Progression from Asymptomatic to Symptomatic Gallstones: The Risk Factors

A medicine,pointing at a plastic model of a gall bladder. Image taken with Canon EOS 1 Ds Mark II and EF 70-200 mm USM L 2,8. XXL size image.
Researchers sought to assess the rate of symptom development in patients with asymptomatic gallstones, identify the factors tied to the progression of symptomatic gall stones, and develop a clinical prediction model.

Approximately 22% of patients with asymptomatic gallstones became symptomatic after 10 years with 25% of these patients needing interventional procedures. Moreover, several risk factors, like obesity, predicted disease progression. These are the findings of a study published in Clinical Gastroenterology and Hepatology.

Asymptomatic gallstones are common yet there is limited knowledge on how they develop. Due to sparse data, consensus guidelines for the optimal management of asymptomatic gallstones does not exist. The objective of the current study was to assess the natural history of asymptomatic gallstones in a large contemporary population, identify risk factors associated with the development of asymptomatic to symptomatic gallstones, and develop a prediction model of symptomatic gallstones over a 10-year period.

Researchers performed a retrospective cohort study of 49,414 patients with gallstones identified via ultrasound or computed tomography between January 1996 and December 2016 within the Cleveland Clinic Health System. Following application of inclusion criteria, the study included 22,257 patients with asymptomatic gallstones.

After a median follow-up of 4.6 years, asymptomatic gallstones became symptomatic in 14.5% of patients with linearly increasing cumulative incidence as time progressed. After 5, 10, and 15 years, 10.1%±0.22%, 21.5%±0.39%, and 32.6%±0.83% developed symptomatic gallstones. Approximately 25% of these patients needed interventional procedures.

Strongest risk factors predicting the progression from asymptomatic to symptomatic gallstones included female gender (hazard ratio [HR], 1.50; 95% CI, 1.39-1.61), younger age at onset (HR every 5 years, 1.15; 95% CI, 1.14-1.16), multiple stones (HR, 2.42; 95% CI, 2.25-2.61), large stones (HR, 2.03; 95% CI, 1.80-2.29), gallbladder polyps (HR, 2.55; 95% CI, 2.14-3.05), hyperlipidemia (HR, 1.47; 95% CI, 1.36-1.58 ), tobacco use (HR, 1.38; 95% CI, 1.28-1.48), sludge (HR, 1.63; 95% CI, 1.44-1.85), and chronic hemolytic anemia (HR, 1.90; 95% CI, 1.33-2.72).

Obesity was also a strong predictor for the development of symptomatic gallstones. Patients who classified as overweight with a body mass index (BMI) between 25 and 29.9 demonstrated a HR of 1.22, while patients classified as obese with BMIs between 30 to 34.9, 35 to 39.9, and 40 or greater demonstrated HRs of 1.55, 1.73, and 1.60, respectively.

Use of statins decreased risk for developing complicated symptomatic gallstones (HR, 0.61; 95% CI, 0.57-0.66).

Study limitations included the retrospective design lending toward omissions and diagnostic misclassifications, the possibility of symptomatic gallstones at baseline, inability to assess certain risk factors based on available data, and underestimation of event rate due to inability to record events outside of the Cleveland Clinic Health System.

“By combining risk factors commonly available at the time of diagnosis, we derived a risk prediction model offering good discrimination and calibration,” the researchers concluded. “Such a model could easily be adapted for use in clinical care to aid in shared decision-making regarding prophylactic surgery for [asymptomatic gallstones].”


Morris-Stiff G, Sarvepalli S, Hu B, et al. The natural history of asymptomatic gallstones: A longitudinal study and prediction model. Clin Gastroenterol Hepatol. Published online May 2, 2022. doi:10.1016/j.cgh.2022.04.010