Cholangitis

Etiology

Acute cholangitis occurs most commonly from bacterial infection of the bile ducts. For the development of acute cholangitis, there must be obstruction of biliary flow. Complete obstruction can lead to increased biliary pressure, which frequently leads to bacteremia.[5] The most common cause of biliary obstruction is caused by choledocholithiasis. Other causes include benign or malignant strictures of biliary ducts, pancreatic cancer, ampullary adenoma or cancer, porta hepatis tumor, parasites (Clonorchis sinensis, Fasciola hepatica), roundworm (Ascaris lumbricoides), tapeworm (Taenia saginata),[6] biliary sludge deposits due to biliary stent obstruction, gallstone impaction in the neck of the gallbladder or the cystic duct leading to compression on common bile or common hepatic duct known as Mirizzi syndrome, peri-ampullary diverticulum of the duodenum leading to biliary obstruction known as Lemmel syndrome and acquired immunodeficiency syndrome (AIDS).[3]

The pathogens identified as causative agents of acute ascending cholangitis are gram-negative and anaerobic organisms, the most common including Escherichia coli, Klebsiella, Enterobacter, Pseudomonas, and Citrobacter.[7] Iatrogenic introduction of bacteria commonly occurs post-endoscopic retrograde cholangiopancreatography (ERCP) in individuals with biliary obstruction.[2][8] The most important risk factors for the development of acute cholangitis include increased triglyceride intake, non-active/sedentary lifestyle, body mass index (BMI) greater than 30, as well as rapid weight loss.[3]

Epidemiology

Cholangitis is relatively uncommon. On average, in the United States, there are less than 200,000 cases of acute cholangitis annually. The average age of individuals affected is 50 to 60 years old. Males and females are affected equally.[3] In hospitalized patients with gallstone disease, 6% to 9% are diagnosed with acute cholangitis in the United States.[6] The prevalence of cholelithiasis varies among different ethnicities. It is more prevalent in Native Americans and Hispanics, less so among Whites, and is far less common in Asians and African Americans.[9] In addition, Asian populations and countries with intestinal parasites and individuals with sickle cell disease are at increased risk.

Pathophysiology

Acute cholangitis is a condition caused by acute inflammation and infection of the biliary duct system as well as the obstruction of biliary flow that leads to increased bacteria and endotoxins in the vascular and lymphatic drainage systems. Normally as bile flows through the biliary duct system, the bile duct epithelium secretes IgA, which is an anti-adherent factor towards bacteria to flush out the ducts. However, when the intra-biliary pressure exceeds the bacteriostatic abilities of the biliary epithelium, this leads to increased inflammation and infection, leading to potentially fatal complications such as biliary septicemia and hepatic abscesses.[10][11]

As for biliary obstruction, which is most commonly due to underlying mechanical cholestasis such as choledocholithiasis, it is partially believed that the cholesterol bile ductal stones are colonized by a biofilm by a bacterial pathogen and upon multiplication is thought to lead to obstruction-induced mucosa inflammatory cytokine production. Primary bile duct stones are thought to be caused by the biliary infection itself, with both processes leading to ascending infection throughout the biliary system.[12][13][10]

Histopathology

Histological images of cholangitis reveal neutrophils within the lumens of the interlobular and infiltrating bile duct epithelium. Additionally, percutaneous liver biopsies often show cholestasis within hepatic parenchyma and neutrophils involving the bile duct lumen.[14]

History and Physical

There is a spectrum of clinical presentations of cholangitis, ranging from mild forms to severe forms, including overwhelming fulminant sepsis. Symptoms include fever, chills, malaise, rigors, generalized abdominal pain, jaundice, pruritus, and pale stools. Medical history, including cholelithiasis, recent cholecystectomy, post-ERCP, prior history of cholangitis, and history of AIDS, may increase the risk of cholangitis. Individuals with cholangitis tend to appear quite ill and often present with severe sepsis or septic shock. On physical exam, they present with fever, right upper quadrant tenderness, jaundice, abdominal distension, altered mental status, or hemodynamic instability.

The definitive diagnosis of acute cholangitis would include systemic signs of infection as well as confirmatory evidence of purulent bile by endoscopic, percutaneous, or surgical means. Although feasible, it proves invasive and may not be the best use of resources. Therefore clinical tools such as the Charcot triad and Tokoyo guidelines have been implemented in clinical practice.

Charcot triad describes cholangitis as clinical findings of fever, right upper abdominal pain, and jaundice. The Reynolds pentad adds altered mental status and sepsis to the triad. Many patients with acute cholangitis do not present with classic symptoms and signs.[15] Charcot triad has a high specificity (95.9%), while sensitivity is low (26.4%).[6][16] Approximately 90% present with fever, while 60 to 70% are jaundiced.[10] The Tokyo guidelines (2018) have a sensitivity of 100% and specificity of 87.4%, which is significantly higher than the Charcot triad.[17] Tokoyo guidelines include two of three Charcot criteria plus systemic inflammation (increased white blood cell count and C-reactive protein elevation) plus abnormal liver tests and imaging suggestive of biliary dilatation and evidence of etiology (e.g., biliary stones, strictures, and stents).[10][18][19] Both the Charcot/Pentad triad and Tokyo guidelines are useful guidelines to aid in diagnosing acute cholangitis.

Evaluation

The diagnosis of cholangitis is characterized by clinical presentation, abnormal laboratory results, and imaging studies implying infection and biliary obstruction.[3] Lab tests for acute cholangitis include complete blood count, complete metabolic profile, liver function tests, reactive proteins, coagulation profile, blood cultures, urinalysis, blood type, screen, and crossmatch along with a lipase level. Leukocytosis with neutrophil predominance is a common finding, with leukopenia being commonly found in septic or immunocompromised individuals. Liver function results consistent with cholestasis revealing hyperbilirubinemia and increased alkaline phosphatase (ALP) and gamma-glutamyl transverse (GGT).[6]

The first-line imaging study of choice is abdominal ultrasonography. It is highly sensitive and specific in examing the gallbladder and investigating for biliary duct dilatation. A classic finding of ascending cholangitis is the thickening of the walls of the bile ducts, dilatation of biliary ducts, including the common bile duct, as well as evidence of cholelithiasis and pyogenic material. It can help differentiate intrahepatic versus extrahepatic obstruction. However, a normal abdominal sonogram does not necessarily rule out ascending cholangitis. Abdominal computed tomography (CT) can be performed as an adjunct to investigate co-existing pathologies such as hepatic/pancreatic tumors, metastasis, or hepatic abscess.[20] Dilated intrahepatic and extrahepatic ducts, as well as inflammation of the biliary tree, can be appreciated. Another advantage is CT that can help to investigate differential diagnoses, including diverticulitis and pyelonephritis. One major disadvantage is that CT has poor sensitivity for the diagnosis of choledocholithiasis.

The most sensitive modalities for detecting common bile duct stones are magnetic resonance cholangiopancreatography (MRCP). MRCP is a noninvasive imaging study that can detect the cause and the level of biliary obstruction, including choledocholithiasis, strictures, and biliary dilatations.[16][20] ERCP is essential to both diagnosis and treatment as it detects the site of obstruction and helps in drainage of the biliary tree and for retrieval of biopsy and culture specimens from the biliary system. ERCP should be used in patients with high clinical suspicion and those that will benefit from therapeutic intervention.[21]

Treatment / Management

The goal of treating acute cholangitis is managing both the biliary infection and the obstruction. The mainstay of treatment is antibiotic therapy directed towards enteric pathogens and biliary drainage. Acute emergency management entails assessing ABC (airway, breathing, circulation), cardiac monitoring and pulse oximetry, obtaining intravenous access, providing aggressive fluid and electrolyte replacement as appropriate, and supportive care. Initiation of early intravenous antibiotics known to achieve high biliary concentrations such as fluoroquinolones, extended-spectrum penicillins, carbapenems, and aminoglycosides is required. In more severe cases, adequate hemodynamic support, including vasopressors, may be needed. Hospitalization is necessary for cases of acute cholangitis, with mild to moderate cases managed in the general medical units, while those with severe disease and signs of sepsis and hemodynamic instability to be admitted to intensive care units.[10]

In mild cases, the majority of patients respond to medical therapy. Those who do not respond to medical therapy require immediate decompression.[22] In severely ill patients with sepsis, treatment is immediate or emergent biliary drainage. Those who are clinically improving after medical therapy may be candidates for decompression prior to hospital discharge.[23] Biliary decompression or drainage can be achieved by ERCP, percutaneous transhepatic cholangiography (PTC), endoscopic ultrasonography (EUS)-guided drainage, or surgical drainage. ERCP is the gold standard and treatment of choice for biliary decompression, as it is effective in 94 to 98% of cases.[24] If a biliary stricture is present, a trans-papillary biliary stent can be placed for biliary drainage.[6][16] Due to higher rates of complications from surgical intervention, surgery is reserved for patients who decompensate despite optimal medical management and endoscopic/percutaneous biliary drainage.[6](B3)

Differential Diagnosis

Symptoms and signs of acute cholangitis mimic other diseases of the liver and intestine. Following differentials should be ruled out in these patients:

• Acute cholecystitis
• Hepatitis
• Liver cirrhosis
• Liver failure
• Hepatic abscess
• Pancreatitis
• Perforated peptic ulcer
• Acute appendicitis
• Diverticulitis
• Pyelonephritis
• Mesenteric ischemia
• Septic shock

Prognosis

In patients with mild cases of acute cholangitis, 80-90% of patients respond to medical therapy and have a good prognosis.[22] Individuals who present with early signs of multiple organ failure such as altered mental status, renal failure, hemodynamic instability, and those who are not responding to conservative management and antibiotic treatment should undergo emergent biliary drainage.[25] Early biliary drainage leads to faster clinical improvement and decreased mortality. The overall mortality is less than 10% after biliary drainage.[16] However, the diagnosis can be missed in 25% of the severe cases presenting with sepsis.[24]

Without prompt treatment, these patients have a mortality rate of 50%.[16] Elderly individuals with renal failure, liver abscess, or malignancy are at high risk of mortality. The major cause of death in these individuals is multiple organ failure with septic shock.[26] Causes of death in individuals who survive the initial stages of acute cholangitis include multiple organ failure, pneumonia, and heart failure.[27]

Complications

Acute cholangitis can range in severity from mild disease to liver or multiorgan failure. Following complications are associated with cholangitis:

• Hepatic abscess
• Acute cholecystitis
• Portal vein thrombosis
• Acute biliary pancreatitis
• Liver failure
• Acute renal failure
• Bacteremia/septicemia
• Multiple organ failure