Jaundice is a manifestation of elevated serum bilirubin, and can have many causes, some of which can be life-threatening. This issue will help the emergency clinician narrow down the differential diagnosis to determine a cause and allow for swift disposition:

•  Is bilirubin elevated because of increased production, impaired uptake, impaired conjugation, obstruction, hepatocellular injury, or inherited disorder?
•  What are the laboratory tests you need to order to uncover the cause?
•  Which imaging study should you order first?
•  Which scans can offer therapeutic as well as imaging options?
•  What are the key indicators of life-threatening causes of jaundice: acetaminophen overdose, ascending cholangitis, pancreatic mass, and hemolysis?
•  What is the critical window of time for treating acetaminophen-induced liver injury?
•  How can you tell when neonatal jaundice is life-threatening?
•  What are the red flags of jaundice in a pregnant patient?
•  How should a liver transplant patient be managed?

1. Abstract
2. Case Presentations
3. Introduction
4. Critical Appraisal of the Literature
5. Selected Abbreviations
6. Etiology and Pathophysiology
   1. Conditions That Cause Indirect Hyperbilirubinemia
      1. Increased Bilirubin Production
      2. Impaired Hepatic Bilirubin Uptake
      3. Impaired/Decreased Conjugation
   2. Conditions That Cause Direct Hyperbilirubinemia
   3. Extrahepatic Biliary Obstruction
   4. Intrahepatic Cholestasis
7. Differential Diagnosis
8. Prehospital Care
9. Emergency Department Evaluation
   1. Initial Stabilization
   2. History
   3. Physical Examination
10. Diagnostic Studies
    1. Laboratory Testing
       1. Comprehensive Metabolic Panel Testing
          • Liver Function Tests
          • Chemistry Panel
       2. Complete Blood Cell Count
       3. Coagulation Studies
       4. Other Tests
       5. Summary of Laboratory Studies
    2. Imaging Studies
       1. Ultrasound
       2. Computed Tomography
       3. Hepatobiliary Iminodiacetic Acid Scanning
       4. Endoscopic Retrograde Cholangiopancreatography
       5. Magnetic Resonance Cholangiopancreatography
       6. Percutaneous Transhepatic Cholangiography
       7. Which Imaging Modality Is Right for My Patient?
11. Treatment
    1. Hemolysis
    2. Extrahepatic Obstruction
    3. Hepatocellular Injury
       1. Managing Encephalopathy
       2. Managing Coagulopathy
       3. Antibiotic Administration
       4. Consideration for Transplantation
    4. Acetaminophen-Induced Liver Injury
12. Special Circumstances
    1. Pediatric Patients
    2. Jaundice in Pregnancy
       1. Hyperemesis Gravidarum
       2. Intrahepatic Cholestasis of Pregnancy
       3. Infectious Causes
       4. Acute Fatty Liver of Pregnancy
    3. Transplant Patients
13. Controversies and Cutting Edge
14. Disposition
15. Summary
16. Risk Management Pitfalls for Jaundice in the Emergency Department
17. Case Conclusions
18. Clinical Pathway for Managing Jaundice in the Emergency Department
19. Tables and Figures
    1. Table 1. Published Guidelines on Jaundice
    2. Table 2. Causes of Indirect Hyperbilirubinemia
    3. Table 3. Causes of Hemolysis
    4. Table 4. Causes of Direct Hyperbilirubinemia
    5. Table 5. Causes of Extrahepatic Cholestasis
    6. Table 6. Causes of Intrahepatic Cholestasis
    7. Table 7. Differential Diagnosis of Hepatocellular Jaundice
    8. Table 8. Life-Threatening Conditions Presenting With Jaundice
    9. Table 9. Historical Factors in Jaundice
    10. Table 10. Clinical Syndromes Suggested by History
    11. Table 11. Stages of Hepatic Encephalopathy
    12. Table 12. Peripheral Smear Findings
    13. Table 13. Intravenous Antibiotic Doses for Ascending Cholangitis
    14. Table 14. Causes of Neonatal Hyperbilirubinemia
    15. Table 15. Risk Factors for Severe Neonatal Hyperbilirubinemia
    16. Table 16. American Academy of Pediatrics Recommendations for Initiating Treatment for Hyperbilirubinemia
    17. Figure 1. Gallstones Shown on Ultrasound
    18. Figure 2. Computed Tomography Scan of Pancreatic Mass Obstructing the Common Bile Duct and Pancreatic Duct
20. References

Abstract

There are approximately 52,000 visits a year to emergency departments for patients presenting with jaundice. While many of these patients will not have immediately life-threatening pathology, it is essential that the emergency clinician understands the pathophysiology of jaundice, as this will guide the appropriate workup to detect critical diagnoses. Patients who present with jaundice could require intravenous antibiotics, emergent surgery, and, in severe cases, organ transplantation. This issue will focus on the challenge of evaluating and treating the jaundiced patient in the ED using the best available evidence from the literature.

Case Presentation

You are in the middle of a busy Monday afternoon shift in the ED. The chief complaint on the track board simply states, “other complaint,” but one look at the patient tells you why he is here. The patient is a middle-aged man with no prior medical history who states that his family has been telling him for the last 2 to 3 weeks that his eyes are yellow. He also admits to occasional nausea, vomiting, poor appetite, weight loss, and diffuse itching. There is no history of fever, abdominal pain, heavy alcohol use, or recent acetaminophen ingestion. Your physical examination is remarkable for icteric sclerae, jaundice of his face and upper chest, and mild, nontender hepatomegaly. You want to order imaging in addition to lab work, but wonder which is the better choice: CT or ultrasound?

A second patient, a young woman, presents via EMS. The EMTs state they were called to the house for altered mental status. There was nobody in the home to provide collateral information, but they did notice numerous empty medication bottles, though they were unsure what kinds of medications they were. The patient is responsive only to painful stimuli. Vital signs are otherwise stable, but you notice scleral icterus, diffuse jaundice, and petechiae on examination. You are obviously concerned about an ingestion, but you wonder whether you should begin N-acetyl-cysteine therapy empirically.

Finally, your colleague in the adjacent pod calls you over for a second opinion on a 10-day-old infant. The mother states that she has been told that the baby had breast-milk jaundice and asks if there anything that she needs to do. She states that the baby is healthy, eating appropriately, and gaining weight. Your colleague asks if there is anything that he needs to do for this infant and what he should tell the mother.

Introduction

Jaundice is not a diagnosis, but rather a physical manifestation of elevated serum bilirubin. It is not a common primary chief complaint. Instead, the jaundiced patient often presents with symptoms related to the underlying pathology, such as abdominal pain, pruritus, vomiting, or substance ingestion. Unconjugated hyperbilirubinemia can be neurotoxic in neonates, causing encephalopathy (kernicterus) and death. In adults, however, jaundice serves as a marker for potentially serious hematologic or hepatobiliary dysfunction, such as massive hemolysis, fulminant hepatic failure, or ascending cholangitis. Fortunately, the majority of jaundiced patients have a more indolent course.

The frequency and etiology of jaundice varies, depending on the population studied.¹ The National Hospital Ambulatory Medical Care Survey (NHAMCS) collects data on the utilization of ambulatory care services, including emergency department (ED) visits. Analysis of approximately 1.2 billion ED visits from 2003 to 2012 via the NHAMCS database revealed that 530,000 patients had a chief complaint or final diagnosis of jaundice, an average of 52,500 visits per year.² These data underestimate the true number, as they fail to account for patients who were jaundiced on physical examination but had an alternative final diagnosis. For example, a Dutch study of 702 adults presenting with jaundice over a 2-year period found 20% to be due to pancreatic or biliary carcinoma, 13% due to gallstones, and 10% due to alcoholic cirrhosis.³ A study of 732 patients in the United States reported that ischemic liver injury (from sepsis or other causes of hypotension) was the most common cause of new-onset jaundice, at 22%. Acute liver disease secondary to nonalcoholic causes occurred in 13% of patients; viral hepatitis occurred in 9%; and drug-induced liver injury occurred in 4%.⁴ Most of the drug-induced cases resulted from acetaminophen toxicity.⁴

This issue of Emergency Medicine Practice focuses on the pathophysiology, evaluation, and treatment of the jaundiced patient in the ED using the best available evidence from the literature.

Critical Appraisal of the Literature

A PubMed search was performed using the term jaundice, limited to a major term. Further limits were used to include articles only in English, adult subjects, and a time limit of the last 10 years. Over 700 articles were identified, which provided a framework for further review. The Cochrane Database of Systematic Reviews and the National Guideline Clearinghouse were also consulted. Table 1, lists guidelines related to jaundice that are helpful for the practicing emergency clinician.

Because the clinical manifestation of jaundice can include so many etiologies, the results were extensive. Therefore, the resulting sources compiled come from a wide variety of disciplines and are varied in strength and type.

Risk Management Pitfalls for Jaundice in the Emergency Department

4. “The patient wasn’t encephalopathic the other day when I saw her; now she is back and obtunded.”

The initial stages of hepatic encephalopathy can be subtle. Combine this with the fact that some patients may underplay their symptoms or have a depressed neurological baseline, and initial stages of hepatic encephalopathy can be hard to diagnose. Questioning the family or caregiver about the patient’s behavior may help detect early signs of hepatic encephalopathy. All patients with jaundice and hepatic encephalopathy should be admitted.

5. “The patient had no abdominal tenderness, so I didn’t consider cholangitis as a possibility.”

Only 50% to 75% of patients with acute cholangitis manifest Charcot triad (fever, jaundice, right upper quadrant tenderness). These signs can be absent, especially in the elderly and the immunocompromised. A high index of suspicion should be maintained in all patients with fever and jaundice.

7. “I waited to call surgery for that patient with ascending cholangitis.”

Ascending cholangitis is a potentially fatal cause of jaundice. Many patients will resolve with antibiotics and supportive measures; however, some patients will require biliary drainage. Surgery should be consulted as soon as the diagnosis is made, in order to evaluate for biliary drainage.

Tables and Figures

References

Evidence-based medicine requires a critical appraisal of the literature based upon study methodology and number of subjects. Not all references are equally robust. The findings of a large, prospective, randomized, and blinded trial should carry more weight than a case report.

To help the reader judge the strength of each reference, pertinent information about the study, such as the type of study and the number of patients in the study is included in bold type following the references, where available. In addition, the most informative references cited in this paper, as determined by the author, are highlighted.

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98. Keadey MT LD. The Solid-Organ Transplant Patient. In: Rosen, ed. Rosen’s Emergency Medicine: Concepts and Clinical Practice. Vol 6th. New York: Mosby; 2006:2846-2854. (Textbook chapter)
99. Stockmann HB, Hiemstra CA, Marquet RL, et al. Extracorporeal perfusion for the treatment of acute liver failure. Ann Surg. 2000;231(4):460-470. (Review)
100. Stutchfield BM, Simpson K, Wigmore SJ. Systematic review and meta-analysis of survival following extracorporeal liver support. Br J Surg. 2011;98(5):623-631. (Review and meta-analysis; 74 studies)
101. Lee WM. Acute liver failure. N Engl J Med. 1993;329(25):1862-1872. (Review)

Points & Pearls Excerpt

• Jaundice has a broad differential. It can result from a multitude of hepatic and hematologic pathologies, including obstructive process, hepatocellular process, or hemolytic/hematopoietic process.
• The history and physical examination are particularly important in narrowing the differential for jaundice.
• Studies have shown that clinical estimates of serum bilirubin have shown poor interrelater reliability. Skin examination alone is insufficient in judging serum bilirubin levels.

• Lalani T, Couto CA, Rosen MP, et al. ACR appropriateness criteria jaundice. J Am Coll Radiol. 2013;10(6):402-409. (Consensus statement) DOI: https://doi.org/10.1016/j.jacr.2013.02.020
• Pasanen PA, Partanen KP, Pikkarainen PH, et al. A comparison of ultrasound, computed tomography and endoscopic retrograde cholangiopancreatography in the differential diagnosis of benign and malignant jaundice and cholestasis. Eur J Surg. 1993;159(1):23-29. (Prospective; 220 patients) https://inis.iaea.org/search/search.aspx?orig_q=RN:25018170
• Kiewiet JJ, Leeuwenburgh MM, Bipat S, et al. A systematic review and meta-analysis of diagnostic performance of imaging in acute cholecystitis. Radiology. 2012;264(3):708-720. (Review) DOI: https://doi.org/10.1148/radiol.12111561
• Williams EJ, Green J, Beckingham I, et al. Guidelines on the management of common bile duct stones (CBDS). Gut. 2008;57(7):1004-1021. (Consensus guideline) DOI: http://dx.doi.org/10.1136/gut.2007.121657
• Smilkstein MJ, Knapp GL, Kulig KW, et al. Efficacy of oral N-acetylcysteine in the treatment of acetaminophen overdose. Analysis of the national multicenter study (1976 to 1985). N Engl J Med. 1988;319(24):1557-1562. (Retrospective; 2540 patients) DOI: http://dx.doi.org/10.1056/NEJM198812153192401
• Wolf SJ, Heard K, Sloan EP, et al. Clinical policy: critical issues in the management of patients presenting to the emer-gency department with acetaminophen overdose. Ann Emerg Med. 2007;50(3):292-313. (Practice guideline) DOI: https://doi.org/10.1016/j.jen.2008.02.004
• Knox TA, Olans LB. Liver disease in pregnancy. N Engl J Med. 1996;335(8):569-576. (Review) DOI: https://doi.org/10.1056/NEJM199608223350807
• Lee WM. Acute liver failure. N Engl J Med. 1993;329(25):1862- 1872. (Review) DOI: https://doi.org/10.1056/NEJM199312163292508