Table 1: Non genetic risk factors for gallbladder stones including modifiable, potentially modifiable and non-modifiable factors.

Factor

 

Pathogenic mechanism (s)

Stone Type

Intervention

Dietary

 

 

 

 

 

Westernized diet

- high-calorie

- low-fiber

- high-refined carbohydrate

- high-lipid

Hepatic hypersecretion, associated metabolic factors, gallbladder stasis

Cholesterol

Modifiable

Lifestyles

 

 

 

 

 

Rapid weight loss (bariatric surgery of morbid obesity), very low calorie diet)

Hypersecretion of biliary mucin, hepatic hypersecretion, gallbladder stasis

Cholesterol

Modifiable

 

Physical inactivity (especially in men)

hepatic hypersecretion, intestinal and gallbladder hypomotility, decreased excretion of bile acids, increased serum triglycerides and insulin release

Cholesterol

Modifiable

 

Smoking

Metabolic factors? Others?

Cholesterol/Pigment

Modifiable

 

High Alcohol intake

Liver damage, reduced bile acid synthesis

Black pigment

Modifiable

Associated

 

 

 

 

 

Obesity

hepatic hypersecretion, gallbladder stasis

Cholesterol

Modifiable

 

Metabolic syndrome, Insulin resistance

Obesity, hepatic hypersecretion, dyslipidemia

Cholesterol

Modifiable

 

Hypertriglyceridemia

 

Association with other metabolic abnormalities, hepatic hypersecretion of cholesterol

Cholesterol

Modifiable

 

Micronutrients abnormalities: low serum magnesium

Insulin resistance and deranged serum LDL- and HDL-cholesterol

Cholesterol

Modifiable

 

Vitamin B-12/folic acid deficient diet

Hemolytic anemia

Black pigment

Modifiable

 

Pregnancy

Steroid hormones, gallbladder stasis, hepatic hypersecretion

Cholesterol

Potentially modifiable

 

Gallbladder stasis (total parenteral nutrition, total gastrectomy with lymph node dissection, vagotomy, spinal cord injury, somatostatinoma, octreotide)

Increased bile concentration and precipitation/crystallization of cholesterol

Cholesterol

Potentially modifiable

 

Estrogens and oral contraceptives.

Hepatic hypersecretion, gallbladder stasis

Cholesterol

Potentially modifiable

 

Drugs: fibrates, octreotide, ceftriaxone, calcineurin inhibitors (tacrolimus, ciclosporin)

Precipitation in bile (ceftriaxone), hepatic hypersecretion, inhibition of hepatic bile salt export pump, bile concentration

Cholesterol

Potentially modifiable

 

Diabetes mellitus*

Metabolic abnormalities, gallbladder stasis, autonomic neuropathy

Cholesterol

Potentially modifiable

Others

 

 

 

 

 

Female gender

Pregnancies, steroid hormones, hepatic hypersecretion

Cholesterol

Non-modifiable

 

Increasing age

Metabolic risks, hemolytic anemia

Cholesterol, Pigment

Non-modifiable

 

Hemolytic anemia, sickle cell disease

Increased calcium bilirubinate concrements, gallbladder stasis

Black pigment

Non-modifiable/ Potentially modifiable

 

Liver cirrhosis

Gallbladder stasis, hyperestrogenism, bile salt malabsorption, increased enterohepatic circulation of bilirubin

Black pigment/Cholesterol

Non-modifiable/Potentially modifiable

 

Cystic fibrosis

 

Increased biliary concentration of conjugated and unconjugated bilirubin and calcium, increased enterohepatic circulation of bilirubin

Black pigment

Non-modifiable/Potentially modifiable

 

Crohn’s disease, extended ileal resection

Increased biliary concentration of conjugated and unconjugated bilirubin and calcium, increased enterohepatic circulation of bilirubin

Cholesterol/Black pigment

Non-modifiable/Potentially modifiable

 

Infections (e.g., biliary strictures, duodenal diverticula, cholangitis, pancreatic insufficiency)

Bile duct (Clonorchis sinensis, Ascaris lumbricoides, Opistorchis viverrini)

HCV infection

Bacterial b-glucuronization with biotransformation of conjugated to unconjugated bilirubin, precipitation together with calcium and long-chain fatty acids

Black pigment/brown pigment

Non-modifiable/Potentially modifiable

 

*conditions especially associated with gallbladder stasis. Adapted from Portincasa et al. [2,49] with permission.