New determinants for gallstone disease?
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Gallstone disease is highly prevalent in Denmark and other countries of northern Europe, and cholecystectomy for the treatment of clinical gallstone disease is one the most frequently performed surgical procedures. Research efforts for the identification of mechanisms involved in gallstone formation have a long history and the most established include bile cholesterol saturation, gallbladder motor function, and the enterohepatic circulation of secondary bile salts produced by fecal microbiota. A small number of determinants that are believed to affect these mechanisms have been identified until now. However, much of this research on determinants for gallstone disease has been hampered by insufficient study designs and by insufficient assessment of gallstone disease by only assessing the selected minority of people with clinical gallstone disease. In a Danish general-population cohort screened for gallstone disease with multiple ultrasound examinations, it was possible to both confirm previously identified determinants and to identify new determinants for gallstone disease. Temporal associations for incident gallstone disease and female sex, BMI, non-HDL cholesterol, and inverse associations for increasing alcohol consumption and cessation of hormone replacement therapy in females were confirmed. New determinants included testosterone and increase in SHBG in males which had directly and inverse associations with incident gallstone disease, respectively. All of the identified determinants for incident gallstone disease found in this thesis can be linked to the three biological mechanisms of gallstone formation. Other modifiable factors such as tobacco smoking, coffee consumption, dietary habits, physical activity, and blood pressure were not identified as determinants of incident gallstone disease in this thesis. Previous findings from other studies may be hampered by study design without exploration of temporal associations or due to selective assessment of gallstone disease. A common information bias for all existing literature exploring lifestyle habits and gallstone disease is the self-reported exposures which may cause misclassification bias. If explored in future studies, assessment of lifestyle habits should include objective measures in order to contribute any further to existing evidence on determinants for gallstone disease. Associations for biomarkers of insulin resistance and gallstone disease prevalence were found. Insulin resistance probably mediates the association between BMI and gallstone disease. Although only cross-sectional, the association for both BMI and insulin resistance with gallstone disease seems well established based on existing experimental and observational evidence. New cross-sectional associations for gallstone disease prevalence were identified for biomarkers of systemic inflammation, genetic risk for obesity or diabetes type 2, and for biomarkers of renal function. Levels of vitamin D were not identified as the cause of the higher northern European gallstone disease prevalence, although birth during season of low sun and vitamin D exposure seemed associated. Future clinical or larger population-based interventional trials aiming at changing body weight, circulating levels of non-HDL cholesterol, or alcohol consumption are supported by the findings of this PhD thesis. Screening of gallstone disease through ultrasound examinations should be performed in future interventional trials aiming at preventing cardiovascular disease in order to monitor the effects of such interventions on gallstone formation and, further, to avoid the selection bias caused by just assessing clinical gallstone disease. Screening for gallstone disease on the population-level is not recommended due to an assumed increase in clinical gallstone disease without a survival advantage of treatment. Explorations of male reproductive hormones, biomarkers of systemic inflammation, circulating levels of vitamin D, and genetic risk alleles should be repeated in future cohort studies before these possible determinants may be subject for future strategies for prevention or treatment of gallstone disease.