Gallstone risk increases for females (especially before menopause) and for people near or above 40 years; the condition is more prevalent among both North and South Americans and among those of European descent than among other ethnicities. A lack of melatonin could significantly contribute to gallbladder stones, as melatonin inhibits cholesterol secretion from the gallbladder, enhances the conversion of cholesterol to bile, and is an antioxidant, which is able to reduce oxidative stress to the gallbladder. Researchers believe that gallstones may be caused by a combination of factors, including inherited body chemistry, body weight, gallbladder motility (movement), and low calorie diet. The absence of such risk factors does not, however, preclude the formation of gallstones.

Nutritional factors that may increase risk of gallstones include constipation; eating fewer meals per day; low intake of the nutrients folate, magnesium, calcium, and vitamin C; low fluid consumption; and, at least for men, a high intake of carbohydrate, a high glycemic load, and high glycemic index diet. Wine and whole-grained bread may decrease the risk of gallstones.

Rapid weight loss increases risk of gallstones. Patients taking orlistat, a weight loss drug, may already be at increased risk for the formation of gallstones. Weight loss with orlistat can increase the risk of gallstones. On the contrary, ursodeoxycholic acid (UDCA), a bile acid, also a drug marketed as Ursodiol, appears to prevent formation of gallstones during weight loss. A high fat diet during weight loss also appears to prevent gallstones.

Cholecystokinin deficiency caused by celiac disease increases risk of gallstone formation, especially when diagnosis of celiac disease is delayed.

Pigment gallstones are most commonly seen in the developing world. Risk factors for pigment stones include hemolytic anemias (such as from sickle-cell disease and hereditary spherocytosis), cirrhosis, and biliary tract infections. People with erythropoietic protoporphyria (EPP) are at increased risk to develop gallstones. Additionally, prolonged use of proton pump inhibitors has been shown to decrease gallbladder function, potentially leading to gallstone formation.

Cholesterol modifying medications can affect gallstone formation. Statins inhibit cholesterol synthesis and there is evidence that their use may decrease the risk of getting gallstones. Fibrates increase cholesterol concentration in bile and their use has been associated with an increased risk of gallstones.

A prospective study in 1994 noted that body mass index remains the strongest predictor of symptomatic gallstones among young women. Other risk factors are having over four pregnancies, weight gain, and cigarette smoking. Alcohol was shown to have an inverse relationship between use and gallbladder disease.

Women are almost twice as likely as men to form gallstones especially during the fertile years; the gap narrows after the menopause. The underlying mechanism is female sex hormones; parity, oral contraceptive use and estrogen replacement therapy are established risk factors for cholesterol gallstone formation. Female sex hormones adversely influence hepatic bile secretion and gallbladder function. Estrogens increase cholesterol secretion and diminish bile salt secretion, while progestins act by reducing bile salt secretion and impairing gallbladder emptying leading to stasis. A new 4th generation progestin, drospirenone, used in some oral contraceptives may further heighten the risk of gallstone disease and cholecystectomy; however, the increased risk is quite modest and not likely to be clinically meaningful.

A retrospective (historical) cohort study was performed on a very large data base including 1980 and 1981 Medicaid billing data from the states of Michigan and Minnesota in which 138,943 users of OCs were compared with 341,478 nonusers. Oral contraceptives were shown as risk factors for gallbladder disease, although the risk is of sufficient magnitude to be of potential clinical importance only in young women.

The 1984 Royal College of General Practitioners' Oral Contraception Study suggests that, in the long-term, oral contraceptives are not associated with any increased risk of gallbladder disease, although there is an acceleration of the disease in those women susceptible to it.

Newer research suggests otherwise. A 1993 meta-analysis concludes that oral contraceptive use is associated with a slightly and transiently increased rate of gallbladder disease, but laters confirms that modern low-dose oral contraceptives are safer than older formulas, though an effect cannot be excluded.

A 2001 comparative study of the IMS LifeLink Health Plan Claims Database interpreted that in a large cohort of women using oral contraceptives, there was found a small, statistically significant increase in the risk of gallbladder disease associated with desogestrel, drospirenone and norethisterone compared with levonorgestrel. No statistically significant increase in risk was associated with the other formulations of oral contraceptive (etynodiol diacetate, norgestrel and norgestimate).

Cholesterol gallstone formation risk factors include age, female sex, family history, race, pregnancy, parity, obesity, birth control, diabetes mellitus, cirrhosis, prolonged fasting, rapid weight loss, total parenteral nutrition, ileal disease and impaired gallbladder emptying.

Patients that have gallstones and biliary colic are at increased risk for complications, including cholecystitis. Complications from gallstone disease is 0.3% per year and therefore prophylactic cholecystectomy are rarely indicated unless part of a special population that includes porcelain gallbladder, individuals eligible for organ transplant, diabetics and those with sickle cell anemia.

Cholesterol gallstones develop when bile contains too much cholesterol and not enough bile salts. Besides a high concentration of cholesterol, two other factors are important in causing gallstones. The first is how often and how well the gallbladder contracts; incomplete and infrequent emptying of the gallbladder may cause the bile to become overconcentrated and contribute to gallstone formation. This can be caused by high resistance to the flow of bile out of the gallbladder due to the complicated internal geometry of the cystic duct. The second factor is the presence of proteins in the liver and bile that either promote or inhibit cholesterol crystallization into gallstones. In addition, increased levels of the hormone estrogen, as a result of pregnancy or hormone therapy, or the use of combined (estrogen-containing) forms of hormonal contraception, may increase cholesterol levels in bile and also decrease gallbladder movement, resulting in gallstone formation.

Acute cholangitis carries a significant risk of death, the leading cause being irreversible shock with multiple organ failure (a possible complication of severe infections). Improvements in diagnosis and treatment have led to a reduction in mortality: before 1980, the mortality rate was greater than 50%, but after 1980 it was 10–30%. Patients with signs of multiple organ failure are likely to die unless they undergo early biliary drainage and treatment with systemic antibiotics. Other causes of death following severe cholangitis include heart failure and pneumonia.

Risk factors indicating an increased risk of death include older age, female gender, a history of liver cirrhosis, biliary narrowing due to cancer, acute renal failure and the presence of liver abscesses. Complications following severe cholangitis include renal failure, respiratory failure (inability of the respiratory system to oxygenate blood and/or eliminate carbon dioxide), cardiac arrhythmia, wound infection, pneumonia, gastrointestinal bleeding and myocardial ischemia (lack of blood flow to the heart, leading to heart attacks).

In the Western world, about 15% of all people have gallstones in their gallbladder but the majority are unaware of this and have no symptoms. Over ten years, 15–26% will suffer one or more episodes of biliary colic (abdominal pain due to the passage of gallstones through the bile duct into the digestive tract), and 2–3% will develop complications of obstruction: acute pancreatitis, cholecystitis or acute cholangitis. Prevalence of gallstone disease increases with age and body mass index (a marker of obesity). However, the risk is also increased in those who lose weight rapidly (e.g. after weight loss surgery) due to alterations in the composition of the bile that makes it prone to form stones. Gallstones are slightly more common in women than in men, and pregnancy increases the risk further.

Biliary pain is most frequently caused by obstruction of the common bile duct or the cystic duct by a gallstone. However, the presence of gallstones is a frequent incidental finding and does not always necessitate treatment, in the absence of identifiable disease. Furthermore, biliary pain may be associated with functional disorders of the biliary tract, so called acalculous biliary pain (pain without stones), and can even be found in patients post-cholecystectomy (removal of the gallbladder), possibly as a consequence of dysfunction of the biliary tree and the sphincter of Oddi. Acute episodes of biliary pain may be induced or exacerbated by certain foods, most commonly those high in fat.

There is a 2-3:1 male-to-female predilection in primary sclerosing cholangitis. PSC can affect men and women at any age, although it is commonly diagnosed in the fourth decade of life, most often in the presence of inflammatory bowel disease (IBD). PSC progresses slowly and is often asymptomatic, so it can be present for years before it is diagnosed and before it causes clinically significant consequences. There is relatively little data on the prevalence and incidence of primary sclerosing cholangitis, with studies in different countries showing annual incidence of 0.068–1.3 per 100,000 people and prevalence 0.22–8.5 per 100,000; given that PSC is closely linked with ulcerative colitis, it is likely that the risk is higher in populations where UC is more common. In the United States, an estimated 29,000 individuals have PSC.

Cholecystitis occurs when the gallbladder becomes inflamed. Gallstones are the most common cause of gallbladder inflammation but it can also occur due to blockage from a tumor or scarring of the bile duct. The greatest risk factor for cholecystitis is gallstones. Risk factors for gallstones include female sex, increasing age, pregnancy, oral contraceptives, obesity, diabetes mellitus, ethnicity (Native North American), rapid weight loss.

The development of any of the cancers associated with PSC predicts a poor prognosis. Complications from PSC-associated cancers account for 40% of deaths from PSC. Primary sclerosing cholangitis is one of the major known risk factors for cholangiocarcinoma, a cancer of the biliary tree, for which the lifetime risk among patients with PSC is 10-15%. This represents a 400-fold greater risk of developing cholangiocarcinoma compared to the general population. Surveillance for cholangiocarcinoma in patients with PSC is encouraged, with some experts recommending annual surveillance with a specialized imaging study and serum markers, although consensus regarding the modality and interval has yet to be established. Similarly, a screening colonoscopy is recommended in people who receive a new diagnosis of primary sclerosing cholangitis since their risk of colorectal cancer is 10 times higher than that of the general population.

PSC is strongly associated with inflammatory bowel disease (IBD), in particular ulcerative colitis (UC) and to a lesser extent Crohn's disease. As many as 5% of patients with IBD are co-diagnosed with PSC and approximately 70% of people with PSC have IBD. Of note, the presence of colitis appears to be associated with a greater risk of liver disease progression and bile duct cancer (cholangiocarcinoma) development, although this relationship remains poorly understood. Close monitoring of PSC patients is vital.

Various forms of gallbladder disease such as gallstones and gallbladder polyps are also common in those with PSC. Approximately 25% of people with PSC have gallstones. Ultrasound surveillance of the gallbladder every year is recommended for people with PSC. Any person with PSC who is found to have a mass in the gallbladder should undergo surgical removal of the gallbladder due to the high risk of cholangiocarcinoma. Osteoporosis (hepatic osteodystrophy) and hypothyroidism are also associated with PSC.

The clinical course of biliary sludge can do one of three things: (1) it can resolve completely, (2) wax and wane, or (3) progress to gallstones. If the biliary sludge has a cause (e.g. pregnancy), it oftentimes is resolved when the underlying cause is removed.

Gallstones blocking the flow of bile account for 90% of cases of cholecystitis (acute calculous cholecystitis). Blockage of bile flow leads to thickening and buildup of bile causing an enlarged, red, and tense gallbladder. The gallbladder is initially sterile but often becomes infected by bacteria, predominantly "E. coli", "Klebsiella", "Streptococcus", and "Clostridium" species. Inflammation can spread to the outer covering of the gallbladder and surrounding structures such as the diaphragm, causing referred right shoulder pain.

There are seven classes of medications associated with acute pancreatitis: statins, ACE inhibitors, oral contraceptives/hormone replacement therapy (HRT), diuretics, antiretroviral therapy, valproic acid, and oral hypoglycemic agents. Mechanisms of these drugs causing panreatitis are not known exactly; but it is possible that statins has direct toxic effect on the pancreas or through the long term accumulation of toxic metabolites. Meanwhile, ACE inhibitors causes angioedema of the pancreas through the accumulation of bradykinin. Oral contraceptives/HRT causes arterial thrombosis of the pancreas through the accumulation of fat (hypertriglyceridemia). Diuretics such as furosemide has direct toxic effect on the pancreas. Meanwhile, thiazide diuretics causes hypertriglyceridemia and hypercalcemia, where the latter is the risk factor for pancreatic stones. HIV infection itself can cause a person to more likely to get pancreatitis. Meanwhile, antiretroviral drugs may cause metabolic disturbances such as hyperglycemia and hypercholesterolemia, which predisposes to pancreatitis. Valproic acid may have direct toxic effect on the pancreas. There are various oral hypoglycemic agents that contributes to pancreatitis including metformin. But, glucagon-like peptide-1 (GLP-1) is more strongly associated with pancreatits by promoting inflammation.

Atypical antipsychotics such as clozapine, risperidone, and olanzapine can also cause pancreatitis.

While stones can frequently pass through the common bile duct (CBD) into the duodenum, some stones may be too large to pass through the CBD and may cause an obstruction. One risk factor for this is duodenal diverticulum.

The prevalence of biliary sludge is low in the general population. It has been reported that the prevalence ranges from 0-0.20% in men and 0.18-0.27% in women. However, in patients with certain conditions, the prevalence may be higher.

This obstruction may lead to jaundice, elevation in alkaline phosphatase, increase in conjugated bilirubin in the blood and increase in cholesterol in the blood. It can also cause acute pancreatitis and ascending cholangitis.

Eighty percent of cases of pancreatitis are caused by alcohol or gallstones. Gallstones are the single most common cause of acute pancreatitis. Alcohol is the single most common cause of chronic pancreatitis.

Mortality is indirect and caused by complications. After cholangitis occurs, patients typically die within 5–10 years.

The assertion that porcelain gallbladder increases the incidence of gallbladder cancer is widely taught in medical schools but is based on studies from 1931 and 1962. A prominent study aid for surgical residents even states that the risk of cancer in a porcelain gallbladder is 15%. The precise nature of the association between gallbladder cancer and porcelain gallbladder is uncertain. Two articles published in 2001 examined the association between cancer of the gallbladder and calcified gallbladder. The first study reviewed 10,741 cholecystectomies and found that the 88 patients with gallbladder cancer did not have calcified gallbladders while the 15 patients with porcelain gallbladders did not have gallbladder cancer. The second study reviewed 25,900 gallbladder specimens and found 150 patients with cancer and 44 patients with calcified gallbladders of two types (intramural calcification and selective mucosal calcification). The selective mucosal calcification group showed a 7% incidence of cancer with a significant odds ratio of 13.89.

An article published in 2013 reviewed 111 studies and found 340 patients with gallbladder wall calcification showed a 21% overall rate of gallbladder malignancy; however, when studies with obvious selection bias were excluded the rate of gallbladder malignancy fell to 6%. Comparatively, a matched cohort without gallbladder calcification showed a 1% rate of gallbladder malignancy.

Caroli disease is typically found in Asia, and diagnosed in persons under the age of 22. Cases have also been found in infants and adults. As medical imaging technology improves, diagnostic age decreases.

Laparoscopic cholecystectomy has been used to treat the condition when due to dyskinesia of the gallbladder.

Symptoms may persist after cholecystectomy, and have been linked to the use of proton pump inhibitors.

Osteopathic treatment, oral magnesium supplementation with 325 mg and the use of digestive enzymes caused improvement in one case.

Biliary dyskinesia is a disorder of some component of biliary part of the digestive system in which bile physically can not move normally in the proper direction through the tubular biliary tract. It most commonly involves abnormal biliary tract peristalsis muscular coordination within the gallbladder in response to dietary stimulation of that organ to squirt the liquid bile through the common bile duct into the duodenum. Ineffective peristaltic contraction of that structure produces postprandial (after meals) right upper abdominal pain (cholecystodynia) and almost no other problem. When the dyskinesia is localized at the biliary outlet into the duodenum just as increased tonus of that outlet sphincter of Oddi, the backed-up bile can cause pancreatic injury with abdominal pain more toward the upper left side. In general, biliary dyskinesia is the disturbance in the coordination of peristaltic contraction of the biliary ducts, and/or reduction in the speed of emptying of the biliary tree into the duodenum.

In RPC the gallstones found within the biliary system are calcium bilirubinate stones or pigmented calcium stones. Calcium bilirubinate stones are prevalent in Asia and very rare in Europe and the United States. In addition to the presence of these friable concretions of various shapes and sizes within the biliary tree, the bile is often muddy in consistency and contains numerous fine particles of calcium bilirubinate. This differs greatly from cholesterol stones, which are common in Europe and the United States. Pure cholesterol stones contain >96% cholesterol whereas mixed cholesterol stones contain 71.3% cholesterol. The formation of calcium bilirubinate stones in RPC has been attributed to the high incidence of infection with "Escherichia coli" in the bile. In humans, the majority of bilirubin is excreted in the bile as bilirubin glucuronide.

Hepatolithiasis is associated with Clonorchis sinensis and Ascaris lumbricoides infestation of the liver. This theory is based on high incidence of dead parasites or ova within stone in autopsy findings.

It can occur as a complication following biliary trauma (such as cholelithiasis), as an iatrogenic effect or as a result of a penetrating injury.