Dagny Ståhlberg

Pouchitis following pelvic pouch operation for ulcerative colitis

AIM: This study was undertaken to assess the risk for pouchitis in patients with ulcerative colitis who underwent surgery with colectomy, restorative pelvic pouch, and ileoanal anastomosis and to evaluate possible factors predictive for pouchitis development. PATIENTS AND METHODS: All patients receiving a pelvic pouch because of ulcerative colitis at Huddinge University Hospital between 1980 and 1993 (n=149; 89 men) were prospectively evaluated for symptoms suggestive of pouchitis. Diagnosis of pouchitis was based on occurrence of certain symptoms in combination with endoscopic findings. Pouchitis was divided into mild and severe, and the time span until the first attack of mild or severe pouchitis was calculated for each patient. RESULTS: Median follow-up time was 54 (5–152) months. The absolute cumulative risk of developing mild pouchitis was 21, 26, and 39 percent at 6, 12, and 48 months, respectively. The corresponding cumulative risk of developing severe pouchitis was 9, 11, and 14 percent, respectively. Risk for both groups together was 51 percent at 48 months. The occurrence of pouchitis, calculated at six-month intervals after closure of the loop ileostomy, was highest (23.1 percent) during the first six months. Incidence during the next six-month period was 11.4 percent and then only 3.1 percent thereafter. Thirty-two patients (21.5 percent) had chronic continuous symptoms requiring long-term metronidazole treatment, and 14 (9.4 percent) of those had chronic severe pouchitis. In two patients, removal of the pouch and permanent ileostomy became necessary. Extracolonic manifestations and early onset of ulcerative colitis were predictive factors for developing pouchitis. Former smoking seemed to be a protective factor. CONCLUSION: The risk for pouchitis was highest during the initial six-month period. Cumulative risk leveled off after two years but was substantial (51 percent) at four years. Less than 10 percent of patients had severe, chronic pouchitis, and only two patients (1.3 percent) had their pouches removed.

Neoplastic Transformation of the Pelvic Pouch Mucosa in Patients With Ulcerative Colitis

BACKGROUND & AIMS Some patients with ulcerative colitis (UC) receiving an ileal pelvic pouch with ileoanal anastomosis (IPAA) develop persistent severe villous atrophy in the pouch mucosa. To investigate if mucosal atrophy indicates a risk for subsequent neoplastic transformation of the ileal pouch mucosa, a follow-up study was undertaken. METHODS Seven patients with UC and an IPAA in whom persistent severe atrophy (type C) developed and 14 control patients with no or only slight atrophy (type A) were prospectively surveyed by flexible videoendoscopy with multiple biopsies for assessment of possible neoplastic changes. RESULTS The median time of the pouch in function was 9 years for both groups. Dysplasia was found in 5 of 7 patients in the type C group (71%) compared with none in the type A group (P < 0.001). Four patients had low-grade dysplasia, and 1 patient had sequential multifocal development into high-grade dysplasia. Multifocal DNA aneuploidy was found in 2 patients, 1 with low-grade and 1 with high-grade dysplasia. CONCLUSIONS Patients with UC and a long-standing IPAA who develop persistent severe mucosal atrophy are at risk also of neoplastic transformation of the pouch mucosa.

Bile acid sequestrants: mechanisms of action on bile acid and cholesterol metabolism

SummaryInterruption of the enterohepatic circulation of bile acids by cholestyramine or colestipol influences the hepatic metabolism of cholesterol in many ways. The synthesis of bile acids is increased, as reflected by a several-fold increase in the activity of the cholesterol 7a hydroxylase, the rate-determining enzyme in bile acid synthesis. The increased metabolism of cholesterol to bile acids causes an enhanced demand of cholesterol in the hepatocytes, which respond with both new synthesis of cholesterol, as reflected in a several-fold increase of the HMG-CoA reductase activity, and increased expression of LDL receptors. As a consequence, the plasma level of LDL-cholesterol is lowered. The hepatic secretion rate of VLDL particles is increased. Cholestyramine therapy does not affect the output of biliary lipids or the cholesterol saturation of bile, indicating that treatment with bile acid sequestrants should not be associated with any increased risk of gallstone formation.

Hepatic cholesterol metabolism in estrogen-treated men

Operative liver biopsies were obtained from two male patients who developed gallstone disease during estrogen treatment of metastatic prostatic carcinoma. The heparin-sensitive binding of 125I-low-density lipoprotein (LDL) to liver homogenates (reflecting the expression of the LDL receptor) was determined, together with the activities of the rate-limiting enzymes in cholesterol synthesis [3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase], bile acid production (cholesterol 7 alpha-hydroxylase), and cholesterol esterification (acyl CoA:cholesterol acyl transferase). The results were related to data available in 18 patients (5 male, 13 female) who underwent cholecystectomy because of gallstone disease. The hepatic 125I-LDL-binding activity was increased threefold compared with five controls, and the activity of HMG-CoA reductase was increased twofold. There was no major difference in the activities of cholesterol 7 alpha-hydroxylase or acyl CoA:cholesterol acyl transferase. The concentration of free and total cholesterol in liver microsomes was approximately 30% lower in the estrogen-treated men than in 11 controls. The results indicate that estrogen at pharmacological doses stimulates hepatic LDL-receptor expression and HMG-CoA reductase activity in men. The increased LDL-receptor expression could in part explain the enhanced plasma clearance of injected 125I-LDL and hence the reduction in plasma LDL cholesterol previously shown to occur in estrogen-treated men.

Atrophy and neoplastic transformation of the ileal pouch mucosa in Patients with ulcerative colitis and primary sclerosing cholangitis: A case control study

AbstractINTRODUCTION: Patients with ulcerative colitis and primary sclerosing cholangitis have an increased risk of developing carcinoma both in the bile ducts and in the colon. PURPOSE: To investigate whether this patient group also has an increased risk of developing atrophy and neoplasia in the ileal pouch mucosa after construction of a pelvic pouch with an ileoanal anastomosis or a continent Kock ileostomy. METHODS: Flexible video endoscopic examinations of the ileal pouch were performed in 16 patients with ulcerative colitis and primary sclerosing cholangitis and in 16 matched patients with ulcerative colitis without sclerosing cholangitis. Biopsies were sampled from different locations in the pouch for histologic assessment of mucosal atrophy and dysplasia and for flow cytometric DNA analysis assessing chromosomal aberrations. RESULTS: The patients with sclerosing cholangitis developed moderate or severe atrophy in the pouch significantly more often (P < 0.01). Persistent severe mucosal atrophy was revealed in eight patients with sclerosing cholangitis and only in two controls. One patient with sclerosing cholangitis had high-grade dysplasia in multiple locations. Low-grade dysplasia was assessed in three patients with sclerosing cholangitis and in two of the controls. DNA aneuploidy was displayed in three patients, all with sclerosing cholangitis and dysplasia. All patients with neoplastic transformation had a pouch with ileoanal anastomosis and a long pouch duration (> 8 years). CONCLUSION: Patients with ulcerative colitis and primary sclerosing cholangitis with an ileal reservoir are more prone to developing mucosal atrophy in the pouch and seem to have a higher risk of neoplastic transformation in the pouch mucosa than patients with ulcerative colitis without sclerosing cholangitis.

Age-related changes in the metabolism of cholesterol in rat liver microsomes

The effects of aging on the hepatic metabolism of cholesterol were studied in 1-, 6- and 24-month-old male Sprague-Dawley rats. Microsomal 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase activity, which regulates cholesterol biosynthesis, decreased from 835±144 (SEM) pmol/min/mg protein in the youngest group to 219±34 and 205±53 pmol/min/mg protein (p<0.001) in the 6- and 24-month-old groups, respectively. Cholesterol 7α-hydroxylase activity, which governs bile acid synthesis, was gradually reduced from 70±14 pmol/min/mg protein in the 1-month-old group to 32±7 and 16±3 pmol/min/mg protein (p<0.05) in the 6- and 24-month-old groups, respectively. Acyl coenzyme A:cholesterol acyltransferase activity, which catalyzes the esterification of cholesterol, averaged 431±47 and 452 ±48 pmol/min/mg protein in the 1- and 6-month-old groups, respectively, and was increased to 585±55 pmol/min/mg protein (p<0.05) in the 24-month-old group. The level of total cholesterol showed an age-related increase from 1.56±0.16 mg/g liver in the 1-month-old group to 1.70±0.15 and 2.20±0.19 mg/g liver (p<0.05) in the 6- and 24-month-old groups, respectively. The increase was mainly caused by an accumulation of esterified cholesterol. We conclude that a marked decrease in HMG-CoA reductase occurs between 1 and 6 months of age; thereafter the enzyme activity stays unchanged. The activity of cholesterol 7α-hydroxylase decreases progressively and drastically with age, whereas the capacity for esterifying cholesterol increases slightly. We speculate that the reduced conversion of cholesterol to bile acids may be one explanation of the age-related increase of plasma cholesterol seen in rats.

Effects of bezafibrate on hepatic cholesterol metabolism

SummaryThe influence of bezafibrate treatment on hepatic cholesterol metabolism was studied in rats and in humans. The activities of the three key enzymes involved in cholesterol metabolism [3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, cholesterol 7 α-hydroxylase, and acyl-coenzyme A: cholesterol acyltransferase (ACAT)] were suppressed by bezafibrate treatment in rats, but only the ACAT activity was significantly decreased when the activity was related to total liver weight. In humans, HMG-CoA reductase activity was increased about twice in the treated normolipidemic gallstone patients. In contrast, the concentration of lathosterol in serum decreased, indicating depression of the cholesterol synthesis. The increase in HMG-CoA reductase activity may be a compensatory effect of an inhibition of some other enzymes in the synthesis of cholesterol, as in vitro study on liver microsomes excluded a direct inhibitory effect of bezafibrate on HMG-CoA reductase. The ACAT activity was not significantly changed, and the cholesterol 7 a-hydroxylase activity was decreased by 55–60% compared with controls. The LDL-receptor-binding activity was unaffected by bezafibrate treatment.

Lithogenic diet and gallstone formation in mice: integrated response of activities of regulatory enzymes in hepatic cholesterol metabolism

Supersaturation of bile with cholesterol is a prerequisite of the development of gallstones. With the intention to study the integrated response of enzymes regulating hepatic cholesterol metabolism during gallstone formation we used an established model for the induction of cholesterol gallstone disease in mice. Ten mice were fed on a lithogenic diet containing 10 g cholesterol/kg and 5 g cholic acid/kg for 8 weeks and were compared with ten mice fed on a standard pellet diet. Cholesterol crystals or gallstones developed in 90% of gallbladders in treated mice. The lithogenic diet had an inhibitory effect on the rate-limiting enzyme of cholesterol biosynthesis, hepatic 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase (EC 1.1.1.88) activity, 39.6 (SEM 2.8) v. 171.0 (SEM 47.3) pmol/min per mg protein. Cholesterol 7 alpha-hydroxylase (EC 1.14.13.17) activity, regulating bile acid synthesis, was decreased by 80%, and this was assumed to be due to cholic acid in the diet. The cholesterol-enriched diet also induced a tenfold increase in cholesterol esterification rate in the liver, i.e. acyl-CoA:cholesterol acyl transferase (ACAT; EC 2.3.1.26) activity. The total, as well as esterified, cholesterol contents of liver homogenates were significantly higher in cholesterol- and cholic acid-treated mice and correlated well with the ACAT activity (rs 0.72 (P < 0.005), and rs 0.68 (P < 0.01) respectively). A significantly higher ACAT activity was obtained in mice given cholesterol and cholic acid even when the enzyme was saturated with exogenous cholesterol, thus indicating an increased amount of the enzyme. The formation of gallstones is dependent on a delicate balance between lithogenic factors (increased absorption of cholesterol and reduced secretion of bile acids) and defence mechanisms (decreased synthesis and increased esterification of cholesterol). In the specific animal model studied here the two defence mechanisms cannot compensate for the increased absorption of cholesterol and the reduced synthesis of bile acids.

Effects of pregnenolone-16α-carbonitrile on the metabolism of cholesterol in rat liver microsomes

The effects of pregnenolone-16α-carbonitrile (PCN) on hepatic metabolism of cholesterol were studied in rat liver microsomes in order to clarify the underlying mechanisms of the PCN-induced biliary hypersecretion of cholesterol. Male Sprague-Dawley rats were fed a diet supplemented with 0.05% of PCN for one week. The microsomal activity of 3-hydroxy-3-methylglutaryl coenzyme A reductase, regulating cholesterol biosynthesis, decreased from 577 ± 46 (SEM) to 367 ± 38 pmol/min/mg protein compared to the controls. Cholesterol 7 α-hydroxylase activity, governing bile acid synthesis, was 9.0 ± 1.1 pmol/min/mg protein in the treated group and 34.8 ± 7.4 pmol/min/mg protein in the controls, a reduction of 74% (P<0.01). The acyl CoA:cholesterol acyltransferase (ACAT) activity, catalyzing the esterification of cholesterol, remained unchanged, as did the levels of total and free cholesterol in liver homogenates and microsomes. The results of this study provide evidence that the increase in biliary cholesterol secretion during PCN treatment is not caused by a change in ACAT activity, but can be explained by a decreased catabolism of cholesterol to bile acids.

Instant technetium 99m hexamethyl propylenamine oxime-labeled leukocyte scan compared with colonoscopy in early assessment of disease extent and activity in acute colitis

AIM: This study was undertaken to evaluate technetium 99m (Tc 99m) hexamethyl propylenamine oxime (HMPAO)-labeled leukocyte scintigraphy for assessment of disease extent and activity in acute colitis. PATIENTS AND METHODS: Twenty-seven patients, hospitalized because of acute watery and/or bloody diarrhea, were investigated using both total colonoscopy and Tc 99m HMPAO-labeled leukocyte scintigraphy within 48 hours after admittance. RESULTS: Final diagnoses were ulcerative colitis in 14 patients, Crohns disease in 7 patients, and infectious colitis in 6 patients. Using colonoscopy as the reference method, the maximum extent of colitis was correctly assessed by the leukocyte scan in 18 patients (67 percent), although rectal engagement was not visualized in 5 (19 percent). In six additional patients, there was almost complete agreement between the two methods. One other patient, with left-sided ulcerative colitis, was erroneously assessed as having total extent. Two other patients (one with Crohns colitis and one with infectious colitis) had different segments incorrectly assessed. Sensitivity, specificity, and diagnostic accuracy of scintigraphy in detecting active inflammatory segments were 0.85, 0.83, and 0.85, respectively. Intensity of inflammatory activity assessed by the leukocyte scan correlated significantly with colonoscopic assessment (r=0.719;P<0.0001). CONCLUSION: Information regarding extent, localization, and disease activity in patients with acute colitis of inflammatory or infectious origin may be satisfactorily obtained using Tc 99m HMPAO-labeled leukocyte scanning. The noninvasive nature of the method makes it an attractive early alternative to other investigational procedures such as total colonoscopy or barium examination, particularly in cases with an established diagnosis of inflammatory bowel disease.