In the emergency department, there is a 45 year old obese female from Spain, named Valencia, who came in with right upper quadrant and epigastric pain that began suddenly a couple of hours ago, right after her lunch. The pain is steady in nature, and radiates to the right shoulder. Her temperature is 38 °C or 100.4 °F and on physical examination, there is pain with deep palpation of the right upper quadrant. At the same time, at the gastroenterology clinic, a 64- year old Caucasian female, named Ashley, is incidentally found to have diffuse gallbladder calcification on an abdominal x- ray. She is totally asymptomatic except for some episodes of vague abdominal pain after meals. Both Valencia and Ashley have gallbladder diseases.
The gallbladder’s job is to basically store and concentrate bile. When you eat high fat foods, they make their way to the small intestine, and stimulate the enteroendocrine cells to secrete cholecystokinin into the bloodstream. Cholecystokinin, in turn, makes its way to the gallbladder and tells it to squeeze bile out into the small intestine. Now, bile’s a fat emulsifier, essentially helping to break fats or lipids into small “micelles”, making them easier to absorb. Remember that bile is mostly made up of bile salts and acids, cholesterol, phospholipids, proteins, bilirubin and small amounts of various other compounds, like water, electrolytes, and bicarbonate.
Now, there are multiple types of gallstones, and the process of gallstones formation is called cholelithiasis. So, let’s start with cholesterol gallstones. Remember for your exams that these are the most common type, accounting for around 75–90% of cases of all gallstones. Generally speaking, cholesterol stones have a characteristic yellow color and are radiolucent, meaning that they can’t be seen on X-ray. This is very high yield and is often used as a clue on your exams! However remember that these stones can be seen on X-ray in rare cases when they bind with enough calcium. Now, precipitation of cholesterol occurs when there’s an imbalance between the concentration of cholesterol, bile salts and acids or phospholipids. In other words, this occurs either when there’s too much cholesterol in the bile, or when there are not enough bile salts and acids or phospholipids. Risk factors are commonly tested and include things like female sex, pregnancy and oral contraceptive pills, obesity, and age, especially after 40. These can be remembered by the 4 F’s—female, fertile, fat, and forty. That’s mostly because female sex as well as pregnancy and oral contraceptive pills are associated with higher estrogen levels, which then increase the activity of HMG-CoA reductase, the enzyme responsible for cholesterol synthesis in the liver. Higher progesterone levels also reduce bile acid secretion. Obesity is associated with increased cholesterol levels, while it is unclear why age is related. Less common risk factors include medications, like fibrates. Fibrates work by inhibiting an enzyme called cholesterol 7ɑ-hydroxylase, which catalyzes the rate-limiting step in the synthesis of bile acids. Once fibrates inhibit this enzyme, they increase the cholesterol content of bile, but at the same time, they decrease the production of bile acids. Eventually, this results in decreased cholesterol solubility and easier formation of the cholesterol stone. Next, bare in mind that anything affecting the terminal ileum, like Crohn’s disease, or ileal resection, can reduce the reabsorption of bile acids into the circulation and back to the liver. On another level, gallbladder stasis, or inactivity, has also been linked to forming stones. If the bile just sits there, it can cause the solid to separate and precipitate out. Risk factors for that include pregnancy, since progesterone also slows gallbladder emptying, rapid weight loss, medications like octreotide, and high spinal cord injuries. Also, prolonged parenteral nutrition favors biliary stasis because lack of food in your intestines results in decreased cholecystokinin release, which leads to biliary stasis. Finally, increased incidence of cholesterol gallstones is found among certain ethnicities, particularly Indigenous people of North America and Europeans.