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.