In this 12 year prospective cohort study among men, we found that a high intake of carbohydrate was positively associated with the risk of symptomatic gall stone disease. A significant positive association was also found for dietary glycaemic load and glycaemic index.
Epidemiological studies of carbohydrate or sugar intake and risk of gall stone disease have not been consistent. In a cross sectional study of gall stone disease in Copenhagen, ascertained by ultrasonography, higher intake of refined sugar was not significantly associated with increased gall stone prevalence.18
In a population based health survey in Mexican Americans, in which participants were questioned about any history of gall bladder disease, high level of sucrose intake was not significantly related to the risk of gall stone disease.19
In two larger case control studies, one in Italy and the other in Australia, an increased risk with sugar intake was seen.16,33
In a prospective cohort study in the Netherlands, a twofold greater risk of clinically diagnosed gall stones was found for the highest tertile of sugar intake relative to the lowest.17
In a population study in Italy, a positive association was observed between high carbohydrate intake and an increased risk of gall stones diagnosed in an ultrasonographic survey.20
The inconsistency among these studies may be due to lack of long term dietary information, imprecise or non-validated assessment of nutrients, suboptimal study design, small sample size, or different definitions of disease end points.
High intake of carbohydrate stimulates hepatic synthesis of VLDL cholesterol, raises plasma triglycerides, and reduces HDL cholesterol.6,7
In a prospective, randomised, long term outpatient study in free living subjects lasting up to two years,34
a diet with high carbohydrate and low fat content was associated with an increase in plasma triglyceride level and a reduction in HDL cholesterol level. Low plasma HDL cholesterol and high triglyceride were found to be associated with an increased risk of gall stone disease.5,35
In addition, a low fat, high carbohydrate diet may increase the incidence of glucose intolerance, type 2 diabetes mellitus, hyperinsulinaemia, and insulin resistance, and thereby may facilitate gall stone formation.14,15
In metabolic trials, low fat, high carbohydrate diets decreased insulin sensitivity in subjects.36,37
In subjects who were prone to insulin resistance, these diets further worsened dyslipidaemia.38
Moreover, diets with high glycaemic index and glycaemic load diets have been reported to increase postprandial glucose and insulin responses, derange lipid profiles, and decrease insulin sensitivity,12,39,40
which may increase the risk of gall stones.
Men with a high carbohydrate intake tended to have a generally healthy lifestyle (see table 1), which may protect against gall stone disease. Our detailed analyses took into account the differences in lifestyle, and these adjustments appeared to strengthen the associations. It indicated that the associations were independent of these known risk factors.
The prospective design of our study avoids the potential for differential recall of intake by gall stone cases and non-cases because all data on food were collected before the diagnosis of symptomatic gall stone disease. Also, consistently high follow up rates reduce the possibility that our results are biased by men lost to follow up in this cohort. Thus these potential biases would have been minimal.
The possibility of misclassification might be of concern because information on nutrient intake was collected by self report. Random within person variation could attenuate any true association of interest but the semiquantitative food frequency questionnaire was designed to minimise this error by assessing average long term dietary intake during the successive follow up periods. These repeated measurements took into account possible changes in diet with time, and reduced random variation in reporting. Although the total effects of carbohydrate intake may not be fully captured by the questionnaire, any measurement errors would be expected to be unrelated to the end points because of the prospective design. Thus any non-differential misclassification would most likely bias the relative risks toward null and weaken, rather than strengthen, any true relationship.
Our results were restricted to men with surgical cholecystectomy or diagnostically confirmed but unremoved symptomatic gall stones. The results may not be generalisable to the entire population with gall stones; however, the study focused on clinically relevant gall stone disease.
In this large study population it was not possible to perform diagnostic screening procedures for the presence of gall stones. It is likely that the positive correlations found are related to an increasing risk for the transition from asymptomatic to symptomatic gall stones. Because most gall stones are silent, it is likely that there was considerable under ascertainment of gall stones. It was not likely that the presence of silent gall stones at baseline was associated with the reporting. As relative risk estimation in follow up cohort studies would not be biased by uniform under ascertainment,29
our results were not likely biased due to silent gall stones.
In conclusion, our findings suggest that a high intake of carbohydrate, glycaemic load, and glycaemic index increases the risk of symptomatic gall stone disease among men. These results add to the concern that low fat, high carbohydrate diets may not be an optimal dietary recommendation.