["TRECID", TNFalpha related chronic inflammatory diseases - a new multiple diseases bridging concept]. / "TRECID": TNFalpha-assoziierte chronisch entzündliche Erkrankungen - Eine neue Krankheits-übergreifende Sichtweise.

The pro-inflammatory cytokine TNF alpha (TNF) has a key position in the pathogenesis of various infectious and inflammatory diseases. Clarification of its pivotal role in the pathogenesis of rheumatoid arthritis, spondyloarthritis, uveitis, psoriasis and inflammatory bowel disease has resulted in the successful development of TNF- blocking therapies, which have disease-modifying properties that exceed the effects of conventional therapeutic options. For this reason data on the concurrence of several chronic inflammatory diseases have led to the hypothesis of common pathogenetic processes of cytokine dysregulation. The acronym TRECID describes this concept of "TNF RElated Chronic Inflammatory Diseases". Physicians of different specialties have integrated new therapeutic options with TNF-blocking therapies into their strategies for the management of the affected patients. Thus the concept of TRECID can be regarded as a role model for a dynamic, interdisciplinary cooperation based on shared pathophysiological aspects.

The role of fatty acid hydrolase gene variants in inflammatory bowel disease.

BACKGROUND: Recent studies suggest a role for the endocannabinoid system, including fatty acid amide hydrolase (FAAH), in intestinal inflammation. AIM: To analyse FAAH expression and the FAAH 385 C/A (p.Pro129Thr; rs324420) single nucleotide polymorphism (SNP) in-patients with Crohn's disease (CD) and ulcerative colitis (UC). PATIENTS AND METHODS: Genomic DNA from 1008 individuals (CD: n = 435; UC: n = 167; controls: n = 406) was analysed for the FAAH 385 C/A SNP. We determined FAAH mRNA expression by quantitative PCR in CD and UC lesions as well as in intestinal epithelial cells (IECs). RESULTS: There were no significant differences regarding the frequency of this SNP in the three study groups (CD, UC, controls). However, CD patients homozygous for the FAAH p.Pro129Thr polymorphism were more likely to develop a severe disease phenotype associated with fistulas (P = 0.03, OR 3.12, 95% CI 1.08-8.98) and extra-intestinal manifestations (P = 0.005, OR 4.29, CI 1.49-12.35). In UC, homozygous carriers had an earlier disease onset than wild-type carriers (P = 0.01). FAAH mRNA expression correlated with IL-8 mRNA expression in CD lesions (r = 0.53). However, pro-inflammatory stimuli did not significantly increase FAAH mRNA expression in IECs. CONCLUSION: The FAAH p.Pro129Thr polymorphism may modulate the CD phenotype.

The role of the selenoprotein S (SELS) gene -105G>A promoter polymorphism in inflammatory bowel disease and regulation of SELS gene expression in intestinal inflammation.

Recently, a -105G>A promoter polymorphism coding for selenoprotein S (SELS) has been shown to increase proinflammatory cytokine expression. We, therefore, analyzed SELS expression and potential phenotypic consequences of the -105G>A polymorphism in patients with inflammatory bowel disease (IBD). SELS mRNA was measured by quantitative polymerase chain reaction (PCR) in intestinal epithelial cells (IEC) after stimulation with proinflammatory cytokines and in human colonic biopsies of IBD patients as well as in murine models of ileitis and murine cytomegalovirus (MCMV) colitis. Genomic DNA from 563 individuals (Crohn's disease: n = 205; ulcerative colitis: n = 154; controls: n = 204) was analyzed for the presence of the SELS-105G>A polymorphism and the three nucleotide-binding oligomerization domain-containing protein 2 (NOD2)/caspase recruitment domain-containing protein 15 (CARD15) variants p.Arg702Trp, p.Gly908Arg and p.Leu1007fsX1008. SELS mRNA expression was increased in IEC after stimulation with proinflammatory cytokines, while its expression was not significantly altered in murine ileitis and MCMV colitis and in inflamed ileal and colonic lesions in IBD patients compared with normal controls. The SELS-105G>A polymorphism was observed with similar frequencies in IBD patients and controls and was not associated with a certain disease phenotype or serum tumor necrosis factor alpha (TNF-alpha) levels in these patients. Medium serum TNF-alpha was 1.27 pg/ml in IBD patients, while none of the controls had TNF-alpha concentrations above the detection threshold (P < 0.0001). SELS mRNA expression is upregulated by proinflammatory cytokines in IECs but the SELS-105G>A polymorphism is not associated with IBD susceptibility and does not contribute to a certain disease phenotype or increased TNF-alpha levels in IBD patients.

Adalimumab in patients with Crohn's disease--safety and efficacy in an open-label single centre study.

AIM: To evaluate the efficacy and safety of adalimumab, a human antitumour necrosis factor-alpha antibody, in induction and maintenance of remission in patients with Crohn's disease either refractory or intolerant to infliximab in a single centre cohort. METHODS: Sixteen Crohn's disease patients received 160 mg adalimumab subcutaneously in week 0, followed by 80 mg every other week. Clinical response was assessed based on Crohn's disease activity index and laboratory parameters (leukocyte count, C-reactive protein). In all patients genotyping for CARD15 variants and the +1059G/C polymorphism in the C-reactive protein gene was performed. RESULTS: In 10 of 16 patients (63%) treated with adalimumab, remission (CDAI score <150) was induced for at least 8 weeks independent of CARD15 or +1059G/C CRP status. In six of these 10 patients ongoing remission is observed now for more than 24 weeks. Adalimumab significantly decreased C-reactive protein serum levels and Crohn's disease activity index. There was one serious complication (fungal pneumonia). Six patients intermittently developed minor dermatological problems resolving after topical therapy. Otherwise, treatment was generally well tolerated. CONCLUSION: Adalimumab can induce and maintain remission in patients with moderate to severe Crohn's disease intolerant or refractory to infliximab. Further experience from larger cohorts is required to evaluate dose regimen and safety profiles in Crohn's disease therapy.

The +1059G/C polymorphism in the C-reactive protein (CRP) gene is associated with involvement of the terminal ileum and decreased serum CRP levels in patients with Crohn's disease.

BACKGROUND: Serum C-reactive protein (CRP) levels influence the response to anti-tumour necrosis factor (TNF) therapies. AIM: To analyse the influence of the +1059G/C CRP polymorphism on CRP serum levels and disease susceptibility in patients with Crohn's disease (CD). METHODS: Using restriction fragment length polymorphism (RFLP) analysis, genomic DNA from 241 CD patients and 199 unrelated controls was analysed for the +1059G/C substitution in the CRP gene and the common caspase-activation recruitment domain 15 (CARD15) variants. RESULTS: Homozygous C/C carriers were detected only among CD patients (P = 0.066). Patients with ileal involvement (L1 and L3 phenotype) were found in only 58.4% of patients with the wildtype G/G genotype but in 88.2% of the heterozygous G/C carriers (OR 5.26; 95% CI 1.19-23.92) and four of the five C/C homozygous carriers (80%; OR 4.55; 95% CI 1.64-16.67; P = 0.008 for hetero- and homozygous carriers vs. wildtype) which was independent of the presence of CARD15 variants. Increased CD activity was associated with increased CRP serum levels (P < 0.005). For Crohn's disease activity index (CDAI) < 150, C/C homozygosity for the +1059 G/C polymorphism was associated with significantly lower CRP serum levels (P < 0.01). CONCLUSIONS: The C allele of the CRP +1059G/C polymorphism is associated with decreased serum CRP levels and increased likelihood of disease involvement of the terminal ileum in CD patients.

Low frequency of colorectal dysplasia in patients with long-standing inflammatory bowel disease colitis: detection by fluorescence endoscopy.

BACKGROUND AND STUDY AIM: Patients with long-standing inflammatory bowel disease (IBD) have an increased risk of developing colonic dysplasias. Dysplastic changes in flat mucosa are likely to be missed by conventional colonoscopy. Endoscopic fluorescence imaging, using 5-aminolevulinic acid (5-ALA) as photosensitizer, has evolved as a new technique to differentiate between normal colonic mucosa and dysplasia. We combined this technique with random biopsies to prospectively evaluate the occurrence of dysplasias in patients with long-standing IBD. PATIENTS AND METHODS: 52 colonoscopies were performed in 42 consecutive patients (n = 28 with ulcerative colitis, n = 11 with Crohn's colitis, n = 3 with indeterminate colitis; mean age 43 years, range 21 - 78) with long-standing IBD colitis (median disease duration 14 years, range 3 - 40). All patients were in clinical remission. Patients were examined using both conventional white light and by fluorescence colonoscopy using oral 5-ALA. Four biopsies were taken every 10 cm from mucosa of normal appearance. In addition, macroscopically suspicious and fluorescence-positive areas were biopsied. RESULTS: A total of 688 biopsies of red-fluorescent (n = 20) and nonfluorescent (n = 662) areas of mucosa were taken. Dysplasia was detected histopathologically in only two of the biopsies. These biopsies were taken from two polypoid lesions which were fluorescence-negative. CONCLUSIONS: The rate of colonic dysplasia in patients with long-standing IBD colitis may be lower than previously reported.

6-Thioguanine treatment in inflammatory bowel disease: a critical appraisal by a European 6-TG working party.

Recently, the suggestion to use 6-thioguanine (6-TG) as an alternative thiopurine in patients with inflammatory bowel disease (IBD) has been discarded due to reports about possible (hepato) toxicity. During meetings arranged in Vienna and Prague in 2004, European experts applying 6-TG further on in IBD patients presented data on safety and efficacy of 6-TG. After thorough evaluation of its risk-benefit ratio, the group consented that 6-TG may still be considered as a rescue drug in stringently defined indications in IBD, albeit restricted to a clinical research setting. As a potential indication for administering 6-TG, we delineated the requirement for maintenance therapy as well as intolerance and/or resistance to aminosalicylates, azathioprine, 6-mercaptopurine, methotrexate and infliximab. Furthermore, indications are preferred in which surgery is thought to be inappropriate. The standard 6-TG dosage should not exceed 25 mg daily. Routine laboratory controls are mandatory in short intervals. Liver biopsies should be performed after 6-12 months, three years and then three-yearly accompanied by gastroduodenoscopy, to monitor for potential hepatotoxicity, including nodular regenerative hyperplasia (NRH) and veno-occlusive disease (VOD). Treatment with 6-TG must be discontinued in case of overt or histologically proven hepatotoxicity.

Polymorphisms in the DLG5 and OCTN cation transporter genes in Crohn's disease.

BACKGROUND AND AIMS: Recent data suggest identification of causal genetic variants for inflammatory bowel disease in the DLG5 gene and in the organic cation transporter (OCTN) cluster, both situated in previously described linkage regions. PATIENTS AND METHODS: The polymorphisms in DLG5 (113 G-->A, 4136 C-->A, and DLG5_e26), SLC22A4 (1672 C-->T), and SLC22A5 (-207 G-->C) were assessed in 625 patients with Crohn's disease (CD), 363 patients with ulcerative colitis (UC), and 1012 healthy controls. Association with disease susceptibility, clinical phenotypes, and possible genetic interactions of these polymorphisms with disease associated CARD15/NOD2 mutations was analysed. RESULTS: No significant association of DLG5 polymorphisms with CD or UC was observed. Homozygosity for the OCTN-TC haplotype was associated with an increased CD risk (OR = 1.65), which was even greater in the presence of CARD15 mutations. Genotype-phenotype analysis revealed that this association was particularly strong in patients with colonic disease. The TC haplotype was associated with non-fistulising non-fibrostenotic disease, an earlier age of disease onset, and reduced need for surgery. CONCLUSION: Our observations argue against a role of DLG5 polymorphisms in the susceptibility for inflammatory bowel disease, whereas the OCTN polymorphisms are associated with CD. However, due to the comparable weak association observed herein, extended linkage disequilibrium analyses of these variants with the IBD5 haplotype tagged single nucleotide polymorphims might be advisable before definitive conclusions about their causative role in CD can be drawn.

Crohn disease of the small bowel proximal to the terminal ileum: detection by MR-enteroclysis.

BACKGROUND: Although Crohn disease (CD) can affect the entire alimentary tract, the proportion of patients with small-bowel inflammation proximal to the terminal ileum is still unclear. Magnetic resonance imaging (MRI) combined with small-bowel enteroclysis can detect inflammatory lesions of the small bowel. Hence, we applied MR-enteroclysis to assess the percentage of patients with small-bowel inflammation proximal to the terminal ileum among patients with CD and abdominal pain. METHODS: Twenty-five consecutive patients with low, active CD of the colon and/or terminal ileum and episodes of abdominal pain were examined by both MR-enteroclysis and conventional enteroclysis. The findings of MR-enteroclysis were compared with endoscopic and histological results in the terminal ileum and conventional enteroclysis in the small bowel proximal to the terminal ileum. RESULTS: In 13 of the 25 patients, inflammation of the small bowel proximal to the terminal ileum was shown by MR-enteroclysis, whereas in only 4 of the 25 patients, signs of inflammation of the small bowel proximal to the terminal ileum were shown by conventional enteroclysis, all of which were demonstrated by MR-enteroclysis. MR-enteroclysis confirmed the findings in 22 of 25 patients in whom endoscopy and histology had shown inflammation (16 of 18) or no inflammation (6 of 7) of the terminal ileum. CONCLUSION: In symptomatic patients with CD even of low activity, inflammation of the small bowel proximal to the terminal ileum is frequent.

[Inflammatory bowel diseases (IBD) -- critical discussion of etiology, pathogenesis, diagnostics, and therapy]. / Chronisch entzündliche Darmerkrankungen -- Kritische Diskussion von Atiologie, Pathogenese, Diagnostik und Therapie.

AIMS: Crohn's disease and ulcerative colitis are the most frequent inflammatory bowel diseases (IBD) with a prevalence of approximately one out of 500. Cytokine research opened new and potent treatment options and thus stimulated clinical and basic research.However, the IBD still remain a challenge for patients and physicians,demanding close cooperation between gastroenterologists,radiologists and surgeons. The basic understanding of IBD,which is necessary for efficient diagnostic and therapeutic concepts is reviewed. METHODS: Based upon recent publications and our clinical experience we discuss aspects of etiology,pathogenesis,diagnostics,and therapy of Crohn's disease and ulcerative colitis. RESULTS: A genetically influenced, exaggerated and sustained immune response against the own gut flora seems to be one of the most important factors in the pathogenesis of IBD. Not less important are environmental influences. For instance, cigarette smoking had been judged to have some negative influence on the natural course of Crohn's disease.Now,however, recent studies show that smoking is even a significant independent risk factor in the pathogenesis of IBD. Since IBD and especially Crohn's disease can effect the whole body, detailed analysis of inflammatory organ involvement is necessary before therapy. For instance, the MRI enteroclysis technique adds a necessary diagnostic tool for the exploration of those parts of the small bowel that cannot been reached by routine endoscopy like the upper ileum and the lower jejunum. In terms of therapy, a change of paradigms can be observed: patients will no longer be treated only when symptoms arise, but will early be integrated into a therapeutic concept, which is determined by site and extent of the disease and adapted to the abilities and needs of the patient.Furthermore,immunosuppressive agents like azathioprine and 6-mercaptopurine will establish as central concept in the medical treatment of IBD. DISCUSSION: IBD-therapy should rather be adapted to the patient's individual inflammatory pattern than be oriented to schematic treatment rules. New endoscopic and radiologic techniques provide the necessary diagnostic tools.

[MRI in Crohn's disease after transduodenal contrast administration using negative oral MRI contrast media]. / MRT-Diagnostik des Morbus Crohn nach transduodenaler Füllung mit negativem oralem MR-Kontrastmittel.

PURPOSE: To compare the efficacy and quality of conventional and MR enteroclysis with different filling methods regarding the assessment of extension and extraluminal manifestations in Crohn's disease. MATERIAL AND METHODS: 190 patients with known Crohn's disease were studied following small bowel enteroclysis, after oral administration or direct transduodenal filling in the MRI-department.T1- and T2-weighted breathhold MRI-scans w/o spectral fat suppression w/o i.v. Gd-DTPA were applied using negative oral superparamagnetic contrast media. RESULTS: Typical findings were marked bowel wall thickening with laminated wall contrast enhancement. In 135 patients 98,2% of affected bowel segments, 97,5% of stenoses and all 16 fistulas were detected, when conventional enteroclysis was employed as standard of reference. Additional important extraluminal findings such as ileoileal (n = 18), ileosigmoidal adhesions (n = 12), extraluminal abscesses (n = 35) and pseudotumors (n = 8) were visualized in 73/135 patients. Concerning the distension of jejunum and ileum, oral filling was rated significantly inferior to transduodenal filling in all small bowel segments,whereas filling in the MRI-unit was rated superior to fluoroscopic, mostly due to a mean transport time of 20 min to the MRI-unit. CONCLUSION: No clinically important findings of enteroclysis were missed when using MRI. Therefore, in patients with Crohn's disease, conventional enteroclysis can be replaced by MRI. For optimal bowel distension oral contrast administration is inferior to transduodenal filling, if a larger time delay between filling and the MRI-scan can be avoided.

[Pathogenesis and epidemiology of sigmoid diverticulosis]. / Pathogenese und Epidemiologie der Sigmadivertikulose.

From an epidemiological point of view, left-sided diverticulosis represents a civilizational disease of Western countries. It occurs rarely during childhood and frequently in later years. A diet high in fat and meat, low in vegetables, and with insufficient fiber content apparently encourages its genesis. Physical activity seems to counteract diverticulosis while alcohol consumption, smoking, and caffeine ingestion have no effect. The extent of diverticulosis is not commensurate with the extent of complaints. Only a few patients with diverticula develop diverticulitis. Pathogenetically, several factors play a role in the development of diverticulosis. Elevated intraluminal pressure as well as acquired structural changes of the intestinal wall seem to be decisive factors, which intensify with increasing age. These changes are caused by ultrastructural alterations of the muscle and connective tissue related to collagen and elastin metabolism, which presumably can be genetically determined. Intestinal disturbances of innervation and motility also contribute to the formation of diverticula. The term "hypersegmentation" is an attempt to combine these factors into a single pathogenetic model.

Colonic mucosal proliferation is related to serum deoxycholic acid levels.

BACKGROUND: Hyperproliferation of the colorectal mucosa is regarded as an early step in colorectal carcinogenesis. Deoxycholic acid, a secondary bile acid, stimulates colorectal epithelial proliferation in animals and is considered a tumor promoter in human colorectal carcinogenesis. The aim of this study was to investigate the correlation between colorectal mucosal proliferation and the serum deoxycholic acid level. METHODS: From each of 19 patients (10 men and 9 women) with (n = 3) or without (n = 16) colorectal adenoma, 18 biopsy specimens were obtained by colonoscopy, 3 from each of the 6 colonic segments. A crude nuclei fraction was prepared, and DNA was stained by propidium iodide to determine the proliferative index (the percentage of cells in the S and G2/M phases of the cell cycle) by flow cytometry. Serum levels of deoxycholic acid were determined by gas-liquid chromatography. RESULTS: The colonic proliferation rates (median of the values obtained in all segments, 14.1%; range, 10.0-18.7%) and the fasting serum deoxycholic acid levels (median, 0.86 micromol/L; range, 0.28-1.58 micromol/L) showed a significant correlation (r = 0.51, P = 0.03). Serum lithocholic, cholic, chenodeoxycholic, and ursodeoxycholic acid levels were not correlated with the proliferation rates. CONCLUSIONS: Levels of deoxycholic acid in serum are correlated with the rates of the colorectal mucosa. These results are consistent with the concept that deoxycholic acid promotes colorectal carcinogenesis.

Detection of colonic dysplasia by light-induced fluorescence endoscopy: a pilot study.

Light-induced fluorescence endoscopy (LIFE) has been shown to differentiate between normal mucosa and dysplastic lesions, and dysplastic lesions of the colon occult to routine white-light colonoscopy may thus be visualized by LIFE. We compared the sensitivity and specificity of LIFE to routine white-light colonoscopy in patients with colonic dysplasia. In a pilot study 20 patients with colonic adenoma, inflammatory bowel disease, or with a history of colon cancer were screened for colonic dysplasia during routine colonoscopy. Forty-two sites of mucosal abnormalities regarded as suspicious for dysplasia during white-light colonoscopy were additionally examined with a prototype LIFE system. Biopsies were taken from all 42 colonic sites. The LIFE images were classified as positive or negative for dysplasia. Sensitivity and specificity were calculated by correlating positive and negative findings to the histopathological results. Histopathology detected 21 adenomas with low-grade dysplasia and one with high-grade dysplasia. All dysplastic lesions were found by routine white-light endoscopy. The specificity of conventional white-light endoscopy was 80%. Of the 22 dysplastic lesions 20 were detected by LIFE (sensitivity 91%). The specificity of LIFE was 90% (two false-positive results). LIFE combined with conventional endoscopy may thus improve the detection of colonic dysplasia.

Increased cell proliferation of the gastric mucosa in first-degree relatives of gastric carcinoma patients.

BACKGROUND: Studies not considering Helicobacter pylori infection have suggested the presence of a hereditary risk for gastric carcinoma. However, other studies have identified intrafamilial clustering of H. pylori infection as a causal factor in gastric carcinogenesis. This prompted the authors to study the effect of H. pylori and hereditary factors on the proliferation of gastric mucosa because hyperproliferation appears to be an early step in carcinogenesis. METHODS: In a total of 39 patients (19 first-degree relatives of patients with gastric carcinoma and 20 dyspeptic controls), 2 biopsy specimens each from the antrum and corpus were examined histologically. In addition, crude nuclei fractions were prepared from other biopsy specimens obtained in the same manner. Nuclei were fixed in 70% ethanol and stained with propidium iodine prior to measurement. A cell cycle analysis was performed using a flow cytometer. For analysis a proliferative index (PI) (percentage of nuclei in the S- and G2/M-phases) was calculated. RESULTS: In comparison with control patients, first-degree relatives of gastric carcinoma patients had increased mucosal proliferation of the antrum (Student's t test, P = 0.017). After excluding patients with H. pylori infection (12 in each group), relatives of gastric carcinoma patients had significantly increased proliferation not only in the antrum (PI: 16.5 vs. 12.1; P = 0.043), but also in the corpus (PI: 17.2 vs. 13.0; P = 0.024). CONCLUSIONS: A family history of gastric carcinoma may increase the risk for developing gastric carcinoma via mucosal hyperproliferation, irrespective of H. pylori infection.

Histological diagnosis of Helicobacter pylori gastritis is predictive of a high risk of gastric carcinoma.

Chronic Helicobacter pylori infection has been identified as a major risk factor for the subsequent development of gastric carcinoma On the basis of seroepidemiological studies the relative risk for infected persons was estimated to range between 3 and 6. Our study attempted to determine the relative risk of gastric carcinoma in H. pylori-infected individuals based on the histological evaluation of gastritis in gastric carcinoma patients in the light of a declining prevalence of H. pylori infection in Western countries. We histologically determined the H. pylori infection rate in 215 patients with early gastric carcinoma (tumor stage pT1), and compared it with that of 215 asymptomatic persons matched by age and sex who were tested by the 13C urea breath test. On the basis of these data an odds ratio of 16.7 (CI 9.6-29.1) was calculated for the relative risk of developing gastric carcinoma in H. pylori-infected people. The histological diagnosis of gastritis permits a separate risk assessment for patients with autoimmune gastritis, and by excluding these patients from the analysis we calculated an odds ratio for H. pylori-infected persons of 150 (CI 36.4-622.9). The endoscopic-histological diagnosis of H. pylori infection is associated with an increased risk of the subsequent development of gastric carcinoma of approximately 150-fold compared with H. pylori-negative patients who do not have chronic atrophic corpus gastritis of the autoimmune type (type A gastritis).

Plasma deoxycholic acid is related to deoxycholic acid in faecal water.

Bile acids are considered as a risk factor for colorectal carcinogenesis. They were analysed in samples of faecal water and plasma of fasting heparine blood from 23 urolithiasis patients. Linear regression showed that the highest percentage of variance (52%) was explained by the model: plasma deoxycholic acid (micromol/l) = -3.11 + 0.96(+/-0.25*) 10log deoxycholic acid in faecal water (micromol/l) + 0.35(+/-0.15*) pH of faecal water -0.41(+/-0.19#) defacation frequency (number of stools/day); *P < 0.05, #P = 0.055. In future studies, analysing blood levels of unconjugated deoxycholic acid may substitute faecal measurements.

Unconjugated secondary bile acids in the serum of patients with colorectal adenomas.

A positive association between deoxcholic acid (DCA) in the serum and colorectal adenomas, the precursors of colorectal cancer has recently been found, which supported the hypothesis of a pathogenic role of DCA in colonic carcinogenesis. This approach was based on the hypothesis that DCA formed in the colon is absorbed into the portal venous blood and exhibits a constant spillover to the systemic circulation. To further substantiate this hypothesis this study investigated whether in the serum of adenoma patients DCA was higher in the unconjugated fraction, which originates directly from the colon. DCA was found to be 2.8-fold higher in the unconjugated fraction of patients with colorectal adenomas than in controls (0.89 v 0.32 mumol/l, p < 0.0025), 1.9-fold in the total DCA fraction (1.89 v 0.95 mumol/l, p < 0.0001), and 1.4-fold in the conjugated fraction (0.67 v 0.47 mumol/l, p < 0.05). It was further found that the bacterial isomerisation product 3 beta-DCA was twofold higher in the unconjugated fraction of adenoma patients than in controls (0.08 v 0.04 mumol/l, p = 0.27), 1.8-fold in the total iso-DCA fraction (0.11 v 0.06 mumol/l, p < 0.05), and 1.5-fold in the conjugated iso-DCA fraction (0.03 v 0.02 mumol/l, p = 0.68). The data suggest that the positive association between the serum DCA concentration and colorectal adenoma as described previously results from the DCA fraction that is absorbed from the colon. This further supports a pathogenic role of DCA in the carcinogenesis of colorectal cancer.

Variation of serum bile acids in patients with colorectal adenomas during a one-year follow-up.

We were recently able to show that patients with colorectal adenomas have an increased serum level of the secondary bile acid deoxycholic acid [Bayerdörffer et al.: Gastroenterology 1993; 104:145-151]. The course of individual serum bile acids was followed for 1 year in a random subgroup of these patients. The individual serum bile acids of 39 patients, 10 men with adenoma, 12 men without adenoma, 8 women with adenoma, and 9 women without adenoma, were determined at 6-month intervals by gas liquid chromatography (GC). The mean individual differences in serum bile acids between baseline and 6-month follow-up and baseline and 12-month follow-up ranged from +19 to -15 nmol/l in men with adenoma, and from +66 to -64 nmol/l in men without adenoma. In women, the ranges were +73 to -74 nmol/l in those with adenoma and +33 to -81 nmol/l in those without adenoma. The variations of the relative percentages of the individual bile acids in the three investigations were lower than those of the absolute values. The differences between the baseline, the 6-month, and the 12-month follow-up were not significant for the major bile acids deoxycholic acid, chenodeoxycholic acid and cholic acid. The main finding, namely an increase in the serum levels and the relative proportion of deoxycholic acid in men with colorectal adenomas remained unchanged throughout the follow-up. The data indicate that measurement of the bile acid pattern by GC is a useful and reproducible parameter in investigating the role of secondary bile acids in the pathogenesis of colorectal cancer.

Decreased high-density lipoprotein cholesterol and increased low-density cholesterol levels in patients with colorectal adenomas.

OBJECTIVE: To study the relation between serum lipoprotein levels and the frequency of colorectal adenomas, the benign precursors of colorectal cancer. DESIGN: Cross-sectional. SETTING: University hospital in Germany. PATIENTS: The study included 822 of 1124 consecutive patients who underwent colonoscopy at our institution (302 patients were excluded because of malignant disease, chronic inflammatory bowel disease, familial polyposis, partial colectomy, or other chronic diseases). Of the 822 study patients, 194 had colorectal adenoma. MEASUREMENTS: Serum cholesterol fractions (high-density lipoprotein [HDL], low-density lipoprotein [LDL], and very low-density lipoprotein [VLDL]) and presence or absence of adenomas; univariate and logistic regression analyses were carried out to evaluate the association between serum HDL, LDL, and VLDL cholesterol levels and the frequency of colorectal adenoma. RESULTS: Univariate analysis of the total patient group showed that the HDL cholesterol level was inversely related to the frequency of colorectal adenoma (odds ratio, 0.36; 95% Cl, 0.21 to 0.62) and that LDL and VLDL cholesterol levels were positively associated with adenoma frequency (odds ratio, 2.31 [Cl, 1.36 to 3.92] and 1.72 [Cl, 1.03 to 2.86], respectively). Univariate analysis of the subgroup of 89 patients with high-risk adenomas showed an inverse association between such adenomas and HDL cholesterol (odds ratio, 0.37; Cl, 0.18 to 0.76). A logistic regression analysis that included age and body mass index showed an association between lipoprotein levels and the presence of adenomas. The relative strength (in descending order) of these associations was as follows: HDL, LDL, VLDL, and total serum cholesterol. A logistic regression analysis of patients with high-risk adenoma showed a significant association between such adenomas and the HDL cholesterol level. CONCLUSIONS: Patients with colorectal adenomas have lower HDL cholesterol levels and higher LDL and VLDL cholesterol levels; these lipoproteins may have prognostic significance for the development of colorectal adenomas.