Long-term outcome after surgery for Crohn's anal fistula.

AIM: Treatment of Crohn's anal fistula remains challenging and little is known about factors associated with healing. The aim of this study was to assess the rate of healing after surgical treatment and analyse clinical variables related to healing. METHOD: A total of 119 patients [63 women, mean age 36 (±13.7) years] with histopathologically verified Crohn's disease underwent a surgical procedure for anal fistula at four main referral centres in Sweden, January 1998 to December 2009. Baseline and treatment-related variables were recorded and analysed for correlation with fistula healing at a final follow-up after a mean of 7.2 (median 7.1, 1.0-17.5) years. RESULTS: Of the 119 patients 62 (52%) were healed at final follow-up. Fourteen healed after one procedure and the remaining 48 healed after a further median of 4.0 (2-20) procedures. Ten (8%) patients were subjected to a proctectomy. Final healing was more common in patients operated with a procedure aiming at eradicating the fistula (P = 0.0001), without proctitis (P = 0.02) and a shorter duration of Crohn's disease (P = 0.0019). CONCLUSION: Long-term healing of a Crohn's anal fistula can be expected in about half of the patients, usually after repeated surgical treatment. The probability for cure was higher when a curative operation was performed in a patient without proctitis and with a shorter duration of Crohn's disease. An attempt to close a Crohn's anal fistula is thus often worthwhile.

Effects of human intestinal flora on mutagenicity of and DNA adduct formation from food and environmental mutagens.

Although the intestinal flora is believed to have a critical role in carcinogenesis, little is known about the role of the human intestinal flora on the effects of mutagens in vivo. The aim of the present study was to address a possible role of the human intestinal flora in carcinogenesis, by exploiting human-flora-associated (HFA) mice. The capacity of human faeces to activate or inactivate 2-amino-3-methyl-3H:-imidazo[4,5-f]quinoline (IQ) and 2-nitrofluorene was determined using the Ames assay. Human faecal suspensions that were active in this regard were then selected and orally inoculated into germfree NMRI mice to generate HFA mice. HFA, germfree, conventionalized and conventional mice were administered IQ, 2-amino-9H:-pyrido[2,3-b]indole (2-amino-alpha-carboline; AAC) and 2-nitrofluorene. The activity of human intestinal flora against mutagens could be transferred into the mice. In comparing germfree mice and mice harbouring an intestinal flora, the presence of a flora was essential for the activities of faeces against mutagens. After administration of IQ and 2-nitrofluorene, DNA adducts were observed in the mice with a flora, while adducts were extremely low or absent in germfree animals. DNA adducts after AAC treatment were higher in germfree mice in some tissues including colon than in mice with bacteria. Differences in DNA adduct formation were also observed between HFA mice and mice with mouse flora in many tissues. These results clearly indicate that the intestinal flora have an active role in DNA adduct formation and that the role is different for the different chemicals to which the animals are exposed. The results also demonstrate that the human intestinal flora have different effects from the mouse flora on DNA adduct formation as well as in vitro metabolic activities against mutagens. Studies using HFA mice could thus provide much-needed information on the role of the human intestinal flora on carcinogenesis in vivo.

Effects of colectomy on bile composition, cholesterol saturation and cholesterol crystal formation in humans.

Total or subtotal colectomy is the surgical treatment of choice for patients with ulcerative colitis. Recently it has been reported that colectomy may lead to increased lithogenicity of bile, short nucleation time, cholesterol crystal formation, and gallstone disease. We examined whether colectomy in patients with ulcerative colitis leads to changes in bile composition that predisposes to cholesterol crystal formation and cholesterol gallstone disease. Ten consecutive patients who had previously undergone ileostomy and colectomy because of ulcerative colitis were admitted for ileal pouch surgery. At operation bile was obtained by puncture of the gallbladder. Controls were 35 patients undergoing cholecystectomy (23 for cholesterol gallstone disease and 12 for reasons other than gallstone disease). The gallbladder bile was analyzed for cholesterol crystals, bile acid, and biliary lipid composition, cholesterol saturation, and nucleation time. The colectomized patients had normal biliary lipid composition, normal cholesterol saturation, and normal nucleation time, in contrast to gallstone patients who displayed highly supersaturated bile with a short nucleation time. Thus patients with ileostomy after colectomy because of ulcerative colitis have normal cholesterol saturation and nucleation time of bile.

Clinical value of symptom assessment in patients with constipation.

PURPOSE: This study was designed to evaluate symptoms and clinical findings in a prospective series of patients with chronic constipation. METHODS: A total of 155 consecutive patients with intractable constipation underwent detailed symptom registration, anorectal manometry, electromyography, colonic transit time measurement, and defecography. RESULTS: All investigations were completed by 134 patients (112 females) with a median age of 52 (range, 17-79) years. Whole-gut transit time was delayed in 55 patients (41 percent), pelvic floor dysfunction was diagnosed in 59 patients (44 percent), but in 35 percent of patients both transit time and pelvic floor function were found to be normal. Three symptoms were shown to have an independent value for the diagnosis of slow-transit constipation. Patients with slow transit more often reported two or fewer stools per week (84 vs. 46 percent), laxative dependence (87 vs. 44 percent), and a history of constipation since childhood (58 vs. 22 percent) than did those with normal transit. Pelvic floor dysfunction was associated with a higher prevalence of backache (53 vs. 33 percent) and a lower prevalence of normal stool frequency (19 vs. 36 percent), heartburn (12 vs. 27 percent), and a history of anorectal surgery (7 vs. 21 percent) compared with those with normal pelvic floor function. All four symptoms retained an independent value in the logistic regression analysis for pelvic floor dysfunction. Two symptoms characterized the group with normal transit and normal pelvic floor function: normal stool frequency and alternating diarrhea and constipation. CONCLUSIONS: Symptoms are good predictors of transit time but poorer predictors of pelvic floor function in patients with constipation.

Biofeedback training in patients with fecal incontinence.

PURPOSE: This study was undertaken to assess the functional results of biofeedback training in patients with fecal incontinence in relation to clinical presentation and anorectal manometry results. METHODS: Twenty-six consecutive patients with fecal incontinence were treated with biofeedback training using anorectal manometry pressure for visual feedback. Ten patients had passive incontinence only, six patients had urge incontinence, and ten patients had combined passive and urge incontinence. RESULTS: Patients with urge incontinence had a lower maximum voluntary contraction pressure (92+/-12 mmHg) and a lower maximum tolerable volume (78+/-13 ml) than patients with passive incontinence (140+/-43 mmHg and 166+/-73 ml). Twenty-two patients completed the treatment, five patients (23 percent) showed excellent improvement, nine patients (41 percent) had good results, and eight (36 percent) patients showed no improvement. At follow-up on average of 21 months after therapy, 41 percent of our patients reported continued improvement. The maximum tolerable volume was higher in those with excellent (140.4+/-6.8 ml) or good (156.3+/-6.64 ml) results of therapy than it was in those with poor results (88.5+/-2.5 ml). Greater asymmetry of the anal sphincter also correlated to poor results. CONCLUSION: Biofeedback therapy improved continence immediately after training and at follow-up after 21 months, but the initial results were better. The urge fecal incontinence seems to be related to function of the external anal sphincter and to the maximum tolerable volume. Low maximum tolerable volume and anal sphincter asymmetry were associated with a poor outcome of therapy.

Constipation assessed on the basis of colorectal physiology.

BACKGROUND: Constipation is a collective term for symptoms of different aetiologies and pathophysiologies. Our aim was to determine the prevalence of colorectal pathophysiology findings in a prospective series of patients with chronic constipation. METHODS: A total of 155 consecutive patients with chronic constipation underwent anorectal manometry, electromyography (EMG), the balloon expulsion test, colonic transit-time study, and defecography. RESULTS: All investigations were completed by 134 patients (112 females) with a median age 52 (range, 17-79) years. Patients were categorized on the basis of transit time and pelvic-floor function as belonging to 1 of 4 groups: slow-transit constipation (STC) (delayed transit time but normal pelvic-floor function, n = 28), pelvic-floor dysfunction (PFD) (pelvic-floor dysfunction and normal transit time, n = 32), combined slow transit and pelvic-floor dysfunction (STC + PFD) (n = 27), and normal-transit constipation (NTC) (normal transit time and normal pelvic-floor function, n = 47). There was no difference between diagnostic groups in anal sphincter pressures. However, rectal sensitivity to balloon distension was lower (P < 0.05) in patients with delayed transit. Paradoxical puborectalis contraction (PPC) was found on EMG in 42 patients (31%). The prevalence of PPC was higher (P < 0.001) in patients with pelvic-floor dysfunction. Inability to evacuate the rectal balloon was reported by 37% of patients with pelvic-floor dysfunction and 12% of patients with normal pelvic-floor function (P < 0.001). Rectocele was the only anatomic abnormality at defecography which was associated with poor rectal emptying. CONCLUSIONS: About two-thirds of our patients with constipation had objective evidence of delayed transit or pelvic-floor dysfunction. No single test could reliably identify any of the pathophysiologic subgroups of constipation.

Biapenem versus imipenem/cilastatin in the treatment of complicated intra-abdominal infections: report from a Swedish Study Group.

118 patients with complicated intra-abdominal infections participated in an open randomized comparative multicenter trial in order to compare the clinical and microbiological efficacy and safety of biapenem with imipenem/cilastatin (Tienam). 31 men and 27 women (mean age 52.3 years) were enrolled in the biapenem group, and 43 men and 17 women (mean age 52.3 years) in the imipenem/cilastatin group. The patients received either biapenem 500 mg every 8 h or imipenem/cilastatin 500 mg/500 mg every 6 h by intravenous infusion for up to 13 days (mean 6.5 days). 28/43 evaluable patients (65.1%) receiving biapenem and 27/40 evaluable patients (67.5%) in the imipenem/cilastatin group were clinically cured. The microbiological response was satisfactory in 28/43 evaluable patients (65.1%) receiving biapenem and in 27/40 evaluable patients (67.5%) receiving imipenem/cilastatin. No significant differences in clinical or microbiological efficacy between the two treatment groups were found. The present study shows that biapenem may be useful in the treatment of intra-abdominal infections.

Apparent selective bile acid malabsorption as a consequence of ileal exclusion: effects on bile acid, cholesterol, and lipoprotein metabolism.

A new model has been developed to characterise the effect of a standardised ileal exclusion on bile acid, cholesterol, and lipoprotein metabolism in humans. Twelve patients treated by colectomy and ileostomy for ulcerative colitis were studied on two occasions: firstly with a conventional ileostomy and then three months afterwards with an ileal pouch operation with an ileoanal anastomosis and a protective loop ileostomy, excluding on average 95 cm of the distal ileum. The ileostomy contents were collected during 96 hours and the excretion of bile acids and cholesterol was determined using gas chromatography-mass spectrometry. Fasting blood and duodenal bile samples were collected on two consecutive days. After the exclusion of the distal ileum, both cholic and chenodeoxycholic acid excretion in the ileostomy effluent increased four to five times without any change in cholesterol excretion. Serum concentrations of lathosterol (a marker of cholesterol biosynthesis) and 7 alpha-hydroxycholesterol (a marker for bile acid biosynthesis) were increased several fold. Plasma concentrations of total VLDL triglycerides were also increased whereas the concentrations of total and LDL cholesterol, and apolipoprotein B were decreased. There were no changes in biliary lipid composition or cholesterol saturation of bile. The results show that the exclusion of about 95 cm of distal ileum causes malabsorption of bile acids but apparently not of cholesterol. The bile acid malabsorption leads to increased synthesis of both bile acids and cholesterol in the liver. It is suggested that bile acids can regulate cholesterol synthesis by a mechanism independent of the effect of bile acids on cholesterol absorption. The enhanced demand for cholesterol also leads to a decrease in plasma LDL cholesterol and apolipoprotein B concentrations. The malabsorption of bile acids did not affect biliary lipid composition or cholesterol saturations of VLDL triglycerides.

12 alpha-hydroxylase activity in human liver and its relation to cholesterol 7 alpha-hydroxylase activity.

Interruption of the enterohepatic circulation by cholestyramine causes a several-fold increase in bile acid synthesis, reflected in a stimulation of cholesterol 7 alpha-hydroxylase activity; the synthesis of cholic acid being stimulated to a greater extent than chenodeoxycholic acid. It is not known if this preferential increase in cholic acid is due to an increase of the 12 alpha-hydroxylase activity. The present study aimed at investigating the 12 alpha-hydroxylase activity and its relation to cholesterol 7 alpha-hydroxylase activity in liver microsomes of patients with different levels of cholesterol 7 alpha-hydroxylase activity. Liver biopsies were obtained from four gallstone-free patients, and seven untreated and two cholestyramine-treated gallstone patients undergoing cholecystectomy, and four patients with Crohn's disease undergoing intestinal resection. The combined group of cholestyramine-treated and ileum-resected patients had four times higher cholesterol 7 alpha-hydroxylase activity and two times higher 12 alpha-hydroxylase activity than the other patients. A positive correlation was obtained between cholesterol 7 alpha-hydroxylase activity and 12 alpha-hydroxylase activity (r = +0.69; n = 16). These results indicate that the increased ratio between the synthesis of cholic acid and chenodeoxycholic acid during cholestyramine treatment is due to a compensatory increase of the 12 alpha-hydroxylase activity.

Dose-dependent absorption of amoxicillin in patients with an ileostomy.

Amoxicillin was given as single doses of 375, 700, 1500, 3000 and 6000 mg an oral suspension to four volunteers with an ileostomy and with no active intestinal disease after an overnight fast. The excretion of amoxicillin and its penicilloic acid was followed in samples taken from the ileostomy and in urine produced over 6 h. Beta-lactamase activity was measured in ileal fluid and none was found. The percentage of the dose recovered from the ileostomy increased successively from 8% at the lowest dose to 77% at the highest dose. A complementary excretion pattern of amoxicillin was found in the urine, amounting to 70% recovery at the lowest dose to 23% at the highest dose. The results confirm the dose-dependence of the absorption of amoxicillin, which could at least in part be due to specialised absorption of this drug in humans.

Hepatic metabolism of cholesterol in Crohn's disease. Effect of partial resection of ileum.

To study cholesterol metabolism in Crohn's disease and especially the effect of ileum resection, liver biopsy specimens were obtained from patients undergoing partial ileal resection because of Crohn's disease (n = 17) and patients with Crohn's colitis undergoing colectomy (n = 3). Gallstone-free patients (n = 16) undergoing cholecystectomy because of adenomyomas or polyps of the gallbladder served as controls. The mean levels of cholesterol 7 alpha-hydroxylase activity and 3-hydroxy-3-methylglutaryl coenzyme A reductase activity, rate-determining enzymes in bile acid, and cholesterol synthesis, respectively, were twofold to threefold higher in the ileum-resected patients than in the controls. Significant positive correlations were obtained between length of resected ileum and cholesterol 7 alpha-hydroxylase activity. Provided patients who had received total parenteral nutrition preoperatively were excluded from analysis, a significant correlation was also observed between length of resected ileum and 3-hydroxy-3-methylglutaryl coenzyme A reductase activity. Significant positive correlations were also obtained between length of resected ileum and serum levels of 7 alpha-hydroxycholesterol (a marker for bile acid biosynthesis) and lathosterol (a marker for cholesterol synthesis). The plasma levels of total and low-density lipoprotein cholesterol were negatively correlated to the length of resected ileum. The expression of hepatic low-density lipoprotein-receptor binding activity was determined in five of the patients and in three of the controls. A significant positive correlation was observed between 3-hydroxy-3-methylglutaryl coenzyme A reductase activity and low-density lipoprotein-receptor binding activity. The results show that malabsorption of bile acids leads to parallel stimulation of cholesterol synthesis, cholesterol degradation, and low-density lipoprotein-receptor expression in human liver. The resulting effect in the present patients was a significant reduction in low-density lipoprotein cholesterol.

Studies on the regulation of cholesterol 7 alpha-hydroxylase and HMG-CoA reductase in rat liver: effects of lymphatic drainage and ligation of the lymph duct.

Lymphatic drainage leads to a significant stimulation of both the cholesterol 7 alpha-hydroxylase and HMG-CoA reductase activity in rats (Björkhem et al. 1978. Biochem. Biophys. Res. Commun. 85: (532-540). This finding was confirmed here and it was also shown that ligation of the lymph duct leads to a similar but less pronounced effect. Ligation of the lymph duct or lymph fistulation of bile duct-ligated or cholestyramine-treated rats did not further increase 7 alpha-hydroxylase or the HMG-CoA reductase activity. However, treatment of lymph fistula rats with cholestyramine led to a significant further stimulation of both 7 alpha-hydroxylase and HMG-CoA reductase activity. Intravenous infusion of lymph into bile fistula rats led to a significant inhibition of both cholesterol 7 alpha-hydroxylase activity and HMG-CoA reductase activity. A corresponding infusion of cholesterol-enriched Intralipid led to inhibition of HMG-CoA reductase without effect on cholesterol 7 alpha-hydroxylase activity. The results show that cholesterol 7 alpha-hydroxylase is feedback-regulated by bile acids in a situation where the flux of cholesterol to the liver is interrupted also. The possibility is discussed that there is a factor in the lymph that down-regulates cholesterol 7 alpha-hydroxylase. If such a factor exists, it requires an intact enterohepatic circulation for its effect. The stimulatory effect of cholestyramine on HMG-CoA reductase also in lymph fistula rats shows that the previously demonstrated suppressive effect of bile acids on HMG-CoA reductase is not only due to the effect of bile acids on intestinal absorption of cholesterol.(ABSTRACT TRUNCATED AT 250 WORDS)

Polyglycolic acid (Dexon) mesh for packing to control intra-abdominal bleeding. Case report.

Profuse bleeding from parasacral veins during abdominoperineal excision of the rectum for carcinoma was controlled by packing the pelvic cavity with polyglycolic acid (Dexon) mesh. The mesh pack could be left in place without giving rise to infection or otherwise interfering with the postoperative course.

Effect of sitosterol on the rate-limiting enzymes in cholesterol synthesis and degradation.

Attempts were made to develop an animal model for phytosterolemia. Infusion of Intralipid containing 0.2% sitosterol in rats gave circulating levels of sitosterol of about 2.5 mmol/l, which is similar to or higher than those present in patients with untreated phytosterolemia. In addition, the infusions gave serum levels of cholesterol nearly twice those obtained in rats infused with Intralipid alone or Intralipid containing 0.2% cholesterol. The hepatic HMG-CoA reductase activity was unaffected or slightly increased by the sitosterol infusions (not statistically significant). The cholesterol 7 alpha-hydroxylase activity was slightly depressed (ca. 30%). In the case of 7 alpha-hydroxylation of endogenous cholesterol, the depression reached statistical significance (p less than 0.05). The microsomal content of sitosterol in the sitosterol-infused rats was about 30% of that of microsomal cholesterol. The effect of sitosterol on 7 alpha-hydroxylation of cholesterol was investigated by incubations of acetone powder of rat liver microsomes with mixtures of cholesterol and sitosterol. Sitosterol mixed with cholesterol to a composition similar to that found in the above microsomal fraction had a depressing effect on 7 alpha-hydroxylation of cholesterol. This degree of depression was of the same magnitude as that found in the sitosterol infusion experiments. The possibility is discussed that the hypercholesterolemia obtained in the beta-sitosterol-infused rats is due to the inhibitory effect of sitosterol on the cholesterol 7 alpha-hydroxylase.

Studies on the link between HMG-CoA reductase and cholesterol 7 alpha-hydroxylase in rat liver.

Under most experimental conditions, there is a covariation between the rate-limiting enzyme in cholesterol biosynthesis, HMG-CoA reductase, and the rate-limiting enzyme in bile acid biosynthesis, cholesterol 7 alpha-hydroxylase. The most simple explanation for the coupling between the two enzymes is that newly synthesized cholesterol is a substrate for an unsaturated cholesterol 7 alpha-hydroxylase and that substrate availability is of major regulatory importance for this enzyme. The following results seem, however, to rule out that such a simple regulatory mechanism is of major importance and that HMG-CoA reductase activity per se is of importance in the regulation of cholesterol 7 alpha-hydroxylase. 1) The apparent degree of saturation of cholesterol 7 alpha-hydroxylase, as measured in vitro in rat liver microsomes, was found to be relatively high (70-90%) under most experimental conditions, including starvation, cholestyramine treatment, and cholesterol treatment. A significant decrease in the degree of saturation was obtained first after a drastic reduction of total concentration of cholesterol in the microsomes by treatment with high doses of triparanol, an inhibitor of cholesterol biosynthesis. 2) The stimulatory effect of cholesterol feeding on cholesterol 7 alpha-hydroxylase activity in rats seems to be an effect on the enzyme activity (enzyme induction?) rather than an effect on substrate availability. Thus, the stimulatory effect of cholesterol feeding was retained also after almost complete removal of the endogenous cholesterol by extraction with acetone.(ABSTRACT TRUNCATED AT 250 WORDS)

On the possible use of the serum level of 7 alpha-hydroxycholesterol as a marker for increased activity of the cholesterol 7 alpha-hydroxylase in humans.

The possibility was investigated that the serum level of 7 alpha-hydroxycholesterol can be used as a marker for cholesterol 7 alpha-hydroxylase activity. Six patients with gallstone disease were found to have a mean level of 7 alpha-hydroxycholesterol in serum of 30 +/- 4 ng/ml (mean +/- SEM) as measured by isotope dilution-mass spectrometry, using deuterated 7 alpha-hydroxycholesterol as internal standard. After treatment with cholestyramine in a dose of 8 g twice daily for 2-3 weeks preoperatively, the serum level increased to 128 +/- 20 ng/ml (P less than 0.001). Eight other patients with gallstone disease had a mean level of 7 alpha-hydroxycholesterol in serum of 29 +/- 7 ng/ml. Treatment with chenodeoxycholic acid, 15 mg per kg body weight per day for 3-4 weeks before surgery, decreased the mean level to 20 +/- 7 ng/ml (P greater than 0.05). The activity of the cholesterol 7 alpha-hydroxylase in liver biopsies taken during operation was found to be 38 +/- 5 pmol/min per mg of protein in the group of patients treated with cholestyramine and 1.3 +/- 0.5 pmol/min per mg in the group of patients treated with chenodeoxycholic acid. Liver biopsies from a group of untreated patients (n = 13) had a mean cholesterol 7 alpha-hydroxylase activity of 7.6 +/- 1.5 pmol/min per mg.(ABSTRACT TRUNCATED AT 250 WORDS)

The pool of free cholesterol is not of major importance for regulation of the cholesterol 7 alpha-hydroxylase activity in rat liver microsomes.

The relationship between the cholesterol 7 alpha-hydroxylase activity and the pool of free cholesterol in rat liver microsomes was studied under experimental conditions aimed to stimulate (biliary drainage, cholestyramine treatment, and lymphatic drainage) as well as inhibit (chenodeoxycholic acid treatment) bile acid synthesis. Highly accurate methods based on isotope dilution-mass spectrometry were used both for assay of the cholesterol 7 alpha-hydroxylase activity and the concentration of free cholesterol in the microsomes. In the assay of the cholesterol 7 alpha-hydroxylase, only endogenous cholesterol was used as substrate for the enzyme. Under the experimental conditions employed, the concentration of microsomal free cholesterol remained essentially unchanged in spite of a more than 20-fold variation in enzyme activity. It is concluded that the total pool of free cholesterol in the microsomes is not of major regulatory importance for the cholesterol 7 alpha-hydroxylase in rats.