GALLBLADDER

Cholangitis: Deadly Cause of Right Upper Quadrant Abdominal Pain

Author: George C. Willis, MD, FAAEM, FACEP (Director of Undergraduate Medical Education, Department of Emergency Medicine, University of Maryland School of Medicine) // Edited by: Jennifer Robertson, MD, MSEd and Alex Koyfman, MD (@EMHighAK, EM Attending Physician, UT Southwestern Medical Center / Parkland Memorial Hospital)

Case 1

A 54-year-old female presents to the emergency department (ED) complaining of right upper quadrant (RUQ) abdominal pain.  She had presented two months prior with similar symptoms and was diagnosed with cholelithiasis. She was discharged home with pain medications and surgical follow up.  However, her symptoms returned and are more severe this visit. She is vomiting, has a fever of 39.2 °C and is tachycardic at 131 beats per minute (bpm). A quick bedside RUQ ultrasound reveals gallstones but no wall thickening, sludge, or pericholecystic fluid.  She is once again diagnosed with cholelithiasis. Luckily, though, the surgeon-on-call agrees to admit the patient and perform a cholecystectomy the following morning.  Upon reassessing the patient, however, something seems missing.  Despite medications and intravenous fluids, she does not look well and she remains febrile and tachycardic. What are you missing in this acutely ill patient?

Case 2

Emergency Medical Services (EMS) brings an 84-year-old male from his nursing home with a chief complaint of altered mental status. The patient has a history of dementia and other chronic medical conditions. You look through his nursing home paperwork, which includes a discharge summary from four months ago that describes hospitalization in which he received a cholecystectomy.

On exam, the patient is non-verbal from a previous stroke and is unable to provide any history.  He is febrile, tachycardic, tachypneic, and hypotensive.  You initiate a suspected sepsis workup which includes intravenous fluid resuscitation, bloodwork, imaging studies, and broad-spectrum antibiotics.  You suspect a urinary tract infection as the culprit of his symptoms as his chronic indwelling catheter is crusted over. An aspiration pneumonia is also considered given his coarse lung sounds on exam.

Surprisingly, however, the patient’s urinalysis (UA) and chest x-ray are normal. His white blood cell count (WBC) is 22,000, his lactate is rising despite fluid resuscitation and he remains hypotensive.  A diagnosis of meningitis is considered and a lumbar puncture may be next. However, cholangitis remains in your differential given the patient’s recent cholecystectomy.

Background

Around 10-15% of patients worldwide have gallstones, with the majority experiencing little to no symptoms.1 Out of these patients, only 2-3% will experience obstructive complications, which includes pancreatitis, cholecystitis, and cholangitis.1,2 Acute or ascending cholangitis is a rare disease characterized by an infection of the common bile duct (CBD). It can be life-threatening if not treated appropriately. Although biliary stone disease is the most common etiology, there are other causes of cholangitis including previous biliary tree instrumentation, biliary stenosis, helminthic infections, and neoplastic disease.3,4 The prevalence of cholangitis is equal between both genders and occurs more commonly after the fifth decade of life.

So how does this disease process manifest?  Recall that the intrahepatic biliary ducts and the cystic duct join to form the common bile duct that drains bile into the duodenum via the Sphincter of Oddi.  Normally, the biliary system is a low-pressure, forward flow system that flushes any bacteria out into the duodenum.  In cholangitis, an obstruction occurs in the common bile duct and cessation of forward flow causes increased pressure in the biliary tract.  Consequently, bacteria from the duodenum have easier access to the biliary parenchyma and the bloodstream, thus predisposing the patient to local and systemic infection.

When Jean-Martin Charcot first described cholangitis in the late 1800s, the mortality was 100%.  Subsequently, advances in biliary drainage techniques and newer antibiotic regimens have lowered the current mortality to anywhere between 5 and 30%.  Currently, the most common cause of death is multi-organ failure and irreversible circulatory collapse.3,4  Delay in diagnosis and management are key contributors to the persistently high mortality rates even to this day. In two studies, endoscopic retrograde cholangiopancreatography (ERCP) studies that were delayed were associated with increase in-hospital lengths of stays and worsened morbidity and mortality rates.5,6

Diagnostic Dilemma

Up until recently, physicians had to rely on their clinical exam to diagnose cholangitis.  For years, the presence of the classic signs and symptoms of Charcot’s triad or Reynold’s pentad had been the only criteria to confirm the diagnosis.  Charcot’s triad includes right upper quadrant abdominal pain, fever, and jaundice, while the addition of mental status change and hypotension constitutes Reynold’s pentad.  Charcot’s triad is anywhere between 72 and 95% specific for cholangitis, although there is about an 11% false positive rate in cholecystitis.7,8 Reynold’s pentad signifies more severe disease, but it is rare and shows up in less than 10% of patients with cholangitis.8  Despite its low sensitivity rate of 26%, providers were forced to use the absence of Charcot’s triad to rule out the diagnosis of cholangitis. 7

Reliance on Charcot’s triad alone is problematic.  All three parts of Charcot’s triad appear in only 50-70% of patients with cholangitis.9 Therefore, patients may only present with one or two symptoms of Charcot’s triad.  Abdominal pain is the most common complaint and is seen in about 80% of patients with cholangitis.8,10 However, patients, especially elderly patients, may present without abdominal pain. They may also present with clinical manifestations of sepsis alone, leading the provider to search for more common sources of sepsis.  These patients may also be unable to provide any history of abdominal pain due to baseline cognitive disorders, mechanical ventilation, sepsis causing altered sensorium, and medications.  A 2005 study looking at delays in the diagnosis of elderly patients with cholangitis found that those who presented atypically (i.e., with falls or confusion) took, on average, nine days to receive the proper diagnosis. It also took 16 days to perform a therapeutic ERCP compared to only 4 days in those patients who presented with abdominal pain.11

Similarly, fever and jaundice are also variable in presentation.  Studies show that anywhere between 40 and 80% of patients with cholangitis will have fever.8,10 Fever can be absent due to a number of factors including lower baseline core body temperature (especially in the elderly), medications, and immunosuppression.  Jaundice may not manifest itself initially. It is also less common than abdominal pain and fever, occurring in 50-70% of patients with cholangitis.8 One study looked at biliary dilatation in patients diagnosed with cholangitis and found that 18% had no biliary dilatation.12 Subsequently, this group of patients had lower bilirubin levels than those with biliary dilatation. Thus, this group of patients were  less likely to have clinically-evident jaundice, despite having similar elevations in liver transaminases.12 Another study found that 16% of elderly patients are also less likely to manifest jaundice despite significant hyperbilirubinemia.11

So reliance on clinical signs alone is not helpful and thus, imaging is recommended. Ultrasound is typically the initial study to evaluate patients with RUQ abdominal pain.  Unfortunately, while it is very good at detecting gallbladder stones and biliary duct dilatation, it is poor at visualizing choledocholithiasis and it can miss other possible etiologies of CBD dilatation.10 Computed tomography (CT) is adequate for visualizing CBD dilatation and is much better at diagnosing etiologies for CBD dilation, including CBD stones.10,13 However, CT has a sensitivity of about 60% for diagnosing the findings in cholangitis and will miss a fair number of cholangitis patients.13-15

Evidence-Based Diagnostic Criteria

Due to a lack of evidence-based criteria for diagnosing acute cholangitis, a group of hepatobiliary specialists drafted the Tokyo Guidelines in 2007 (TG07).8 These guidelines established a new set of diagnostic criteria for diagnosing cholangitis. The  criteria included Charcot’s triad, but also added laboratory values and imaging findings to supplement those cases where Charcot’s triad was not completely present. These additional studies include (1) evidence of an inflammatory response defined by an elevated C-reactive protein (CRP), an abnormal white blood cell count, or other markers of inflammation, (2) evidence of abnormal liver function tests defined by elevations in aspartate aminotransferase (AST), alanine transaminase (ALT), or alkaline phosphatase, or (3) imaging evidence of biliary dilatation or an etiology of obstruction.8 Subsequent studies have validated these criteria externally with good results, showing a sensitivity of 64% and a specificity of 69%.16 These criteria have been cited well over 200 times since the original Tokyo Guidelines publication and have become the gold standard worldwide for diagnosing cholangitis.17

However, by 2012, a committee of hepatobiliary specialists reconvened in Japan and performed their own multicenter retrospective trial to revise TG07. In their study, they found the TG07 criteria to have a sensitivity of 83% and specificity of 80% with a 12% false positive rate in cases of acute cholecystitis.7 They sought to improve the sensitivity and specificity further and decrease the false positive rate, and thus, developed the Tokyo Guidelines 2013 (TG13).  These criteria are as following:

1) Fever >38 deg. C and/or chills

2) Lab evidence of inflammation (WBC < 4 or > 12, CRP > 1)1) Jaundice (Total bilirubin > 2)

3) Lab evidence of abnormal liver transaminases (AST, ALT, GGT, Alk phos >    1.5 X normal

4) Biliary dilatation on imaging

5) Evidence of etiology (i.e. malignancy, stenosis) on imaging

*Suspected diagnosis = 1 item in A + 1 item in B or C

**Definite diagnosis = 1 item in A, B, and C18

Using the TG13, the sensitivity increased to 91% and the specificity only decreased slightly to 78% and the false positive rate decreased to 5%.18 The TG13 criteria can be applied to patients with and without abdominal pain who present with undifferentiated sepsis. Now, practitioners have reliable criteria consisting of data that is obtainable in an emergency department workup.

Bottom line: Ruling in or out the diagnosis of cholangitis is no longer based on clinical exam alone.  The addition of imaging and bloodwork to the clinical exam are much more reliable.

ED Management

Resuscitation, antibiotics and consultation for early biliary decompression are the mainstays of cholangitis treatment. Resuscitation is important to maintain hemodynamic stability. Hemodynamic stability is also necessary to make sure that antibiotics perfuse the infected regions, namely the biliary tree.  Cardiac and blood pressure monitoring should be reassessed frequently as tachycardia and hypotension due to sepsis can quickly develop.  Patients should be treated early with intravenous fluids and, if needed, vasoactive agents.  Laboratory studies directed at cholangitis are important, but other laboratory markers for sepsis will help with directing therapy as well.  Obtain serial lactate measurements, venous blood gas for acid-base disturbance, and urine output measurements to help direct any hemodynamic therapy.  Blood cultures are not routinely useful unless disease severity is high where multi-organ dysfunction is present.  Although blood cultures are positive in anywhere between 22 and 71% of cholangitis cases, typical causative organisms are not known to cause vegetations and are often susceptible to the antibiotic regimen.19,20 Therefore, blood cultures often do not provide any additional information.

Antibiotic regimens should be directed toward Gram-negative species and, less commonly, anaerobes and Gram-positive species.  Cultures taken from biliary fluid and blood in patients with cholangitis reveal Escherichia coli in more than 50% of cases.  Other culprits are typically other Gram-negative species and anaerobic species.  In recent years, there has been an increase in resistance of Gram-negative bacilli to typical antimicrobials and occasional Gram-positive organisms (i.e. Enterococcus), especially in hospital-acquired infections. Antibiotics need to be effective at treating the causative organisms but also need to be concentrated in the bile in order to be effective.  First generation cephalosporins and fluoroquinolones are adequate in mild disease.20 Once organ failure begins to manifest, coverage for hospital-acquired infections should occur.  Third or fourth generation cephalosporins or piperacillin-tazobactam are better options. Vancomycin or linezolid should be administered to cover Gram-positive organisms and metronidazole should be given to cover anaerobes.20 The carbapenems or aztreonam are acceptable alternatives.

Early biliary decompression will also help with source control.  Before antimicrobial therapy was introduced, biliary decompression was the only way to treat cholangitis.  Gastroenterology consultation for ERCP should occur early if suspicion is high.  ERCP is usually effective at diagnosing and relieving obstructions that may be present.

Take Home Points

– Always think about cholangitis in any ill-appearing patient with RUQ pain or undifferentiated sepsis.

-Charcot’s triad and Reynold’s pentad are not reliable. Absence of these clinical findings does not rule out cholangitis.  Use the total picture with clinical exam, labwork, and imaging studies.

Early antibiotics and consultation for biliary decompression are mainstays of therapy.

References / Further Reading

  1. Sekimoto M, Takada T, Kawarada Y, et al. Need for criteria for the diagnosis and severity assessment of acute cholangitis and cholecystitis: Tokyo Guidelines. J Hepatobiliary Pancreat Surg. 2007;14(1):11-14.
  2. Williams EJ, Green J, Beckingham I, et al. Guidelines on the management of common bile duct stones (CBDS). Gut. 2008;57(7):1004-1021.
  3. Kimura Y, Takada T, Kawarada Y, et al. Definitions, pathophysiology, and epidemiology of acute cholangitis and cholecystitis: Tokyo Guidelines. J Hepatobiliary Pancreat Surg. 2007;14(1):15-26.
  4. Kimura Y, Takada T, Strasberg SM, et al. TG13 current terminology, etiology, and epidemiology of acute cholangitis and cholecystitis. Journal of hepato-biliary-pancreatic sciences. 2013;20(1):8-23.
  5. Khashab MA, Tariq A, Tariq U, et al. Delayed and unsuccessful endoscopic retrograde cholangiopancreatography are associated with worse outcomes in patients with acute cholangitis. Clin Gastroenterol Hepatol. 2012;10(10):1157-1161.
  6. Navaneethan U, Gutierrez NG, Jegadeesan R, et al. Delay in performing ERCP and adverse events increase the 30-day readmission risk in patients with acute cholangitis. Gastrointest Endosc. 2013;78(1):81-90.
  7. Kiriyama S, Takada T, Strasberg SM, et al. TG13 guidelines for diagnosis and severity grading of acute cholangitis (with videos). Journal of hepato-biliary-pancreatic sciences. 2013;20(1):24-34.
  8. Wada K, Takada T, Kawarada Y, et al. Diagnostic criteria and severity assessment of acute cholangitis: Tokyo Guidelines. J Hepatobiliary Pancreat Surg. 2007;14(1):52-58.
  9. Takada T, Kawarada Y, Nimura Y, et al. Background: Tokyo Guidelines for the management of acute cholangitis and cholecystitis. J Hepatobiliary Pancreat Surg. 2007;14(1):1-10.
  10. Mosler P. Diagnosis and management of acute cholangitis. Curr Gastroenterol Rep. 2011;13(2):166-172.
  11. Rahman SH, Larvin M, McMahon MJ, Thompson D. Clinical presentation and delayed treatment of cholangitis in older people. Dig Dis Sci. 2005;50(12):2207-2210.
  12. Hong MJ, Kim SW, Kim HC, Yang DM. Comparison of the clinical characteristics and imaging findings of acute cholangitis with and without biliary dilatation. Br J Radiol. 2012;85(1020):e1219-1225.
  13. Balthazar EJ, Birnbaum BA, Naidich M. Acute cholangitis: CT evaluation. J Comput Assist Tomogr. 1993;17(2):283-289.
  14. Kim SW, Shin HC, Kim HC, Hong MJ, Kim IY. Diagnostic performance of multidetector CT for acute cholangitis: evaluation of a CT scoring method. Br J Radiol. 2012;85(1014):770-777.
  15. Lee NK, Kim S, Lee JW, et al. Discrimination of suppurative cholangitis from nonsuppurative cholangitis with computed tomography (CT). Eur J Radiol. 2009;69(3):528-535.
  16. Yokoe M, Takada T, Mayumi T, et al. Accuracy of the Tokyo Guidelines for the diagnosis of acute cholangitis and cholecystitis taking into consideration the clinical practice pattern in Japan. Journal of hepato-biliary-pancreatic sciences. 2011;18(2):250-257.
  17. Takada T, Strasberg SM, Solomkin JS, et al. TG13: Updated Tokyo Guidelines for the management of acute cholangitis and cholecystitis. Journal of hepato-biliary-pancreatic sciences. 2013;20(1):1-7.
  18. Kiriyama S, Takada T, Strasberg SM, et al. New diagnostic criteria and severity assessment of acute cholangitis in revised Tokyo Guidelines. Journal of hepato-biliary-pancreatic sciences. 2012;19(5):548-556.
  19. Tanaka A, Takada T, Kawarada Y, et al. Antimicrobial therapy for acute cholangitis: Tokyo Guidelines. J Hepatobiliary Pancreat Surg. 2007;14(1):59-67.
  20. Gomi H, Solomkin JS, Takada T, et al. TG13 antimicrobial therapy for acute cholangitis and cholecystitis. Journal of hepato-biliary-pancreatic sciences. 2013;20(1):60-70.

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