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

Hepatolithiasis is the presence of gallstones in the biliary ducts of the liver. Treatment is usually surgical. It is rare in Western countries, but prevalent in East Asia.

The gallstones are normally found proximal to the left and right hepatic ducts. The causes of the disease are poorly understood, but it is suspected that genetics, diets and environmental causes may contribute. It is more common in those of low socioeconomic status who suffer from malnutrition. Typically is strikes between 50 and 70 years old, with neither men nor women more likely to acquire it.

The prevalence in east Asia ranges is as high as 30-50%, while in the west it is rare. However, immigration has increased its prevalence in the West. Countries that have seen more economic development have also seen a reduction in the rates of the disease.

Some patients have these gallstones with no symptoms and the disease is only detected through abdominal imaging. For those with symptoms, common ones are abdominal pain, jaundice and fever. The gallstones can cause more serious conditions like fibrinolys disorder or gallstone pancreatitis.

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.

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.

Suppurative cholangitis, liver abscess, empyema of the gallbladder, acute pancreatitis, thrombophlebitis of hepatic or portal veins, and septicemia are acute complications of the disease, to which patients may succumb during the acute attacks.

Chronically, complications include cholangiocarcinoma and intraductal papillary neoplasm.

Approximately 15,000 new cases of liver and biliary tract carcinoma are diagnosed annually in the United States, with roughly 10% of these cases being Klatskin tumors. Cholangiocarcinoma accounts for approximately 2% of all cancer diagnoses, with an overall incidence of 1.2/100,000 individuals. Two-thirds of cases occur in patients over the age of 65, with a near ten-fold increase in patients over 80 years of age. The incidence is similar in both men and women.

Because of their location, these tumors tend to become symptomatic late in their development and therefore are not usually resectable at the time of presentation. This is variable as, due to obstruction, jaundice may present early and compel the patient to seek help. Complete resection of the tumor offers hope of long-term survival, and of late there has been renewed interest in liver transplantation from deceased donors along with add on therapy. Prognosis remains poor.

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.

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.