Ascending cholangitis

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Anila Hussain, MD [2]

Ascending Cholangitis, also known as acute cholangitis is a systemic disease caused by the inflammation and infection of the biliary tree most commonly following an obstruction in the biliary tract. It is characterized by a triad (Charcot’s Triad) of fever, jaundice and right upper quadrant pain. A pentad (also known as Reynold’s pentad) can also be seen in which altered mental status and sepsis are present in addition to usual findings. The severity of disease range anywhere from mild infection to life-threatening sepsis by the translocation of bacteria into the bloodstream.^[1]

Dr. Jean-Martin Charcot, a French physician, is credited with discovering cholangitis in the late 19th century. He referred to the condition as “hepatic fever.” Charcot’s triad of fever, jaundice, and right upper quadrant abdominal pain is the classical presentation of cholangitis. By adding septic shock and mental status changes to the list of symptoms, Dr. B. M. Reynolds and Dr. Everett L. Dargan changed Charcot’s triad to Reynold’s pentad. Until 1968, the mainstay of treatment of cholangitis was surgery, with the exploration of the bile duct and excision of gallstones, until the advent of endoscopic retrograde cholangiopancreatography (ERCP).

Acute cholangitis may be classified into grade I, II, or III, depending on the severity of the condition. The severity assessment criteria for acute cholangitis according to Tokyo guidelines is as follows:^[2][3][4]Grade I – Grade I, or mild acute cholangitis, does not meet the criteria of either grade II (moderate) or grade III (severe) acute cholangitis. The patient responds to initial medical treatment, grade II – Grade II, or moderate acute cholangitis, is characterized by the presence of any two of the following: abnormal white blood cell (WBC) count: >12,000/mm³, <4,000/mm, Fever ≥39°C, age ≥75 years, elevated total bilirubin ≥5 mg/dl, decreased albumin level <0.7 x standard, grade III – Grade III, or severe acute cholangitis, is characterized by the onset of dysfunction in at least one of the following: Cardiovascular system: decreased blood pressure that necessitates the administration of dopamine (>5 μg/kg/min) or norepinephrine, neurological system: abnormal consciousness, Respiratory system: PaO2/FiO2 ratio <300, Renal system: serum creatinine >2.0 mg/dl, decreased urine output, hepatic system: PT-INR >1.5, hematological system: platelet count < 100,000/ml.

Main factors that are involved in the pathogenesis of ascending cholangitis include obstruction of the biliary tract, increased intraluminal pressure and the infection of bile. Bacterial contamination alone in absence of obstruction does not usually result in cholangitis. However increased pressure within the biliary system (above 20 cmH₂O)^[5] resulting from obstruction in the bile duct widens spaces between the cells lining the duct, bringing bacterially contaminated bile in contact with the bloodstream while affecting the function of infection prevention macrophages (Kupffer cells) at the same time. In addition, high biliary pressure also spreads the infection into biliary canaliculi, hepatic veins and perihepatic lymph vessels resulting in bacteremia (bacteria in the bloodstream).

Any condition that leads to stasis or obstruction of bile in the common bile duct can lead to bacterial infection and cholangitis. Most common causes include bile duct stones and benign or malignant strictures. Less common causes include parasitic infection, malignancy, or extrinsic compression by the pancreas. Partial obstruction has a higher rate of infection as compared to complete obstruction.^[6]

Ascending cholangitis must be differentiated from other diseases that cause abdominal pain and fever, such as acute cholecystitis, acute hepatitis, acute pancreatitis, diverticulitis, biliary leakage or stricture, hepatic abscess, duodenal and gastric ulcer, cholestatic liver disease and pancreatic cancer.

Ascending cholangitis is a relatively uncommon disease. It usually occurs following other diseases that lead to biliary infection and stasis. 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, cholecystitisor acute cholangitis^[7]. 0.5-2.4 percent people can develop acute cholangitis following ERCP. Mortality rate of acute cholangitis after the year 2000 was found to be 2700-10,000 per 100,000 people^[8]. More commonly seen in Latin-Americans and Native American, However anyone can be affected by the disease. Risk is higher in old age particularly more than 70 years of age^[9]. Ascending cholangitis affects men and women equally although the gallstones are more frequently seen in women. Parasitic infections, specifically including the species Ascaris, Opisthorchis, Clonorchis, Fasciola and Echinococcus, are commonly associated with cholangitis outside of the United States.

Common risk factors in the development of ascending cholangitis include bile duct stones, history of gall stones, biliary strictures, and biliary tract surgery. Less common factors include immunodeffeciency, comorbidities and sclerosing cholangitis. There is a higher risk of acute cholangitis in patients with advanced age (>70) and smoking.^[10]

The cancer predominantly associated with cholangitis is cholangiocarcinoma. There are no accepted screening programs for either disease. However, methods for detecting early onsets of cholangitis and cholangiocarcinoma include using biochemical markers, scanning using positron emission tomography (PET) scan or magnetic resonance imaging (MRI), and endoscopic procedures such as endosonography and endoscopic retrograde cholangiopancreatography.^[11]

The severity of ascending cholangitis can range anywhere from mild to life-threatening and can be fatal if left untreated. Complications of acute cholangitis may include sepsis, hepatic abscesses, liver failure, renal failure, pancreatitis as well as postoperative complications like pneumonia, respiratory failure, heart failure, cardiac arrhythmias, cardiac ischemia, gastrointestinal bleeding, bile leaking into peritoneum or abdomen, renal abscess, fistulae, wound infection, wound dehiscence and disseminated intravascular coagulation (DIC)^[12]. Acute cholangitis bears a significant risk of death, with the leading cause being irreversible shock with multiple organ failure (which could have multiple possible complications of severe infections). Modern improvements in diagnosis and treatment have led to a reduction in mortality. Prognosis is good for patients who have quick and adequate drainage where there is an improvement in hemodynamic and inflammatory parameters. Prognosis of the disease depends on the severity of the illness. Poor outcomes are seen if urgent surgery is required for drainage.

MRCP is the diagnostic study of choice for identifying lesions of the biliary tree with sensitivity comparable to that of endoscopic retrograde cholangiopancreaticography (ERCP). However, ERCP is the gold standard test in the diagnosis of ascending cholangitis and is the test of choice for patients who may need therapeutic drainage.

Symptoms

Ascending Cholangitis, also known as acute cholangitis is a systemic disease caused by the inflammation and infection of the biliary tree most commonly following an obstruction in the biliary tract. It is characterized by a triad (Charcot’s Triad) of fever, jaundice and right upper quadrant pain. A pentad (also known as Reynold’s pentad) can also be seen in which altered mental status and sepsis are present in addition to usual findings. The typical clinical picture with a triad is present in only 50 to 70 percent of cases.^[13]

History

Patients with ascending cholangitis may have a positive history of gallstones, common bile duct stones, recent cholecystectomy, endoscopic procedures like cholangiogram or ERCP, previous history of cholangitis, and HIV.

Patients with ascending cholangitis usually appear sick and fatigued. Physical examination of patients is usually remarkable for fever, abdominal tenderness and jaundice. Other findings that may be seen include hypotension, tachycardia and altered mental status in patients with septic shock or elderly.

Certain laboratory tests may be helpful in the diagnosis of cholangitis. Some commonly conducted tests include complete blood count, basic metabolic panel, liver function tests, blood culture, and other body fluid cultures. Findings include leucocytosis, elevated liver enzymes, elevated CRP and ESR, abnormal serum electrolytes. Positive bile and blood cultures may also be seen.

There are no specific electrocardiographic findings regarding ascending cholangitis.

There are no particular x-ray findings associated with ascending cholangitis. However, gallstones may be visible on radiographs in 15-20 percent of the cases depending on the degree of calcification. An ileus can also be seen sometimes.

A trans-abdominal ultrasound is the initial test of choice in patients with suspicion of ascending cholangitis to detect common bile duct stones or dilatation^[14]. USG is both sensitive and specific in detecting bile duct dilatation yet has a lower sensitivity for detecting bile duct stones. However, bile duct dilatation is not always seen in initial stages of bile duct obstruction making it less reliable^[15]. The main finding of ascending cholangitis on an ultrasound is the thickening of the bile duct walls.

Ct scan can be used to detect the bile duct dilatation with diagnosis of possible causes of cholangitis. Unenhanced and contrast enhanced MDCT scan has moderate sensitivity and specificity for detection of bile duct stones.^[16]

Magnetic resonance cholangiopancreaticography (MRCP) is highly sensitive and accurate in the diagnosis of choledocholithiasis^[17] and biliary abnormalities in the patients of cholangitis. It is performed in patients with negative ultrasound and CT scan but have a suspicion of acute cholangitis. It is used as a non-invasive tool to localize lesions within the biliary tree. Common MR findings seen in acute cholangitis include increased peri-ductal signal intensity, transient peri-ductal signal difference, abscess, thrombosis and ragged duct.^[18]

Other tests in diagnosis of ascending cholangitis include ERCP which is a gold standard test in diagnosis of acute cholangitis. It is used both for diagnostic and therapeutic purposes, however, it is preferred a therapeutic drainage method. ERCP has a higher rate of complications as compared to other endoscopic procedures.^[19]

The main goal of treatment of acute cholangitis is treating both causes of acute cholangitis that are the biliary infection and biliary obstruction. Therefore, both antibiotic therapy and biliary drainage are important components of therapy in addition to supportive care. Empiric antibiotics of choice usually include piperacillin-tazobactam, ticarcillin-clavulanate, ceftriaxone plus metronidazole or ampicillin-sulbactam. The urgency of treatment depends on the illness severity. About 80 percent of patients with mild cholangitis respond well to medical therapy and 10-15 percent who do not respond need surgical or endoscopic intervention. Markers for these people are persistent abdominal pain, hypotension, fever >102 F, and confusion.. Sick patients should be promptly resuscitated and transferred to the intensive care unit for further management and immediate decompression should be done.

Surgical or endoscopic drainage may be needed in addition to the medical therapy in patients with moderate to severe ascending cholangitis or those with mild cholangitis not responding to medical treatment. Different procedures of biliary drainage include ERCP, PTC, EUS- guided drainage and open surgical drainage. If attempts at an endoscopic papillotomy or percutaneous transhepatic drainage of the common bile duct are unsuccessful, surgical exploration should be carried out to control sepsis.^[20] Clinical studies show that emergency surgery for patients suffering from acute cholangitis results in improved postoperative morbidity and mortality rates.^[21]

There are no established measures for the primary prevention of cholangitis in otherwise healthy people.

Secondary prevention strategies for cholangitis include continued treatment of predisposing causes in appropriate patients to avoid the recurrence of cholangitis :

• If the biliary infection was developed due to instrumentation of biliary tract, Appropriate antiniotics should be given in addition to biliary drainage to treat the infection:^[22][23][24]
• If the cause of ascending cholangitis is a gallstones/cholelithiais/choledocholithiasis – Initially endoscopic papilotomy/sphincterotomy should be done for biliary drainage and stone removal followed by elective laparoscopic cholecystectomy as drainage and stone extraction from bile duct will not reduce the risk of recurrence of cholangitis.^[25][26]

According to some studies, early ERCP is considered safe as well as cost effective in the treatment of mild to moderate ascending cholangitis. It reduces the duration of hospital stay and antibiotics are needed for fewer days thus making it a cost effective intervention.^[27]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Anila Hussain, MD [2]

Main factors that are involved in the pathogenesis of ascending cholangitis include obstruction of the biliary tract, increased intraluminal pressure and the infection of bile. Bacterial contamination alone in absence of obstruction does not usually result in cholangitis. However increased pressure within the biliary system (above 20 cmH₂O)^[1] resulting from obstruction in the bile duct widens spaces between the cells lining the duct, bringing bacterially contaminated bile in contact with the bloodstream while affecting the function of infection prevention macrophages (Kupffer cells) at the same time. In addition, high biliary pressure also spreads the infection into biliary canaliculi, hepatic veins and perihepatic lymph vessels resulting in bacteremia (bacteria in the bloodstream).

Bile is produced by the liver, and serves to eliminate cholesterol and bilirubin from the body, as well as emulsifying of fats to make them more soluble in water and aid in their digestion. Bile is formed in the liver by hepatocytes (liver cells) and excreted into the common hepatic duct. Part of the bile is stored in the gall bladder because of back pressure (exerted by the sphincter of Oddi) and may be released at the time of digestion. The gallbladder also concentrates the bile by absorbing water and dissolved salts from it. All bile reaches the duodenum (first part of the small intestine) through the common bile duct and the ampulla of Vater. The sphincter of Oddi, located at the junction of the ampulla of Vater and the duodenum, is a circular muscle that controls the release of both bile and pancreatic secretions into the digestive tract.

The biliary tree is normally relatively free of bacteria because of certain protective mechanisms.

• The sphincter of Oddi acts as a mechanical barrier.
• The biliary system normally has low pressure (8 to 12 cmH₂O)^[2] and allows bile to flow freely through.
• The continuous forward flow of the bile in the duct flushes bacteria, if present, into the duodenum, and does not allow the establishment of an infection.
• The constitution of bile—bile salts and immunoglobulin secreted by the epithelium of the bile duct also has a protective role.

Main factors that are involved in the pathogenesis of ascending cholangitis include

• Obstruction of biliary tract
• Increased intraluminal pressure
• Infection of bile

Bacteria gain entry to the biliary system when normal defense mechanisms are disrupted. Bacterial contamination alone in absence of obstruction does not usually result in cholangitis. However increased pressure within the biliary system (above 20 cmH₂O)^[1] resulting from obstruction in the bile duct widens spaces between the cells lining the duct, bringing bacterially contaminated bile in contact with the bloodstream. It also adversely affects the function of Kupffer cells, which are specialized macrophage cells that assist in preventing bacteria from entering the biliary system. Finally, increased biliary pressure decreases production of IgA immunoglobulins in the bile^[3] . In addition, high biliary pressure spreads the infection into biliary canaliculi, hepatic veins and perihepatic lymph vessels resulting in bacteremia (bacteria in the bloodstream) and gives rise to the systemic inflammatory response syndrome (SIRS) comprising fever (often with rigors), tachycardia, increased respiratory rate and increased white blood cell count; SIRS in the presence of suspected or confirmed infection is called sepsis. Biliary obstruction itself disadvantages the immune system and impairs its capability to fight infection, by impairing the function of certain immune system cells (neutrophil granulocytes) and modifying the levels of immune hormones (cytokines).

In ascending cholangitis, it is assumed that organisms migrate backward up the bile duct from the duodenum as a result of partial obstruction and decreased the function of the sphincter of Oddi or portal venous blood. Other theories about the origin of the bacteria, such as through the portal vein or transmigration from the colon, are considered less likely.

On gross pathology following are characteristic findings of cholangitis^[4]

• Thickening of bile ducts
• Bile stasis (cholestasis) as shown by greenish discoloration of parenchyma
• Abscesses or pus in the bile duct, as seen in the picture (seen more commonly in acute suppurative cholangitis)
• Erosions or ulcers in the bile duct

On microscopic histopathological analysis, the following features are characteristic findings of acute cholangitis:

• Cholestasis of bile canaliculi and/or ducts with or without neutrophils
• Presence of neutrophils in the ductular walls and lumina.

• Acute cholangitis in a patient with multiple bile duct procedures. After the biopsy, removal of bile duct stones released pus^[5].

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