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.

Bile acid malabsorption was first recognized in patients with ileal disease. When other causes were recognized, and an idiopathic, primary form described, a classification into three types was proposed:

- Type 1: Bile acid malabsorption, secondary to ileal resection, or ileal inflammation (e.g. in Crohn's disease)

- Type 2: Idiopathic bile acid malabsorption, Primary bile acid diarrhea

- Type 3: Secondary to various gastrointestinal diseases including cholecystectomy, vagotomy, small intestinal bacterial overgrowth, radiation enteropathy, celiac disease, chronic pancreatitis, etc.

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.

Bile acid malabsorption, known also as bile acid diarrhea, is a cause of several gut-related problems, the main one being chronic diarrhea. It has also been called bile acid-induced diarrhea, cholerheic or choleretic enteropathy and bile salt malabsorption. It can result from malabsorption secondary to gastrointestinal disease, or be a primary disorder, associated with excessive bile acid production. Treatment with bile acid sequestrants is often effective.

Possible causes:

- pregnancy

- androgens

- birth control pills

- antibiotics (such as TMP/SMX)

- abdominal mass (e.g. cancer)

- biliary atresia and other pediatric liver diseases

- biliary trauma

- congenital anomalies of the biliary tract

- gallstones

- acute hepatitis

- cystic fibrosis

- intrahepatic cholestasis of pregnancy (obstetric cholestasis)

- primary biliary cirrhosis, an autoimmune disorder

- primary sclerosing cholangitis, associated with inflammatory bowel disease

- some drugs (e.g. flucloxacillin and erythromycin)

Drugs such as gold salts, nitrofurantoin, anabolic steroids, chlorpromazine, prochlorperazine, sulindac, cimetidine, erythromycin, estrogen, and statins can cause cholestasis and may result in damage to the liver.

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.

The disease is typically progressive, leading to fulminant liver failure and death in childhood, in the absence of liver transplantation. Hepatocellular carcinoma may develop in PFIC-2 at a very early age; even toddlers have been affected.

Exocrine pancreatic insufficiency (EPI) is the inability to properly digest food due to a lack of digestive enzymes made by the pancreas. EPI is found in humans afflicted with cystic fibrosis and Shwachman–Diamond syndrome. It is caused by a progressive loss of the pancreatic cells that make digestive enzymes. Chronic pancreatitis is the most common cause of EPI in humans. Loss of digestive enzymes leads to maldigestion and malabsorption of nutrients.

Cholestasis is a condition where bile cannot flow from the liver to the duodenum. The two basic distinctions are an obstructive type of cholestasis where there is a mechanical blockage in the duct system that can occur from a gallstone or malignancy, and metabolic types of cholestasis which are disturbances in bile formation that can occur because of genetic defects or acquired as a side effect of many medications.

Biliary atresia seems to affect females slightly more often than males, and Asians and African Americans more often than Caucasians. It is common for only one child in a pair of twins or within the same family to have the condition. There seems to be no link to medications or immunizations given immediately before or during pregnancy. Diabetes during pregnancy particularly during the first trimester seems to predispose to a number of distinct congenital abnormalities in the infant such as sacral agenesis and the syndromic form of biliary atresia.

The pancreas is central in the pathophysiology of both major types of diabetes mellitus. In type 1 diabetes mellitus, there is direct damage to the endocrine pancreas that results in insufficient insulin synthesis and secretion. Type 2 diabetes mellitus, which begins with insulin resistance, is characterized by the ultimate failure of pancreatic β cells to match insulin production with insulin demand.

Neonatal cholestasis defines persisting conjugated hyperbilirubinemia in the newborn with conjugated bilirubin levels exceeding 15% (5.0 mg/dL) of total bilirubin level. The disease is either due to defects in bile excretion from hepatocytes or impaired bile flow.

General presentations in neonates include abdominal pain and general GI upset. Physical examination may show palpable liver and enlarged spleen. Differential diagnosis typically presents with a host of possibilities, many of them not treatable. Histopathology shows dilated bile duct system at all levels and bile duct proliferation in response to back pressure. The incidence has been found to be about 1:2,500 live births.

Cholestasis means "the slowing or stopping of bile flow" which can be caused by any number of diseases of the liver (which produces the bile), the gallbladder (which stores the bile), or biliary tract (also known as the biliary tree, the conduit that allows the bile to leave the liver and gallbladder and enter the small intestine). When this occurs, conjugated bilirubin and the waste products that usually would be cleared in bile reflux back into the bloodstream. This causes a primarily conjugated hyperbilirubinemia and jaundice; the liver conjugates the bile to make it water-soluble and because the bile has already been processed by the liver, when it gets backed up because of a blockage and is refluxed into the blood, the blood will have high levels of conjugated bilirubin. This is in contrast to primarily unconjugated hyperbilirubinemia which is the water-insoluble form that is bound to serum albumin; the liver has not had a chance to conjugate the bilirubin yet and can be caused either because too much unconjugated bilirubin is made (such as in massive hemolysis or ineffective erythropoiesis) or because too little is conjugated (Gilbert's disease or Crigler-Najjar syndrome). Unconjugated hyperbilirubinemia does not typically cause pruritus.

It is thought that bile salts that deposit into the skin are responsible for the pruritus (itching) but the levels of bilirubin in the bloodstream and the severity of the pruritus does not appear to be highly correlated. Patients that have been administered bile salt chelating agents do report some relief, however, and patients that have complete liver cell failure (and therefore cannot make these products to begin with) do not have pruritus. This suggests that products made by the liver must have some role in pruritus although it is not known exactly which product is responsible.

The annual incidence of chronic pancreatitis is 5 to 12 per 100,000 persons, the prevalence is 50 per 100,000 persons.

Some cases of biliary atresia may result from exposure to aflatoxin B1, and to a lesser extent aflatoxin B2 during late pregnancy. Intact maternal detoxification protects baby during intrauterine life, yet after delivery the baby struggles with the aflatoxin in its blood and liver. Moreover, the baby feeds aflatoxin M1 from its mom, as aflatoxin M1 is the detoxification product of aflatoxin B1. It is a milder toxin that causes cholangitis in the baby.

There are isolated examples of biliary atresia in animals. For instance, lambs born to sheep grazing on land contaminated with a weed (Red Crumbweed) developed biliary atresia at certain times. The plants were later found to contain a toxin, now called biliatresone Studies are ongoing to determine whether there is a link between human cases of biliary atresia and toxins such as biliatresone. There are some indications that a metabolite of certain human gut bacteria may be similar to biliatresone.

The main purpose of the gastrointestinal tract is to digest and absorb nutrients (fat, carbohydrate, protein, micronutrients (vitamins and trace minerals), water, and electrolytes. Digestion involves both mechanical and enzymatic breakdown of food. Mechanical processes include chewing, gastric churning, and the to-and-fro mixing in the small intestine. Enzymatic hydrolysis is initiated by intraluminal processes requiring gastric, pancreatic, and biliary secretions. The final products of digestion are absorbed through the intestinal epithelial cells.

Malabsorption constitutes the pathological interference with the normal physiological sequence of digestion (intraluminal process), absorption (mucosal process) and transport (postmucosal events) of nutrients.

Intestinal malabsorption can be due to:

- Mucosal damage (enteropathy)

- Congenital or acquired reduction in absorptive surface

- Defects of specific hydrolysis

- Defects of ion transport

- Pancreatic insufficiency

- Impaired enterohepatic circulation

A 2009 study which followed 189 patients found no excess mortality despite the increased risk of pancreatic cancer.

Blind loop syndrome is a complication of surgical operations of the abdomen, as well as inflammatory bowel disease or scleroderma. Another cause is jejunoileal diverticula.

Some individuals may benefit from diet modification, such as a reduced fat diet, following cholecystectomy. The liver produces bile and the gallbladder acts as reservoir. From the gallbladder, bile enters the intestine in individual portions. In the absence of gallbladder, bile enters the intestine constantly, but in small quantities. Thus, it may be insufficient for digestion of fatty foods. Postcholecystectomy syndrome treatment depends on the identified violations that led to it. Typically, the patient is recommended dietary restriction table with fatty foods, enzyme preparations, antispasmodics, sometimes cholagogue.

If the pain is caused by biliary microlithiasis, oral ursodeoxycholic acid can alleviate the condition.

A trial of bile acid sequestrant therapy is recommended for bile acid diarrhoea.

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.

The serum bilirubin level is an indicator of the prognosis of PBC, with levels of 2–6 mg/dL having a mean survival time of 4.1 years, 6–10 mg/dL having 2.1 years and those above 10 mg/dL having a mean survival time of 1.4 years.

After liver transplant, the recurrence rate may be as high as 18% at 5 years, and up to 30% at 10 years. There is no consensus on risk factors for recurrence of the disease.

Complications of PBC can be related to chronic cholestasis or cirrhosis of the liver. Chronic cholestasis leads to osteopenic bone disease and osteoporosis, alongside hyperlipidaemia and vitamin deficiencies.

Patients with PBC have an increased risk of hepatocellular carcinoma compared to the general population, as is found in other cirrhotic patients. In patients with advanced disease, one series found an incidence of 20% in men and 4% in women.

The overgrowth of bacteria in the small intestine is prevented by various mechanical and chemical factors which include the constant peristaltic movement of contents along the length of the gastrointestinal tract and the antibacterial properties of gastric secretions, pancreatic secretions and bile.

It follows that a disruption of any of these factors could lead to bacterial overgrowth and indeed BLS has been found to occur in persons with anatomical anomalies that result in stagnation. BLS has also been associated with achlorhydria, dysmotility, fistulae, and strictures. Chronic or high dose opioid therapy may contribute to BLS by reducing gastric motility.

Due to the disruption of digestive processes by the overgrowth of intestinal bacteria malabsorption of bile salts, fat and fat-soluble vitamins, protein and carbohydrates results in damage to the mucosal lining of the intestine by bacteria or via the production of toxic metabolites.

Among the causes of chronic pancreatitis are the following:

The relationship between etiologic factors, genetic predisposition, and the pace of disease progression requires further clarification, though recent research indicates smoking may be a high-risk factor to develop chronic pancreatitis. In a small group of patients chronic pancreatitis has been shown to be hereditary. Almost all patients with cystic fibrosis have established chronic pancreatitis, usually from birth. Cystic fibrosis gene mutations have also been identified in patients with chronic pancreatitis but in whom there were no other manifestations of cystic fibrosis. Obstruction of the pancreatic duct because of either a benign or malignant process may result in chronic pancreatitis.

treatment of HP resemble that of chronic pancreatitis of other causes. Treatment focuses on enzyme and nutritional supplementation, pain management, pancreatic diabetes, and local organ complications, such as pseudocysts, bile duct or duodenal obstruction.(PMC1774562)

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