To Örebro University

Introduction: Recent years have seen significant research advances within the gastroenterological field. Some of these consist of the recognition of serrated polyps as a precursor to colorectal cancer, and the realization of the health economic burden associated with gastrointestinal diseases.

Aim: In this thesis, we aim to validate the specificity of serrated polyps in the ESPRESSO cohort (Paper I). We also aim to estimate work loss in patients with celiac disease, including the temporal relationship of work loss before and after diagnosis (Paper II).

Method: By using the ESPRESSO cohort, we collected data on patients with serrated polyps and patients with celiac disease. In Paper I, the specificity of serrated polyps in the ESPRESSO cohort were validated by a structured retrospective review of patient chart. In Paper II, we estimated work loss in patients with celiac disease as compared withgeneral-population comparators matched on age, sex, county of residence and year of diagnosis.

Result: The presence of a serrated polyp was confirmed in 101 out of 106 individuals identified through the ESPRESSO cohort, yielding a positive predictive value of 95% (95% confidence interval: 89-98%). Patients with celiac disase had 42.5 lost work days as compared to 28.6 days in comparators (mean difference, 14.7; 95% confidence interval, 13.2-16.2), corresponding to a relative increase of 49%. Excess work loss in patients with celiac disease was observed even 5 years before diagnosis and remained eleveated during the years after diagnosis this loss. Notebly, the excess work loss was concentrated to a small proportion while most celiac patients did not have any work loss before or after diagnosis. 

Conclusion: The ESPRESSO cohort has a high specificity for serrated polyps. Patients with celiac disease miss more work days than the general population even before diagnosis, and this loss persists after diagnosis.

BACKGROUND: Celiac disease (CD) affects around 1% of the population worldwide. Data on work disability in celiac patients remain scarce. We estimated work loss in celiac patients including its temporal relationship to diagnosis.

METHODS: Through biopsy reports from Sweden's 28 pathology departments, we identified 16,005 working-aged patients with prevalent CD (villus atrophy) as of January 1, 2015, and 4,936 incident patients diagnosed with CD in 2008-2015. Each patient was matched to up to 5 general-population comparators. Using nationwide social insurance registers, we retrieved prospectively-recorded data on compensation for sick leave and disability leave to assess work loss in patients and comparators.

RESULTS: In 2015, patients with prevalent CD had a mean of 42.5 lost work days as compared with 28.6 in comparators (mean difference: 14.7, 95%CI: 13.2-16.2), corresponding to a relative increase of 49%. More than half of the work loss (60.1%) in celiac patients was derived from a small subgroup (7%) while 75.4% had no work loss. Among incident patients, the annual mean difference between patients and comparators was 8.0 (5.4-10.6) lost work days 5 years before CD diagnosis, which grew to 13.7 (9.1-18.3) days 5 years after diagnosis. No difference in work loss was observed between patients with or without mucosal healing at follow-up.

CONCLUSIONS: Celiac patients lost more work days than comparators before their diagnosis, and this loss increased after diagnosis. Identifying patients with an increased risk of work loss may serve as a target to mitigate work disability, and thereby reduce work loss, in CD.

Celiac disease (CD) is an immune‐mediated disease triggered by gluten intake and affects around 1% of the population worldwide. Although patients with CD have an increased use of healthcare, data on work disability remains scarce. To estimate work loss in patients with CD before and after diagnosis. We identified 16,005 working‐age patients with prevalent CD, and 4,936 incident working‐age patients diagnosed in 2008‐2015 through biopsy reports from Sweden’s 28 pathology departments. CD was defined by presence of villus atrophy (Marsh 3) on biopsy (gold standard). Each patient was compared to up to 5 matched general‐population comparators. Using nationwide social insurance registers, we retrieved prospectively‐recorded data on compensation for sick leave and disability. In 2015, patients with prevalent CD had a mean of 42.5 (95%CI: 40.9‐44.1) lost work days as compared with 28.6 (27.9‐29.2) in the general‐population comparators, corresponding to a relative difference of 49%. Among incident patients, the annual mean difference between patients and comparators was 8.0 (5.4‐10.6) lost work days 5 years before CD diagnosis, which grew to 13.7 (9.1‐18.3) days 5 years after diagnosis. In addition to the continuously increasing mean difference in lost work days over time, there was also a transient increase in work loss in patients with CD during the year of diagnosis (mean difference: 15.6 days, 95%CI: 13.1‐18.0). Patients with CD miss more work days than comparators before their diagnosis, and this loss increases and persists after diagnosis despite presumed installation of treatment with gluten‐free diet. 

INTRODUCTION: Celiac disease (CD) affects 1% of the population. Its effect on healthcare cost, however, is barely understood. We estimated healthcare use and cost in CD, including their temporal relationship to diagnosis.

METHODS: Through biopsy reports from Sweden's 28 pathology departments, we identified 40,951 prevalent patients with CD (villous atrophy) as of January 1, 2015, and 15,086 incident patients with CD diagnosed in 2008-2015, including 2,663 who underwent a follow-up biopsy to document mucosal healing. Each patient was compared with age- and sex-matched general population comparators (n = 187,542). Using nationwide health registers, we retrieved data on all inpatient and nonprimary outpatient care, prescribed diets, and drugs.

RESULTS: Compared with comparators, healthcare costs in 2015 were, on average, $1,075 (95% confidence interval, $864-1,278) higher in prevalent patients with CD aged <18 years, $715 ($632-803) in ages 18-64 years, and $1,010 ($799-1,230) in ages ≥65 years. Half of all costs were attributed to 5% of the prevalent patients. Annual healthcare costs were $391 higher 5 years before diagnosis and increased until 1 year after diagnosis; costs then declined but remained 75% higher than those of comparators 5 years postdiagnosis (annual difference = $1,044). Although hospitalizations, nonprimary outpatient visits, and medication use were all more common with CD, excess costs were largely unrelated to the prescription of gluten-free staples and follow-up visits for CD. Mucosal healing in CD did not reduce the healthcare costs.

DISCUSSION: The use and costs of health care are increased in CD, not only before, but for years after diagnosis. Mucosal healing does not seem to lower the healthcare costs.

Background: Long-term colorectal cancer incidence and mortality after colorectal polyp removal remains unclear. We aimed to assess colorectal cancer incidence and mortality in individuals with removal of different histological subtypes of polyps relative to the general population.

Methods: We did a matched cohort study through prospective record linkage in Sweden in patients aged at least 18 years with a first diagnosis of colorectal polyps in the nationwide gastrointestinal ESPRESSO histopathology cohort (1993-2016). For each polyp case, we identified up to five matched reference individuals from the Total Population Register on the basis of birth year, age, sex, calendar year of biopsy, and county of residence. We excluded patients and reference individuals with a diagnosis of colorectal cancer either before or within the first 6 months after diagnosis of the index polyp. Polyps were classified by morphology codes into hyperplastic polyps, sessile serrated polyps, tubular adenomas, tubulovillous adenomas, and villous adenomas. Colorectal cancer cases were identified from the Swedish Cancer Registry, and cause-of-death data were retrieved from the Cause of Death Register. We collected information about the use of endoscopic examination before and after the index biopsy from the Swedish National Patient Registry, and counted the number of endoscopies done before and after the index biopsies. We calculated cumulative risk of colorectal cancer incidence and mortality at 3, 5, 10, and 15 years, and computed hazard ratios (HRs) and 95% CIs for colorectal cancer incidence and mortality using a stratified Cox proportional hazards model within each of the matched pairs.

Findings: 178 377 patients with colorectal polyps and 864 831 matched reference individuals from the general population were included in our study. The mean age of patients at polyp diagnosis was 58.6 (SD 13.9) years for hyperplastic polyps, 59.7 (14.2) years for sessile serrated polyps, 63.9 (12.9) years for tubular adenomas, 67.1 (12.1) years for tubulovillous adenomas, and 68.9 (11.8) years for villous adenomas. During a median of 6.6 years (IQR 3.0-11.6) of follow-up, we documented 4278 incident colorectal cancers and 1269 colorectal cancer-related deaths in patients with a polyp, and 14 350 incident colorectal cancers and 5242 colorectal cancer deaths in general reference individuals. The 10-year cumulative incidence of colorectal cancer was 1.6% (95% CI 1.5-1.7) for hyperplastic polyps, 2.5% (1.9-3.3) for sessile serrated polyps, 2.7% (2.5-2.9) for tubular adenomas, 5.1% (4.8-5.4) for tubulovillous adenomas, and 8.6% (7.4-10.1) for villous adenomas compared with 2.1% (2.0-2.1) in reference individuals. Compared with reference individuals, patients with any polyps had an increased risk of colorectal cancer, with multivariable HR of 1.11 (95% CI 1.02-1.22) for hyperplastic polyps, 1.77 (1.34-2.34) for sessile serrated polyps, 1.41 (1.30-1.52) for tubular adenomas, 2.56 (2.36-2.78) for tubulovillous adenomas, and 3.82 (3.07-4.76) for villous adenomas (p<0.05 for all polyp subtypes). There was a higher proportion of incident proximal colon cancer in patients with serrated (hyperplastic and sessile) polyps (52-57%) than in those with conventional (tubular, tubulovillous, and villous) adenomas (30-46%). For colorectal cancer mortality, a positive association was found for sessile serrated polyps (HR 1.74, 95% CI 1.08-2.79), tubulovillous adenomas (1.95, 1.69-2.24), and villous adenomas (3.45, 2.40-4.95), but not for hyperplastic polyps (0.90, 0.76-1.06) or tubular adenomas (0.97, 0.84-1.12).

Interpretation: In a largely screening-naive population, compared with individuals from the general population, patients with any polyps had a higher colorectal cancer incidence, and those with sessile serrated polyps, tubulovillous adenomas, and villous adenomas had a higher colorectal cancer mortality.

Background: Little is known about the natural history of serrated polyps (SPs), partly due to the lack of large-scale epidemiologic data. In this study, we examined the validity of SP identification according to SNOMED (Systematised Nomenclature of Medicine) codes and free text from colorectal histopathology reports.

Methods: Through the ESPRESSO (Epidemiology Strengthened by histoPathology Reports in Sweden) study, we retrieved data on SPs from all pathology departments in Sweden in 2015-2017 by using SNOMED codes and free-text search in colorectal histopathology reports. Randomly selected individuals with a histopathology report of SPs were validated against patient charts using a structured, retrospective review.

Results: SPs were confirmed in 101/106 individuals with a histopathology report of SPs, yielding a positive predictive value (PPV) of 95% (95%CI = 89-98%). By year of diagnosis, the PPV was 89% (95%CI = 69-97%), 96% (95%CI = 81-99%) and 97% (95%CI = 89-99%) for individuals diagnosed before 2001 (n = 19), between 2001 and 2010 (n = 26) and after 2010 (n = 61), respectively. According to search method, the PPV for individuals identified by SNOMED codes was 100% (95%CI = 93-100%), and 93% (95%CI = 86-97%) using free-text search. Recorded location (colon vs. rectum) was correct in 94% of all SP histopathology reports (95%CI = 84-98%) identified by SNOMED codes. Individuals with SPs were classified into hyperplastic polyps (n = 34; 32%), traditional serrated adenomas (n = 3; 3%), sessile serrated adenomas/polyps (SSA/Ps) (n = 70; 66%), unspecified SPs (n = 3, 3%), and false positive SPs (n = 5, 5%). For individuals identified by SNOMED codes, SSA/Ps were confirmed in 49/52 individuals, resulting in a PPV of 94% (95%CI: 84-98%). In total, 57% had >= 2 polyps (1: n = 44, 2-3: n = 33 and >= 4: n = 27). Some 46% of SPs (n = 71) originated from the proximal colon and 24% were >= 10 mm in size (n = 37). Heredity for colorectal cancer, intestinal polyposis syndromes, or both was reported in seven individuals (7%). Common comorbidities included diverticulosis (n = 45, 42%), colorectal cancer (n = 19, 18%), and inflammatory bowel disease (n = 10, 9%).

Conclusion: Colorectal histopathology reports are a reliable data source to identify individuals with SPs.