Michael J. Burt

High incidence of Crohn's disease in Canterbury, New Zealand: Results of an epidemiologic study

Background: Inflammatory bowel disease (IBD) has increased exponentially in industrialized nations over the last 50 years. Previous New Zealand studies have shown that IBD is less common than in other countries; however, clinical observations suggested a high incidence and prevalence of IBD in Canterbury, particularly Crohns disease (CD). Aim: This study aimed to determine the descriptive epidemiology of IBD in Canterbury. Methods: Canterbury IBD patients, recruited using multiple strategies, gave informed consent, permission for clinical record review, completed a questionnaire, and were bled for DNA extraction as part of the Canterbury IBD Project. Cases were confirmed using standard criteria, and completeness of recruitment was validated using capture‐recapture methods. Demographic and phenotypic data were extracted from case notes. One thousand four hundred twenty patients (715 CD, 668 ulcerative colitis [UC]) were recruited (>91% of Canterbury IBD patients). Results: In 2004, age‐standardized (World Health Organization World Standard Population) IBD, CD, and UC incidence rates were 25.2, 16.5, and 7.6/100,000/year, respectively. The IBD, CD, and UC point prevalences on 1 June, 2005 were 308.3, 155.2, and 145.0/100,000, respectively. CD patients were more likely than UC patients to be female (61.4% vs. 47.1%) and to be younger (median age, 39.9 years vs. 43.7 years). The percent of IBD patients who were white was 97.5%. Conclusion: IBD is at least as common in Canterbury as in other western regions. CD incidence and prevalence are amongst the highest ever reported and are higher than for UC. IBD population characteristics are otherwise similar to other countries. The Canterbury IBD Project will be a valuable tool for future population‐based IBD epidemiology and genetics research.

The significance of haemochromatosis gene mutations in the general population: implications for screening

Background—Haemochromatosis is associated with mutations in the HFE gene but the significance of these mutations in the general population is unknown. Aims—To determine the frequency ofHFE gene mutations in the general population, their effect on serum iron indexes, and their role in screening for haemochromatosis. Methods—Deoxyribonucleic acid (DNA) from 1064 randomly selected subjects was analysed for the C282Y and H63D mutations in the HFE gene. Serum iron, transferrin saturation, and ferritin were measured and individuals with increased iron indexes were investigated to confirm or exclude a clinical diagnosis of haemochromatosis. Results—Mutations were identified in 409 individuals (38.4%) with heterozygote (carrier) frequencies of 13.2% and 24.3% for the C282Y and H63D mutations respectively. Heterozygosity for either mutation significantly increased serum iron and transferrin saturation but despite a similar trend for ferritin, this was only significant for C282Y homozygotes. Five individuals (0.47%) were homozygous for the C282Y mutation, three of whom had haemochromatosis confirmed by liver biopsy (0.28%). The other two C282Y homozygotes would not have been detected by phenotypic screening alone. Conclusions—HFE mutations are present in 38.4% of the population, affect serum iron indexes, and are important determinants of iron status. The population frequency of genetically defined haemochromatosis (C282Y homozygosity) is approximately one in 200 and is higher than the prevalence of clinically apparent haemochromatosis.

Adult coeliac disease: prevalence and clinical significance.

Background and Aims : Although coeliac disease is a common condition, the role of population screening is not clear. The aim of this study was to determine the prevalence and clinical significance of coeliac disease in the adult population of Christchurch, New Zealand.

Population-based epidemiology study of autoimmune hepatitis: A disease of older women?

Background and Aim:  The etiology of autoimmune hepatitis (AIH) is unknown, and limited epidemiological data are available. Our aim was to perform a population based epidemiological study of AIH in Canterbury, New Zealand.

Thiopurine S‐methyltransferase (TPMT) genotype does not predict adverse drug reactions to thiopurine drugs in patients with inflammatory bowel disease

Background : Azathioprine and mercaptopurine (MP) are well established treatments for inflammatory bowel disease but they have severe adverse effects that prevent their use in some patients. The likelihood and type of adverse effect may relate to thiopurine methyltransferase (TPMT) enzyme activity and genotype.

Gallbladder Polyps: Prospective Study

The aim of this study was to describe the natural history of gallbladder polyps. Thirty‐eight subjects who had been previously identified as having gallbladder polyps in an epidemiologic study of gallstone prevalence in 627 diabetic subjects and matched controls were followed longitudinally. Follow‐up sonograms were obtained on 33 and 22 of the 38 subjects at 2 and 5 years, respectively. Prevalence for gallbladder polyps in this population was 6.7%, with a marked male predominance (odds ratio 2.3). No statistical difference in prevalence was found between diabetic subjects and nondiabetic controls. Ninety percent of the polyps were less than 10 mm in diameter, with no polyp being larger than 12 mm. During the follow‐up period no changes suggestive of malignant transformation were observed. In conclusion, we found that gallbladder polyps were relatively common and that few significant changes occurred over a 5 year period. In asymptomatic subjects in whom gallbladder polyps less than 10 mm in diameter are found incidentally, the likelihood of malignant transformation is low.

Use of 99mTc-DISIDA biliary scanning with morphine provocation for the detection of elevated sphincter of Oddi basal pressure

BACKGROUND Endoscopic biliary manometry is useful in the assessment of patients with types II and III sphincter of Oddi dysfunction, but it is time consuming and invasive. AIM To investigate the role of 99mTc-DISIDA scanning, with and without morphine provocation, as a non-invasive investigation in these patients compared with endoscopic biliary manometry. SUBJECTS AND METHODS A total of 34 patients with a clinical diagnosis of type II (n=21) or III (n=13) sphincter of Oddi dysfunction were studied. Biliary scintigraphy with 100 MBq of 99mTc-DISIDA was carried out with and without morphine provocation (0.04 mg/kg intravenously) and time/activity curves were compared with the results of subsequent endoscopic biliary manometry. RESULTS Eighteen (nine type II, nine type III) of the 34 (53%) patients had sphincter of Oddi basal pressures above the upper limit of normal (40 mm Hg). In the standard DISIDA scan without morphine, no significant differences were observed in time to maximal activity (Tmax) or percentage excretion at 45 or 60 minutes between those with normal and those with abnormal biliary manometry. However, following morphine provocation, median percentage excretion at 60 minutes was 4.9% in those with abnormal manometry and 28.2% in the normal manometry group (p=0.002). Using a cut off value of 15% excretion at 60 minutes, the sensitivity for detecting elevated sphincter of Oddi basal pressure by the morphine augmented DISIDA scan was 83% and specificity was 81%. Also, 14 of the 18 patients with abnormal manometry complained of biliary-type pain after morphine infusion compared with only two of 16 patients in the normal manometry group (p=0.001). CONCLUSIONS 99mTc-DISIDA with morphine provocation is a useful non-invasive investigation for types II and III sphincter of Oddi dysfunction to detect those with elevated sphincter basal pressures who may respond to endoscopic sphincterotomy.

Effect of inflammatory bowel disease classification changes on NOD2 genotype–phenotype associations in a population-based cohort

Background: NOD2 mutations are associated with Crohns disease (CD) in Caucasian clinic‐based cohorts. Data from population‐based cohorts are limited. Clinic‐based studies may overestimate this association. Genotype–phenotype relationships are yet to be assessed using the Montreal classification. We hypothesized that the NOD2–CD association would be weaker in a population‐based cohort, and that the Montreal classification would strengthen genotype–phenotype associations. Methods: A population‐based case‐control study was performed including 91% of all people in Canterbury, New Zealand, with inflammatory bowel disease (IBD); NOD2 genotyping was performed and patients were phenotyped according to the Vienna and Montreal classification systems. Results: The NOD2 genotype was available on 684 CD, 643 ulcerative colitis (UC), 36 indeterminate colitis/IBDU (IBD unclassified) patients, and 201 controls. Control frequencies for the 702W, 908R, and 1007fs alleles were 0.030, 0.012, and 0.010, respectively, compared with 0.074, 0.027, and 0.040 for CD. The 702W (P = 0.001) and 1007fs (P = 0.002) alleles were significantly associated with CD. Younger age of diagnosis (<17 years) was associated with 1 (odds ratio (OR) 1.9 [95% confidence intervals 0.98–3.6]) or 2 (OR 6.5 [2.3–18.6]) NOD2 mutations compared with diagnosis >40 years. Ileal disease was most strongly associated with NOD2 mutations (1 mutation OR 3.9 [2.4–6.3], 2 mutations OR 6.7 [2.4–18.5]). Penetrating disease was associated with NOD2 mutations using the Montreal but not the Vienna classification. Conclusions: The association between NOD2 mutations and CD was found to be weaker in our population‐based cohort than in previous studies that used referral‐based cohorts. Application of the Montreal classification led to a strengthening of the NOD2 genotype–phenotype association. (Inflamm Bowel Dis 2007)

Trinucleotide repeat variants in the promoter of the thiopurine S-methyltransferase gene of patients exhibiting ultra-high enzyme activity.

Thiopurine S-methyl transferase (TPMT) is a cytosolic enzyme that catalyses the S-methylation of the thiopurine immunosuppressants. To date, 22 variants have been identified that are predictive of decreased TPMT activity. In contrast, no molecular explanation has been found for the 1–2% of Caucasians who exhibit ultra-high TPMT activity. Here, we report the characterization of polymorphisms within a trinucleotide (GCC) repeat element of the TPMT promoter in two patients with inflammatory bowel disease exhibiting the highest TPMT activity from two testing centres. The first patient was heterozygous for a variant allele carrying seven GCC repeats [(GCC)7], whereas the second patient was heterozygous for a variant allele containing five GCC repeats [(GCC)5]. Fifty patients with inflammatory bowel disease with normal TPMT activity were all homozygous for six GCC repeats [(GCC)6]. Of 200 healthy controls, five were found to be heterozygous for the (GCC)7 variant. Within in vitro reporter gene assays, the mean luciferase activities of the (GCC)6, (GCC)7, and (GCC)5 constructs were 8.0±0.26, 13.2±0.10 and 12.3±0.12, respectively. The significant increase in activity observed for (GCC)5 and (GCC)7 compared with (GCC)6 (P-value ≤0.001) strongly suggests that alteration in the number of trinucleotide repeats is responsible for the ultra-high TPMT activity observed in these patients.

surveillance for Dysplasia in Patients With Inflammatory Bowel Disease: A National Survey of Colonoscopic Practice in New Zealand

BACKGROUNDPatients with chronic ulcerative colitis and Crohn’s colitis have an increased risk of colorectal cancer. Because of this, surveillance colonoscopy is practiced.AIMSWe aimed to describe the practice of surveillance colonoscopy in New Zealand, with comparison among specialties, and with practice internationally.SUBJECTSNew Zealand colonoscopists (both physicians and surgeons) looking after patients with inflammatory bowel disease were surveyed to evaluate attitudes about surveillance colonoscopy and ways in which colonoscopy results are interpreted.METHODSA postal survey assessed the colonoscopist’s understanding of how and why surveillance colonoscopy is undertaken and their interpretation of the results from such evaluations.RESULTSOf the196 physicians and surgeons surveyed, 180 responded (92 percent). Sixty responses were excluded. Only 24 of 120 respondents (20 percent) correctly defined dysplasia. The median number of biopsies taken at colonoscopy was 17. Eighty of 120 (67 percent) and 77 of 120 (64 percent) doctors underestimate the risk of invasive malignancy if low-grade or high-grade dysplasia, respectively, is identified. The colectomy referral rate for dysplasia-associated lesion or mass was 115/120 (96 percent); that for high-grade dysplasia was 110/120 (92 percent); and that for low-grade dysplasia was 26/120 (22 percent). Thirty of 120 (25 percent) doctors offer patients the option of colectomy after 20 years of colitis. Seventy of 120 (58 percent) doctors sought the opinion of a second pathologist if dysplasia was found. There were differences in responses between specialist groups, with colorectal surgeons most likely to correctly define dysplasia and appreciate the significance of low-grade dysplasia.CONCLUSIONSMany New Zealand colonoscopists have a poor understanding of the definition and importance of dysplasia associated with colitis. Although colectomy referral rates are higher in this study than in similar studies, low-grade dysplasia is often not referred for colectomy. Improved education may improve surveillance practice.