Continuing Education Activity

Acute cholangitis, also known as ascending cholangitis, is a life-threatening condition that is caused by an ascending bacterial infection of the biliary tree. Delay in diagnosis and treatment can lead to septic shock. This activity reviews the evaluation and management of acute cholangitis and highlights the role of the interprofessional team in the care of patients with this condition.

Objectives:

• Identify the etiology of acute cholangitis.
• Describe the typical presentation of acute cholangitis.
• Summarize the treatment considerations for patients with acute cholangitis.
• Explain the importance of improving care coordination among the interprofessional team to enhance the delivery of care for patients with acute cholangitis.

Introduction

Acute cholangitis, also known as ascending cholangitis, is a life-threatening condition caused by an ascending bacterial infection of the biliary tree.[1] Choledocholithiasis is the most common cause, with infection-causing stones in the common bile duct leading to partial or complete obstruction of the biliary system.[2] The diagnosis is made by clinical presentation, abnormal laboratory results, and imaging studies implying infection and biliary obstruction.[3]

Initial medical therapy relies on early fluid resuscitation and appropriate antibiotic coverage. Delay in treatment can lead to septic shock. Depending on the course and severity, a biliary drainage procedure may be performed with the assistance of endoscopic and surgical resources.[4] Acute cholangitis is a treatable condition when managed appropriately. However, mortality can be quite high if there is a significant delay in treatment. There are various types of cholangitis, including primary biliary cholangitis, IgG4-related autoimmune cholangitis, and primary sclerosing cholangitis.[3] By far, the most common is acute bacterial cholangitis and will be the focus of this review article.

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]

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

Consultations

Immediate consultation with surgery and gastroenterology is warranted in many cases. Severely ill-appearing patients that present with hemodynamic instability, multiple organ failure, or evidence of hepatic abscess will need immediate biliary decompression (e.g., ERCP or PTC). Even those individuals with mild cases and presentations may benefit from a consultation, including the use of additional imaging modalities such as EUS and MRCP.

Deterrence and Patient Education

Patients should be educated on their risk factors for acute cholangitis and advised to reduce modifiable factors with a low-fat diet, increased physical activity, and healthy weight when possible. Individuals with a history of gallstone and biliary ductal diseases should be educated on the clinical presentation of cholangitis and advised to seek immediate medical attention when symptoms arise. Early identification and treatment of symptomatic cholelithiasis in high-risk patients could decrease the risk of cholangitis. A diligent search for common bile duct stones in patients presenting with cholecystitis may decrease risk also. For individuals that undergo ERCP, prophylactic antibiotics prior to the procedure can decrease the risk of cholangitis. Patients who have recurrent acute cholangitis may benefit from prophylactic antibiotics to help reduce the incidence and severity of the disease.

Pearls and Other Issues

Acute cholangitis is a life-threatening medical condition that can be treated if identified early. High clinical suspicion is necessary to correctly diagnosis this condition. It rarely presents with the classic triad of fever, jaundice, and right upper quadrant abdominal pain. Ultrasound can be useful; however, CT is often required to aid in diagnosis and identify potential sources of obstruction. Early antibiotics and fluid resuscitation are key to initial management. Early consultation with gastroenterologists and surgical specialties is essential. Be mindful that many individuals require biliary decompression and intensive care management.

Enhancing Healthcare Team Outcomes

Acute cholangitis is a life-threatening condition if not intervened early with medical management or surgical intervention. It is important to recognize cholangitis promptly and understand the risk factors of this condition. Tokyo guidelines proposed an evidence-based management bundle to help guide clinical practice for patients with acute cholangitis. A relevant example of bundle effectiveness is the Surviving Sepsis Campaign guidelines introduced in 2008. Several reports since they came out have shown a marked reduction of in-hospital mortality rates in those institutions compliant with care bundles.[17]

The management bundle includes the diagnostic tools highlighted in the recent update, the Tokyo 2018 guidelines, and includes additional diagnostic and prognostic elements. It also includes helpful timelines for favorable responses to initial treatment in patients with mild cases, as well as the performance of the biliary tract drainage in those with moderate and severe disease. There are also helpful criteria to identify those patients who may benefit from ICU-level care and patient transfer to a hospital capable of providing endoscopic or percutaneous transhepatic biliary drainage. The bundle can be found in a simple checklist that is not only great for healthcare providers to follow but can help ensure the use of the bundle throughout the patients' hospital course.

That is why all interprofessional team members who engage with cholangitis cases need to be aware of these recommendations and engage in open communication and information sharing with other healthcare team members, particularly if they are less familiar with such cases and/or recommendations. This interprofessional team would include clinicians, specialists, nurses, and pharmacists, each contributing from their areas of expertise. An interprofessional team of clinicians and nurses is necessary to utilize these guidelines and improve patient outcomes. Future evaluations of these bundles are promising in hopes of improving prognosis and enhancing team performance.[28] [Level 5]