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- Wixner, Jonas, 1980-
(författare)
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Gastrointestinal disturbances in hereditary transthyretin amyloidosis
- 2014
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- BackgroundTransthyretin amyloid (ATTR) amyloidosis is a systemic disorder caused by amyloid deposits formed by misfolded transthyretin (TTR) monomers. Two main forms exist – wild-type and hereditary ATTR amyloidosis, the latter associated with TTR gene mutations. Wild-type ATTR amyloidosis has a late onset and primarily cardiac manifestations, whereas hereditary ATTR amyloidosis is a rare autosomal dominant condition with a considerable phenotypic diversity. Both disorders are present all over the world, but endemic areas of the hereditary form are found in Sweden, Portugal, Brazil and Japan. Gastrointestinal (GI) complications are common in hereditary ATTR amyloidosis and play an important role in the patients’ morbidity and mortality. Malfunction of the autonomic and enteric nervous systems has been proposed to contribute to the GI disturbances, but the underlying mechanisms have not been fully elucidated. The aims of this thesis were to assess the prevalence of GI disturbances for different subtypes of ATTR amyloidosis, to further explore the mechanisms behind these disturbances, and to evaluate the outcome of the patients’ GI function after liver transplantation, which currently is the standard treatment for hereditary ATTR amyloidosis.MethodsThe Transthyretin Amyloidosis Outcomes Survey (THAOS) is the first global, multicenter, longitudinal, observational survey that collects data on patients with ATTR amyloidosis. THAOS enrollment data were used to assess the prevalence of GI symptoms and to evaluate their impact on nutritional status (mBMI) and health-related quality of life (EQ-5D Index Score). Data from routine investigations of heart-rate variability and cardio-vascular response to tilt tests were utilized to evaluate the impact of autonomic neuropathy on the scintigraphically measured gastric emptying half-times in Swedish patients with hereditary ATTR amyloidosis. Gastric wall autopsy specimens from Japanese patients with hereditary ATTR amyloidosis and Japanese non-amyloidosis controls were analyzed with immunohistochemistry and computerized image analysis to assess the densities of interstitial cells of Cajal (ICC) and nervous tissue. Data from gastric emptying scintigraphies and validated questionnaires were used to evaluate the outcome of Swedish patients’ GI function after liver transplantation for hereditary ATTR amyloidosis.ResultsSixty-three percent of the patients with TTR mutations and 15 % of those with wild-type ATTR amyloidosis reported GI symptoms at enrollment into THAOS. Subsequent analyses focused on patients with TTR mutations and, among them, unintentional weight loss was the most frequent symptom (32 %) followed by early satiety (26 %). Early-onset patients (<50 years of age) reported GI symptoms more frequently than late-onset cases (70 % vs. 50 %, p <0.01), and GI symptoms were more common in patients with the V30M mutation than in those with non-V30M mutations (69 % vs. 56 %, p <0.01). Both upper and lower GI symptoms were significant negative predictors of nutritional status and health-related quality of life (p <0.01 for both). Weak but significant correlations were found between gastric emptying half-times and the function of both the sympathetic (rs = -0.4, p <0.01) and parasympathetic (rs = -0.3, p <0.01) nervous systems. The densities of c-Kit-immunoreactive ICC were significantly lower in the circular (median density 0.0 vs. 2.6, p <0.01) and longitudinal (median density 0.0 vs. 1.8, p <0.01) muscle layers of the gastric wall in patients compared to controls. Yet, no significant differences in protein gene product 9.5-immunoreactive nervous cells were found between patients and controls either in the circular (median density 3.0 vs. 6.8, p = 0.17) or longitudinal (median density 1.4 vs. 2.5, p = 0.10) muscle layers. Lastly, the patients’ GI symptoms scores had increased slightly from before liver transplantation to the follow-ups performed in median two and nine years after transplantation (median score 7 vs. 10 vs. 13, p <0.01). However, their gastric emptying half-times (median half-time 137 vs. 132 vs. 125 min, p = 0.52) and nutritional statuses (median mBMI 975 vs. 991 vs. 973, p = 0.75) were maintained at follow-ups in median two and five years after transplantation.ConclusionGI disturbances are common in hereditary ATTR amyloidosis and have a negative impact on the patients’ nutritional status and health-related quality of life. Fortunately, a liver transplantation appears to halt the progressive GI involvement of the disease, although the patients’ GI symptoms tend to increase after transplantation. An autonomic neuropathy and a depletion of gastrointestinal ICC seem to contribute to the GI disturbances, but additional factors must be involved.
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| 2. |
- Boks, Marije, et al.
(författare)
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Increased incidence of late-onset inflammatory bowel disease and microscopic colitis after a Cryptosporidium hominis outbreak
- 2022
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Ingår i: Scandinavian Journal of Gastroenterology. - : Taylor & Francis Group. - 0036-5521 .- 1502-7708. ; 57:12, s. 1443-1449
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: In 2010, 27,000 inhabitants (45% of the population) of Östersund, Sweden, contracted clinical cryptosporidiosis after drinking water contaminated with Cryptosporidium hominis. After the outbreak, local physicians perceived that the incidence of inflammatory bowel disease (IBD), including ulcerative colitis (UC), Crohn's disease (CD), and IBD-unclassified, and microscopic colitis (MC) increased. This study assessed whether this perception was correct.MATERIALS AND METHODS: This observational study included adult patients (≥18 years old) from the local health care region who were diagnosed with pathology-confirmed IBD or MC during 2006-2019. We collected and validated the diagnosis, date of diagnosis, age at diagnosis, and sex from the Swedish quality register SWIBREG and electronic patient records. Population data were collected from Statistics Sweden. The incidences for 2006-2010 (pre-outbreak) and 2011-2019 (post-outbreak) were evaluated by negative binomial regression analysis and presented as incidence rate ratios (IRRs). Data were analyzed for IBD, for UC and CD separately, and MC.RESULTS: During the study period, we identified 410 patients with new onset IBD and 155 new cases of MC. Overall, we found a trend toward an increased incidence of IBD post-outbreak (IRR 1.39, confidence interval (CI) 0.99-1.94). In individuals ≥40 years old, the post-outbreak incidence significantly increased for IBD (IRR 1.69, CI 1.13-2.51) and CD (IRR 2.23, CI 1.08-4.62). Post-outbreak incidence of MC increased 6-fold in all age groups (IRR 6.43, CI 2.78-14.87).CONCLUSIONS: The incidence of late-onset IBD and MC increased after the Cryptosporidium outbreak. Cryptosporidiosis may be an environmental risk factor for IBD and MC.
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| 3. |
- Boks, Marije, et al.
(författare)
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Persisting symptoms after Cryptosporidium hominis outbreak : a 10-year follow-up from Östersund, Sweden
- 2023
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Ingår i: Parasitology Research. - : Springer Nature. - 0932-0113 .- 1432-1955. ; 122:7, s. 1631-1639
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Tidskriftsartikel (refereegranskat)abstract
- In late 2010, an outbreak of Cryptosporidium hominis affected 27,000 inhabitants (45%) of Östersund, Sweden. Previous research shows that abdomen and joint symptoms commonly persist up to 5 years post-infection. It is unknown whether Cryptosporidium is associated with sequelae for a longer duration, how persisting symptoms present over time, and whether sequelae are associated with prolonged infection. In this prospective cohort study, a randomly selected cohort in Östersund was surveyed about cryptosporidiosis symptoms in 2011 (response rate 69.2%). A case was defined as a respondent reporting new diarrhoea episodes during the outbreak. Follow-up questionnaires were sent after 5 and 10 years. Logistic regressions were used to examine associations between case status and symptoms reported after 10 years, with results presented as adjusted odds ratios (aOR) with 95% confidence intervals. Consistency of symptoms and associations with case status and number of days with symptoms during outbreak were analysed using X 2 and Mann–Whitney U tests. The response rate after 10 years was 74% (n = 538). Case status was associated with reporting symptoms, with aOR of ~3 for abdominal symptoms and ~2 for joint symptoms. Cases were more likely to report consistent symptoms. Cases with consistent abdominal symptoms at follow-up reported 9.2 days with symptoms during the outbreak (SD 8.1), compared to 6.6 days (SD 6.1) for cases reporting varying or no symptoms (p = 0.003). We conclude that cryptosporidiosis was associated with an up to threefold risk for reporting symptoms 10 years post-infection. Consistent symptoms were associated with prolonged infection.
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| 4. |
- Widbom, Lovisa, 1994-
(författare)
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Lifestyle, biomarkers and the risk of developing inflammatory bowel disease
- 2023
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Introduction: Inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn’s disease (CD), is a chronic disease causing inflammation in the gut mucosa. The pathogenesis involves alteration in gut microbiota and in the intestinal barrier due to genetic factors, environmental exposure and dysregulation of the immune response. Several environmental risk factors and risk genes have been identified, but still, the pathogenesis is not fully understood. Methods: Included papers are all case-control studies based on previously collected data stored with the biobank in Umeå, Sweden. Cases are individuals that participated in the Northern Sweden Health and Disease Study (NSHDS) at least one year before developing IBD. Information was available for all cases regarding age, time and place for inclusion in NSHDS, height and weight, sex and tobacco use. Part of the cases also had available data from a detailed food-frequency questionnaire. For each available case, controls matched for age, sex and time and place were selected. Analysed factors included tobacco use, with smoking and snuff use analysed separately), cotinine (a metabolite of nicotine), iron status (including ferritin, iron, transferrin and transferrin saturation), B-vitamins and tryptophan metabolites. Results: Smoking was associated with an increased risk of developing IBD both based on questionnaire data and using cotinine as a marker for exposure. Snuff use was not associated with risk for developing IBD. A lower ferritin was associated with an increased risk of developing IBD, whereas no association was seen for other iron status analytes. When analysing iron deficiency based on ferritin and CRP, it was shown that iron deficiency was more common among men before onset of IBD, whereas no difference was seen for women. Active vitamin B6 was lower among cases compared to controls, as well as an index indicating functional B6 deficiency. Kynurenic acid and xanthurenic acid, both tryptophan metabolites with immunomodulatory properties, were lower among cases than controls. For CD only, picolinic acid was lower among cases later developing IBD.Discussion: Smoking increases the risk of developing both UC and CD. Snuff use did not increase the risk for IBD, indicating that tobacco exposure is not the reason for increased IBD risk. Low ferritin indicates an early pathological process affecting iron storage unrelated to inflammation. Changes in vitamin B6 and tryptophan metabolites might indicate early pathological processes possibly related to gut microbiota changes. To conclude, this dissertation shows that multiple differences between individuals later developing IBD and controls can be seen years before IBD diagnosis. Some of which give insight to early pathophysiology in IBD.
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