Andreas Rydning

Carnitine levels in human serum in health and disease

Abstract The level of carnitine in serum was examined in a control group and in different patient groups. A radiometric assay of carnitine with carnitine acetyltransferase and radioactively labeled acetyl-CoA was used. By the addition of dithionitrobenzoic acid (DTNB) to the incubation mixture to trap the CoASH released, the formation of radioactive acetylcarnitine was proportional to the carnitine concentration over a wide range. Carnitine was extracted from plasma after ethanol addition and the recovery of [ Me - 3 H] carnitine added to serum was 102%. The serum level of carnitine was reduced in patients with myotonia congenita, Crohns disease in some patients with malabsorption and in cases of anorexia nervosa. During hemodialysis the carnitine concentration was reduced to 25% of the value occurring before dialysis. Normal levels of carnitine were found in ulcerative colitis patients, most patients with malabsorption, in liver cirrhosis, in right-sided heart failure with liver stasis, in juvenile and adult onset diabetes, and in cardiomyopathies. Two patients with progressive cardiac failure with icterus and oliguria showed an eight-fold increase in serum carnitine levels.

A characterization in childhood inflammatory bowel disease, a new population-based inception cohort from South-Eastern Norway, 2005–07, showing increased incidence in Crohn's disease

Objective. Owing to rising incidence rates in inflammatory bowel disease (IBD), there has been increased interest in causal relationships in pediatric disease. The present population-based inception cohort was recruited in the Oslo area from 2005 to 2007, with the aim of conducting a detailed characterization of treatment-naïve patients at diagnosis. Material and methods. After an invitation was extended to all general practitioners in the catchment area, patients aged <18 years with suspected IBD were diagnosed by proximal and distal endoscopy, MRI, demographic, clinical, and histological and molecular characteristics. Symptomatic non-IBD patients served as controls. Results. Of 100 pediatric patients, 62 had IBD (39 Crohns disease (CD), 19 ulcerative colitis (UC), 4 IBD unclassified (IBDU)) and 38 other diseases. Median age at diagnosis for IBD was 13.1 years (56.4% males), median symptom duration 6 months, and 69% L3 (Vienna classification). With 195,000 children aged <18 years in the catchment area, the incidence rate of IBD per 100,000/years inhabitants was 10.9 (6.8 for CD, 3.6 for UC, and 0.6 IBDU) and for those aged <16 years (178,500) the incidence rate was 10.6. The higher NOD2 allele frequency among children may partly contribute to the increase. Conclusions. The results indicate a marked rise in the incidence of CD in contrast to no increase in UC in South-Eastern Norway, compared with the figures from the last 15 years. Time from onset of symptoms to diagnosis still represents a challenge for early characterization in IBD.

Evaluation of disease activity in IBD at the time of diagnosis by the use of clinical, biochemical, and fecal markers

Abstract Objective. The present population based adult cohort was part of a new prospective study of patients with inflammatory bowel disease (IBD) in South-Eastern Norway, the Inflammatory Bowel South-Eastern Norway II study, investigating disease characteristics in an attempt to improve our knowledge regarding factors related to early clinical phenotype and disease activity. Material and methods. Patients suspected to have IBD on the basis of predefined symptoms, including abdominal pain, diarrhea, and/or blood in stool for more than 10 days were examined at the local hospital. Colonoscopy with biopsies was performed and blood and stool samples were taken. Results. In ulcerative colitis (UC) patients, the median Simple Clinical Colitis Activity Index (SCCAI) was 4 (range 0–10) in mild and 6 (range 0–14) in patients with moderate or severe endoscopic activity of inflammation (p = 0.002). The calprotectin concentration in feces was significantly related to the SCCAI (p = 0.034) and the Mayo endoscopic subscore (p = 0.031). There was a significant association between the C-reactive protein (CRP) value, leucocytes and thrombocytes and the SCCAI, but only leucocytes were significantly associated with the Mayo endoscopic subscore. In Crohns disease (CD) patients, there was no statistical significant association between the Harvey-Bradshaw Index (HBI) and the endoscopic grade of mucosal inflammation (p = 0.8). The calprotectin concentration in feces was significantly related to the endoscopic activity score (p = 0.004), but not to the HBI (p = 0.5). HBI was significantly related to the CRP value (p = 0.047) and thrombocytes (p = 0.03). Conclusions . In UC, both biochemical and fecal markers are related to disease activity and extent of disease, whereas in CD, the fecal calprotectin concentration is a reliable marker of mucosal affection, but not for systemic disease activity.

High dose ursodeoxycholic acid in primary sclerosing cholangitis does not prevent colorectal neoplasia

Patients with primary sclerosing cholangitis (PSC) and inflammatory bowel disease (IBD) have a high risk of developing colorectal cancer and dysplasia. Ursodeoxycholic acid (UDCA) has been suggested to have chemopreventive effects on the development of colorectal cancer and dysplasia but long‐term data and larger trials are lacking.

Relationship between clinical parameters and the colitis-colorectal cancer interval in a cohort of patients with colorectal cancer in inflammatory bowel disease.

Objective. Inflammatory bowel disease (IBD) is associated with an increased risk of colorectal cancer (CRC), but more knowledge is needed about the possible relationship between clinical parameters and the time to development of cancer in IBD. The aim of the study was to determine the variability of the colitis-CRC interval and to analyze the association with clinical variables in an attempt to gain information on predictive factors of time to cancer within a relatively large cohort of CRC patients. Material and methods. Patients diagnosed with IBD prior to 1 May 2005 at three university hospitals in Oslo were matched against the CRC files at the Cancer Registry of Norway. Only histological re-confirmed IBD and adenocarcinoma of the colorectum were included. Results. Sixty-one patients with CRC in ulcerative colitis and 6 in Crohns disease, including 13 CRC in primary sclerosing cholangitis (PSC), covering a follow-up of 1625 patient years, were identified. The median time from diagnosis of IBD to CRC was 17 years. Seven of 58 patients (12%) developed CRC within 10 years from onset of IBD symptoms and 14/67 (21%) within 10 years after the diagnosis of IBD. The colitis-CRC interval decreased by a factor of 0.154 (p=0.018) when age at onset of IBD increased by one year. Mean age at onset of IBD was 30 years in patients with Dukes’ stage C or D compared with 20 years in Dukes’ stage A or B patients (p=0.017). The colitis-CRC interval decreased by a factor of 0.138 (p=0.003) when the percentage of the colitis-CRC interval with active symptoms increased by 1%. Patients with PSC were significantly younger at onset of IBD symptoms (+PSC: 19 years versus no PSC:29 years, p=0.04), but the colitis-CRC interval was similar to IBD without PSC (17 years versus 20 years, p=0.236). Mean duration of the colitis-CRC interval was not related to family history or drug consumption prior to CRC. Conclusions. In the present cohort, for whom the median time from diagnosis of IBD to CRC was 17 years, 21% of the cancers developed before 10 years of disease, which is before colonoscopic screening is usually recommended. High age at onset of IBD may be related to a more aggressive development of CRC in IBD and early inclusion in screening programs might be considered for this group of patients. Symptom activity but not the diagnosis of PSC, family history of CRC or IBD or drug treatment seems to have an effect on the colitis-CRC interval.

Healing of benign gastric ulcer with low-dose antacids and fiber diet

A randomized, double-blind, placebo-controlled trial was conducted to determine the efficacy of a low-dose aluminum-magnesium antacid regimen (Link one tablet q.i.d.) (total neutralizing capacity 120 mmol HCl/day) in combination with a high- or a low-fiber diet in ulcer healing and relief of symptoms in patients with benign gastric ulcer. After 6 wk, the ulcer healed in 28 (67%) of the 42 patients treated with antacids compared with 11 (25%) of the 44 patients treated with placebo (p less than 0.001). Antacids were also significantly more effective than placebo in the relief of symptoms. The dietary treatment did not significantly influence ulcer healing or ulcer symptoms. Constipation was more frequently seen with the low- than with the high-fiber diet (p less than 0.01). No significant side effects from antacids were recorded.

Incidence and clinical presentation of IBD in children: comparison between prospective and retrospective data in a selected Norwegian population.

Objective. The results of recent research suggest that there is an increasing incidence of inflammatory bowel disease (IBD) among children. Newly diagnosed IBD was compared between two consecutive 6-year periods in the same catchment area of southeastern Norway. Material and methods. Children subjected to endoscopy from 1993 to 2004 were recorded retrospectively in the first 6-year period and prospectively for the subsequent period. The mean size of the child population under 16 years in the area was 70,500. The study reports on incidence numbers, age at diagnosis, disease distribution and clinical presentation at diagnosis. Results. There were 23 incident cases of IBD in the first period and 25 in the subsequent period. The rates of Crohns disease (CD) for the two periods were, respectively, 1.95 and 3.64, and for ulcerative colitis (UC) 3.67 and 2.05/100,000 children/year. Total incidence rates of IBD for the two periods were 5.6 and 5.7, respectively, similar to the findings of the IBSEN study of 1990–94. The change in CD and UC rates from the first to the second period can be explained by better methods of diagnosis. Conclusions. The total incidence of IBD was not changed between time periods, whereas a trend towards an increase in CD and a reduction in UC was recorded. The incidence rates are in accordance with previously reported national and international data from the past decade. The extent of disease in CD and UC may indicate a serious prognosis of IBD among children.

Two distinct groups of colorectal cancer in inflammatory bowel disease.

Background: The histological variability in colitis‐associated colorectal cancer (CRC in inflammatory bowel disease [IBD]) and the association to clinical factors is unknown. Methods: In population‐based material including 67 patients with CRC in IBD, histopathology of the cancers and tissue samples from different colorectal localizations were reevaluated, and relationships to clinical factors analyzed. Results: Forty‐three of 60 patients (75%) showed dysplasia in the colorectum apart from the cancer, while 17 (25%) had no dysplasia at cancer diagnosis. Mean age at onset of IBD was 22 years in patients with and 34 years in patients without dysplasia (P = 0.01). The mean duration of colitis‐CRC interval was 21 years in patients with and 16 years in patients without dysplasia (P = 0.02). The latter group included all patients with a colitis‐CRC interval <10 years. Active inflammation was more likely to occur in patients with dysplasia (odds ratio [OR] 4.2). The 2 groups were not discriminated by gender, family history of CRC or IBD, diagnosis of PSC, medical treatment, active symptoms, or histological features like type of cancer and differentiation. In multiple logistic regression analysis the age at onset of IBD was the strongest predictive variable for dysplasia at cancer diagnosis (P = 0.025). Conclusions: Widespread neoplasia occurs in the majority of cases with CRC in IBD and is associated with early onset of IBD. Localized neoplasia occurs in about a quarter of the patients and shows an association with late‐onset IBD. The 2 groups probably represent different pathogenetic entities of neoplasia in IBD. This might have consequences for surveillance strategies.

Reduced expression of aquaporins in human intestinal mucosa in early stage inflammatory bowel disease

Objectives The aim of this study was to investigate the relationship between aquaporin (AQP) water channel expression and the pathological features of early untreated inflammatory bowel disease (IBD) in humans. Methods Patients suspected to have IBD on the basis of predefined symptoms, including abdominal pain, diarrhea, and/or blood in stool for more than 10 days, were examined at the local hospital. Colonoscopy with biopsies was performed and blood samples were taken. Patients who did not meet the diagnostic criteria for IBD and who displayed no evidence of infection or other pathology in the gut were included as symptomatic non-IBD controls. AQP1, 3, 4, 5, 7, 8, and 9 messenger RNA (mRNA) levels were quantified in biopsies from the distal ileum and colon by quantitative real-time polymerase chain reaction. Protein expression of selected AQPs was assessed by confocal microscopy. Through multiple alignments of the deduced amino acid sequences, the putative three-dimensional structures of AQP1, 3, 7, and 8 were modeled. Results AQP1, 3, 7, and 8 mRNAs were detected in all parts of the intestinal mucosa. Notably, AQP1 and AQP3 mRNA levels were reduced in the ileum of patients with Crohn’s disease, and AQP7 and AQP8 mRNA levels were reduced in the ileum and the colon of patients with ulcerative colitis. Immunofluorescence confocal microscopy showed localization of AQP3, 7, and 8 at the mucosal epithelium, whereas the expression of AQP1 was mainly confined to the endothelial cells and erythrocytes. The reduction in the level of AQP3, 7, and 8 mRNA was confirmed by immunofluorescence, which also indicated a reduction of apical immunolabeling for AQP8 in the colonic surface epithelium and crypts of the IBD samples. This could indicate loss of epithelial polarity in IBD, leading to disrupted barrier function. Conclusion AQPs 1 and 8 and the aquaglyceroporins AQPs 3 and 7 are the AQPs predominantly expressed in the lower intestinal tract of humans. Their expression is significantly reduced in patients with IBD, and they are differentially expressed in specific bowel segments in patients with Crohn’s disease and ulcerative colitis. The data present a link between gut inflammation and water/solute homeostasis, suggesting that AQPs may play a significant role in IBD pathophysiology.

Widespread but not localized neoplasia in inflammatory bowel disease worsens the prognosis of colorectal cancer

Background: Patients with inflammatory bowel disease (IBD) are at increased risk of colorectal cancer (CRC). Recently, new phenotypes of CRC in IBD have been suggested. Studies of the prognosis of CRC in IBD have shown conflicting results. The aim of the study was to analyze factors for prognosis in CRC‐IBD, including the impact of the new phenotypes. Methods: By using the nationwide, population‐based Cancer Registry of Norway, we compared survival of a CRC‐IBD cohort with CRC in the background population (all‐CRC), adjusting for the topographical distribution of dysplasia at cancer diagnosis (widespread versus localized neoplasia in IBD) and other factors. We also analyzed prognostic factors within CRC‐IBD. Results: The mean age at CRC diagnosis was 43 years in widespread, 52 years in localized neoplasia IBD, and 70 years in all‐CRC (P < 0.05). Adjusted for cofactors, prognosis of CRC‐IBD was poorer compared to all‐CRC (mortality rate ratio [MRR] 3.71, 95% confidence interval [CI]: 2.54–5.42, P < 0.001). Prognosis of widespread neoplasia IBD was poorer compared to all‐CRC (MRR 4.27, 95% CI: 2.83–6.44, P < 0.001) and compared to localized neoplasia IBD (MRR 3.58, 95% CI: 0.87–14.72, P = 0.076). Survival was not significantly different between localized neoplasia IBD and all‐CRC (P = 0.132). Conclusions: The results demonstrate lower age and poorer survival of CRC in IBD compared to CRC in the background population. The unfavorable effect of IBD on prognosis of CRC was pronounced in widespread neoplasia IBD. The diagnosis of this phenotype seems to be an important prognostic sign in patients with CRC in IBD. (Inflamm Bowel Dis 2010;)