Gallstones (Cholelithiasis): Causes

Pathogenesis (development of disease)

Pathogenesis includes the following factors:

• High levels of cholesterol in the bile fluid.
• Long retention time of bile in the gallbladder
• Incomplete gallbladder emptying

Neutrophil granulocytes (belong to the leukocytes/white blood cells; specialized immune cells) contribute to the formation of gallstones: When they try to take up crystals, they die and put their DNA (deoxyribonucleic acid; deoxyribonucleic acid / genetic information) like a net over the crystals. These nets (neutrophil extracellular traps, NETs) surround the crystals, clumping them together and causing gallstones to form. The main site of stone formation is the gallbladder. 80% of gallstones are cholesterol stones, which are bright and often large. Cholesterol is not soluble can only be kept in solution by a sufficient amount of bile acids – it is “coated” by them. If there is an imbalance between bile acids and cholesterol – too little bile acids and too much cholesterol – cholesterol particles can clump together and gallstones form. Black pigment stones often develop in chronic recurrent hemolysis (dissolution of red blood cells), for example in the context of sickle cell anemia (med.: Drepanozytose; also sickle cell anemia). Other risk factors for black pigment stones are cirrhosis of the liver and advanced age.brown pigment stones are formed by bacterial decomposition of bilirubin (a breakdown product of hemoglobin; has a yellow-brownish color). During this process, the calcium salt of bilirubin is formed, which constitutes the main mass of the stone. Bacterial colonization occurs in cholangitis (inflammation of the bile duct) and in stenosis (narrowing) of the bile ducts. When biliary colic occurs, there is usually an entrapment of the gallstone – either by migration or as a result of de novo formation in dilated bile duct – in the ductus cysticus (bile duct). Smaller concretions may reach the ductus choledochus (common bile duct) (= choledocholithiasis). These often remain attached to the papilla Vateri (papilla duodeni major; small elevation with a sphincter over the so-called ampulla Vateri, the common mouth of the common bile duct (ductus choledochus) and pancreatic duct (ductus pancreaticus) into the duodenum).

Etiology (Causes)

Biographic causes

• Genetic predisposition – gallstones in the family.
  • Genetic risk depending on gene polymorphisms:
    • Genes/SNPs (single nucleotide polymorphism; English : single nucleotide polymorphism):
      • Genes: ABCG5
      • SNP: rs11887534 in the gene ABCG5
        • Allele constellation: CG (2.0-fold).
        • Allele constellation: CC (7.0-fold)
  • Genetic diseases
    • Sickle cell anemia (med.: drepanocytosis; also sickle cell anemia, sickle cell anemia) – genetic disease with autosomal recessive inheritance affecting erythrocytes (red blood cells); it belongs to the group of hemoglobinopathies (formation of an irregular hemoglobin called sickle cell hemoglobin, HbS).
• Ethnic origin – the incidence of gallstones is highest in North American Indians and Chileans of Ibero-American descent, high in North Americans and Europeans, and rare in Asians and Japanese
• Anatomic biliary anomalies – congenital changes in the bile ducts.
• Hormonal factors – gravidity (pregnancy; increased cholesterol excretion due to estrogen depletion).

Behavioral causes

• Nutrition
  • Too high calorie intake
  • Too high fat diet
  • Diet high in cholesterol
  • High intake of refined carbohydrates
  • Low fiber diet
  • Too rapid weight loss, for example, by fasting – can also lead to gallstones via mobilization of tissue cholesterol. About 10 to 20% of these people develop gallstones
  • Weight fluctuations – normal weight men whose weight fluctuates widely have an increased risk of developing symptomatic gallstone disease
• Physical activity
  • Lack of physical activity – can lead to obesity.
• Overweight (BMI ≥ 25; obesity).

Disease-related causes

• Chronic hemolysis – dissolution of red blood cells leading to breakdown products – also pigment stones.
• Diabetes mellitus
• Diseases of the ileum – “scimitar”, part of the small intestine – which lead to impaired enterohepatic circulation, e.g., enteritis, Crohn’s disease
• Parasitic diseases of the bile ducts – more common in Asia than in Germany, leads to pigment stones.
• Severe liver diseases such as alcoholic cirrhosis, primary biliary cholangitis/bile duct inflammation (PBC, synonyms: non-purulent destructive cholangitis; formerly primary biliary cirrhosis), chronic intrahepatic cholestasis (bile stasis).

Laboratory diagnoses – laboratory parameters that are considered independent risk factors.

• Hyperlipoproteinemia (lipid metabolism disorder) – hypercholesterolemia, hypertriglyceridemia.

Medication

• Ciclosporin (cyclosporin A) – drug that suppresses the immune response by inhibiting the enzyme calcineurin.
• Ceftriaxone (antibiotic).
• Colestyramine (anion exchange resin) – active substance from the group of lipid-lowering agents, which is mainly used to lower cholesterol levels in the blood.
• Clofibrate (lipid-lowering agent) – lowers VLDL synthesis in the liver.
• Octreotide – synthetic analog of the peptide hormone somatostatin, which is a drug.
• Estrogens – e.g., birth control pills, hormone preparations, etc., containing estrogenBeachte: Risk-benefit balance of estrogen-based hormone therapy for the prevention of gallstones: This should take into account the increased risk of gallbladder stones and biliary symptoms from estrogens.

Operations

• Resection of the small intestine (ileum) – bile salts are then absorbed only limited.

Other causes

• Artificial feeding
• Rapid weight loss