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.

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

Rarely, in cases of severe inflammation, gallstones may erode through the gallbladder into adherent bowel potentially causing an obstruction termed gallstone ileus.

Other complications include ascending cholangitis if there is a bacterial infection which can cause purulent inflammation in the biliary tree and liver, and acute pancreatitis as blockage of the bile ducts can prevent active enzymes being secreted into the bowel, instead damaging the pancreas.

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.

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.

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.

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

A biliary fistula often occurs in be suspected in a person who has recently undergone a surgical procedure, Pain may occur if the leaked bile is also infected, which can subsequently lead to biliary peritonitis.

Extensive ascites may accumulate, especially in the setting of sterile bile leakage, which is often asymptomatic in nature.

In the United States, the annual incidence is 18 cases of acute pancreatitis per 100,000 population, and it accounts for 220,000 hospitalizations in the US. In a European cross-sectional study, incidence of acute pancreatitis increased from 12.4 to 15.9 per 100,000 annually from 1985 to 1995; however, mortality remained stable as a result of better outcomes. Another study showed a lower incidence of 9.8 per 100,000 but a similar worsening trend (increasing from 4.9 in 1963-74) over time.

In Western countries, the most common cause is alcohol, accounting for 65 percent of acute pancreatitis cases in the US, 20 percent of cases in Sweden, and 5 percent of those in the United Kingdom. In Eastern countries, gallstones are the most common cause of acute pancreatitis. The causes of acute pancreatitis also varies across age groups, with trauma and systemic disease (such as infection) being more common in children. Mumps is a more common cause in adolescents and young adults than in other age groups.

Stones can cause disease by several mechanisms:

- Irritation of nearby tissues, causing pain, swelling, and inflammation

- Obstruction of an opening or duct, interfering with normal flow and disrupting the function of the organ in question

- Predisposition to infection (often due to disruption of normal flow)

A number of important medical conditions are caused by stones:

- Nephrolithiasis (kidney stones)

- Can cause hydronephrosis (swollen kidneys) and renal failure

- Can predispose to pyelonephritis (kidney infections)

- Can progress to urolithiasis

- Urolithiasis (urinary bladder stones)

- Can progress to bladder outlet obstruction

- Cholelithiasis (gallstones)

- Can predispose to cholecystitis (gall bladder infections) and ascending cholangitis (biliary tree infection)

- Can progress to choledocholithiasis (gallstones in the bile duct) and gallstone pancreatitis (inflammation of the pancreas)

- Gastric calculi can cause colic, obstruction, torsion, and necrosis.

Locoregional complications include pancreatic pseudocyst (Most common, occurring in up to 25% of all cases) and phlegmon / abscess formation, splenic artery pseudoaneurysms, hemorrhage from erosions into splenic artery and vein, thrombosis of the splenic vein, superior mesenteric vein and portal veins (in descending order of frequency), duodenal obstruction, common bile duct obstruction, progression to chronic pancreatitis, pancreatic ascites, pleural effusion, sterile/infected pancreatic necrosis.

In kidney stones, calcium oxalate is the most common mineral type (see Nephrolithiasis). Uric acid is the second most common mineral type, but an "in vitro" study showed uric acid stones and crystals can promote the formation of calcium oxalate stones.

In surgical pathology, strawberry gallbladder, more formally cholesterolosis of the gallbladder and gallbladder cholesterolosis, is a change in the gallbladder wall due to excess cholesterol.

The name "strawberry gallbladder" comes from the typically stippled appearance of the mucosal surface on gross examination, which resembles a strawberry. Cholesterolosis results from abnormal deposits of cholesterol esters in macrophages within the lamina propria (foam cells) and in mucosal epithelium. The gallbladder may be affected in a patchy localized form or in a diffuse form. The diffuse form macroscopically appears as a bright red mucosa with yellow mottling (due to lipid), hence the term "strawberry" gallbladder.

It is not tied to cholelithiasis (gallstones) or cholecystitis (inflammation of the gallbladder).

Black pigment gallstones can form in Rokitansky–Aschoff sinuses of the gallbladder after the fourth to fifth decades of life in absence of the typical risk factors for bilirubin suprasaturation of bile. Hence, they are associated with gallstones (cholelithiasis). Cases of gall bladder cancer have also been reported to arise from Rokitansky–Aschoff sinuses.

They form as a result of increased pressure in the gallbladder and recurrent damage to the wall of the gallbladder.

Although most patients present without any known risk factors evident, a number of risk factors for the development of cholangiocarcinoma have been described. In the Western world, the most common of these is primary sclerosing cholangitis (PSC), an inflammatory disease of the bile ducts which is closely associated with ulcerative colitis (UC). Epidemiologic studies have suggested that the lifetime risk of developing cholangiocarcinoma for a person with PSC is on the order of 10%–15%, although autopsy series have found rates as high as 30% in this population.

Certain parasitic liver diseases may be risk factors as well. Colonization with the liver flukes "Opisthorchis viverrini" (found in Thailand, Laos PDR, and Vietnam) or "Clonorchis sinensis" (found in China, Taiwan, eastern Russia, Korea, and Vietnam) has been associated with the development of cholangiocarcinoma. Patients with chronic liver disease, whether in the form of viral hepatitis (e.g. hepatitis B or hepatitis C), alcoholic liver disease, or cirrhosis of the liver due to other causes, are at significantly increased risk of cholangiocarcinoma. HIV infection was also identified in one study as a potential risk factor for cholangiocarcinoma, although it was unclear whether HIV itself or other correlated and confounding factors (e.g. hepatitis C infection) were responsible for the association.

Infection with the bacteria "Helicobacter bilis" and "Helicobacter hepaticus" species can cause biliary cancer.

Congenital liver abnormalities, such as Caroli's syndrome (a specific type of five recognized choledochal cysts), have been associated with an approximately 15% lifetime risk of developing cholangiocarcinoma. The rare inherited disorders Lynch syndrome II and biliary papillomatosis have also been found to be associated with cholangiocarcinoma. The presence of gallstones (cholelithiasis) is not clearly associated with cholangiocarcinoma. However, intrahepatic stones (called hepatolithiasis), which are rare in the West but common in parts of Asia, have been strongly associated with cholangiocarcinoma. Exposure to Thorotrast, a form of thorium dioxide which was used as a radiologic contrast medium, has been linked to the development of cholangiocarcinoma as late as 30–40 years after exposure; Thorotrast was banned in the United States in the 1950s due to its carcinogenicity.

NAFLD can also be caused by some medications (drug-induced illness):

- Amiodarone

- Antiviral drugs (nucleoside analogues)

- Aspirin rarely as part of Reye's syndrome in children

- Corticosteroids

- Methotrexate

- Tamoxifen

- Tetracycline

The percentage of people with non-alcoholic fatty liver disease ranges from 9 to 36.9% in different parts of the world. Approximately 20% of the United States population have non-alcoholic fatty liver, and the number of people affected is increasing. This means about 75 to 100 million people in the United States are affected.

The rates of non-alcoholic fatty liver disease is higher in Hispanics, which can be attributed to high rates of obesity and type 2 diabetes in Hispanic populations. Non-alcoholic fatty liver disease is also more common among men than women in all age groups until age 60, where the prevalence between sex equalize. This is due to the protective nature of estrogen. Fatty liver and NASH occur all ages, with the highest rates in the 40- to 49-year-old age group. It is the most common liver abnormality in children ages 2 to 19.

The role of "Helicobacter pylori" in functional dyspepsia is controversial, and no clear causal relationship has been established. This is true for both the symptom profile and pathophysiology of functional dyspepsia. Although some epidemiologic studies have suggested an association between "H. pylori" infection and functional dyspepsia, others have not. The discrepancy may stem in part from differences in methodology and lack of adequate consideration of confounding factors such as past history of peptic ulcer disease and socioeconomic status. Controlled trials disagree about whether or not "H. pylori" eradication is beneficial in functional dyspepsia, with roughly half of the trials showing improvement and the other half no improvement. In a recent multicenter U.S. trial that randomized 240 patients to treatment or placebo, and followed patients for 12 months, 28% of treated patients versus 23% of those receiving placebo reported relief of symptoms at the 12-month follow-up. Similarly, recent European trials have not shown significant differences in symptoms after "H. pylori" eradication as compared with controls. Systematic reviews of eradication have been conducted, with varying results. A systematic review in the Annals of Internal Medicine suggested no statistically significant effect, with an odds ratio (OR) for treatment success versus control of 1.29 (95% CI, 0.89–1.89; P = 0.18). Still, no effect was seen after adjusting for heterogeneity and for cure of "H. pylori". In contrast, a Cochrane review found a small but statistically significant effect in curing symptoms ("H. pylori" cure vs placebo, 36% vs 30%, respectively).

There are a number of systemic diseases that may involve dyspepsia, including coronary disease, congestive heart failure, diabetes mellitus, hyperparathyroidism, thyroid disease, and chronic renal disease.

The most common physical indications of cholangiocarcinoma are abnormal liver function tests, jaundice (yellowing of the eyes and skin occurring when bile ducts are blocked by tumor), abdominal pain (30%–50%), generalized itching (66%), weight loss (30%–50%), fever (up to 20%), and changes in the color of stool or urine. To some extent, the symptoms depend upon the location of the tumor: patients with cholangiocarcinoma in the extrahepatic bile ducts (outside the liver) are more likely to have jaundice, while those with tumors of the bile ducts within the liver more often have pain without jaundice.

Blood tests of liver function in patients with cholangiocarcinoma often reveal a so-called "obstructive picture," with elevated bilirubin, alkaline phosphatase, and gamma glutamyl transferase levels, and relatively normal transaminase levels. Such laboratory findings suggest obstruction of the bile ducts, rather than inflammation or infection of the liver parenchyma, as the primary cause of the jaundice.

Polypoid lesions of the gallbladder affect approximately 5% of the adult population. The causes are uncertain, but there is a definite correlation with increasing age and the presence of gallstones (cholelithiasis). Most affected individuals do not have symptoms. The gallbladder polyps are detected during abdominal ultrasonography performed for other reasons.

The incidence of gallbladder polyps is higher among men than women. The overall prevalence among men of Chinese ancestry is 9.5%, higher than other ethnic types.

Most polyps are benign and do not need to be removed. Polyps larger than 1 cm with co-occurring gallstones occurring in people over the age of 50 may have the gallbladder removed (cholecystectomy), especially if the polyps are several or appear malignant. Laparoscopic surgery is an option for small or solitary polyps.

Opisthorchiasis is prevalent where raw cyprinid fishes are a staple of the diet. Prevalence rises with age; children under the age of 5 years are rarely infected by "Opisthorchis viverrini". Males may be affected more than females. The WHO estimates that foodborne trematodiases (infection by worms or "flukes", mainly "Clonorchis", "Opisthorchis", "Fasciola" and "Paragonimus" species) affect 56 million people worldwide and 750 million are at risk of infection. Eighty million are at risk of opisthorchiasis, 67 million from infection with "Opisthorchis viverrini" in Southeast Asia and 13 million from "Opisthorchis felineus" in Kazakhstan, Russia including Siberia, and Ukraine. In the lower Mekong River basin, the disease is highly endemic, and more so in lowlands, with a prevalence up to 60% in some areas of northeast Thailand. However, estimates using newer polymerase chain reaction-based diagnostic techniques indicate that prevalence is probably grossly underestimated. In one study from the 1980s, a prevalence of over 90% was found in persons greater than 10 years old in a small village near Khon Kaen in northeast Thailand in the region known as Isaan. Sporadic cases have been reported in case reports from Malaysia, Singapore, and the Philippines. Although overall prevalence declined after initial surveys in the 1950s, increases since the 1990s in some areas seem associated with large increases in aquaculture.

Both experimental and epidemiological evidence strongly implicates "Opisthorchis viverrini" infections in the etiology of a malignant cancer of the bile ducts (cholangiocarcinoma) in humans which has a very poor prognosis. "Clonorchis sinensis" and "Opisthorchis viverrini" are both categorized by the International Agency for Research on Cancer (IARC) as Group 1 carcinogens.

In humans, the onset of cholangiocarcinoma occurs with chronic opisthorchiasis, associated with hepatobiliary damage, inflammation, periductal fibrosis and/or cellular responses to antigens from the infecting fluke. These conditions predispose to cholangiocarcinoma, possibly through an enhanced susceptibility of DNA to damage by carcinogens. Chronic hepatobiliary damage is reported to be multi-factorial and considered to arise from a continued mechanical irritation of the epithelium by the flukes present, particularly via their suckers, metabolites and excreted/secreted antigens as well as immunopathological processes. "In silico" analyses using techniques of genomics and bioinformatics is unraveling information on molecular mechanisms that may be relevant to the development of cholangiocarcinoma.

In regions where "Opisthorchis viverrini" is highly endemic, the incidence of cholangiocarcinoma is unprecedented. For instance, cholangiocarcinomas represent 15% of primary liver cancer worldwide, but in Thailand's Khon Kaen region, this figure escalates to 90%, the highest recorded incidence of this cancer in the world. Of all cancers worldwide from 2002, 0.02% were cholangiocarcinoma caused by "Opisthorchis viverrini". The cancer of the bile ducts caused by opisthorchiasis occur in the ages 25–44 years in Thailand. A few cases have appeared in later life among veterans of the Vietnam war in the United States, who consumed poorly cooked fish from streams in endemic areas near the border of Laos and Vietnam.