Cholecystitis and Cholangitis

Pathogenesis

Cholecystitis is inflammation of the gallbladder and can be divided into two groups: that caused by obstructive stones (calculous or cholelithiasis) and that occurring in the absence of stones (acalculous). The former is by far the more common in adults, but the latter is the more common in children. ^, Cholelithiasis frequently is found in asymptomatic individuals; only an estimated 1%–3% of people with gallstones develop acute cholecystitis. Gallstones can occur in a variety of circumstances and can be broadly classified by their appearance. Nonpigmented or cholesterol stones are formed when high levels of cholesterol in the bile causes a precipitate to form. Cholesterol stones are not thought to be infectious in origin. Black pigmented stones are also not caused by infection and are associated with hemolysis such as can be seen in persons with a hemoglobinopathy (e.g., spherocytosis, thalassemia, sickle cell anemia), advancing age, and cirrhosis. Brown pigmented stones are indicative of colonization or infection, most often caused by bacteria. They are formed when bacterial β-glucuronidase deconjugates bile acids that then precipitate. Although the presence of stones itself is not indicative of inflammation, cases of pediatric calculous cholecystitis may be due to a chronic process, leading to delayed diagnosis. In one study of children undergoing cholecystectomy for gallstone disease, only 5% had inflammation noted by preoperative ultrasonography, but 87% had evidence of chronic inflammation upon histologic examination.

Acalculous cholecystitis involves gallbladder wall inflammation and possibly necrosis, often with biliary sludging. It was first described as a complication of a critical illness, such as a major surgery (e.g., cardiothoracic), a trauma, or burns. The condition has since been found to be a complication of autoinflammatory and autoimmune diseases (e.g., Kawasaki disease, systemic lupus erythematous) and recently has been associated with infection in otherwise healthy children. ^, The list of infectious agents associated with acalculous cholecystitis is long and includes Mycoplasma pneumoniae , Salmonella enterica serovar Typhi and nontyphoidal species, Shigella species, Streptococcus pyogenes , Streptococcus pneumoniae , Acinetobacter baumannii , Burkholderia cepacia , Stenotrophomonas maltophilia , Candida species, hepatitis A virus, Epstein-Barr virus, and cytomegalovirus. ^{, ,} Helminthic infections, including the round worm Ascaris lumbricoides , the liver flukes Clonorchis sinensi , Fasciola hepatica , Opisthorchis viverrini , can cause eosinophilic cholecystitis. Although the pathogenesis steps are not well elucidated, it is thought that events such as hypoperfusion or release of inflammatory mediators trigger biliary system injury and inflammation. Sludging of the bile due to poor gallbladder emptying can be caused by prolonged fasting or parenteral nutrition, medications such as diuretics and ceftriaxone (pseudolithiasis) and biliary dyskinesia. Finally, cholecystitis can follow obstruction of the cystic duct as can be caused by anatomic abnormalities, postsurgical stricture, or malignancy-associated stenosis.

Acute cholangitis is a systemic process that results from obstruction of bile flow in combination with bacterial growth in the bile. Biliary infection alone is insufficient. Progressive obstruction from any cause leads to increased intraductal pressure with cholangiovenous and cholangiolymphatic reflux. Superinfection of the stagnant bile with organisms of gut flora follows, along with edema and congestion, further compromising the blood supply and lymphatic drainage. Tissue necrosis follows, favoring further bacterial proliferation. Bacteria translocate into the bloodstream, causing septicemia. ^, The risk of bacteremia and septicemia is high, and mortality is 2.7%–10%. ^{, ,}

Portoenterostomy (i.e., Kasai procedure), the classic surgical procedure performed for biliary atresia, predisposes children to recurrent cholangitis. Use of the intestinal conduit to restore bile flow from the liver to the small intestine can allow ascent of intestinal flora and cholangitis. ^, Cholangitis following Kasai procedure frequently recurs and is a risk factor for progression to need of a liver transplant. This has led some groups to routinely prescribe a corticosteroid and antibiotic prophylactically for up to 12 months following the procedure. The efficacy of this approach is a subject of study in the field. ^, Cholangitis can also occur, although less frequently, in children who have undergone orthotopic liver transplantation using a Roux-en-Y procedure for a biliary conduit.

Other rare causes of impaired biliary drainage predisposing to cholangitis include choledochal cyst, Caroli disease, primary sclerosing cholangitis, biliary stricture after abdominal trauma, prior duct surgery, cystic fibrosis, and tumors of the extrahepatic ducts (e.g., rhabdomyosarcoma, neuroblastoma). Immunoglobulin G subclass 4–related sclerosing cholangitis is associated with autoimmune pancreatitis and involvement of many other organs.

Although infection alone does not frequently cause cholangitis, in areas of high endemicity biliary obstruction can result from parasites migrating into the biliary tract. Most commonly, helminthic infections, including the round worm Ascaris lumbricoides , the liver flukes Clonorchis sinensi , Fasciola hepatica , and Opisthorchis viverrine , can migrate from the duodenum to the common bile duct and into the liver where they grow and obstruct the biliary system.