enema in the evening (i.e. 2 mg/day) or budesonide enema b.i.d. (i.e. 4 mg/day) until remission (absence of clinical symptoms and endoscopic healing) or at most 8 weeks. Patients in remission were randomized to either budesonide enema or placebo enema twice weekly for 24 weeks or until relapse. RESULTS: The remission rates at 4 weeks were 33% for o.d. and 41% for b.i.d. regimens (NS) and correspondingly 51% and 54% at 8 weeks (NS). The b.i.d. group had an increased frequency of impaired adrenal function, 32% versus 4.8% (P = 0.001). The relapse rates during maintenance treatment with budesonide enema and placebo were 15% versus 24% after 8 weeks, 31% versus 27% after 16 weeks and 41% versus 51% after 24 weeks (NS). CONCLUSION: Budesonide enema 2 mg o.d. appears to be the optimal dosage in active distal UC. We could not show that budesonide enema twice weekly is sufficient to maintain remission.

In vitro determination of active bile acid absorption in small biopsy specimens obtained endoscopically or surgically from the human intestine.

BACKGROUND: In the construction of a Kock reservoir for continent urinary diversion, 70 cm of the distal ileum are used. Impaired absorption of bile acids in these patients might cause diarrhoea. Data on the absorption of bile acids in different parts of the human intestine are limited. METHODS: Biopsies were taken during endoscopy from the duodenum, the terminal ileum or the right colon, and during surgery 10, 50, 100 and 150 cm proximally to the ileo-caecal valve using standard endoscopy biopsy forceps. The biopsy specimens were incubated in vitro with radio-labelled taurocholic acid at 37 degrees C for 22 or 45 min The radioactivity was determined using the liquid scintillation technique. RESULTS: A linear increase in the uptake was observed, with increased concentrations of taurocholic acid between 100 and 500 microm in all specimens tested, that represented passive uptake or unspecific binding. The active uptake could be calculated from the intercept of the line representing passive uptake with the ordinate. The active uptake in the terminal ileum was 3-4 times greater than 100 cm proximal to the valve. CONCLUSIONS: The active absorption of bile acids in humans can be determined in small biopsy specimens taken using standard biopsy forceps during endoscopy or surgery. This method is suitable for clinical studies of bile acid absorption. Active uptake of bile acids not only takes place in the very distal part of the ileum but also to a considerable degree 100 cm proximally to the ileo-colonic valve. This should be taken into account when selecting the ileal segment for continent urinary diversion.

Long-term course in collagenous colitis and the impact of bile acid malabsorption and bile acid sequestrants on histopathology and clinical features.

BACKGROUND: Bile acid malabsorption is common in collagenous colitis, although long-term follow-up data on the impact of bile acids are limited. The aim was to study whether bile acid malabsorption is a permanent finding, with an impact on histopathology and clinical features in collagenous colitis. METHODS: The objective was to reinvestigate 27 patients with collagenous colitis > or = 3 years after index investigation. The clinical course was evaluated by means of an interview, a review of the hospital records and registration of symptoms over a period of 7 days. The patients were invited to undergo a repeat colonoscopy and 75SeHCAT measurement. Initial and follow-up data and 75SeHCAT values from 29 controls were compared. RESULTS: The median follow-up time was 4.2 (range 3-5.3) years. Twenty-two patients underwent a repeat 75SeHCAT test, 23 patients a colonoscopy and in 25 patients the clinical course could be evaluated. The 75SeHCAT values were abnormal in 32% at follow-up versus 44% at index, and the median retention value was 19% (range 2-69) versus 12% (range 0.5-41) (P = 0.024) although lower than in the control groups figure of 38% (range 8-91) (P < 0.005). Histopathology had improved independently of bile acid malabsorption, gender, smoking and autoimmune disease at follow-up. Four were normalized. Patients on bile acid binders had no significant change of histopathology. Four patients had recovered, seven displayed an intermittent course and 14 had continuous diarrhoea. CONCLUSIONS: Collagenous colitis and bile acid malabsorption seem to be associated yet independent disorders. The histopathology improves during the long-term course although only a few patients resolve.

Vitamin B12 metabolism after urinary diversion with a Kock ileal reservoir.

OBJECTIVE: To elucidate the influence of construction of a Kock reservoir for urinary diversion using 70 cm of the distal ileum on vitamin B12 metabolism. MATERIAL AND METHODS: Blood samples for determination of cobalamin concentrations were drawn up to 18 years after construction of a Kock reservoir in 97 patients. Preoperative values were obtained in 20 of these patients. Pre- and postoperative Schilling tests and analyses of methylmalonic acid and homocysteine concentrations were performed in subgroups. RESULTS: The operation did not induce a significant decrease in cobalamin uptake as reflected in the pre- and postoperatively performed Schilling tests. No significant decline in cobalamin concentration postoperatively was noted. The value of analysis of methylmalonic acid and homocysteine concentrations in finding patients with cobalamin deficiency is limited by the fact that kidney function influences the results. Ten per cent of the patients did develop true cobalamin deficiency. A postoperative vitamin B12 value below 200 pmol/l indicates a 50% risk of later cobalamin deficiency. CONCLUSIONS: The construction of a Kock reservoir does not per se cause cobalamin deficiency. Substitution should be instituted at a postoperative concentration below 200 pmol/l.

Eosinophilic hepatic necrosis in hypereosinophilic syndrome.

Hypereosinophilic syndrome has been reported to be associated with liver disease, predominantly in men, in the form of acute and chronic active hepatitis with an inflammatory infiltrate that is mainly composed of eosinophils. We describe a female patient with peripheral blood and bone marrow eosinophilia, in whom liver biopsy displayed areas of necrosis with eosinophilic inflammation, with other regions showing features of chronic hepatitis. The patient also had antimitochondrial antibodies in serum. She responded favorably to immunosuppressive therapy.

Impact of bile acid malabsorption on steatorrhoea and symptoms in patients with chronic diarrhoea.

OBJECTIVE: Bile acids are important for fat absorption. The relationship between bile acid malabsorption and steatorrhoea and gastrointestinal symptoms in patients with chronic diarrhoea has only been studied on a limited scale. DESIGN: Ninety-four patients referred for chronic diarrhoea were prospectively investigated with the 75SeHCAT test, a faecal fat excretion test and registration of symptoms in addition to the standard clinical work-up. METHODS: The correlation between the 75SeHCAT value and the faecal fat excretion was calculated for different groups of patients. Symptoms were registered in a questionnaire over a period of seven consecutive days. RESULTS: Forty-two patients had a 75SeHCAT value < 10%. Mild steatorrhoea was common in patients with non-organic bile acid malabsorption (50%) and in patients with functional diarrhoea (38%). There was no correlation between low 75SeHCAT values and steatorrhoea, although some patients with severe organic disease had a concomitant malabsorption of fat and of bile acids. In coeliac disease, severe steatorrhoea was common even in patients with high 75SeHCAT values. Patients with bile acid malabsorption had more frequent (P < 0.008) and looser (P= 0.0021) stools compared with patients with functional diarrhoea. There was no difference in abdominal pain, distension or flatulence. CONCLUSION: Mild steatorrhoea is common in both non-organic bile acid malabsorption and functional diarrhoea. The 75SeHCAT value cannot predict the risk of steatorrhoea. The high prevalence of bile acid malabsorption in patients with chronic diarrhoea and the absence of specific symptoms, except frequent and more liquid stools, indicates that the 75SeHCAT test should be performed early in the investigation of these patients.

Role of bile acids and bile acid binding agents in patients with collagenous colitis.

BACKGROUND: In a retrospective study bile acid malabsorption was observed in patients with collagenous colitis. AIMS: To study the occurrence of bile acid malabsorption and the effect of bile acid binders prospectively in patients with chronic diarrhoea and collagenous colitis. METHODS: Over 36 months all patients referred because of chronic diarrhoea completed a diagnostic programme, including gastroscopy with duodenal biopsy, colonoscopy with biopsies, and the (75)Se-homocholic acid taurine ((75)SeHCAT) test for bile acid malabsorption. Treatment with a bile acid binder (cholestyramine in 24, colestipol in three) was given, irrespective of the results of the (75)SeHCAT test. RESULTS: Collagenous colitis was found in 28 patients (six men, 22 women), 27 of whom had persistent symptoms and completed the programme. Four patients had had a previous cholecystectomy or a distal gastric resection. The (75)SeHCAT test was abnormal in 12/27 (44%) of the collagenous colitis patients with (75)SeHCAT values 0.5-9.7%, and normal in 15 patients (56%). Bile acid binding treatment was followed by a rapid, marked, or complete improvement in 21/27 (78%) of the collagenous colitis patients. Rapid improvement occurred in 11/12 (92%) of the patients with bile acid malabsorption compared with 10/15 (67%) of the patients with normal (75)SeHCAT tests. CONCLUSION: Bile acid malabsorption is common in patients with collagenous colitis and is probably an important pathophysiological factor. Because of a high response rate without serious side effects, bile acid binding treatment should be considered for collagenous colitis, particularly patients with bile acid malabsorption.

Bile acid malabsorption after continent urinary diversion with an ileal reservoir.

PURPOSE: We determine the effect of urinary diversion with a Kock ileal reservoir on bile acid absorption and bowel habits. MATERIALS AND METHODS: We asked 96 patients with a Kock ileal urinary reservoir to record bowel habits and abdominal symptoms for 1 week. Data on 75 patients were further analyzed. Bile acid absorption was determined in 29 healthy control subjects, in 17 before and 6 months after continent urinary diversion, and in 21, 2 to 14 years postoperatively. Bile acid absorption was considered pathological when retention of less than 10% of an oral capsule containing selenium-75 labeled tauroselcholic acid (SeHCAT) was noted after 1 week. RESULTS: Mean number of defecations plus or minus standard deviation was 9.4 +/- 6.1 (75 cases). Of the patients 13% had 15 or more stools per week and 15% complained of always having loose stools. Mean value for the SeHCAT test was 32 +/- 19% preoperatively and 17 +/- 16% 6 months postoperatively (p = 0.0023). The corresponding value for healthy controls was 39 +/- 18%. Significant relationships were found between the results of the SeHCAT test postoperatively, and the number of stools per week and consistency of the feces. All patients with more than 10 defecations per week had a pathological SeHCAT test. CONCLUSIONS: Most patients with an ileal urinary reservoir have fairly normal bowel habits. Bile acid absorption is significantly reduced postoperatively and approximately a third of the patients have a pathological SeHCAT test. Preoperative investigation of bowel habits is recommended and a SeHCAT test should be performed in patients with frequent, loose defecations. Other types of diversion should be offered when preoperative retention is below 10 to 20% especially in patients with impaired anal control.

Segmental epidural analgesia for labor and delivery.

A study to evaluate segmental epidural analgesia in labor is described. Bupivacaine (0.25 per cent) was used during the first stage of labor and for the second stage, either 3 per cent - Chloroprocaine delivered through the catheter (Group I) or 1 per cent Lidocaine as a perineal infiltrate (Group II) was used. There were 124 full term patients of whom, 36 were nulliparous and 88 were multiparous. The effects of segmental epidural analgesia on maternal blood pressure, pain relief, preservation of lower limb motor power, duration and progress of labor, and fetal outcome were evaluated. Pain relief during the first stage of labor was satisfactory in 114 (92 per cent) of the patients. There were no significant changes in maternal blood pressure, motor power in lower limbs, efficiency of uterine contractions and internal rotation of the presenting part when analgesia was effective. The use of 2-Chloroprocaine for second stage pain relief required low forceps delivery in 84 (91 per cent) patients, as compared to 14 (44 per cent) patients that had 1 per cent Lidocaine local infiltration. Fetal outcome, was excellent in all cases in that the one minute Apgar score was never lower than 7.