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- Rendek, Zlatica, 1983-
(författare)
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Faecal Calprotectin Diagnostics : Focus on Primary Care and Suspected Sources of Error
- 2023
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Patients with gastrointestinal symptoms often present a diagnostic challenge for general practitioners. Faecal calprotectin (FC) is commonly used as a marker of intestinal inflammation and is useful for differentiating between inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS), as well as for the follow-up of patients with IBD and monitoring treatment response. However, several other causes of increased FC levels have been acknowledged, including intake of non-steroidal anti-inflammatory drugs or proton pump inhibitors and respiratory infections. Currently, there is insufficient knowledge about how these factors affect FC levels. It is crucial that physicians who use calprotectin as a diagnostic tool have the ability to conduct a sound evaluation of the test result to ensure accurate clinical decisions, and potentially avoid unnecessary referrals and invasive investigations.The aim of this thesis was to investigate the contribution of FC in the diagnostics of gastrointestinal disease in primary care, its diagnostic value and accuracy as a predictor of gastrointestinal disease and the influence of different sources of error on calprotectin levels. In particular, the effects of oral diclofenac (a non-steroidal anti-inflammatory drug [NSAID]), omeprazole (a proton pump inhibitor [PPI]) and respiratory tract infection on FC levels are investigated. The normalization interval after cessation of diclofenac and omeprazole is assessed.The first study is a retrospective analysis of data on all FC tests on adults conducted in primary care in Östergötland County in 2010. A higher proportion of patients with a positive FC result were diagnosed with IBD and organic gastrointestinal disease compared with those with a negative FC result. Predictors of IBD were positive FC, diarrhoea, rectal bleeding and male sex. Predictors of organic gastrointestinal disease were found to be positive FC, age >35 years, abnormal clinical findings and duration <3 months. FC had the highest sensitivity and negative predictive value compared with demographic factors, symptoms and duration. Intake of NSAIDs, PPIs and acetyl salicylic acid showed marginal effects on the diagnostic accuracy of FC for IBD and organic gastrointestinal disease. Among patients with a negative FC test, on whom no further investigations were performed, no missed diagnoses of IBD or organic gastrointestinal disease were detected at a 5-year follow-up.The second study investigates the effect of diclofenac intake on FC levels. We found that shortterm intake of oral diclofenac was associated with increased FC levels and that FC returned to normal within 2 weeks of cessation.The third study reports on a randomized open-label clinical trial and investigates the effect of omeprazole, diclofenac and co-administration of these drugs on FC levels. The findings regarding diclofenac were consistent with those of the second study. Short-term intake of omeprazole alone or when co-administered with diclofenac was associated with increased FC levels. The normalization interval was 3 weeks after cessation.The fourth study, a prospective cohort study, examines the effect of an acute respiratory tract infection on the FC level. Faecal and salivary calprotectin levels were not found to be increased during respiratory tract infections. This study did not confirm any correlation between calprotectin levels in saliva and faeces during infection.In conclusion, FC reliably rules out IBD and contradicts the presence of other organic gastrointestinal diseases in patients with gastrointestinal symptoms attending primary care. Patients with a positive FC test together with other symptoms, such as diarrhoea, rectal bleeding, short duration or age >35 years should be prioritized for further investigations. Short-term intake of diclofenac, omeprazole, or their co-administration in healthy individuals is associated with increased FC levels. In patients with an increased FC level on diclofenac, it is sufficient to repeat the FC test 2 weeks after cessation. In patients on omeprazole alone or when co-administered with diclofenac, the FC test should be repeated 3 weeks after cessation. Acute respiratory tract infections were not found to be associated with increased faecal or salivary calprotectin levels.
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| 2. |
- Blomdahl, Julia, 1991-
(författare)
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Non-Alcoholic Fatty Liver Disease : Insights into Alcohol Consumption, Genetics, and Proteomics
- 2023
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- NAFLD (Non-Alcoholic Fatty Liver Disease) affects approximately a quarter of the global population and is closely linked to type 2 diabetes mellitus and obesity. The disease spectrum ranges from steatosis and steatohepatitis to fibrosis, cirrhosis, and hepatocellular cancer. However, accurately predicting which patients will experience a progressive disease course remains a significant challenge. The variant gene of PNPLA3 is known to be associated with NAFLD and a more progressive disease, although its precise function remains unclear. Patients with NAFLD typically consume small to moderate amounts of alcohol, with recommended thresholds set at a maximum of 210 gram per week for males and 140 grams per week in females. However, the impact of alcohol consumption on liver disease in NAFLD remains disputed, with conflicting research findings. Liver biopsy is considered the gold standard for diagnosing NAFLD. However, due to its impracticality for such a large population with the condition, various non-invasive methods have been explored for diagnosing and evaluating NAFLD. This thesis aimed to investigate the potential effects of moderate alcohol consumption on NAFLD histology, explore the potential role of variant PNPLA3 in NAFLD, and assess the use of proteomics in classifying fibrosis. In Papers I and II, moderate alcohol consumption was assessed through questionnaires, clinical interviews, and measurement of the direct alcohol biomarker phosphatidylethanol (PEth). Paper I, a cross-sectional study including 86 participants, showed an association between moderate consumption and advanced fibrosis. Moderate consumption was defined as consuming more than 66 grams of ethanol per week or a PEth-value over 50 ng/mL. Notably, individuals with both moderate alcohol consumption and a diagnosis of type 2 diabetes exhibited significantly more advanced fibrosis. Paper II was a cohort study where 82 participants were followed over 17.2 years. Similarly, participants with moderate alcohol consumption displayed significant fibrosis progression. The strongest association was observed in participants with PEth-value of 48 ng/mL or higher, or those with binge drinking. In Paper III, the potential role of variant PNPLA3 was explored, exhibiting impaired autophagic flux and reduced lipophagy in variant PNPLA3 cells. Liver biopsies of NAFLD individuals with variant PNPLA3 displayed an accumulation of lipid droplets positive for both PNPLA3 and LC3 (a common marker of the autophagosome). This suggests that PNPLA3 is part of the lipophagy process, which is impaired in the variant gene and contributes to steatosis. Paper IV examined two independent NAFLD cohorts. In the discovery cohort, 60 participants with biopsy-proven NAFLD were included, while 59 participants were included in the validation cohort. The study evaluated 266 proteins and found that a biomarker model combining ACE2, HGF, and IGFBP-7 distinguished between different fibrosis stages (F0–1 and F2–4) in both cohorts. In summary, measuring phosphatidylethanol is advisable in NAFLD patient evaluations. Elevated PEth-levels (≥48 ng/mL) or alcohol consumption exceeding 66 grams per week should warrant advice to abstain from alcohol. PNPLA3 is implicated in NAFLD pathophysiology, potentially through impaired lipophagy. While its clinical application remains uncertain, genetic profiling for NAFLD risk assessment may become part of future non-invasive approaches. Additionally, proteomics holds promise for non-invasive NAFLD assessment, with the combination of ACE2, HGF, and IGFBP-7 identifying significant fibrosis in two separate cohorts.
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